Plasma D-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke.

BACKGROUND AND PURPOSE: Cancer patients with cryptogenic stroke often have high plasma D-dimer levels and lesions in multiple vascular regions. Hence, if patients with cryptogenic stroke display such characteristics, occult cancer could be predicted. This study aimed to investigate the clinical characteristics of cryptogenic stroke as the first manifestation of occult cancer and to determine whether plasma D-dimer levels and lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. METHODS: Between January 2006 and October 2015, data on 1225 patients with acute ischaemic stroke were extracted from the stroke database of Osaka University Hospital. Among them, 184 patients were classified as having cryptogenic stroke, and 120 patients without a diagnosis of cancer at stroke onset were identified. Clinical variables were analyzed between cryptogenic stroke patients with and without occult cancer. RESULTS: Among 120 cryptogenic stroke patients without a diagnosis of cancer, 12 patients had occult cancer. The body mass index, hemoglobin levels and albumin levels were lower; plasma D-dimer and high-sensitivity C-reactive protein levels were higher; and lesions in multiple vascular regions were more common in patients with than in those without occult cancer. Multiple logistic regression analysis revealed that plasma D-dimer levels (odds ratio, 3.48; 95% confidence interval, 1.68-8.33; P = 0.002) and lesions in multiple vascular regions (odds ratio, 7.40; 95% confidence interval, 1.70-39.45; P = 0.01) independently predicted occult cancer. CONCLUSIONS: High plasma D-dimer levels and lesions in multiple vascular regions can be used to predict occult cancer in patients with cryptogenic stroke.

Influence of neutralizing antibodies to adalimumab and infliximab on the treatment of psoriasis.

BACKGROUND: Current treatment with biologics has produced dramatic therapeutic effects in patients with psoriasis, although these agents occasionally decrease in efficacy. One of the main factors responsible for this attenuation is attributed to the development of antidrug antibodies (ADAs). OBJECTIVES: To analyse the relationship between serum drug concentrations, the presence of ADAs and treatment efficacy of adalimumab and infliximab, and to determine the optimal use of these biologics. METHODS: This was a 1-year prospective study in the dermatology departments of Kobe University Hospital and collaborating hospitals. All patients starting a regimen of adalimumab and infliximab for psoriasis were included. We measured the serum concentration of the drugs and titres of antibodies to adalimumab and infliximab, as well as the Psoriasis Area and Severity Index scores at weeks 0, 4, 12, 24 and 48 during the first year of treatment. RESULTS: We observed a 50% positive rate of ADAs to adalimumab, and a 41% positive rate of ADAs to infliximab. The titres of ADAs showed a wide range from low to high titres. In the high-titre groups, the patients exhibited a decreased clinical response, and demonstrated a negative correlation between titre and clinical response. However, an equivalent therapeutic effect was observed between the low-titre group and the group with no antibodies detected for adalimumab. For infliximab, the patients with ADAs showed decreased clinical response. An apparent negative correlation between antibody production and reduced clinical response was observed. CONCLUSIONS: Two biologics, adalimumab and infliximab, showed different therapeutic behaviour. The measurement of ADAs and drug concentrations has important implications for treatment with biologics.

[C-reactive protein, white blood cell and body temperature following cardiovascular surgery, as predicting factors of postoperative infection].

The aim of this study is to clarify the relationship between CRP and postoperative infection after cardiovascular surgery. We had 5 cases of surgical site infection, and 3 cases of infective endocarditis (IE) among 57 patients selected for this study out of 405 patients who had undergone cardiovascular surgery from May 1995 to March 2005. CRP, WBC and body temperature (BT) were evaluated during 1 week after the operation. Our results showed not only that the mean value of CRP level in the 49 non-infection patients attained the peak on the 2nd or 3rd day after the operation (18.2 +/- 4.7 and 17.7 +/- 5.7 mg/dl), but also that each patient in this group showed the same pattern of CRP sequence. CRP in the 5 cases of postoperative infection showed different patterns from that in the non-infection group. CRP in 3 cases of valve replacement for IE showed significantly higher level than that in 16 cases of valve replacement without IE through 1 week after the surgery. WBC level in the non-infection group reached the peak just after the operation (11.3 +/- 4.4 x 10(3)/microl) and then decreased gradually during 1 week after the operation. WBC in the 3 cases of valve replacement for IE, did not show different sequence pattern from that in the 16 cases of valve replacement without IE. WBC in a case of postoperative mediastinal infection showed a similar pattern of sequence to that in the non-infection group although it showed a remarkably high level of CRP sequence through 1 week after the surgery. BT in the non-infection group became the lowest just after the operation and reached the peak 8 hours after the operation. It then decreased gradually during 1 week after the operation. Our study demonstrates that CRP sequence after the surgery might be useful to detect postoperative infection after cardiovascular surgery.

[Coronary artery bypass grafting to left anterior descending coronary artery diagnosed by multidetector-row computed tomography].

A 64-year-old male received coronary angiography because of chest pain. Although coronary angiography showed total occlusion of right coronary artery (RCA) # 2 and left anterior descending branch (LAD) #6, and a significant stenosis of left circumflex (LCx) #11, it could not visualize LAD distal to LAD # 6. Since coronary multidetector-row computed tomography (MD CT) could visualize the distal LAD, coronary artery bypass grafting (CABG) was indicated for this patient. Left internal thoracic artery (LITA) was anastomosed to LAD and saphenous vein graft (SVG) was used for distal anastomoses to obtuse marginal branch (OM) and 4-posterior descending branch (# 4 PD). Postoperative course was uneventful. LITA anastomosed to LAD and SVG to OM and # 4 PD were visualized by postoperative coronary angiography. MD CT in addition to coronary angiography was demonstrated useful to assess precise lesions of the coronary artery disease in this case.

Identification of two Fas-associated phosphatase-1 (FAP-1) promoters in human cancer cells.

Fas-associated phosphatase-1 (FAP-1) has been reported as a negative regulator of Fas-mediated signal transduction in human cancer cells. To obtain insights into the potential carcinogenesis of the FAP-1 gene, we investigated its transcriptional regulation in normal and cancerous cells. To identify the FAP-1 promoter sequences, we first isolated P1 and cosmid clones that contained the regulatory region upstream from the FAP-1 gene by using the PCR products of 5' rapid amplification of cDNA end (5'-RACE) as probes. Genomic analysis of positive clones revealed that the major FAP-1 mRNA was transcribed from its proximal promoter (pPRM) in all human cancer cell lines tested, but 1 additional large transcript derived from its distal promoter (dPRM) was found in the human colon cancer cell line DLD-1. This suggests that the FAP-1 gene may be aberrantly dysregulated in some types of human cancers, including colon carcinoma. Sequence analysis of the region upstream from the FAP-1 gene strongly suggests that the transcript of the FAP-1 gene may be controlled by a variety of transcriptional regulatory elements, including NF-kappa B, NF-IL6, and p53 in its 2 promoters. These results imply that the FAP-1 gene may be a target gene under the control of important apoptosis-related nuclear factors in human cancers.

Electropharmacologic effects of pilsicainide, a pure sodium channel blocker, on the remodeled atrium subjected to chronic rapid pacing.

Clinical experience suggests that sodium channel blockers are effective in converting atrial fibrillation of recent onset but not chronic atrial fibrillation. We investigated changes in the electrophysiologic effects of pilsicainide, a pure sodium channel blocker, on the canine atrium during chronic rapid pacing (400/min). Three pairs of bipolar electrodes were sutured to the right atrial appendage in six dogs. Five days later, rapid atrial pacing was started after baseline measurements of the effective refractory period (ERP), the intra-atrial conduction velocity, the atrial wavelength, and the inducibility of atrial fibrillation. These studies were repeated at 2, 7, and 14 days of pacing, both before and after pilsicainide administration. Before pacing, pilsicainide increased ERP more than it decreased conduction velocity, causing an increase of wavelength, particularly at faster rates. However, this use-dependent prolongation of ERP disappeared after 2 days of pacing. Thus, pilsicainide failed to prolong ERP during chronic pacing, allowing progressive shortening of wavelength in the remodeled atrium. The effect of sodium channel blockers on atrial refractoriness may decline as rapid atrial excitation persists, limiting the usefulness of these agents for the treatment of chronic atrial fibrillation.

Activation of inositol 1,4,5-trisphosphate receptor is essential for the opening of mouse TRP5 channels.

We studied the opening mechanism of Ca(2+)-permeable channels formed with mouse transient receptor potential type 5 (mTRP5) using Xenopus oocytes. After stimulation of coexpressed muscarinic M(1) receptors with acetylcholine (ACh) in a Ca(2+)-free solution, switching to 2 mM Ca(2+)-containing solution evoked a large Cl(-) current, which reflects the opening of endogenous Ca(2+)-dependent Cl(-) channels following Ca(2+) entry through the expressed channels. The ACh-evoked response was not affected by a depletion of Ca(2+) store with thapsigargin but was inhibited by preinjection of antisense oligodeoxynucleotides (ODNs) to G(q), G(11), or both. The mTRP5 channel response was also induced by a direct activation of G proteins with injection of guanosine 5'-3-O-(thio)triphosphate (GTP gamma S). The ACh- and GTP gamma S-evoked responses were inhibited by either pretreatment with a phospholipase C inhibitor, U73122, or an inositol-1,4,5-trisphosphate (IP(3)) receptor inhibitor, xestospongin C (XeC). An activation of IP(3) receptors with injection of adenophostin A (AdA) evoked the mTRP5 channel response in a dose-dependent manner. The AdA-evoked response was not suppressed by preinjection of antisense ODNs to G(q/11) or U73122 but was suppressed by either preinjection of XeC or a peptide mimicking the IP(3) binding domain of Xenopus IP(3) receptor. These findings suggest that the activation of IP(3) receptor is essential for the opening of mTRP5 channels, and that neither G proteins, phosphoinositide metabolism, nor depletion of the Ca(2+) store directly modifies the IP(3) receptor-linked opening of mTRP5 channels.

Recovery of electrophysiological parameters after conversion of atrial fibrillation.

We investigated the recovery of electrophysiological parameters from electrical remodeling after conversion of chronic lone atrial fibrillation in humans. Clinical studies have shown that the longer atrial fibrillation lasts, the more difficult it becomes to maintain the sinus rhythm after cardioversion. To explore the effects of the duration of atrial fibrillation on changes of electrophysiological parameters after conversion, we determined the atrial effective refractory period and P wave duration during right atrial pacing at 1 and 24 h after electrical cardioversion in 15 patients with chronic lone atrial fibrillation (median duration, 6 months). By 24 h after cardioversion, the effective refractory period at a pacing cycle length of 600 ms increased from 225+/-19 to 254+/-27 ms. However, the P wave duration did not decrease significantly 24 h after conversion. As the duration of atrial fibrillation became longer, the prolongation of effective refractory period was more delayed (P<0. 001, r=0.82), and the shortening of P wave duration was significantly smaller within 24 h after cardioversion (P<0. 001, r=0.67). After cardioversion of chronic lone atrial fibrillation, the recovery of shortened atrial refractoriness and prolonged intraatrial conduction time is dependent on the duration of preexisting atrial fibrillation.

Pancytopenia in tuberous sclerosis.

A 46-year-old woman with edema and pancytopenia was referred for further evaluation. She was diagnosed as tuberous sclerosis with clinical manifestations such as facial adenoma sebaceous, ungual and periungual fibroma, subependymal nodules and renal angiomyolipoma. Her edema seemed due to hypercardiac function induced by massive anemia. X-ray revealed extraordinary thickening of the cortex of long bones of the extremities as well as patchy osteosclerotic findings in vertebra, suggesting that hematopoietic space was significantly reduced. Pancytopenia improved after splenectomy. Histological examination revealed several intrasplenic hemangiomas but its relationship to hypersplenism was not clear. It seemed that her massive pancytopenia was induced by a combination of hypersplenism and significant reduction in hematopoetic space. In tuberous sclerosis, various systemic complications sometimes induce severe hematological abnormalities. According to previous literatures, the present case of tuberous sclerosis manifested the most outstanding hematological complications.

Electrophysiologic findings of a patient with inappropriate sinus tachycardia cured by selective radiofrequency catheter ablation.

Radiofrequency catheter ablation (RFCA) for inappropriate sinus tachycardia (IST) is associated with a high recurrence rate and sometimes requires pacemaker implantation, especially after extensive ablation. We report a patient with drug-refractory IST who was successfully treated by selective RFCA to the 2 earliest activation sites. During tachycardia, the earliest atrial activation preceded the surface P wave by 50 ms or more, whereas it was only 27 ms for the rest of the right atrium after ablation. Our patient had the longest activation period during tachycardia among the reported patients. In IST patients, a longer activation time at the site of the earliest atrial activation may imply that the abnormality is confined to a small area within the sinus node and may predict the efficacy of selective RFCA.

Negative regulation of Fas-mediated apoptosis by FAP-1 in human cancer cells.

FAP-1 (Fas-associated phosphatase-1) was previously identified as a protein that associates with a negative regulatory domain (C-terminal 15 amino acids) of Fas using the yeast 2-hybrid system. Functional analysis indicated that FAP-1 expression correlates with resistance to Fas-induced apoptosis in human cancer cells. We first generated anti-FAP-1 polyclonal antibody and confirmed the interaction of FAP-1 and Fas in vivo. FAP-1 interacted with wild-type, but not mutant, Fas (tPLV) in 293T cells after transfecting FAP-1 and Fas or its mutant. To investigate the functional role of FAP-1 in Fas-mediated signal transduction, we established stable transfectants of FAP-1 in 3 human cancer cell lines. Apoptosis assays demonstrated that cancer cells over-expressing FAP-1 increased the resistance to Fas-induced apoptosis by the anti-Fas antibody CH-11 in contrast with the wild types or the vector-transfected cells. In addition, FAP-1 regulated the activity of both caspases 3 and 8. Our data indicate a functional role for FAP-1 as a negative regulator of Fas-mediated apoptosis in human cancer cells and suggest that an additional signal-transducing molecule may be required for complete suppression of Fas-mediated apoptosis.

Salutary antiarrhythmic effect of combining a K channel blocker and a beta-blocker in a canine model of 7-day-old myocardial infarction.

We sought to examine whether the antiarrhythmic effect of E4031 (E), or I(Kr) channel blocker, is affected by beta-adrenergic stimulation using isoproterenol (Iso) or by beta-adrenergic blockade (betaB) using, ONO1101, in a canine myocardial infarction model. Electrophysiologic studies were performed in 10 dogs with 7-day-old myocardial infarctions. Local QT intervals were measured at 47 sites on the infarcted myocardium using a mapping electrode. QT dispersion (QTd), as defined by the coefficient of variation of QT intervals, was obtained. Inducibility of ventricular arrhythmias was examined by programmed stimulation. These procedures were repeated during administration of E, E + Iso, and E + betaB. The effect of prolonging local QT intervals by E was counteracted by Iso, and was accentuated by betaB. The amount of prolongation was dependent on the baseline QT intervals, and QTd showed a tendency to decrease with E, to increase with E + Iso, and significantly decreased with E + betaB. Ventricular tachyarrhythmias were induced in a half of dogs with E + Iso, but were not induced with E + betaB. In the presence of adrenergic activation, I(Kr) blockers may exhibit a decreased antiarrhythmic effect. Beneficial synergism can be expected when an I(Kr) blocker is combined with a beta-blocker in the subacute phase of myocardial infarction.

Determination of refractory periods and conduction velocity during atrial fibrillation using atrial capture in dogs: direct assessment of the wavelength and its modulation by a sodium channel blocker, pilsicainide.

OBJECTIVES: The purposes of this study were to measure the atrial refractory period and the conduction velocity (CV) during atrial fibrillation (AF) and to explore the antiarrhythmic mechanism of a sodium channel blocker, pilsicainide, during AF. BACKGROUND: Sodium channel blockers not only decrease the CV, but also prolong the atrial refractory period, particularly during rapid excitation. Because these effects on the wavelength are counteractive and rate dependent, it is critical to measure these parameters during AF. METHODS: In eight dogs, after AF was induced under vagal stimulation, a single extra-stimulus was repeatedly introduced from the left atrium and its capture was statistically determined for each coupling interval. The local CV was also measured during constant capture of the fibrillating atrium by rapid pacing. The same procedure was repeated after pilsicainide administration. RESULTS: Pilsicainide significantly increased the mode of AF intervals from 81 +/- 10 to 107 +/- 16 ms (p < 0.01). While the CV was decreased from 0.9 +/- 0.1 to 0.7 +/- 0.1 m/s (p < 0.02), the effective refractory period during AF was increased from 69 +/- 11 ms to 99 +/- 17 ms (p < 0.01). As a result, the wavelength was significantly increased by pilsicainide from 6.6 +/- 0.9 to 7.6 +/- 1.2 cm (p < 0.05). CONCLUSIONS: During AF, whereas the sodium channel blocker pilsicainide decreases CV, it lengthens the wavelength by increasing the refractory period, an action that is likely to contribute to the drug's ability to terminate the arrhythmia. The direct measurement of refractoriness and CV during AF may provide new insights into the determinations of the arrhythmia and antiarrhythmic drug action.

Comparison of nerve growth factor mRNA expression in cardiac and skeletal muscle in streptozotocin-induced diabetic mice.

To address the role of nerve growth factor (NGF) in diabetes mellitus (DM)-induced cardiac autonomic neuropathy, we quantitated and compared the expression of NGF mRNA in the cardiac and the skeletal muscle in experimental DM mice with the RT-PCR-HPLC method, which we have developed previously, using a NGF deletion mutant RNA as an internal standard. DM was induced in ICR mice via intraperitoneal injection of streptozotocin. RT-PCR was performed using total RNA extracted from left ventricle and soleus muscle, and the levels of NGF mRNA were quantitated by HPLC analysis. NGF mRNA content of the cardiac muscle was 17-fold higher than the skeletal muscles in control mice. NGF mRNA content of the cardiac muscle in diabetic mice at 6 weeks was 4.0-fold higher than that in the control mice, while that of the skeletal muscle in diabetic mice was not different from the controls. These results indicated that the DM-induced increase in NGF mRNA content was higher in cardiac muscle than skeletal muscle, and that NGF might play an important role in cardiac autonomic neuropathy.

Successful stenting on tortuous coronary artery with accordion phenomenon: strategy--a case report.

Guidewire manipulation through tortuosities is difficult. Straightening a tortuous coronary artery by using a stiff guidewire has been recognized to induce vessel wall shortening referred to as an "accordion phenomenon." With inappropriate identification as dissection or thrombus formation, the risk of performing unnecessary dilation at the pseudo-narrowing site exists. The authors describe here two cases showing the accordion phenomenon induced by a stiff guidewire during successful stenting at a tortuous right coronary artery. In another case, the authors experienced an "accordion phenomenon" at the proximal edge of the Palmaz-Schatz stent implanted in a tortuous right coronary artery. The stent edge was better positioned at the straight portion than at the contour portion in a tortuous coronary artery.

Angioplasty/bypass combination therapy in an 89-year-old man with left main trunk disease.

We report a case of an 89-year-old man presenting with unstable angina and left main trunk disease. Minimally invasive direct coronary artery bypass grafting supplemented by catheter intervention was successfully performed. In view of the increasing elderly population, angioplasty/bypass combination therapy may be an important alternative for elderly coronary artery disease patients.

Mutational analysis of the PTEN gene in head and neck squamous cell carcinoma.

Loss of heterozygosity (LOH) at chromosome band 10q23 occurs frequently in a wide variety of human tumors. A recently identified candidate tumor suppressor gene, PTEN located on 10q23, is mutated in multiple advanced cancers. To explore whether PTEN is associated with human squamous cell carcinoma of the head and neck (SCCHN), DNAs from both normal muscle and tumor tissue in 19 SCCHN were used for detecting LOH at chromosome 10q23 and mutational analysis of PTEN by direct polymerase chain reaction (PCR)-DNA sequencing. LOH at 10q23 was identified in 6/15 SCCHN. Mutation of PTEN was identified in 3/19 SCCHN. Of these 3 patients, 2 had stage IV disease; the third patient, with recurrent, metastatic and stage III disease, showed a 36 bp germline heterozygous deletion within intron 7. Furthermore, a missense mutation at codon 501 (TCT --> TTT: Ser --> Phe) in exon 8 was also found in tumor from the same patient. Our results suggest that PTEN may play a role in the genesis of some SCCHNs.

Differential effects of N-acetylcysteine on nitroglycerin- and nicorandil-induced vasodilation in human coronary circulation.

We investigated the role of the availability of sulfhydryl groups during vasodilation of the human coronary circulation induced by nitroglycerin and nicorandil. In patients with normal coronary arteries (n = 29) or with coronary artery disease (CAD; n = 26), coronary blood flow (CBF) and epicardial coronary artery diameter after intracoronary administration of 50 microg nitroglycerin or 0.5 mg nicorandil were measured, before and after the intravenous infusion of saline or 100 mg/kg of N-acetylcysteine (NAC). In normal subjects, saline infusion did not alter the nitroglycerin- and nicorandil-induced vasodilation in large epicardial coronary artery. In contrast, NAC potentiated both nitroglycerin- and nicorandil-induced vasodilation. In patients with CAD, nitroglycerin and nicorandil induced less dilation than in normal subjects. NAC augmented the nitroglycerin- and nicorandil-induced vasodilation in the small epicardial coronary artery, but not in the large epicardial segments. In both groups, NAC potentiated the increase in CBF in response to nitroglycerin. However, NAC had no effects on the CBF response to nicorandil. Sulfhydryl availability is at least one determinant of the in vivo responsiveness to nitroglycerin of conductance and resistance vessels in normal human coronary circulation. In patients with CAD, external augmentation of sulfhydryl availability did not affect the depressed response to nitroglycerin in the large epicardial coronary artery. Although nicorandil acts as an NO donor, similar to nitroglycerin, in dilating the epicardial coronary artery, other effects, such as the opening of K(ATP) channel, play a more important role in the nicorandil-induced vasodilation of resistance vessels.

Discordant prolongation of the refractory period and repolarization time by a class III agent, E4031, in the healing phase of myocardial infarction.

Susceptibility to reentrant tachyarrhythmias and the antiarrhythmic efficacy of class III agents are related more to the duration of the refractory period (ERP) than to the repolarization time (RT). We measured both ERP and RT in a canine model of healing myocardial infarction, and evaluated the effect of a class III agent (E4031) on these parameters and on the inducibility of ventricular tachyarrhythmias. ERP and RT on the unipolar electrogram were measured at several cycle lengths in the normal (NZ) and infarct zones (IZ), respectively, in 10 canine myocardial infarction models and extrastimulation was used to induce ventricular arrhythmias. Measurements were repeated after E4031 administration. At baseline, both ERP and RT were significantly longer in IZ than in NZ with ERP/RT ratio also higher in IZ. This ratio tended to increase at longer cycle lengths. E4031 increased ERP and RT both in NZ and IZ at all cycle lengths, but increased the ERP/RT ratio predominantly in IZ. E4031 prevented induction of sustained VT or VF, which was inducible in 3 out of 10 dogs at baseline, although it facilitated induction of VF in 1 dog with no baseline arrhythmia. By increasing the ERP/RT ratio, class III drugs may shorten the relative refractory period in IZ at the expense of a greater ERP difference created between NZ and IZ.