Comprehensive validation of early diagnostic algorithms for myocardial infarction in the emergency department.

OBJECTIVE: To comprehensively evaluate diagnostic algorithms for myocardial infarction using a high-sensitivity cardiac troponin I (hs-cTnI) assay. PATIENTS AND METHODS: We prospectively enrolled patients with suspected myocardial infarction without ST-segment elevation from nine emergency departments in Japan. The diagnostic algorithms evaluated: (i) based on hs-cTnI alone, such as the European Society of Cardiology (ESC) 0/1-h or 0/2-h and High-STEACS pathways; or (ii) used medical history and physical findings, such as the ADAPT, EDACS, HEART, and GRACE pathways. We evaluated the negative predictive value (NPV), sensitivity as safety measures, and proportion of patients classified as low or high-risk as an efficiency measure for a primary outcome of type 1 myocardial infarction or cardiac death within 30 days. RESULTS: We included 437 patients, and the hs-cTnI was collected at 0 and 1 hours in 407 patients and at 0 and 2 hours in 394. The primary outcome occurred in 8.1% (33/407) and 6.9% (27/394) of patients, respectively. All the algorithms classified low-risk patients without missing those with the primary outcome, except for the GRACE pathway. The hs-cTnI-based algorithms classified more patients as low-risk: the ESC 0/1-h 45.7%; the ESC 0/2-h 50.5%; the High-STEACS pathway 68.5%, than those using history and physical findings (15-30%). The High-STEACS pathway ruled out more patients (20.5%) by hs-cTnI measurement at 0 hours than the ESC 0/1-h and 0/2-h algorithms (7.4%). CONCLUSIONS: The hs-cTnI algorithms, especially the High-STEACS pathway, had excellent safety performance for the early diagnosis of myocardial infarction and offered the greatest improvement in efficiency.

Selective interference of mTORC1/RAPTOR protects against human disc cellular apoptosis, senescence, and extracellular matrix catabolism with Akt and autophagy induction.

OBJECTIVE: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that integrates nutrients to execute cell growth and protein synthesis. We hypothesized that mTOR is essential for the intervertebral disc, the largest avascular, low-nutrient organ. Our objective was to elucidate roles of mTOR signaling in human disc cells. DESIGN: The mTOR exists in two complexes: mTORC1 containing the regulatory-associated protein of mTOR (RAPTOR) and mTORC2 containing the rapamycin-insensitive companion of mTOR (RICTOR). To analyze their functions in human disc nucleus pulposus cells, RNA interference (RNAi) of mTOR targeting mTORC1 and mTORC2, RAPTOR targeting mTORC1, or RICTOR targeting mTORC2 or rapamycin, a pharmacological mTORC1 inhibitor, was applied. First, mTOR signaling including Akt, p70/ribosomal S6 kinase (p70/S6K), and autophagy were assessed. Then, apoptosis, senescence, and matrix metabolism were evaluated under pro-inflammatory interleukin-1 beta (IL-1ß) stimulation. RESULTS: Western blotting showed significant decreases in specific proteins by each RNAi (all P < 0.0001). In mTOR signaling, RNAi of mTOR and RICTOR decreased p70/S6K and Akt phosphorylation, whereas RAPTOR RNAi decreased p70/S6K but increased Akt phosphorylation. All RNAi treatments increased light chain 3 (LC3)-II and decreased p62/sequestosome 1 (p62/SQSTM1), indicating enhanced autophagy. In apoptosis, IL-1ß-induced terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and poly (ADP-ribose) polymerase (PARP) and caspase-9 cleavage decreased by RAPTOR RNAi. In senescence, IL-1ß-induced senescence-associated beta-galactosidase (SA-ß-gal)-positive cells and p16/INK4A expression also decreased by RAPTOR RNAi. In matrix metabolism, RAPTOR RNAi reduced IL-1ß-induced catabolic matrix metalloproteinase (MMP) release and activation and up-regulated anabolic gene expression. These findings were all consistent with rapamycin administration. Additional disc-tissue analysis detected expression and phosphorylation of mTOR-signaling molecules in varying ages. CONCLUSION: Selective interference of mTORC1/RAPTOR protects against inflammation-induced apoptosis, senescence, and matrix catabolism possibly through Akt and autophagy induction in human disc cells.

A phase I/II trial of irinotecan plus amrubicin supported with G-CSF for extended small-cell lung cancer.

OBJECTIVE: This study reports the findings of a Phase I/II, cohort, dose-escalation trial of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor. This study aimed to determine the dose-limiting toxicity of the combination and to define the maximum-tolerated dose, as a recommended dose for Phase II trials. We also sought to obtain preliminary data on the efficacy of this combination as a frontline therapy for extensive-disease small-cell lung cancer. METHODS: We included 23 chemo-naïve patients with extensive-disease small-cell lung cancer in the trial. The amrubicin dose was escalated from 35 to 40 mg/m(2) (Levels 1 and 2, respectively) to determine the dose-limiting toxicity, with an unchanged dose of irinotecan at 50 mg/m(2). RESULTS: Of nine patients, three experienced dose-limiting toxicities at Level 1 of prolonged Grade 4 neutropenia, Grade 3 febrile neutropenia and Grade 3 febrile neutropenia with Grade 3 diarrhea. At Level 2, two patients experienced dose-limiting toxicities of Grade 4 neutropenia and Grade 3 neutropenia with Grade 4 diarrhea. The maximum-tolerated doses and recommended doses for amrubicin and irinotecan were therefore determined to be 35 and 50 mg/m(2), respectively. The Level 1 trial was then expanded to 21 patients, 14 (70%) of whom showed partial responses to the recommended dose. The median progression-free and overall survival times were 6.37 and 15.21 months, respectively. CONCLUSIONS: The combination of amrubicin and irinotecan with the support of granulocyte colony-stimulation factor produced a potent effect in chemo-naïve extensive-disease small-cell lung cancer patients. The use of biomarkers for this regimen may identify patients who are likely to suffer from treatment-ending severe adverse effects.

Phase-specific developmental and reproductive strategies in the desert locust.

Locusts modify developmental and reproductive traits over successive generations depending on the population density. A trade-off between developmental rate and body size and between progeny size and number is often observed in organisms. In this study, we present evidence that this rule is evaded by desert locusts, Schistocerca gregaria Forskål, which often undergo outbreaks. Under isolated conditions, large hatchlings, typical of the gregarious forms, grow faster but emerge as larger adults than do small hatchlings typical of the solitarious forms, except for some individuals of the latter group that undergo extra molting. Under crowded conditions, large and small hatchlings grow at a similar rate, but the former become larger adults than the latter. Small hatchlings show a trade-off between development time and body size at maturation, but this constraint is avoided by large hatchlings. Phase-specific, as well as body size-dependent, differences are also detected in reproductive performance. As adult body size increases, females of a solitarious line produce more but slightly smaller eggs, whereas those of a gregarious line produce more and larger eggs. Total egg mass per pod is larger in gregarious forms than in solitarious forms. A trade-off between egg size and number is shown by a solitarious line but not by a gregarious line that produces relatively large eggs with similar numbers of eggs per pod. These results suggest that phase transformation involves not just a shift of resource allocation but also an enhanced capability expressed in response to crowding.

Calcium pyrophosphate dihydrate deposition in the transverse ligament of the atlas: an unusual cause of cervical myelopathy.

A 75-year-old male presented with progressive myelopathy due to massive retro-odontoid deposits of calcium pyrophosphate dehydrate (CPPD) crystals. Magnetic resonance imaging revealed a non-enhanced isointense extradural mass on a T1-weighted image and a heterogeneous intense mass on a T2-weighted image. Computed tomography (CT) showed linear calcification within the mass. The mass was resected via a posterolateral approach resulting in marked improvement of the symptoms. Histological examination revealed birefringent rhomboid crystals consistent with CPPD. The preoperative differential diagnosis of periodontoid CPPD deposition disease in the elderly population should be considered, particularly if CT studies demonstrate small areas of calcification within the retro-odontoid mass.

Altered regulation of c-jun and its involvement in anchorage-independent growth of human lung cancers.

The c-jun oncogene is frequently overexpressed in non-small-cell lung cancers (NSCLC), but its functional involvement in lung cancer development has not been clearly elucidated. In this study, we found that among the immediate-early serum responsible genes, exemplified by c-jun, c-fos and c-myc, induction of c-jun in a human bronchial epithelial cell line, BEAS-2B, was dependent on anchorage, in contrast to clear induction of c-fos and c-myc under both anchorage-dependent and -independent conditions. In fact, forced expression of c-jun in BEAS-2B cells significantly increased cell viability and colony formation in soft agar. Furthermore, we also found that such anchorage-dependent regulation of c-jun was lost in a significant fraction of human lung cancer cell lines. Interestingly, suppressed anchorage-independent but not anchorage-dependent growth was noted by constitutive expression of a dominant-negative c-jun mutant in a lung cancer cell line showing dysregulated and sustained c-jun expression in the absence of anchorage. These findings suggest that dysregulated c-jun expression may be involved in the acquisition of anchorage independence in the process of human lung carcinogenesis.

Phase-related morphological changes induced by [His7]-corazonin in two species of locusts, Schistocerca gregaria and Locusta migratoria (Orthoptera: Acrididae).

The effects of a neurohormone, [His(7)]-corazonin, on phase-related morphological traits (F/C and E/F ratios; F = length of the hind femur, C = maximum width of the head; E = length of fore wing) were re-examined in the desert locust, Schistocerca gregaria Forskål. The F/C ratio was significantly different between adults with five and six nymphal instars, respectively, indicating that they need to be analysed separately. Injections of the synthesized peptide (1 nmol) into individually-reared (solitary) nymphs at the second and third instars caused a shift in classical morphometric ratio towards the value typical for crowded (gregarious) individuals in both sexes. The E/F ratio, which is smaller in solitary locusts than in gregarious ones, was also influenced significantly by injections of [His(7)]-corazonin into individually-reared locusts. The effect of [His(7)]-corazonin on E/F ratios was shown more clearly when the nymphs were injected at a higher dose (2 nmol) at the beginning of the third instar. Single injections of the peptide into individually-reared nymphs at different instars revealed that the earlier the injection the larger the 'gregarizing' effects of the peptide on F/C and E/F ratios. The same tendency was also detected in Locusta migratoria Linnaeus. These results supported the hypothesis that [His(7)]-corazonin plays an important role in the control of phase polymorphism in locusts.

Classification of abomasal displacement in cows according to histopathology of the liver and clinical chemistry.

Histopathological features of livers and blood chemical values in cows with abomasal displacement were investigated. Liver biopsy samples were collected during redressment operations in 92 cows with abomasal displacement, and the samples were stained with haematoxylin and eosin or periodic acid Schiff (PAS). Blood was collected for chemical tests. Livers were histopathologically divided into the following four types: normal histology cases (21%), fatty degeneration cases (36%), cloudy swelling cases (19%) and fatty degeneration cases with cloudy swelling (24%). The number of PAS-positive samples was significantly higher in the normal histology group and significantly lower in the severe fatty degeneration group and severe cloudy swelling group. Cows with fatty degeneration had significantly higher levels of serum 3-hydroxybutyric acid, non-esterified fatty acid and aspartate aminotransferase than did those with cloudy swelling or normal histology. The results indicate that the morbid conditions of cows with abomasal displacement can be classified into four types.

Association between the dopamine D2 receptor A2/A2 genotype and smoking behavior in the Japanese.

For the study presented here, we investigated possible links between the dopamine D2 receptor (DRD2) TaqIA genotype (DRD2*A) and smoking behavior in a total of 332 Japanese individuals. For the first time, functional insertion/deletion polymorphism (-141C Ins/Del) in the DRD2 promoter was also examined in relation to smoking behavior. The distribution of the DRD2*A genotype was significantly different among current, former, and never-smokers (P = 0.001; chi(2) test), and smoking appeared to be associated with the DRD2 A2/A2 genotype, showing marked contrast to previous reports for non-Hispanic whites in the United STATES: Multivariate logistic regression analysis incorporating age, sex, genotype, and smoking status as variables revealed that DRD2 A2/A2 genotype was significantly associated with an increased risk of predisposition to smoking behavior in the Japanese (odds ratio, 3.680; 95% confidence interval, 1.499-9.052). In contrast, such an increased risk was not observed in terms of association with the -141C Ins/Del polymorphism. These findings suggest an association of the DRD2*A genotype with an increased risk of being predisposed to smoking behavior in the Japanese and suggest the possible existence of ethnic group-specific differences, which warrant additional studies on the underlying molecular mechanism.

Trisomy 14 with thrombocytosis and monocytosis.

It has been reported that trisomy 14 is associated with myeloid malignancies, but a case with increased platelet count has also been reported. However, the clinical significance of trisomy 14 is still uncertain. We report a patient with trisomy 14 with thrombocytosis and a gradual increase in monocytosis. He was treated with hydroxyurea, cytarabine and aclarubicin in low doses and his quality of life was maintained for a period of about 1 year from blastic crisis. Hydroxyurea, cytarabine or aclarubicin in low doses may be the treatment of choice for trisomy 14 patients with respect to the patients' quality of life.

Case report ganglion cysts of the bilateral cruciate ligaments.

Ganglion cysts originating from the cruciate ligaments have been reported rarely. A 38-year-old woman developed symptoms of knee pain with 10 degrees loss of knee extension. Preoperative magnetic resonance imaging showed a well-demarcated cystic mass surrounding the posterior cruciate ligament so clearly that further examination was not recommended. Because examination under anesthesia confirmed full extension of the knee, we presumed that pain produced by compression caused the diminished extension, and that mechanical block was not the reason. During arthroscopic examination, a mass was impinged between the anterior cruciate ligament and the intercondylar notch when extension of the knee was attempted. The mass was resected and immediate improvement was noted. The patient had experienced the same episode in the contralateral knee and removal of a ganglion cyst on the cruciate ligament 10 years ago. At the latest follow-up she was completely symptom free in both knees without any sign of recurrence.

[Nontuberculous mycobacterial disease in a general hospital].

Annual incidence of nontuberculous mycobacterial (NTM) disease has been gradually increasing in the last 10 years in Japan. It is likely to encounter this disease not only in hospitals specialized in mycobacterial diseases but also in general hospitals. NTM were isolated from 97 cases between January 1990 and June 1996 at our hospital. Out of them, 41 patients were diagnosed as NTM disease. Mycobacterium avium complex (MAC) was the most frequent pathogens (68.3%) and M. kansasii (22%) was the next. Other pathogens were M. chelonae (4.9%), M. fortuitum (2.4%) and M. szulgai (2.4%). Results obtained in our hospital were very similar to the rates which have been reported previously. Patients with MAC infection showed relatively poor prognosis (eight patients were died out of 28 patients with MAC) in this study compared with the cases reported in previous papers, and this result could be explained by the severity of illness when they were admitted to our hospital, the insufficiency of the initial treatment which should be started with the combined use of three to four antibacterial drugs including clarithromycin, and to a low dosage of clarithromycin compared with conventionally adopted dosage. Unlike tuberculosis, human to human transmission is considered to be negligible in the case of NTM disease, and general hospitals are able to provide medical care to the patients with NTM disease. Rather, if general hospitals which are located in the region near to the patients residence can play more active role in the treatment of NTM disease, it would be more beneficial to patients requiring long-term follow-up observation. Based on the result that similar therapeutic results were obtained for infections with other NTM as reported in previous papers, it is indicated that general hospitals are able to provide medical care to patients with NTM disease if therapeutic regimens recommended by specialist are sufficiently understood and applied.

Aspects of CO2 laser engraving of printing cylinders.

Results of the experimental and theoretical investigations of CO(2) laser-engraved cylinders are presented. The processed surfaces of test samples are examined by a phase-stepping laser interferometer, digital microscope, and computer-controlled profilometer. Fourier analysis is made on the patterns parallel to the axis of the laser-scribed test ceramic cylinders. The problem of the visually observed banding is discussed.

[A case of dural arteriovenous fistula in the transverse and sigmoid sinus which developed over five years].

We report a case of dural arteriovenous fistula (dAVF) of the transverse and sigmoid sinus which developed over five years. The patient was a 64-year-old man, who had a history of congestive heart failure and transient ischemic attack (TIA). No abnormal lesions were detected in the cerebral angiograms five years prior to the time the etiology of his TIA was investigated. He suddenly suffered from left hemiparesis and the CT scan showed right parietal subcortical hemorrhage. Right carotid angiogram demonstrated dAVF of the transverse and sigmoid sinus supplied by the right occipital and ascending pharyngeal arteries. We thought the reason for the subcortical hemorrhage in this patient was due to the disturbance of venous return in the right cerebral hemisphere. We underwent direct embolization of the right transverse sinus by interlocking detachable coils. Postoperative cerebral angiograms demonstrated the disappearance of dAVF and he was discharged. Whether dAVF is a congenital anomaly or not, has been controversial. Since the dAVF in this case had newly developed over five years, it is suggested that dAVF is an acquired lesion.

Mixed connective tissue disease associated with acute polyradiculoneuropathy.

A rare case of mixed connective tissue disease (MCTD) with acute polyradiculoneuropathy is reported. A 23-year-old woman presented with high body temperature, arthralgia and a headache, and developed gait disturbance two weeks later. She had many clinical features common to patients with MCTD. Her neurological manifestations were diagnosed as acute polyradiculoneuropathy based on the clinical picture, combined with supportive ancillary data, including cerebrospinal fluid (CSF) analysis, electrophysiological evaluation, sural nerve biopsy, peroneus brevis muscle biopsy, and magnetic resonance imaging (MRI). Her neurologic deficits, as well as associated laboratory findings, were improved by corticosteroid therapy.

YM-50001: a novel, potent and selective dopamine D4 receptor antagonist.

We investigated some in vitro pharmacological properties of a novel human dopamine D2-like receptor antagonist, YM-50001 [(R)-5-chloro-4-cyclopropylacarbonylamino-2-methoxy-N-[1-(3-methox ybenzyl)- 3-pyrrolidinyl]benzamide monooxalate]. Receptor binding studies revealed that YM-50001 had a potent affinity for human D4 receptors (Ki = 5.62 nM). YM-50001 displayed weak or negligible affinity for other neurotransmitter receptors including human D2 and D3 receptors. YM-50001 shifted the dopamine response curve on each human D2-like receptor subtype-mediated low-Km GTPase activity to the right. YM-50001 also exhibited good D4 selectivity with respect to D2-like receptor antagonism in the functional assay. These results indicate that YM-50001 is a novel, potent and selective D4 receptor antagonist.

[Bilateral carotid endarterectomy for patients with bilateral carotid artery stenosis].

In a couple of recent randomized trials, the benefits of unilateral carotid endarterectomy (CEA) have been reevaluated in symptomatic patients with severe stenosis. In contrast, the operative indication, procedure, and perioperative management of bilateral CEAs for patients with bilateral carotid artery stenosis are still controversial. In this report, we reviewed 7 patients who underwent bilateral CEAs at out institute during the last 10 years, with regard to the clinical feature, angiographical findings, operative procedure, surgical results and long-term prognosis. The patients ranged from 52 to 73 years in age, and included six males and one female. Clinical symptoms were asymptomatic in 1 patient, transient ischemic attack in 2, reversible ischemic neurological deficits in 2, minor completed stroke in 1, and major completed stroke in 1. The angiographical carotid artery stenosis in the dominant side of symptomatic cases was 50% in 3, 70% in 1, 90% in 2, and ulceration in 4 cases. The stenosis in the non-dominant side of symptomatic cases was 60% in 1, 70% in 3, 90% in 2, and 4 cases with ulceration. One case among the asymptomatic cases had bilateral 80-90% stenosis. We staged bilateral CEAs, in the dominant side first except in one case among the symptomatic cases and on the more severely stenotic side first in the asymptomatic cases. During CEA, an external shunt was placed in 1 case, but no internal shunt was used in any of the cases. Perioperative complications were found in 2 patients, transient bilateral hypoglossal nerve palsy and local hemorrhage in the other case. Totally, all of 7 cases (14 consecutive CEAs) have been performed with satisfactory results. No mortality and no permanent morbidity has resulted. In the follow-up period (mean: 38.3 month), 1 patient was found to have developed cerebral infarction in the ipsilateral carotid artery territory. From our own small experience and from that in the literature, CEAs for bilateral carotid artery stenosis should be performed in the dominant side first. Then, after a certain period, from 2 to 6 weeks, the CEA should be performed in the non-dominant side.

Dopamine D3 and D4 receptor antagonists: synthesis and structure--activity relationships of (S)-(+)-N-(1-Benzyl-3-pyrrolidinyl)-5-chloro-4- [(cyclopropylcarbonyl) amino]-2-methoxybenzamide (YM-43611) and related compounds.

In this study, we synthesized a series of (S)-N-(3-pyrrolidinyl)benzamide derivatives, 1, 2a-d, 5a-1, and 7, and their enantiomers, (R)-1 and (R)-5c-e, and evaluated their binding affinity for cloned dopamine D2, D3, and D4 receptors and their inhibitory activity against apomorphine-induced climbing behavior in mice. The results indicate that D2, D3, and D4 receptors have different bulk tolerance (D4 > D3 > D2) for the substituent of the 4-amino group (R1) on the benzamide nuclei and that cyclopropyl-, cyclobutyl-, and cyclopentylcarbonyl groups likely possess adequate bulkiness with respect to D3 and D4 affinity and selectivity over D2 receptors in this series. The results also suggested that the N-substituent (R2) on the pyrrolidin-3-yl group performs an important role in expressing affinity for D2, D3, and D4 receptors and selectivity among the respective subtypes. One of the compounds, (S)-(+)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-[(cyclopropylcarbonyl+ ++) amino]-2-methoxybenzamide (5c) (YM-43611), showed high affinity for D3 and D4 receptors (Ki values of 21 and 2.1 nM, respectively) with 110-fold D4 selectivity and 10-fold D3 preference over D2 receptors and weak or negligible affinity for representative neurotransmitter receptors. Compound 5c displayed potent antipsychotic activity in inhibiting apomorphine-induced climbing behavior in mice (ED50 value, 0.32 mg/kg sc).