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Silmitasertib (CX-4945) is currently being investigated in clinical trials against various types of cancer. The U.S. Food and Drug Administration (FDA) has already granted orphan drug designation to the compound for the treatment of advanced cholangiocarcinoma, medulloblastoma, and biliary tract cancer. Silmitasertib inhibits the serine/threonine protein kinase CK2, which exerts a proliferation-promoting and anti-apoptotic effect on cancer cells. In view of current and future applications, the measurement of silmitasertib levels in plasma is expected to play an important role in the evaluation of therapeutic and toxic concentrations in cancer patients. In the present work, we therefore present an LC–MS/MS method for the quantification of silmitasertib in human plasma. Using a simple liquid–liquid extraction with ethyl acetate and a mixture of n-hexane and ethyl acetate, this method can be performed in any laboratory with mass spectrometry. The validation was carried out according to the FDA guideline.

Summary: Background: The RECcording COurses of vasculaR Diseases (RECCORD) registry established by the German Society of Angiology – Society for Vascular Medicine aimed to address the lack in contemporary real-world data regarding current practice of medical and interventional care in vascular patients. We herein report the demographic and procedural characteristics of the first 1000 patients undergoing endovascular revascularization (EVR) for symptomatic peripheral artery disease (PAD). Patients and methods: RECCORD is an observational, prospective, multicenter, all-comers registry. Only patients undergoing EVR for symptomatic PAD are included and followed up for at least 1 year. Demographic characteristics, comorbidities, previous peripheral vascular interventions, medication, clinical stage of lower extremity artery disease (Rutherford category), hemodynamic parameters, and procedural data including complications are recorded via an entirely web-based platform. Results: Of the first 1000 patients (mean age 70 ± 10 years, 35% female) with 1096 EVR at 1477 vascular segments of the lower extremities, 25.0% were at the stage of chronic limb threatening ischemia (CLTI) and 75.0% at non-CLTI. The femoropopliteal segment was the dominant target lesion site (61.0%), followed by iliac (26.4%) and below-the-knee EVR (10.3%). Only angioplasty was performed in 130 EVR (11.9%), adjunctive drug coated balloons (DCB) in 498 (45.4%), additional stenting in 633 (57.8%). Debulking devices were used in 106 (9.7%) EVR. Clinical (Rutherford categories) and hemodynamic parameters (ankle-brachial-index) as well as secondary preventive medication were significantly improved post EVR. Periprocedural complications occurred in 63 (5.7%) EVR with pseudoaneurysm as the leading complication type in 26 (2.4%) EVR. Conclusions: The baseline data of the first 1000 patients from the RECCORD registry representing the real-world setting illustrate that the majority of EVR are performed in patients with claudication. Adjunctive use of DCB and stenting are the dominant types of EVR, while periprocedural complications are at an acceptable low rate.

Endocrine disrupting chemicals (EDC) include synthetic compounds that mimic the structure or function of natural hormones. While most studies utilize live embryos or primary cells from adult fish, these cells rapidly lose functionality when cultured on plastic or glass substrates coated with extracellular matrix proteins. This study hypothesizes that the softness of a matrix with adhered fish cells can regulate the intercellular organization and physiological function of engineered hepatoids during EDC exposure. We scrutinized this hypothesis by culturing zebrafish hepatocytes (ZF-L) on collagen-based hydrogels with controlled elastic moduli by examining morphology, urea production, and intracellular oxidative stress of hepatoids exposed to 17β-estradiol. Interestingly, the softer gel drove cells to form a cell sheet with a canaliculi-like structure compared to its stiffer gel counterpart. The hepatoids cultured on the softer gel exhibited more active urea production upon exposure to 17β-estradiol and displayed faster recovery of intracellular reactive oxygen species level confirmed by gradient light interference microscopy (GLIM), a live-cell imaging technique. These results are broadly useful to improve screening and understanding of potential EDC impacts on aquatic organisms and human health.

As a result of the RAINBOW trial, ramucirumab plus paclitaxel was established as a second-line treatment of advanced gastric cancer. Regarding the safety of ramucirumab plus paclitaxel in the Japanese, a subgroup analysis of the RAINBOW trial was conducted. The incidence of neutropenia was higher in Japanese patients. However, information is lacking concerning the safety of ramucirumab after marketing in Japanese patients. Therefore, the aim of this study was to evaluate the safety of ramucirumab in Japanese patients with advanced gastric cancer. The inclusion criteria were patients diagnosed with advanced gastric cancer who had commenced treatment with ramucirumab plus paclitaxel or paclitaxel only at Ogaki Municipal Hospital (Gifu, Japan) between January 2015 and December 2016. There were 26 patients in the ramucirumab plus paclitaxel group and 22 patients in the paclitaxel only group. Treatment-related adverse events were documented in 100.0% of the patients in the ramucirumab plus paclitaxel group (Grade 3-4, 73.1%) and 90.9 % of the patients in the paclitaxel only group (Grade 3-4, 45.5 %). The most frequently observed adverse event in both treatment groups was anemia. The second common adverse event was neutropenia. The incidence of neutropenia of Grade ≥3 was significantly higher in the ramucirumab plus paclitaxel group than in the paclitaxel only group. In conclusion, the incidence of neutropenia is high. However, we believe that ramucirumab plus paclitaxel can be safely administered.

Abstract. Background: The prevalence of peripheral artery disease (PAD) is increasing worldwide. Revascularization procedures constitute a cornerstone of the therapy in PAD, not only in critical limb ischaemia but increasingly also in patients with intermittent claudication. The German Society of Angiology – Society for Vascular Medicine is establishing a nationwide, prospective, multicentre registry to address the lack of contemporary real life data regarding current practice of medical and interventional care in vascular patients and its subsequent long-term outcome. Patients and methods: The RECording COurses of vasculaR Diseases registry (RECCORD registry) is an observational, prospective, multicentre, all-comers registry platform. In the initial phase, patients referred for endovascular revascularization of PAD of the lower limbs will be prospectively included and followed up for at least one year. At baseline, data on patients’ demographic characteristics, comorbidities, previous peripheral interventions, medication, and clinical stage of PAD (Rutherford category), haemodynamic parameters, and procedural data including complications will be assessed. Major adverse cardiac and limb events will be recorded at planned (at six and 12 months) and at any unplanned visits. The therapeutic management will be exclusively left to the discretion of the vascular specialists. Results and conclusions: The RECCORD registry will provide a comprehensive dataset depicting the current real life practice and outcome of vascular care. The seven predefined quality indicators will be used for benchmarking the participating centres. Moreover, identifying factors promoting a favourable outcome might pave the way for an evidence-based therapeutic strategy and a dedicated therapeutic pathway for patients with PAD including patient-oriented best interventional approaches. In the future, the RECCORD registry may provide a general platform to study the courses of various defined vascular diseases in order to get detailed insights into the real life current practice of health care provided to vascular patients.

Introduction Prophylaxis is effective in reducing the number of bleeding episodes in patients with severe or moderately severe haemophilia A and B, including those with inhibitors. However, data, predominantly from observational studies, suggest more equivocal effects on health-related quality of life (HRQoL). Aim To examine the impact of prophylaxis on HRQoL from prospective clinical trials. Methods We performed a systematic literature review of clinical trials evaluating the efficacy of prophylaxis with factor VIII, FIX or bypassing agents. Trials assessing HRQoL via validated instruments were selected and summarized. Results Thirteen trials (haemophilia A [n = 8]; haemophilia B [n = 2]; inhibitors [n = 3]) met all inclusion criteria. HRQoL instruments included the EQ-5D, SF-36, Haem-QoL-A, Haem-A-QoL, Haemo-QoL and CHO-KLAT. Improvements in HRQoL following prophylaxis were observed with the EQ-VAS, SF-36 and haemophilia-specific instruments in adult patients and were associated with reduced pain, fewer restrictions in physical activities and better general health. Prophylaxis led to statistically significant or clinically meaningful HRQoL improvement in six trials and non-significant improvement in four trials; two trials found no improvement and one reported no data. Despite study differences, consistent trends suggested that patients previously treated solely on-demand and those who experienced marked reductions in the frequency of bleeding with prophylaxis had a greater improvement in HRQoL. Conclusion Contrary to findings of observational studies, the results from the majority of prospective trials using validated instruments showed positive trends for improved HRQoL with prophylaxis in adults.

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a cellular adhesion molecule of the Ig superfamily, is associated with early stages of angiogenesis. In vitro, CEACAM1 regulates proliferation, migration, and differentiation of murine endothelial cells. To prove that CEACAM1 is functionally involved in the regulation of vascular remodeling in vivo, we analyzed 2 different genetic models: in Ceacam1-/- mice, the Ceacam1 gene was deleted systemically, and in CEACAM1(endo+) mice, CEACAM1 was overexpressed under the control of the endothelial cell-specific promoter of the Tie2 receptor tyrosine kinase. In Matrigel plug assays, Ceacam1-/- mice failed to establish new capillaries whereas in CEACAM1(endo+) mice the implants were vascularized extensively. After induction of hind limb ischemia by femoral artery ligation, Ceacam1-/- mice showed significantly reduced growth of arterioles and collateral blood flow compared with their WT littermates. In agreement with a causal role of CEACAM1 in vascular remodeling, CEACAM1(endo+) mice exhibited an increase in revascularization and collateral blood flow after arterial occlusion. Our findings indicate that CEACAM1 expression is important for the establishment of newly formed vessels in vivo. Hence CEACAM1 could be a future target for therapeutic manipulation of angiogenesis in disease.

Background— Neutrophils and monocytes are centrally linked to vascular inflammatory disease, and leukocyte-derived myeloperoxidase (MPO) has emerged as an important mechanistic participant in impaired vasomotor function. MPO binds to and transcytoses endothelial cells in a glycosaminoglycan-dependent manner, and MPO binding to the vessel wall is a prerequisite for MPO-dependent oxidation of endothelium-derived nitric oxide (NO) and impairment of endothelial function in animal models. In the present study, we investigated whether heparin mobilizes MPO from vascular compartments in humans and defined whether this translates into increased vascular NO bioavailability and function. Methods and Results— Plasma MPO levels before and after heparin administration were assessed by ELISA in 109 patients undergoing coronary angiography. Whereas baseline plasma MPO levels did not differ between patients with or without angiographically detectable coronary artery disease (CAD), the increase in MPO plasma content on bolus heparin administration was higher in patients with CAD ( P =0.01). Heparin treatment also improved endothelial NO bioavailability, as evidenced by flow-mediated dilation ( P P r =0.69, P Conclusions— Mobilization of vessel-associated MPO may represent an important mechanism by which heparins exert antiinflammatory effects and increase vascular NO bioavailability. These data add to the growing body of evidence for a causal role of MPO in compromised vascular NO signaling in humans.

Purpose: To present a novel method for analyzing the voltage waveform from high-frequency X-ray generators for radiographic systems. Material and Methods: The output signal of the actual voltage across the tube of a high-frequency generator was measured using the built-in voltage sense taps that are used for voltage regulation feedback in X-ray generators. The output signal was stored in an analyzing recorder, and the waveforms were analyzed using FFT analysis. The FFT analysis of high-frequency generators consisted of obtaining the power spectrum, comparing the major frequency components in the tube voltage waveforms, and examining the intensity of each frequency component. Results: FFT analysis enables an objective comparison of the complex tube voltage waveforms in high-frequency X-ray generators. FFT analysis detected the change in the X-ray tube voltage waveform that occurred when there were problems with the high-frequency generator. Conclusion: High-frequency X-ray generators are becoming the universal choice for radiographic systems. The X-ray tube voltage and its waveform are important features of an X-ray generator, and quality assurance (QA) is important, too. As a tool for engineers involved in the design and development of X-ray generators, we can see that our methods (FFT analysis) might have some value as a means of describing generator performance under varying conditions. Furthermore, since the X-ray tube voltage waveform of a high-frequency generator is complex, FFT analysis may be useful for QA of the waveform.

Congenital anomalies of the coronary arteries occur in 0.2-1.2% of the general population; they cause 12% of sports-related sudden cardiac deaths and 1.2% of non-sports-related deaths. We review some of the substantial advances that have been made both, in the understanding of the embryonic development of the coronary arteries and in the clinical diagnosis and management of their anomalies. In this second part of our review we elucidate recent approaches to defining coronary anomalies and provide information on their incidence and prognosis. In addition, we discuss the options for screening large populations for potentially lethal coronary malformations and elucidate the role of invasive diagnostic modalities such as intravascular ultrasound, flow wire and pressure wire. The clinical relevance of coronary anomalies is discussed particularly for the ill-defined group of anomalies that only occasionally cause severe clinical events comprising anomalous origination of a coronary artery from the opposite sinus (ACAOS), coronary artery fistulae and myocardial bridging. Finally, we provide an update on current diagnostic and therapeutic recommendations.

Congenital anomalies of the coronary arteries occur in 0.2-1.2% of the general population and may cause substantial cardiovascular morbidity and mortality. We review some of the advances that have been made both, in the understanding of the embryonic development of the coronary arteries (part I) and in the clinical diagnosis and management of their anomalies (part II). In this first part of our review we elucidate basic mechanisms of coronary vasculogenesis, angiogenesis and embryonic arteriogenesis. Moreover, we review the role of cellular progenitors such as epicardium-derived cells, cardiac neural crest cells and cells of the peripheral conduction system. Then we discuss the role of growths factors (such as FGV, HIF 1, PDGF B, TGFbeta1, VEGF, and VEGFR-2) and genes (such as FOG-2, VCAM-1, Bves, and RALDH2) at different states of coronary development. and we discuss the role of the cardiac neural crest in the concurrence of coronary anomalies with aortic root malformations. This part of the article is designed to review major determinants of coronary vascular development to provide a better understanding of the multiplicity of options and mechanisms that may give rise to coronary anomaly. To this end, we highlight results from experiments that provide insight in mechanisms of coronary malformation.

An escape vehicle was designed to provide an emergency evacuation for crew members living on a space station. For maximum escape capability, the escape vehicle needs to have the ability to safely evacuate a station in a contingency scenario such as an uncontrolled (e.g., tumbling) station. This emergency escape sequence will typically be divided into three events: The first separation event (SEP1), the navigation reconstruction event, and the second separation event (SEP2). SEP1 is responsible for taking the spacecraft from its docking port to a distance greater than the maximum radius of the rotating station. The navigation reconstruction event takes place prior to the SEP2 event and establishes the orbital state to within the tolerance limits necessary for SEP2. The SEP2 event calculates and performs an avoidance burn to prevent station recontact during the next several orbits. This paper presents the tools and results for the whole separation sequence with an emphasis on the two separation events. The first challenge includes collision avoidance during the escape sequence while the station is in an uncontrolled rotational state, with rotation rates of up to 2 degrees per second. The task of avoiding a collision may require the use of the Vehicle's de-orbit propulsion system for maximum thrust and minimum dwell time within the vicinity of the station vicinity. The thrust of the propulsion system is in a single direction, and can be controlled only by the attitude of the spacecraft. Escape algorithms based on a look-up table or analytical guidance can be implemented since the rotation rate and the angular momentum vector can be sensed onboard and a-priori knowledge of the position and relative orientation are available. In addition, crew intervention has been provided for in the event of unforeseen obstacles in the escape path. The purpose of the SEP2 burn is to avoid re-contact with the station over an extended period of time. Performing this maneuver requires knowledge of the orbital state, which is obtained during the navigation state reconstruction event. Since the direction of the delta-v of the SEP1 maneuver is a random variable with respect to the Local Vertical Local Horizontal (LVLH) coordinate system, calculating the required SEP2 burn is a challenge. This problem was solved using elements of neural network theory for model-free function approximation and decision making.

The feasibility of gene therapy for cardiovascular diseases related to atherosclerosis is a topic that needs to be addressed. Most recent papers have dealt with technical aspects and feasibility and most of the genes transferred were reporter genes like those for β-galactosidase or luciferase. This may mean that the ideal vector, one that is not pathogenic or immunotolerant but is still efficient, is still not available. The results of these studies are ambiguous and it has been doubted whether the genes targeted really affect the disease. Further efforts are therefore needed to elucidate the underlying pathophysiology.

Growth of coronary collaterals can change markedly the natural history of coronary artery disease: Stenoses and occlusions of the coronary arteries, even of the left main coronary artery, can be survived without infarction provided that the stenosing process has not progressed too fast, since the process of collateral development by growth needs time (a few weeks).1 2 3 However, in most cases, thrombus formation proceeds faster than vascular growth and infarcts develop. In many cases, collaterals, although they cannot prevent infarction in the majority of cases, may limit the damage and infarcts are smaller than expected from the size of the region at risk.4 Understanding collateral growth may mean to be potentially and eventually able to stimulate it by the injection of drugs, by the injection of growth factors, or by somatic gene therapy in patients at risk of infarction. In the past we have shown that collaterals grow by DNA synthesis and mitosis of endothelial and smooth muscle cells.3 These cells are quiescent in normal adult arteries, with their population kinetics close to zero. Under abnormal conditions a rapid conversion to G1 can occur and the cell cycle can be completed in ≈22 hours.3 With rapidly progressing stenosis in dogs (3 days from the onset of stenosis to complete occlusion), the labeling index of the endothelium of the midzone segment reached 7.5% and was followed by a wave of smooth muscle cell mitosis of only slightly lesser magnitude. Since controlled and regulated growth does not proceed without the presence and action of growth factor peptides and their receptors, several groups have investigated that aspect.5 6 7 8 The growth factors that are potentially involved in the process of cardiac collateralization are aFGF, bFGF, VEGF, IGF-1, and PDGF.7 9 10 11 12 13 …

Here, we report the existence of endothelial precursor (EPC) and stem cells in a distinct zone of the vascular wall that are capable to differentiate into mature endothelial cells, hematopoietic and local immune cells, such as macrophages. This zone has been identified to be localized between smooth muscle and adventitial layer of human adult vascular wall. It predominantly contains CD34-positive (+) but CD31-negative (-) cells, which also express VEGFR2 and TIE2. Only few cells in this zone of the vascular wall are positive for CD45. In a ring assay using the fragments of human internal thoracic artery (HITA), we show here that the CD34+ cells of the HITA-wall form capillary sprouts ex vivo and are apparently recruited for capillary formation by tumor cells. New vessels formed by these vascular wall resident EPCs express markers for angiogenically activated endothelial cells, such as CEACAM1, and also for mature endothelial cells, such as VE-cadherin or occludin. Vascular wall areas containing EPCs are found in large and middle sized arteries and veins of all organs studied here. These data suggest the existence of a `vasculogenic zone' in the wall of adult human blood vessels,which may serve as a source for progenitor cells for postnatal vasculogenesis,contributing to tumor vascularization and local immune response.

Collateral growth is characterized by macrophage accumulation, suggesting an important role of circulating cells. To study origin and function of macrophages during arteriogenesis, we related the extent of macrophage accumulation to vascular proliferation and investigated the fate of fluorescently (CMFDA) labeled blood cells that were injected at the time of femoral artery occlusion. The effect of bone marrow depletion via cyclophosphamide before femoral artery occlusion on collateral proliferation and macrophage accumulation was studied, and we looked for the presence of bone marrow-derived stem cells in the vicinity of growing collateral vessels. Finally, we investigated the arteriogenic effect of macrophage activation via MCP-1 in bone marrow-depleted animals. Maximal macrophage accumulation occurred during the first 3 days after femoral artery occlusion and paralleled the extent of vascular proliferation. Fluorescently labeled leukocytes homed to spleen and wound but they were absent in proliferating collateral arteries during maximal macrophage accumulation. Depletion of circulating cells did neither affect macrophage accumulation nor collateral growth. Staining of monocyte-depleted animals for BrdUrd and ED2, αSMA, or VE-Cadherin demonstrated local proliferation of macrophages and vascular cells, whereas C-Kit, SSEA1, or Thy1-positive bone marrow-derived stem cells were not detectable. Enhancement of macrophage accumulation via MCP-1 was independent of circulating monocytes and promoted arteriogenesis in the absence of direct effects on vascular cells. We propose that the initial phase of vascular growth is characterized by local proliferation of tissue resident precursors rather than by migration of blood born cells. The full text of this article is available online at http://circres.ahajournals.org.

It has been demonstrated in several studies that collateral growth is associated with accumulation of macrophages around proliferating vessel. Macrophages are known to secrete vascular growth factors and metalloproteinases. Both are necessary for the development of a proper vasculature. Recent studies suggest that certain subpopulations of macrophages are also capable of transdifferentiating into vascular cells. There are good reasons to assume that shear force rises dramatically in preexisting arteriolar shunts after occlusion of the main supplying vessel. Based upon these two findings it was hypothesized that high shear forces lead to homing of circulating monocytes to the growing collateral artery. The majority of studies, however, indicate that monocytes home under low shear force conditions. Our own observations in monocyte depleted animals suggest that proliferation and transdifferentiation of tissue macrophages occurs locally in growing collateral vessels and is independent of circulating cells. We thus propose that local proliferation and transdifferentiation of tissue macrophages rather than homing of circulating monocytes play a major role in arteriogenesis.

Behçet's disease (BD) is widely known to be strongly associated with human leukocyte antigen (HLA) B51 in many different ethnic groups.Recently, HLA-B51 allele typing of Greek BD patients was performed to study the distribution of B*5101-B*5107 alleles in this Greek population, the B51 antigen strongly associated with BD was found to be predominantly encoded by allele B*5101. As it is now known that the B51 antigen can be encoded by 21 alleles, B*5101-B*5121, we performed HLA-B*51 allele genotyping among 58 Greek patients with BD. After serological HLA typing, typing of HLA-B*51 alleles was performed using the polymerase chain reaction-sequencing-based typing (PCR-SBT) method. The frequency of the B51 antigen was found to be significantly higher in the patient group as compared with the control group (75.9% of patients vs 22.0% of controls. In the genotyping of B51 alleles, 34 out of 44 B51-positive patients possessed B*5101, 13 out of the 44 carried B*5108. In contrast, all of the 9 B51-positive normal controls carried B*5101. This study revealed a strong association between Greeks with BD, both B*5101, B*5108, provided important insights into the molecular mechanism underlying the association between HLA status, this disease.

The neuroleptic malignant syndrome (NMS) is a rare complication of antipsychotic therapy. We report on a 65-year-old patient who was treated with haloperidol, diazepam and mirtazapin because of a severe depressive episode with psychotic symptoms. He exhibited most of the signs and symptoms characteristic of NMS, e.g.: hyperthermia, rigidity, elevated creatine phosphokinase, leukocytosis, elevated liver enzymes, reduced consciousness and autonomic nervous system disturbances. A secondary pneumonia was diagnosed 2 days after the onset of the NMS, which might have been due to chest wall rigidity. Intensive care treatment consisted of immediate discontinuation of the offending agent, supportive therapy with rehydratation and catecholamines as well as application of dantrolen. After 23 days of intensive therapy all pathological parameters were normalised and the patient was transferred to an internal ward. Three main theories on the pathogenesis of NMS exist: 1. blockade of central receptors, 2. a skeletal muscle target model and 3. sympathoadrenal hyperactivity. The differential diagnosis includes among others malignant hyperthermia and serotonin syndrome.

The patient was a 74-year-old man, a physician, whose chief complaint was an unproductive cough. The shadow of a mass was seen at the hilum of the left lung, and the mediastinal lymph nodes on both sides were swollen. No histological diagnosis was obtained even after bronchoscopy, including transbronchial needle aspiration biopsy, but large-cell carcinoma of the lung was diagnosed on the basis of ultrasound-guided biopsy of a shadow in the liver suspected of being a metastatic tumor (T2N3M1, Stage IV). Two courses of chemotherapy (CBCDA + VDS) failed to gain any improvement, and the pain resulting from recurrent bone metastases was managed mainly by the administration of the best supportive care. The patient was readmitted to the hospital after development of numbness in the right upper extremity followed by complication of pneumonia and heart failure, and he passed away. Autopsy revealed a primary hilar lung tumor with a histological diagnosis of poorly differentiated adenocarcinoma.

Coagulation factor XII (FXII) is activated on contact with various biologic surfaces, including subendothelial tissues and lipoprotein particles. Thus, the plasma level of activated FXII (XIIa) might represent vascular lesions or be a marker of abnormal lipid metabolism. A 46C/T polymorphism was recently described in the FXII gene close to the ATG translation initiation codon, which was associated with inter-individual variation of plasma FXII zymogen levels. The present paper reports the association of the 46C/T polymorphism with plasma XIIa levels in apparently healthy subjects, and in patients with ischemic cerebrovascular disease (CVD) and arteriosclerosis obliterans (ASO). XIIa levels were not significantly different between patients and controls, but were strongly dependent on XII 46C/T genotypes (2.07 +/- 0.81, 1.65 +/- 0.63, and 0.93 +/- 0.41 ng/ml for C/C, C/T, and T/T genotypes, respectively; P0.0001). This association was evident for each group studied (P0.0001 for CVD and controls; P= 0.0007 for ASO). There were positive correlations between plasma FXII clotting activity and XIIa levels. In a univariate analysis, XIIa correlated with total cholesterol, triglycerides, plasminogen activator inhibitor-1, and C-reactive protein (CRP), although the presence of conventional cardiovascular risk factors (male sex, smoking, hypertension, hypercholesterolemia, diabetes) did not significantly increase XIIa. Stepwise regression analyses revealed that the XII clotting activity had the strongest association with XIIa. In conclusion, XIIa levels depended on XII 46C/T genotype and correlated with some cardiovascular risk factors. Thus, the FXII genotype should be taken into consideration for interpretation of plasma XIIa levels.

We report a 16-year-old Japanese male with lipoid proteinosis showing various skin manifestations. The patient was born to nonconsanguineous parents and none of his relatives was similarly affected. The patient suffered from a hoarse voice and refractory temporal epilepsy from early childhood. Computed tomography scanning of the brain showed bilateral calcification in the temporal lobes, a characteristic feature of lipoid proteinosis. On physical examination, various skin manifestations, including papules and haemorrhagic blisters, acne-like scars at sites of minor trauma or friction, and beads of small papules along the free margins of the eyelids were noted. A skin biopsy showed deposits of homogeneous hyaline-like material, positive on periodic acid-Schiff staining, throughout the dermis, particularly around small blood vessels. It is noteworthy that a range of characteristic skin lesions can be present in a patient with lipoid proteinosis even with mild systemic involvement.

Genotype Distribution of the 46C/T Polymorphism of Coagulation Factor XII in the Japanese Population: Absence of Its Association with Ischemic Cerebrovascular Disease

We report a 54-year-old Japanese man who was diagnosed as progressive multifocal leukoencephalopathy (PML). He had been maintained on regular hemodialysis for 10 years. He was admitted to our hospital with chief complaints of visual disturbance and disorientation. On neurological examination, he was somnolent, and showed mild weakness in the right upper and lower limbs. Deep tendon reflexes were brisk on the right upper and bilateral lower limbs. Sensory examination revealed no abnormal findings. The cerebrospinal fluid (CSF) showed five mononuclear cells/mm3, protein 39 mg/dl and glucose 38 mg/dl. Brain MRI revealed multiple hyperintense lesions in T2-images, which were confined to the white matter of bilateral occipital and the left frontal lobes without an enhancement after gadolinium administration. Using polymerase chain reaction, we amplified the JCV regulatory region from the CSF of the patient. The amplified product contained a rearranged regulatory region that could have been generated from the archetype by deletion and amplification. PML was diagnosed on the basis of these findings. The patient died 7 months after onset of the symptoms. The diagnosis of PML was confirmed by the postmortem findings. The present case indicates that PCR of JCV from CSF is very useful for definitive diagnosis of PML.

Signals initiated through both the TCR complex and CD28 are required for optimal activation of T lymphocytes. Recently, it has been demonstrated that CD28 interacts with two different ligands, designated CD80 (B7/B7-1) and CD86 (B70/B7-2). We have produced stable transfectants that express CD80, CD86, or both ligands and have examined their ability to costimulate T cell proliferation, cytokine production, and the generation of CTL. When we used small, resting human peripheral blood T cells as responders, both CD80 and CD86 transfectants efficiently costimulated anti-CD3 mAb-induced proliferation and the secretion of IL-2 and IFN-gamma. Additionally, both CD80 and CD86 transfectants were able to generate functional CTL. The magnitude and kinetics of these responses were similar, which indicates that both ligands provide efficient costimulatory signals. Because many APCs coexpress both CD80 and CD86, we compared the ability of anti-CD80 and anti-CD86 mAbs to inhibit allogeneic MLR stimulated with B lymphoblastoid cell lines and showed that it is necessary to inhibit interactions with both ligands to optimally block CD28-dependent proliferation. Given the limited homology of CD80 and CD86, it was surprising that the binding of CD28-Ig fusion protein to CD80 and that to CD86 transfectants were essentially indistinguishable. Binding of CTLA-4-Ig fusion protein to both transfectants also was quite similar, but was of higher affinity than CD28-Ig binding. Results from these studies indicate that both CD80 and CD86 are potent and similar costimulators of T lymphocytes. Therefore, the role of CD80 and CD86 in an immune response may be determined primarily by their differential expression on APC.