5-aminosalicylic acid Introduction MEMS electrical switch has the advantages of small volume

MEMS electrical switch has the advantages of small volume and smart response, so it 5-aminosalicylic acid is promising for power supply controlling system application in varied forms. Farrington et al. [1] proposed a hybrid electrical switch which can deliver significant reductions in switching elements, cabling, cost and power consumption. Chui [2] put forward MEMS electrical switches used for interferometric modulator, which may form the row or column select functions for the display. Deylitz et al. [3] invented an electrical switch which includes a locking device. Verma and Kaushik [4] studied RF MEMS capacitive switch based on a fixed–fixed beam structure, which is designed to achieve low actuation voltage and good reliability. Baghchehsaraei et al. [5] presented a waveguide SPST switch based on a MEMS reconfigurable surface and its RF performances are superior attributed to the high level of processing circuit integration. Guo et al. [6] designed a MEMS acceleration switch with an easy-latching/difficult-releasing latching mechanism, in which all the contacts and support beams are separated from the proof mass to prevent the contacts from opening due to the impact resulting from the rebound or vibration once the switch is latched. Kim et al. [7] devised an acceleration switch capable of increasing the threshold acceleration, in which the comb drive actuators are used in the design to tune the threshold acceleration.
In recent years, MEMS technology also has been integrated closely with advanced weapon system due to the smart requirements for weapon system [8]. Robinson et al. [9–11] proposed a MEMS safety and arming mechanism and carried out the demo launch and ballistic tests. Jing et al. come up with a MEMS safety mechanism of fuze in small caliber rocket round according to the amplitude and duration of acceleration. It can identify the launching environment and perform actions by the Z-shaped teeth, but it is not suitable for the fuze in medium and large caliber ammunition [12]. Liu et al. [13] designed a MEMS zigzag slot which is applied to the safety and arming mechanism in small caliber projectile fuze of Objective Individual Combat Weapon (OICW), but zone of intolerance cannot be used in the fuze in medium and large caliber projectile.

Device structure and function
The switch proposed in this paper is a mechanical inertial electrical switch. The switch is normally in off-state. It is actuated to be in on-state only when fuze is launched smoothly, while it still holds an off-state in any accidental falling impact. It is designed with the performance of reacting to launching acceleration quickly and reliably. And it also needs to keep the on-state in order to ensure that the power and circuit work continuously. It consists of three parts, a spring–mass system with zigzag slot in mass, a latching and electrical connection mechanism, and a movement-limit mechanism. Fig. 1 shows the structure diagram of the MEMS inertial electrical switch.
The switch has the functions of acceleration response, acceleration amplitude and pulse width recognition, which is actuated by an inertial force. The MEMS spring–mass system is mainly used to detect acceleration undergone by fuze. When fuze is undergoing an acceleration, the mass will be moved. The zigzag slot in mass has damping effect on mass movement, which can be used reasonably to distinguish the fuze launching acceleration from accident falling impact [14].
The latching and electrical connection mechanism also reacts to acceleration load, and it can be impacted by moving mass. When the latching and electrical connection mechanism transforms from off-state to on-state, it can keep latching by its resilience. The movement-limit mechanism, including side board and stoppers, is used to prevent the proof mass from producing a large lateral jumping and limit the Y-axis displacement of the proof mass.

Model and theoretical analysis

Results and simulation analysis

On physical examination erythema vesicle formation and erosions involving the

On physical examination, erythema, vesicle formation, and erosions involving the lip, face, neck, trunk, limbs, and genitals were observed (Figure 1). His laboratory investigation results on admission were as follows: white blood cell count, 1.246 × 109/L; absolute neutrophil count, 81.7%; eosinophil count, 0%; hemoglobin level, 110 g/L; and platelet count, 232 × 109/L. Levels of antinuclear antibody, ds-DNA, and anti-BP180 antibody were within normal ranges. Nikolsky\’s sign was negative. Ophthalmological evaluation did not reveal any eye involvement. A skin biopsy specimen taken from his right thigh showed slight hyperkeratosis, many necrotic keratinocytes in the epidermis, subepidermal bulla formation, and vacuolar degeneration of the basal layer with infiltrations mainly comprising lymphocytes and eosinophils. In addition, lymphocytes and eosinophils had infiltrated the vessels of the superficial 12-O-tetradecanoyl phorbol-13-acetate (Figure 2).
On the 23rd day, the eruption was improved and therefore we discontinued oral PSL. The drug-induced lymphocyte stimulation test (DLST) performed at that point was negative for TS-1 (stimulation index, 162%). On the 43rd day (20 days after discontinuing PSL), the results of closed patch tests performed using 50%, 25%, and 12.5% TS-1 on the lesional area were negative, but the DLST result was positive (stimulation index, 366%). We diagnosed the condition as TS-1-associated. SJS was diagnosed on the basis of the clinical course and laboratory results.

A total of 25 cases involving TS-1-associated drug eruptions were analyzed (Table 1). Levels of antinuclear antibody were positive in Cases 1 and 23. The results of patch tests were negative in Cases 2, 11, 13, 17, and our case. The DLST results were positive in Case 2 and our case, but the results were negative in Cases 13, 15, and 17. The results of drug challenge test were positive in Cases 1, 4, 9, 11, and 12.
In patients who are suspected to develop allergic reactions, DLST involving the incorporation of [3H]thymidine ratio into the DNA of lymphocytes derived from patients, is generally employed for identifying drugs that could induce allergy. However, DLST results may show a false-negative response because of steroid, antitumor, and immunosuppressive drugs. Immediately after the onset of drug allergies, patients are also thought to be more susceptible to false-negative reactions. In view of the occurrence of false-negative results, the possibility of drug-induced allergy in patients receiving TS-1 should be carefully evaluated using a combination of other clinical examinations.
Common features of drug-related lupus are as follows: rare cutaneous manifestations, a high incidence of antihistone antibodies, and reversible symptoms after withdrawal of offending agents. The frequency of discoid lupus erythematosus-like eruption is about 10% among all cases of drug eruptions induced by FU, based on the statistical report of Fukuda, but the finding is the proportion of drug-related lupus (9 of 24; 37.5%) in this study. Basal cells are the target cells most affected by FU agents, because they are stem cells and are multipotent. Therefore, basal cells damaged by FU agents seem to be highly susceptible to ultraviolet light (UVL) irradiation, which induces liquefaction changes and patchy lymphocytic infiltrations. Drug-related lupus by FU agent may be an excellent model for understanding the pathomechanisms of development of discoid lesions.
Bleomycin and cisplatin are known to induce systemic sclerosis-like reactions in a genetically susceptible host. Similarly, toxic effects or immune system modulation by the FU might be responsible for systemic sclerosis-like reactions.
FU exerts its antitumor effects through several mechanisms, including inhibition of RNA synthesis and function, inhibition of thymidylate synthase activity, and incorporation into DNA, leading to DNA strand breaks. When FU is orally administered, extensive first-pass metabolism of FU in the gastrointestinal wall and liver decreases FU plasma levels and causes severe intestinal mucosal damage. The potent inhibition of dihydropyrimidine dehydrogenase by gimeracil present in TS-1 may expose the patient to a high level of active FU metabolite. This may induce a high incidence of drug eruption.

To clarify the reason for a higher

To clarify the reason for a higher association of Castleman\’s disease in our study, we compared our study with other previously reported case series with PNP patients of Castleman\’s disease. Minouni et al reported 14 cases in children and adolescents, of which 12 were associated with Castleman\’s disease. They concluded that PNP in children and adolescents is most often a presenting sign of occult Castleman\’s disease. This is consistent with one of our patients (Case 1), who presented with longstanding mucocutaneous lesions since his adolescence and a mediastinal Castleman\’s disease complicated with focal follicular dendritic cell sarcoma was eventually identified more than 10 years later. Similar findings were reported in another two studies reporting PNP cases exclusively associated with Castleman\’s disease. The average age in both studies was young. However, only one of the four patients with Castleman\’s disease in our study is young. Therefore, age of the patients in our study could not account for the higher association. The possible reason is that there is genetic predisposition because around 77% of PNP patients are associated with Castleman\’s disease in China. Although the ethnic groups in Mainland China are more diverse than those in Taiwan, the majority of people are Han Chinese in both regions.
LP-like lesions are the main presentations in PNP patients associated with Castleman\’s disease. Consistent with this serine protease inhibitors finding, three of four patients associated with Castleman\’s disease in our study have LP-like lesions as their main clinical manifestation. In addition, LP-like lesions present in all three patients were associated with malignant thymoma in this study and were the predominant clinical presentations in two of them. Although the association of pemphigus and thymoma is well established, pemphigus-like presentations are not the main finding in PNP patients associated with malignant thymoma in this study. There are some explanations for our observations. In addition to pemphigus, several reports have indicated that thymoma may be associated with LP and graft-versus-host-like diseases. Moreover, thymoma has been linked to numerous autoimmune diseases, including myasthenia gravis, hypogammaglobulinemia, alopecia areata, and pure red cell aplasia. The fact that thymus is an important immune organ to maintain central tolerance may explain the occurrence of immune dysregulation in the setting of thymic tumors. A previous study provided evidence to support this notion, demonstrating that circulating CD45RA+CD8+ T cells are significantly increased in patients with thymoma compared with normal controls, and intratumoral T cell development that is abnormally skewed toward the CD8+ phenotype. Therefore, we propose that these abnormal CD8+ T cells in patients with thymoma may account for the development of clinical LP-like presentations and histopathological lichenoid infiltrations in our patients. However, further investigations are needed to confirm our hypothesis.
The mortality rate of this study was 64%, which is comparable to the previous reports. Leger et al found that the 1-year overall survival rate was 49%, which was consistent with our observation that most nonsurvivors died within 1 year after diagnosis. The development of respiratory symptoms might be the most important risk factor for mortality in our study. Six of seven expired patients had respiratory symptoms, including dry cough and dyspnea. Four of them had a confirmed diagnosis of BO. In line with our finding, pulmonary injury with respiratory failure has been demonstrated to be the cause of death in most PNP patients associated with Castleman\’s disease. In addition, infections account for death in the majority of cases in another study, which might have resulted from the use of high dose immunosuppressants. Indeed, high-dose corticosteroids and/or combined with other immunosuppressants or immunomodulators were used in all of our patients. Several episodes of infections were encountered in our patients as above mentioned. We think that infections work synergistically with respiratory involvements in these patients leading to a fatal outcome. In addition to these causes of death, PNP patients with EM-like skin lesions have been demonstrated to have a more severe and rapid fatal outcome. Four patients with EM-like presentations in our study did have more refractory courses and all of them died.

Although MF is the most common

Although MF is the most common variant of CTCL, it is still a relatively uncommon malignancy, with estimated annual incidences 3.6–4.5/one million person-years in the United States. The majority, about 70%, of patients are whites, while blacks, Hispanics, and Asians constitute 14%, 9%, and 7% of MF cases in the United States, respectively. Compared with the Western countries, MF was rare whereas extranodal natural killer/T-cell lymphoma, nasal type, was more common in Taiwan. Although the prognosis of MF patients with limited patches and plaques is favorable, there is a considerable racial difference showing a higher incidence and poorer outcome among blacks than whites. It has been suggested that blood eosinophilia may contribute to this racial difference. However, population-based information about Asians, American Indians, and Hispanics is limited. Recent epidemiological data about East-Asians with MF has been reported in Hong Kong, Singapore, and Japan. To the best of our knowledge, few studies conducted in Taiwan in the past 10 years have provided racial profiles. Herein, we retrospectively reviewed the medical data of MF patients in a referral center in central Taiwan and investigated the indigenous demographic, clinicopathologic, laboratory, and prognostic characteristics of MF.



We compared the characteristics of our MF patients with several previous reported case series focused on different races (Table 3). Our data showed the classic 2:1 male to female ratio was consistent with the ratio reported in whites, but was different from the 1:1 ratio in another case series focused on Taiwanese, reported by Hsiao and Lee. A 2:1 male to female ratio was reported in Hong Kong and Singapore, where Chinese made up the majority of the population. In several Japanese studies, the mean or median age at diagnosis of MF was ≥60 years old. We noted an approximately 15-year difference in age at diagnosis between Taiwanese and Japanese patients. Both the study by Hsiao and Lee and our study revealed that the MF candesartan cilexetil manufacturer in Taiwan was about 10 years younger than that in the West, mainly the United States. In contrast, the mean age at diagnosis in Taiwanese was similar to that in African Americans. A difference in the mean age at diagnosis, 59.2 years in whites, 51.5 years in African Americans, versus 51.3 years in Asian/Pacific Islanders, has also been noted in the literature. In the present study, 50% of patients were aged <40 years at diagnosis. Seven patients (31.8%) experienced onset of symptoms in the age range 20–40 years, while one patient did not have an established diagnosis until the mid-forties. Five patients (22.7%) presented with initial cutaneous manifestations before the age of 20 years. Among these pediatric patients, three (13.6%) had a definite diagnosis of MF established before age 20 years. In general, MF predominantly affects older adults. Those diagnosed before 20 years of age were reported to account for only 0.5–5% of all MF patients. However, in a Singapore study, more than 25% of patients were <20 years old and less than one-third were >50 years old. It is possible that the incidence of MF in pediatric patients and young adults has been underestimated. Therefore, clinicians should be more alert to the possibility of MF in these age groups.
Up to 86% of patients presented with patches and plaques in the present study. There is a global consensus that most patients have initial manifestations of limited or generalized patches and/or plaque disease. Despite the difficulty of diagnosing MF, it was considered as the first or second differential diagnosis during the first visit in 63.7% of cases in our study. Dermatologists in a tertiary referral center might be more aware of the symptoms and signs of MF; however, interpersonal and intrapersonal variations require further study. MF is most frequently misdiagnosed as eczema, as it was in a study conducted in Hong Kong. Because pruritus was not found in 45.5% of our MF patients, it could be a key to differentiating eczema from MF. With 40.9% patients reporting itchiness, clinicopathologic correlation remains the gold standard diagnosis of MF. In this study, one of the three pediatric patients presented with the hypopigmented variant. The association between hypopigmented MF and young age has been reported. Hypopigmented MF was also associated with a more indolent clinical course and better prognosis. Among our patients, 18.2% had advanced stage disease, IIB or higher. In contrast, none had Stage IIB disease or higher in the previous Taiwanese study. Other studies on MF in Asian patients revealed that Stage IIB disease or higher accounted for 7.0% of patients in Singapore, 17.5% in Hong Kong, and 16.2% and 22.0%, respectively, in two reports in Japan. In the West, those with Stage IIB disease or higher accounted for 29.4% of patients with MF reported in the United Kingdom, and 28.5% and 33.7%, respectively, in two reports in the United States. It is worth noting that the proportion of patients with advanced clinical stage seems to be higher in Western populations than in Asian populations. Further study will be needed to determine whether advanced disease is less common in Asian patients. Two patients with Stages IIB or higher were associated with disease-specific death in this study. It is not unexpected that patients staged as IIB to IV at diagnosis were more likely to have disease progression or die of MF than patients with an early stage at diagnosis. Several studies demonstrated that more advanced skin involvement, the T stage of TNMB classification, was associated with MF-specific death. Because of the limited number of cases, our study did not reflect the correlation between each TNMB stage and survival.

Amphotericin B mg daily was prescribed

Amphotericin B 50mg daily was prescribed. However, acute renal failure with oliguria developed 4 days after treatment. Antifungal agent was shifted to voriconazole 400 mg daily (8 mg/kg). One week later, his skin lesions improved, leaving only slight erosion over the right arm (B). Due to symptoms of gastrointestinal upset that developed, the dosage of voriconazole was decreased to 200 mg daily and continued for another week. Then, icteric sclera developed. His family refused further antifungal treatment owing to his age, persistent dyspepsia, and the potential liver toxicity of the medication. However, recurrence of erosions and ulcerations were noted over the right arm days later. Voriconazole 200 mg daily (4 mg/kg) was reinitiated. Due to the deterioration of hepatic function, voriconazole was then decreased to 75 mg daily. Even under the adjusted dosage of voriconazole use, his skin condition gradually improved, leaving only scaling. During hospitalization, he developed a catheter-related blood stream infection with vancomycin-resistant and . Finally, the patient died from septic shock even under systemic Tasquinimod and a total of 11 weeks of voriconazole treatment.
is a saprophytic fungus with a global distribution, such as soil and stagnant water, agricultural land, thorny shrubs, and in temperate climates. infections are uncommon, even in immunocompromised individuals. Caira et al reported that overall incidence of was about 0.08% in a 20-year retrospective survey of 8633 patients with newly diagnosed acute leukemia in Italy. From 1995 to 2014, there were only two reported cases of infection in Taiwan; one with mycetoma and the other with nonmycetoma at presentation. However, increased frequency and high mortality rates of invasive infections were noted in immunocompromised hosts. In an Australian surveillance study of , skin/subcutaneous tissue accounted for 14.5% of the primary sites of infection. The most common skin manifestations are multiple subcutaneous nodules in a sporotrichoid distribution after injuries. Other rare skin manifestations are non–mycetoma-like cutaneous and subcutaneous infections, which present as necrotic ulcer encased by a circumferential area of extensive skin sloughing, violaceous discoloration, and erythema. A similarity in clinical presentation was noted between our patient and that of the previously reported case mentioned above.
has been reported to have very high levels of antifungal resistance, most notoriously to amphotericin B. Voriconazole is a compound with low minimal inhibitory concentration values. Micafungin and posaconazole are reported to have moderate activity against the majority strains of . A combination of two antifungal agents with different mechanisms or antifungal treatment used in combination with surgical intervention may be warranted for intractable cases. The synergistic interaction between azoles and terbinafine blocks different steps of the fungal ergosterol biosynthesis pathway. In a case report, surgical debridement and intralesional injection of voriconazole (a concentration of 3 mg/mL, once weekly for 2 weeks) were used to treat successfully a patient with a hepatic contraindication for voriconazole.
Our patient had impaired liver function and underlying chronic hepatitic C status so azole could only be used sparingly. Extensive surgical debridement might not be appropriate for patients with advanced age. Intralesional injection of voriconazole may be considered in such patients. In summary, this is the first formally reported case of non-mycetomatous infection in an immunocompetent patient in Taiwan, who received oral voriconazole but eventually died of a hospital-acquired infection.

Hypertrichosis lanuginosa acquisita (HLA) is a paraneoplastic hair disorder, which is characterized by fine, long, nonpigmentous hair on the face. HLA could evolve in association with nonmalignant disorders such as human immunodeficiency virus, hyperthyroidism, hypothyroidism and with use of certain drugs. Malignancy-related HLA is predominant in female patients, and the most commonly associated malignancy in female patients with HLA is a colon adenocarcinoma. Literature reports regarding lymphoma-related HLA are rare. So far, only two lymphoma-associated HLA cases have been reported in the literature. In both cases, the patients were female. Herein, we present the case of a systemic diffuse large B-cell lymphoma-associated HLA.

The values of the projectile aerodynamic

The values of the projectile aerodynamic and physical parameters required to compute the aerodynamic jump associated with the projectile in-bore tilt are tabulated in Table 2. Referring to Fig. 1 in order to compute the lateral throw-off associated with the 5.56 mm CT projectile tilt, the following parameters are required (in caliber)
The computed deflections for the various test cases are shown in Table 3. For these calculations, the initial roll angle, , for the projectile was not available experimentally. However, using a high-fidelity 6-DOF model of the 5.56 mm projectile, it was possible to determine the initial roll angle that yielded the experimentally determined first maximum yaw. An initial roll angle, , very close to 180° was determined for the horizontally offset chamber, whereas initial roll angle, , very close to 270° was determined for the vertically offset chamber. A comparison between the experimentally determined MPI and the theoretically determined MPI is shown in Fig. 9. Although the comparison is not perfect, the general trend in the deflection of the MPI is well picked up by theoretical model. The discrepancies could be due to the rough approximation made when estimating the static unbalance of the projectile due to the projectile tilt. Furthermore, the MPI were determined using a single sample of less than 30 rounds due to the misfired rounds. Additional firing could possibly yield slightly different MPI.


Compared to the conventional munitions, the design of dual-spin projectile with canards is becoming increasingly popular. The increase in popularity of dual-spin projectile is attributed to its increased accuracy and cost effectiveness. Costello et al. [1] established a 7-DOF dynamic model to investigate the dynamic properties of a dual-spin projectile with canards, and the model was used to solve for angle of attack, swerving dynamics and YO-01027 factors. Grignon et al. [2] discussed the relationship between gyroscopic stability and the moment of inertia through numerical simulations. The stability and design of the trajectory control autopilot for 155 mm dual-spin projectiles with different types of canards were modeled and analyzed in references [3–6]. Liu et al. [7] studied the swerving orientation of a spin-stabilized projectile with fixed canards. Nevertheless, of all the works on the dynamic properties of dual-spin projectiles stated previously, none has discussed the impact of spin rate on the forward section of trajectory and its effect on the trajectory. When the forward body of projectile is rolling, a cyclical yawing force is applied on the projectile, which impacts the angular and translational motions. To analyze the influence of frequency of the cyclical force on angular and translational motions during flight of projectile and get an appropriate frequency, the response of the projectile under a cyclical force is studied in this paper.

Dynamic model

Angular motion
When a spin-stabilized projectile flies normally, the total yaw angle is used to represent the angular motion and is related to the force acting on an object. According to the definition, the total yaw angle can be obtained by subtracting the angle of velocity vector from the angle of object\’s axis .

Numerical simulation
To verify the resonance phenomena at different frequencies, a typical 155 mm projectile was simulated with the 7-DOF model that was proposed in section 2.2, and the rotation rate of the forward part was set from 0.5 to 35 Hz. The parameters of the typical 155 mm projectile used in this analysis were listed in Table 1[9]. In the simulation, the total yawing force acting on the canards was 20 N.
Figs. 5 and 6 show the total yaw angle of the projectile acted with the cyclical yawing force at different frequency during the entire flight period. Figs. 7 and 8 show the range and drift of the dual-spin projectile with canards spinning at different rate. The black lines in Figs. 7 and 8 show the range and drift of a typical projectile without the cyclical yawing force.

Por eso subordinar a un poder externo

Por eso, subordinar ubiquitin e3 ligase un poder externo y ajeno al guardián armado del territorio propio, el ejército nacional —así sea por instrucción, conocimientos, doctrina o abastecimiento— es subordinar el poder al cual sirve ese ejército y el territorio que supone proteger.

Según los equilibrios surgidos de la Segunda Guerra Mundial, la onu y su Consejo de Seguridad serían los depositarios últimos del derecho a la “violencia legítima”. Es sabido que esta ficción desterritorializada nunca funcionó de ese modo. Cada Estado nacional, grande o pequeño, reclama para sí en su territorio ese derecho sustentado en sus armas, es decir, en la posesión de los medios materiales para ejercerlo.
Tal vez el documento que mejor expresó la conciencia y los sentimientos surgidos de aquella vivencia universal de destrucción y muerte, y los derechos a que esa conciencia aspiraba, haya sido la Declaración Universal de los Derechos Humanos de diciembre de 1948. Su artículo 25, por ejemplo, establece los fundamentos de lo que sería un Estado social universal:
Pero la realización de este “ideal común por el que todos los pueblos y naciones deben esforzarse”, según dice el preámbulo del documento —ideal que en este siglo xxi tomó color de utopía—, quedaba librada a la instancia de “los Estados miembros” de la onu, es decir, al fin de cuentas a los depositarios nacionales y territoriales del ejercicio de la violencia legítima.
“No nos unió el amor sino el espanto”, podría haber sido la borgiana divisa de ese acto fundador de la Organización de las Naciones Unidas.

Mirando el siglo xx en perspectiva a partir de la segunda posguerra puede verse cómo en esos años fueron creciendo, en los hechos y en las normas jurídicas, el peso organizado del trabajo, los grandes sindicatos por industria, los derechos sociales y sus legislaciones protectoras, los derechos democráticos, el repliegue de las oligarquías de la tierra, un cambio de la relación entre la propiedad estatal y la privada a placental mammals favor de aquélla; en suma,una reconfiguración del poder dentro de la nación y la república y en la distribución y el disfrute de los bienes terrenales (trabajo, salario, salud, educación, cultura, descanso, pensión…).

Uno de los rostros más brutales de esta empresa global de recuperación del poder del dinero se había presentado desde los años 70 con las dictaduras militares de América Latina, en algunas de las cuales grandes empresas multinacionales se asociaron directamente con el poder militar para destruir a sangre y fuego las estructuras de organización obreras, ciudadanas y campesinas. En su forma más tosca y elemental, esta fue una afirmación de la necesaria territorialidad de ese poder, es decir, del ejercicio desnudo de la violencia del Estado sobre los habitantes de un territorio nacional. Las armas, abriendo paso a las nuevas tecnologías, hicieron la tarea.

Desencadenó por otra parte un tumultuoso proceso de apropiación privada de los bienes comunes antes estatizados, un gigantesco despojo a cada comunidad nacional, y la constitución de las cúspides de la burocracia estatal en nueva clase dominante propietaria de vastos capitales privados incorporados ahora a las finanzas mundiales. La magnitud y el dinamismo de este proceso de apropiación por despojo, así como sus repercusiones en los equilibrios mundiales de poder entre naciones y clases, parecen estar todavía lejos de las mediciones existentes y tal vez no tengan antecedentes en la historia. Quienes aún hablan de agonía del capitalismo no saben qué están diciendo.
Es el tumultuoso proceso sin fronteras de la formación de una clase trabajadora o una clase asalariada mundial, según la definición de Michel Husson y otros autores, un proceso tal vez tan prolongado como el que aparece en la obra clásica de E. P. Thompson, La formación de la clase obrera en Inglaterra.

The critical and hitherto unrecognized role of FGF

The critical and hitherto unrecognized role of FGF-2 in the specification of human OPCs via ventral forebrain origins has been clearly demonstrated in this in vitro system. Similarly, we were able to show that SAG is an effective alternative small-molecule agonist of SHH signaling to PM in this system, establishing an optimal working concentration for OLIG2 induction of 1 μM SAG in the presence of 10 ng/ml FGF-2. Robust generation of both OPCs and oligodendrocytes will facilitate the development of an in vitro human myelination assay. Our electrophysiological studies reveal that the majority of human OPCs have sodium bosentan and can fire action potentials, which is consistent with observations in their rat counterparts but in contrast to results in mice. Our system provides a platform for extending such electrophysiological studies to compare OPCs derived from different developmental origins and investigate responses to neurotransmitters such as glutamate and NMDA receptor signaling (Káradóttir et al., 2005).
The observation that human OPCs respond to RXR signaling is exciting, especially when it considered alongside the observation that the borders of chronically active MS plaques contain OPCs expressing RXRγ (Huang et al., 2011). These same areas were previously reported to contain so-called premyelinating oligodendrocytes (Wolswijk, 1998; Chang et al., 2002), and it is thought that their failure to differentiate into myelinating oligodendrocytes is a critical factor in the development of progressive disease. Furthermore, it has been proposed that the key factor influencing this failure of remyelination is age (Franklin, 2002). Intraperitoneal delivery of 9-cis RA (a ligand for RXR activation) to aged rats with a focal area of demyelination was shown to enhance remyelination (Huang et al., 2011). Thus, our data provide further evidence to support a clinical trial of an RXR agonist in patients with secondary progressive MS.

Experimental Procedures


Amyloidosis refers to a group of diseases caused by the extracellular deposition of misfolded fibrillar proteins, leading to multiorgan failure and death (Falk et al., 1997). Familial amyloidosis (AF) occurs when inherited point mutations in the genes coding for abundant serum bosentan proteins such as transthyretin (TTR), fibrinogen, lysozyme, or apolipoproteins lead to clinical disease. The most common form of AF arises from aggregation of mutated TTR, a 55 kDa transport protein predominantly synthesized by the liver (Connors et al., 2003; Falk et al., 1997; Planté-Bordeneuve and Said, 2011). Familial transthyretin amyloidosis (ATTR) is a lethal, autosomal-dominant disease caused by single amino acid substitutions arising from 1 of more than 100 described mutations in the TTR gene (Connors et al., 2003; online amyloidosis mutation database in Rowczenio and Wechalekar [2010]). These single amino acid substitutions destabilize the native homotetrameric structure of circulating TTR, promoting release of amyloidogenic TTR monomers, fibril formation, and deposition as amyloid in target end organs (Ando et al., 2005; Falk et al., 1997). Most amyloidogenic TTR variants target the nervous system and heart, inducing neuropathy and cardiomyopathy (Jacobson et al., 1992, 1997; Planté-Bordeneuve and Said, 2011). The organ distribution and age of onset can vary across families and endemic areas, even with identical TTR mutations. Although transgenic mouse models and immortalized human cell lines have provided some insights into disease pathogenesis (Araki et al., 1994; Kohno et al., 1997; Reixach et al., 2004; Sousa et al., 2002; Tagoe et al., 2007), these systems are independent of the genetic context of the patient.
ATTR represents an important unmet medical need with significant morbidity and early mortality in affected families. Survival after ATTR disease onset is usually only 5–15 years (Benson et al., 2011; Planté-Bordeneuve and Said, 2011). Orthotopic liver transplantation is currently the only US-approved treatment for ATTR. However, only about one-third of patients are candidates for surgery (Monteiro et al., 2004), and cardiomyopathy and neuropathy may continue to worsen after transplantation. Recently, small molecule stabilizers of variant TTR (Tafamidis and diflunisal) shown to inhibit amyloid fibril formation in vitro are being studied in clinical trials (Berk et al., 2012; Coelho et al., 2012). Patient-specific, cell-based models are needed to facilitate the study of the genetic and epigenetic factors in this disease, permitting pharmacogenomic assessments of novel therapeutics.

These findings are consistent with a low SRC activity

These findings are consistent with a low SRC activity which is increased after ex vivo culture (Fig. 4A). In a parallel project, we found that CD34+CD38−/low and not CD34+CD38+ fraction of cultured steady state PB nucleoside analog contains the cells exhibiting the capacity to engraft NSG mice (giving human CD45+, CD33+ (myeloid) and CD19+ (lymphoid) cells in murine bone marrow) (work in progress). Thus, the SP cells were analyzed with respect to CD38 expression (Figs. 3B, C). Taking into account only CD34+CD38−/low SP cells, the phenomenon of increase in absolute cell number after culture persists (10 fold) (Fig. 3F), which is similar to the increase in SRC activity in the same condition (human chimerism increased about 8 fold), suggesting that the HSCs are really highly enriched in this SP CD34+CD38−/low cell fraction. In line with this observation are also our results showing a numerical increase in CD90+ (5.9 fold) and CD133+ (28 fold) subpopulations of SP CD34+CD38−/low cells.
We can thus conclude that the CD34+ cells purified from LRF steady state PB contain a restricted population of short- and long-term repopulating HSC, a finding completely consistent with the one of a low-frequency SP and SP CD34+CD38−/low populations (as well as its CD90+ and CD133+ subpopulations). These populations increase after culture as does the SRC activity.
The following is the supplementary data related to this article.

The authors are thankful to Mrs Elisabeth Doutreloux-Volkmann and Dr Ivana Gadjanski for the language corrections. This project was supported by the grant “No”.

The ability to generate forebrain neurons from embryonic stem cells (ESCs) has provided a new tool for studying the complex relationships between molecular systems and neuronal fate determination (Petros et al., 2011). Several studies have successfully generated cortical interneurons (cINs) from mouse (Maroof et al., 2010; Danjo et al., 2011) and human ESCs (Goulburn et al., 2011), but the derivation efficiencies and ability to produce cIN subgroups is limited. Forced expression of key fate-determining genes can promote the differentiation of ESCs into specific cell fates. There are two primary origins of cINs; those that originate in the medial ganglionic eminence (MGE) or preoptic area and require the transcription factor Nkx2.1 for their fate determination, and those that originate within the caudal ganglionic eminence and are Nkx2.1-independent. Downstream of Nkx2.1, the transcription factor Lhx6 is expressed from cell cycle exit through postnatal development (Liodis et al., 2007), and ectopic Lhx6 expression is sufficient to rescue the loss cIN subgroup markers in Nkx2.1−/− mice (Du et al., 2008). Upstream of Nkx2.1, the morphogen Sonic hedgehog (Shh) is required for the induction and maintenance of Nkx2.1 expression (Fuccillo et al., 2004; Xu et al., 2005). However, it is unknown if the only role for Shh in cIN fate determination is to induce Nkx2.1 expression, or whether Shh functions via additional factors that are required to specify cIN fate.
In this paper we engineered a mouse ESC (mESC) line to both inducibly express Nkx2.1 via doxycycline (Dox) (Kyba et al., 2002), and to express GFP under the control of the Lhx6 promoter. We used this mESC line to (1) determine whether inducible Nkx2.1 expression enhances generation of GFP+ cINs, and (2) study the role of Shh signaling in cIN fate determination. Our results indicate that induced Nkx2.1 expression increases the generation of mESC-derived cINs. Additionally, forced Nkx2.1 expression is sufficient to induce cIN fates in the absence of Shh signaling, suggesting that the primary role of Shh is to maintain Nkx2.1 expression. These findings demonstrate the potential for utilizing temporally controlled gene expression in combination with fate markers to enhance the ESC-derivation of neuronal subgroups and to study the fate determination of forebrain neurons.

br Materials and methods br Results br Discussion In

Materials and methods


In these experiments, we sought to determine the influence of gravitational mechanical unloading on the regenerative ability of bone marrow progenitors and specifically hypothesized that exposure to microgravity may alter the differentiation of bone marrow mesenchymal and hematopoietic cell lineages. To test this hypothesis, we used a combination of ex-vivo primary cell differentiation, genomics, as well as tissue and cellular analysis of in-situ differentiation to characterize the effects of microgravity unloading on the regenerative cellular physiology of the bone marrow compartment.
The choice of the femoral head and neck as a study site is important because this bone region is responsive to impact gravitational load, and because it is distinct from the muscle loading-sensitive ischium region of the pelvis we previously reported in (Blaber et al., 2013). Specifically, bone tissue is exposed to several different types of load, including muscle reaction forces generated by skeletal muscle contractions, ground-reaction forces or weight-bearing forces, and intramedullary pressure gradients, that result in the integration of mechanical signals into architectural alterations commonly known as bone cyproheptadine hcl (Turner, 1998). The importance of both gravitational forces and muscle forces on skeletal regulation is demonstrated through impact versus no-impact exercise training on bone mineral density (BMD) (Kohrt et al., 2009). Athletes who participate in non-weight bearing exercise such as swimming or cycling are shown to have lower BMD levels (Kohrt et al., 2009; Nikander et al., 2005). On the other hand, those involved in high impact (i.e. volleyball, soccer, squash) and weight-bearing (i.e. weight-lifting, skiing) had higher BMD levels, and furthermore athletes involved in high-impact exercise exhibit uniquely higher section modulus levels (an index of the strength of bone against bending) possibly due to increased cortical thickness of the bone (Kohrt et al., 2009; Nikander et al., 2005, 2009). The amount of load on bone varies daily without significant alterations to bone mass and therefore, a physiological range exists whereby bone is fairly unresponsive to changes in load (Carter, 1984). In spaceflight, when gravitational forces are significantly reduced there is a dramatic impact on the skeleton, approximately 10-fold higher than the accelerated bone loss that occurs at the time of menopause in women (Kohrt et al., 2009). This is because the activities that generate gravitational forces also generate muscle reaction forces and therefore, spaceflight reflects a reduction in both loading types (Kohrt et al., 2009). Although exercise countermeasures have been effective in maintaining muscle mass and strength, bone mineral density has proved challenging to preserve with no-impact exercise and therefore highlights the importance of gravitational impact forces in the maintenance of skeletal mass and integrity (Kohrt et al., 2009; Lang et al., 2004). Increased intramedullary pressure and consequently, increased interstitial fluid flow, has been implicated as a mediator of load-induced bone remodeling. Fluid flow has been shown to stimulate bone cells including osteocytes, osteoblasts, and osteoclasts by shear stress, which may result in the production of signaling molecules known to mediate bone remodeling (Reich and Frangos, 1991; Reich et al., 1990; Stevens et al., 2006). In the absence of bone strain, bone formation has been strongly correlated to fluid pressure gradients and decreased femoral intramedullary pressure during hindlimb suspension may result in decreased cell stimulation and consequently decreased bone formation (Stevens et al., 2006; Qin et al., 2003). The response of bone to alterations in load is site-specific and is dependent on the forces placed on it during normal ambulation and in altered gravity environments. Most non-load bearing bones, including the humerii and ribs, are not altered in response to microgravity exposure (Vailas et al., 1990). On the other hand, the non-load bearing calvarial bones have been reported to exhibit increased bone volume in response to spaceflight, which is possibly due to head-ward fluid redistribution reported both during spaceflight and in rodent hindlimb suspension models (Zhang et al., 2013).