Changes in psychophysiological functions during night shift in nurses

 The effects of changing from a full-day to a half-day shift work before a night duty shift on physiological and psychological functions during the night shift were investigated in 12 healthy unmarried nurses working on the same ward of a university hospital. Three shift patterns, i.e., a day shift following a day shift, a night shift following a day shift, and a night shift following a half-day shift, were studied in terms of physical activity level, sympathetic and parasympathetic activity levels, cortisol, prolactin, NK cell activity, and changes in mood states. The change to the half-day shift increased the duration of sleep before night duty by about 86 min and brought wake-up times forward by about 1 h, resulting in increases in rest and time before work. In addition, the change was revealed to reduce the influence of reversed-phase circadian rhythms on autonomic nervous activity during the night shift. The score for sleepiness was significantly lower at 0500 hours following a half-day shift. There were some marginal but not significant differences in the scores reflecting the degree of vigor, tiredness and irritation during the night shift. Although the prolactin concentration was significantly decreased at the start of the night shift after the half-day shift, there was no difference in cortisol concentration or NK cell activity between the usual night shift after a day shift and the night shift after the half-day shift. The half-day shift was not observed to cause any marked change in the fixed biorhythms of these nurses. The cortisol and NK cell activity levels were low during the night shift, suggesting that the night shift itself is a high stress level, which is prejudicial to biodefense. Received: 1 August 1995/Accepted: 8 March 1996     

Application of superb micro-vascular imaging (SMI) in obstetrics

Superb Micro-vascular Imaging (SMI; Toshiba Medical Systems, Tokyo) is a new blood flow imaging technique that employs a unique algorithm to minimize motion artifacts by eliminating signals based on analysis of tissue movement. Compared to conventional blood flow imaging such as color and power Doppler imaging, SMI significantly reduces motion artifacts and can visualize low-velocity blood flow in small vessels. In the present report, the clinical value and future potential of SMI in obstetrics have been demonstrated for the first time. We believe this new blood flow imaging technique is acceptable for obstetricians for the purpose of perinatal clinical assessments.     

A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease.Chronic myeloid leukemia (CML) is a chronic myeloproliferative neoplasm, resulting from a reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34;q11). This lesion was the first recurrent chromosomal abnormality described in cancer (Nowell and Hungerford, 1960; Rowley, 1973) and generates the BCR-ABL oncoprotein, a constitutively activated protein tyrosine kinase (TK; Deininger et al., 2000). Mouse models and human data have demonstrated BCR-ABL expression to be causative in CML (Daley et al., 1990; Heisterkamp et al., 1990; Zhao et al., 2001; Ramaraj et al., 2004; Koschmieder et al., 2005), and this observation has led to the paradigmic development of potent small molecule inhibitors that selectively target ABL enzymatic function and interrupt its oncogenic TK activity. Imatinib mesylate, the prototypic ABL tyrosine kinase inhibitor (TKI), and subsequent second and third generation TKIs, have revolutionized CML treatment (Druker et al., 1996; 2006; Carroll et al., 1997; Heinrich et al., 2000; O’Brien et al., 2003), significantly improving cytogenetic and molecular response rates, keeping the majority of patients in chronic phase, and prolonging overall survival (Druker et al., 2001, 2006; Sawyers et al., 2002; Hughes et al., 2003). However, despite this vast improvement, significant clinical challenges still remain in CML therapy. CML stem cells appear relatively resistant to the effects of TKIs (Copland et al., 2006; Jørgensen et al., 2007; Konig et al., 2008) such that, in the majority of patients, CML is controlled rather than cured. In addition, resistance occurs and this, together with stem cell persistence, facilitates disease transformation. Three distinct phases of the disease have been described. The initial phase, in which ∼85–90% of patients are diagnosed, is the indolent chronic phase (CP), which is readily amenable to treatment. However, without adequate therapy, this almost inevitably progresses to an aggressive acute leukemia of myeloid or lymphoid phenotype (70 and 30%, respectively), termed blast crisis (BC), which may be preceded by an ill-defined intermediate or accelerated phase (AP; during which the levels of myeloblasts in the BM or peripheral blood (PB) are increased but remain <20%). 10–15% of patients present beyond CP and a small percentage of CP cases continue to transform even on TKI therapy. The frequency of transformation is recorded at 3–5% within the first few years of TKI therapy but drops to ∼1% per year thereafter in randomized trials (Druker et al., 2006), although these values have been found to be higher in population-based studies (de Lavallade et al., 2008; Gallipoli et al., 2011). Treatment options for AP and BC are very limited, with response rates to TKIs lower and much less durable. Other options involve highly toxic therapies, such as combination chemotherapy and BM transplantation, and are not available or appropriate for many patients with progression. Therefore, even in the TKI era, the median survival of patients with BC is still dismal at around 6 mo (Hehlmann and Saussele, 2008; Silver et al., 2009), defining it as an unmet clinical need.Although the chronic phase of CML appears almost entirely dependent on BCR-ABL and CML is regarded as an invaluable model of leukemic evolution, the molecular mechanisms underlying disease progression are still poorly annotated. It is generally accepted that additional mutations cooperate with BCR-ABL during progression to BC (Calabretta and Perrotti, 2004), as is demonstrated by the observation that >75% of BC patients harbor additional cytogenetic abnormalities (Mitelman and Levan, 1978; Radich, 2007). There is also good evidence that the BCR-ABL protein itself contributes to the acquisition of further mutations, through its effects on reactive oxygen species induction, DNA damage, DNA repair, apoptosis, and cellular growth (Perrotti et al., 2010; Nieborowska-Skorska et al., 2012; Bolton-Gillespie et al., 2013), and the levels of BCR-ABL protein can indeed increase in the transition from CP to BC (Gaiger et al., 1995). However, to date, only a small number of mutations in specific pathways have been associated with disease progression in CML. For example, mutations or deletions in TP53, ASXL1, and RUNX1 are commonly described in myeloid BC at frequencies ranging between 3 and 25% (Ahuja et al., 1989; Grossmann et al., 2011), 15 and 20% (Boultwood et al., 2010; Grossmann et al., 2011), and 13 and 33% (Grossmann et al., 2011; Zhao et al., 2012) of cases, respectively. Similarly, mutations or deletions in the CDKN2A/B and IKAROS genes have been reported in up to 50 and 80% of patients in lymphoid BCs, respectively (Sill et al., 1995; Mullighan et al., 2008). Modern sequencing technologies and lowered costs have refined the mutational landscape for many tumors (Pleasance et al., 2010a,b; Curtis et al., 2012; Cancer Genome Atlas Research Network, 2013), but as yet have only been used in a directed fashion in CML (Piccaluga et al., 2009; Boultwood et al., 2010; Grossmann et al., 2011). Therefore, the spectrum of mutations that cooperate with BCR-ABL and the majority of pathways and processes that are corrupted by these mutations during the progression of CML to advanced phases, particularly for myeloid transformation, have yet to be fully described.Mouse models have greatly informed cancer biology in general and CML in particular. Several models have been previously generated, in which transgenic BCR-ABL expression is driven by several different promoters after either germline or retroviral integration (Hariharan et al., 1989; Castellanos et al., 1997; Honda et al., 1998; Huettner et al., 2000, 2003; Koschmieder et al., 2005). However, many of these models have failed to recapitulate the human disease by either generating predominantly acute lymphoid leukemias that lacked a preceding chronic phase, or a very rapidly fatal myeloproliferative neoplasm (MPN)–like disease not resembling the human counterpart (Daley et al., 1990; Honda et al., 1998; Huettner et al., 2000; Huettner et al., 2003). Models of BC have also been reported, where BCR-ABL expression has been combined with a known second hit, such as p53 or Dok1/Dok2 loss, or NUP98-HOXA9 or Hes1 overexpression (Skorski et al., 1996; Honda et al., 2000; Dash et al., 2002; Yasuda et al., 2004; Neering et al., 2007). Although confirmatory of the cooperation of specific mutations with BCR-ABL, these models have not informed the broader biology of BC due to their directed nature. Previous attempts to model random secondary mutations using retroviral insertional mutagenesis have also proven of limited value, with two reported studies only documenting three common insertions (Notch 1, Zfp423, and BCR-ABL; Mizuno et al., 2008; Miyazaki et al., 2009). Furthermore, the majority of these models have generated lymphoid leukemias, mainly T-ALL, thereby reducing their relevance for human disease.We therefore set out to generate a novel mouse model of CML progression that would allow us to identify mechanisms of BC progression in an unbiased and tractable manner. Here, we have combined a mouse transposon-based insertional mutagenesis system with a published transgenic mouse model of chronic phase CML (Koschmieder et al., 2005). For the first time, we report a BC model that closely mimics the natural progression of human CML and faithfully recapitulates the cellular and molecular aspects of its biology. We have identified known and novel candidate genes and pathways that, in combination with BCR-ABL, drive disease progression and could act as potential therapeutic targets in BC. Our novel model therefore defines mechanisms of CML progression, identifies therapeutic targets and provides a translational resource to improve clinical outcomes in this aggressive disease.     

Mangosteen pericarp extract inhibits the formation of pentosidine and ameliorates skin elasticity

The inhibition of advanced glycation end-products (AGEs) by daily meals is believed to become an effective prevention for lifestyle-related diseases. In the present study, the inhibitory effect of hot water extracts of mangosteen (Garcinia mangostana L.) pericarp (WEM) on the formation of pentosidine, one of AGEs, in vitro and in vivo and the remedial effect on skin conditions were measured. WEM significantly inhibited pentosidine formation during gelatin incubation with ribose. Several compounds purified from WEM, such as garcimangosone D and rhodanthenone B, were identified as inhibitors of pentosidine formation. Oral administration of WEM at 100 mg/day to volunteer subjects for 3 months reduced the serum pentosidine contents. Because obtaining skin biopsies from healthy volunteers is ethically difficult, AGE accumulation in the skin was estimated by a fluorescence detector. The oral administration of WEM significantly reduced the skin autofluorescence intensity, demonstrating that WEM also reduced AGE accumulation in the skin. Furthermore, the elasticity and moisture content of the skin was also improved by WEM. These results demonstrate that intakes of WEM reduces the glycation stress and results in the improvement of skin conditions.     

A case of bronchostenosis in the allograft after lung transplantation in pulmonary lymphangioleiomyomatosis]

Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease characterized by hamartomatous proliferation of abnormal smooth muscle cells in the lungs. Recently, severe LAM has been listed as an indicated disease for lung transplantation. A 34-yr-old woman with severe pulmonary cystic changes in a chest CT scan was diagnosed as having an isolated form of pulmonary LAM without genetic disorders. Despite intensive progesterone treatment, her pulmonary functions deteriorated rapidly. In January 2001, a left single-lung transplantation was performed from a cadaveric donor. The total operating time was 8 hours and 47 minutes. Total ischemic time was 5 hours and 59 minutes, which was within the permitted time limit. Except for right pneumothorax, the postoperative course was fairly good without any sign of rejection or infection in the allograft. For about two months after transplantation, bronchostenosis occurred in the left lower lobe bronchus, and necessitated a stent placement. During the following three months, stenosis of the bronchi in the anastomotic and peripheral sites occurred repeatedly, which also necessitated stent placement or balloon dilations on each occasion. Despite all the intensive treatment, the bronchostenosis of the peripheral sites still remains and improvement of her pulmonary functions has been poor. Moreover, a recent chest CT scan revealed a progression of the disease in the native lung. Consequently, we registered her as a candidate for transplantation of the right lung. Bronchostenosis should be kept in mind as a complication of lung transplantation.     

Renal and cardiovascular effects of Bothrops marajoensis venom and phospholipase A2

Bothrops marajoensis is found in the savannah of Marajó Island in the State of Pará and regions of Amapá State, Brazil. The aim of the work was to study the renal and cardiovascular effects of the B. marajoensis venom and phospholipase A₂ (PLA₂). The venom was fractionated by Protein Pack 5PW. N-terminal amino acid sequencing of sPLA₂ showed amino acid identity with other lysine K49 sPLA₂s of snake venom. B. marajoensis venom (30 μg/mL) decreased the perfusion pressure, renal vascular resistance, urinary flow, glomerular filtration rate and sodium tubular transport. PLA₂ did not change the renal parameters. The perfusion pressure of the mesenteric bed did not change after infusion of venom. In isolated heart, the venom decreased the force of contraction and increased PP but did not change coronary flow. In the arterial pressure, the venom and PLA₂ decreased mean arterial pressure and cardiac frequency. The presence of atrial flutter and late hyperpolarisation reversed, indicating QRS complex arrhythmia and dysfunction in atrial conduction. In conclusion, B. marajoensis venom and PLA₂ induce hypotension and bradycardia while simultaneously blocking electrical conduction in the heart. Moreover, the decrease in glomerular filtration rate, urinary flow and electrolyte transport demonstrates physiological changes to the renal system.     

A case of neonatal lupus erythematosus presenting delayed dilated cardiomyopathy with circulating autoantibody to annexin A6

Patients with neonatal lupus erythematosus (NLE) often have congenital heart block with or without heart failure and are born to mothers who have anti-SS-A and/or anti-SS-B antibodies. NLE has been considered to result from the placental transmission of maternal autoantibodies into the fetal circulation causing myocardial damage. We report a case of NLE with congenital heart block who had undergone pacemaker implantation at the age of 17, and then developed dilated cardiomyopathy (DCM) at the age of 19, which is much later than in most other cases. The patient's mother was positive for anti-SS-A and anti-SS-B antibodies, whereas the patient was negative for both anti-SS-A and anti-SS-B antibodies. There were some autoantibodies against cell surface antigens of cardiac myocytes in the serum from the patient, and annexin A6 was identified as one of the autoantigens. This is the first report demonstrating that annexin A6 is involved in the myocardial injury in patients with NLE. The results indicate that inhibition of annexin A6 function may prevent autoantibody-mediated myocardial injury in at least some cases of DCM.