The survivin molecule as a double-edged sword in cellular physiologic and pathologic conditions and its role as a potential biomarker and therapeutic target in cancer.
Survivin is a member of the family of apoptosis inhibitory proteins with increased expression level in most cancerous tissues. Evidence shows that survivin plays regulatory roles in proliferation or survival of normal adult cells, principally vascular endothelial cells, T lymphocytes, primitive hematopoietic cells, and polymorphonuclear neutrophils. Survivin antiapoptotic role is, directly and indirectly, related to caspase proteins and shows its role in cell division through the chromosomal passenger complex. Survivin contains many genetic polymorphisms that the role of some variations has been proven in several cancers. The -31G/C polymorphism is one of the most important survivin mutations which is located in the promoter region on a CDE/CHR motif. This polymorphism can upregulate the survivin messenger RNA. In addition, its allele C can increase the risk of cancers in 1.27-fold than allele G. Considering the fundamental role of survivin in different cancers, this protein could be considered as a new therapeutic target in cancer treatment. For this purpose, various strategies have been designed including the prevention of survivin expression through inhibition of mRNA translation using antagonistic molecules, inhibition of survivin gene function through small inhibitory molecules, gene therapy, and immunotherapy. In this study, we describe the structure, played roles in physiological and pathological states and genetic polymorphisms of survivin. Finally, the role of survivin as a potential target in cancer therapy given challenges ahead has been discussed.


A simple serum depletion method for proteomics analysis.
Serum is the body fluid most often used in biomarker discovery. Albumin, the most abundant serum protein, contributes approximately 50% of the serum protein content, with an additional dozen abundant proteins dominating the rest of the serum proteome. To profile this challenging protein mixture by proteomics, the abundant proteins must be depleted to allow for detection of the low-abundant proteins, the primary biomarker targets. Current serum depletion approaches for proteomics are costly and relatively complex to couple with protein digestion. We demonstrate a simple, affordable serum depletion methodology that, within a few minutes of processing, results in two captured serum fractions - albumin-depleted and albumin-rich - which are digested in situ. We believe our method is a useful addition to the biomarker sample preparation toolbox.


Susac syndrome: diverse clinical findings and treatment.
We report a case of a 19-year-old woman presenting bilateral neurosensorial hearing loss, mental abnormalities, and loss of visual field in the left eye. Visual acuity was 20/20 in OD and 20/25 in OS. Patient was examined systemically. Audiometry showed sensorineural hearing loss in both ears. The magnetic resonance imaging (MRI) of brain revealed multiple small lesions in the white matter in both cerebral hemispheres and at the corpus callosum. Fundoscopy showed bilateral normal optic disc and sheathing of the arterioles in the middle periphery of OD. Retinal edema and cotton-wool spots were observed. Fluorescein angiography showed bilateral peripheral occlusive arterial vasculopathy. The patient was diagnosed with Susac syndrome and treated with quetiapine fumarate, flunitrazepam, and prednisone, which resulted in stabile outcome. This case shows that a high index of suspicion leading to early recognition and treatment is important to avoid irreversible damage.


Systematic review of the health-related quality of life issues facing adolescents and young adults with cancer.
For adolescents and young adults (AYAs), the impact of a cancer diagnosis and subsequent treatment is likely to be distinct from other age groups given the unique and complex psychosocial challenges of this developmental phase. In this review of the literature, we report the health-related quality of life (HRQoL) issues experienced by AYAs diagnosed with cancer and undergoing treatment. MEDLINE, EMBASE, CINAHL, PsychINFO and the Cochrane Library Databases were searched for publications reporting HRQoL of AYAs. Issues generated from interviews with AYAs or from responses to patient reported outcome measures (PROMs) were extracted. 166 papers were reviewed in full and comprised 72 papers covering 69 primary studies, 49 measurement development or evaluation papers and 45 reviews. Of the 69 studies reviewed, 11 (16%) used interviews to elicit AYAs' descriptions of HRQoL issues. The majority of the PROMs used in the studies represent adaptations of paediatric or adult measures. HRQoL issues were organised into the following categories: physical, cognitive, restricted activities, relationships with others, fertility, emotions, body image and spirituality/outlook on life. The HRQoL issues presented within this review are likely to be informative to health care professionals and AYAs. The extensive list of issues suggests that the impact of a cancer diagnosis and treatment during adolescence and young adulthood is widespread and reflects the complexities of this developmental phase.


iCVS-Inferring Cardio-Vascular hidden States from physiological signals available at the bedside.
Intensive care medicine is complex and resource-demanding. A critical and common challenge lies in inferring the underlying physiological state of a patient from partially observed data. Specifically for the cardiovascular system, clinicians use observables such as heart rate, arterial and venous blood pressures, as well as findings from the physical examination and ancillary tests to formulate a mental model and estimate hidden variables such as cardiac output, vascular resistance, filling pressures and volumes, and autonomic tone. Then, they use this mental model to derive the causes for instability and choose appropriate interventions. Not only this is a very hard problem due to the nature of the signals, but it also requires expertise and a clinician's ongoing presence at the bedside. Clinical decision support tools based on mechanistic dynamical models offer an appealing solution due to their inherent explainability, corollaries to the clinical mental process, and predictive power. With a translational motivation in mind, we developed iCVS: a simple, with high explanatory power, dynamical mechanistic model to infer hidden cardiovascular states. Full model estimation requires no prior assumptions on physiological parameters except age and weight, and the only inputs are arterial and venous pressure waveforms. iCVS also considers autonomic and non-autonomic modulations. To gain more information without increasing model complexity, both slow and fast timescales of the blood pressure traces are exploited, while the main inference and dynamic evolution are at the longer, clinically relevant, timescale of minutes. iCVS is designed to allow bedside deployment at pediatric and adult intensive care units and for retrospective investigation of cardiovascular mechanisms underlying instability. In this paper, we describe iCVS and inference system in detail, and using a dataset of critically-ill children, we provide initial indications to its ability to identify bleeding, distributive states, and cardiac dysfunction, in isolation and in combination.


Stem cells as tools for studying the genetics of inherited retinal degenerations.
The ability to provide early clinical intervention for inherited disorders is heavily dependent on knowledge of a patient's disease-causing mutations and the resultant pathophysiologic mechanism(s). Without knowing a patient's disease-causing gene, and how gene mutations alter the health and functionality of affected cells, it would be difficult to develop and deliver patient-specific molecular or small molecule therapies. Many believe that the field of stem cell biology holds the keys to the future development of disease-, patient-, and cell-specific therapies. In the case of the eye, which is susceptible to an extremely common late-onset degenerative disease known as age-related macular degeneration, stem cell-based therapies could increase the quality of life for millions of patients worldwide. Furthermore, autologous, patient-specific induced pluripotent stem cells could be a viable source to treat rare Mendelian retinal degenerative diseases such as retinitis pigmentosa, Stargardt disease, and Best disease, to name a few.


Phonological neighbors influence word naming through the least supported phoneme.
Recent research has shown that phonological neighborhood density facilitates naming latencies. In an attempt to extend this work, the authors evaluated the effect of phonological neighborhood distribution by comparing responding to words that consisted of 3 phonemes but differed in the number of phoneme positions that could be changed to form a neighbor (i.e., 2 vs. 3 positions). The results revealed that words in which all 3 positions could be changed to form a neighbor were named more rapidly than were words in which only 2 positions could be changed. The results show that this effect occurs due to a difference between the 2 groups of words in terms of their least supported phoneme (i.e., the phoneme position within a word with which the fewest neighbors overlap). The authors show that differences in terms of the number of neighbors for the least supported phoneme can also explain past research that indicates an effect of phonological neighborhood density on naming. The authors explain the results of this research using the dual-route cascaded model of reading aloud.


Cisapride reverses the anticholinergic effect of disopyramide on the isolated guinea-pig urinary bladder.
The present investigation aims to examine whether the prokinetic agent cisapride is able to reverse disopyramide's anticholinergic effect on the isolated guinea-pig urinary bladder. Acetylcholine, at concentrations ranging from 10(-7) to 10(-3) M, produced a stimulatory effect on the urinary bladder (pEC(50) value=5.1). Disopyramide competitively antagonized the contractile effect of acetylcholine with an ID(50)=4.4 x 10(-6) M. Although cisapride by itself had either no intrinsic contractile action or a modest effect on the urinary bladder, at concentrations ranging from 3 x 10(-7) to 10(-6) M, it significantly reversed the above inhibitory effect of disopyramide, and produced a parallel leftward shift of the concentration-response curve for acetylcholine in the presence of disopyramide. The pEC(50) values for acetylcholine in the presence of 3 x 10(-6) M and 10(-5) M disopyramide were 4.7 and 4.2, respectively, while in the presence of 10(-5) M disopyramide, after pretreatment with 5 x 10(-7) M cisapride, the pEC(50) value for acetylcholine was 4.6. It is concluded that cisapride is effective in reversing the anticholinergic activity of disopyramide on the isolated guinea-pig urinary bladder, probably by facilitating cholinergic neurotransmission.


Cost effectiveness of denosumab versus oral bisphosphonates for postmenopausal osteoporosis in the US.
In the US, 26 % of women aged ≥65 years, and over 50 % of women aged ≥85 years are affected with postmenopausal osteoporosis (PMO). Each year, the total direct health care costs are estimated to be $US12-18 billion. The cost effectiveness of denosumab versus oral bisphosphonates in postmenopausal osteoporotic women from a US third-party payer perspective was evaluated. A lifetime cohort Markov model was developed with seven health states: 'well', hip fracture, vertebral fracture, 'other' osteoporotic fracture, post-hip fracture, post-vertebral fracture, and dead. During each cycle, patients could have a fracture, remain healthy, remain in a post-fracture state or die. Relative fracture risk reductions, background fracture risks, mortality rates, treatment-specific persistence rate, utilities, and medical and drug costs were derived using published sources. Expected costs and quality-adjusted life years (QALYs) were estimated for generic alendronate, denosumab, branded risedronate, and branded ibandronate in the overall PMO population and high-risk subgroups: (a) ≥2 of the following risks: >70 years of age, bone mineral density (BMD) T score less than or equal to -3.0, and prevalent vertebral fracture; and (b) ≥75 years of age. Costs and QALYs were discounted at 3 % annually, and all costs were inflated to 2012 US dollars. Sensitivity analyses were conducted by varying parameters e.g., efficacies of interventions, costs, utilities, and the medication persistence ratio. In the overall PMO population, total lifetime costs for alendronate, denosumab, risedronate, and ibandronate were $US64,400, $US67,400, $US67,600 and $US69,200, respectively. Total QALYs were 8.2804, 8.3155, 8.2735 and 8.2691, respectively. The incremental cost-effectiveness ratio (ICER) for denosumab versus generic alendronate was $US85,100/QALY. Risedronate and ibandronate were dominated by denosumab. In the high-risk subgroup (a), total costs for alendronate, denosumab, risedronate and ibandronate were $US70,400, $US70,800, $US74,000 and $US76,900, respectively. Total QALYs were 7.2006, 7.2497, 7.1969 and 7.1841, respectively. Denosumab had an ICER of $US7,900/QALY versus generic alendronate and dominated all other strategies. Denosumab dominated all strategies in women aged ≥75 years. Base-case results between denosumab and generic alendronate were most sensitive to the relative risk of hip fracture for both drugs and the cost of denosumab. In each PMO population examined, denosumab represented good value for money compared with branded bisphosphonates. Furthermore, denosumab was either cost effective or dominant compared with generic alendronate in the high-risk subgroups.


Power Relations and Health Care Communication in Older Adulthood: Educating Recipients and Providers.
Unequal power relations lie just below the surface in much of today's discourse on health care communication with older adults. Focusing on pathologies or deficits tends to reinforce stereotypes of frailty and dependency, thus framing elders as a vulnerable group requiring special assistance. Implicit stereotyping frequently colors interactions of health care personnel with older clients and their families-interactions likely to affect elders' perceptions and health outcomes. Health care providers need to be attuned to the vast and growing diversity in today's older population, wherein many older adults are exemplars of what it takes to marshal resources and cope with multifaceted challenges. Thus, elders have the potential to teach medical personnel through narratives of resilience as well as tribulation. This potential can be fully realized, however, only in contexts where communication patterns characterized by paternalism, consumerism, and collaboration are mutually recognized and selectively challenged or implemented. Promising interventions to facilitate health care communication in older adulthood might well be directed toward (a) educating both recipients and providers to become more mindful of cues that evoke stereotypical thinking, (b) promoting an institutional culture that normalizes situationally appropriate assertive responses to stereotyping, and (c) formally ratifying older adults' life experience in the training of health care personnel.


Kinetics and thermodynamics of metal-binding to histone deacetylase 8.
Histone deacetylase 8 (HDAC8) was originally classified as a Zn(II)-dependent deacetylase on the basis of Zn(II)-dependent HDAC8 activity in vitro and illumination of a Zn(II) bound to the active site. However, in vitro measurements demonstrated that HDAC8 has higher activity with a bound Fe(II) than Zn(II), although Fe(II)-HDAC8 rapidly loses activity under aerobic conditions. These data suggest that in the cell HDAC8 could be activated by either Zn(II) or Fe(II). Here we detail the kinetics, thermodynamics, and selectivity of Zn(II) and Fe(II) binding to HDAC8. To this end, we have developed a fluorescence anisotropy assay using fluorescein-labeled suberoylanilide hydroxamic acid (fl-SAHA). fl-SAHA binds specifically to metal-bound HDAC8 with affinities comparable to SAHA. To measure the metal affinity of HDAC, metal binding was coupled to fl-SAHA and assayed from the observed change in anisotropy. The metal KD values for HDAC8 are significantly different, ranging from picomolar to micromolar for Zn(II) and Fe(II), respectively. Unexpectedly, the Fe(II) and Zn(II) dissociation rate constants from HDAC8 are comparable, koff ∼0.0006 s(-1), suggesting that the apparent association rate constant for Fe(II) is slow (∼3 × 10(3) M(-1) s(-1)). Furthermore, monovalent cations (K(+) or Na(+)) that bind to HDAC8 decrease the dissociation rate constant of Zn(II) by ≥100-fold for K(+) and ≥10-fold for Na(+), suggesting a possible mechanism for regulating metal exchange in vivo. The HDAC8 metal affinities are comparable to the readily exchangeable Zn(II) and Fe(II) concentrations in cells, consistent with either or both metal cofactors activating HDAC8.


Genotypic variation in the phytoremediation potential of Indian mustard for chromium.
The term "phytoremediation" is used to describe the cleanup of heavy metals from contaminated sites by plants. This study demonstrates phytoremediation potential of Indian mustard (Brasicca juncea (L.) Czern. & Coss.) genotypes for chromium (Cr). Seedlings of 10 genotypes were grown hydroponically in artificially contaminated water over a range of environmentally relevant concentrations of Cr (VI), and the responses of genotypes in the presence of Cr, with reference to Cr accumulation, its phytotoxity and anti-oxidative system were investigated. The Cr accumulation potential varied largely among Indian mustard genotypes. At 100 microM Cr treatment, Pusa Jai Kisan accumulated the maximum amount of Cr (1680 microg Cr g(-1) DW) whereas Vardhan accumulated the minimum (107 microg Cr g(-1) DW). As the tolerance of metals is a key plant characteristic required for phytoremediation purpose, effects of various levels of Cr on biomass were evaluated as the gross effect. The extent of oxidative stress caused by Cr stress was measured as rate of lipid peroxidation. The level of thiobarbituric acid reactive substances (TBARS) was enhanced at all Cr treatments when compared to the control. Inductions of enzymatic and nonenzymatic antioxidants were monitored as metal-detoxifying responses. All the genotypes responded to Cr-induced oxidative stress by modulating nonenzymatic antioxidants [glutathione (GSH) and ascorbate (Asc)] and enzymatic antioxidants [superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR)]. The level of induction, however, differed among the genotypes, being at its maximum in Pusa Jai Kisan and its minimum in Vardhan. Pusa Jai Kisan was grown under natural field conditions with various Cr treatments, and Cr-accumulation capacity was studied. The results confirmed that Pusa Jai Kisan is a hyperaccumulator of Cr and hypertolerant to Cr-induced stress, which makes this genotype a viable candidate for use in the development of phytoremediation technology of Cr-contaminated sites.


Antiplatelet therapy for transient ischaemic attack and minor ischaemic stroke.
Transient ischaemic attacks carry an increased risk of large ischaemic stroke in the 90 days after an event. Patients need to be seen within 24 hours in a dedicated clinic to start secondary prevention. This editorial reviews evidence for consideration of early dual antiplatelet therapy after a transient ischaemic attack.


Changes in pre-hospital management of vascular risk factors among patients admitted due to recurrent stroke in Poland from 1995 to 2013.
The aim of this study was to investigate long-term trends in secondary stroke prevention through management of vascular risk factors directly before hospital admission for recurrent stroke. This is a retrospective registry-based analysis of consecutive recurrent acute stroke patients from a highly urbanized area (Warsaw, Poland) admitted to a single stroke center between 1995 and 2013 with previous ischemic stroke. We compared between four consecutive time periods: 1995-1999, 2000-2004, 2005-2009 and 2010-2013. During the study period, 894 patients with recurrent strokes were admitted (18% of all strokes), including 867 with previous ischemic stroke (our study group). Among those patients, the proportion of recurrent ischemic strokes (88.1% to 93.9%) (p = 0.319) and males (44% to 49.7%) (p = 0.5) remained stable. However, there was a rising trend in patients' age (median age of 73, 74, 76 and 77 years, respectively). There was also an increase in the use of antihypertensives (from 70.2% to 83.8%) (p = 0.013), vitamin K antagonists (from 4.8% to 15.6%) (p = 0.012) and statins (from 32.5% to 59.4%) (p < 0.001). Nonetheless, 21% of patients did not receive any antithrombotic prophylaxis. Tobacco smoking pattern remained unchanged. Our data indicate a clear overall improvement of secondary stroke prevention. However, persistent use of antithrombotic drugs and tobacco smoking after the first ischemic stroke is constantly suboptimal.


Robotic-assisted laparoscopic radical prostatectomy: a report of the current state.
Cancer of the prostate is the most common malignancy diagnosed in the male genitourinary tract. Although a number of treatment options are available for early prostate cancer, the gold standard of treatment remains retropubic radical prostatectomy. However, robotic-assisted laparoscopic radical prostatectomy (RALP) has become a forerunner in treatment options, yielding comparable medium-term perioperative and functional outcomes. For this our team utilized MEDLINE, searching for publications on perioperative and functional outcomes related to robotic prostatectomy. Robotic-assisted prostatectomy has allowed urologists to enter the realm of minimally invasive surgery by incorporating open surgery maneuvers into a laparoscopic environment. To date, RALP perioperative and functional outcomes are comparable to the gold standard; the collection of long-term data is needed in order to establish its true efficacy.


Nationwide microbiological baseline data collected by sponge sampling during 1997 and 1998 for cattle, swine, turkeys, and geese.
During 1997 and 1998, the U.S. Food Safety and Inspection Service completed nationwide microbiological baseline studies on four separate categories of livestock and poultry. Data were collected by sponge-sampling techniques. These studies were designed to provide nationwide estimates of the prevalence of Salmonella and prevalence and concentrations of Escherichia coli in cattle (n = 1,881), swine (n = 2,127), turkeys (n = 1,396), and geese (n = 102) in establishments under federal inspection. Salmonella prevalence ranged from 1.2% in cattle to 6.9% in swine, 13.7% in geese, and 19.6% in turkeys. The prevalence of E. coli was 16.6% in cattle (geometric mean = 0.26 CFU/cm2), 44.1% in swine (mean = 0.78 CFU/cm2), 92.7% in turkey (mean = 2.46 CFU/cm2), and 96.5% in geese (mean = 1.97 CFU/cm2). These values are similar to or somewhat lower than previous baseline values obtained for steers and heifers, cows and bulls, market hogs, and young turkeys. This study is the first in which nationwide microbiological baseline data have been compiled for geese. These data will be useful to individuals working with hazard analysis critical control point plans and risk assessment and to the research and academic communities.


Computer game-based and traditional learning method: a comparison regarding students' knowledge retention.
Educational computer games are examples of computer-assisted learning objects, representing an educational strategy of growing interest. Given the changes in the digital world over the last decades, students of the current generation expect technology to be used in advancing their learning requiring a need to change traditional passive learning methodologies to an active multisensory experimental learning methodology. The objective of this study was to compare a computer game-based learning method with a traditional learning method, regarding learning gains and knowledge retention, as means of teaching head and neck Anatomy and Physiology to Speech-Language and Hearing pathology undergraduate students. Students were randomized to participate to one of the learning methods and the data analyst was blinded to which method of learning the students had received. Students' prior knowledge (i.e. before undergoing the learning method), short-term knowledge retention and long-term knowledge retention (i.e. six months after undergoing the learning method) were assessed with a multiple choice questionnaire. Students' performance was compared considering the three moments of assessment for both for the mean total score and for separated mean scores for Anatomy questions and for Physiology questions. Students that received the game-based method performed better in the pos-test assessment only when considering the Anatomy questions section. Students that received the traditional lecture performed better in both post-test and long-term post-test when considering the Anatomy and Physiology questions. The game-based learning method is comparable to the traditional learning method in general and in short-term gains, while the traditional lecture still seems to be more effective to improve students' short and long-term knowledge retention.


Distinct Tertiary Lymphoid Structure Associations and Their Prognostic Relevance in HER2 Positive and Negative Breast Cancers.
The presence of tumor infiltrating lymphocytes (TIL) is associated with favorable prognosis. Recent evidence suggested that not only their density, but also the spatial organization as tertiary lymphoid structures (TLS), play a key role in determining patient survival. In a cohort of 248 breast cancers, the clinicopathologic association and prognostic role of TLS was examined. Tertiary lymphoid structures were associated with higher tumor grade, apocrine phenotype, necrosis, extensive in situ component, lymphovascular invasion (LVI), and high TIL. For biomarkers, TLS were associated with hormone receptors negativity, HER2 positivity, and c-kit expression. Tertiary lymphoid structures were significantly related to better disease-free survival (DFS) in HER2 positive (HER2+) breast cancers (log-rank = 4.054), which was not dependent on high TIL status. The combined TLS and TIL status was an independent favorable factor associated with DFS in those cases. Interestingly, tumor cell infiltration into the TLS was found in 41.9% of TLS positive cases. It was associated with LVI in HER2 negative (HER2-) TLS positive (particularly estrogen receptor positive [ER+] HER2-) cases. In the ER+ HER2- cases, tumor cell infiltration into TLS was also associated with increased pathologic nodal stage (pN) stage and nodal involvement. Tertiary lymphoid structures showed a similar relationship with clinicopathologic features and biomarkers as TIL. The presence of TLS, irrespective of TIL level, could be an important favorable prognostic indicator in HER2+ breast cancer patients. Given the significance of TLS in promoting effective antitumor immunity, further understanding of its organization and induction may provide new opportunities to improve the current immunotherapy strategies. Despite recent interest on the clinical value of tumor infiltrating lymphocyte (TIL), little was known on the clinical significance on their spatial organization as tertiary lymphoid structures (TLS). Although TLS showed similar relationships with clinicopathologic features and biomarkers as TIL, the prognostic value of TLS, particularly in HER2 positive cancers, was independent of TIL. Moreover, tumor infiltration could be present in TLS which appears to be related to tumor invasion in HER2 negative cancers. Overall, the results demonstrated the additional value for TLS in HER2 cancer subtypes. Further investigations and its standardized evaluation will enhance its use as standard practice.


Spontaneous pulmonary co-metastasis of hepatoblastoma arising within a hepatocellular carcinoma in an aged C57BL/6J mouse.
Murine hepatoblastoma (HB) is a rare spontaneous tumor with controversial histogenesis. It mainly occurs in aged males, frequently in close association with preexisting hepatocellular neoplasms. The present work describes a spontaneous HB arising within a hepatocellular carcinoma (HCC) in a 22-month-old male C57BL/6J mouse. The mouse also developed pulmonary co-metastases with either tumor components physically associated within the same metastatic foci. Microscopically, the HB consisted of a densely cellular neoplastic growth composed of palisades and perivascular pseudorosettes of poorly differentiated primitive cells, with a scant amount of cytoplasm, elongated hyperchromatic nuclei, and a high mitotic rate, whereas the hepatocellular carcinoma was composed of solid areas of neoplastic hepatocytes. Both in primary tumors and their metastases, β-catenin immunohistochemistry revealed a strong nucleocytoplasmic signal in HB cells, while neoplastic hepatocytes displayed a delicate membranous staining pattern. These findings suggest that the Wnt/β-catenin oncogenic pathway is upregulated in murine HB but not in the co-existing HCC, thus providing some insights into their divergent pathogenesis. Coexisting murine HB and HCC have been demonstrated to be completely distinct entities including origin, mutational landscape, and molecular profile. In this context, they might be regarded as collision tumors because of their intimate association, unique histologic features, and distinct immunohistochemical patterns. Nevertheless, the nature of their coevolution and progression to a co-metastatic phenotype reflects a close interdependence and support the overall idea that HB's origin and progression might be promoted by not otherwise specified paracrine stimuli provided by the concurrent hepatocellular tumor (the so called "interaction theory").


Immunostimulatory monoclonal antibodies for hepatocellular carcinoma therapy. Trends and perspectives.
Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.


Weekly high-dose 5-fluorouracil as 24-h infusion and folinic acid (AIO) plus irinotecan as second- and third-line treatment in patients with colorectal cancer pre-treated with AIO plus oxaliplatin.
Our objective was to evaluate the efficacy and safety of high-dose 5-fluorouracil (5-FU) as a 24-h infusion and folinic acid (FA) (AIO regimen) plus irinotecan (CPT-11) after pre-treatment with AIO plus oxaliplatin (L-OHP) in colorectal carcinoma (CRC). Twenty-six patients with non-resectable distant CRC metastases were analyzed for second- or third-line treatment with AIO plus CPT-11 after pre-treatment with AIO plus L-OHP. On an outpatient basis, the patients received a treatment regimen comprising weekly 80 mg/m2 CPT-11 in the form of a 1-h i.v. infusion and 500 mg/m2 FA as a 1- to 2-h i.v. infusion, followed by 2000 mg/m2 5-FU i.v. administered as a 24-h infusion once weekly. A single treatment cycle comprised six weekly infusions followed by 2 weeks of rest. A total of 26 patients received 344 chemotherapy applications with AIO plus CPT-11. The main symptom of toxicity was diarrhea (NCI-CTC toxicity grade 3+4) occurring in five patients (19%; 95% CI 7-39%). Nausea and vomiting presented in two patients (8%; 95% CI 1-25%). The response rate of 26 patients can be summarized as follows: partial remission: n=7 (27%; 95% CI 12-48%); stable disease: n=9 (35%; 95% CI 17-56%) and progressive disease: n=10 (38%; 95% CI 20-59%). The median progression-free survival (n=26) was 5.8 months (range 3-13), the median survival time counted from the treatment start with the AIO plus CPT-11 regimen was 10 months (range 2-24) and counted from the start of first-line treatment (n=26) was 23 months (range 10-66). We conclude that the AIO regimen plus CPT-11 is practicable in an outpatient setting and well tolerated by the patients. Tumor control was achieved in 62% of the patients. The median survival time was 10 months and the median survival time from the start of first-line treatment (n=26) was 23 months.


Relationship between submaximal oxygen uptake, detailed body composition, and resting energy expenditure in overweight subjects.
We investigated the impact of detailed body composition on aerobic fitness to determine whether regional components of fat mass have independent effects on VO2submax , and whether VO2submax and detailed body composition independently explain variation in REE. 71 healthy adults (80% female, 20% male, BMI 28.2-43.8 kg/m(2) ) were investigated. Body composition was measured by the four-compartment model together with whole body magnetic resonance imaging (MRI) to assess high and low metabolic rate organs and regional fat depots. VO2submax was estimated at 75% of predicted maximum heart rate. There was a strong association between VO2submax and FFM and all organ masses except for heart. Skeletal muscle mass accounted for 34.8% of the variance in VO2submax . In addition, subcutaneous adipose tissue (SAT) of extremities explained additional 14.4%. FFM and FM explained 71.3% of the variance in REE. Including the components of FFM and FM, the explained variance in REE increased by about 5.8%; skeletal muscle mass explained 70.0% of the variance in REE and kidney and liver masses explained additional 7.1%. VO2submax correlated with REE. Taking into account body composition, VO2submax did not add to the variance in REE. FFM is a determinant of both VO2submax and REE. Modeling either REE or VO2submax from individual components of FFM, about 77.1% of variance in REE (by muscle, liver and kidneys mass) and 34.8% of variance in VO2submax (by skeletal muscle mass) could be explained. FM explained additional variance in REE, whereas SAT of extremities added to the variance in VO2submax only.


Closure of perimembranous ventricular septal defects with intraoperative device technique: another safe alternative to surgical repair.
This study aims at assessing the safety and feasibility of intraoperative device closure of the perimembranous ventricular septal defect (VSD). Total 89 patients in group I with intraoperative device closure and 58 in group II with surgical repair were enrolled in our hospital to participate in the study from January 2009 to December 2010. In group I, the approach involved a minimal inferior median incision that was performed after full evaluation of the perimembranous VSD by real-time transesophageal echocardiographic guidance, and the insertion of an asymmetric or a symmetric domestically made device was used to occlude the perimembranous VSD. In group I, 83 patients were occluded successfully under this approach. The size of the occluder implanted ranged from 6 to 14 mm. Complete atrioventricular block occurred in one case and Mobitz type II atrioventricular block occurred in one case during the procedure. One patient presented complete atrioventricular block one week after the operation. Two patients converted to surgical repair because of severe intraoperative aortic valve regurgitation. One patient with significant residual shunt transformed to surgical treatment. In our comparative studies, patients in group II experienced significantly longer operative time, ICU stay, and hospital stay (p < 0.001). The cost of group I was less than that of group II (p < 0.001). Minimally invasive transthoracic device closure of the perimembranous VSD with an asymmetric or a symmetric domestically made device without cardiopulmonary bypass is safe and feasible. It should be considered an acceptable alternative to surgery in selected subgroups. However, it is necessary to evaluate the long-term results.


Identification of a DNA Damage-Induced Alternative Splicing Pathway That Regulates p53 and Cellular Senescence Markers.
Cellular responses to DNA damage are critical determinants of cancer development and aging-associated pathogenesis. Here, we identify and characterize a DNA-damage response (DDR) pathway that regulates alternative splicing of numerous gene products, including the human tumor suppressor TP53, and controls DNA damage-induced cellular senescence. In brief, ionizing radiation (IR) inhibits the activity of SMG1, a phosphoinositide-3-kinase-like kinase family member, reducing the binding of SMG1 to a specific region near exon 9 of p53 precursor mRNA and promoting the binding of ribosomal protein L26 (RPL26) to p53 pre-mRNA. RPL26, in turn, is required for the recruitment of the serine/arginine-rich splicing factor SRSF7 to p53 pre-mRNA and generation of alternatively spliced p53β RNA. Disruption of this pathway via selective knockout of p53β by CRISPR/Cas9 or downregulation of pathway constituents significantly reduces IR-induced senescence markers, and cells lacking p53β expression fail to transcriptionally repress negative regulators of cellular senescence and aging.Significance: We identified a new component of the DDR pathway that regulates alternative splicing of messenger RNAs, including human TP53 mRNA. Modulation of this regulatory pathway affects DNA-damage induction of cellular senescence markers. Cancer Discov; 7(7); 766-81. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.


Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: a first evaluation.
To establish frequencies of benzodiazepine and opioid withdrawal symptoms, and correlations with total doses and duration of administration. A prospective, repeated-measures design. Two pediatric intensive care units in a university children's hospital. Seventy-nine children, aged 0 days to 16 yrs, who received intravenous midazolam and/or opioids for >5 days. None. Pediatric intensive care unit nurses assessed withdrawal symptoms using the Sophia Benzodiazepine and Opioid Withdrawal Checklist, which includes all withdrawal symptoms (n = 24) described in the pediatric literature. Over 6 months, 2188 observations in 79 children were recorded. Forty-two percent of observations were performed within 24 hrs after tapering off or discontinuation of medication. Symptoms representing overstimulation of the central nervous system, such as anxiety, agitation, grimacing, sleep disturbance, increased muscle tension, and movement disorder, were observed in >10% of observations. Of symptoms reflecting gastrointestinal dysfunction, diarrhea and gastric retention were most frequently observed. Tachypnea, fever, sweating, and hypertension as manifestations of autonomic dysfunction were observed in >13% of observations. The Spearman's rank-correlation coefficient between total doses of midazolam and maximum sum score (of the Sophia Benzodiazepine and Opioid Withdrawal Checklist) was .51 (p < 0.001). The correlation between total doses of opioids and the maximum sum score was .39 (p < 0.01). A significant correlation (.52; p < 0.001) was also found between duration of use and maximum sum score. This is the first study to report frequencies of all 24 withdrawal symptoms observed in children after decrease or discontinuation of benzodiazepines and/or opioids. Agitation, anxiety, muscle tension, sleeping <1 hr, diarrhea, fever, sweating, and tachypnea were observed most frequently. Longer duration of use and high dosing are risk factors for development of withdrawal symptoms in children.


Effects of ultrasound on functional properties, structure and glycation properties of proteins: a review.
Protein is an indispensable part of life. It provides nutrition for human body and flavor for food. The role of protein depends largely on the functional properties of the protein. Therefore, the elucidation of protein structure and functional properties needs to be further explored. The effects of structural and functional properties of proteins under different ultrasonic treatment conditions were reviewed. The structural changes of protein were studied by hydrogen-deuterium exchange mass spectrometry combined with fluorescence spectrometry and proteomics, and the mechanism of action was determined. The glycation site, the glycation degree, and the glycation characteristics of different sugars were determined. The protein was modified by ultrasound, and the influence of protein structure, physicochemical properties, protein glycation characteristics, and the action mechanism were analyzed by biological mass spectrometry.


Breaking conceptual locks in modelling root absorption of nutrients: reopening the thermodynamic viewpoint of ion transport across the root.
The top-down analysis of nitrate influx isotherms through the Enzyme-Substrate interpretation has not withstood recent molecular and histochemical analyses of nitrate transporters. Indeed, at least four families of nitrate transporters operating at both high and/or low external nitrate concentrations, and which are located in series and/or parallel in the different cellular layers of the mature root, are involved in nitrate uptake. Accordingly, the top-down analysis of the root catalytic structure for ion transport from the Enzyme-Substrate interpretation of nitrate influx isotherms is inadequate. Moreover, the use of the Enzyme-Substrate velocity equation as a single reference in agronomic models is not suitable in its formalism to account for variations in N uptake under fluctuating environmental conditions. Therefore, a conceptual paradigm shift is required to improve the mechanistic modelling of N uptake in agronomic models. An alternative formalism, the Flow-Force theory, was proposed in the 1970s to describe ion isotherms based upon biophysical 'flows and forces' relationships of non-equilibrium thermodynamics. This interpretation describes, with macroscopic parameters, the patterns of N uptake provided by a biological system such as roots. In contrast to the Enzyme-Substrate interpretation, this approach does not claim to represent molecular characteristics. Here it is shown that it is possible to combine the Flow-Force formalism with polynomial responses of nitrate influx rate induced by climatic and in planta factors in relation to nitrate availability. Application of the Flow-Force formalism allows nitrate uptake to be modelled in a more realistic manner, and allows scaling-up in time and space of the regulation of nitrate uptake across the plant growth cycle.


Hepatitis B knowledge and preventive practices of Chinese American immigrants in Southern California.
Chinese American immigrants have higher rates of chronic hepatitis B virus (HBV) infections and consequently higher rates of liver cancer compared to the general U.S. The need to assess this vulnerable population's knowledge and health practices is important to prevent HBV infections and improve outcomes. The purpose of this study was to describe HBV knowledge and preventive practices among Chinese American immigrants in Southern California. Convenience sample of 179 Chinese American immigrants age ≥18 years from Los Angeles County (CA) participated in the study by completing a modified version of the B Free CEED's Hepatitis B Needs Assessment survey. Most participants were knowledgeable of HBV (91.6%) or HBV vaccination (70.5%), yet screening and vaccination for the virus were low (36.9% and 26.3%, respectively). Low knowledge was also found regarding modes of disease transmission. Barriers to engage preventive practices included: "feeling well/no health problems" and "not suggested by a doctor." These findings suggest the need for further education. Nurse practitioners can play a significant role in assessing risk and implementing programs that are community focused, culturally sensitive, and evidence based to improve knowledge, screening, and preventive behaviors on HBV infections for this vulnerable population.


Further analysis of cell membrane changes in genetic hypertension in rats by diphenylhexatriene fluorescence polarization.
Fluorescence polarization of diphenylhexatriene embedded in membranes was used as an index of 'microviscosity' in platelets and erythrocyte ghosts of spontaneously hypertensive rats of the Okamoto-Aoki strain (SHR), Wistar-Kyoto strain (WKY) and of the hypertension-prone and -resistant Sabra strains (SBH and SBN ), and the original Sabra strain (SB). Microviscosity was increased both in erythrocyte ghosts and platelet membranes of male but not female SHR rats compared with WKY rats and in hypertension-prone Sabra rats compared with the original Sabra rats. Acute and chronic salt loading increased the microviscosity of platelet membranes in all strains of rats but had no effect on the erythrocyte membranes. Microviscosities of vesicles made of lipids extracted from SHR and WKY erythrocyte ghosts were similar. This supports the hypothesis that membrane proteins play a major role in the differences in microviscosity observed in SHR rats.


Ubiquitylation of MHC class I by the K3 viral protein signals internalization and TSG101-dependent degradation.
The Kaposi's sarcoma-associated herpes virus gene product K3 (KK3) subverts the MHC class I antigen presentation pathway by downregulating MHC class I from the plasma membrane. We now show that KK3 associates with MHC class I molecules and promotes ubiquitylation of class I after export from the endoplasmic reticulum. Ubiquitylation requires the KK3 N-terminal plant homeodomain and provides the signal for class I internalization at the plasma membrane. Once internalized, ubiquitylated MHC class I is targeted to the late endocytic pathway, where it is degraded. Depletion by small interfering RNA of TSG101, a ubiquitin enzyme 2 variant protein involved in late endosomal sorting, prevents class I degradation and preserves cell surface class I expression in KK3-expressing cells. These results suggest a mechanism by which the KK3-induced class I ubiquitylation provides a signal for both internalization and sorting to the late endosomal pathway for degradation. KK3 is the first viral gene product that subverts the trafficking of a host protein via the ubiquitin-dependent endosomal sorting machinery.


Impact of registration procedures on antibiotic policies.
There is increasing concern over antibiotic resistance and its spread in common bacterial species, such as Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Escherichia coli. This results in increased morbidity and mortality. Over consumption of antibiotics has been reported in many settings and underlines the need for improving antibiotic policies. Crude measures of both antibiotic use and antibiotic resistance do not share a strong cause-and-effect relationship. However, this relationship is highly suggestive at a country level, at a hospital level, at a cohort level and at an individual level. In addition to overuse, antibiotic misuse has also to be considered, because of its impact on promoting antibiotic resistance, related to choice, dosage, dosing regimen or duration of therapy [1].


Cyclometalated Platinum(II) Cyanometallates: Luminescent Blocks for Coordination Self-Assembly.
A family of cyanide-bridged heterometallic aggregates has been constructed of the chromophoric cycloplatinated metalloligands and coordinatively unsaturated d10 fragments {M(PPh3)n}. The tetranuclear complexes of general composition [Pt(C^N)(CN)2M(PPh3)2]2 [C^N = ppy, M = Cu (1), Ag (2); C^N = tolpy (Htolpy = 2-(4-tolyl)-pyridine), M = Cu (4), Ag (5); C^N = F2ppy (HF2ppy = 2-(4, 6-difluorophenyl)-pyridine), M = Cu (7), Ag (8)] demonstrate a squarelike arrangement of the molecular frameworks, which is achieved due to favorable coordination geometries of the bridging ligands and the metal ions. Variation of the amount of the ancillary phosphine (for M = Ag) afforded compounds [Pt(C^N)(CN)2Ag(PPh3)]2 (C^N = ppy, 3; C^N = tolpy, 6); for the latter one an alternative cluster topology, stabilized by the Pt-Ag metallophilic and η1-Cipso(C^N)-Ag bonding, was observed. The solid-state structures of all of the title species 1-8 were determined crystallographically. The complexes exhibit moderately strong room-temperature phosphorescence as crystalline powders (Φem = 16-34%, λem = 470-511 nm). The luminescence studies and time-dependent density functional theory computational analysis indicate that the photophysical behavior is dominated by the 3π-π* electronic transitions localized on the cyclometalated fragment and mixed with MPtLCT contribution, while the d10-phosphine motifs have a negligible contribution into the frontier orbitals and therefore show a little influence on the emission performance of the described compounds.


[Nonsurgical retrieval of intravascular catheter fragments].
The incidence of catheter fragment induced by iatrogenic accident has been increasing because of frequent use of intravenous catheters and catheterization in daily practice. Migrated intravascular fragments from broken catheters were retrieved transcutaneously in four cases. All fragments were removed safely using biotome, multipurpose grasping forceps and basket catheter. But in a case which the fragment was lodged in the pulmonary artery, retrieval was not easy and it took many times. Fragments lodged in the right ventricle and in the pulmonary artery cause many complications including deaths. So broken fragments should be removed as soon as possible, before it migrated to there.


Natural History and Clinical Outcomes of Paravertebral Arteriovenous Shunts.
Paravertebral arteriovenous shunts (PVAVSs) are rare. Whether the intradural venous system is involved in drainage may lead to differences in clinical characteristics through specific pathophysiological mechanisms. This study aims to comprehensively evaluate the natural history and clinical outcomes of PVAVSs with or without intradural drainage. Sixty-four consecutive patients with PVAVSs from 2 institutes were retrospectively reviewed. Lesions were classified as type A (n=28) if the intradural veins were involved in drainage; otherwise, they were classified as type B (n=36). The clinical course from initial presentation to the last follow-up was analyzed. The patients with type A shunts were older at presentation (52.5 versus 35.5 years, P<0.0001) and more likely to have lower spinal segments affected than patients with type B PVAVSs (67.8% versus 13.9%, P=0.00006). After presentation, the deterioration rates related to gait and sphincter dysfunction were significantly higher in patients with type A than type B shunts (gait dysfunction: 71.8%/y versus 17.0%/y, P=0.0006; sphincter dysfunction: 63.7%/y versus 11.3%/y, P=0.0002). According to the angiogram at the end of the latest treatment, 79% of type A and 75% of type B PVAVSs were completely obliterated. If the lesions were partially obliterated, a significantly higher clinical deterioration rate was observed in patients with type A shunts than those with type B shunts (69.9%/y versus 3.2%/y, P=0.0253). Type A PVAVSs feature rapid progressive neurological deficits; therefore, early clinical intervention is necessary. For complex lesions that cannot be completely obliterated, surgical disconnection of all refluxed radicular veins is suggested.


Crystal structure of gluconate 5-dehydrogenase from Lentibacter algarum.
Gluconate 5-dehydrogenase (Ga5DH; EC 22.214.171.124) from Lentibacter algarum (LaGa5DH) was recombinantly expressed in Escherichia coli and purified to homogeneity. The protein was crystallized and the crystal structure was solved at 2.1 Å resolution. The crystal belonged to the monoclinic system, with space group P1 and unit-cell parameters a = 55.42, b = 55.48, c = 79.16 Å, α = 100.51, β = 105.66, γ = 97.99°. The structure revealed LaGaDH to be a tetramer, with each subunit consisting of six α-helices and three antiparallel β-hairpins. LaGa5DH has high structural similarity to other Ga5DH proteins, demonstrating that this enzyme is highly conserved.


Five-year results evaluating the effects of platelet-rich plasma on the healing of intrabony defects treated with enamel matrix derivative and natural bone mineral.
Regenerative periodontal surgery using the combination of enamel matrix derivative (EMD) and natural bone mineral (NBM) with and without addition of platelet-rich plasma (PRP) has been shown to result in substantial clinical improvements, but the long-term effects of this combination are unknown. The goal of this study was to evaluate the long-term (5-year) outcomes after regenerative surgery of deep intrabony defects with either EMD + NBM + PRP or EMD + NBM. Twenty-four patients were included. In each patient, one intrabony defect was randomly treated with either EMD + NBM + PRP or EMD + NBM. Clinical parameters were evaluated at baseline and 1 and 5 years after treatment. The primary outcome variable was clinical attachment level (CAL). The sites treated with EMD + NBM + PRP demonstrated a mean CAL change from 10.5 ± 1.6 to 6.0 ± 1.7 mm (P <0.001) at 1 year and 6.2 ± 1.5 mm (P <0.001) at 5 years. EMD + NBM-treated defects showed a mean CAL change from 10.6 ± 1.7 to 6.1 ± 1.5 mm (P <0.001) at 1 year and 6.3 ± 1.4 mm (P <0.001) at 5 years. At 1 year, a CAL gain of ≥4 mm was measured in 83% (10 of 12) of the defects treated with EMD + NBM + PRP and in 100% (all 12) of the defects treated with EMD + NBM. Compared to baseline, in both groups at 5 years, a CAL gain of ≥4 mm was measured in 75% (nine of 12 in each group) of the defects. Four sites in the EMD + PRP + NBM group lost 1 mm of the CAL gained at 1 year. In the EMD + NBM group, one defect lost 2 mm and four other defects lost 1 mm of the CAL gained at 1 year. No statistically significant differences in any of the investigated parameters were observed between the two groups. Within their limits, the present results indicate that: 1) the clinical outcomes obtained with both treatments can be maintained up to a period of 5 years; and 2) the use of PRP does not appear to improve the results obtained with EMD + NBM.


Contribution of putative efflux pump genes to isoniazid resistance in clinical isolates of Mycobacterium tuberculosis.
Isoniazid (INH) resistance in Mycobacterium tuberculosis has been mainly attributed to mutations in katG (64%) and inhA (19%). However, 20%-30% resistance to INH cannot be explained by mutations alone. Hence, other mechanisms besides mutations may play a significant role in providing drug resistance. Here, we explored the role of 24 putative efflux pump genes conferring INH-resistance in M. tuberculosis. Real-time expression profiling of the efflux pump genes was performed in five INH-susceptible and six high-level INH-resistant clinical isolates of M. tuberculosis exposed to the drug. Isolates were also analyzed for mutations in katG and inhA. Four high-level INH-resistant isolates (minimum inhibitory concentration [MIC] ≥2.5 mg/L) with mutations at codon 315 (AGC-ACC) of katG showed upregulation of one of the efflux genes Rv1634, Rv0849, efpA, or p55. Another high-level INH-resistant isolate (MIC 1.5 mg/L), with no mutations at katG or inhA overexpressed 8/24 efflux genes, namely, Rv1273c, Rv0194, Rv1634, Rv1250, Rv3823c, Rv0507, jefA, and p55. Five of these, namely, Rv0194, Rv1634, Rv1250, Rv0507, and p55 were induced only in resistant isolates. The high number of efflux genes overexpressed in an INH-resistant isolate with no known INH resistance associated mutations, suggests a role for efflux pumps in resistance to this antituberculous agent, with the role of Rv0194 and Rv0507 in INH resistance being reported for the first time.


Anti-ischaemic and anti-anginal activity of atenolol, nifedipine and their combination in stable, chronic effort angina.
To assess the anti-anginal and anti-ischaemic activity of the beta-blocker atenolol (ATN) and the calcium antagonist nifedipine (NIFE) and their combination in coronary patients, a double-blind, cross-over, placebo-controlled study was performed. Ten male patients (mean age: 58 +/- 2.9 years) suffering from a stable effort angina were studied. The study lasted 14 weeks: after 2 weeks of wash-out, patients were randomly assigned to ATN (100 mg/day) and placebo-NIFE, or placebo-ATN and NIFE (10 mg three times/day), or ATN (100 mg) plus NIFE (10 mg three times/day) for 4 weeks. Maximal symptom-limited stress tests on a bicycle (10 watt/min) during the wash-out period (on days 10 and 14) and at the end of each treatment period were performed. All treatments significantly increased the work load at 1 mm ST depression, the angina threshold and the total work, and reduced ST depression at the maximal common work and at the maximal work. Also the atenolol-nifedipine combination significantly reduced ST depression at maximal common work and maximal work as compared to ATN and NIFE alone. In conclusion, this study confirms the anti-ischaemic and anti-anginal activity of both atenolol and nifedipine in stable effort angina and shows that their combination is able to increase anti-ischaemic activity.


Hematopoietic stem cell transplant for erythropoietic porphyrias in pediatric patients.
Cutaneous, hematopoietic, and hepatic manifestations of congenital erythropoietic porphyria (CEP) and erythropoietic protoporphyria (EPP) can be debilitating. We present our institution's experience with five patients with porphyria who underwent hematopoietic stem cell transplant (HSCT). Four patients with CEP, including three under age 2, received myeloablation. One patient with EPP, with prior liver transplant, received reduced intensity conditioning (RIC). Four patients are alive without porphyria symptomology and with full donor chimerism. HSCT corrects the defective heme pathway and should be considered early in patients with severe erythropoietic porphyrias to minimize end-organ damage. RIC regimens can minimize toxicity in patients with comorbidities.


Patterns of Non-Communicable Disease, Multimorbidity, and Population Awareness in Bahir Dar, Northwest Ethiopia: A Cross-Sectional Study.
Ethiopia, like other developing countries, is going through an epidemiological transition, and high rates of non-communicable diseases (NCDs) are having a significant impact on the health system; however, there is limited evidence about community level NCD prevalence, multimorbidity, and population awareness that could inform targeted interventions and policy responses. This study aimed to identify factors associated with NCD prevalence, multimorbidity, and population awareness of NCDs in Bahir Dar, Northwest Ethiopia. A community-based cross-sectional survey was conducted with 417 randomly sampled adults. We performed descriptive and logistic regression analyses to evaluate associations between NCD prevalence (cardiovascular diseases, diabetes, cancer, chronic respiratory diseases, chronic kidney disease, and hypertension) multimorbidity (2 or more NCDs) and demographic, socioeconomic, individual risk factors, anthropometrics, knowledge, and attitude. This study reveals that 24% of participating adults have an NCD, and 8% have multimorbidity. One-third (34.5%) have some NCD knowledge, and 75% consider NCDs more dangerous than communicable diseases. We find low NCD prevalence in participants: younger than 40 years of age (AOR 0.17, 95% CI 0.07 to 0.39); with normal body mass index (AOR 0.27, 0.10 to 0.77) and; with a family history of NCD (AOR 7.7, 4.2 to 14.1). Multimorbidity is lower in young adults (AOR 0.08, 0.03 to 0.26). NCD knowledge is higher in men (AOR 1.76, 1.06 to 2.93) and employed adults (AOR 2.91, 1.52 to 5.57), and NCD attitude in normal-weight adults (AOR 3.23, 1.42 to 7.39). This study reveals a high prevalence of NCD and overall low NCD awareness in the population. Age above 40 years, family history of NCD, and weight in the obese category are significant predictors of NCD prevalence. These findings can help health professionals, health offices, and concerned stakeholders to plan targeted health interventions to reduce NCDs in the population.


Impacts of channel fluctuations on least-squares channel estimation in underwater acoustic communications.
The time-varying multipath introduces major distortions to transmissions in the underwater acoustic communication channel. Channel estimation is often used as one of the central steps to address such distortions in high-rate communication receivers. The focus of this paper is to quantify the impacts of the channel fluctuations on the performance of the least-squares channel estimator. A metric, channel variation ratio (CVR), is defined to describe the rate of fluctuations in the channel impulse responses. Equations are derived to reveal the direct relationships between the CVR and channel estimation performance, which is measured by the channel estimation mean squared error (MSE) and signal prediction error (SPE). The equations show that both the MSE and SPE increase linearly with the CVR. The MSE and SPE metrics both have an error floor for time-varying impulse responses, even with zero ambient noise. It is confirmed that an optimum estimated channel length, achieving the minimum estimation error, exists for time-varying impulse responses. The truncation effects in the channel estimation are also investigated. Experimental data are used to validate the findings.


Non-coding RNAs: the extensive and interactive regulators of the blood-brain barrier permeability.
The blood-brain barrier (BBB), which controls permeability into and out of the nervous system, is a tightly connected, structural, and functional separation between the central nervous system (CNS) and circulating blood. CNS diseases, such as Alzheimer's disease, multiple sclerosis, traumatic brain injury, stroke, meningitis, and brain cancers, often develop with the increased BBB permeability and further leads to irreversible CNS injury. Non-coding RNAs (ncRNAs) are functional RNA molecules that generally lack the coding abilities but can actively regulate the mRNA expression and function through different mechanisms. Various types of ncRNAs, including microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), are highly expressed in brain microvascular endothelial cells and are potential mediators of BBB permeability. Here, we summarized the recent research progress on miRNA, lncRNA, and circRNA roles regulating the BBB permeability in different CNS diseases. Understanding how these ncRNAs affect the BBB permeability shall provide important therapeutic insights into the prevention and control of the BBB dysfunction.


Insulin receptor β-subunit haploinsufficiency impairs hippocampal late-phase LTP and recognition memory.
The insulin receptor (IR) is a protein tyrosine kinase playing a pivotal role in the regulation of peripheral glucose metabolism and energy homoeostasis. IRs are also abundantly distributed in the cerebral cortex and hippocampus, where they regulate synaptic activity required for learning and memory. As the major anabolic hormone in mammals, insulin stimulates protein synthesis partially through the activation of the PI3K/Akt/mTOR pathway, playing fundamental roles in neuronal development, synaptic plasticity and memory. Here, by means of a multidisciplinary approach, we report that long-term synaptic plasticity and recognition memory are impaired in IR β-subunit heterozygous mice. Since IR expression is diminished in type-2 diabetes as well as in Alzheimer's disease (AD) patients, these data may provide a mechanistic link between insulin resistance, impaired synaptic transmission and cognitive decline in humans with metabolic disorders.


The significant role of the Golgi apparatus in cardiovascular diseases.
The Golgi apparatus (GA) is a ribbon-like system of stacks which consist of multiple closely apposed flattened cisternae and vesicles usually localized in the juxta-nuclear area. As for the biological functions, the GA plays a major role in protein biosynthesis, post-translational modification, and sorting protein from ER to plasma membrane and other destinations. Structural changes and functional disorder of the GA is associated with various diseases. Moreover, increasing evidence revealed that swelling, poor development, and other morphological alterations of the GA are linked to cardiovascular diseases such as heart failure (HF), arrhythmia, and dilated cardiomyopathy. Furthermore, dysfunction of the GA is also related to cardiovascular diseases since the GA is extremely responsible for transport, glycosylation, biosynthesis, and subcellular distribution of cardiovascular proteins. This review gives a brief overview of the intricate relationship between the GA and cardiovascular diseases. In addition, we provide a further prospective that the GA may provide diagnosis reference for cardiovascular diseases, and changes in the ultrastructure and morphology of the GA such as swelling, poor development, and fragmentation may serve as a reliable index for cardiovascular diseases.


The V3 loop of human immunodeficiency virus type-1 envelope protein is a high-affinity ligand for immunophilins present in human blood.
Human immunodeficiency virus type-1 (HIV-1) infection requires binding of the envelope protein gp120 to host CD4 receptors and the action of the chemokine receptors CXCR4 or CCR5, which define cell tropism. The proline-containing V3 loop of gp120 determines the selection of the chemokine receptor and participates in conformational changes on binding of gp120 to CD4. In this study, we show that macrophage-tropic and T-cell-tropic V3 loop peptides bind specifically to the active site of the immunophilins FK506-binding protein (FKBP12), and cyclophilins A and B. Macrophage-tropic and T-cell-tropic V3 loop peptides inhibited the peptidyl-prolyl cis-trans isomerase (PPIase) activities of the immunophilins. Kd values in the range 0.036-4.1 microM were determined with V3 loop peptides labeled with an environmentally sensitive fluorophore. The observed binding properties of the V3 loop peptides reveal structural motifs of linear water-soluble peptidic substrates for tight interaction with immunophilins. FKBP12, and cyclophilins A and B were found to be present in normal human blood in the ranges 0.8-1.7, 1.4-2.3 and 2.4-3.1 nM, respectively, as demonstrated by PPIase activity measurements and western blot analysis. Cyclophilins A and B levels in serum of HIV-1-infected individuals were increased 3.6-fold and 1.6-fold. Due to the interaction of immunophilins with V3 loop peptides and with the envelope protein gp120, a role of immunophilins in HIV pathogenesis as conformases or docking mediators seems possible, since immunophilin receptors on cell membranes and immunophilin-related virulence factors of pathogens have been identified.


Post-synthetic modification of tryptophan containing peptides via NIS mediation.
A new efficient method was developed to provide modified tryptophan peptides through NIS (N-iodosuccinimide) mediated N2-selective coupling of a Trp unit with 1,2,3-triazoles, of which, the preliminary spectral properties were also studied.


EXAFS as a tool to interrogate the size and shape of mono and bimetallic catalyst nanoparticles.
The influence of atom packing and the geometric arrangement of atoms on the coordination number(s) and resultant simulated EXAFS spectra for face centrered cubic (fcc), hexagonal close packed (hcp) and body centered cubic (bcc) monometallic structures and fcc bimetallic structures, has been examined for metal clusters with an isotropic diameter up to 3 nm. We observe clear differences as a function of size and shape for all types of packing; in particular the surface aspect ratios (surface-to-bulk) of the shapes strongly influences the 'growth curves' as a function of the number of atoms for all packing types examined. Discrimination between the different types of structure based on the coordination shell occupancy appears possible, although is dependent on the type of packing. For fcc and hcp packing, structures comprising less than 200 atoms, and particularly less than 100 atoms, exhibit strong variation in the first shell coordination number as a function of shape. For bcc structures this dependency of the coordination shell number for small clusters is much less pronounced and in some cases (for higher shell (>N4) coordination numbers) an opposite trend is observed in that the difference in coordination number as a function of shape becomes more marked with an increasing number of atoms. For the fcc bimetallic systems, model structures possessing distinct bimetal distributions, including both non-random and random alloy types, were simulated and examined. Clear variations in both the 1st shell coordination number and in the simulated spectra were observed as a function of the bimetal structure. A dual edge analysis of the data and subsequent examination of the coordination shell numbers as a function of the bimetal distribution enables for the size, composition and distribution of the each species, to be determined.


Artemisia sieberi Besser essential oil and treatment of fungal infections.
A. sieberi essential oil has been used for treatment of hardly curable infectious ulcers in Middle East Medicine and has been famous due to its wormicide effects. In this review, we evaluated the potency of A. sieberi essential oil in treatment of fungal infections. We searched in PubMed Central, Science direct, Wiley, Springer, SID, and accessible books, reports, thesis. There is a lot of mixed information on chemical compositions of A. sieberi essential oil, but most articles reported α, β-thujones as the main components of essential oils. In vitro studies confirmed the antifungal activity of A. sieberi essential oil against saprophytes fungi, dermatophytes, Malassezia sp. and Candida sp. and these results were confirmed in six clinical studies. The clinical studies confirmed the superiority of A. sieberi essential oil (5%) lotion in improvement of clinical signs of fungal superficial diseases, and mycological laboratory examinations of dermatophytosis and pityriasis versicolor diseases than clotrimazole (1%) topical treatment. The recurrence rate of superficial fungal infections with dermatophytosis and pityriasis versicolor was statistically lower in A. sieberi essential oil (5%) lotion than clotrimazole. There are no adverse effects due to the application of A. sieberi essential oil in clinical studies. Despite, the efficacy of A. sieberi essential oil against Candida sp., there is no clinical study about their related infections. Investigation about the effects of A. sieberi essential oil on fungal virulence factors in order to identifying the exact mechanism of antifungal activity and clinical trials on Candida related diseases are recommended.


A comparative analysis on the binding characteristics of various mammalian albumins towards a multitherapeutic agent, pinostrobin.
The interaction of pinostrobin (PS), a multitherapeutic agent with serum albumins of various mammalian species namely, goat, bovine, human, porcine, rabbit, sheep and dog was investigated using fluorescence quench titration and competitive drug displacement experiments. Analysis of the intrinsic fluorescence quenching data revealed values of the association constant, K(a) in the range of 1.49 - 6.12 × 10(4) M(-1), with 1:1 binding stoichiometry. Based on the PS-albumin binding characteristics, these albumins were grouped into two classes. Ligand displacement studies using warfarin as the site I marker ligand correlated well with the binding data. Albumins from goat and bovine were found to be closely similar to human albumin on the basis of PS binding characteristics.


Near field plasmonic gradient effects on high vacuum tip-enhanced Raman spectroscopy.
Near field gradient effects in high vacuum tip-enhanced Raman spectroscopy (HV-TERS) are a recent developing ultra-sensitive optical and spectral analysis technology on the nanoscale, based on the plasmons and plasmonic gradient enhancement in the near field and under high vacuum. HV-TERS can not only be used to detect ultra-sensitive Raman spectra enhanced by surface plasmon, but also to detect clear molecular IR-active modes enhanced by strongly plasmonic gradient. Furthermore, the molecular overtone modes and combinational modes can also be experimentally measured, where the Fermi resonance and Darling-Dennison resonance were successfully observed in HV-TERS. Theoretical calculations using electromagnetic field theory firmly supported experimental observation. The intensity ratio of the plasmon gradient term over the linear plasmon term can reach values greater than 1. Theoretical calculations also revealed that with the increase in gap distance between tip and substrate, the decrease in the plasmon gradient was more significant than the decrease in plasmon intensity, which is the reason that the gradient Raman can be only observed in the near field. Recent experimental results of near field gradient effects on HV-TERS were summarized, following the section of the theoretical analysis.


Water-Based Additive-Free Chromic Inks for Printing of Flexible Photochromics and Electrochromics.
Digital inkjet printing has become one of the most convenient and efficient technologies for coating chromic materials on flexible substrates with complicated patterns. However, the development of water-based, additive-free chromic inks for inkjet printing still remains a challenge. Herein, three ammonium-functionalized colorless viologen derivatives AV, APV, and AQV with excellent water solubilities are utilized as chromes in the chromic inks due to their excellent photochromic and electrochromic properties. Water, ethanol, and ethylene glycol are selected as cosolvents, and their contents in this ternary solvent system have been optimized to achieve comprehensive rheological properties. With the H2O:EtOH:EG weight ratio of 8:1:7, the chromic ink based on AV realizes a viscosity of 4.69 mPa·s, a surface tension of 45.13 mN/m, and a Z value of 3.87. Without adding any additive, the as-prepared chromic inks can be printed on flexible substrates, such as paper and poly(ethylene terephthalate) (PET) films, by a conventional inkjet printer with inherent high resolutions. The printed patterns are initially invisible due to the colorless characteristics of the chromic inks. Interestingly, the printed films are responsive to both light and electric stimuli. Upon irradiation by UV light, a series of sentences with font sizes from 5 to 12 points and four quick response codes with different lattice resolutions clearly appear on the printed paper. Meanwhile, after printing on an indium tin oxide-coated PET substrate, electrochromic devices (ECDs) can be facilely fabricated by covering a hydrogel electrolyte on the printed films. Upon application of different potentials, the assembled ECDs exhibit "Peking Opera facial makeup" patterns with different colors. Therefore, the developed water-based additive-free chromic inks can be utilized for information display and encryption applications.


ANXA1 as a Prognostic and Immune Microenvironmental Marker for Gliomas Based on Transcriptomic Analysis and Experimental Validation.
The tumor microenvironment (TME) plays an important role in the growth and invasion of glioma. This study aimed to analyze the composition of the immune microenvironment in glioma samples and analyze the important differentially expressed genes to identify novel immune-targeted therapy for glioma. We downloaded transcriptomic data of 669 glioma samples from The Cancer Genome Atlas database. CIBERSORT and ESTIMATE methods were used to calculate the proportion of tumor-infiltrating immune cells and ratio of immune and stromal components in the TME. The differentially expressed genes (DEGs) were screened by comparing the genes expressed by both stromal and immune cells. Annexin A1 (ANXA1) was determined to be an important prognostic indicator through the common overlap of univariate Cox regression analysis and protein-protein interaction network analysis. The proportion of tumor-infiltrating immune cells, calculated by CIBERSORT algorithm, had a significant difference in distribution among the high and low ANXA1 expression groups, indicating that ANXA1 could be an important immune marker of TME. Furthermore, ANXA1 level was positively correlated with the histopathological factors and negatively related to the survival of glioma patients based on the analysis of multiple databases. Finally, in vitro experiments verified that antagonizing ANXA1 expression promoted cell apoptosis and inhibited the invasion and migration capacities of glioma cells. Therefore, ANXA1 due to its immune-related functions, can be an important prognostic indicator and immune microenvironmental marker for gliomas. Further studies are warranted to confirm ANXA1 as a potential immunotherapeutic target for gliomas.


A quantitative trait locus for variation in dopamine metabolism mapped in a primate model using reference sequences from related species.
Non-human primates (NHP) provide crucial research models. Their strong similarities to humans make them particularly valuable for understanding complex behavioral traits and brain structure and function. We report here the genetic mapping of an NHP nervous system biologic trait, the cerebrospinal fluid (CSF) concentration of the dopamine metabolite homovanillic acid (HVA), in an extended inbred vervet monkey (Chlorocebus aethiops sabaeus) pedigree. CSF HVA is an index of CNS dopamine activity, which is hypothesized to contribute substantially to behavioral variations in NHP and humans. For quantitative trait locus (QTL) mapping, we carried out a two-stage procedure. We first scanned the genome using a first-generation genetic map of short tandem repeat markers. Subsequently, using >100 SNPs within the most promising region identified by the genome scan, we mapped a QTL for CSF HVA at a genome-wide level of significance (peak logarithm of odds score >4) to a narrow well delineated interval (<10 Mb). The SNP discovery exploited conserved segments between human and rhesus macaque reference genome sequences. Our findings demonstrate the potential of using existing primate reference genome sequences for designing high-resolution genetic analyses applicable across a wide range of NHP species, including the many for which full genome sequences are not yet available. Leveraging genomic information from sequenced to nonsequenced species should enable the utilization of the full range of NHP diversity in behavior and disease susceptibility to determine the genetic basis of specific biological and behavioral traits.


Three urocortins in medaka: identification and spatial expression in the central nervous system.
The urocortin (UCN) group of neuropeptides includes urocortin 1/sauvagine/urotensin 1 (UTS1), urocortin 2 (UCN2) and urocortin 3 (UCN3). In recent years, evidence has accumulated showing that UCNs play pivotal roles in mediating stress response and anxiety in mammals. Evidence has also emerged regarding the evolutionary conservation of UCNs in vertebrates, but very little information is available about UCNs in non-mammalian vertebrates. Indeed, at present, there are no reports of the empirical identification of ucn2 in non-mammalian vertebrates or of the distribution of ucn2 and ucn3 expression in the adult central nervous system (CNS) of these animals. To gain insight into the evolutionary nature of UCNs in vertebrates, we cloned uts1, ucn2 and ucn3 in a teleost fish, medaka and examined the spatial expression of these genes in the adult brain and spinal cord. Although all known UCN2 genes except those in rodents have been reported to likely lack the necessary structural features to produce a functional pre-pro-protein, all three UCN genes in medaka, including ucn2, displayed all of these features, suggesting their functionality. The three UCN genes exhibited distinct spatial expression patterns in the medaka brain: uts1 was primarily expressed in broad regions of the dorsal telencephalon, ucn2 was expressed in restricted regions of the thalamus and brainstem and ucn3 was expressed in discrete nuclei throughout many regions of the brain. We also found that these genes were all expressed throughout the medaka spinal cord, each with a distinct spatial pattern. Given that many of these regions have been implicated in stress responses and anxiety, the three UCNs may serve distinct physiological roles in the medaka CNS, including those involved in stress and anxiety, as shown in the mammalian CNS.


Prevertebral space invasion in head and neck cancer: negative predictive value of imaging techniques.
This study evaluated the diagnostic value of magnetic resonance imaging (MRI) and computed tomography (CT) in prevertebral space invasion in patients with head and neck squamous cell carcinomas (HNSCC). This study retrospectively reviewed 197 patients with advanced primary laryngeal or hypopharyngeal carcinoma who underwent laryngectomy and neck dissection at our institution. The MRI and CT findings were compared with the surgical findings and postoperative pathology. In 191 patients, the macro- and microscopic margins of the surgical specimens were tumor-free. In the remaining 6 patients, prevertebral space involvement was observed intraoperatively. MRI predicted the absence of prevertebral fascia invasion in 40 of 42 patients with a negative predictive value of 100% and specificity of 95.2%, while the negative predictive value and specificity of CT were 99.2% and 88.2%, respectively. Preservation of the retropharyngeal fat plane on MRI reliably predicts the absence of prevertebral space fixation in patients with advanced HNSCC.


Size of variables in mandibular movements in autopsy material.
Autopsy was performed on the right temporomandibular joint in eleven individuals with a mean age of 71 years. Standard positions indicative for protrusion, laterotrusive border movement and posterior opening movement were photographed in the sagittal plane. Size of movements of the disc and condylar head were recorded, as well as movements of a reference point in the mental region. The slope of the anterior discal movement was estimated and mandibular rotation during posterior opening was registered. Centre of rotation during the hinge movement was in all cases located to the craniodorsal part of the condylar head. Attempt to construct centres of rotation in the eminence and condylar head for the horizontal movements was in vain. The discussion deals with the influence of the specific kind of material on the results and the possible systematic differences to clinical material.


[Post transfusion purpura--a serious underdiagnosed delayed post-transfusion event].
Post-transfusion purpura (PTP), a delayed post-transfusion event, is underdiagnosed, not only in Poland. Thrombocytopenia results from the destruction of patients' and transfused platelets by platelet specific antibodies (anti-HPA). The incidence of PTP is not estabilished. Analysis of 10 cases with PTP diagnosed in Poland during last 25 years. 9 women and 1 man with normal platelet count who developed thrombocytopenia with diathesis haemorrhagica after transfusion of red cells or/and platelets. Platelet specific antibodies (anti-HPA) were examined by the platelet immunofluorescence test and by the monoclonal immobilization of platelet antibodies (MAIPA) assay; leucocyte antibodies by standard lymophocytotoxicity test (LCT). In all 10 patients the PTP was diagnosed because: 1) thrombocytopenia with diathesis haemorrhagia occured 3-10 days after the transfusion (in 5 cases blood was transfused during the operation), 2) in all the patients anti-HPA were detected (in 9- anti-HPA-1a, in 1 case anti-HPA-3a), 3) a primary HPA alloimmunization was very probable. A recovery of platelets count occured in 6 patients within 8-34 days after corticosteroids and/or IVIG, however, therapeutic effect of them was difficult to assess due to a great probability of spontaneous remission up to 1 month. Four patients died due to their basic disease although the impact of the PTP cannot be excluded. The diagnosis of PTP was possible because of the detection of anti-HPA antibodies in patients who developed thrombocytopoenia after blood transfusion.


Current diagnosis of histoplasmosis.
Histoplasmosis is a common infection endemic in many regions of America, Asia, India and Africa, with sporadic cases also occurring throughout the world. Although excellent laboratory methods for diagnosis are available, there are deficiencies that must be met by continued research. Clinicians and laboratory directors must be familiar with the uses and limitations of a battery of serologic and mycological tests to accurately diagnose histoplasmosis. Research is needed to reduce false-negative and false-positive results, and to improve the identification of the organism in tissues. Approaches to the diagnosis of histoplasmosis and areas that require further research will be reviewed.


Microglial autophagy in cerebrovascular diseases.
Microglia are considered core regulators for monitoring homeostasis in the brain and primary responders to central nervous system (CNS) injuries. Autophagy affects the innate immune functions of microglia. Recently some evidence suggests that microglial autophagy is closely associated with brain function in both ischemic stroke and hemorrhagic stroke. Herein, we will discuss the interaction between autophagy and other biological processes in microglia under physiological and pathological conditions and highlight the interaction between microglial metabolism and autophagy. In the end, we focus on the effect of microglial autophagy in cerebrovascular diseases.


Localization of myosin filaments in smooth muscle.
Thick myosin filaments, in addition to actin filaments, were found in sections of glycerinated chicken gizzard smooth muscle when fixed at a pH below 6.6. The thick filaments were often grouped into bundles and run in the longitudinal axis of the smooth muscle cell. Each thick filament was surrounded by a number of thin filaments, giving the filament arrangement a rosette appearance in cross-section. The exact ratio of thick filaments to thin filaments could not be determined since most arrays were not so regular as those commonly found in striated muscle. Some rosettes had seven or eight thin filaments surrounding a single thick filament. Homogenates of smooth muscle of chicken gizzard also showed both thick and thin filaments when the isolation was carried out at a pH below 6.6, but only thin filaments were found at pH 7.4. No Z or M lines were observed in chicken gizzard muscle containing both thick and thin filaments. The lack of these organizing structures may allow smooth muscle myosin to disaggregate readily at pH 7.4.


Selective application of neuroendocrine markers in the diagnosis and treatment of small cell lung cancer.
Here, we explored the potential application and selection of neuroendocrine biomarkers in the diagnosis and treatment of small cell lung cancer. We retrospectively analyzed 118 patients with small cell lung cancer (SCLC), 166 patients with non-small cell lung cancer (NSCLC), 33 patients with benign lung disease (BLD), and 200 healthy individuals admitted to Zhejiang Provincial People's Hospital between January 1, 2015 and May 31, 2019. All the patients were newly diagnosed with either SCLC, NSCLC, or BLD and previously untreated. Peripheral blood levels of ProGRP, NSE, CEA, and CYFRA21-1 were analyzed during the follow-up treatment, and 2-fold upper limit of reference intervals were defined as effective elevation. We used paired results to analyze the diagnostic efficiency of proGRP and NSE on SCLC. In the 118 SCLC patients, proGRP levels were significantly higher compared with NSE levels. The diagnostic efficiencies of NSE and ProGRP for SCLC were 0.8554 and 0.9053, respectively. The combined diagnostic efficiency (0.9426) was higher relative to NSE, but there was no significant difference compared with proGRP. The effective elevation rate of proGRP was 45.3% higher than that of NSE in the limited stage of SCLC. In the extensive disease of SCLC patients, 70.7% cases had more than 10-fold increase in proGRP value, whereas 56.9% cases had less than 5-fold increase in NSE value. Compared with pre-treatment, the median concentrations of proGRP increased by 204.0% higher than that of NSE (71.3%) in the progressive group. Besides, the dynamic change in imaging characteristics and tumor size had a strong correlation with the levels of proGRP. ProGRP is a reliable neuroendocrine biomarker in SCLC. The effective elevation of proGRP has a potential diagnostic and efficacy value in the evaluation of SCLC. However, the combined detection of proGRP and NSE does not significantly improve the diagnosis of lung cancer.


[Intensive psychiatric treatment system for bulimic patients by group therapy].
Concurrent bulimia nervosa/purging type and anorexia nervosa/binge-purging type including binge eating and purging behaviors are considered chronic types of eating disorders. The bulimic patients in this study had both these disorders. Psychiatric treatment for patients with eating disorders must focus on therapy of these bulimic patients, because bulimic patients are more prevalent in the psychiatric hospital and clinic, and they have more comorbid psychiatric disorders and more other addictive behaviors than other patients with eating disorders. We have devised an intensive psychiatric treatment system for bulimic patients by group therapy that consists of inpatient treatment, group therapy for parents and group rehabilitation. Inpatient treatment, called the Eating Disorders Education Program (EDEP), consists of group psychological education, group cognitive-behavioral therapy, group nutrition education, and group exercise. Group therapy for parents consists of psychological education and group meetings. Group rehabilitation consists of many group activities in a house named "Mimoza". Bulimic patients come to understand their own disorders and symptoms objectively and understand recovery from their disorders by the intensive treatment system. Bulimic patients generally recover very slowly from eating disorders, but our intensive psychiatric treatment system promotes rapid recovery.


[Chromosome studies of personnel exposed to electromagnetic radiation at radar centers].
The possibility that chromosome alterations take place in personnel exposed to electromagnetic radiation in radar centres has been studied. The study was carried out "blind" on short-term cultures of peripheral blood, some 450 metaphases being analysed for each case. No aberrations were found in either radar operators or controls and there was no statistically significant difference between them.


[Construction of a versatile degrading bacteria Pseudomonas putida KT2440-DOP and its degrading characteristics].
Triazophos is a kind of organophosphorous pesticide which was widely used by farmers all over the world in 1990's. It is effective in controlling pesticide but harmful to human beings. Bioremediation is an effective and economic method to treat environment that has been polluted by hazardous organic compounds, so researchers paid much attention in this area. Most of which focused on isolating functional bacteria, studying its degrading mechanism, and cloning degradation-related genes. MP-4 was isolated from soil polluted by Triazophos for a long time and identified as Ochrobactrum sp.. The triazophos hydrolase (tpd) gene was cloned by the method of shotgun cloning, and the sequences were determined and analyzed. In the former tests it was found that there was only 18 base pairs different in tpd gene from mpd gene, which was isolated from methyl parathion degrading strain Pseudomonas putida DLL-1. Enzyme TPD can hydrolyze triazophos and methyl parathion while MPD cannot hydrolyze triazophos. Pseudomonas putida KT2440 is a metabolically versatile saprophytic soil bacterium that has been certified as a biosafety host for the cloning of foreign genes. This bacterium is known for its diverse metabolism and potential for development of biopesticides and plant growth promoters because of its ability to colonize rhizosphere of crop plants. Tpd gene was isolated from the genomic DNA of Ochrobactrum sp. MP-4 by PCR amplification. Recombinant plasmids pTPD was constructed by ligating tpd gene into broad host vector pBBRMCS-5. With the help of plasmid pRK2013, pTPD was transferred into Pseudomonas putida KT2440 to construct KT2440-DOP. KT2440-DOP can degrade many organophosphate pesticides and aromatics compounds. The specific activity of organophosphate hydrolase of KT2440-DOP was approximately 2 times of MP-4. Later, parameters affecting bioremediation of Organophosphate pesticide in soil using KT2440-DOP will be studied.


[Far-advanced otosclerosis].
The aim of this study was to report a series of patients with far-advanced otosclerosis who were unable to benefit from hearing aids. Among patients with profound hearing loss, it is particularly useful to diagnose far-advanced otosclerosis even if relatively rare, because stapes surgery can improve hearing to a level allowing conventional hearing aid use (sometime the only choice before cochlear implant). We retrospectively reviewed the charts of 7 patients (9 operated ears) in order to highlight diagnostic criteria, surgical indications and results of stapes surgery (stapedectomy or stapedotomy). Diagnosis of far-advanced otosclerosis was based on clinical presentation, course of hearing loss, positive family history of otosclerosis, and results of CT scan which was helpful in all the cases. Obliterative otosclerosis was found in 55% of the cases. Success of stapes surgery was observed in 89%, with no significant difference between stapedectomy or stapedotomy. Although rare, far-advanced otosclerosis must be diagnosed because patients can benefit from stapes surgery (and subsequently fitting of appropriate hearing aids).


"The pain isn't as disabling as it used to be": how can the patient experience empowerment instead of vulnerability in the consultation?
This study explores how doctors can help patients transform vulnerability into strength, instead of increasing a feeling of disempowerment. The authors analysed their findings from four previously written articles based on qualitative interviews with 10 women with chronic pain, comparing the reported negative consultation experiences with the beneficial effects of good treatment experiences, in order to identify potentials for change. Altering the way in which the women are encountered may empower and help them deal with a painful life. Doctors can challenge stereotyped macro-structures of women's "unexplained" pain as hysteria by admitting the shortcomings of medical knowledge. The blame is then put on the medical discipline instead of the individual patient who presents bodily symptoms or reveals help-seeking behaviour that does not fit with biomedical expectations of what illness is and how it should be performed. Thus, the vulnerable position described by the patients can be converted or transformed into strength or resources in spaces that promote empowerment through recognition. Although doctors may feel helpless or puzzled in the consultation, they must take the responsibility for turning the consultation into a space for empowerment of the patient.


Structural effects of biologically relevant rhodamines on spectroscopy of fluorescence fluctuations.
Exciton coupling in pi-pi complexes between the indole ring and other pi systems is known to enhance the efficiency of energy and electron transfer. Rhodamines' xanthylium rings allow the formation of weakly or nonfluorescent complexes with the amino acid tryptophan. Thus, because of the short distance of the participating electronic clouds, intrinsic electron transfer-induced fluorescence quenching occurs. In solution, the rate constant of electron transfer is known to be limited by collision interactions at the contact distance. By contrast, in protein local environments tryptophan residues can be either exposed or buried in hydrophobic regions. Herein, I report on the properties of aromatic derivatized rhodamines, among which is one with a bound phenylalanine amino acid group. Encompassed is the spectroscopic and kinetic information in bulk and at the single-molecule levels both in free solution and in the presence of human serum albumin. Spectroscopic characteristics are focused with special emphasis on enhanced fluorescence that is addressed considering optimized geometries and electronic spectra. The importance of the probes associated with peptides and metal ions both in condensed phase or interfaces and as substrates with proteins is put into perspective.


Plasma Free Fatty Acids in Hyperemesis Gravidarum Pregnancy.
We evaluated the free fatty acids differences in plasma between hyperemesis gravidarum(HG) and healthy pregnant in first trimester pregnancy. We aimed to compare the plasma levels of DHA, AA and EPA, between HG patients and healthy pregnant women. Fifty-two pregnants were involved in the study. Twenty-six pregnants of them were HG as study group, and twenty-six pregnants were enrolled as healthy pregnant women at the similar gestational age. The saturated fatty acids C14, C15, C16, C18, C20, C22, and C24; the omega-3 fatty acids eicosapentaenoic acid, (EPA) and docosahexaenoic acid, (DHA); the omega-6 fatty acids linoleic acid, arachidonic acid (AA), and homo-gamma-linolenic acid; and the omega-9 fatty acids oleic acid, erucic acid, and nervonic acid were analysed by gas chromatography. Statistically differences was not seen between the groups with maternal age, gestational age, or plasma levels of EPA, DHA, and AA. Statistically significant difference was seen between the groups with plasma levels of C20 and C22(p<0.05). C20 was declined but C22 was rised in the HG patients. EPA, DHA, or AA, which related to placental and fetal neural development are not changing from Hyperemesis gravidarum.