Chylothorax and Recurrent Laryngeal Nerve Injury Associated With Robotic Video-Assisted Mediastinal Lymph Node Dissection.
Although the technical aspects of robotic video-assisted thoracic surgery (RVATS) for lung resections may be advantageous, compared with standard thoracoscopy, complications of chylothorax and recurrent laryngeal nerve injury (RLNI) associated with mediastinal lymph node dissection (MLND) may be significant. Consecutive patients who underwent RVATS anatomic lung resection for suspected or confirmed cancer and experienced RLNI or chylothorax were identified and reviewed from a prospectively maintained database. Complications were graded according to the Common Terminology Criteria for Adverse Events version 3.0. From July 28, 2010, to December 20, 2013, 251 patients underwent RVATS segmentectomy, lobectomy, or bilobectomy with MLND. Eleven patients (4.4%) experienced MLND-related complications and composed the study group; 81.8% were right-sided resections, and the median lymph node counts in right station IV and station VII were 9 (range, 1-23) and 5.5 (range, 1-10); 72.7% of the cases were performed for early-stage I and II lung cancers. Chylothorax [6/251 (2.4%)] and RLNI [6/251 (2.4%)] were significantly more common in the RVATS group than in the open thoracotomy and standard VATS groups. Complications requiring procedural intervention (Grade 3) are as follows: 4 cases of RLNI in patients undergoing percutaneous vocal cord medialization and 3 cases of chylothorax in patients undergoing image-guided thoracic duct embolization or maceration. No operative interventions were required. RVATS MLND may be associated with increased rates of chylothorax and RLNI. Attention must be paid to identifying potential technical pitfalls with RVATS lung resections, adjusting surgical techniques accordingly, and minimizing patient morbidity.


Functional information from clinically-derived drug resistant forms of the Candida glabrata Pdr1 transcription factor.
Azole drugs are the most frequently used antifungal agents. The pathogenic yeast Candida glabrata acquires resistance to azole drugs via single amino acid substitution mutations eliciting a gain-of-function (GOF) hyperactive phenotype in the Pdr1 transcription factor. These GOF mutants constitutively drive high transcription of target genes such as the ATP-binding cassette transporter-encoding CDR1 locus. Previous characterization of Pdr1 has demonstrated that this factor is negatively controlled by the action of a central regulatory domain (CRD) of ~700 amino acids, in which GOF mutations are often found. Our earlier experiments demonstrated that a Pdr1 derivative in which the CRD was deleted gave rise to a transcriptional regulator that could not be maintained as the sole copy of PDR1 in the cell owing to its toxically high activity. Using a set of GOF PDR1 alleles from azole-resistant clinical isolates, we have analyzed the mechanisms acting to repress Pdr1 transcriptional activity. Our data support the view that Pdr1-dependent transactivation is mediated by a complex network of transcriptional coactivators interacting with the extreme C-terminal part of Pdr1. These coactivators include but are not limited to the Mediator component Med15A. Activity of this C-terminal domain is controlled by the CRD and requires multiple regions across the C-terminus for normal function. We also provide genetic evidence for an element within the transactivation domain that mediates the interaction of Pdr1 with coactivators on one hand while restricting Pdr1 activity on the other hand. These data indicate that GOF mutations in PDR1 block nonidentical negative inputs that would otherwise restrain Pdr1 transcriptional activation. The strong C-terminal transactivation domain of Pdr1 uses multiple different protein regions to recruit coactivators.


Minimum number of 2'-O-(2-aminoethyl) residues required for gene knockout activity by triple helix forming oligonucleotides.
Triple helix forming oligonucleotides (TFOs) that bind chromosomal targets in living cells may become tools for genome manipulation, including gene knockout, conversion, or recombination. However, triplex formation by DNA third strands, particularly those in the pyrimidine motif, requires nonphysiological pH and Mg(2+) concentration, and this limits their development as gene-targeting reagents. Recent advances in oligonucleotide chemistry promise to solve these problems. For this study TFOs containing 2'-O-methoxy (2'-OMe) and 2'-O-(2-aminoethyl) (2'-AE) ribose substitutions in varying proportion have been constructed. The TFOs were linked to psoralen and designed to target and mutagenize a site in the hamster HPRT gene. T(m) analyses showed that triplexes formed by these TFOs were more stable than the underlying duplex, regardless of 2'-OMe/2'-AE ratio. However, TFOs with 2'-AE residues were more stable in physiological pH than those with only 2'-OMe sugars, as a simple function of 2'-AE content. In contrast, gene knockout assays revealed a threshold requirement--TFOs with three or four 2'-AE residues were at least 10-fold more active than the TFO with two 2'-AE residues. The HPRT knockout frequencies with the most active TFOs were 300-400-fold above the background, whereas there was no activity against the APRT gene, a monitor of nonspecific mutagenesis.


Formation of 2-chlorobenzylidenemalononitrile (CS riot control agent) thermal degradation products at elevated temperatures.
2-Chlorobenzylidenemalononitrile (CS riot control agent) has been shown to produce a number of thermal degradation products when dispersed at high temperature. We hypothesized that these CS-derived compounds are formed by energy input from heating during the dispersion process. Here we identified organic CS-derived compounds formed from purified CS subjected to temperatures ranging from 300 to 900 degrees C in an inert atmosphere with analysis of tube furnace effluent by gas chromatography and mass spectrometry. We conclude that the production of many CS-derived compounds previously observed during high-temperature dispersion is likely to be heat related.


Effect of calcium on fatty acid bioaccessibility during in vitro digestion of Cheddar-type cheeses prepared with different milk fat fractions.
Calcium plays an important role in intestinal lipid digestion by increasing the lipolysis rate, but also limits fatty acid bioaccessibility by producing insoluble Ca soaps with long-chain fatty acids at intestinal pH conditions. The aim of this study was to better understand the effect of Ca on the bioaccessibility of milk fat from Cheddar-type cheeses. Three anhydrous milk fats (AMF) with different fatty acid profiles (olein, stearin, or control AMF) were used to prepare Cheddar-type cheeses, which were then enriched or not with Ca using CaCl2 during the salting step. The cheeses were digested in vitro, and their disintegration and lipolysis rates were monitored during the process. At the end of digestion, lipids were extracted under neutral and acidic pH conditions to compare free fatty acids under intestinal conditions in relation to total fatty acids released during the digestion process. The cheeses prepared with the stearin (the AMF with the highest ratio of long-chain fatty acids) were more resistant to disintegration than the other cheeses, owing to the high melting temperature of that AMF. The Ca-enriched cheeses had faster lipolysis rates than the regular Ca cheeses. Chromatographic analysis of the digestion products showed that Ca interacted with long-chain fatty acids, producing Ca soaps, whereas no interaction with shorter fatty acids was detected. Although higher Ca levels resulted in faster lipolysis rates, driven by the depletion of reaction products as Ca soaps, such insoluble compounds are expected to reduce the bioavailability of fatty acids by hindering their absorption. These effects on lipid digestion and absorption are of interest for the design of food matrices for the controlled release of fat-soluble nutrients or bioactive molecules.


Stem-like cancer cells are inducible by increasing genomic instability in cancer cells.
The existence of cancer stem cells (CSCs) or stem-like cancer cells (SLCCs) is regarded as the cause of tumor formation and recurrence. However, the origin of such cells remains controversial with two competing hypotheses: CSCs are either transformed from tissue adult stem cells or dedifferentiated from transformed progenitor cells. Compelling evidence has determined the chromosomal aneuploidy to be one of the hallmarks of cancer cells, indicating genome instability plays an important role in tumorigenesis, for which CSCs are believed to be the initiator. To gain direct evidence that genomic instability is involved in the induction of SLCCs, we utilized multiple approaches to enhance genomic instability and monitored the percentage of SLCC in cultured cancer cells. Using side population (SP) cells as a marker for SLCC in human nasopharyngeal carcinoma (NPC) and CD133 for human neuroblastoma cells, we found that DNA damage inducers, UV and mitomycin C were capable of increasing SP cells in NPC CNE-2 and neuroblastoma SKN-SH cells. Likewise, either overexpression of a key regulator of cell cycle, Mad2, or knock down of Aurora B, an important kinase in mitosis, or Cdh1, a key E3 ligase in cell cycle, resulted in a significant increase of SP cells in CNE-2. More interestingly, enrichment of SP cells was observed in recurrent tumor tissues as compared with the primary tumor in the same NPC patients. Our study thus suggested that, beside transformation of tissue stem cells leading to CSC generation, genomic instability could be another potential mechanism resulting in SLCC formation, especially at tumor recurrence stage.


Megatrends in hospital information systems.
The "megatrends" identified for hospital information system in this article require an innovative shift in hospital management perspective. Hospital chief executive officers and decision-makers must adopt a new model for planning and utilizing hospital information systems resources. Because of changes in the healthcare environment, prospective payment strategies for using information are very different from former retrospective reimbursement methods. The purpose of this article has been to identify emerging "megatrends" for structuring future hospital information systems. The primary causes of these significantly different demands is the prospective payment system. Medicare DRGs will probably expand into an all-encompassing payment plan which will alter the essence of hospital information systems. This article has reviewed the challenges of these "megatrends," and provided some preliminary management strategies for addressing these new demands on healthcare professionals.


[Normal gamma globulin levels in liver cirrhosis: a prognostic indicator and improved survival].
Serum levels of gammaglobulins were evaluated in a population of 1334 patients with liver cirrhosis (mean age +/- SD 54.8 +/- 10.9; 898 males). Hypergammaglobulinemia was not as frequently observed as described in the literature 278 patients (20.8%) had gammaglobulin levels lower than 1.5 g/dl (first group) and the other 1056 had more than 1.5 g/dl of gammaglobulins (second group). At analysis of survival curves the first group had a median survival time of over 60 months, significantly higher than the 37.6 months of the other patients, when compared with the Lee-Desu statistic (p less than 0.01). Moreover, the patients of the first group had a lower incidence of ascites as compared to the second group (28% versus 45%; p less than 0.001), hepatic encephalopathy (7% versus 14%; p less than 0.01) and hepatocellular carcinoma (5.7% versus 8.4%; n.s.). The presence and the degree of oesophageal varices were significantly lower in the patients of the first group than in the others (p less than 0.001); a number of laboratory tests for the evaluation of liver cell function and the Child class distribution were more favourable in the first group than in that of hypergammaglobulinemic patients. normal blood gamma globulin level is not uncommon in liver cirrhosis and it may be considered a positive prognostic factor, which identifies a group of patients with a better quality of life, a lower incidence of decompensation symptoms and a longer survival time.


Rutin treats myocardial damage caused by pirarubicin via regulating miR-22-5p-regulated RAP1/ERK signaling pathway.
Our experiments have previously demonstrated that rutin (RUT) can improve myocardial damage caused by pirarubicin (THP). However, the underlying molecular mechanisms remain uncertain. In this study, we developed an microRNA (miRNA) chip by replicating the rat model of THP-induced myocardial injury and identified miR-22-5p and the RAP1-member of RAS oncogene family/extracellular regulated protein kinases (RAP1/ERK) signaling pathway as an object of study. Also, in vivo experiments demonstrated that THP caused abnormal changes in the electrocardiogram, cardiac function, and histomorphology in rats (P < .01). THP also reduces the expression of miR-22-5p (P < .01) and increases the levels of RAP1/ERK signaling pathway-related proteins (P < .01, P < .05). RUT significantly improved THP-induced myocardial damage (P < .01), increased the expression of miR-22-5p (P < .01), and decreased the levels of RAP1/ERK signaling pathway-related proteins (P < .01, P < .05). In vitro studies confirmed that Rap1a is one of the target genes of miR-22-5p. miR-22-5p overexpression in cardiomyocytes can affect the RAP1/ERK pathway and reduce reactive oxygen species production and cardiomyocyte apoptosis caused by THP (P < .01), which is consistent with the effect of RUT. Our results indicate that RUT treats THP-induced myocardial damage, which may be achieved by upregulating miR-22-5p, causing changes in its target gene Rap1a and the RAP1/ERK pathway.


[Mixed dementia: a neuropathologic point od view].
Alzheimer's disease (AD) and vascular dementia (VaD) are the most frequent causes of dementia in the elderly. Although AD can be diagnosed with a very high degree of accuracy, the distinction between pure AD, VaD and mixed dementia (MD), where both pathologies co-exist in the same patient, remains a controversial issue and one of the most difficult diagnostic challenges. MD represents a very frequent pathology, especially in the elderly, as underlined by the neuropathological studies. However, the respective importance of degenerative and vascular lesions, their interaction in the genesis of dementia and the mere existence of mixed dementia are still debated. Accurate diagnosis of MD is of crucial significance for epidemiologic purposes and for preventive and therapeutic strategies. Until recently, pharmacological studies have generally focused on pure diseases, either AD or VaD, and have provided little data on the best therapeutic approach to MD. This review will provide an overview of neuropathological aspects of MD in the elderly, which appears to be one of the most common forms of dementia.


Effect of concomitant use of benzodiazepines and other drugs on the risk of injury in a veterans population.
Benzodiazepines comprise a class of drugs that when used as monotherapy are generally acknowledged to pose a risk for injury by increasing the likelihood of falls, fall-related injuries, adverse drug events and car accidents. Benzodiazepines may also be used concomitantly with other high risk medications that may further exacerbate the risk of injury. The aim of this study is to examine the occurrence of the concomitant use of benzodiazepines and other drugs and then quantify the indirect effect of these drug combinations on the likelihood of an injury-related health care episode. A multivariate model was specified that included outpatient prescription data and inpatient/outpatient medical utilisation records for 13,745 patients at a Veterans Administration hospital system over a 3-year period (1999-2001). We analysed 1,33,872 outpatient benzodiazepine prescriptions and >1.5 million non-benzodiazepine prescriptions for the study population. Micromedex software was used to identify combinations of benzodiazepines and other drugs that are likely to result in 'major' interactions. We then further restricted our focus to the use of these drug combinations within a 30-day period prior to an injury-related medical event. The adjusted odds ratio on a variable characterising concomitant use of a benzodiazepine and another drug within this period was used to quantify the relative risk of injury. The principal outcome was the estimated risk of an injury-related health care episode within a 30-day period when taking both a benzodiazepine and another drug with a 'major' severity rating as defined by Micromedex. The risk of injury was adjusted for comorbidities, hospital discharges, marital status, age, mean arterial pressure and body mass index, as well as the dose of benzodiazepine (converted to diazepam equivalents) and duration of benzodiazepine treatment. Of the 1,110 unique individuals who experienced an injury, 790 (71.2%) patients had used a benzodiazepine in combination with another drug. Furthermore, only 4.3% (320/7522) of the patients taking benzodiazepines who did not have concomitant drug use experienced an injury. The occurrence of this concomitant use increased the odds of an injury >2-fold in the model. Dose and duration of benzodiazepine use, as well as certain comorbidities, were also associated with an increased risk for injury, whereas being married reduced the risk. This is the first large-scale study to quantify the impact of concomitant use of benzodiazepines and other drugs on the risk of injury in a population of Veterans Administration patients. It demonstrates the utility of expanding the focus of inappropriate medication usage to include analyses that link potentially inappropriate drug use with health care utilisation for injuries.


Proximal tibial epiphysiodesis to reduce tibial plateau slope in young dogs with cranial cruciate ligament deficient stifle.
The purpose of this study was to evaluate the ability of proximal tibial epiphysiodesis to reduce the tibial plateau slope in young dogs with cranial cruciate ligament (CCL) deficient stifles. Of the 14 treated dogs, eight had a bilateral injury, for a total of 22 joints. After physical and radiographical examination and measurement of tibial plateau slope, all of the dogs underwent surgery. Insertion of the screw was placed in the most proximal part of the tibial plateau, in its medio-lateral centre, aiming to the tibial shaft and using a K wire predriven as a guide; correct position of the screw was confirmed with intraoperative fluoroscopy or radiography. In all of the dogs the tibial slope was decreased at the time of physis fusion and the degree of change depended on the age and the breed of the dog at the time of surgery. The minimum change was 4 degrees and the maximum was 24 degrees. There was a statistically significant difference between tibial slope measured before surgery compared to tibial slope measured at the last follow-up visit after surgery. This study shows that the partial proximal tibial fusion in dogs with ACL injuries was effective in reducing the tibial slope during the residual growing time to such an extent to stabilize the joint, provided that the surgery had been carried out when there was still residual growing potential. The technique appeared to be mini-invasive and malalignment complications could be avoided by correct and precise insertion of the screw.


Positive surgical margins in cancer of the larynx.
In order to determine what should be done for laryngeal cancer patients when surgical margins are positive, and to evaluate their prognosis, a retrospective review of 21 laryngeal cancer patients with positive surgical margins out of 714 surgically treated cases (2.9%) was carried out. Nineteen patients were treated with postoperative radiation therapy. Two patients who had had endolaryngeal partial laryngectomy were treated with vertical partial laryngectomy. Two patients were lost to follow-up. Ten patients (10/19; 53%) were recurrence-free. Four patients had local, two had regional, and two had locoregional recurrences. Only one patient with a local recurrence could be salvaged with total laryngectomy and is disease-free. One patient developed liver metastasis. Nineteen patients had a mean and median disease-free survival of 48 and 36 months, respectively. Nine out of fourteen patients (64%) treated curatively were recurrence-free. The patients with positive margins developed significantly more locoregional recurrences than those with free margins (P < 0.05). We conclude that surgical margins must be checked peroperatively with frozen sections to make sure that they are free. The margins of every laryngectomy specimen must be diligently examined. If positive, re-excision, postoperative radiotherapy and chemotherapy are treatment alternatives. They should not just be managed with close follow-up. However, whatever treatment is applied, the prognosis for patients with positive margins is significantly worse than for those with free margins.


[Corticosteroid therapy for nephrotic syndrome].
Although the cause of primary nephrotic syndrome remains unclear, the progress of basic science has indicated that immune T cell disorders lead to glomerular dysfunctions. Patients with primary nephrotic syndrome and some of secondary nephrotic syndrome are, thereby, initially treated with high dose of corticosteroids. Steroid responsiveness is an important prognostic indicator of the disease, and in steroid-resistant patients, immunosuppressive agents and the methylprednisolone pulse therapy are recommended. Although a treatment based on corticosteroids has brought about clinical benefits, several adverse effects, including various opportunistic infections, osteoporosis/bone fracture, aseptic necrosis of femoral head, and so on, are frequent and sometimes severe and suitable preventions and urgent treatments are prerequisite in such patients.


Early life stress enhances angiotensin II-mediated vasoconstriction by reduced endothelial nitric oxide buffering capacity.
We reported previously that maternal separation (MS) sensitizes adult rats to angiotensin II (Ang II)-induced hypertension. The aim of this study was to investigate the vascular reactivity to Ang II and the role of renin-angiotensin system components, reactive oxygen species production, and NO synthase (NOS) buffering capacity mediating the exacerbated Ang II-induced responses. MS rats were separated from their mothers for 3 h/d from days 2 to 14 of life. Controls were nonhandled littermates. At 12 weeks of age, aortic Ang II-induced constriction was greater from MS rats compared with controls (P<0.05); moreover, endothelial denudation abolished this difference. The response to other constrictors was unchanged. Angiotensin type 2 receptor function was reduced in aortic Ang II-induced constriction from MS rats compared with controls. Angiotensin type 1 receptor function was similarly abolished in both groups. However, protein expressions of angiotensin type 1 and angiotensin type 2 receptors were similar in aortic rings from MS and control rats. Preincubation with superoxide inhibitor or scavenger attenuated the Ang II-induced vasoconstriction in control but not in MS rats. However, acute preincubation with an NOS inhibitor enhanced aortic Ang II-induced constriction in aorta from control rats, but this effect was significantly reduced in MS rats compared with control rats. Accordingly, a further increase in Ang II-induced hypertension attributed to chronic NOS inhibition (days 10 to 13) was blunted in MS rats compared with control rats. Similar NOS expression and activity were observed in control and MS rats. In conclusion, MS induces a phenotype with reduced endothelial NOS buffering capacity leading to dysfunctional endothelial Ang II-mediated signaling and sensitization to Ang II-induced vasoconstriction.


[Treatment of sensorineural hearing loss with delayed onset of vertigo (report of 13 cases)].
Sensorineural hearing loss with delayed onset of vertigo (SHL-DV) is a syndrome consisting of preexisting SHL and subsequent episodes of vertigo. The possible underlying pathophysiology is delayed endolymphatic hydrops. This paper details our clinical experience with 8 patients with SHL-DV caused by otitis media and 6 patients following sudden deafness and hearing loss due to an unknown cause. The average period of onset of vertigo after the occurance of the hearing loss was 22.6 years. The average period of vertigo was 6.2 years. Surgical treatment was performed in 13 patients (14 ears) because of disabling vertigo. Endolymphatic sac decompression was performed in 2 ears, transmastoid labyrinthectomy in 3 ears, gentamycin perfusion of the tympanic cleft in 3 ears, streptomycin perfusion of the labyrinth in 6 ears. Follow-up for 13 patients who had surgery averaged 2.3 years, all patients were cured of their episodic vertigo. Three patients underwent surgical labyrinthectomy suffering with total hearing loss, but aminoglycoside antibiotics induced labyrinthectomy preserving some hearing. We conclude that chemical labyrinthectomy is the therapy of choice for the severe SHL-DV who has serviceable hearing.


Dynamic linkages between climatic variables and agriculture production in Malaysia: a generalized method of moments approach.
Climate change continues to pose a threat to the agricultural sectors worldwide, jeopardizing food and nutritional security, which is a critical component of the sustainable development agenda. Consequently, this study attempts to examine the impact of climatic variables (CO2 emissions, energy resources, rainfall, temperature, fossil fuel consumption, and humidity) on agricultural production of rice, cereals, vegetables, coffee, and agriculture value added (as a percentage of GDP) in the Malaysian context. To this end, this study applied a generalized method of moments (GMM) estimator on the data obtained from the metrological station Malaysia, Department of Statistics Malaysia and World Development Indicators (WDI) spanning the period 1985-2016. The results revealed that temperature and energy consumption negatively and significantly affect rice and vegetable production, while the negative effect of rainfall, temperature, fossil fuel consumption, and humidity on cereal production is insignificant. The results also confirmed that CO2 emissions have a negative and significant impact on coffee production. Likewise, temperature, energy consumption, and fossil fuel consumption exhibit a negative and significant influence on agriculture value added. These observations evidenced the adverse effect of climate change on various agricultural products in Malaysia. Therefore, in order to ensure robust and sustainable agricultural output in Malaysia, policymakers as well as environmentalists should work together to formulate appropriate adaptation strategies.


Fabrication of Polysulfobetaine Gradient Coating via Oxidation Polymerization of Pyrogallol To Modulate Biointerfaces.
A surface with a gradient physical or chemical feature, such as roughness, hardness, wettability, and chemistry, serves as a powerful platform for high-throughput investigation of cell responses to a biointerface. In this work, we developed a continuous antifouling gradient surface using pyrogallol (PG) chemistry. A copolymer of a zwitterionic monomer, sulfobetaine methacrylate, and an amino monomer, aminoethyl methacrylate, were synthesized (pSBAE) and deposited on glass slides via the deposition of self-polymerized PG. A gradient of pSBAE was fabricated on glass slides in 7 min in the presence of an oxidant, ammonium persulfate, by withdrawing the reaction solution. The modified glass slide showed a wettability gradient, determined by measuring the water contact angle. Cell adhesion and protein adsorption were well correlated with surface wettability. We expect that this simple and faster method for the fabrication of a continuous chemical gradient is applicable for high-throughput screening of surface properties to modulate biointerfaces.


[Comparison of duplex systems and simple Doppler equipment in obstetric diagnosis].
Duplex systems are normally used in obstretric Doppler sonography. The fact that these systems are technically complex and very costly to some extent contradicts the use of Doppler sonography as a screening method. This study examines whether simplex Doppler systems without tomographic imaging and not involving costly technology, such as frequency analysis, are as suitable for Doppler examination in pregnancy as the costly duplex systems. Examinations of 83 patients between GW 32 and 42 showed that both the umbilical and uterine arteries can be reliably identified using the simplex Doppler unit. A comparison of Doppler curves obtained with duplex and simplex Doppler systems showed that the two devices produced the same results. The Doppler curves were compared both as regards their geometry, according to the score described by Fendel et al. (1988), as well as on the basis of calculated parameters. The scores were correlated to delivery mode and birth weight. However, the fetal aorta cannot be reliably located with the simplex Doppler unit unless it has been tomographically imaged beforehand. Doppler examination of the umbilical and uterine arteries provides the best information for selection of high-risk pregnancies. It therefore appears sufficient to screen patients with the simplex Doppler described here and to perform more detailed diagnostic investigations with a duplex systems in the event of pathologic findings.


Can serial scintigraphic studies detect delayed fracture union in man?
The uptake of the bone-seeking tracer technetium-99m-methylenediphosphonate increases following bone fracture as bone healing occurs. To investigate the pattern of change in normal healing and compare it with delayed union and nonunion, an analysis of automated computer profiles was carried out on serial scan data for 22 patients. The type of fracture (simple, comminuted, etc.) influenced the appearance of the activity profile; however, no significant differences in the patterns of change were noted between normal healing and delayed or non-union.


The Obstetric Regulations 1986, 21 April 1986.
These New Zealand Regulations revoke and replace the Obstetric Regulations 1975. They include provisions on the staffing of maternity hospitals (Reg. 3); the use of facilities in maternity hospitals (Reg. 4); the obligations on the part of medical practitioners to notify septic conditions, etc. (Reg. 6); the keeping of clinical records with respect to maternity patients (Reg. 9); and the maintenance, availability, and retention of registers and clinical records (Reg. 10).


Predictive factors for recurrence of simple bone cyst of the proximal humerus.
To evaluate factors predictive of recurrence following curettage of simple bone cysts (SBCs) in the proximal humerus. Records of 29 male and 3 female patients aged 3 to 22 (mean, 11) years who underwent curettage with or without bone grafting for a solitary SBC in the proximal humerus were reviewed. The appearance, size, location, activity level, and fracture pattern of each cyst were recorded. The cyst index indicated the risk of refracture. Recurrence was defined as a refracture or enlargement of the cyst. 31 patients presented with a pathological fracture. The main symptoms were pain (n=30), loss of function (n=22), and mass/swelling (n=15). 25 patients gave a history of trauma. The duration of symptoms was less than one month. 10 patients had recurrence after a mean of 10 (range, 4-27) months; 5 were refractures and another 5 were enlargement of the cysts. Six were treated conservatively and eventually healed, whereas 4 underwent further curettage. Factors predictive of recurrence were patient age 5 years or younger (p=0.014), right-sided cyst (p=0.01), larger cyst (p=0.039), multilocular cyst (p=0.004) and unimpacted fracture (p=0.04). Recurrence was not related to gender, cyst location, or cyst activity level. Most SBCs heal even if the fracture is treated expectantly. SBCs should be left alone unless symptomatic. If curettage is performed, grafts or bone substitutes should be used. More aggressive treatment might be necessary for unimpacted fractures to minimise the risk of recurrence.


Genetics and function of neocortical GABAergic interneurons in neurodevelopmental disorders.
A dysfunction of cortical and limbic GABAergic circuits has been postulated to contribute to multiple neurodevelopmental disorders in humans, including schizophrenia, autism, and epilepsy. In the current paper, I summarize the characteristics that underlie the great diversity of cortical GABAergic interneurons and explore how the multiple roles of these cells in developing and mature circuits might contribute to the aforementioned disorders. Furthermore, I review the tightly controlled genetic cascades that determine the fate of cortical interneurons and summarize how the dysfunction of genes important for the generation, specification, maturation, and function of cortical interneurons might contribute to these disorders.


Days gained response discriminates treatment response in patients with recurrent glioblastoma receiving bevacizumab-based therapies.
Accurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze days gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies. DG response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N = 62). Kaplan-Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM. In patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan-Meier analysis showed significant differences in OS and PFS at DG cutoffs consistent with previously identified values from newly diagnosed GBM using T1-weighted gadolinium-enhanced magnetic resonance imaging (T1Gd). DG scores for bevacizumab monotherapy patients only approached significance for PFS. Cox regression showed that increases of 25 DG on T1Gd imaging were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy patients. DG has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.


Isolating human antibody against human hepatocellular carcinoma by guided-selection.
With the pComb3X-displaying Fab antibody libraries, to achieve the humanization of murine HAb18 against HCC by guided selection. With the optimized primers, the human Fd and C(L) repertoire genes were amplified by RT-PCR from PBMC of HCC patients. The Fd repertoire genes were paired with murine HAb18 C(L) gene to construct pComb3X-displaying hybrid Fab library. The recombinant HAb18GE was used as antigens to select the target antibodies and got the Fd fragments. Then the human C(L) genes were paired with the selected human Fds to construct human Fab library. After the panning, the complete human Fab antibodies were got and analyzed. With the murine HAb18 C(L) gene as template, the heavy chain Fd shuffling was achieved by panning the hybrid Fab library. Then with the selected Fds as template, the human Fabs were obtained through the light chain shuffling. Two of the resulting human Fabs (HuFab2 and HuFab11), with same Fd and different light chains, bound to HAb18G/CD147 specifically. The competitive ELISA, Western blotting, FCM, fluorescent cell staining and so on demonstrated that the human Fabs resembled its parental murine Fab in that they both perhaps recognized the same epitope. K(D) indicated (HuFab2=210 nm and HuFab11=280 nm) the selected Fabs had available affinity. Through guided-selection, we got the available human Fab antibodies for the subsequent research. These results suggest that guided selection is a promising strategy in murine mAb humanization.


Drug recognition of DNA. Proposal for GC minor groove specific ligands: vinylexins.
In a previous publication in this journal we have proposed an isolexin-like prototype of a GC minor groove specific ligand. The present paper is devoted to refinements of this prototype (increase in specificity and in DNA binding energy). It is shown that only a very limited improvement can be obtained by increasing the proton accepting capabilities of the heteroaromatic ring systems of the prototype, although these rings interact directly with the proton donating NH2 group of guanine. On the other hand a significant increase both in GC specificity and in DNA binding energy is obtained by replacing the NH linkers of the isolexin by C = C double bonds (yielding what we term "vinylexins"). Specificity is still largely conserved and the DNA binding energy is significantly increased in monocationic vinylexins, which should thus be efficient GC minor groove specific ligands. The outstanding importance for the GC specificity of the C = C linkers is evidenced by the disappearance of this specificity when these linkers are replaced by peptide bonds (peptilexins). On the other hand vinylexins with proton donating heteroaromatic rings are, as expected, AT specific. The vinylexin family may thus represent universal minor groove binding agents susceptible to bind to any given base pair sequence of DNA, following the positioning of their proton donor and proton acceptor rings. This study confirms the insufficiency of purely geometrical and/or hydrogen bonding considerations for the correct estimation of GC versus AT specificity of groove binding ligands. These can only be accounted for by taking into consideration the overall electronic properties of the interacting species and explicitly calculating the energies of complex formation including all the relevant contributions.


Phylogenetic footprinting of the human cytochrome c oxidase subunit VB promoter.
The human COX5B gene encodes subunit Vb of cytochrome c oxidase (COX). COX Vb is 1 of the 10 subunits of the mitochondrial COX complex encoded by a nuclear gene. We have defined a region in the human COX5B promoter essential for gene expression and shown by phylogenetic footprinting of 11 primate COX5B promoters that many cis-regulatory elements in this region are evolutionarily conserved. The transcription start site of human COX5B was mapped 58 bp upstream of the initiation Met codon by primer extension using a thermostable reverse transcriptase. A 475-bp region (-456 to +20) of the human COX5B gene was shown to function as a promoter for the chloramphenicol acetyl transferase (CAT) gene in expression vectors when transfected into HeLa cells. The human COX5B gene is located in a CpG island and contains several potential binding sites for the transcription factor Sp1, but no consensus TATA box element. Several sequence elements associated with the transcriptional regulation of respiratory genes were also found in the promoter and 5' flanking region, including a single NRF-1 site and two 9-bp direct repeats containing binding sites for ets-domain proteins, such as NRF-2/GABP. Many features of the human COX5B promoter are conserved in the COX5B promoters of primates, in particular, the presence of a single binding site for NRF-1 and multiple sites for Sp1 and NRF-2/GABP. Electrophoretic mobility shift assays demonstrate that the conserved NRF-1 site in primate COX5B promoters is specifically recognized by a factor present in HeLa nuclear extracts. Phylogenetic footprinting has identified additional conserved elements that may also function as binding sites for regulatory factors.


Expression of pERK and pAKT in pediatric high grade astrocytomas: correlation with YKL40 and prognostic significance.
The Ras signaling pathway, consisting of mitogen-activated protein kinase (MAPK) and PI3K/AKT signaling, is a prominent oncogenic pathways in adult diffuse gliomas, but few studies have evaluated such pathways in pediatric malignant gliomas. We investigated by immunohistochemistry MAPK and AKT signaling in a series of 28 pediatric high-grade gliomas (WHO grade III and IV). We sought a possible association of phospho-ERK (p-ERK) and phospho-AKT (p-AKT) with expression of other proteins involved in the Ras pathway, that is, YKL40, epidermal growth factor receptor (EGFR), EGFR vIII and c-Met. Moreover we correlated the expression of p-ERK and p-AKT with prognosis. No cases showed expression for c-Met and EGFR, and only one case was positive for EGFR vIII. YKL-40 protein was expressed in 43% of cases. We detected expression of p-ERK and p-AKT in 61% and 57%, respectively, of pediatric high grade gliomas. Statistical analysis comparing the two groups in term of high and low p-ERK and p-AKT expression showed a trend toward worse overall survival in patients with high expression of p-AKT. The activation of ERK and AKT suggest a possible role of this protein in inducing activation of the Ras signaling pathway in pediatric high-grade gliomas. Moreover high levels of p-AKT are associated with worse overall survival.


Dermatologic Diagnosis: Leukocytoclastic Vasculitis.
Leukocytoclastic vasculitis (LCV), also termed hypersensitivity vasculitis, is a small-vessel vasculitis. The skin is the organ most commonly involved in LCV. Typical presentation is a painful, burning rash predominantly in the lower extremities. The most common skin manifestation is palpable purpura. Other skin manifestations include maculopapular rash, bullae, papules, plaques, nodules, ulcers, and livedo reticularis.


The mechanism of high-yielding chiral syntheses catalysed by wild-type and mutant forms of aspartate aminotransferase.
The ability of aspartate aminotransferase to catalyse beta-elimination of alpha-amino acids that have a good leaving group at C beta has been exploited in the synthesis of novel amino acids by the inclusion of appropriate nucleophiles as co-substrates. Two compounds, L-serine O-sulphate and 3-chloro-L-alanine, were used as beta-elimination substrates. Nucleophiles used successfully as co-substrates were thiosulphate, 2-mercaptoethanol, mercaptoacetate and aminoethylthiopseudourea. The synthesis achieved using serine O-sulphate and thiosulphate was found to produce sulphocysteine with a yield of 70%. Circular dichroism demonstrated that the compound was a single enantiomer and, therefore, that nucleophilic addition had taken place on the enzyme. The initial rate of synthesis was 10% of the rate at which the enzyme catalyses its normal transamination reaction. The synthetic reaction was accompanied by minor side reactions that led to small amounts of additional amino acid and oxo acid products through partitions of the main reaction at two stages in the mechanism. By mutating Arg292, which is the residue that binds the distal carboxyl group of natural substrates, the wild-type enzyme was converted to a form that could discriminate completely between serine O-sulphate and chloroalanine as beta-eliminating substrate. Similar alterations in nucleophile cosubstrate specificity were also observed. Whereas, for example, the wild-type enzyme catalysed syntheses between 3-chloroalanine and either mercaptoethanol or mercaptoacetate with equal facility, the Arg292Asp enzyme showed complete preference for mercaptoethanol. The system should be of general use in the synthesis of novel amino acids as single enantiomers with potentially interesting biological activities.


Hydrostatic leg ulcers: a new classification.
The classification of leg ulcers into standard aetiologies was conducted using a sample of 205 patients referred to the department of dermatology, Malmö University Hospital in Sweden. Patients with venous ulcers formed the largest group (51%). Classification was not possible in 31 patients (approximately 15%) and this formed the second largest group. A comparison of ulcer characteristics between this unclassified group and the venous ulcer group showed that the unclassified ulcers occur in patients with little or no venous disease and display different characteristics from venous ulcers. As a result of these differences, we propose that there should be a further classification of ulcers, known as 'hydrostatic' ulcers. The identification of this type of ulcer has important consequences for future ulcer management as these patients will not require venous surgery or further compression therapy following healing.


Zinc finger proteins as designer transcription factors.
Recent progress in the design and selection of novel zinc finger proteins with desired DNA binding specificities now allows construction of tailor-made DNA-binding proteins that specifically recognize almost any predetermined DNA sequence. Such novel or "designer" zinc finger proteins with desired DNA binding specificities can serve as efficient transcription factors in various mammalian cell lines. In addition, they may be broadly useful in the regulation of endogenous genes in transgenic organisms and eventually in gene therapy applications. In this report, we use a series of transient and stable transfection experiments to demonstrate that the expression of a target gene can be controlled by changing the in vivo concentration of designer zinc finger proteins in a dose-dependent manner. We also report that designer zinc finger proteins can access their binding sites integrated into the genome and function as potent transcription factors. Our results suggest that designer zinc finger transcription factors that specifically recognize appropriate sites in the promoter of a target gene may have broad applications in the post-genomic era.


Relationship between the frequency of nursing activities and adverse outcomes in patients with acute coronary syndrome: A retrospective cohort study.
The aim of this retrospective cohort study was to identify the relationship between the frequency of nursing activities during the first hospitalization and adverse outcomes in patients with acute coronary syndrome by using electronic health records. Patients diagnosed with acute coronary syndrome from April 2010 to April 2015 were examined for eligibility based on 36 months of major adverse cardiac events as the main outcome. Among the 652 patients who were enrolled, 66 patients experienced major adverse cardiac events. The average frequency of nursing activities was 1098.7 (±2703.8), and four variables (length of hospital stay, albumin level, hemoglobin level, and frequency of nursing activities) were significantly associated with 36 months of major adverse cardiac events. After adjusting for these variables, the frequency of nursing activities was found to be the only significant factor associated with the incidence of 36 months of major adverse cardiac events. This finding suggests that patients with acute coronary syndrome who require more frequent nursing activities during the first hospitalization could be vulnerable to adverse outcomes and should be closely monitored.


Changes in galectin-7 and cytokeratin-19 expression during the progression of malignancy in thyroid tumors: diagnostic and biological implications.
Galectin-7 is associated with p53-dependent onset of apoptosis and proliferation control/differentiation in keratinocyte development. It is also up-regulated in chemically induced rat mammary carcinogenesis. Because the levels of expression of galectin-7 have never been investigated in thyroid tumors (in contrast to those of galectin-1 and -3 associated with malignancy), we initiated analysis of the expression of galectin-7 in benign and malignant thyroid lesions together with that of cytokeratin-19 (CK19), a marker already demonstrated to be useful in diagnosing this kind of lesion. The immunohistochemical expression levels were quantitatively determined by means of computer-assisted microscopy on a series of 84 thyroid lesions including 10 multinodular goiters, 32 adenomas, and 42 carcinomas. Our data clearly indicate a marked down-regulation of galectin-7 expression in a large proportion of adenomas (including the normomacrofollicular, microfollicular, and trabecular variants) if compared with carcinomas. In accordance with results of previous studies, a marked up-regulation of CK19 expression was observed in the thyroid carcinomas, and this contrasted in particular with the low CK19 expression observed in the microfollicular adenomas. Of importance for diagnostic implications, the combination of these two markers enabled our series of microfollicular adenomas (characterized by low galectin-7 and CK19 expression) to be efficiently distinguished from the encapsulated follicular variant of papillary thyroid carcinomas (high galectin-7 and CK19 expression).


Three-dimensional structure of RBcel1, a metagenome-derived psychrotolerant family GH5 endoglucanase.
RBcel1 is an endoglucanase belonging to glycoside hydrolase family 5 subfamily 5 (GH5_5) that was recently identified from a soil metagenome library from the Antarctic. Unlike its closest structural homologue (Cel5A from Thermoascus aurantiacus), this enzyme was reported to be able to catalyze transglycosylation reactions and has putatively been implicated in the bacterial cellulose-synthesis process. Here, the structure of RBcel1 at 1.4 Å resolution, solved by molecular replacement, is reported. The structure and putative substrate-binding site are described and compared with those of other GH5_5 subfamily members.


Most gamma delta T cells develop normally in the absence of MHC class II molecules.
MHC class I and class II molecules are essential for intrathymic maturation of a normal repertoire of alpha beta T cells. The development of gamma delta T cells may similarly require exposure to conventional MHC or MHC-like molecules for appropriate negative and positive selection. The availability of mice that are devoid of cell surface expression of MHC class II molecules allowed us to test directly the hypothesis that conventional class II molecules play a role in the development of gamma delta T cells. The proportions of gamma delta cells in thymus, lymph nodes, and spleens were indistinguishable between class II-deficient mice and littermate controls by FACS analysis. gamma delta T cells from class II-deficient mice proliferated normally in response to anti-TCR mAb. Examination of epidermal sheets from ear, torso, and tail skin demonstrated that class II-deficient mice had the same population density and distribution of gamma delta+ dendritic epidermal T cells as that of control littermates. gamma delta Cells in the epidermis of class II-deficient mice expressed Thy-1 and CD3 and were predominantly V gamma 3+. There were no significant differences in the immunophenotype of class II-deficient mice and their normal littermates in two-color immunofluorescence analysis of intestinal intraepithelial lymphocytes. Class II-deficient mice and control mice had 29 to 39% gamma delta bearing intestinal intraepithelial lymphocytes, of which 16 to 21% expressed V delta 4. Dendritic cells that stained positively for Thy-1, CD3, and gamma delta were identified in the vaginal epithelium of class II-deficient mice and their normal littermates. Our results indicate that MHC class II expression is not essential for the development of most gamma delta T cells.


Research on Preparation Methods of Carbon Nanomaterials Based on Self-Assembly of Carbon Quantum Dots.
Here, based on self-assembly of carbon quantum dots (CDs), an innovative method to prepare nanomaterials under the action of a metal catalyst was presented. CDs were synthesized by a one-step hydrothermal method with citric acid (CA) as the carbon source, ethylenediamine (EDA) as the passivator and FeSO4•7H2O as the pre-catalyst. In the experiment, it was found that the nano-carbon films with a graphene-like structure were formed on the surface of the solution. The structure of the films was studied by high-resolution transmission electron microscopy (HRTEM), Fourier transform infrared (FT-IR), etc. The results demonstrated that the films were formed by the self-assembly of CDs under the action of the gas-liquid interface template and the metal catalyst. Meanwhile, the electrochemical performance of the films was evaluated by linear cyclic voltammetry (CV) and galvanostatic charge discharge (GOD) tests. In addition, the bulk solution could be further reacted and self-assembled by reflux to form a bifunctional magnetic-fluorescent composite material. Characterizations such as X-ray diffractometer (XRD), fluorescence spectra (FL), vibrating sample magnetometer (VSM), etc. revealed that it was a composite of superparamagnetic γ-Fe2O3 and CDs. The results showed that self-assembly of CDs is a novel and effective method for preparing new carbon nanomaterials.


[Asbestos and malignant pleural mesothelioma: molecular, cellular and physiopathological aspects].
Asbestos is known as mutagenic and carcinogenic for human and is responsible for many pulmonary diseases including asbestosis, bronchogenic carcinoma and malignant pleural mesothelioma. Occupational exposure to asbestos is involved in 70-80% of all malignant pleural mesothelioma. The later presents a growing challenge for both researcher and clinician. The diagnosis of malignant pleural mesothelioma is difficult and the current treatments did not show significant improvement of the survival. The increasing incidence of malignant pleural mesothelioma, its gravity and its human, social and financial consequences are of high concern in public health. In this paper we summarize the so far knowledge on cellular, molecular and pathophysiological events involved in genesis and development of malignant pleural mesothelioma. Finally, the paper also report recent data sourced from the study of malignant pleural mesothelioma transcriptome using high-throughput technologies such as gene expression array. These data should improve the accuracy of mesothelioma diagnosis and therapy.


A novel HLA-A*02 allele, A*02:436, was identified by sequencing-based typing.
A novel allele A*02:436 was identified in a Chinese individual by sequence-based typing method.


Behavioral parenting skills as a novel target for improving medication adherence in young children: Feasibility and acceptability of the CareMeds intervention.
In pediatric cancer care, medication non-adherence is a significant driver of avoidable suffering and death. There is a lack of interventions designed for families of young children, where patient medication refusal/avoidance is a common barrier to adherence. We developed the CareMeds intervention which focuses on caregiver skills training to help young children take medicine calmly and without use of restraint techniques. The goal of this preliminary study was to assess the acceptability and feasibility of the CareMeds intervention. Caregivers of pediatric cancer patients (ages 2-10) whose children were on a home-based oral medication regimen were recruited to participate. Feasibility was examined through study enrollment and retention rates as well as reasons for refusal and drop out. Acceptability was evaluated through usability of and engagement with intervention components and an acceptability questionnaire. Feasibility: We recruited N = 9 caregivers to participate in this intervention pilot study and had a 75% enrollment rate. Reasons for declining included scheduling concerns (n = 2) and lack of interest (n = 1). The participant retention rate was 100% with 100% adherence to intervention sessions. Acceptability: Parents rated the sessions and resource materials as acceptable and reported frequent use of skills taught in the intervention. The CareMeds intervention is an acceptable and feasible strategy for caregivers of pediatric cancer patients and warrants future research to examine the efficacy of behavioral parenting skills interventions to improve medication adherence in young children.


[Dynamics of the activity of lysosomal and membrane-transport enzymes of human coronary arteries in atherosclerosis (based on specimens of early autopsy].
The time course of the activity of lysosome (LE) and membrane-transport (MTE) enzymes in the cells of human coronary arteries was studied histochemically and lipid metabolism in the plasma was studied biochemically. it is shown that the formation of atherosclerotic lesions and exacerbation of the disease in the endothelium and macrophages is followed by the enhancement of positive correlation between the atherogenic ration and the activity of LE and MTE and the alteration of this correlation between these enzymes. In the sedentary mesenchymal cells the progress of atherosclerosis results in the alteration of positive correlation between both LE and MTE and between these enzymes and atherogenic ration. Atherosclerosis remission is followed by partial restoration of the above correlations between the activity of LE and MTE in the cells of atherosclerotic lesions of the coronary arteries intima.


New insight into a microfluidic-based bipolar system for an electrochemiluminescence sensing platform.
In this work, a novel style of a microfluidic-based bipolar system with two-direction driving electrodes and dual-channel configuration was described for the first time, which could reach 100% current efficiency in theory. More importantly, the background signal from the integrated driving electrodes was completely eliminated, when this unique design was used to construct an electrochemiluminescence (ECL) sensing platform. First, universal pH indicator was employed to study the mechanism and demonstrate that this new bipolar system possessed 100% current efficiency theoretically. Then, the Ru(bpy)₃²⁺/TPrA ECL system was introduced to construct the dual-channel bipolar ECL sensing platform, and the results of visual ECL experiments proved that the background signals from the driving electrodes were completely dispelled with our design. To illustrate the promising applications of this dual-channel device, TPrA, dopamine (DA), H₂O₂, and K₃Fe(CN)₆ were detected as model targets under different principles.


The binding of the 69- and 100-kD forms of 2',5'-oligoadenylate synthetase to different polynucleotides.
Three major forms of 2',5' oligoadenylate (2-5A) synthetase are induced in interferon (IFN)-treated human cells: 40-46, 69, and 100 kD. Here we studied the binding and activation of the 69- and 100-kD forms to single-stranded (ss) or double-stranded (ds) RNAs. The 69- and 100-kD form enzymes purified by immunoaffinity chromatography, were shown to be activated by synthetic dsRNAs poly(I).poly(C) or poly(A).poly(U) whereas ssRNAs poly(I), poly(C), poly(A), poly(U), and poly(G) had no effect. Both enzymes were also partially purified by binding to dsRNA or ssRNA-Sepharose. The synthetases bound to dsRNA Sepharose were partially activated but required the addition of soluble poly(I).poly(C) for maximal activity. The synthetases bound to ssRNA-Sepharose manifested no activity but became activated in the presence of soluble dsRNA, poly(I).poly(C). However, activation of such ssRNA-bound enzymes by dsRNA did not result in their dissociation from the ssRNA-Sepharose. These results indicate the presence of different polynucleotide binding sites on the 69- and 100-kD forms of 2-5A synthetase: a specific dsRNA binding site essential for activation and another polynucleotide binding site or sites which, although not specific, might be important for the optimal conformation of these proteins in cells.


Evolution of a CAM anatomy predates the origins of Crassulacean acid metabolism in the Agavoideae (Asparagaceae).
Crassulacean acid metabolism (CAM) is a modified form of photosynthesis that has arisen independently at least 35 times in flowering plants. The occurrence of CAM is often correlated with shifts to arid, semiarid, or epiphytic habits, as well as transitions in leaf morphology (e.g. increased leaf thickness) and anatomy (e.g. increased cell size and packing). We assess shifts between C3 and CAM photosynthesis in the subfamily Agavoideae (Asparagaceae) through phylogenetic analysis of targeted loci captured from the nuclear and chloroplast genomes of over 60 species. Carbon isotope data was used as a proxy for mode of photosynthesis in extant species and ancestral states were estimated on the phylogeny. Ancestral character state mapping suggests three independent origins of CAM in the Agavoideae. CAM species differ from C3 species in climate space and are found to have thicker leaves with densely packed cells. C3 ancestors of CAM species show a predisposition toward CAM-like morphology. Leaf characteristics in the ancestral C3 species may have enabled the repeated evolution of CAM in the Agavoideae subfamily. Anatomical changes, including a tendency toward 3D venation, may have initially arisen in C3 ancestors in response to aridity as a way to increase leaf succulence for water storage.


Assessment of sclerostin levels in the gingival crevicular fluid of patients with periodontitis: A clinico-biochemical crosssectional study.
Sclerostin, a glycoprotein, plays a key role in regulating bone mass. In this study, sclerostin levels in the gingival crevicular fluid (GCF) were assessed in patients with Stage III Grade C generalized periodontitis (SIII-GC) and Stage III Grade B generalized periodontitis (SIII-GB). This cross-sectional study included 30 participants divided equally into three groups: group I (gingival health), group II (SIII-GC), and group III (SIII-GB). Clinical periodontal parameters like plaque index (PI), gingival bleeding index (GBI), probing pocket depth (PD), and clinical attachment level (CAL) were recorded. A sandwich ELISA was used to determine the sclerostin levels in GCF samples. One-way ANOVA and post hoc Tukey tests were used to analyze the clinical parameters and GCF sclerostin levels. The association between GCF sclerostin levels and periodontal parameters was assessed using Pearson's correlation coefficient (r). Patients in groups II and III had much higher sclerostin levels in their GCF than in group I (P≤0.05). In contrast, no significant difference in sclerostin levels was observed between the two diseased conditions (P=0.841). Concerning periodontal parameters, a statistically significant difference was observed between the three groups. There was a positive correlation between the periodontal clinical parameters and the expression levels of sclerostin in GCF (P≤0.05). Increased expression of sclerostin in GCF in patients with periodontitis indicated that it could be considered a reliable biomarker of periodontal disease activity.


Uptake and distribution of sodium and potassium by corn seedlings : I. Role of the mesocotyl in ;sodium exclusion'.
The distribution of sodium and potassium throughout corn (Zea mays L. [A632 x Crows 3640] x Oh 43) plants is not simply a matter of uptake by cortical cells and irreversible delivery to the xylem for upward transport. We show that sodium, but not potassium, accumulates in the mesocotyl of corn seedlings grown on NaCl medium. Upon transfer to NaCl-free medium, total sodium is reduced by export through the roots but remains at high levels within the mesocotyl. We report experiments which consider uptake from the xylem.Shoots excised at the seed were allowed to transpire solutions containing (22)Na and (42)K. Potassium uptake within the mesocotyl was very sensitive to concentration, increasing 27-fold between 1 and 10 millimolar. Sodium uptake was dependent upon the square root of the concentration suggesting active accumulation. At sodium concentrations below 1 millimolar, more than 80% of the sodium in the plant was retained in the mesocotyl. Both the uptake by and retention within the mesocotyl were dependent upon transpiration rate as well as concentration. We discuss the limitations of measuring uptake from a finite, depletable medium. The mesocotyl is a modified root with a cuticularized epidermis. We discuss the feasibility of using this ;plastic-coated root' as a model for root transport studies.


Percutaneous transluminal dilatation in the treatment of renal vascular hypertension.
Twenty-six patients with renal vascular hypertension were treated with percutaneous transluminal dilatation. Twenty-one were followed for more than 1 year; 18 underwent repeat angiography. Recurrence of stenosis was shown angiographically in one of six patients with fibromuscular disease and in 12 of 12 patients with atherosclerotic disease. The procedure was more likely to result in cure of hypertension (six of 10) in patients with fibromuscular disease than in patients with atherosclerotic disease (one of 16). Although percutaneous transluminal angioplasty provides the advantages of simplicity, reduced cost, and probably reduced risk, long-term utility of the procedure remains to be established. A prospective randomized trial, establishment of a registry, or both would serve this purpose.


Therapy discontinuation or substitution in patients with cardiovascular disease, switching among different products of the same off-patent active substance: a 'real-world' retrospective cohort study.
The present study investigated the effects of switching to different products of the same off-patent active substance (brand name or generic) on therapy discontinuation or substitution with another molecule of the same class, in patients with cardiovascular disease treated with statins and antihypertensives in a 'real-world' setting. A retrospective cohort study in a 'real-world' setting. Analysis of data performed by integrating administrative databases that included approximately two million individuals who are assisted by the National Health System from three Local Health Units located in three different regions of Italy. All patients aged ≥18 years with at least one prescription of simvastatin, ramipril or amlodipine in the period 1 January to 31 December 2010 were included and followed up for 2 years. Prescription refills occurring during follow-up were evaluated. Frequency of discontinuation of therapy or substitution with another molecule of the same class (eg, from simvastatin to a different statin) during follow-up was identified. During follow-up, therapy discontinuation or substitution was found to be more frequent in patients switching to a different product of the same active substance compared with non-switching patients (11.5% vs 10.8% and 22.2% vs 20.8% (p=0.002), respectively, in the simvastatin group; 4.0% vs 3.5% and 24.6% vs 22.7% (p<0.001), respectively, in the amlodipine group). In the ramipril group, 8% of patients undertook a therapy substitution to another molecule; no trend towards a lower percentage of substitution was observed in the non-switching group, while 18% of patients discontinued treatment, with a significant difference in favour of patients not switching. These findings were partially confirmed by multivariate analysis. Switches among products of the same active substance are quite common in patients with cardiovascular disease. Our study suggests that switching may expose patients to a higher risk of therapy discontinuation or substitution.


Tibial nerve branching in the tarsal tunnel.
Tarsal tunnel syndrome is an infrequent and probably underdiagnosed clinical condition. Diagnosis and treatment depend on understanding the tibial branching pattern within the tarsal tunnel. A total of 68 foot dissections were performed. Bifurcation into the medial and lateral plantar nerves occurred within the tunnel in 93% and proximal in 7%. Proximal bifurcation may predispose to tarsal tunnel syndrome, and its infrequent occurrence correlates with the infrequent clinical diagnosis. Nine different calcaneal branching patterns were noted; they provide an anatomical explanation for heel sparing. An understanding of anatomic variations should aid in providing complete surgical release and in avoiding accidental heel denervations.


[An experimental study on anti-aging action of Cordyceps extract].
To investigate anti-aging effect and mechanism of Cordyceps extract(CSE) on aged mice induced by D-galactose. The aged mice were induced by D-galactose. Meanwhile, they were treated with three doses of CSE. Then the ability of learning and memory, the activity of antioxidase in the different tissue, the contents of MDA of brain and liver were measured after 6 weeks. CSE could significantly increase the ability of learning and memory, improve the activity of SOD of red blood cells, brain and liver, the activity of Na(+) -K(+) -ATPE of brain, the activity of CAT and GSH-Px of blood, and remarkably decrease the activity of MAO of brain and the contents of MDA of brain and liver. CSE has good anti-aging effects on the aged mice, which is probably due to effects of improving antioxidation and removing free radicals.


[Dose loads on and radiation risk values for cosmonauts on a mission to Mars estimated from actual Martian vehicle engineering development].
The current design philosophy of a Mars orbiting vehicle, takeoff and landing systems and the transport return vehicle was taken into consideration for calculating the equivalent doses imparted to cosmonaut's organs and tissues by galactic cosmic rays, solar rays and the Earth's radiation belts, values of the total radiation risk over the lifespan following the mission and over the whole career period, and possible shortening of life expectancy. There are a number of uncertainties that should be evaluated, and radiation limits specified before setting off to Mars.


Combined confocal/en face T-scan-based ultrahigh-resolution optical coherence tomography in vivo retinal imaging.
Combined confocal scanning ophthalmoscopy/en face T-scan-based ultrahigh-resolution optical coherence tomography (OCT) of the human retina in vivo is reported for the first time to our knowledge. The system uses a superluminescent diode-based broadband source, which gives an axial resolution of 3.2 microm in the retina. We demonstrate acquisition of T-scan-based OCT B-scan and simultaneous confocal/C-scan images of the human retina of large lateral size (covering a field of up to 20 degrees ) at a frame rate of 2Hz.


A Preliminary Investigation of Caffeinated Alcohol Use During Spring Break.
Caffeinated alcoholic beverages (e.g., Red Bull and vodka) are popular but associated with negative consequences. CABs may be particularly popular during Spring Break, a potentially risky social event. We aimed to identify the prevalence of Spring Break caffeinated alcohol use, determine how caffeinated alcohol use Spring Break drinking habits differ from usual, and examine the association between Spring Break caffeinated alcohol use and alcohol-related problems. Data were collected from 95 college students during March of 2013 and 2014. Students completed questionnaires of their alcohol and caffeinated alcohol use before and during Spring Break and Spring Break alcohol-related problems. Approximately 54% of students used caffeinated alcohol during Spring Break. Spring Break caffeinated alcohol use was associated with more alcohol-related problems, even after controlling for other alcohol consumed and Spring Break vacation status. Caffeinated alcoholic beverages are commonly consumed during Spring Break and their use uniquely predicted harms. Prevention efforts placed on caffeinated alcoholic beverage users may be helpful in reducing Spring Break-related harms.


Functional characterization of embryonic stem cell-derived cardiomyocytes using scanning ion conductance microscopy.
We report here the novel use of scanning ion conductance microscopy (SICM) to produce surface images of embryonic stem cell-derived cardiomyocytes (ESCM) to identify individual contracting cardiomyocytes among different cell types. By measuring amplitude and rhythm we can quantitate contraction of ESCM. This method gives, within the same experiment, an assessment of the number and position of ESCM within the layer of mixed cell types, as well as an accurate measure of the response of individual ESCM. Using different modulators of contraction as examples we showed how SICM could be used for recording their responses. We subsequently demonstrated that this model can be used to investigate the protective effect of antiarrhythmogenic drugs.


Reduction of gastric ulcer recurrence after suppression of Helicobacter pylori by cefixime.
The effect on the recurrence of gastric ulcers after suppression of Helicobacter pylori by combined treatment with cimetidine and the antimicrobial drug cefixime was investigated. Twenty one of 43 patients with endoscopically proved gastric ulcer and H pylori infection were randomly assigned to receive cimetidine 800 mg daily for 12 weeks; the remaining 22 patients received cimetidine 800 mg daily for 12 weeks plus cefixime 100 mg daily for the last two weeks. After treatment, 88% of 17 patients on cimetidine only remained H pylori positive, whereas combined administration of cimetidine and cefixime had suppressed H pylori in 78% of 18 patients (p less than 0.05). Seventeen patients in the former group whose ulcers healed but who remained H pylori positive and 18 patients in the latter group whose ulcers healed and who were no longer infected with H pylori continued to be followed after treatment. These patients underwent endoscopy to detect ulcer recurrence if symptomatic, or at 12 and 24 weeks if asymptomatic. At 12 weeks, recurrence was observed in seven of 15 (47%) patients in whom H pylori persisted, but in only one of 14 (7%) patients in whom H pylori had been suppressed (p less than 0.05). At 24 weeks, however, recurrence rates were similar between the two groups. These findings indicate that H pylori infection may be closely related to early ulcer recurrence.


Effect of time at 37 degrees C on the creep and metallurgical characteristics of amalgam.
When aged at 37 degrees C for six months, dental amalgam exhibits a marked decrease in the property of creep. The objective of this study was to investigate the relationship between this decrease in creep and selected metallurgical characteristics. The formation of beta 1 (Ag-Hg), the grain size of gamma 1 (Ag-Hg), and the composition of gamma 1 were chosen for investigation. Creep was determined according to ADA Specification test No. 1, beta 1 was measured by x-ray diffraction, and gamma 1 grain size and gamma 1 composition were determined by electron-probe microanalysis. The results showed that the decrease in creep was related to beta 1 formation and not to changes in either gamma 1 grain size or gamma 1 composition.


New pyridobenzoxazepine derivatives derived from 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13): chemical synthesis and pharmacological evaluation.
A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D(2L) and D(4), serotonin 5-HT(1A) and 5-HT(2A), and adrenergic α(2A) receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine, JL13 (1), and other diarylazepine derivatives. In terms of multireceptor target strategy, 2 and 5 present the most promising in vitro binding profile. Bulky, polar, and more flexible side chains are not favorable in this context. Compounds 2 and 5 were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to 1 and other second-generation antipsychotic drugs, repeated treatment with 2 significantly increased D(1) and D(4) receptors in nucleus accumbens and caudate putamen and D(2) receptors in medial prefrontal cortex and hippocampus, while 5 significantly increased D(2) and D(4) receptors in nucleus accumbens. In addition, 2 increased 5-HT(1A) and decreased 5-HT(2A) receptors in cerebral cortex. In contrast, 5 did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of 2 as a novel second-generation antipsychotic agent.


Clearance of t-PA, PAI-1, and t-PA-PAI-1 complex in an isolated perfused rat liver system.
The role of physiologic inhibitors of tissue-type plasminogen activator (t-PA) in its clearance has not yet been defined. In this study, the clearance of t-PA, plasminogen activator inhibitor 1 (PAI-1), and t-PA-PAI-1 complex was determined in an isolated perfused rat liver system. The clearance of t-PA-PAI-1 complex was twice as fast as that of t-PA, whereas PAI-1 was cleared slowly. The half-lives for t-PA, determined by a two-compartmental pharmacokinetic model, were: alpha, 20.1 minutes, and beta, 120.0 minutes. The corresponding values for t-PA-PAI-1 complex were: alpha, 9.7 minutes, and beta, about 7 hours. The model microconstants were computed for t-PA and t-PA-PAI-1 complex and the marked difference between the "on" microconstants k12 for t-PA (0.026 +/- 0.001 min-1) and t-PA-PAI-1 complex (0.090 +/- 0.025 min-1) suggests that the effect on binding to liver cells is the most important factor in the faster clearance of t-PA-PAI-1 complex when compared with t-PA.


Hand kinematics of piano playing.
Dexterous use of the hand represents a sophisticated sensorimotor function. In behaviors such as playing the piano, it can involve strong temporal and spatial constraints. The purpose of this study was to determine fundamental patterns of covariation of motion across joints and digits of the human hand. Joint motion was recorded while 5 expert pianists played 30 excerpts from musical pieces, which featured ∼50 different tone sequences and fingering. Principal component analysis and cluster analysis using an expectation-maximization algorithm revealed that joint velocities could be categorized into several patterns, which help to simplify the description of the movements of the multiple degrees of freedom of the hand. For the thumb keystroke, two distinct patterns of joint movement covariation emerged and they depended on the spatiotemporal patterns of the task. For example, the thumb-under maneuver was clearly separated into two clusters based on the direction of hand translation along the keyboard. While the pattern of the thumb joint velocities differed between these clusters, the motions at the metacarpo-phalangeal and proximal-phalangeal joints of the four fingers were more consistent. For a keystroke executed with one of the fingers, there were three distinct patterns of joint rotations, across which motion at the striking finger was fairly consistent, but motion of the other fingers was more variable. Furthermore, the amount of movement spillover of the striking finger to the adjacent fingers was small irrespective of the finger used for the keystroke. These findings describe an unparalleled amount of independent motion of the fingers.


Successful Treatment of Paradoxical Puborectalis Contraction and Intractable Anorectal Pain With Sacral Neuromodulation.
Paradoxical puborectalis contraction (PPC) is a syndrome of obstructed defecation associated with a cluster of complaints including rectal pain, incomplete evacuatory sensation, prolonged repetitive straining with bowel movements, and the need for digital manipulation. Traditional treatment has yielded mixed results. We present a case of PPC successfully treated with staged sacral neuromodulation and review her diagnostic features, medical regimen, and prior unsuccessful interventions tried. Symptoms were analyzed using a visual analog scale pain score (0-10). Criteria to progress to implantation of the pulse generator included a pain score less than 3 during test stimulation and/or greater than 50% decrease in the pain score compared to baseline.Our patient had a pain score of 0 (baseline 8) with stage 1 sacral neuromodulation. In addition, she had dramatic relief in her straining with bowel movements and need for digital manipulation. Her pulse generator was implanted after a 2-week trial, and she has experienced a lasting improvement at her follow-up of 2 years. Sacral neuromodulation is an established therapy for overactive bladder syndrome, urinary retention, and fecal incontinence. In urology, the use of sacral neuromodulation has been described to benefit some patients with pelvic floor pain. Sacral neuromodulation can be a successful treatment for PPC and functional anorectal pain with resulting improvement in quality of life without the sequelae of an invasive and irreversible surgery.


Bullous Sweet syndrome associated with an aseptic splenic abscess.
Sweet syndrome is a rare disorder characterized by fever and painful erythematous plaques containing dense dermal neutrophilic infiltrates. Extracutaneous manifestations include alveolitis, sterile osteomyelitis, and arthritis. We present a patient with a bullous presentation of Sweet syndrome who developed an aseptic splenic abscess.


Poly(l-histidine) based triblock copolymers: pH induced reassembly of copolymer micelles and mechanism underlying endolysosomal escape for intracellular delivery.
Various poly(l-histidine) based amphiphilic copolymers have been developed for intracellular drug delivery due to the pH responsive properties and the escape from endolysosomal pathway. However, the pH induced reassembly of copolymer micelles and the assumed endolysosome membrane rupture during the copolymer facilitated endolysosomal escape have never been elucidated. To address these issues, a series of poly(ethylene glycol)-poly(d,l-lactide)-poly(l-histidine) (mPEG-PLA-PHis) with different degrees of polymerization of PLA and PHis block were synthesized. The self-assembly and reassembly behaviors of the copolymers were characterized using transmission electron microscopy (TEM), (1)H NMR, fluorescence probe technique, and dynamic light scattering (DLS). The copolymers self-assembled into micelles with PLA and unprotonated PHis blocks as hydrophobic core and PEG as hydrophilic shell at neutral pH. The changes in TEM images, (1)H NMR spectrum of PHis peak, pyrene fluorescene spectrum, and particle size as well as size distribution over the pH range from pH 8.5 to 4.5 suggest that the copolymer micelles reassembled into micelles with PLA as hydrophobic core and protonated PHis and PEG as hydrophilic shell under acidic environment. The pH induced reassembly triggered the incoporated doxorubicin (DOX) release, as indicated by the in vitro accelerated drug release and enhanced cytotoxicity. The integrity of endolysosome membrane during the copolymer facilitated DOX endolysosomal escape was observed by confocal laser scan microscopy (CLSM) and further evaluated by hemolysis test and calculation of the critical size of endolysosomal membrane. The results indicate that the endolysosomal membrane remained intact during the copolymer facilitated endolysosomal escape of DOX. It is more reasonable to ascribe the PHis based copolymer facilitation endolysosomal escape to the "proton sponge" hypothesis without rupturing the endolysosomal membrane.


Development and validation of prognostic nomogram for germ cell testicular cancer patients.
The purpose of our study was to establish a reliable and practical nomogram based on significant clinical factors to predict the overall survival (OS) and cancer-specific survival (CSS) of patients with germ cell testicular cancer (GCTC). Patients diagnosed with GCTC between 2004 and 2015 were obtained from the SEER database. Nomograms were constructed using the R software to predict the OS and CSS probabilities and the constructed nomograms were validated and calibrated. A total of 22,165 GCTC patients were enrolled in the study, including the training cohort (15,515 patients) and the validation cohort (6,650 patients). In the training cohort, multivariate Cox regression showed that age, race, AJCC stage, SEER stage and surgery were independent prognostic factors for OS, while age, race, AJCC stage, TM stage, SEER stage and radiotherapy were independent prognostic factors for CSS. Based on the above Cox regression results, we constructed prognostic nomograms of OS and CSS in GCTC patients and found that the OS nomograms had higher C-index and AUC compared to TNM stage in the training and validation cohorts. In addition, in the training and external validation cohorts, the calibration curves showed a good consistency between the predicted and actual 3-, 5- and 10-year OS and CSS rates of the nomogram. The current prognostic nomogram can provide a personalized risk assessment for the survival of GCTC patients.


Familial aggregation of multiple sclerosis: Results from the national registry of the disease in Saudi Arabia.
Multiple Sclerosis (MS) is a chronic CNS inflammatory disease commonly affecting young adults. Both genetics and environmental factors have been reported to have a role in pathophysiology of the disease. This article aims to report familial nature and aspects of MS in Saudi Arabia. The study utilized data collected by the National Saudi MS Registry between 2015 and 2018; especially data relevant to the familial history of MS. SPSS 22 was used for all analysis and reporting. Statistical significance was set at p-value < 0.05. The registry included 20 hospitals and a total of 2516 patients from the different regions of Saudi Arabia with median age 32.00 (Range: 11-63) and 66.5% being female. About 12.8% of all registered patients reported a family history of MS (95%CI: 11.2-13.9). Reported parental consanguinity was significantly higher among patients with family history (FMS) (56.3%) compared to non-FMS patients (27.9%). 42.53% of FMS patients reported having siblings affected with MS (95%CI: 37.01-48.21), with more female siblings affected than males (63.4% vs 36.6% respectively). Our Findings suggested that FMS was less prevalent than what was reported previously; however, parental consanguinity was significantly more prevalent among FMS patients than non-FMS. Our findings were in line with those reported in recent studies in the region, but lower than those reported by western countries indicating that increasing prevalence of MS in Saudi Arabia could be multifactorial and other environmental factors should be considered for understanding this recent rise in the prevalence of MS in Saudi Arabia.


Irradiated fibroblasts increase interleukin-6 expression and induce migration of head and neck squamous cell carcinoma.
Cytotoxic effects of radiation play an important role in the treatment of head and neck cancer. However, irradiation is known to lead to the migration of various cancer cells, including those of head and neck cancer. Recently, fibroblasts in the cancer microenvironment have been reported to be involved in this mechanism. Nevertheless, the mechanism underlying migration of head and neck cancer cells remains unclear. Herein, we aimed to elucidate this migration mechanism induced by irradiation in terms of the interaction of head and neck cancer cells with fibroblasts. We used the head and neck squamous cell carcinoma (HNSCC) cell lines SAS and FaDu as well as fibroblast cell lines. These cells were irradiated and their viability was compared. In fibroblasts, changes in interleukin-6 (IL-6) secretion caused by irradiation were measured by enzyme-linked immunosorbent assay (ELISA). The cell migration ability of cancer cells was evaluated via a migration assay using a semipermeable membrane. HNSCC cells were cocultured with irradiated and nonirradiated fibroblasts, and their migration ability under each condition was compared. We also examined the effect of IL-6 on the migration of HNSCC cells. Furthermore, to investigate the effect of fibroblast-derived IL-6 on the migration ability of HNSCC cells, we conducted a coculture study using IL-6 neutralizing antibody. Irradiation reduced the survival of HNSCC cells, whereas fibroblasts were resistant to irradiation. Irradiation also increased IL-6 secretion by fibroblasts. Migration of HNSCC cells was enhanced by coculture with fibroblasts and further enhanced by coculture with irradiated fibroblasts. We also confirmed that the migration of HNSCC cells was induced by IL-6. The enhanced migration of cancer cells caused by coculturing with fibroblasts was canceled by the IL-6 neutralizing antibody. These results show that fibroblasts survive irradiation and induce the migration ability of HNSCC cells through increased secretion of IL-6.


Repression of E-cadherin by SNAIL, ZEB1, and TWIST in invasive ductal carcinomas of the breast: a cooperative effort?
It has been suggested that down-regulation of E-cadherin in invasive breast ductal carcinomas is mediated by the aberrant expression of several of its transcriptional repressors, but their inhibitory role and clinical importance are not yet well established. We investigated gene and protein expression patterns of the E-cadherin repressors SNAIL, ZEB1, and TWIST in relation to clinicopathologic parameters, in a series of 88 patients with invasive breast ductal carcinomas. Up-regulation of SNAIL messenger RNA (P = .008) and down-regulation of TWIST (P = .022) were associated with triple-negative tumors, whereas ZEB1 gene expression was more frequent in hormone-positive tumors (P = .004). Loss of E-cadherin was found in 19% of the tumors, but it did not correlate with aberrant expression of any of the repressors investigated herein. Nonetheless, we found that ZEB-1 protein overexpression inversely correlated with high tumor grade (P = .018), nuclear grade (P = .002), and presence of lymph nodes (P = .001), and these data were consistent with the gene expression data for ZEB1. Clinically, down-regulation of ZEB1 messenger RNA was associated with poor overall survival (P = .011) and disease-free survival (P = .053), whereas patients with TWIST negative tumors had a worse overall survival (P = .008) and disease-free survival (P = .006). Our data indicate that deregulation of TWIST is somehow important in the aggressiveness of triple-negative carcinomas and poor patient outcome, whereas down-regulation of ZEB1 seems to play a role in tumor spread, metastases, and poor survival.


Low Levels of Vitamin D in a Cohort of Women with Impalpable Breast Lesions from Rio de Janeiro/Brazil
Background: Low levels of vitamin D have been described as a risk factor for the development of breast cancer. The aim of this study was to evaluate the serum levels of vitamin D (25OHD) in patients with impalpable breast lesions comparing with a control group. Methods: Vitamin D quantification (25OHD) was assessed in the plasma of 65 patients with impalpable breast lesions and from 20 health controls using a chemiluminescent microparticle immunoassay. Pearson's chi-square test and nonparametric t-Student were used to evaluate statistical significance between the clinical variables and the means of quantification of vitamin D. The receiver operating characteristic (ROC) curve was used to evaluate the correlation between age and vitamin sufficiency for the cases and the controls. Results: The prevalence of vitamin D deficiency and/or insufficiency in women with malignant lesions was 84% and 60% for the control group. Using the chi-square or Fisher's exact test, the relationship between vitamin D levels and age presented significant association only for the control group (P=0.002). Using ROC curve, the plot area (0.778) for the control group defined a cut-off value of 45 years to age, with specificity and sensitivity of 60% and 50%, respectively. Thus, the odds ratio for vitamin D insufficiency in women over 45 years was 1.37 (P=0.011). For the case group, clinical characteristics, histological grade, and lymph node involvement did not show any significant association. Conclusion: The prevalence of vitamin D deficiency/insufficiency is high in women with impalpable breast lesions, as well as in the control group, even in a tropical city. According to the results the age advancement may be involved with the decrease in vitamin D levels in plasma, but there was no statistical association between low levels of Vitamin D and breast cancer.


Effects of somatostatin, naloxone and prochlorperazine on the control of ventilation in man.
In seven normal subjects the ventilatory responses to progressive isocapnic hypoxia and hyperoxic hypercapnia were measured during rebreathing. During an infusion of somatostatin (10 nmol/min) the mean hypoxic response decreased by 66% (control: -1.6 SD 1.2 litres min-1 %-1 SaO2; somatostatin: -0.6 SD 0.7) but the mean hypercapnic response was unchanged (control: 2.0 SD 0.8 litre min-1 mmHg-1; somatostatin: 2.3 SD 1.2). There was no change in resting VO2 or VCO2 during somatostatin infusion. The opiate antagonist, naloxone (0.1 mg/kg, intravenously), caused little change in either response (mean hypoxic response: -1.7 SD 1.0 litre min-1 %-1 SaO2; mean hypercapnic response: 2.4 SD 0.9 litre min-1 mmHg-1). In five of the subjects the dopamine antagonist, prochlorperazine (10 mg, intravenously), increased the mean hypoxic response by 134% (control: -1.9 SD 1.4 litres min-1 %-1 SaO2; after prochlorperazine: -3.8 SD 1.6; P less than 0.05). The mean hypercapnic response after this drug was also increased (control: 2.1 SD 1.0 litre min-1 mmHg-1; after prochlorperazine: 3.1 SD 1.0) but this change did not achieve significance. The selective effect of somatostatin on the hypoxic response, suggestive of an action on the carotid body, was not inhibited by prior injection of either naloxone or prochlorperazine, and its mode of action remains to be found.


Getting the first birth right: A retrospective study of outcomes for low-risk primiparous women receiving standard care versus midwifery model of care in the same tertiary hospital.
There is national and international concern for increasing obstetric intervention in childbirth and rising caesarean section rates. Repeat caesarean section is a major contributing factor, making primiparous women an important target for strategies to reduce unnecessary intervention and surgeries in childbirth. The aim was to compare outcomes for a cohort of low risk primiparous women who accessed a midwifery continuity model of care with those who received standard public care in the same tertiary hospital. A retrospective comparative cohort study design was implemented drawing on data from two databases held by a tertiary hospital for the period 1 January 2010 to 31 December 2011. Categorical data were analysed using the chi-squared statistic and Fisher's exact test. Continuous data were analysed using Student's t-test. Comparisons are presented using unadjusted and adjusted odds ratios, with 95% confidence intervals (CIs) and p-values with significance set at 0.05. Data for 426 women experiencing continuity of midwifery care and 1220 experiencing standard public care were compared. The study found increased rates of normal vaginal birth (57.7% vs. 48.9% p=0.002) and spontaneous vaginal birth (38% vs. 22.4% p=<0.001) and decreased rates of instrumental birth (23.5% vs. 28.5% p=0.050) and caesarean sections (18.8% vs. 22.5% p=0.115) in the midwifery continuity cohort. There were also fewer interventions in this group. No differences were found in neonatal outcomes. Strategies for reducing caesarean section rates and interventions in childbirth should focus on primiparous women as a priority. This study demonstrates the effectiveness of continuity midwifery models, suggesting that this is an important strategy for improving outcomes in this population.


Immunological Aspects of Chytridiomycosis.
Amphibians are currently the most threatened vertebrate class, with the disease chytridiomycosis being a major contributor to their global declines. Chytridiomycosis is a frequently fatal skin disease caused by the fungal pathogens Batrachochytrium dendrobatidis (Bd) and Batrachochytrium salamandrivorans (Bsal). The severity and extent of the impact of the infection caused by these pathogens across modern Amphibia are unprecedented in the history of vertebrate infectious diseases. The immune system of amphibians is thought to be largely similar to that of other jawed vertebrates, such as mammals. However, amphibian hosts are both ectothermic and water-dependent, which are characteristics favouring fungal proliferation. Although amphibians possess robust constitutive host defences, Bd/Bsal replicate within host cells once these defences have been breached. Intracellular fungal localisation may contribute to evasion of the induced innate immune response. Increasing evidence suggests that once the innate defences are surpassed, fungal virulence factors suppress the targeted adaptive immune responses whilst promoting an ineffectual inflammatory cascade, resulting in immunopathology and systemic metabolic disruption. Thus, although infections are contained within the integument, crucial homeostatic processes become compromised, leading to mortality. In this paper, we present an integrated synthesis of amphibian post-metamorphic immunological responses and the corresponding outcomes of infection with Bd, focusing on recent developments within the field and highlighting future directions.


Endovascular management of symptomatic cerebral malperfusion due to carotid dissection after type A aortic dissection repair.
Type A acute aortic dissection is a surgical emergency, and supra-aortic trunk involvement may be complicated by stroke in 6% to 20% of cases. A 66-year-old Caucasian female patient underwent a composite repair of the ascending aorta for type A aortic dissection. Postoperative period was complicated by episodes of "drop attack." Doppler ultrasound of supra-aortic trunks revealed an intimal flap occluding right internal carotid artery. Multiple stenting was performed from carotid bifurcation to internal carotid artery in order to exclude the dissection intimal flap. After endovascular procedure physiatrist considered that motor functional improvement was better than expected, and we support that endovascular resolution of carotid malperfusion led to a better outcome. According to other experience, endovascular procedure resulted as a safe and effective way. Moreover, ultrasound monitoring of supra-aortic trunks in postoperative period is recommended.