Peripheral Neutrophil to Lymphocyte Ratio Improves Prognostication in Colon Cancer.
We studied the role of peripheral neutrophil to lymphocyte ratio (NLR) on survival outcomes in colon and rectal cancer to determine if its inclusion improved prognostication within existing staging systems. Disease-free (DFS) and overall survival (OS) hazard ratios (HRs) of pretreatment NLR were calculated for 2536 patients with stage I to III colon or rectal cancer and adjusted for age, positive/total number of nodes, T stage, and grade. The association of NLR with clinicopathologic features and survival was evaluated and compared with the American Joint Committee on cancer (AJCC) TNM staging and Memorial Sloan Kettering Cancer Center (MSKCC) models. High NLR was significantly associated with worse DFS (HR, 1.36; 95% confidence interval [CI], 1.08-1.70; P = .009) and OS (HR, 1.65; 95% CI, 1.29-2.10; P < .0005) in all stages for patients with colon, but not rectal, cancer. High NLR was significantly associated with site-specific worse prognosis, which was stronger in the left versus right colon; an inverse relationship with grade was found. The impact of high NLR on DFS and OS occurred early, with the majority of deaths within 2 years following surgery. Adjusted HRs for 5-year and 2-year outcomes in colon cancer per each additional 2-unit increase in NLR were 1.15 (95% CI, 1.08-1.23) and 1.20 (95% CI, 1.10-1.30), respectively. The addition of NLR enhanced the prognostic utility of TNM (TNM alone vs. TNM + NLR: concordance index, 0.60 vs. 0.68), and MSKCC (MSKCC alone vs. MSKCC + NLR: concordance index, 0.71 vs. 0.73) models for colon cancer patients. NLR is an independent prognostic variable for nonmetastatic colon cancer that enhances existing clinical staging systems.


Effect of different disaccharides on the integrity and fertilising ability of freeze-dried boar spermatozoa: a preliminary study.
Freeze-drying spermatozoa is a developing technique that facilitates semen storage and transport. However, freeze-dried sperm exhibits impaired DNA integrity, which is associated with reduced fertilizing ability. Boar spermatozoa were freeze-dried in three different freeze-drying EDTA buffers with trehalose (75mM) and lactose (75mM) (EDTA-TL), (2) with sucrose (75mM) and lactose (75mM) (EDTA-SL) or just lactose (150mM) (EDTA-LL) using two freeze-drying protocols. In experiment 1 a one-step protocol was used and in experiment 2 a two-steps protocol was used. Spermatozoa were stored in1.5 mL cryo-tubes and 1.5 mL glass ampules at both 16 degree C and 25 degree C for 1 month. Successfully freeze-dried spermatozoa were stained with acridine-orange to assess chromatin stability. Freeze-drying was most successful when the 2-step protocol was used (experiment 2). Chromatin stability was greater in samples stored in glass ampules compared to cryo tubes. Chromatin stability was also greater in samples freeze-dried in EDTA-LL compared to EDTA-SL or EDTA-TL buffers. Spermatozoa freeze-dried in EDTA-LL and stored for 14 and 28 days at either 16 degree C or 25 degree C were utilized for ICSI. Two pronuclear formation wasgreatest using spermatozoa stored at 25 degree C (69.23%) and for 28 days (50%). Although 16 degree C spermatozoa samples had better stable chromatin, 25 degree C spermatozoa samples offered better two pronuclear formation results. In conclusion, boar spermatozoa freeze-dried using media containing disaccharides exhibit high chromatin stability and are able to fertilise oocytes following ICSI. Disaccharides may therefore advance the development of freeze-drying techniques for spermatozoa enabling ease of sperm storage and transportation.


Large-alphabet encoding for higher-rate quantum key distribution.
The manipulation of high-dimensional degrees of freedom provides new opportunities for more efficient quantum information processing. It has recently been shown that high-dimensional encoded states can provide significant advantages over binary quantum states in applications of quantum computation and quantum communication. In particular, high-dimensional quantum key distribution enables higher secret-key generation rates under practical limitations of detectors or light sources, as well as greater error tolerance. Here, we demonstrate high-dimensional quantum key distribution capabilities both in the laboratory and over a deployed fiber, using photons encoded in a high-dimensional alphabet to increase the secure information yield per detected photon. By adjusting the alphabet size, it is possible to mitigate the effects of receiver bottlenecks and optimize the secret-key rates for different channel losses. This work presents a strategy for achieving higher secret-key rates in receiver-limited scenarios and marks an important step toward high-dimensional quantum communication in deployed fiber networks.


Activation of NOD receptors by Neisseria gonorrhoeae modulates the innate immune response.
NOD1 and NOD2 are members of the NOD-like receptor family of cytosolic pattern recognition receptors that recognize specific fragments of the bacterial cell wall component peptidoglycan. Neisseria species are unique amongst Gram-negative bacteria in that they turn over large amounts of peptidoglycan during growth. We examined the ability of NOD1 and NOD2 to recognize Neisseria gonorrhoeae, and determined the role of NOD-dependent signaling in regulating the immune response to gonococcal infection. Gonococci, as well as conditioned medium from mid-logarithmic phase grown bacteria, were capable of activating both human NOD1 and NOD2, as well as mouse NOD2, leading to the activation of the transcription factor NF-κB and polyubiquitination of the adaptor receptor-interacting serine-threonine kinase 2. We identified a number of cytokines and chemokines that were differentially expressed in wild type versus NOD2-deficient macrophages in response to gonococcal infection. Moreover, NOD2 signaling up-regulated complement pathway components and cytosolic nucleic acid sensors, suggesting a broad impact of NOD activation on innate immunity. Thus, NOD1 and NOD2 are important intracellular regulators of the immune response to infection with N. gonorrhoeae. Given the intracellular lifestyle of this pathogen, we believe these cytosolic receptors may provide a key innate immune defense mechanism for the host during gonococcal infection.


A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice.
A conventional view of the pathogenesis of systemic lupus erythematosus has emerged. The role of B cells is to secrete pathogenic autoantibodies, while the role of T cells is to provide help for autoantibody-producing B cells. A problem with this view is that spontaneous T cell activation as well as T cell infiltration of organs such as kidney and skin are prominent features in systemic lupus erythematosus patients and murine models of lupus. The identification of T cell infiltrates, in particular, suggests that autoantibody-mediated damage may be only part of the story and that T cells could also play a primary role in immune-mediated pathology. To test the role of B cells directly, we previously generated autoimmune-prone MRL-lpr/lpr mice that lack B cells. The complete absence of T cell infiltrates in these mice was surprising, and it prompted us to examine whether a key role of B cells in disease evolution is to prime autoreactive T cells. Here we demonstrate, by comparing B cell-deficient and control mice, that the expansion of activated and memory T cells in the MRL-lpr/lpr mouse is indeed highly dependent on B cells. These results suggest a novel role for B cells in autoimmune disregulation.


[Natural history of Kawasaki disease vasculitis].
Kawasaki disease is an acute vasculits syndrome of unknown etiology, which mainly affects small and medium arteries particularly coronary arteries in infants and young children. The cardiovascular problems include coronary artery lesions that develop the aneurysm formation, thrombotic occlusion, progression to coronary artery disease, and pre- mature atherosclerosis. However, the long-term consequences of these cardiovascular problems are still uncertain. In this article the long-term spectrums of Kawasaki disease vasculitis are described by our long-term follow-up study of 2,450 patients from clinical and pathological aspects. We like to emphasize that the long-term cardiovascular prob- lems are important issues not only in children but also in adulthood.


Environmental Benefits of Novel Nonhuman Food Inputs to Salmon Feeds.
Global population growth and changing diets increase the importance, and challenges, of reducing the environmental impacts of food production. Farmed seafood is a relatively efficient way to produce protein and has already overtaken wild fisheries. The use of protein-rich food crops, such as soy, instead of fishmeal in aquaculture feed diverts these important protein sources away from direct human consumption and creates new environmental challenges. Single cell proteins (SCPs), including bacteria and yeast, have recently emerged as replacements for plant-based proteins in salmon feeds. Attributional life cycle assessment is used to compare salmon feeds based on protein from soy, methanotrophic bacteria, and yeast ingredients. All ingredients are modeled at the industrial production scale and compared based on seven resource use and emissions indicators. Yeast protein concentrate showed drastically lower impacts in all categories compared to soy protein concentrate. Bacteria meal also had lower impacts than soy protein concentrate for five of the seven indicators. When these target meals were incorporated into complete feeds the relative trends remain fairly constant, but benefits of the novel ingredients are dampened by high impacts from the nontarget ingredients. Particularly, primary production requirements (PPR) are about equal and constant across all feeds for both analyses since PPR was driven by fishmeal and oil. The bacteria-based feed has the highest climate change impacts due to the use of methane to feed the bacteria who then release carbon dioxide. Overall, the results of this study suggest that incorporating SCP ingredients into salmon feeds can help reduce the environmental impacts of salmon production. Continued improvements in SCP production would further increase the sustainability of salmon farming.


[Stab wound of the urinary bladder with peritonitis].
In the paper a rare case is presented of intraperitoneal damage to the urinary bladder in a 27-year-old, significantly psychophysically handicapped man. The damage was caused by introduction of a foreign body through the urethra by another person and was diagnosed intraoperationally.


Grape seed proanthocyanidins regulate mitophagy of endothelial cells and promote wound healing in mice through p-JNK/FOXO3a/ROS signal pathway.
Skin wound healing is a dynamic and complex process that involves multiple physiological and cellular events. Grape seed proanthocyanidins (GSP) have strong anti-oxidation and elimination of oxygen free radicals, and have been shown to significantly promote wound healing, but the underlying mechanism remains unclear. Studies have indicated that reactive oxygen species (ROS) acts as an upstream signal to induce mitophagy, suggesting that GSP can regulate mitophagy through the signal pathway. This study aimed to investigate whether GSP regulates mitophagy by down-regulating oxidative stress to promote wound healing. In vivo, GSP treatment accelerated wound healing, granulation tissue formation, collagen deposition, and angiogenesis in mice. Moreover, GSP down-regulated ROS levels and promoted the expression of antioxidant proteins by up-regulating the expression of p-JNK/FOXO3a protein, thereby regulating the expression of mitophagy-related proteins. In vitro, 4 μg/mL GSP showed no apparent toxic effects on cells and effectively reduce the oxidative stress damage of cells induced by H2O2. Western blot and superoxide anion fluorescence probe further confirmed that GSP effectively reduced Dihydroethidium content and up-regulated the expression of antioxidant proteins by activation of p-JNK/FOXO3a protein expression, thereby regulating mitophagy. Taken together, the findings from in vitro and in vivo experiments provide new insights into the promotion of wound healing by GSP.


Cytotoxic CD8+ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.
Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4+ T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8+ T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8+ T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8+ T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1)G93A mutant decreased spinal motoneuron loss. Using motoneuron-CD8+ T cell coculture systems, we found that mutant SOD1-expressing CD8+ T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1G93A CD8+ T cells. Activated mutant SOD1 CD8+ T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8+ T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS.


Covalent flavinylation of 6-hydroxy-D-nicotine oxidase analyzed by partial deletions of the gene.
The expression of the enzymatically active 6-hydroxy-D-nicotine oxidase (6-HDNO) from Arthrobacter oxidans requires the covalent attachment of FAD to the polypeptide chain. How this modification takes place and at what time during the synthesis of the polypeptide is not known. We investigated the possibility of cotranslational flavinylation by generating various deletions of the 6-HDNO gene carried on appropriate plasmid vectors. The polypeptides expressed from these plasmids were analyzed for their ability to incorporate [14C]FAD covalently in an Escherichia coli-derived coupled transcription/translation system. The data show that removal of approximately 40% from the carboxy-terminal part of the 6-HDNO polypeptide did not inhibit the covalent flavinylation of the truncated protein. A fusion protein, consisting of the truncated 6-HDNO polypeptide and the beta-lactamase of pBR322, was also covalently flavinylated. The amino acid sequence surrounding the histidine residue, assumed to bind FAD, was shown to be situated approximately 70 amino acid residues from the amino-terminal end of the 6-HDNO polypeptide. Removal of the first 30 amino acids did not abolish covalent flavinylation. Flavinylation could no longer be detected, however, if a short amino acid sequence, consisting of seven residues, replaced the amino acid sequence upstream of the histidine. These findings prove, in our opinion, that cotranslational flavinylation takes place in the synthesis of 6-HDNO.


Disseminated invasive aspergillosis caused by Aspergillus felis in a cat.
A 2-year-old male desexed Ragdoll cat with a 1-year history of sneezing and nasal discharge presented with a large subcutaneous cervical mass, identified as the right medial retropharyngeal lymph node on computed tomography (CT). A right orbital mass, destructive sino-nasal cavity disease and multiple pulmonary nodules were also identified. Aspergillus felis was cultured from the lymph node. After treatment with posaconazole and liposomal amphotericin B the lymph node enlargement and orbital mass resolved but left frontal sinus involvement and pulmonary lesions persisted despite additional caspofungin therapy. The cat was euthanized 14 months after diagnosis with dysphagia and chronic progressive exophthalmos. A meningeal granuloma with intravascular fungal hyphae was identified at post-mortem and A felis was cultured from the left frontal sinus and a right retrobulbar fungal granuloma. This case demonstrates that disseminated disease is a possible sequel to invasive fungal rhinosinusitis caused by A felis in cats.


Beyond the blame game.
The federal government announced the establishment of the National Health and Hospitals Reform Commission (NHHRC) in February 2008 to advise on future directions of health care delivery in Australia. In late April, the NHHRC issued its first report, Beyond the blame game, giving its views on key issues for the proper function of the Australian Health Care Agreements. In this report, the NHHRC has proposed 44 benchmarks to be met by both federal and state governments, where performance should have clear consequences for the accountable party.


Left ventricular myocardium metastasis in a patient with primary renal cell carcinoma detected by 18F-FDG PET/CT.
Cardiac metastases from renal cell carcinoma are rare but should be recognized when present. We report PET/CT findings in a patient with headache and diplopia and cerebral metastasis from an unknown primary of clear cell adenocarcinoma origin. PET/CT revealed uptake with a left renal cell carcinoma, and revealed multiple metastatic lesions, including an FDG-avid metastasis within the left ventricular myocardium.


[Establishment of anterior cruciate ligament reconstruction model in cynomolgus monkey with autogenous hamstring tendon transplantation].
To investigate the feasibility of establishing an anterior cruciate ligament (ACL) reconstruction model using hamstring tendon autograft in cynomolgus monkeys. Twelve healthy adult male cynomolgus monkeys, weighing 8-13 kg, were randomly divided into two groups ( n=6). In the experimental group, the ACL reconstruction model of the right lower limb was prepared by using a single bundle of hamstring tendon, and the ACL of the right lower limb was only cut off in the control group. The survival of animals in the two groups was observed after operation. Before operation and at 3, 6, and 12 months after operation, the knee range of motion, thigh circumference, and calf circumference of the two groups were measured; the anterior tibial translation D-value (ATTD) was measured by Ligs joint ligament digital body examination instrument under the loads of 13-20 N, respectively. At the same time, the experimental group underwent MRI examination to observe the graft morphology and the signal/ noise quotient (SNQ) was caculated. All animals survived to the end of the experiment. In the experimental group, the knee range of motion, thigh circumference, and calf circumference decreased first and then gradually increased after operation; the above indexes were significantly lower at 3 and 6 months after operation than before operation ( P<0.05), and no significant difference was found between pre-operation and 12 months after operation ( P>0.05). In the control group, there was no significant change in knee range of motion after operation, showing no significant difference between pre- and post-operation ( P>0.05), but the thigh circumference and calf circumference gradually significantly decreased with time ( P<0.05), and the difference was significant when compared with those before operation ( P<0.05). At 6 and 12 months after operation, the thigh circumference and calf circumference were significantly larger in the experimental group than in the control group ( P<0.05). At 3 and 6 months after operation, the knee range of motion was significantly smaller in the experimental group than in the control group ( P<0.05). Under the loading condition of 13-20 N, the ATTD in the experimental group increased first and then decreased after operation; and the ATTD significantly increased at 3, 6 months after operation when compared with the value before operation ( P<0.05). But there was no significant difference between the pre-operation and 12 months after operation ( P>0.05). There was no significant change in ATTD in the control group at 3, 6, and 12 months after operation ( P>0.05), and which were significantly higher than those before operation ( P<0.05). At each time point after operation, the ATTD was significantly smaller in the experimental group than in the control group under the same load ( P<0.05). The MRI examination of the experimental group showed that the ACL boundary gradually became clear after reconstruction and was covered by the synovial membrane. The SNQ at each time point after operation was significantly higher than that before operation, but gradually decreased with time, and the differences between time points were significant ( P<0.05). The ACL reconstruction model in cynomolgus monkey with autogenous hamstring tendon transplantation was successfully established.


Synthesis and immunoreactivity of neoglycoproteins containing the trisaccharide unit of phenolic glycolipid I of Mycobacterium leprae.
The trisaccharide segment, O-(3,6-di-O-methyl-beta-D-glucopyranosyl)-(1----4)-O-(2,3-di-O-methyl- alpha-L-rhamnopyranosyl)-(1----2)-3-O-methyl-L-rhamnopyranose, of the Mycobacterium leprae-specific phenolic glycolipid I has been synthesized as its 8-(methoxycarbonyl)octyl glycoside and coupled to a carrier protein, to produce a leprosy-specific neoglycoprotein, the so-called natural trisaccharide-octyl-bovine serum albumin (NT-O-BSA). Special features of the synthetic strategy were the use of silver trifluoromethanesulfonate (triflate) to promote glycosylation, resulting in the rhamnobiose in high yield and absolute stereospecificity. The terminal 3,6-di-O-methyl-D-glucopyranosyl group was introduced after O-deallylation of the rhamnobiose. Removal of protecting groups yielded the trisaccharide hapten suitable for coupling to carrier protein. Poly(acrylamide)-gel electrophoresis of the neoglycoprotein demonstrated its purity, and subsequent immunoblotting with a monoclonal antibody directed to the terminal 3,6-di-O-methyl-beta-D-glucopyranosyl epitope of the native glycolipid demonstrated its antigenicity. Comparative serological testing in enzyme-linked immunosorbent assays of NT-O-BSA, the corresponding disaccharide-containing products, and another trisaccharide-containing neoglycoprotein, O-(3,6-di-O-methyl-beta-D-glucopyranosyl)-(1----4)-O-(2,3-di-O- methyl-alpha-L-rhamnopyranosyl)-(1----2)-(3-O-methyl-alpha-L-rhamnopy ran osyl)- (1----4')-oxy-(3-phenylpropanoyl)-BSA (NT-P-BSA) [Fujiwara et al., Agric. Biol. Chem., 51 (1987) 2539-2547] against sera from leprosy patients and control populations showed concordance; the presence of the innermost sugar did not contribute significantly to sensitivity or specificity. The di- and tri-saccharide-containing neoantigens, on account of ready availability and solubility, provide greater flexibility than the native glycolipid for the serodiagnosis of leprosy.


Regulatory perspective on remaining challenges for utilization of pharmacogenomics-guided drug developments.
Pharmacogenomics-guided drug development has been implemented in practice in the last decade, resulting in increased labeling of drugs with pharmacogenomic information. However, there are still many challenges remaining in utilizing this process. Here, we describe such remaining challenges from the regulatory perspective, specifically focusing on sample collection, biomarker qualification, ethnic factors, codevelopment of companion diagnostics and means to provide drugs for off-target patients. To improve the situation, it is important to strengthen international harmonization and collaboration among academia, industries and regulatory agencies, followed by the establishment of an international guideline on this topic. Communication with a regulatory agency from an early stage of drug development is also a key to success.


Psychopathology, quality of life and risk factors in children and adolescents with recent-onset epilepsy.
The aim of this study was to describe the distribution, timing, and risk factors for psychopathology and to further examine the quality of life (QoL) in an Italian sample of children with recent onset epilepsy. Sociodemographic and psychosocial variables, family factors, as well as illness-related factors themselves were examined in order to clarify the relationship among these variables, psychopathology and QoL. For this purpose, 49 children and adolescents (4-18 years), consecutively referred to a Neurophysiology Service, were evaluated by a multidisciplinary team using dimensional as well as categorical instruments both self-administered (self-report and proxy-report) and interviewer administered. Forty-five percent of the patients exhibited one or more Axis I disorders (DSM-IV) when evaluated with K-SADS-PL interview. It's worth noting that preadolescent and adolescent patients tend to underestimate their problems compared to their parents'opinion, when answering self-administer questionnaires. Self-reported QoL appeared to be generally satisfactory. Social and family factor, as well as epilepsy related factors appeared to be linked both to the presence of psychopathology and to the QoL. Patients affected by psychiatric disorders exhibited the poorest QoL. Also after many years from the onset, childhood epilepsy frequently fosters negative consequences in terms of social life, work, psychopathology and life expectancy. The ability of health services and public health measures to prevent and treat psychiatric comorbidity may have a pivotal role in enhancing patients' QoL.


Intraoperative discovery of melanosis coli during emergent bowel resection for perforation.
A patient was taken to the operating room with a presumptive diagnosis of necrotic small bowel and colon. During the procedure, it was noted that she had black mucosa throughout the colon. Several factors suggested viable colonic tissue, and the decision was made to not resect the colon as originally planned. Final pathology of the specimen would later reveal melanosis coli, an ultimately benign diagnosis. Further questioning of the patient found that she had taken a herbal laxative supplement containing several components which are known to cause melanosis coli. We hope that this case report will serve as a reminder to surgeons and clinicians to remember melanosis coli as a clinical entity when confronted with blackened or darkened colonic mucosa. On review of available literature, we identified other cases in which melanosis coli was discovered intraoperatively, and we propose a number of factors to support intraoperative decision making.


Epidemiological Features of Nontraumatic Spontaneous Subarachnoid Hemorrhage in China: A Nationwide Hospital-based Multicenter Study.
Nontraumatic spontaneous subarachnoid hemorrhage (SAH) is associated with a high mortality. This study was conducted to investigate the epidemiological features of nontraumatic spontaneous SAH in China. From January 2006 to December 2008, the clinical data of patients with nontraumatic SAH from 32 major neurosurgical centers of China were evaluated. Emergent digital subtraction angiography (DSA) was performed for the diagnosis of SAH sources in the acute stage of SAH (≤3 days). The results and complications of emergent DSA were analyzed. Repeated DSA or computed tomography angiography (CTA) was suggested 2 weeks later if initial angiographic result was negative. A total of 2562 patients were enrolled, including 81.4% of aneurysmal SAH and 18.6% of nonaneurysmal SAH. The total complication rate of emergent DSA was 3.9% without any mortality. Among the patients with aneurysmal SAH, 321 cases (15.4%) had multiple aneurysms, and a total of 2435 aneurysms were detected. The aneurysms mostly originated from the anterior communicating artery (30.1%), posterior communicating artery (28.7%), and middle cerebral artery (15.9%). Among the nonaneurysmal SAH cases, 76.5% (n = 365) had negative initial DSA, including 62 cases with peri-mesencephalic nonaneurysmal SAH (PNSAH). Repeated DSA or CTA was performed in 252 patients with negative initial DSA, including 45 PNSAH cases. Among them, the repeated angiographic results remained negative in 45 PNSAH cases, but 28 (13.5%) intracranial aneurysms were detected in the remaining 207 cases. In addition, brain arteriovenous malformation (AVM, 7.5%), Moyamoya disease (7.3%), stenosis or sclerosis of the cerebral artery (2.7%), and dural arteriovenous fistula or carotid cavernous fistula (2.3%) were the major causes of nonaneurysmal SAH. DSA can be performed safely for pathological diagnosis in the acute stage of SAH. Ruptured intracranial aneurysms, AVM, and Moyamoya disease are the major causes of SAH detected by emergent DSA in China.


Recruitment of endoplasmic reticulum-targeted and cytosolic mRNAs into membrane-associated stress granules.
Stress granules (SGs) are membraneless organelles composed of mRNAs and RNA binding proteins which undergo assembly in response to stress-induced inactivation of translation initiation. In general, SG recruitment is limited to a subpopulation of a given mRNA species and RNA-seq analyses of purified SGs revealed that signal sequence-encoding (i.e., endoplasmic reticulum [ER]-targeted) transcripts are significantly underrepresented, consistent with prior reports that ER localization can protect mRNAs from SG recruitment. Using translational profiling, cell fractionation, and single molecule mRNA imaging, we examined SG biogenesis following activation of the unfolded protein response (UPR) by 1,4-dithiothreitol (DTT) and report that gene-specific subsets of cytosolic and ER-targeted mRNAs can be recruited into SGs. Furthermore, we demonstrate that SGs form in close proximity to or directly associated with the ER membrane. ER-associated SG assembly was also observed during arsenite stress, suggesting broad roles for the ER in SG biogenesis. Recruitment of a given mRNA into SGs required stress-induced translational repression, though translational inhibition was not solely predictive of an mRNA's propensity for SG recruitment. SG formation was prevented by the transcriptional inhibitors actinomycin D or triptolide, suggesting a functional link between gene transcriptional state and SG biogenesis. Collectively these data demonstrate that ER-targeted and cytosolic mRNAs can be recruited into ER-associated SGs and this recruitment is sensitive to transcriptional inhibition. We propose that newly transcribed mRNAs exported under conditions of suppressed translation initiation are primary SG substrates, with the ER serving as the central subcellular site of SG formation.


Successful treatment of refractory complete separation of an esophagojejunal anastomosis after laparoscopic total gastrectomy: a case report.
Anastomotic leakage after total gastrectomy occurs despite improvements in surgical techniques and patient management. Although many cases of dehiscence can be managed non-operatively, major leakage requires a second surgery and can potentially lead to death. Therefore, accurate and immediate diagnosis and treatment are essential. In this report, we describe a 66-year-old Japanese man who was diagnosed with a complete separation of an esophagojejunal anastomosis after laparoscopic total gastrectomy with oral contrast radiography using Gastrografin®. The severe complication was successfully treated by re-anastomosis after two emergency drainage surgeries. After the second surgery, the esophageal end formed a fistula with the jejunum, but balloon dilation failed to open the fistula. Therefore, oral ingestion and conservative treatment were considered unsuitable, and we performed esophagojejunal re-anastomosis 7 months after the first surgery. At a follow-up examination 2 years after re-anastomosis, the patient weighed 47 kg, and his ingestion had recovered to 80% of that before surgery. Complete separation of an esophagojejunal anastomosis is a rare but severe complication of total gastrectomy. Therefore, we consider that once separation is diagnosed, aggressive and urgent re-operation and effective drainage are useful. Moreover, it is necessary to take great care to minimize the operative morbidity associated with esophagojejunal anastomosis.


Calcium-entry blockers and arterial compliance in hypertension.
Calcium-entry blockers dilate small arteries as well as large arteries, particularly in the brachial and the carotid circulations. This dilating effect is associated with an increase in systemic and brachial arterial compliance, which is poorly related to the level in blood pressure. Calcium-entry blockers are able to reverse the reduced arterial compliance observed in patients with essential hypertension, with important consequences to the structure and function of the heart and large vessels.


Transcriptional networks specifying homeostatic and inflammatory programs of gene expression in human aortic endothelial cells.
Endothelial cells (ECs) are critical determinants of vascular homeostasis and inflammation, but transcriptional mechanisms specifying their identities and functional states remain poorly understood. Here, we report a genome-wide assessment of regulatory landscapes of primary human aortic endothelial cells (HAECs) under basal and activated conditions, enabling inference of transcription factor networks that direct homeostatic and pro-inflammatory programs. We demonstrate that 43% of detected enhancers are EC-specific and contain SNPs associated to cardiovascular disease and hypertension. We provide evidence that AP1, ETS, and GATA transcription factors play key roles in HAEC transcription by co-binding enhancers associated with EC-specific genes. We further demonstrate that exposure of HAECs to oxidized phospholipids or pro-inflammatory cytokines results in signal-specific alterations in enhancer landscapes and associate with coordinated binding of CEBPD, IRF1, and NFκB. Collectively, these findings identify cis-regulatory elements and corresponding trans-acting factors that contribute to EC identity and their specific responses to pro-inflammatory stimuli.


Pallister-Killian syndrome in a two-year-old boy.
Pallister-Killian syndrome (PKS) is a rare, sporadic, multisystem developmental disorder characterized by craniofacial dysmorphic features. We report a case of a two-year-old boy with PKS to highlight the cutaneous findings and emphasize the importance of diagnostic skin biopsies in patients with cutaneous pigmentation changes and distinctive facial features.


Third party bargaining and contract terms: a link over time?
To evaluate whether prior pharmacy bargaining process strategies and pharmacy dependence on third parties affect the bargaining power of pharmacies in price negotiations with third parties. One-time survey. Random sample of 900 independent and small chain pharmacies in nine states: Colorado, Connecticut, Georgia, Kentucky, Minnesota, Oklahoma, Oregon, Pennsylvania, and Wisconsin. Two hundred sixteen of the returned surveys contained sufficient responses for this analysis. Survey data on pharmacy bargaining power and prior pharmacy bargaining strategies, pharmacy dependence, and market characteristics were analyzed using multiple regression in a previously developed and modified provider/third party bargaining model. Pharmacy bargaining power. Pharmacy bargaining power varied across our sample. Pharmacy bargaining power was positively related to whether a pharmacy previously bargained with the third parties, negatively related to prior requests for contract changes, and negatively related to the pharmacy's dependence on third parties in total. Pharmacy bargaining power is related to the bargaining strategies employed by pharmacies during the previous year and the dependence of pharmacies on third party payers in total. With the prevalence of "take-it-or-leave-it" contracts from third parties, prior pharmacy bargaining behavior may affect the initial terms of the contracts that pharmacies are offered.


Impact of structure and morphology on charge transport in semiconducting oligomeric thin-film devices.
We investigated various thin-film morphologies of vacuum-deposited highly luminescent 2,5-di-n-octyloxy-1,4-bis[4'-(styryl)styryl]benzene (Ooct-OPV5) in a typical light-emitting-diode device structure. Important modifications in the thin-film morphology and structure were obtained by changing the substrate temperature in the range 23-90 degrees C. Structural analysis by X-ray and electron diffraction provided clear evidence for polymorphism in evaporated thin films of Ooct-OPV5. Concomitantly, the hole mobility in the corresponding devices was determined by transient electroluminescence measurements. We demonstrate that the substrate temperature T(sub) is a key parameter that controls the hole mobility of the devices. Increasing T(sub) between 23 and 84 degrees C results in a progressive increase of the zero-field hole mobility from 10(-6) to 10(-4) cm(2) V(-1) s(-1). The increase in hole mobility is correlated to the average grain size in the thin films. In addition, we give evidence for the existence of a peculiar growth mode in the bulk crystal structure of Ooct-OPV5, whereby the (a,b) and (b,c) planes can grow in a homoepitaxial manner.


Circadian rhythms in airline pilots submitted to long-haul transmeridian flights.
Circadian rhythms shift out of phase after transmeridian flights. Desynchronization between body rhythms and the environment is linked to jet lag, which depends on age, flight direction, and number of time zones crossed. To investigate this problem in airline pilots, we performed a multivariate analysis of their circadian systems during Madrid-Mexico-Madrid flights (-7 time zones, n = 12) and Madrid-Tokyo-Madrid flights (+8 time zones, n = 21). Telemetry was used to record pilots' activity, skin temperature, and heart rate, obtaining 6 d of continuous data, including 2 d before the flight, the flights themselves, 2 d at the stopover, and 1 d after the return flight. Time series were analyzed by cosinor, and the resulting parameters of the rhythms were compared by ANOVA and Tukey contrasts in every category formed by the age groups (under and over 50 yr old) and flight direction groups. Subjective time estimation of short, intermediate, and long intervals was recorded. Other psychological variables were measured, including anxiety, tiredness, and performance. Activity/rest and heart rate rhythms appeared to be linked to a "weak oscillator." Temperature rhythms manifested a rigid response after the phase shifts of the light/dark cycle, closely related to the biological clock. Subjective time appreciation tended to be overestimated without exhibiting a clear circadian component, but attributable to fatigue and stress. Psychometric evaluation showed that desynchronization affected all the pilots. Some results showed an age-related variability with a more marked influence in younger pilots. No consistent effects regarding flight direction were found.


Human plasma ATP concentration.
Human plasma ATP concentration is reported in many studies as roughly 1000 nmol/L. The present study tested the hypothesis that the measured plasma ATP concentration is lower if ATP release from formed blood elements is inhibited during blood sample processing. A second hypothesis was that pretreatment with aspirin to inhibit platelets would reduce the measured plasma concentration of ATP. Blood was sampled from the antecubital vein in 20 healthy individuals 30 and 60 min after ingestion of aspirin (325 mg) or placebo. Aliquots of each blood sample were added to the usual EDTA/saline solution to inhibit ATP catabolism, or to a new stabilizing solution designed to both stop ATP catabolism and inhibit ATP release from blood elements. The stabilizing solution contained NaCl, EDTA, tricine buffer, KCl, nitrobenzylthioinosine, forskolin, and isobutylmethylxanthine. Plasma ATP was measured with the luciferin-luciferase assay with standard additions in each sample to determine ATP content. Hemoglobin concentration was used as an index of sample hemolysis, and the plasma ATP concentration was corrected for the hemolysis component. Aspirin pretreatment had no effect on plasma ATP concentrations. However, use of the stabilizing solution resulted in mean (SD) ATP concentrations 8-fold lower than the use of EDTA alone [28 (16) vs 236 (201) nmol/L; P <0.001]. When precautions are taken to inhibit ATP release from blood elements during sample preparation, human venous plasma ATP concentration is much lower than previously reported.


Local Referral of High-risk Patients to High-quality Hospitals: Surgical Outcomes, Cost Savings, and Travel Burdens.
We sought to assess the potential changes in Medicare payments and clinical outcomes of referring high-risk surgical patients to local high-quality hospitals within small geographic areas. Previous studies have documented a benefit in referring high-risk patients to high-quality hospitals on a national basis, suggesting selective referral as a mechanism to improve the value of surgical care. Practically, referral of patients should be done within small geographic regions; however, the benefit of local selective referral has not been studied. We analyzed data on elderly Medicare beneficiaries undergoing any of 4 elective inpatient surgical procedures between 2012 and 2014. Hospitals were categorized into Metropolitan Statistical Areas by zip code and stratified into quintiles of quality based on rates of postoperative complications. Patient risk was calculated by modeling the predicted risk of a postoperative complication. Medicare payments for each surgical episode were calculated. Distances between patients' home zip code and high- and low-quality hospitals were calculated. One quarter of high-risk patients underwent surgery at a low-quality hospital despite the availability of a high-quality hospital in their small geographic area. Shifting these patients to a local high-quality hospital would decrease spending 12% to 37% ($2,500 for total knee and hip replacement, $6,700 for colectomy, and $11,400 for lung resection). Approximately 45% of high-risk patients treated at low-quality hospitals could travel a shorter distance to reach a high-quality hospital than the low-quality hospital they received care at. Complication rates and Medicare payments are significantly lower for high-risk patients treated at local high-quality hospitals. This suggests triaging high-risk patients to local high-quality hospitals within small geographic areas may serve as a template for improving the value of surgical care.


Does lateral lymph node dissection improve survival in rectal carcinoma? Examination of node metastases by the clearing method.
The treatment of rectal carcinoma by lateral lymph node dissection has risks and benefits. Therefore, we investigated the therapeutic efficacy of lateral lymph node dissection. We studied 198 patients with rectal carcinoma who underwent lateral lymph node dissection. Metastases to the lymph nodes were examined by the clearing method. The incidence of urinary and male sexual dysfunction was determined by measuring the residual urine volume and individual interview 1 year after operation. The rate of metastasis to lateral lymph nodes was 11.1 percent, and metastasis to the lateral lymph nodes occurred more frequently with lower rectal carcinoma classified as pT3 or pT4 in the TNM system. The rate of local recurrence was 12.5 percent and the 5-year survival rate after curative resection was 70.1 percent. The 5-year survival rate in patients with metastasis to the lateral lymph nodes was 25.1 percent, and this rate was significantly lower than the 5-year survival rate of 74.3 percent in patients without metastasis to the lateral lymph nodes. Urinary dysfunction was observed in 67.5 percent of patients, and male sexual dysfunction was found in 97.4 percent of men younger than 60 years of age with prior sexual ability. The prognosis for patients with metastasis to the lateral lymph nodes is poor, and the improvement in survival rate from lateral lymph node dissection is minimal.


Strengthening adult mosquito surveillance in Africa for disease control: learning from the present.
Mosquito surveillance is essential to successfully control and eliminate mosquito-borne diseases. Yet, it is often done by numerous organizations with little collaboration, incomplete understanding of existing gaps, and limited long-term vision. There is a clear disconnect between entomological and epidemiological indices, with entomological data informing control efforts inadequately. Here, we discuss current mosquito surveillance practises across the heterogeneous disease landscape in Africa. We advocate for the development of mosquito surveillance strategic plans to increase the impact and functionality of mosquito surveillance. We urge for a proactive approach to set up centralized mosquito data systems under the custodian of national governments, focus on epidemiologically relevant mosquito data, and increase the robustness of mosquito surveillance using a more spatially explicit sampling design.


An ab initio study of the photodissociation of CH2I and CH2I.
Photodissociation of the CH2I radical and the CH2I+ cation is studied by means of high-level ab initio calculations, including spin-orbit effects. Potential-energy curves (PEC) along the dissociating bond distances involved in some fragmentation pathways of these species are computed for the ground and several excited electronic states. Based on the PECs obtained, the possible photodissociation mechanisms are analyzed and suggested. Significant differences are found between the fragmentation dynamics of the neutral radical and that of the cation. While a relatively simple dissociation dynamics is predicted for CH2I, more complex fragmentation mechanisms involving internal conversion and couplings between different excited electronic states are expected for CH2I+. The species studied here are relevant to atmospheric chemistry, and the present work can help to understand better how their photodissociation may affect chemical processes in the atmosphere.


Photoprocesses in protoplanetary disks.
Circumstellar disks are exposed to intense ultraviolet (UV) radiation from the young star. In the inner disks, the UV radiation can be enhanced by more than seven orders of magnitude compared with the average interstellar radiation field, resulting in a physical and chemical structure that resembles that of a dense photon-dominated region (PDR). This intense UV field affects the chemistry, the vertical structure of the disk, and the gas temperature, especially in the surface layers. The parameters which make disks different from more traditional PDRs are discussed, including the shape of the UV radiation field, grain growth, the absence of PAHs, the gas/dust ratio and the presence of inner holes. Illustrative infrared spectra from the Spitzer Space Telescope are shown. New photodissociation cross sections for selected species, including simple ions, are presented. Also, a summary of cross sections at the Lyman alpha 1216 A line, known to be strong for some T Tauri stars, is made. Photodissociation and ionization rates are computed for different radiation fields with color temperatures ranging from 30000 to 4000 K and grain sizes up to a few microm. The importance of a proper treatment of the photoprocesses is illustrated for the transitional disk toward HD 141569A which includes grain growth.


Laparoscopic surgery in a paediatric patient with Down's syndrome and patent foramen ovale.
The safety of laparoscopic surgery in infants with congenital heart disease has been a subject of controversy despite potential benefits over open surgery. The authors present the anaesthetic management of a 6-month-old female infant with Down's syndrome with a small patent foramen ovale with left to right shunt who successfully underwent laparoscopic coloplasty. There were no intraoperative or postoperative complications. In addition to the routine anaesthetic considerations for any surgical patient, the choice of the anaesthetic technique in patients undergoing laparoscopic procedures should consider the effect on the patient's underlying cardiorespiratory function of pneumoperitoneum and carbon dioxide insufflation.


Age differences in the retrieval of information from semantic memory.
An experiment was conducted to determine the speed with which old and young individuals could either generate an example of a category or decide if two words were related. In one condition, generation and decision trials were blocked together, while in the other condition trials were mixed randomly. No interactions between age and the mixed/blocked variable were observed in the decision task. However, in the generation task young individuals showed differentially lower reaction times in the blocked trials condition. It was argued that the differences between the performance of the two age groups reflected age differences in the utilization of automatic and effortful processing strategies. A second experiment was performed to examine the activation of semantic memory in an automatized processing task. While there was an overall age decrement in reaction time, the amount of facilitation in the retrieval processes was equal for both age groups.


[Ethnography of the determinants of eating behaviour in diabetic schooolchildren in Yaounde].
Objective: Failure to comply with dietary recommendations exposes young insulin-dependent diabetics to a risk of acute complications of diabetes and is a subject of major concern for health care professionals, who expected young diabetics to effectively adopt the recommended eating behaviour based on the revised diet. However, the revised diet initiated by health care professionals in Cameroon has been shown to have a limited efficacy. The objective of this study was to elucidate the motivations underlying poor compliance young diabetics with dietary recommendations and which simultaneously determine their eating behaviour. Methods: The study was conducted in Yaoundé and was based on observations and biographical interviews with 13 students between the ages of 15 and 20 years with a diagnosis of diabetes for at least 6 months. Data were analysed by content analysis. Results: The results revealed negative perceptions of diabetes and treatment, encouraging young diabetics not to comply with the recommended eating and an influence of their social environment, i.e. school characteristics, peers and family, on their eating behaviour. Conclusion: The eating behaviour of young diabetics is determined equally by individual motivations related to their perceptions and social motivations. These motivations must be taken into account by health care professionals to promote better adherence of patients to dietary recommendations.


2‑Deoxy‑D‑glucose initiates hepatocyte differentiation in human induced pluripotent stem cells.
To initiate hepatocyte differentiation in human induced pluripotent stem (iPS) cells, cells are cultured in a medium lacking glucose but supplemented with galactose (hepatocyte selection medium, HSM) or in medium supplemented with oncostatin M and small molecules (hepatocyte differentiation inducer, HDI). In the present study, 2‑Deoxy‑D‑glucose (2DG), an analogue of glucose, was utilized instead of glucose deprivation and the effect of 2DG supplementation on iPS differentiation was examined. First, 201B7 cells, an iPS cell line, were cultured in HSM or HDI media for 2 days and then subjected to reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) in order to analyze expression levels of established hepatocyte markers, including cytosolic aspartate aminotransferase (AST), mitochondrial AST, alanine aminotransferase (ALT), and glycerol kinase. mRNA expression levels of mitochondrial AST, ALT, and glycogen synthase significantly increased following culture in HSM and HDI compared with ReproFF media. Cytosolic AST mRNA expression levels significantly increased following culture in HDI compared with ReproFF media, but not in HSM. To test the effect of 2DG on iPS differentiation, 201B7 cells were cultured in ReproFF, a feeder‑free medium that retains pluripotency, supplemented with 2DG. Following 7 days of culture, the cells were subjected to RT‑qPCR to analyze expression levels of α‑fetoprotein (AFP), a marker of immature hepatocytes. AFP mRNA expression levels significantly increased with the addition of 0.1 µM 2DG in the media, and galactose addition acted synergistically with 2DG to further upregulate AFP expression. In conclusion, the present study demonstrated that hepatocyte differentiation was initiated in iPS cells cultured in HSM and HDI media and that 2DG could be used as a supplement instead of glucose deprivation to initiate hepatocyte differentiation in iPS cells.


Detection of Chromosomal Abnormalities with Different In Situ Hybridisation Techniques--the Usefulness in the Qualification of Cancer Patients for Molecularly-Targeted Therapies.
Proper qualification of patients with cancer for an effective treatment regiment is essential to rationalize therapy benefit and costs. The early detection of genetic disorders that are responsible for the stimulation of uncontrolled cancer cells proliferation makes it possible to select a group of patients with a high probability of response to molecularly-targeted therapy. Data has shown that careful analysis of genes mutation using different PCR and sequencing techniques or chromosomal aberrations using in situ hybridization (ISH) techniques have a predictive value for drug targeted therapy. Overexpression of receptors and gene amplification has been reported in various cancers. Their detection is still a considerable challenge, which is connected with the unsatisfactory quality of DNA and low mutated cells percentage compared to cells with no genetic abnormalities in tested material. Different techniques of standardization were performed to prevent false negative results and to increase the sensitivity of qualitative and quantitative evaluation of chromosomal abnormalities. Immunohistochemistry (IHC) technique is useful in the screening of receptor expression in paraffin-embedded tissue samples in different malignant diseases. Whereas ISH techniques, especially fluorescence in situ hybridization (FISH), are now considered the diagnostic gold standard method in detection chromosomal aberrations. Moreover, molecular biology techniques, which are using molecular probes and real-time PCR and quantitative PCR techniques, were also applied for the detection of chromosomal changes. In order to identify the best genetic marker for treatment regiment, it is important to compare results of different studies, which are evaluating the sensitivity of diagnostic techniques and treatment response after a suitable selection factors based on genetic aberrations profile.


Totally asymmetric exclusion process on chains with a double-chain section in the middle: computer simulations and a simple theory.
Computer simulations of the totally asymmetric simple-exclusion process on chains with a double-chain section in the middle are performed in the case of random-sequential update. The outer ends of the chain segments connected to the middle double-chain section are open, so that particles are injected at the left end with rate alpha and removed at the right end with rate beta. At the branching point of the graph (the left end of the middle section) the particles choose with equal probability 1/2 which branch to take and then simultaneous motion of the particles along the two branches is simulated. With the aid of a simple theory, neglecting correlations at the junctions of the chain segments, the possible phase structures of the model are clarified. Density profiles and nearest-neighbor correlations in the steady states of the model at representative points of the phase diagram are obtained and discussed. Cross correlations are found to exist between equivalent sites of the branches of the middle section whenever they are in a coexistence phase.


Solution-processed flexible MAPbI3 photodetectors with ZnO Schottky contacts.
With higher detectivity, lower response time, and good mechanical flexibility, perovskite photodetectors are supposed to be a promising alternative as the next generation of photodetectors. In this work, we fabricate a low temperature-processed flexible photodetector with ITO-ZnO Schottky contact via ALD technique which has a lower dark current decreasing from 2.04×10-8 A/cm2 to 1.70×10-9 A/cm2 under -0.5 V bias voltage actuation. With 530 nm laser irradiation, the flexible device exhibits excellent performance in detectivity of 6.19×1012 Jones and LDR of 103dB. It also exhibits superior bending stability after 5000 bending circles.


Transient sinus bradycardia in a child during the course of acute hepatitis A.
Cardiovascular complications in acute hepatitis A are reported rarely. In this report, we describe a case of a previously healthy girl who developed transient sinus bradycardia during the course of acute hepatitis A.


Patient-assigned health utility values for controlled and uncontrolled pemphigus vulgaris and foliaceus.
The assessment of health-related quality of life (HRQoL) in patients with pemphigus is now of increasing interest due to the availability of highly effective new therapies. Preference-based HRQoL values or health utilities required for medical and financial decision-making are not yet available directly from pemphigus patients. To obtain health utility values for current health and hypothetical health states from the perspective of pemphigus patients. A cross-sectional questionnaire survey was carried out with pemphigus patients. Disease severity was rated by Autoimmune Bullous Skin Disorder Intensity Score (ABSIS). Patients were asked to evaluate their current health as well as three common hypothetical pemphigus health states [uncontrolled pemphigus vulgaris (PV), uncontrolled pemphigus foliaceus (PF) and controlled PV/PF] by using composite time trade-off (cTTO). Multiple regression was applied to explore determinants of utility values. Responses of 108 patients (64.8% women, mean age 57.4 years) were analysed. Mean ABSIS score was 11.6. The mean utility values for the hypothetical uncontrolled PV, uncontrolled PF and controlled PV/PF health states were 0.41, 0.52 and 0.66 with cTTO. The mean cTTO scores for current health were higher compared with the hypothetical health states (0.76; P < 0.001). Patients with higher ABSIS, worse pain intensity scores and those having a caregiver reported lower utility values for current health (P < 0.05). In pemphigus, HRQoL impairment expressed in utility values seems to be considerable, especially in comparison with other chronic dermatological conditions (e.g. psoriasis, atopic eczema, chronic hand eczema). These health utilities inform physicians, policymakers and funders about the overall extent of health loss in pemphigus and provide evidence to guide medical decisions and cost-effectiveness analyses of treatment strategies. Future research is needed to evaluate the caregiver burden in pemphigus.


Chemical synthesis and biological evaluation of palmerolide A analogues.
Molecular design and chemical synthesis of several palmerolide A analogues allowed the first structure activity relationships (SARs) of this newly discovered marine antitumor agent. From several analogues synthesized and tested (ent- 1, 5- 14, 21- 26, 50, 51), compounds 25 (with a phenyl substituent on the side chain) and 51 (lacking the C-7 hydroxyl group) were the most interesting, exhibiting approximately a 10-fold increase in potency and equipotency, respectively, to the natural product. These findings point the way to more focused structure activity relationship studies.


High incidence of antibiotic resistance among bacteria in 4 intensive care units at a university hospital in Sweden.
The frequency of antibiotic resistance among bacteria in 4 intensive care units (ICUs) at a university hospital in Sweden was investigated annually from 1993 to 1996. An increase in ampicillin-resistant enterococci from 1993 to 1995 was seen which was due to a shift from Enterococcus faecalis to Enterococcus faecium. After a special infection control programme was instituted, the rate of ampicillin resistance among enterococci and the number of E. faecium isolates declined during 1996. The oxacillin resistance rates for Staphylococcus aureus were < or = 2%, while most of the coagulase-negative staphylococci (CNS) were oxacillin resistant. No vancomycin-resistant enterococci or staphylococci were seen. The ciprofloxacin resistance rate for CNS and Enterococci spp. were high. Relatively, high levels of resistance to cefotaxime and piperacillin/tazobactam among Enterobacter spp. were also seen. During 1995 and 1996 Pseudomonas aeruginosa showed increasing resistance to ceftazidime, ciprofloxacin and piperacillin/tazobactam. This was due to an outbreak among rather few patients. The overall resistance rates for Gram-negative bacteria were low for aminoglycosides and imipenem. From 1993 to 1996 the total antibiotic consumption decreased by 27% in the whole hospital and 16.5% in the ICUs. However, the reduced antibiotic consumption was paralleled with a 23% decrease in the total number of patients treated in the hospital from 1993 to 1996. In contrast there was an 11.5% increase in the number of ICU patients treated during this period. The conclusion is that all ICUs within a hospital should have a programme for 'on-line' antibiotic resistance surveillance of drugs used in that unit in order to change the empiric treatment when there is an increase in antibiotic resistance. It is also important to survey the antibiotic consumption in the ICUs in order to avoid further selective pressure on bacteria showing increased resistance rates.


Seizure recurrence after reduction of an antiepileptic drug in patients with unprovoked seizures and severe neurological abnormalities.
A prospective study of antiepileptic drug (AED) reduction in patients with unprovoked seizures and severe neurological abnormalities after a seizure-free period of more than 5 years was performed. From a hospital for severely handicapped children (150 patients) and an institution for mentally handicapped people (89 persons), 13 patients were enrolled to this study after informed consent was obtained. All patients had experienced a seizure-free period of more than 7 years (median, 10 years). The patients had IQs of less than 50 and were almost dependent in their life. Five patients had additional motor deficits. The patients had been taking one to three AED (mean, 1.9) before reduction and only one AED was withdrawn. During the following 2years, four of the 13 patients (31%) showed a recurrence of seizures. The age at the time of the last seizure was lower in the seizure-free patients. As to the 10 patients with onset ages of 10 or less, a significant factor as to seizure recurrence was whether or not seizures were controlled before the age of 11 years (P < 0.05, Fisher's exact probability test). It is suggested that a patient with severe neurological abnormalities, in whom epilepsy or unprovoked seizures are controlled before the age of 11 years (i.e. before adolescence) could be a candidate for the reduction of AED.


A brief study of toxic effects of some medicinal herbs on kidney.
Increased use of complementary and alternative herbal medicines in the treatment of various diseases.Some herbal therapies may be causes of potential toxicity that may be renal toxicity caused by the ingestion of herbs. The goal of this study is the toxic and beneficial effects of medicinal herbs on renal health by which evidence for benefit or toxicity has been found. Included are nephrotoxicity from aristolochic acid and other components within herbs, herb-drug interactions, heavy metal toxicity in herbs and adulterants during careless preparation of herbal medicine, resulting in adverse renal effects and renal toxicity from contaminants within the extracts. The review aims to provide knowledge and guide to encourage future toxicity studies on the kidney by medicinal herbs.


[The diabetic patient in the dental clinic, update and innovation].
Type 2 Diabetes is a non-curable multi system disease that affect around 9% of the world population. Therefore, the incidence for the general dentist to come across a diabetic patient is very high. The medical treatment in diabetes is graded according to the severity of the disease. In the last decade new drugs and treatment modalities were developed. The implication of diabetes and its complications in the oral cavity are significant. Beside the emergency events that might take place in a diabetic patient, one must take under consideration the influence of the dental treatment on the glycemic control and vis-a-vis the influence of the glycemic control on the oral tissue health and response for treatment.


[District program to improve the cardiovascular risk of resistant hypertensive patients in general medicine].
To try to improve the cardiovascular risk of resistant hypertensive patients in general medicine in Brittany after using french hypertension recommendations. 581 hypertensive patients under 3 antihypertensive drugs have asked for an exoneration of the patients' social contribution: 297 (51%) were uncontrolled at their general practitioner (GP) among whom 106 (36%) have refused to take part in the program. 191 resistant hypertensive patients followed by 170 different GP have been pre-included. After a meeting between the social security physician, the GP measured blood pressure (BP) with a validated BP device and passed it on to the patient for a self-BP measurement (SBPM). In the case of a confirmed resistance, after specialist opinion, the treatment was then modified and the patient was checked after four months by his GP for a new clinical and self BP measurement. After the initial automated BP measurement by GP, 51 patients (27%) had in fact controlled hypertension. Out of 136 resistant hypertensive patients (mean: 63 ys) during consultation (60% with systolic isolated hypertension), 121 (89%) have been closely followed during the whole study period among who 114 were also resistant with SBPM (94%). Only 8 patients (6%) were controlled at home. A check-up with specialist opinion was conducted: ECG (82%), echocardiography (59%), vascular echography (35%), funduscopy (30%), plasma renin/aldosterone measurement (15%), renal artery exploration (26%). Eight (7%) secondary hypertension have been founded. After 4 months, 32 (26%) obtained controlled hypertension during GP consultation and 15% during SBPM but the 20/32 controlled patients (62%) had a masked hypertension. Cholesterol levels (63% of dyslipidemics) and the body mass index (80% of overweighed patients) have not varied. On the contrary, 12/28 (48%) has stopped smoking. The coronary risk using Anderson's model has only decreased from 16.5% to 13.8%. If this health program has shown its feasibility and the good participation of the GPs, treatment of hypertension and others risk factors really remains insufficient. On the contrary, the use of a validated automatic BP device has been really well carried out. Its use has allowed reclassifying as controlled one third of the resistant hypertensive patients and as uncontrolled at home one patient out of two which were controlled with GP. These results prove the necessity to increase this BP measurement technique in this population.


Determination of genes, restriction sites, and DNA sequences surrounding the 6S RNA template of bacteriophage lambda.
A major product of the transcription of bacteriophage lambda DNA in vitro is the 6S RNA. This article presents a detailed mapping of restriction endonuclease cleavage sites about the region of the 6S RNA template within the lambda genome. Restriction fragments defined by these sites have been used to localize the 6S RNA template within the physical and genetic maps of the lambda genome. Nucleotide sequence analysis of one of these fragments has largely confimed the nucleotide sequence of the 6S RNA reported previously and has indicated the sequence of DNA that immediately follows the 6S RNA template. This article reports the nucleotide sequence following a known site of transcription termination by RNA polymerase of Escherichia coli.


Intramuscular neural distribution of the teres minor muscle using Sihler's stain: application to botulinum neurotoxin injection.
The aim of this study was to elucidate the intramuscular arborization of the teres minor muslce for effective botulinum neurotoxin injection. Twelve specimens from 6 adult Korean cadavers (3 males and 3 females, age ranging from 66 to 78 years) were used in the study. The reference line between the 2/3 point of the axillary border of the scapula (0/5), where the muscle originates ant the insertion point of the greater tubercle of the humerus (5/5). The most intramuscular neural distribution was located on 1/5-3/5 of the muscle. The tendinous portion was observed in the 3/5-5/5. The result suggests the botulinum neurotoxin should be delivered in the 1/5-3/5 area of the teres minor muscle.


Carotid body chemosensory responses in mice deficient of TASK channels.
Background K(+) channels of the TASK family are believed to participate in sensory transduction by chemoreceptor (glomus) cells of the carotid body (CB). However, studies on the systemic CB-mediated ventilatory response to hypoxia and hypercapnia in TASK1- and/or TASK3-deficient mice have yielded conflicting results. We have characterized the glomus cell phenotype of TASK-null mice and studied the responses of individual cells to hypoxia and other chemical stimuli. CB morphology and glomus cell size were normal in wild-type as well as in TASK1(-/-) or double TASK1/3(-/-) mice. Patch-clamped TASK1/3-null glomus cells had significantly higher membrane resistance and less hyperpolarized resting potential than their wild-type counterpart. These electrical parameters were practically normal in TASK1(-/-) cells. Sensitivity of background currents to changes of extracellular pH was drastically diminished in TASK1/3-null cells. In contrast with these observations, responsiveness to hypoxia or hypercapnia of either TASK1(-/-) or double TASK1/3(-/-) cells, as estimated by the amperometric measurement of catecholamine release, was apparently normal. TASK1/3 knockout cells showed an enhanced secretory rate in basal (normoxic) conditions compatible with their increased excitability. Responsiveness to hypoxia of TASK1/3-null cells was maintained after pharmacological blockade of maxi-K(+) channels. These data in the TASK-null mouse model indicate that TASK3 channels contribute to the background K(+) current in glomus cells and to their sensitivity to external pH. They also suggest that, although TASK1 channels might be dispensable for O(2)/CO(2) sensing in mouse CB cells, TASK3 channels (or TASK1/3 heteromers) could mediate hypoxic depolarization of normal glomus cells. The ability of TASK1/3(-/-) glomus cells to maintain a powerful response to hypoxia even after blockade of maxi-K(+) channels, suggests the existence of multiple sensor and/or effector mechanisms, which could confer upon the cells a high adaptability to maintain their chemosensory function.


Functional Implications of Cathelicidin Antimicrobial Protein in Breast Cancer and Tumor-Associated Macrophage Microenvironment.
It is well-established that tumor-associated macrophages (TAMs) play an important role in breast cancer development. Accumulating evidence suggested that human cathelicidin antimicrobial protein (CAMP), which is mainly expressed in host defense cells such as macrophages, is crucial not only in combating microorganisms but also promoting tumor growth. Here we report the interaction of CAMP with TAMs in breast cancer. CAMP expression was upregulated in cancer tissues and in the circulation of breast cancer patients. Surgical removal of tumor decreased CAMP peptide serum level. Knockdown of CAMP decreased cell proliferation and migration/invasion ability in breast cancer cells. CAMP expression was altered during macrophage M1/M2 polarization and was expressed predominantly in M2 phenotype. In addition, breast cancer cells co-cultured with macrophages upregulated CAMP expression and also increased cancer cell viability. Xenograft tumors reduced significantly upon CAMP receptor antagonist treatment. Our data implicated that CAMP confers an oncogenic role in breast cancer and plays an important role in the tumor microenvironment between TAMs and breast cancer cells, and blocking the interaction between them would provide a novel therapeutic option for this malignant disease.


[Prospects of immunomorphological study of glomerulonephritis].
A structural immunomorphological analysis of the renal glomerulus and immunocompetent cells, detailed characterization of the interaction between the glomerular cells and those of immune system as well as between glomerular cells themselves are thought to be essential for elucidation of patho- and morphogenesis of glomerulonephritis (GN). Such conclusion has been reached basing on long-term experience with GN study gained by the authors and relevant literature data. In line with standard light optical, histochemical and immunohistochemical methods there should be introduced comprehensive immuno- and electron-microscopic studies of renal biopsies and glomerular cell culture.


Preliminary mapping of void fractions and sound speeds in gassy marine sediments from subbottom profiles.
Bubbles of gas (usually methane) in marine sediments affect the load-bearing properties of the seabed and act as a natural reservoir of "greenhouse" gas. This paper describes a simple method which can be applied to historical and future subbottom profiles to infer bubble void fractions and map the vertical and horizontal distributions of gassy sediments, and the associated sound speed perturbations, even with single-frequency insonification. It operates by identifying horizontal features in the geology and interpreting any perceived change of depth in these as a bubble-mediated change in sound speed.


The anti-inflammatory mechanism of antidepressants - SSRIs, SNRIs.
The cytokine theory of depression no longer brings about any doubts. Experiments and research studies conducted in the last ten years have confirmed that both physical and psychological (emotional) stress increases the likelihood of occurrence of mental disorders (including depressive disorders) owing to the action of a series of hormonal and biochemical mechanisms. Selective serotonin reuptake inhibitors (SSRI) as well as serotonin and norepinephrine reuptake inhibitors (SNRIs) are some of the most commonly applied drugs in the world during pharmacotherapy of recurrent depressive disorder. The underestimated anti-inflammatory and anti-oxidative effect may be one of the potential mechanisms of action of the preparations mentioned above. The detailed specificity of action of this mechanism still remains unknown. The aim of our work will be to perform a review of contemporary literature in order to present the latest scientific reports regarding the anti-inflammatory effects of SSRIs and SNRIs. The mechanism of anti-inflammatory action may serve as a possible explanation for the efficacy of antidepressants from the groups of SSRIs and SNRIs.


Treatment-related changes in urinary excretion of high and low molecular weight proteins in patients with idiopathic membranous nephropathy and renal insufficiency.
In patients with idiopathic membranous nephropathy, an increased urinary excretion of high (IgG) and low [beta(2)-microglobulin (beta(2)M), alpha(1)-microglobulin (alpha(1)M)] molecular weight proteins predicts prognosis and precedes renal insufficiency. We have studied the changes in the urinary excretion of these proteins in patients with idiopathic membranous nephropathy and renal insufficiency during and after treatment with cyclophosphamide and steroids, and investigated their value in predicting long-term outcome. Standardized measurements of urinary IgG, albumin, beta(2)M and alpha(1)M were performed at 0, 2, 6 and 12 months in 11 patients, at 12 months in 25 patients and in 17 of these last patients after 2-5 years. We observed a rapid improvement of glomerular permselectivity and tubular protein reabsorption within 2 months after the start of therapy. Despite a partial remission of proteinuria within 12 months in most patients, evidence of tubulo-interstitial injury remained apparent. Neither absolute levels of urinary IgG, beta(2)M or alpha(1)M at baseline or at 12 months nor the percentage reduction between baseline and 12 months clearly predicted the occurrence of a remission or a relapse to nephrotic range proteinuria. In the case of a persistent stable remission, we observed a gradual decrease of urinary beta(2)M towards normal values. In patients with idiopathic membranous nephropathy and renal insufficiency, treatment with cyclophosphamide and steroids resulted in an improvement of glomerular permeability and tubular proteinuria. Tubular proteinuria remained present for many years, even in patients with stable remission of proteinuria. Measurements of urinary proteins at 12 months after treatment start lacked predictive accuracy.


Establishing quantitative light-induced fluorescence cut-offs for the detection of occlusal dentine lesions.
The aims of this in vitro study were, first, to define suitable cut-off values for the detection of occlusal dentine lesions by means of quantitative light-induced fluorescence (QLF), and, second, to compare the validity of light microscopy (LM) and microradiography (MR) as reference standards. Fifty-four third molar occlusal fissures with sound sites or non-cavitated lesions were examined. Standard QLF equipment was used to capture, display, store, and analyze fluorescence images. Each tooth was cut into sections in the bucco-lingual direction using a microtome saw, and the caries levels were subsequently assessed with the two reference methods. The histological examination with LM indicated that 46% of the specimens had carious lesions progressing into the dentine compared with 41% measured using MR (D3-4 level). Using optimal cut-off levels for the detection of dentine lesions, the sensitivity and specificity values were > 80%. The area under the receiver operating characteristic curve was slightly higher for MR (0.91-0.93) than for LM (0.88-0.89). The results of this study give a good idea of suitable cut-off points for the detection of occlusal dentine lesions using QLF. Owing to the small number of specimens in this study, further studies should be carried out before establishing definite cut-offs.


Revisiting targeted therapy and immunotherapy for advanced cholangiocarcinoma.
Cholangiocarcinoma (CCA) is a rare and aggressive type of malignant tumor. In the past few years, there has been an increase in the incidence of CCA. Surgery is the only effective treatment but is only suitable for a small percentage of patients. Comprehensive treatment is the normal therapy for terminal CCA patients, depending basically on gemcitabine and cisplatin combination chemotherapy. In the past decade, the emergence of next-generation sequencing technology can be used for the identification of important molecular features of CCA, and several studies have demonstrated that different CCA subtypes have unique genetic aberrations. Targeting fibroblast growth factor receptor (FGFR), isocitrate dehydrogenase (IDH) and epidermal growth factor receptor 2 (EGFR2) are emerging targeted therapies. In addition, researches have indicated that immunotherapy has a key function in CCA. There is ongoing research on programmed cell death protein 1 inhibitors (PD-1), chimeric antigen receptor T cells (CAR-T) and tumor-infiltrating leukocyte (TILs). Researches have shown that targeted therapy, immunotherapy, and conventional chemotherapy in CCA had certain mechanistic links, and the combination of those can greatly improve the prognosis of advanced CCA patients. This study aimed to review the research progress of targeted therapy and immunotherapy for CCA.


Effects of positive end-expiratory pressure on oscillated flow rate during high-frequency chest compression.
To investigate the effects of positive end-expiratory pressure (PEEP) on end-expiratory lung volume (EELV) and mean oscillated flow rate (VOSC) during high-frequency chest compression (HFCC) in normal subjects and patients with severe COPD. Comparative study. Pulmonary function and lung mechanics laboratory, University of Alberta Hospitals. Six normal subjects (five male; one female) and six patients with clinically stable COPD (five male; one female) with hypercapnia. A pneumatic vest system was operated at 10 Hz with a mean chest wall pressure of 16 cm H2O to provide the HFCC. A closed-circuit spirometer system permitted measurement of HFCC- and PEEP-induced changes in EELV that were expressed as per cent baseline functional residual capacity (FRC). An isothermic chamber connected near the mouthpiece permitted measurement of VOSC. For the normal subjects, HFCC caused a significant decrease in EELV to 82.0% of FRC (p < or = 0.01) and the addition of 4.8+/-0.5 cm H2O of PEEP during HFCC increased EELV to 97.5% FRC. In the COPD patients, HFCC decreased EELV to 92.3% of FRC (p < or = 0.01), and the addition of 3.7+/-1.0 cm H2O of PEEP increased EELV to 98.4% FRC. For the normal subjects, increasing EELV to near FRC caused VOSC during expiration to increase 14.6% (p < or = 0.01), but there was no significant effect on VOSC during inspiration (5.1% increase). In the COPD patients, PEEP increased VOSC during both inspiration (30.5%) and expiration (57.0%) (both, p < or = 0.01). Addition of a modest amount of PEEP during HFCC prevents the decrease in EELV and increases VOSC during both phases of spontaneous breathing in COPD patients. This higher VOSC during HFCC+PEEP may improve the effectiveness of HFCC in clearing mucus from the lungs of patients with airway disease.


Differential Expression of Zinc-Dependent HDAC Subtypes and their Involvement in Unique Pathways Associated with Carcinogenesis.
The present study aims to identify the effect of ZnHDACs expression on the survival of the patients. Further, reveal the unique and common genes associated with each ZnHDACs and their associated pathways. The patient data was obtained from the Cancer Genome Atlas Program (TCGA) database and was analyzed using cBioportal and Gene Expression Profiling Interactive Analysis 2(GEPIA2) online tools. Protein-protein interactions and functional interactomic analysis were done using STRING, DAVID, and KEGG pathway databases. HDAC1, 2, 8, 11 were over-expressed and, HDAC4, 5, 6, 7, and 10 were down-regulated in all the cancer types, but there are few exceptional expression patterns such as HDAC7 and HDAC10 overexpression in HNSC, HDAC3 down-regulation in LUAD, and PRAD. The unique genes interacting with each ZnHDACs provided a better understanding of ZnHDAC's putative role in carcinogenesis. The present study reported that JARID2, stem cell regulation gene uniquely interacts with HDAC1, BPTF-CHRAC-BAZIA axis, enzymes for chromatin modeling selectively interacting with only HDAC2, HDAC3 in H2A acetylation via DMAP1 and YEATS4. HDAC6 associated unique genes regulate protein stability, HDAC7 in subnuclear localization and splicing, HDAC8 in telomere maintenance, HDAC9 in chromosomal rearrangements, and HDAC11 in maintaining histone core and folding. The unique genes and pathways associated with a particular ZnHDACs could provide a wide window for interrogating these genes for obtaining putative drug targets.


Scaffold/matrix attachment regions from CHO cell chromosome enhanced the stable transfection efficiency and the expression of transgene in CHO cells.
Two scaffold/matrix attachment regions (S/MARs) from Chinese hamster ovary (CHO) cell chromosomes were identified computationally and cloned as the domain boundaries regions. As partition chromosomes in independently regulated units to increase the exogenous gene expression, these two S/MARs (MAR1 and MAR6) flanked expression vectors were respectively transfected into CHO cells. The results showed that MAR1 and MAR6 were much more potent to increase the stable transfection efficiency than the chicken lysozyme gene 5' S/MARs, which had been experimentally identified to increasing the expression of heterologous gene. Moreover, MAR6 is more active in mediating high and consistent gene expression in CHO cells than the chicken lysozyme gene 5' S/MARs.


Acute hemiplegia in Kawasaki disease and infantile polyarteritis nodosa.
Although aseptic meningitis, lethargy and irritability occur frequently in Kawasaki disease and infantile polyarteritis nodosa, other neurological manifestations are rare. The authors report one case of Kawasaki disease and one of infantile polyarteritis nodosa, both associated with acute hemiplegia. Both patients had received courses of oral corticosteroids for their underlying disease prior to the onset of the hemiplegia. Pathological studies, as well as the four previously reported cases, are reviewed.


Application of Ionic Liquid Crosslinked Hydrogel for Removing Heavy Metal Ions from Water: Different Concentration Ranges with Different Adsorption Mechanisms.
Heavy metal wastewater poses a significant environmental challenge due to its harmful effect on organisms and difficult biodegradation. To address this issue, hydrogel has been used as a promising solution for the adsorption of heavy metal ions in water, offering advantages such as low cost, simple design, and environmental friendliness. In this study, we synthetized a novel poly-acrylamide/acrylic acid/vinyl imidazole bromide (PAM/AA/[Vim]Br2) hydrogel as an effective adsorbent for the removal of NiII, CuII, ZnII, and CrIII from water. The structure of the hydrogel was characterized by using techniques such as Fourier transform infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). By exploring various parameters such as monomer ratio, neutralization degree, crosslinking agent addition amount, and initiator addition amount, the highest swelling ratio of the PAM/AA/[Vim]Br2 hydrogel reached 40,012%. One of the notable aspects of this study lay in the investigation of the adsorption behavior of the hydrogel towards heavy metal ions at different concentrations. The adsorption isotherm calculations and X-ray photoelectron spectroscopy (XPS) analysis revealed distinct adsorption mechanisms. At low concentrations, the hydrogel exhibits a multilayer physical adsorption mechanism, with heavy metal ion removal rates exceeding 80%; while at high concentrations, it demonstrates a monolayer chemical adsorption mechanism, with heavy metal ion removal rates above 90%. This dual mechanism approach distinguishes our study from previous reports on the removal of heavy metal ions using hydrogels and shows good ion adsorption efficiency at both high and low concentrations. To the best of our knowledge, this is the first report to explore the removal of heavy metal ions from water using hydrogels with such intriguing dual mechanisms. Overall, the utilization of the PAM/PAA/[Vim]Br2 hydrogel as an adsorbent for heavy metal ion removal presents a promising and innovative approach, contributing to the development of environmentally friendly solutions for heavy metal wastewater treatment.


Analysis of the Heyd-Scuseria-Ernzerhof density functional parameter space.
The Heyd-Scuseria-Ernzerhof (HSE) density functionals are popular for their ability to improve upon the accuracy of standard semilocal functionals such as Perdew-Burke-Ernzerhof (PBE), particularly for semiconductor band gaps. They also have a reduced computational cost compared to hybrid functionals, which results from the restriction of Fock exchange calculations to small inter-electron separations. These functionals are defined by an overall fraction of Fock exchange and a length scale for exchange screening. We systematically examine this two-parameter space to assess the performance of hybrid screened exchange (sX) functionals and to determine a balance between improving accuracy and reducing the screening length, which can further reduce computational costs. Three parameter choices emerge as useful: "sX-PBE" is an approximation to the sX-LDA screened exchange density functionals based on the local density approximation (LDA); "HSE12" minimizes the overall error over all tests performed; and "HSE12s" is a range-minimized functional that matches the overall accuracy of the existing HSE06 parameterization but reduces the Fock exchange length scale by half. Analysis of the error trends over parameter space produces useful guidance for future improvement of density functionals.


Mediation analysis with intermediate confounding: structural equation modeling viewed through the causal inference lens.
The study of mediation has a long tradition in the social sciences and a relatively more recent one in epidemiology. The first school is linked to path analysis and structural equation models (SEMs), while the second is related mostly to methods developed within the potential outcomes approach to causal inference. By giving model-free definitions of direct and indirect effects and clear assumptions for their identification, the latter school has formalized notions intuitively developed in the former and has greatly increased the flexibility of the models involved. However, through its predominant focus on nonparametric identification, the causal inference approach to effect decomposition via natural effects is limited to settings that exclude intermediate confounders. Such confounders are naturally dealt with (albeit with the caveats of informality and modeling inflexibility) in the SEM framework. Therefore, it seems pertinent to revisit SEMs with intermediate confounders, armed with the formal definitions and (parametric) identification assumptions from causal inference. Here we investigate: 1) how identification assumptions affect the specification of SEMs, 2) whether the more restrictive SEM assumptions can be relaxed, and 3) whether existing sensitivity analyses can be extended to this setting. Data from the Avon Longitudinal Study of Parents and Children (1990-2005) are used for illustration.


Acquisition of a second multi-drug resistance-encoding element by IncM1 plasmid pACM130 abolished conjugative transfer.
Within the IncM plasmid family there is a lineage that has a transposon Tn1721-based multiple-resistance island inserted in the backbone gene mucB. So far, this group includes R1215, p202c, pIGT15, pARM26, and pACM1, from Europe and the USA. A new member of this group, pACM130, was isolated at the same American hospital as pACM1 and has a similar resistance island, but also carries a copy of Tn1331 that interrupts the traY gene in the conjugation operon. The conjugative phenotype of this plasmid has been abolished, though pACM130 could be mobilized by an intact traY cloned into a laboratory vector and transformed into the same donor bacterium.


Missed cardiac tamponade.
Cardiac tamponade can have an insidious onset, becoming life threatening when an adequate cardiac output can no longer be maintained. This case provides an example of a presentation where all the classic signs were present but unfortunately they were missed, in this way providing good revision of what these signs are. It gives some anaesthetic and procedure based perspectives for this rare presentation. It is noteworthy for the speed at which symptoms and signs resolved after the tamponade was relieved.


Regulation of Salmonella-induced neutrophil transmigration by epithelial ADP-ribosylation factor 6.
Salmonella typhimurium elicits an acute inflammatory response in the host intestinal epithelium, characterized by the movement of polymorphonuclear leukocytes (PMN) across the epithelial monolayer to the intestinal lumen. It was recently shown that SipA, a protein secreted by S. typhimurium, is necessary and sufficient to drive PMN transmigration across model intestinal epithelia (Lee, C. A., Silva, M., Siber, A. M., Kelly, A. J., Galyov, E., and McCormick, B. A. (2000) Proc. Natl. Acad Sci. USA 97, 12283-12288). However, the epithelial factors responsible for this process have not been identified. Here, for the first time, we demonstrate that S. typhimurium-induced PMN transmigration across Madin-Darby canine kidney-polarized monolayers is regulated by the GTPase ARF6. Apically added S. typhimurium promoted the translocation of ARF6 and its exchange factor ARNO to the apical surface. Overexpression of a dominant-negative mutant of ARF6 inhibited Salmonella-induced PMN transmigration, which was due to a reduction in apical release of the PMN chemoattractant PEEC (pathogen-elicited epithelial chemoattractant), without affecting bacterial internalization. Furthermore, ARF6 and its effector phospholipase D (PLD) were both required for bacteria-induced translocation of protein kinase C (PKC) to membranes. These results describe a novel signal transduction pathway, in which Salmonella initiates an ARF6- and PLD-dependent lipid signaling cascade that, in turn, directs activation of PKC, release of PEEC, and subsequent transepithelial PMN movement.


Rapid extraction of grass pollen allergens and separation of their active fractions.
The immediate effects of nasal provocation tests with dry grass pollen, correlated with recent botanical evidence of almost instant release of allergens from the pollen wall, suggested that prolonged extraction of pollens was unnecessary and perhaps undesirable. It has now been shown that all the active allergens from undefatted dry grass pollens of the 12 major British species are extracted completely in 15 min. Gel chromatography of such rapid extracts has shown clear-cut separation of active from inactive material, as confirmed by skin and nasal provocation testing. It is probable that active fractions thus obtained contain the only pollen allergens of importance to clinical allergy. Further purification may produce specific allergens useful for the accurate standardisation of vaccines.


Effects of deuterium oxide on Streptococcus mutans and Pseudomonas aeruginosa.
A complex aggregation of microorganisms growing on a solid substrate is termed a biofilm and is considered to be an etiological agents. Pseudomonas aeruginosa and Streptococcus mutans are representative bacteria in such biofilms. It is well known that deuterium oxide (D₂O) causes toxic effects on a number of biological systems. We investigated the effects of D₂O on growth and biofilm formation of P. aeruginosa and S. mutans. These bacteria were incubated in medium containing D₂O (100%, 75% or 0%) at 37°C for 24hr, 48 hr or 72 hr. Growth of P. aeruginosa was inhibited by D₂O within the first 48 hr. However, after 72 hr, growth rate was seen to increase in the D₂O-containing medium compared with in medium without D₂O. In contrast, the growth of S. mutans in the D₂O medium was inhibited within 72 hr. The biofilm formation of P. aeruginosa was increased in the D₂O medium. Biofilm formation of S. mutans in the D₂O medium increased compared with in the medium without D₂O, but this increase was only temporary in the case of P. aeruginosa. Compared to biofilm formation in 0% D₂O medium marked as 100%, the biofilm formation rate of S. mutans in 75% D₂O medium was 143% at 24 hr, 146% at 48 hr and 130% at 72 hr. In other D₂O concentration media biofilm formation was lower. In 100% D₂O medium, biofilm formation rate decreased from 114% at 24 hr to 56% at 72 hr. The biofilm formation rate of P. aeruginosa in 100% D₂O medium was 172% at 24 hr, but decreased to 88% at 72 hr. Biofilm formation of P. aeruginosa in 75% and 0% D₂O media showed no significant difference. We consider that these results were due to stress or alteration in bacterial metabolisms.


A standardized representation of spinal quality of motion.
The experimentally determined torque-rotation curve of the lumbar spine is mathematically described with a proposed dual-inflection point Boltzmann equation. The result is a method for describing functional spinal unit motion data. The benefit of the model is that each of the coefficients has a specific meaning in relation to the torque-rotation curve: the points A and B identify the respective minimum and maximum rotations of the functional spinal unit, m1 and m2 indicate the inflection points of the curve where the stiffness changes markedly, and α1 and α2 are associated with the rates of change of the curve at m1 and m2, respectively. The dual-inflection point Boltzmann captures the full quality of motion of the spinal segment and can also be used to derive relevant parameters such as range of motion, midrange stiffness, and hysteresis.


Desperate Prawns: Drivers of Behavioural Innovation Vary across Social Contexts in Rock Pool Crustaceans.
Innovative behaviour may allow animals to cope with changes in their environment. Innovative propensities are known to vary widely both between and within species, and a growing body of research has begun to examine the factors that drive individuals to innovate. Evidence suggests that individuals are commonly driven to innovate by necessity; for instance by hunger or because they are physically unable to outcompete others for access to resources. However, it is not known whether the factors that drive individuals to innovate are stable across contexts. We examined contextual variation in the drivers of innovation in rock pool prawns (Palaemon spp), invertebrates that face widely fluctuating environments and may, through the actions of tides and waves, find themselves isolated or in groups. Using two novel foraging tasks, we examined the effects of body size and hunger in prawns tested in solitary and group contexts. When tested alone, small prawns were significantly more likely to succeed in a spatial task, and faster to reach the food in a manipulation task, while hunger state had no effect. In contrast, size had no effect when prawns were tested in groups, but food-deprived individuals were disproportionately likely to innovate in both tasks. We suggest that contextual variation in the drivers of innovation is likely to be common in animals living in variable environments, and may best be understood by considering variation in the perception of relative risks and rewards under different conditions.