Evaluation of C-Reactive Protein Level in Patients with Pain Form of Temporomandibular Joint Dysfunction.
Temporomandibular joint dysfunction is a functional disorder concerned with the abnormal functioning of the muscles of the stomatognathic system and temporomandibular joints involved in the dynamic movements of the jaw and surrounding structures. The aim of the study was to compare the level of C-reactive protein in patients with pain and painless forms of temporomandibular joint dysfunction. Materials and methods. The study group consisted of 72 patients who reported to the prosthetic treatment because of temporomandibular joint dysfunction. The study group included 36 patients with pain form of dysfunction, and the control group included 36 patients with painless form of disorder. Each patient underwent specialized examination of functional disorders in order to diagnose the type of dysfunction and was commissioned to carry out a study of the blood test concerned with evaluation of the C-reactive protein (CRP) level in the same analytical laboratory. The results of the investigation were subjected to statistical analysis. The research obtained approval from the Ethics Committee of the Jagiellonian University (KBET/125/L/2013). Level of Evidence for primary research was established as type V. Results. The mean values of C-reactive protein levels in both groups were in the normal range and did not differ statistically significantly, which indicates the fact that the pain form of the temporomandibular joint disorders is not associated with inflammation of the soft tissues of the joint. Conclusion. Painful form of the temporomandibular joint dysfunctions is not connected with the inflammation of joints.


Unexpected deposition patterns of recombinant proteins in post-endoplasmic reticulum compartments of wheat endosperm.
Protein transport within cereal endosperm cells is complicated by the abundance of endoplasmic reticulum (ER)-derived and vacuolar protein bodies. For wheat storage proteins, two major transport routes run from the ER to the vacuole, one bypassing and one passing through the Golgi. Proteins traveling along each route converge at the vacuole and form aggregates. To determine the impact of this trafficking system on the fate of recombinant proteins expressed in wheat endosperm, we used confocal and electron microscopy to investigate the fate of three recombinant proteins containing different targeting information. KDEL-tagged recombinant human serum albumin, which is retrieved to the ER lumen in leaf cells, was deposited in prolamin aggregates within the vacuole of endosperm cells, most likely following the bulk of endogenous glutenins. Recombinant fungal phytase, a glycoprotein designed for secretion, was delivered to the same compartment, with no trace of the molecule in the apoplast. Glycan analysis revealed that this protein had passed through the Golgi. The localization of human serum albumin and phytase was compared to that of recombinant legumin, which contains structural targeting information directing it to the vacuole. Uniquely, legumin accumulated in the globulin inclusion bodies at the periphery of the prolamin bodies, suggesting a different mode of transport and/or aggregation. Our results demonstrate that recombinant proteins are deposited in an unexpected pattern within wheat endosperm cells, probably because of the unique storage properties of this tissue. Our data also confirm that recombinant proteins are invaluable tools for the analysis of protein trafficking in cereals.


Quality of palliative care in children with cancer in Lebanon.
There is a growing research interest in pediatric palliative care in Lebanon. To date the existing studies have focused on the perspective of parents of children with cancer. The purpose of this study was to evaluate the quality of life (QoL), symptom prevalence and management, functional ability, and the quality of care among children with cancer at the Children's Cancer Center of Lebanon. A cross-sectional survey design was used. A convenience sample of 85 patients on therapy aged 7 to 18 years participated in the study between 2010 and 2011. Using face to face interviews, a combination of four instruments were administered in Arabic. The mean age of the participants was 12.5 years, with the majority having leukemia. Overall, the children had satisfactory health-related QoL, with the exception of the nausea and worry subscales, had no limitations in functional abilities, and were satisfied with the care that they received. In children between 7 to 12 years, the most common symptoms were lack of appetite, pain, and nausea, while adolescents between 13 to 18 years experienced lack of energy, irritability, and pain. Pain and nausea were the most frequently treated symptoms. Although the participants reported satisfactory QoL, yet symptom management was inadequate and mainly focused on treating the physical symptoms. It is recommended to provide both pharmacological and psychological interventions in order to alleviate symptom burden and hence improve QoL in children with cancer.


Mechanisms of tissue injury in lupus nephritis.
Systemic lupus erythematosus is a prototypic autoimmune disease characterized by autoantibody production and immune complex formation/deposition in target organs such as the kidney. Resultant local inflammation then leads to organ damage. Nephritis, a major cause of morbidity and mortality in patients with lupus, occurs in approximately 50% of lupus patients. In the present review, we provide an overview of the current research and knowledge concerning mechanisms of renal injury in both lupus-prone mouse models and human lupus patients.


The rational design and construction of a cuboidal iron-sulfur protein.
Rational protein design is an emerging approach for testing general theories of protein chemistry through the creation of new structures and functions. Here we present the first successful introduction by rational design of a [Fe4S4] cuboidal cluster into the hydrophobic core of Escherichia coli thioredoxin, a protein normally devoid of metal centers. Cuboidal [Fe4S4] is one of the stable forms of self-assembled iron-sulfur clusters that are thought to represent some of the earliest evolved biological redox centers. [Fe4S4] clusters have been recruited for use in a variety of proteins whose functions are central to many of the major biochemical processes ranging from simple soluble electron-transfer agents, to membrane-bound components of electron-transfer chains, to electron reservoirs in complex metalloenzymes such as nitrogenase. By situating an [Fe4S4] cluster into a protein environment not previously adapted by evolution we can explore the factors by which their activity is modulated by the protein matrix.


Improved method of porcine pancreas procurement with arterial flush and ductal injection enhances islet isolation outcome.
Several pancreas procurement procedures have been used for porcine islet isolation; however, their impact on outcomes has not been extensively studied. We evaluated an advanced procurement technique for porcine islet isolation designed to reduce warm ischemia, to remove blood content, and enhance cooling of the pancreas by implementing a vascular flush and ductal preservation. Pancreata procured from adult Landrace pigs were divided into 3 different surgical protocols: Pancreatectomy utilizing only surface cooling (group 1; n = 24); surface cooling and ductal injection with cold preservation solution before pancreatectomy (group 2; n = 12); or surface cooling, ductal injection, and an approach by selectively flushing through the celiac trunk and the superior mesenteric artery (group 3; n = 14). We assessed the islet isolation results and quality using in vitro and in vivo assays. Significantly higher overall yield and islet yield per gram pancreas were obtained from group 3 pigs compared with the other groups. Measurements of islet viability after 7 days of culture, as assessed by oxygen consumption rate per DNA, showed that group 3 islets displayed the highest values. Sustained normoglycemia was observed in diabetic nude mice transplanted with 2000 islet equivalents from all 3 groups. This study demonstrated that an advanced pancreas procurement technique including ductal preservation and selective arterial flush with cold preservation solution provided significant improvements in porcine islet isolation outcomes.


Different effects of immobilization stress on the mRNA expression of antioxidant enzymes in rat peripheral organs.
To understand the role of antioxidant enzymatic defenses in reactive oxygen species (ROS) injury following immobilization stress, we examined the effect on mRNA expression of four antioxidant enzymes, manganese superoxide dismutase (Mn-SOD), copper and zinc containing SOD (Cu/Zn-SOD), glutathione peroxidase (GPx) and catalase (CAT), in peripheral rat organs. Immediately after 6h of immobilization, the mRNA levels of all antioxidants examined were markedly decreased in the liver, while 24 h after the cessation of immobilization, the mRNA expressions recovered to baseline levels. In contrast, the adrenal mRNA levels of Mn-SOD and CAT were increased by stress, and the increased levels of these mRNAs were maintained 24h after cessation of stress. The stress did not affect the mRNA levels of antioxidants in the heart, lung and kidney. Our results suggest that the antioxidant defense status in peripheral tissues is influenced by immobilization stress and that tissue-specific regulation mechanisms of antioxidant enzymes exist in rats.


[The biological activity and physicochemical properties of a new bacteriocin from a strain of Pseudomonas cepacia 5779].
Pseudomonas cepacia 5779 bacteriocin (cepaciacin) whose producer was revealed due to application of the special screening system has been studied for its certain biological and physicochemical properties. Possessing a narrow range of action, it inhibits only the P. cepacia strains. Its biosynthesis occurs more intensely on the rich nutrient media, the highest quantities of cepaciacine being revealed at the terminal stage of the produced log growth. UV irradiation or mitomycin C introduction into the medium stimulated biosynthesis of this bacteriocin. Cepaciacin P. cepacia 5779 is a complex consisting of several protein subunits and carbon part. The protein-carbohydrate ratio is 3:1. The molecular weight of the complex is 1.8 x 10(6) Da. Lipopolysaccharides isolated from the indicator strain being added, cepaciacine loses its activity. This bacteriocin is stable in the narrow range of pH, thermolabile, decomposes under the effect of proteases and is, evidently, a representative of a new type of the bacteriocin-like substances.


Effects of single doses of the converting enzyme inhibitor cilazapril in normal volunteers.
The new converting enzyme inhibitor cilazapril, or RO 31-2848, was evaluated in 14 healthy male volunteers. In a pilot study in two subjects, the inhibiting capacity of single oral doses of 5 and 10 mg on the pressure and heart rate response to exogenous angiotensin I was assessed. Both doses reduced the blood pressure response to angiotensin I to 10% of control within 45 min and for the 4 h tested. In the main study, 12 volunteers each received two single oral doses of cilazapril at a 2-week interval, and plasma converting enzyme and renin activity, blood angiotensin I, plasma immunoreactive angiotensin II and aldosterone were measured serially. Single doses of 1.25, 2.5, 5, and 10 mg of cilazapril were tested in groups of six subjects each. All doses inhibited plasma converting enzyme activity by 90% for at least 8 h and induced the expected pattern of changes of the renin-angiotensin-aldosterone system. Only slight dose-dependent variations in the effect were observed. Basic heart rate and blood pressure were not altered by any of the doses, which all were well tolerated. These data suggest that cilazapril is a very potent and long-acting new converting enzyme inhibitor.


CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells.
Immunotherapies with chimeric antigen receptor (CAR) T cells and checkpoint inhibitors (including antibodies that antagonize programmed cell death protein 1 [PD-1]) have both opened new avenues for cancer treatment, but the clinical potential of combined disruption of inhibitory checkpoints and CAR T cell therapy remains incompletely explored. Here we show that programmed death ligand 1 (PD-L1) expression on tumor cells can render human CAR T cells (anti-CD19 4-1BBζ) hypo-functional, resulting in impaired tumor clearance in a sub-cutaneous xenograft model. To overcome this suppressed anti-tumor response, we developed a protocol for combined Cas9 ribonucleoprotein (Cas9 RNP)-mediated gene editing and lentiviral transduction to generate PD-1 deficient anti-CD19 CAR T cells. Pdcd1 (PD-1) disruption augmented CAR T cell mediated killing of tumor cells in vitro and enhanced clearance of PD-L1+ tumor xenografts in vivo. This study demonstrates improved therapeutic efficacy of Cas9-edited CAR T cells and highlights the potential of precision genome engineering to enhance next-generation cell therapies.


[Anesthesia management of caesarean section for pregnant women complicated with Takayasu's arteritis].
Takayasu's arteritis is a rare, idiopathic, chronic inflammatory disease. Its course is unpredictable, but slow progression is usual, leading to stenosis, occlusion, or aneurismal degeneration of the aorta or its major branches. We present the anesthesia management of pregnancy in four women admitted to Peking University Third Hospital for caesarean section from year 2006 to 2015 complicated with Takayasu's arteritis and review this disease with special reference to natural history, diagnostic criteria, classification, prognostic factors, and anesthesia considerations. Anesthesiological data were retrospectively analyzed for clinical manifestations, anesthesia process, perioperative complications, and pregnancy outcome. One patient received only epidural anesthesia, while the other three patients received combined spinal and epidural anesthesia (CSEA). Surgeries for all the four patients were successful with stable vital signs. We found comprehensive examinations including whether the disease was in the active phase and the clinical classification of the disease before conception was recommended for patients diagnosed with Takayasu's arteritis. CSEA and continuous epidural block could be both used as anesthesiological method in patients with Takayasu's arteritis. During the surgery, to avoid rapid hemodynamic fluctuations and protect the major organs' function is very essential to allow for a satisfactory outcome.


Diagnostic Accuracy Comparison of Artificial Immune Algorithms for Primary Headaches.
The present study evaluated the diagnostic accuracy of immune system algorithms with the aim of classifying the primary types of headache that are not related to any organic etiology. They are divided into four types: migraine, tension, cluster, and other primary headaches. After we took this main objective into consideration, three different neurologists were required to fill in the medical records of 850 patients into our web-based expert system hosted on our project web site. In the evaluation process, Artificial Immune Systems (AIS) were used as the classification algorithms. The AIS are classification algorithms that are inspired by the biological immune system mechanism that involves significant and distinct capabilities. These algorithms simulate the specialties of the immune system such as discrimination, learning, and the memorizing process in order to be used for classification, optimization, or pattern recognition. According to the results, the accuracy level of the classifier used in this study reached a success continuum ranging from 95% to 99%, except for the inconvenient one that yielded 71% accuracy.


Thoracic coarctation associated with neurofibromatosis.
A child with neurofibromatosis and hypertension also demonstrated renal artery stenosis, the most common cause of hypertension in children with neurofibromatosis; abdominal coarctation, which has previously been described; and thoracic coarctation, which to our knowledge, has not been previously reported. Rib notching may appear in patients with uncomplicated nueorfibromatosis, but the possibility of associated thoracic coarctation must also be considered in these patients.


Coinfection of Parvovirus B19 with Influenza A/H1N1 Causes Fulminant Myocarditis and Pneumonia. An Autopsy Case Report.
Parvovirus-B19 (PVB19) is a frequent causative agent of myocarditis. For unclear reasons, viral reactivation can cause acute myocarditis, a leading cause of sudden death in the young. Influenza A/H1N1(2009) virus (IAV/H1N1) is known for causing flu/pneumonia, but the heart is rarely involved. Co-infections of cardiotropic viruses are rarely reported and the mechanisms of viral interactions remain unknown. A 5-year old girl had a flu-like syndrome, when she suddenly presented with a respiratory distress and cardiac arrest. At autopsy, the lungs were found haemorrhagic. Lungs' histology showed severe bronchiolitis, diffuse haemorrhagic necrosis, and mononuclear inflammation. In the heart, a moderate inflammation was found with no necrosis. IAV/H1N1 was detected in nasal and tracheal swabs, lungs, and the heart. The viral load was high in the lungs, but low in the heart. PVB19 was detected in the heart with a high viral load. Viral co-infection increases the risk of severe outcome but the mechanisms of interaction between viruses are poorly understood. In our case, viral loads suggested a reactivated PVB19-induced acute myocarditis during an IAV/H1N1 pneumonia. Viral interactions may involve an IAV/H1N1-induced cytokine storm, with a fulminant fatal outcome. Clinically, our case shows the importance of investigating inflammatory pathways as therapeutic targets.


Parkinson's disease: chameleons and mimics.
Parkinson's disease (PD) is a common neurodegenerative condition that usually presents with symptoms related to asymmetric bradykinesia, resting tremor, rigidity and postural instability. Making the correct diagnosis can be challenging as many conditions-including tremor, gait and atypical parkinsonian disorders-can mimic PD. PD can present with unanticipated motor and non-motor symptoms, and so can masquerade as a number of rheumatological, neurological, sleep and mood disorders. Careful clinical assessment, informed by well-validated diagnostic criteria, is important in the initial diagnostic formulation. In uncertain or ambiguous cases, follow-up with monitoring of the treatment response usually gives the correct diagnosis, as validated in postmortem follow-up studies. 'Premotor' PD-a range of non-motor symptoms, particularly sleep disorders and constipation, which can occur up to 20 years before PD motor onset-is common. The presence of non-motor features in early disease sometimes supports the diagnosis of PD. Here we give an overview of the diagnosis of PD and its most important chameleons and mimics, and review the recent advances in structural and functional imaging in parkinsonism.


Heart Rate Measures From Wrist-Worn Activity Trackers in a Laboratory and Free-Living Setting: Validation Study.
Wrist-worn activity trackers are popular, and an increasing number of these devices are equipped with heart rate (HR) measurement capabilities. However, the validity of HR data obtained from such trackers has not been thoroughly assessed outside the laboratory setting. This study aimed to investigate the validity of HR measures of a high-cost consumer-based tracker (Polar A370) and a low-cost tracker (Tempo HR) in the laboratory and free-living settings. Participants underwent a laboratory-based cycling protocol while wearing the two trackers and the chest-strapped Polar H10, which acted as criterion. Participants also wore the devices throughout the waking hours of the following day during which they were required to conduct at least one 10-min bout of moderate-to-vigorous physical activity (MVPA) to ensure variability in the HR signal. We extracted 10-second values from all devices and time-matched HR data from the trackers with those from the Polar H10. We calculated intraclass correlation coefficients (ICCs), mean absolute errors, and mean absolute percentage errors (MAPEs) between the criterion and the trackers. We constructed decile plots that compared HR data from Tempo HR and Polar A370 with criterion measures across intensity deciles. We investigated how many HR data points within the MVPA zone (≥64% of maximum HR) were detected by the trackers. Of the 57 people screened, 55 joined the study (mean age 30.5 [SD 9.8] years). Tempo HR showed moderate agreement and large errors (laboratory: ICC 0.51 and MAPE 13.00%; free-living: ICC 0.71 and MAPE 10.20%). Polar A370 showed moderate-to-strong agreement and small errors (laboratory: ICC 0.73 and MAPE 6.40%; free-living: ICC 0.83 and MAPE 7.10%). Decile plots indicated increasing differences between Tempo HR and the criterion as HRs increased. Such trend was less pronounced when considering the Polar A370 HR data. Tempo HR identified 62.13% (1872/3013) and 54.27% (5717/10,535) of all MVPA time points in the laboratory phase and free-living phase, respectively. Polar A370 detected 81.09% (2273/2803) and 83.55% (9323/11,158) of all MVPA time points in the laboratory phase and free-living phase, respectively. HR data from the examined wrist-worn trackers were reasonably accurate in both the settings, with the Polar A370 showing stronger agreement with the Polar H10 and smaller errors. Inaccuracies increased with increasing HRs; this was pronounced for Tempo HR.


Crystal structure of Cd,Zn metallothionein.
The anomalous scattering data from five Cd in the native protein were used to determine the crystal structure of cadmium, zinc (Cd,Zn) metallothionein isoform II from rat liver. The structure of a 4-Cd cluster was solved by direct methods. A 2.3 A resolution electron density map was calculated by iterative single-wavelength anomalous scattering. The structure is folded into two domains. The amino terminal domain (beta) of residues 1 to 29 enfolds a three-metal cluster of one Cd and two Zn atoms coordinated by six terminal cysteine thiolate ligands and three bridging cysteine thiolates. The carboxyl terminal domain (alpha) of residues 30 to 61 enfolds a 4-Cd cluster coordinated by six terminal and five bridging cysteine thiolates. All seven metal sites have tetrahedral coordination geometry. The domains are roughly spherical, and the diameter is 15 to 20 A; there is limited contact between domains. The folding of alpha and beta is topologically similar but with opposite chirality. Redundant, short cysteine-containing sequences have similar roles in cluster formation in both alpha and beta.


[Morphology of the rat's brain in and after a space flight: ultrastructure of the "blue spot"].
Electron microscopy was used to explore ultrastructure of the livor extracted from the brain of rats on day-13 aboard U.S. space shuttle Columbia (STS-58), and in 5-6 hrs. after landing following the 14-d mission. As compared with the ground controls, the rats flown in microgravity reduced the total number of axodendrite synapses (ADS) by 21% and functional ADS--by 39.7%. After touchdown the total ADS number remained lowered by 16.5%; however, the percentage of highly active ADS exceeded this parameter in the ground controls. Results of the analysis of the ADS number in conjunction with the ultrastructural changes in axonal terminals and dendrites suggest a sharp decrease of the afferent influx towards the livor neurons during microgravity, whereas modifications of the livor neuron ultrastructure point to a decline in their functional activity. These data serve as an experimental proof of the hypothesized development of the hyponoradrenergic syndrome by mammals in microgravity.


Genetic risk factors for superficial vein thrombosis.
Inherited thrombophilic states are associated with an increased risk for deep vein thrombosis (DVT), but whether they are also risk factors for superficial vein thrombosis (SVT) is uncertain. We assessed the risk conferred by inherited thrombophilic states in patients with a first episode of SVT in whom the coexistence of DVT had been ruled out by ultrasonography. Sixty-three patients with SVT, after exclusion of patients with varicose veins, malignant or autoimmune disease, and 537 healthy individuals were investigated. The G1691A mutation in the factor V gene, the G20210A mutation in the prothrombin gene, and deficiencies of the naturally occurring inhibitors of coagulation (antithrombin, protein C, protein S) were searched. The prevalence of each thrombophilic state was higher in patients than in controls. The odds ratios for SVT were 6.1 (95% confidence interval [CI], 2.6 to 14.2) in patients with the G1691A factor V mutation, 4.3 (95% CI, 1.5 to 12.6) in those with the G20210A prothrombin mutation, and 12.9 (95% CI, 3.6 to 46.2) in those with deficiencies of the naturally occurring inhibitors of coagulation taken together. Risks did not substantially change when the analysis was restricted to 43 patients who had SVT as their only thrombotic manifestation, being 4.3 (95% CI, 1.5 to 12.3) in patients with factor V mutation, and 3.6 (95% CI, 1.0 to 13.1) in those with the prothrombin mutation. Among the circumstantial risk factors investigated (surgery, trauma, prolonged immobilization, oral contraceptives and pregnancy or puerperium), pregnancy or puerperium was the most frequently associated with SVT, being present in 38% of women. Our findings indicate that inherited thrombophilic states are associated with an increased risk for SVT. Hence, a laboratory search of these alterations is recommended in patients with SVT, because it allows the identification of patients at high risk of DVT in whom antithrombotic prophylaxis is particularly warranted.


Effectiveness of one-to-one peer support for patients with severe mental illness - a randomised controlled trial.
One-to-one peer support is a resource-oriented approach for patients with severe mental illness. Existing trials provided inconsistent results and commonly have methodological shortcomings, such as poor training and role definition of peer supporters, small sample sizes, and lack of blinded outcome assessments. This is a randomised controlled trial comparing one-to-one peer support with treatment as usual. Eligible were patients with severe mental illnesses: psychosis, major depression, bipolar disorder or borderline personality disorder of more than two years' duration. A total of 216 patients were recruited through in- and out-patient services from four hospitals in Hamburg, Germany, with 114 allocated to the intervention group and 102 to the control group. The intervention was one-to-one peer support, delivered by trained peers and according to a defined role specification, in addition to treatment as usual over the course of six months, as compared to treatment as usual alone. Primary outcome was self-efficacy measured on the General Self-Efficacy Scale at six-month follow-up. Secondary outcomes included quality of life, social functioning, and hospitalisations. Patients in the intervention group had significantly higher scores of self-efficacy at the six-month follow-up. There were no statistically significant differences on secondary outcomes in the intention to treat analyses. The findings suggest that one-to-one peer support delivered by trained peer supporters can improve self-efficacy of patients with severe mental disorders over a one-year period. One-to-one peer support may be regarded as an effective intervention. Future research should explore the impact of improved self-efficacy on clinical and social outcomes.


[Neuropsychological changes in epilepsy].
The neuropsychological assessment of the epileptic patient is a very important aspect of diagnosis and treatment. It may be used to contribute to localization of the hemisphere involved in the seizures, differentiate situations of anxiety or depression or when planning treatment for rehabilitation. We review the different aspects of neuropsychological changes in patients with epilepsy. Firstly we review the different tests used in the neuropsychological assessment of epilepsy. Dodrill's neuropsychological battery of tests, in which the patients score less than the controls, is the most commonly used. We then evaluate and study the so-called 'transient cognitive disorder'. We also study memory problems in epilepsy. There may be episodes of seizures with amnesic features ('amnesic epileptic seizures'). Finally, the possibility of neuropsychological dysfunction secondary to antiepileptic drugs should always be considered. Epileptic patients have lower scores than persons taken as controls for the results of various neuropsychological tests, although there is less difference between the two groups when the patient group is made up of persons with a normal intelligence quotient. Transient cognitive involvement is common in epileptics and may cause underachievement at school or psychological problems. Memory disorders, particularly subjective, are common in epileptics, although neuropsychological tests other than those generally used may be necessary to evaluate this. It is possible that such memory disorders, if occurring as seizures, may be due to amnesic partial crises, which should always be differentiated from the diagnosis of transient global amnesia. Almost all antiepileptic drugs can cause negative neuropsychological effects, especially the benzodiazepines and barbiturates.


Conservation and variation of nucleotide sequences in Escherichia coli strains isolated from nature.
A group of Escherichia coli isolates from nature were compared with one another and with laboratory strains of E. coli with respect to size distribution of chromosomal restriction endonuclease fragments and differences in nucleotide sequences in selected small portions of the genomes. The estimated frequency of base substitutions in nucleotide sequences in and near the trp operons of 26 of the 28 E. coli strains examined ranged from 0.008 to 0.066. Nucleotide sequences in or near lambda prophage homologs were significantly more variable than the sequences in or near trp, tnaA, and thyA genes. Thus, the lambda-homologous regions may have a significant horizontal component in their evolutionary histories, having undergone genetic exchange, whereas the trp, tnaA, and thyA regions may have solely vertical evolutionary histories. The relatedness of the E. coli strains in the genetic regions studied indicated that laboratory strains are not more closely related to one other than they are to isolates from nature. The isolates from natural populations did not form groups related either by host taxa or by geographical region of isolation.


Appearance of a new trimethoprim resistance gene, dhfrIX, in Escherichia coli from swine.
A new gene, dhfrIX, coding for a trimethoprim-resistant dihydrofolate reductase (DHFR), was found in porcine isolates of Escherichia coli. The new enzyme, DHFR IX, containing 178 amino acids, showed an amino acid similarity of about 26% with DHFR I and the chromosomal DHFR of E. coli K-12. The dhfrIX gene was observed to occur on two distinctly different transferable plasmids, although a fragment of about 2.9 kb, including dhfrIX, had an identical restriction enzyme digestion map in each case. The new plasmid-borne dhfrIX gene mediates resistance to a drug level of only about 250 micrograms/ml, as compared with more than 1,000 micrograms/ml for the more frequently encountered dhfrI gene. The new plasmid-borne trimethoprim resistance gene could have been selected and spread as a consequence of the extensive use of trimethoprim in veterinary practice in Sweden. It will be important to try to follow its possible occurrence in human pathogens as well.


Activity monitoring and an enzyme immunoassay for milk progesterone to aid in the detection of estrus.
The accuracy and efficiency of estrus detection using an electronic activity monitor tag in conjunction with an enzyme immunoassay for milk progesterone were studied during 55 observed estrous periods in 37 cows. At approximately 30 d postpartum, cows were equipped with an activity tag and visually observed for estrus, an activity tag with a flashing light-emitting diode, or both twice daily. Milk progesterone concentrations were determined from cows observed in estrus or with an activated tag. Mean daily activity was greater on the day of estrus than during any of the 3 d preceding or 3 d following estrus. Functioning activity tags correctly identified 55% of all visually observed estrous periods that coincided with low milk progesterone levels. The overall accuracy of a flag by the tag for identifying true estrus was 21%. The enzyme immunoassay for milk progesterone was in agreement with 98% of all visually observed estrous periods and false flags committed by the tags. Although the activity tags detected some cows in estrus, a more durable and reliable tag must be developed before it is of practical value to dairy producers.


Giant vesical calculus. A case report.
An exceptional case of bladder stone is presented. The case is unusual as regards the size of the stone and the fact that the patient did not seek medical assistance much earlier, as this was readily available. Furthermore, recovery after removal of the stone was remarkably quick, as evidenced by the clinical picture as well as the blood and urine biochemical values. The fact that the patient did not return for follow-up seems to confirm that cure was complete. The pathogenesis of the stone remains unknown.


Maintaining skin health in older people.
The article examines general skin care for older people, skin barrier function and the skin changes associated with the ageing process. Skin assessment and the use of washing products and emollients are discussed. Methods by which older people and nursing staff can help to promote and improve skin health are identified.


Position statement of ANCP and SBGG on shared decision-making in palliative care.
Health care for patients with serious illnesses usually implies the need to make a large number of decisions, ranging from how information is shared to which diagnostic or therapeutic procedures will be adopted. The method of such decision-making has important implications from an individual and collective point of view and may contribute to either relieving or aggravating suffering. In this consensus document, the Bioethics Committee of the Brazilian National Academy of Palliative Care (ANCP) and the Permanent Committee on Palliative Care of the Brazilian Geriatrics and Gerontology Society (SBGG) adopt the principles of compassionate listening proposed by Saunders, of the nature of suffering proposed by Cassel, of dignity-preserving care proposed by Chochinov, and of cultural humility as a starting point for the construction of an official position of ANCP and SBGG on shared decision-making in palliative care. The position statement posits that, unlike paternalistic and consumerist models, the decision-making process in the sphere of palliative care must follow the mutualistic model of shared decision, where decisions are built based on dialogue between healthcare professionals and patients/family. The document sets forth the assumptions of this process, the limits of autonomy of patients/family and healthcare professionals and the distinction between futile and potentially inappropriate treatments, besides ratifying its incompatibility with any forms of coercion and conflict of interest foreign to the best interests of patients.


Anesthesia information management systems: a survey of current implementation policies and practices.
Anesthesia information management systems (AIMS) implementation is increasing, but there are no published recommendations from anesthesia professional societies to guide configuration and policy decisions that affect billing, security, medical-legal, and compliance issues. A 45-question structured survey was developed by a committee of the Society for Technology in Anesthesia and was sent to the clinical administrator at 18 separate institutions, comprising six different installed AIMS systems. The primary goal of the survey was to establish a baseline of current policies and practices. There was more than two-third agreement among respondents for only 25% of questions. A number of configurations reported may increase exposure to billing denial, Medicare and Medicaid noncompliance, security breeches, and medical-legal defense difficulties. Developing guidelines by anesthesia professional organizations such as Society for Technology in Anesthesia to assist in the configuration of AIMS is recommended to help anesthesia departments avoid problems that may result in significant financial and legal risk.


Adult age differences in visual search as a function of stimulus mapping and processing load.
Previous research has indicated age-related declines in visual search and memory search performance. Recent nondevelopmental evidence suggests that after extensive practice with a consistent stimulus set, performance in search tasks becomes independent of information load. Eight volume (mean age 23.55 years) and eight elderly (mean age 74.92 years) females searched for either two or four target letters which appeared individually in displays of one, four, or nine letters using either an unchanging memory set (consistent mapping) or changing memory sets (varied mapping); subjects performed over six sessions. Under the varied mapping condition the traditional pattern of age-associated decrement in search was obtained, while in the consistent mapping condition adult age differences were attenuated. These findings supported the hypothesis that age-related decrements in visual search can be eliminated, or at least minimized, when various control processes such as selective attention are short-circulated by automatic information processing.


Modeling materials and processes in hybrid/organic photovoltaics: from dye-sensitized to perovskite solar cells.
CONSPECTUS: Over the last 2 decades, researchers have invested enormous research effort into hybrid/organic photovoltaics, leading to the recent launch of the first commercial products that use this technology. Dye-sensitized solar cells (DSCs) have shown clear advantages over competing technologies. The top certified efficiency of DSCs exceeds 11%, and the laboratory-cell efficiency is greater than 13%. In 2012, the first reports of high efficiency solid-state DSCs based on organohalide lead perovskites completely revolutionized the field. These materials are used as light absorbers in DSCs and as light-harvesting materials and electron conductors in meso-superstructured and flat heterojunction solar cells and show certified efficiencies that exceed 17%. To effectively compete with conventional photovoltaics, emerging technologies such as DSCs need to achieve higher efficiency and stability, while maintaining low production costs. Many of the advances in the DSC field have relied on the computational design and screening of new materials, with researchers examining material characteristics that can improve device performance or stability. Suitable modeling strategies allow researchers to observe the otherwise inaccessible but crucial heterointerfaces that control the operation of DSCs, offering the opportunity to develop new and more efficient materials and optimize processes. In this Account, we present a unified view of recent computational modeling research examining DSCs, illustrating how the principles and simulation tools used for these systems can also be adapted to study the emerging field of perovskite solar cells. Researchers have widely applied first-principles modeling to the DSC field and, more recently, to perovskite-based solar cells. DFT/TDDFT methods provide the basic framework to describe most of the desired materials and interfacial properties, and Car-Parrinello molecular dynamics allow researchers the further ability to sample local minima and dynamical fluctuations at finite temperatures. However, conventional DFT/TDDFT has some limitations, which can be overcome in part by tailored solutions or using many body perturbation theory within the GW approach, which is however more computationally intensive. Relativistic effects, such as spin-orbit coupling, are also included in simulations since they are fundamental for addressing systems that contain heavy atoms. We illustrate the performance of the proposed simulation toolbox along with the fundamental modeling strategies using selected examples of relevant isolated device constituents, including dye and perovskite absorbers, metal-oxide surfaces and nanoparticles, and hole transporters. We critically assess the accuracy of various computational approaches against the related experimental data. We analyze the representative interfaces that control the operational mechanism of the devices, including dye-sensitized TiO2/hole transporter and organohalide lead perovskite/TiO2, and the results reveal fundamental aspects of the device's operational mechanism. Although the modeling of DSCs is relatively mature, the recent "perovskite storm" has presented new problems and new modeling challenges, such as understanding exciton formation and dissociation at interfaces and carrier recombination in these materials.


Dabigatran and warfarin in vitamin K antagonist-naive and -experienced cohorts with atrial fibrillation.
The comparison of anticoagulants dabigatran and warfarin might be most equitable in vitamin K antagonist (VKA)-naive patients. Warfarin and 2 doses of dabigatran-110 mg BID (D110) and 150 mg BID (D150)-were compared in a balanced population of VKA-naive (≤62 days of lifetime VKA exposure, with 33% never prescribed a VKA) and VKA-experienced patients with atrial fibrillation (n=18 113). For VKA-naive and -experienced patients assigned warfarin, the time in therapeutic range (international normalized ratio 2.0 to 3.0) was 62% and 67%, respectively, and 61% and 66% for those never and ever prescribed a VKA. In VKA-naive patients, stroke and systemic embolism rates were 1.57%, 1.07%, and 1.69% per year for D110, D150, and warfarin, respectively. D110 was similar to warfarin (P=0.65); D150 was superior (P=0.005). Major bleeding rates were 3.11%, 3.34%, and 3.57% per year, respectively. D110 and D150 were similar to warfarin (P=0.19 and P=0.55). Intracranial bleeding rates were 0.19%, 0.33%, and 0.73% per year, respectively. D110 and D150 were lower than warfarin (P<0.001 and P=0.005). In VKA-experienced patients, stroke and systemic embolism rates were 1.51%, 1.15%, and 1.74% per year for D110, D150, and warfarin, respectively. D110 was similar to warfarin (P=0.32); D150 was superior (P=0.007). Major bleeding rates were 2.66%, 3.30%, and 3.57% per year, respectively. D110 was lower than warfarin (P=0.003); D150 was similar (P=0.41). Intracranial bleeding rates were 0.26%, 0.32%, and 0.79% per year, respectively. D110 and D150 were lower than warfarin (P<0.001 for both). Results were similar for patients never on a VKA. Previous VKA exposure does not influence the benefits of dabigatran at either dose compared with warfarin. http://www.clinicaltrials.gov. Unique identifier: NCT00262600.


Water Extract of Desalted Salicornia europaea Inhibits RANKL-Induced Osteoclast Differentiation and Prevents Bone Loss in Ovariectomized Mice.
Osteoporosis, which is often associated with increased osteoclast activity due to menopause or aging, was the main focus of this study. We investigated the inhibitory effects of water extract of desalted Salicornia europaea L. (WSE) on osteoclast differentiation and bone loss in ovariectomized mice. Our findings revealed that WSE effectively inhibited RANKL-induced osteoclast differentiation, as demonstrated by TRAP staining, and also suppressed bone resorption and F-actin ring formation in a dose-dependent manner. The expression levels of genes related to osteoclast differentiation, including NFATc1, ACP5, Ctsk, and DCSTAMP, were downregulated by WSE. Oral administration of WSE improved bone density and structural parameters in ovariectomized mice. Dicaffeoylquinic acids (DCQAs) and saponins were detected in WSE, with 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA being isolated and identified. All tested DCQAs, including the aforementioned types, inhibited osteoclast differentiation, bone resorption, and the expression of osteoclast-related genes. Furthermore, WSE and DCQAs reduced ROS production mediated by RANKL. These results indicate the potential of WSE and its components, DCQAs, as preventive or therapeutic agents against osteoporosis and related conditions.


[Dermatomyositis and small cell tumor of the kidney].
Dermatomyositis is an inflammation of the striated muscle with an important leukocyte infiltrate which is accompanied by a characteristic cutaneous exanthema. In the international classification we find DM associated with neoplasm in 10% of cases. It is accepted that neoplasms are related to DM if it does not exceed it in two years (prior o after the onset of the disease. The most commonly associated are lung, ovary and breast cancers. In the pas ten years only two cases of DM associated to renal cancer (both in renal cell cancers) have been published. In this article we present a case history of a woman with a DM associated to a renal oat-cell carcinoma. Also, we will review the literature on this theme and will evaluate the predictive parameters of the presence of malignancies in this pathology.


Differential Expression of Prostaglandin E2 Receptors in Porcine Kidney Transplants.
Acute rejection of a kidney allograft results from adaptive immune responses and marked inflammation. The eicosanoid prostaglandin E2 (PGE2) modulates the inflammatory response, is generated by cyclooxygenase 2 (COX-2), and binds to 1 of the 4 G protein-coupled E prostanoid cell surface receptors (EP1-4). Receptor activation results in in proinflammatory (EP1 and EP3) or anti-inflammatory (EP2 and EP4) responses. We theorized that expression of the components of the COX-PGE2-EP signaling pathway correlates with acute rejection in a porcine model of allogeneic renal transplantation. COX-2 enzyme and EP receptor protein expression were quantitated with western blotting and immunohistochemistry from allotransplants (n = 18) and autotransplants (n = 5). Linear regression analysis was used to correlate EP receptor expression with the Banff category of rejection. Pigs with advanced rejection demonstrated significant increases in serum PGE2 metabolites, while pigs with less rejection demonstrated higher tissue concentrations of PGE2 metabolites. A significant negative correlation between COX-2 expression and Banff category of rejection (R = -0.877) was shown. Rejection decreased expression of EP2 and EP4. For both receptors, there was a significant negative correlation with the extent of rejection (R = -0.760 and R = -0.891 for EP2 and EP4, respectively). Rejection had no effect on the proinflammatory receptors EP1 and EP3. Downregulation of COX-2 and the anti-inflammatory EP2 and EP4 receptors is associated with acute rejection in unmatched pig kidney transplants, suggesting that the COX-2-PGE2-EP pathway may modulate inflammation in this model. Enhancing EP2 and/or EP4 activity may offer novel therapeutic approaches to controlling the inflammation of acute allograft rejection.


Results of chiropractic treatment of lumbopelvic fixation in 44 patients admitted to an orthopedic department.
The objectives of this study were to report on and evaluate the results of chiropractic care for patients with low back pain in an orthopedic department. The target group consisted of 44 consecutive patients who experienced sudden and painful low back pain caused by lumbar flexion and rotation without axial loading. Clinical and neurologic examinations by orthopedic surgeons revealed no pathology; in addition, skeletal radiography, computerized tomography, and magnetic resonance imaging findings were all normal. Diagnosis before hospitalization was acute sciatica in all cases. Examination by the doctor of chiropractic indicated that the patients had lumbopelvic fixation. According to preestablished inclusion and exclusion criteria, 33 patients were treated in the chiropractor's clinic, whereas 11 who could not be transported were initially treated by the chiropractor in the hospital. The mean follow-up was 2 years. All but two patients returned to work. The period of sick leave among the patients was reduced by two thirds as compared with that associated with conventional medical treatment. To our knowledge, this is the first report on the work of a chiropractor participating within an orthopedic department of a Norwegian hospital as initiated by the hospital and with full support of the staff. The results support the initiative of the Norwegian government to increase reference to chiropractors in treating patients with neuromusculoskeletal dysfunctions. Based on our experience, we believe that the inclusion of chiropractors within hospital orthopedic departments is feasible and provides a patient care resource that may benefit not only the patients but also the department as a whole.


Access to treatment and educational inequalities in cancer survival.
The public health care systems in the Nordic countries provide high quality care almost free of charge to all citizens. However, social inequalities in health persist. Previous research has, for example, documented substantial educational inequalities in cancer survival. We investigate to what extent this may be driven by differential access to and utilization of high quality treatment options. Quasi-experimental evidence based on the establishment of regional cancer wards indicates that (i) highly educated individuals utilized centralized specialized treatment to a greater extent than less educated patients and (ii) the use of such treatment improved these patients' survival.


Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.
To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2+/-1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from normocholesterolemic mothers (n = 22), hypercholesterolemic mothers (n = 33), and mothers who were hypercholesterolemic only during pregnancy (n = 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age (R = -0.88, P < 0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones (R = 0.86, P = 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651+/-87,449 and 451,255+/-37,448 micron2 per section, respectively; mean+/-SD) than aortas from normocholesterolemic mothers (61,862+/-9,555 micron2; P < 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde- and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL). 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/ macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL. In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia. The fact that in very early lesions LDL and OxLDL are frequently found in the absence of monocyte/macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo.


Intracellular lucifer yellow injection in fixed brain slices combined with retrograde tracing, light and electron microscopy.
The present paper contains a full methodological description of iontophoretic Lucifer Yellow injections in fixed brain slices in mammals. In brief, cortical tissue was either perfused or immersion-fixed in paraformaldehyde. After Vibratome sectioning, tissue slices were transferred to epifluorescence microscopes equipped with long distance objectives. Under visual guidance, neurons were selectively impaled with Lucifer Yellow-filled electrodes and intracellularly injected until all dendrites appeared brightly fluorescent. Excellent dendritic staining was obtained in both perfusion-fixed cat visual cortex and immersion-fixed human brain biopsies. Dendritic spines, varicosities and growth cones could be readily discerned. Filling of axonal collaterals was, however, incomplete. Callosally projecting neurons in cat visual cortex were retrogradely traced with a mixture of the fluorescent tracers Fast Blue and DiI. Subsequently the morphology of labelled cells was determined by intracellular Lucifer Yellow injection. Although the Fast Blue fluorescence had become undetectable in filled neurons the granular red appearance of DiI was still discernible. Hence the neuronal composition of even relatively sparse projections can be demonstrated. To obtain permanent preparations, dye-filled neurons were immersed in a diaminobenzidine solution and irradiated with epifluorescent illumination until all visible fluorescence had faded. Photo-oxidation resulted in the intracellular formation of a homogeneously distributed brown reaction product visible with the light microscope. Brief osmication enhanced the staining contrast, thus providing a Golgi-like image. Subsequent electron microscopy of photo-converted cells showed the fine granular nature of the electron opaque reaction product, thus revealing numerous cytological features. The precipitate was homogeneously distributed throughout the entire cytoplasm and nucleus, extending into dendrites and axon. Any apparent leakage of the label into the extracellular space was not observed. Intracellular staining in fixed tissue yields a high number of neurons with extensive filling of dendritic arbors. Photo-oxidation provides stable, non-fading preparations with the option of subsequent electron microscopy. In addition, the technique can be combined with immunocytochemistry and a variety of fluorescent tracer substances. These features, combined with its high selectivity and relative methodological simplicity, render the method to be a promising alternative to classical neuroanatomical approaches.


Congenital insensitivity to pain with anhidrosis: ocular and systemic manifestations.
To report the incidence and severity of the ophthalmologic manifestations in patients with congenital insensitivity to pain with anhidrosis. Fifteen Bedouin children with congenital insensitivity to pain with anhidrosis underwent complete ocular examination, including refraction and assessment of corneal sensation, and a detailed neurologic examination, including measurement of median nerve motor and sensory conduction. Patients with corneal ulcers were treated appropriately. In the 15 children (eight girls and seven boys, with a mean age of 3.75 +/- 2.67 years; range, 9 months to 9 years), corneal sensation was absent in both eyes. Corneal opacities were present in 10 children, five of whom had bilateral corneal opacities. Corneal ulcers were found in seven children, two of whom had bilateral ulcers, and in three children the ulcers recurred. The corneal ulcers were characterized by very poor healing. The surgical procedures included four lateral tarsorrhaphies, two corneal patch grafts, and one penetrating keratoplasty. All the patients had self-inflicted injuries varying from skin ulcers, burns, and bone fractures to autoamputations of fingertips and tongues. Many patients showed delayed healing and repair of bone and skin injuries. All patients had attacks of hyperpyrexia, moderate mental retardation, and hypotonicity with absent superficial sensation to light touch. Results of median nerve motor and sensory conduction studies were within normal limits. The patients with congenital insensitivity to pain and anhidrosis and absent corneal sensation showed a marked tendency to develop corneal ulcers that healed poorly. Congenital insensitivity to pain and anhidrosis, although rare, should be considered in the differential diagnosis of neurotrophic keratitis.


Effect of health literacy on quality of life among patients with chronic heart failure in China.
Despite advances in treatment and management, Chronic heart failure (CHF) is still associated with poor prognosis, a high rate of hospitalization and readmission, and reduced quality of life (QOL). However, the relationship between QOL and health literacy in patients with CHF remains unclear. This study aimed to examine the association between health literacy and QOL, among Chinese patients with CHF. This is a cross-sectional study of a convenience sample from a cardiovascular hospital in Henan Province in China. Subjects completed a self-administered questionnaire that assessed the heart failure-specific health literacy score. QOL was measured using the Minnesota Living with heart failure scale. Unadjusted and adjusted multiple linear regression were used to explore the association between health literacy and QOL. This study sampled 299 patients, with a mean age of 61.9 ± 14.9 years old. The association between health literacy and QOL was significant only in the unadjusted model (P < 0.001) and was no longer statistically significant after controlling for covariates. The final best-fitted model identified 9 significant predictors, accounting for 38.6% of the variance in quality of life. This study suggests that there is no relationship between health literacy and QOL in Chinese CHF patients after adjusting for covariates. Residence, monthly income, self-care management, self-efficacy and social support are significantly associated with QOL. Compared patients with high health literacy, patients with low health literacy may have problems comprehending healthcare information and following disease management instructions, which might contribute to diminished QOL. Therefore, in clinical practice, effective interventions such as creating appropriate materials for low-literacy patients and performing education to raise self-care management, self-efficacy, might improve the QOL of patients with CHF.


Serum testosterone:estradiol ratio and the development of hepatocellular carcinoma among male cirrhotic patients.
The reason for the large male predominance in the occurrence of hepatocellular carcinoma (HCC) remains unknown, and sex hormones may contribute to this phenomenon. We examined possible associations of serum levels of testosterone, free testosterone, estradiol, sex hormone binding globulin, and testosterone:estradiol ratio (T:E2 ratio) with HCC development in a follow-up study of 46 Japanese male patients with liver cirrhosis predominantly of hepatitis C virus origin (76%). Serum samples were collected between December 1985 and December 1987, and the patients were completely followed until the end of 1995 for an average of 5.1 years. During the follow-up period, 20 patients (43%) developed HCC. Univariate analysis demonstrated that serum T:E2 ratio and testosterone were significant predictors of HCC; the hazard ratios (and 95% confidence intervals) in the middle and upper tertiles relative to the lower tertile were 2.0 (0.5-7.6) and 4.0 (1.1-14.6; P trend = 0.03) for T:E2 ratio and 0.8 (0.2-3.1) and 2.9 (1.0-8.5; P trend = 0.05) for testosterone. Adjustment for age, serum albumin, hepatitis virus markers, and other clinicobiological variables substantially increased the corresponding hazard ratios. In multivariate analysis, serum free testosterone appeared to be associated with increased risk, yet independent associations with estradiol and sex hormone binding globulin were not evident. These results indicate that elevated serum testosterone, together with decreased serum estrogens, may promote the development of HCC in cirrhosis.


Toxic Byproduct Formation during Electrochemical Treatment of Latrine Wastewater.
Electrochemical systems are an attractive option for onsite latrine wastewater treatment due to their high efficiency and small footprint. While concerns remain over formation of toxic byproducts during treatment, rigorous studies examining byproduct formation are lacking. Experiments treating authentic latrine wastewater over variable treatment times, current densities, chloride concentrations, and anode materials were conducted to characterize byproducts and identify conditions that minimize their formation. Production of inorganic byproducts (chlorate and perchlorate) and indicator organic byproducts (haloacetic acids and trihalomethanes) during electrolysis dramatically exceeded recommendations for drinking water after one treatment cycle (∼10-30 000 times), raising concerns for contamination of downstream water supplies. Stopping the reaction after ammonium was removed (i.e., the chlorination breakpoint) was a promising method to minimize byproduct formation without compromising disinfection and nutrient removal. Though treatment was accelerated at increased chloride concentrations and current densities, byproduct concentrations remained similar near the breakpoint. On TiO2/IrO2 anodes, haloacetic acids (up to ∼50 μM) and chlorate (up to ∼2 μM) were of most concern. Although boron-doped diamond anodes mineralized haloacetic acids after formation, high production rates of chlorate and perchlorate (up to ∼4 and 25 μM) made them inferior to TiO2/IrO2 anodes in terms of toxic byproduct formation. Organic byproduct formation was similar during chemical chlorination and electrolysis of wastewater, suggesting that organic byproducts are formed by similar pathways in both cases (i.e., reactions with chloramines and free chlorine).


Protein interaction networks as metric spaces: a novel perspective on distribution of hubs.
In the post-genomic era, a central and overarching question in the analysis of protein-protein interaction networks continues to be whether biological characteristics and functions of proteins such as lethality, physiological malfunctions and malignancy are intimately linked to the topological role proteins play in the network as a mathematical structure. One of the key features that have implicitly been presumed is the existence of hubs, highly connected proteins considered to play a crucial role in biological networks. We explore the structure of protein interaction networks of a number of organisms as metric spaces and show that hubs are non randomly positioned and, from a distance point of view, centrally located. By analysing how the human functional protein interaction network, the human signalling network, Saccharomyces cerevisiae, Arabidopsis thaliana and Escherichia coli protein-protein interaction networks from various databases are distributed as metric spaces, we found that proteins interact radially through a central node, high degree proteins coagulate in the centre of the network, and those far away from the centre have low degree. We further found that the distribution of proteins from the centre is in some hierarchy of importance and has biological significance. We conclude that structurally, protein interaction networks are mathematical entities that share properties between organisms but not necessarily with other networks that follow power-law. We therefore conclude that (i) if there are hubs defined by degree, they are not distributed randomly; (ii) zones closest to the centre of the network are enriched for critically important proteins and are also functionally very specialised for specific 'house keeping' functions; (iii) proteins closest to the network centre are functionally less dispensable and may present good targets for therapy development; and (iv) network biology requires its own network theory modelled on actual biological evidence and that simply adopting theories from the social sciences may be misleading.


[Angio-CT in atheromatous carotid disease].
CT angiography is a diagnostic tool, which is rapidly becoming an important modality for non-invasive evaluation of the neurovasculature. The aim of this article is to review this method, including acquisition and image processing protocols and its application for the evaluation of atherosclerotic stenosis of the carotid artery. Illustrative cases are shown and a revision of the literature is also made.


Agaro-Oligosaccharides Regulate Gut Microbiota and Adipose Tissue Accumulation in Mice.
Gut microbiota are deeply associated with the prevalence of obesity. Agarose is hydrolyzed easily to yield oligosaccharides, designated as agaro-oligosaccharides (AGO). This study evaluated the effects of AGO on obese phenotype and gut microbial composition in mice. Mice were administered AGO in drinking water (AGO-receiving mice). 16S rRNA gene sequencing analyses revealed their fecal microbiota profiles. Serum bile acids were ascertained using a LC-MS/MS system. Compared to the control group, AGO administration significantly reduced epididymal adipose tissue weights and serum non-esterified fatty acid concentrations, but the cecal content weights were increased. Data from the serum bile acid profile show that concentrations of primary bile acids (cholic acid and chenodeoxycholic acid), but not those of secondary bile acids (deoxycholic acid, lithocholic acid, and ursodeoxycholic acid), tended to increase in AGO-receiving mice. 16S rRNA gene sequencing analyses showed that the relative abundances of 15 taxa differed significantly in AGO-receiving mice. Of these, the relative abundances of Rikenellaceae and Lachnospiraceae were found to be positively correlated with epididymal adipose tissue weight. The relative abundances of Bacteroides and Ruminococcus were correlated negatively with epididymal adipose tissue weight. Although the definitive role of gut microbes of AGO-received mice is still unknown, our data demonstrate the possibility that AGO administration affects the gut microbial composition and inhibits obesity in mice.


Cultural variation--nutritional and clinical implications.
Cultural variation may play an important role in human nutrition and must be considered in either clinical or public health intervention particularly in areas with large immigrant populations. Acculturative and environmental change influence the food habits and health of transitional groups. Nutritional assessment may be complicated by cultural variation. The relationship between ethnicity and nutrition may be of evolutionary significance. Food beliefs may have beneficial or detrimental effects on health status. The study of acculturating populations may elucidate the pathogenesis of nutrition-related chronic diseases. Appreciation of the interaction of culture and nutrition may be of benefit to physicians and nutritionists in clinical practice and to those concerned with the prevention of nutrition-related chronic diseases.


The Inhibition of Polysialyltranseferase ST8SiaIV Through Heparin Binding to Polysialyltransferase Domain (PSTD).
The polysialic acid (polySia) is a unique carbohydrate polymer produced on the surface Of Neuronal Cell Adhesion Molecule (NCAM) in a number of cancer cells, and strongly correlates with the migration and invasion of tumor cells and with aggressive, metastatic disease and poor clinical prognosis in the clinic. Its synthesis is catalyzed by two polysialyltransferases (polySTs), ST8SiaIV (PST) and ST8SiaII (STX). Selective inhibition of polySTs, therefore, presents a therapeutic opportunity to inhibit tumor invasion and metastasis due to NCAM polysialylation. Heparin has been found to be effective in inhibiting the ST8Sia IV activity, but no clear molecular rationale. It has been found that polysialyltransferase domain (PSTD) in polyST plays a significant role in influencing polyST activity, and thus it is critical for NCAM polysialylation based on the previous studies. To determine whether the three different types of heparin (unfractionated hepain (UFH), low molecular heparin (LMWH) and heparin tetrasaccharide (DP4)) is bound to the PSTD; and if so, what are the critical residues of the PSTD for these binding complexes? Fluorescence quenching analysis, the Circular Dichroism (CD) spectroscopy, and NMR spectroscopy were used to determine and analyze interactions of PSTD-UFH, PSTD-LMWH, and PSTD-DP4. The fluorescence quenching analysis indicates that the PSTD-UFH binding is the strongest and the PSTD-DP4 binding is the weakest among these three types of the binding; the CD spectra showed that mainly the PSTD-heparin interactions caused a reduction in signal intensity but not marked decrease in α-helix content; the NMR data of the PSTD-DP4 and the PSTDLMWH interactions showed that the different types of heparin shared 12 common binding sites at N247, V251, R252, T253, S257, R265, Y267, W268, L269, V273, I275, and K276, which were mainly distributed in the long α-helix of the PSTD and the short 3-residue loop of the C-terminal PSTD. In addition, three residues K246, K250 and A254 were bound to the LMWH, but not to DP4. This suggests that the PSTD-LMWH binding is stronger than the PSTD-DP4 binding, and the LMWH is a more effective inhibitor than DP4. The findings in the present study demonstrate that PSTD domain is a potential target of heparin and may provide new insights into the molecular rationale of heparin-inhibiting NCAM polysialylation.


Rapid and simple kinetics screening assay for electrophilic dermal sensitizers using nitrobenzenethiol.
The need for alternatives to animal-based skin sensitization testing has spurred research on the use of in vitro, in silico, and in chemico methods. Glutathione and other select peptides have been used to determine the reactivity of electrophilic allergens to nucleophiles, but these methods are inadequate to accurately measure rapid kinetics observed with many chemical sensitizers. A kinetic spectrophotometric assay involving the reactivity of electrophilic sensitizers to nitrobenzenethiol was evaluated. Stopped-flow techniques and conventional UV spectrophotometric measurements enabled the determination of reaction rates with half-lives ranging from 0.4 ms (benzoquinone) to 46.2 s (ethyl acrylate). Rate constants were measured for seven extreme, five strong, seven moderate, and four weak/nonsensitizers. Seventeen out of the 23 tested chemicals were pseudo-first order, and three were second order. In three out of the 23 chemicals, deviations from first and second order were apparent where the chemicals exhibited complex kinetics whose rates are mixed order. The reaction rates of the electrophiles correlated positively with their EC3 values within the same mechanistic domain. Nonsensitizers such as benzaldehyde, sodium lauryl sulfate, and benzocaine did not react with nitrobenzenethiol. Cyclic anhydrides, select diones, and aromatic aldehydes proved to be false negatives in this assay. The findings from this simple and rapid absorbance model show that for the same mechanistic domain, skin sensitization is driven mainly by electrophilic reactivity. This simple, rapid, and inexpensive absorbance-based method has great potential for use as a preliminary screening tool for skin allergens.


[Pulmonary hypertension, involvement of the right and left cardiac parts in patients with ankylosing spondylarthritis].
The literature states that pulmonary hypertension (PH) may develop in ankylosing spondylarthritis (AS); however, there are virtually no evidence for its incidence and the specific features of lesions of the right and left cardiac portions. This study was undertaken to determine the incidence of PH and its specific features in patients with AS. Fifty-five patients with AS were examined. There were prevalent patients with predominantly spinal lesions (50.9%), moderate progression of the disease (61.8%), and Grade III sacroileitis (49.1%). PH was detected in 70.96% of the patients, hypertrophy of the right ventricle (RV) was observed in 47.3%, RV dilation was in 34.5%. There were increases in the end systolic size and volume of the left ventricle (LV) in patients with AS (p < 0.05 and p < 0.05, respectively), ventricular septal thickening (p < 0.05), and a tendency for the posterior LV wall to be thickened. LV diastolic dysfunction occurred in 25.9% of the patients with AS. The found changes were interrelated with the duration of disease, the involvement of the vertebral column, the thoracic part in particular. Thus, the high incidence of PH was ascertained in patients with AS. The study confirms that echocardiography is of high informative value in the detection of PH and right cardiac changes in patients with AS, which shows this method to be screening in identifying the above pathology.


Fallopian tube herniation from trocar-site after laparoscopic appendectomy.
Trocar site hernias are a type of incisional hernias and may occur within a variable time shift after surgery. A mean incidence of 1.85% was reported, and the first trocar site hernia was narrated by Maio et al. in 1991 describing small bowel obstruction due to trocar site herniation after laparoscopic cholecystectomy. The 10-mm-trocar port is more frequently problematic, and a trocar site hernia in 5 mm port is very rare. This report unveils a 5mm trocar site herniation of right fallopian tube following laparoscopic appendectomy. In this case study, a 19-year-old female patient applied to the emergency department because of a discharge in the right lower quadrant was reported. She explained that she had undergone laparoscopic appendectomy two days before and discharged the next day uneventfully. The surgical report described a suction drain in the right lower quadrant where the patient was suffering from the discharge. The physical examination revealed no tenderness, but an abdominal CT disclosed an edematous tubular structure herniating from the 5 mm trocar site where the drain was put. She was re-operated laparoscopically due to early trocar site hernia, and the right fallopian tube was observed herniating through the defect. After the reduction into the abdomen, the fallopian tube was observed fine, and the defect was closed using 2/0 polypropylene suture. Trocar site hernias are rare but may cause serious complications after laparoscopic surgery. They may occur early after the surgery, but the time shift is variable. Although mechanical bowel obstructions are more frequent endpoint, it should be remembered that any organ within the abdominal cavity may herniate.


Mini Gold Nanorods with Tunable Plasmonic Peaks beyond 1000 nm.
Gold nanorods of small sizes have larger absorption cross sections and higher photothermal efficiency compared to larger ones. However, tuning the surface plasmon resonance of small gold nanorods remains a challenge because increasing an aspect ratio usually results from increasing dimensions. We demonstrate the synthesis of mini gold nanorods with tunable longitudinal surface plasmon resonance from ~600 to >1300 nm accompanied by precise control over widths <10 nm. Two weak reducing agents, ascorbic acid and even milder hydroquinone, were applied to a seed-mediated growth method to tune the aspect ratios of mini gold nanorods from 2.2 to 10.8 corresponding to average dimensions 19.3 × 9.0 nm through 93.1 × 8.7 nm, respectively. This seed-mediated growth of mini gold nanorods results in an average 96% of rods and yields of at least 79% based on gold ion reduction. The extinction coefficients of mini gold nanorods were established based on the gold content from inductively coupled plasma mass spectrometry. The longitudinal extinction coefficients range from 1.6 × 108 to 1.4 × 109 M-1 cm-1 depending on aspect ratio. We show that liter-scale mini gold nanorod syntheses are reproducible, and the dimensions, aspect ratios, and shape percent yields are comparable to those of a small-scale synthesis.


Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice.
Disrupted-in-schizophrenia 1 (DISC1) was initially discovered through a balanced translocation (1;11)(q42.1;q14.3) that results in loss of the C terminus of the DISC1 protein, a region that is thought to play an important role in brain development. Here, we use an inducible and reversible transgenic system to demonstrate that early postnatal, but not adult induction, of a C-terminal portion of DISC1 in mice results in a cluster of schizophrenia-related phenotypes, including reduced hippocampal dendritic complexity, depressive-like traits, abnormal spatial working memory, and reduced sociability. Accordingly, we report that individuals in a discordant twin sample with a DISC1 haplotype, associating with schizophrenia as well as working memory impairments and reduced gray matter density, were more likely to show deficits in sociability than those without the haplotype. Our findings demonstrate that alterations in DISC1 function during brain development contribute to schizophrenia pathogenesis.


Crystalline anatase-rich titanium can reduce adherence of oral streptococci.
Dental implant abutments that emerge through the mucosa are rapidly covered with a salivary protein pellicle to which bacteria bind, initiating biofilm formation. In this study, adherence of early colonizing streptococci, Streptococcus gordonii, Streptococcus oralis, Streptococcus mitis and Streptococcus sanguinis to two saliva-coated anodically oxidized surfaces was compared with that on commercially pure titanium (CpTi). Near edge X-ray absorption (NEXAFS) showed crystalline anatase was more pronounced on the anodically oxidized surfaces than on the CpTi. As revealed by fluorescence microscopy, a four-species mixture, as well as individual bacterial species, exhibited lower adherence after 2 h to the saliva-coated, anatase-rich surfaces than to CpTi. Since wettability did not differ between the saliva-coated surfaces, differences in the concentration and/or configuration of salivary proteins on the anatase-rich surfaces may explain the reduced bacterial binding effect. Anatase-rich surfaces could thus contribute to reduced overall biofilm formation on dental implant abutments through diminished adherence of early colonizers.


Metastable Se6 as a ligand for Ag+: from isolated molecular to polymeric 1D and 2D structures.
Attempts to prepare the hitherto unknown Se(6)(2+) cation by the reaction of elemental selenium and Ag[A] ([A](-) = [Sb(OTeF(5))(6)](-), [Al(OC(CF(3))(3))(4)](-)) in SO(2) led to the formation of [(OSO)Ag(Se(6))Ag(OSO)][Sb(OTeF(5))(6)](2)1 and [(OSO)(2)Ag(Se(6))Ag(OSO)(2)][Al(OC(CF(3))(3))(4)](2)2a. 1 could only be prepared by using bromine as co-oxidant, however, bulk 2b (2a with loss of SO(2)) was accessible from Ag[Al(OC(CF(3))(3))(4)] and grey Se in SO(2) (chem. analysis). The reactions of Ag[MF(6)] (M = As, Sb) and elemental selenium led to crystals of 1/∞{[Ag(Se(6))](∞)[Ag(2)(SbF(6))(3)](∞)} 3 and {1/∞[Ag(Se(6))Ag](∞)}[AsF(6)](2)4. Pure bulk 4 was best prepared by the reaction of Se(4)[AsF(6)](2), silver metal and elemental selenium. Attempts to prepare bulk 1 and 3 were unsuccessful. 1-4 were characterized by single-crystal X-ray structure determinations, 2b and 4 additionally by chemical analysis and 4 also by X-ray powder diffraction, FT-Raman and FT-IR spectroscopy. Application of the PRESTO III sequence allowed for the first time (109)Ag MAS NMR investigations of 4 as well as AgF, AgF(2), AgMF(6) and {1/∞[Ag(I(2))](∞)}[MF(6)] (M = As, Sb). Compounds 1 and 2a/b, with the very large counter ions, contain isolated [Ag(Se(6))Ag](2+) heterocubane units consisting of a Se(6) molecule bicapped by two silver cations (local D(3d) sym). 3 and 4, with the smaller anions, contain close packed stacked arrays of Se(6) rings with Ag(+) residing in octahedral holes. Each Ag(+) ion coordinates to three selenium atoms of each adjacent Se(6) ring. 4 contains [Ag(Se(6))(+)](∞) stacks additionally linked by Ag(2)(+) into a two dimensional network. 3 features a remarkable 3-dimensional [Ag(2)(SbF(6))(3)](-) anion held together by strong Sb-FAg contacts between the component Ag(+) and [SbF(6)](-) ions. The hexagonal channels formed by the [Ag(2)(SbF(6))(3)](-) anions are filled by stacks of [Ag(Se(6))(+)](∞) cations. Overall 1-4 are new members of the rare class of metal complexes of neutral main group elemental clusters, in which the main group element is positively polarized due to coordination to a metal ion. Notably, 1 to 4 include the commonly metastable Se(6) molecule as a ligand. The structure, bonding and thermodynamics of 1 to 4 were investigated with the help of quantum chemical calculations (PBE0/TZVPP and (RI-)MP2/TZVPP, in part including COSMO solvation) and Born-Fajans-Haber-cycle calculations. From an analysis of all the available data it appears that the formation of the usually metastable Se(6) molecule from grey selenium is thermodynamically driven by the coordination to the Ag(+) ions.


Associations of serum IL-18 levels with carotid intima-media thickness.
Elevated circulating levels of IL-18 can predict future coronary heart disease. Although IL-18 is thought to play a crucial role in atherosclerosis, whether circulating IL-18 levels are associated with the severity of atherosclerosis remains to be determined. With the use of B-mode ultrasound, this study examines the relationships of serum IL-18 levels with carotid intima-media thickness (IMT) as a reflector for systemic atherosclerosis. The study comprised 366 patients without histories of cardiovascular accidents. Severity of carotid atherosclerosis was evaluated by the mean max IMT, ie, mean of the maximal wall thickness at 12 carotid segments. Serum IL-18, IL-6, and high-sensitive C-reactive protein (hs-CRP) levels were determined in all patients. Log-transformed IL-18 concentrations were positively correlated with IMT (r=0.36, P<0.001), and the association remained significant (beta=0.20, P<0.001) when controlling for traditional atherosclerotic risk factors, IL-6 and hs-CRP levels. Also, IMT was greater in the highest and the middle tertile of IL-18 levels than in the lowest tertile. Higher serum IL-18 levels appear to be associated with greater carotid IMT, suggesting the link between IL-18 and atherosclerosis.


Piracetam improves visuomotor and cognitive deficits in early Parkinsonism--a pilot study.
The influence of Piracetam on Parkinsonism was studied in 18 patients and 18 matched controls. Clinical, visuomotor and psychometric variables were measured. Piracetam improved visuomotor reaction time (RT) and accuracy in 6 mildly affected and tracing time in 6 moderately affected patients, the clinical condition and the organic brain syndrome in all patients investigated. The improvement of the prolonged RT seems to be correlated with bradyphrenia. No drug influence could be observed in the prolonged interhemispheric transfer time. As the mildly affected patients displayed the clearest effect of Piracetam, its administration in early and mild stage of parkinsonism is recommended.


[Effect of new generation application sorbents on the results of complex treatment in patients with diabetic foot syndrome].
The work objective is the results of complex treatment improvement in patients with diabetic foot syndrome. The work is based on the results of complex treatment analysis data in 32 patients suffering diabetes mellitus, complicated by diabetic foot syndrome. There was proved the efficacy of application in complex of curative measures of the applicating serpent of a new generation Sertasyl, which had lowered the risk of performance of the lower extremities high amputation, trusting necessity of its wide clinical application in such patients.


Role of early plasma membrane events in chemotherapy-induced cell death.
Most current anticancer therapies induce tumor cell death through the induction of apoptosis. However, the pathways leading to cell death are not always understood. For example, for several DNA-damaging agents the specific biochemical lesions (DNA damage) have been associated with the induction of apoptosis. However, several of these DNA-damaging agents (cisplatin, 1-beta-arabinofuranosylcytosine, daunorubicin or doxorubicin) as well as other antitumor agents, such as edelfosine or resveratrol, have been recently shown to induce apoptosis via signaling through plasma membrane lipid rafts involving the death receptor pathway. In this review we focus on the role of early plasma membrane events in chemotherapy-induced cell death. Special attention is given to changes in plasma membrane fluidity, activation of the acid sphingomyelinase and the Fas death pathway in response to chemotherapy as well as their possible interrelationships.


Immune checkpoint blockade therapy: the 2014 Tang Prize in Biopharmaceutical Science.
The first Tang Prize for Biopharmaceutical Science has been awarded to Prof. James P. Allison and Prof. Tasuku Honjo for their contributions leading to an entirely new way to treat cancer by blocking the molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) that turn off immune response. The treatment, called "immune checkpoint blockade therapy," has opened a new therapeutic era. Here the discoveries of the immune checkpoints and how they contribute to the maintenance of self-tolerance, as well as how to protect tissues from the excess immune responses causing damage are reviewed. The efforts made by Prof. Allison and Prof. Honjo for developing the most promising approaches to activate therapeutic antitumor immunity are also summarized. Since these certain immune checkpoint pathways appear to be one of the major mechanisms resulting in immune escape of tumors, the presence of anti-CTLA-4 and/or anti-PD-1 should contribute to removal of the inhibition signals for T cell activation. Subsequently, it will enhance specific T cell activation and, therefore, strengthen antitumor immunity.


Prevalence and prognosis of synchronous distant metastatic tonsil squamous cell carcinomas.
To analyze the prevalence proportions and prognostic factors of synchronous distant metastases in patients with tonsil squamous cell carcinomas (TSCC). TSCC patients were extracted from the Surveillance, Epidemiology and End Results (SEER) database between 2010 and 2014. We examined the association between clinical manifestations and distant metastases using Chi-squared tests. Predictors of 5-year survival were assessed using univariate and multivariate analyses. A total of 6193 patients were analyzed and lung was the most common site of distant metastases. Poorly/undifferentiated differentiation was found to be significantly correlated with lung metastasis (p=0.033) and liver and bone metastases were associated with African American (p=0.000 and p=0.000, respectively). A higher T classification was associated with higher prevalence of lung, liver, bone and brain metastasis (p=0.000, p=0.000, p=0.000 and p=0.007, respectively). The same results were found in N classification in lung, liver, and bone metastasis (p=0.000, p=0.000, and p=0.000, respectively). Worse prognosis was associated with older age, Blacks, lower grade, higher T and N classification, no surgery therapy and more metastatic sites. Lung was the most frequent lesion of synchronous distant metastases and liver and bone metastases were associated with African American. Higher T and N classification were independent prognostic parameters for higher prevalence of lung, bone, liver and brain metastasis. Worse prognosis was associated with older age, African Americans, lower grade, higher T and N classification, no surgery therapy and more metastatic sites.


Rheumatoid arthritis patients' experience of climate care.
The purpose of this qualitative study was to understand and examine how patients with rheumatoid arthritis (RA) experience climate care and its effects. A qualitative approach was chosen for the study. Two men and six women were interviewed according to a semistructured interview guide. The text was analyzed using a manifest content analysis. The analysis resulted in four categories and 10 subcategories. The interviewees experienced climate care positively. The training was perceived increasing gradually. The patients felt that they performed to a maximum capacity during training and were impressed by the staff's enthusiasm and encouragement. The patients felt that they were involved in the goal setting and the choice of treatment, and the staff noticed individual needs. There was a feeling among the patients of being acknowledged by the staff. Information about the disease was perceived as individualized. The climate and beautiful surroundings were viewed as encouraging physical activity and a feeling of well-being. Patients made new friends, had fun together and also shared experiences about their disease. Furthermore, the patients described a sense of belonging to a group as well as a feeling of not being the only one that was sick among the healthy. Not having to do everyday tasks and having time to themselves were perceived positively. Several factors contributed to the positive experiences of climate care; climate, environment, physical activity, social context, staff involvement, and information about the disease were described as interacting together and resulting in a sense of well-being. A proposal for future research would be to examine if/how the various factors might interact and affect the RA patients' illness and quality of life.


Selective effects of ascorbic acid on acetylcholine receptor number and distribution.
Ascorbic acid in soluble extracts of neural tissue can account for the increase in surface acetylcholine receptors (AChR's) seen on L5 myogenic cells treated with crude brain extract (Knaack, D., and T. R. Podleski, 1985, Proc. Natl. Acad. Sci. USA., 82:575-579). The present study further elucidates the nature of the response of L5 cells to ascorbic acid. Light autoradiography showed that ascorbic acid treatment affects both the number and distribution of surface AChR's. Ascorbic acid, like crude brain extracts, caused a three- to fourfold increase in average AChR site density. However, the number of AChR clusters induced by ascorbic acid was only one-fifth that observed with crude brain extract. The rate constant for degradation of AChR in ascorbic acid-treated cells of 0.037 +/- 0.006 h-1 (t1/2 = 19 h) was not significantly different from that in untreated controls of 0.050 +/- 0.001 h-1 (t1/2 = 14 h). The increase in AChR site density is primarily due to a 2.8-fold increase in the average rate of AChR incorporation. Ascorbic acid also stimulates thymidine incorporation and increases the total number of nuclei per culture. However, cellular proliferation is not responsible for the increase in AChR's since 10 microM cytosine arabinofuranoside blocks the mitogenic effect without affecting the AChR increase. The specificity of ascorbic acid on AChR expression was established by showing that (a) ascorbic acid produced only a slight increase in total protein, which can be accounted for by the mitogenic effect, and (b) the normal increase seen in creatine kinase activity during muscle differentiation was not altered by the addition of ascorbic acid. We conclude that the action of ascorbic acid on AChR number cannot be explained by changes in cell growth, survival, differentiation, or protein synthesis. Therefore, in addition to a minor stimulation of AChR clustering, ascorbic acid specifically affects some aspect of the AChR biosynthetic pathway.


Shrimp winch injuries.
Shrimp winch injuries range from phalangeal injuries to life-threatening limb amputations. The injuries often result in significant morbidity, significant cost, and lengthy hospitalizations. There are usually insufficient or nonexistent safety mechanisms on the boats to prevent these injuries. No international, federal, or state agencies regulate safety in the shellfish industry. The injuries are relatively rare, but likely underreported. We retrospectively reviewed 19 cases of injuries resulting from the use of shrimp winches in a 20-year period at our institution. In addition, people who use shrimp winches were interviewed and current regulations were researched. All patients were men with an average age of 46.5 years. There were 17 upper extremity injuries, ranging in severity from crushed finger tips to transhumeral amputations, and two lower extremity injuries. A classification system based on injury pathomechanics and severity is offered. During inspection of local shrimp boats, the winch system was often in poor condition. No International, federal, state, or local regulations guiding the shellfish industry were found. Injuries from the use of shrimp winches are rare, but may be underreported. However, they can be severe when they do occur. Stronger safety guidelines need to be put into practice to prevent these serious injuries.


FOXO1 regulates L-Selectin and a network of human T cell homing molecules downstream of phosphatidylinositol 3-kinase.
In T cells, the PI3K pathway promotes proliferation and survival induced by Ag or growth factors, in part by inactivating the FOXO transcription factor 1. We now report that FOXO1 controls the expression of L-selectin, an essential homing molecule, in human T lymphocytes. This control is already operational in unprimed T cells and involves a transcriptional regulation process that requires the FOXO1 DNA-binding domain. Using transcriptional profiling, we demonstrate that FOXO1 also increases transcripts of EDG1 and EDG6, two sphingosine-1-phosphate receptors that regulate lymphocyte trafficking. Additionally, FOXO1 binds the promoter of the cell quiescence and homing regulator Krüppel-like factor 2 and regulates its expression. Together, these results reveal a new function of FOXO1 in the immune system and suggest that PI3K controls a coordinated network of transcription factors regulating both cell quiescence and homing of human T lymphocytes.


Obesity and aging: determinants of endothelial cell dysfunction and atherosclerosis.
Endothelial cells are both the source and target of factors contributing to atherosclerosis. After the discovery of the endothelium-derived relaxing factor (EDRF) by Robert F. Furchgott in 1980 it soon became clear that endothelial cells also release vasoactive factors distinct from nitric oxide (NO) namely, endothelium-derived contracting factors (EDCF) as well as hyperpolarizing factors (EDHF). Vasoactive factors derived from endothelial cells include NO/EDRF, reactive oxygen species, endothelins and angiotensins which have either EDRF or EDCF functions, cyclooxygenase-derived EDCFs and EDRFs, and EDHFs. Endothelial factors are formed by enzymes such as NO synthase, cyclooxygenase, converting enyzmes, NADPH oxidases, and epoxigenases, among others, and participate in the regulation of vascular homeostasis under physiological conditions; however, their abnormal regulation due to endothelial cell dysfunction contributes to disease processes such as atherosclerosis, arterial hypertension, and renal disease. Because of recent changes in world demographics and the declining health status of the world's population, both aging and obesity as independent risk factors for atherosclerosis-related diseases such as coronary artery disease and stroke, will continue to increase in the years to come. Obesity and associated conditions such as arterial hypertension and diabetes are now also some of the primary health concerns among children and adolescents. The similarities of pathomechanisms activated in obesity and aging suggest that obesity--at least in the vasculature--can be considered to have effects consistent with accelerated, "premature" aging. Pathomechanisms as well as the clinical issues of obesity- and aging-associated vascular changes important for atherosclerosis development and prevention are discussed.


Pyrroloquinoline and pyridoacridine alkaloids from marine sources.
Marine organisms are a rich source for natural products. Pyrrolo[4,3, 2-de]quinolines and pyrido[4,3,2-mn]acridines are of major interest as metabolites in sponges and ascidians. Many of these compounds have generated interest both as challenging problems for structure elucidation and synthesis as well as for their cytotoxicities. The isolation, structure proof, biological activities, chemical properties and synthesis have attracted the attention of chemists, biologists and pharmacists. The principal structural feature of these alkaloids is the core of a planar iminoquinone moiety which can intercalate into DNA and cleave the DNA double helix or inhibit the action of topoisomerase II. Of the makaluvamines, makaluvamine F and A are the most cytotoxic to the HCT 116 cell line. The enhanced toxicity of the makaluvamines towards xrs-6 cells shows that all of the makaluvamines, except makaluvamine B, act like m-AMSA and etoposide in inhibiting topo iso merases via cleavable complex formation, or via the direct induction of DNA double-strand breaks. They are also amongst the most potent inhibitors of topoisomerase II. Both makaluvamine A and C can decrease tumor size in a solid human tumor model. Discorhabdin A and C in contrast are of high cytotoxicity, but they exhibit no inhibition of topoisomerase II. As representatives of the derivatives of pyrido[4,3,2-mn]acridine, cystodytins, kuanoniamines and diplamine are the most potent to inhibit HCT replication. Eilatin, as a 1,10-phenanthroline derivative, can form complexes with metal ions. It has been shown that these metal complexes can bind to DNA by intercalation. The new members of the pyrrolo[4,3,2-de]quinolines and pyrido[4,3, 2-mn]acridines, such as veiutamine, discorhabdin G, tsitsikammamines, epinartins, arnoamines as well as sagitol are reviewed. Some successful syntheses of pyrrolo[4,3,2-de]quinoline ring system and pyrido[4,3,2-mn]acridine ring system are also reviewed in this article.