[Homonymous lateral hemianopsia as a presenting sign of intracranial extracerebral cavernous hemangioma].
A case of intracranial extracerebral cavernous hemangioma of the middle fossa in a woman who suffered from a multiple sclerosis, is reported. Appearance of a lateral hemianopia suggested an other disease than multiple sclerosis to explain this symptom. Intracranial extracerebral cavernous hemangioma is a rare tumor reported more often in the middle fossa than in other sites. It usually produces symptoms by compression of nearby structure. Diagnosis is based on neuroradiological examination and we describe the MRI aspect. It is difficult to remove because of massive hemorrhage.


Risk of simultaneous phenotypic expression of hip and elbow dysplasia in dogs: a study of 1,411 radiographic examinations sent for official scoring.
In order to look for phenotypic correlation between hip (HD) and elbow (ED) dysplasia, we used radiographic scoring obtained from 1,411 dogs of different breeds, which were evaluated for authoritative grading of both conditions. In this population, we found that the risk ratio for an animal to be simultaneously affected by HD and ED is 1.67. For a dog with ED, the risk ratio to be affected by HD increases as the ED grade increases. Similarly, for a dog affected by HD, the risk ratio to be affected by ED increases as the HD grade increases. In a dog affected by HD or ED, the clinician should look for the second condition in the same animal. Due to the low, yet positive correlation, selection against one trait will not affect the other trait sufficiently. Therefore selection has to be conducted at reduction of HD as well as reduction of ED.


Universal Method for Producing Reduced Graphene Oxide/Gold Nanoparticles Composites with Controlled Density of Grafting and Long-Term Stability.
In this study, we report a universal approach allowing the non-covalent deposition of gold nanoparticles on reduced graphene oxide surface in a controlled fashion. We used a modified Hummers method to obtain graphene oxide, which then underwent surficial functionalization with carboxyl moieties coupled with simultaneous reduction. Nanoparticles were synthesized ex-situ and capped with a thiolated poly-ethylene glycol (PEG) ligand. The interactions between the surface of modified graphene oxide and nanoparticle ligands enabled the formation of stable hybrid graphene-nanoparticles materials in the aqueous phase. Using this technique, we were able to cover the surface of graphene with gold nanoparticles of different shapes (spheres, rods, triangles, stars, and bipyramids), broad range of sizes (from 5 nm to 100 nm) and controlled grafting densities. Moreover, materials obtained with this strategy exhibited long-term stability, which coupled with the versatility and facility of preparation, makes our technique appealing in the light of increasing demand for new graphene-based hybrid nanostructures.


Comments on the Institute of Medicine's 2002 report on the safety of anthrax vaccine.
In April 2002, the prestigious Institute of Medicine of the National Academy of Sciences issued a final report on the safety and effectiveness of the anthrax vaccine currently in use by the United States military. It concluded that the present vaccine was completely safe and effective, but ignored evidence of several recent research studies from three different nations that have implicated vaccines, often including anthrax vaccine, in the epidemiology of Gulf War illnesses. Omissions and limitations of that report are discussed.


An overview of recycling and treatment of scrap computers.
In order to recover valuable materials and to minimize the adverse effects of hazardous materials contained in scrap computers, a dismantling practice is commonly adopted to treat scrap computers. By using the dismantling process, both useful and hazardous materials can be manually separated and retrieved. On the basis of the properties of the retrieved materials, they can be sent to appropriate facilities for further recycling or treatment. Among the retrieved materials, the treatment of hazardous materials from cathode ray tubes (CRT) and printed circuit boards with integrated circuits have drawn considerable attention, thus implying that the proper treatment of such materials can greatly assure the successful recycling of scrap computers. For this reason, this study reviews the available technologies which can be applied to treat and recycle cathode ray tube components and printed circuit boards with integrated circuits. Actual recycling data from a scrap computer recycling plant located in Taiwan are also introduced. The data show that this recycling plant can recover 94.75 wt. % and 45.99 wt. % of useful materials from the main machines (i.e., CPU, power supplier, fan, IC boards, DVD drive, CD drive, hard disk, soft disk, shell casing, etc.) and monitors of scrap computers, respectively.


Mechanical properties and in vivo study of modified-hydroxyapatite/polyetheretherketone biocomposites.
Polyether ether ketone (PEEK) has received much attention for its excellent mechanical properties and biocompatibility. Here, the silane coupling agent KH560 [γ-(2,3-epoxypropoxy)propyltrimethoxysilane] is used for graft modification of bioactive HA (hydroxyapatite) particles and for preparing HA/PEEK composites via a hot-press molding method. The prepared HA/PEEK composites were tested for their mechanical properties with SEM (scanning electron microscopy), infrared spectroscopy, and thermo-analysis. The results show that silane coupling KH-560 modifies HA successfully and that the tensile strengths of HA/PEEK and m-HA/PEEK composites indicate an increasing and then a decreasing tendency with increasing HA contents. The non-modified HA/PEEK composites display the same trend as the modified specimens with lower tensile strength and consist of sharp points. When the HA content is 5wt.%, the tensile strength of m-HA/PEEK composite reaches its maximum, which is 23% higher than that of pure PEEK specimens. The in vivo experiments of m-HA/PEEK used a biomechanical push-out test, SEM, optical microscopy, and an Image-Pro Express C image analysis system. The growth of the bone tissues around the m-HA/PEEK composites with an HA content of 5wt.% is better than that of specimens with different HA contents. This finding shows the nano-scale effect of the bioactive filler HA in PEEK substrates, which obviously contributes to the growth of the surrounding bone issues in vivo. This study could provide theoretical support for the further promotion and application of high-performance engineering plastics such as PEEK in biomedical fields.


Obstetricians and their role in cord blood banking: promoting a public model.
Umbilical cord blood, the blood remaining in the umbilical cord at birth, can be collected at birth and be a source of stem cells for a patient in need of a bone marrow transplant. Obstetricians and other health care practitioners are recognized as a patient's primary source for medical information affecting the mother and her neonate and frequently are asked to provide education and guidance regarding options of private and public cord blood banking. As the use of cord blood continues to grow in medicine and research uncovers more potential for cord blood, cord blood banking has become an important resource. The Stem Cell Therapeutic and Research Act has provided funding to expand public banking initiatives in the United States and to create a more ethnically diverse inventory of units. Private storage is not advocated unless there is an identified need in the family such that banked cord blood would offer a benefit. A recent report outlined the challenges of increasing participation and inventory, particularly among minority groups. Obstetricians and other health care practitioners should have a primary role in efforts to increase awareness of umbilical cord blood donation and be involved in initiatives to expand current public banking activities.


Post-stroke recovery: the role of activity-dependent release of brain-derived neurotrophic factor.
Stroke remains the leading cause of long-term disability with no pharmacological approaches available to limit the degree of damage or aid in recovery. Considerable effort has been made to minimize neuronal damage using neuroprotective compounds. However, attempts have so far failed to translate into the clinic. Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase type B are actively produced throughout the brain and are involved in regulating neuronal activity and normal day-to-day function. Further, BDNF has been shown to play a role in both protection and recovery of functions after stroke. This review focuses on the endogenous release of BDNF as well as activity-induced (pharmacological and physical) elevation in BDNF, and the role this plays during both acute (hours to days) and subacute (days to weeks) periods after stroke. Exogenous administration has previously been shown not to cross the blood-brain barrier; therefore, we have focused this review on approaches that allow us to directly stimulate, using pharmacological therapies and mimetics, physical activity and potential drug delivery systems that can be used to administer BDNF. Finally, we also discuss the role of BDNF polymorphisms and the influence of epigenetic regulation of BDNF on post-stroke recovery.


Robot-assisted rectal surgery for malignancy: a review of current literature.
Laparoscopic colorectal surgery is rapidly gaining acceptance for the management of colorectal cancer. However, laparoscopic colorectal surgery is technically more challenging than conventional surgery. This challenge is more profound for laparoscopic rectal cancer, where there is a need to perform a total mesorectal excision (TME), in the confines of the pelvis, with the limitations of the laparoscopic system. The Da Vinci robotic surgical system was designed to overcome the pitfalls of laparoscopic surgery, hence the use of this novel system in colorectal surgery seems logical, in particular with regards to rectal cancer surgery. Recently, there have been an increasing number of reports in the literature on robotic colorectal surgery. The advantages of the robotic surgical system include; 7 degrees of movement, 3 dimensional views, tremor filtration, motion scaling and superior ergonomics. These advantages when applied to robotic TME for rectal cancer surgery may potentially translate to better outcomes. The aim of this review is to summarise the current evidence on clinical and oncological outcomes of robotic rectal cancer surgery.


Emergence of drug resistance-associated mutations in HIV-1 subtype C protease gene in north India.
A major cause of anti-retroviral therapy (ART) failure is the drug resistance-associated mutations in polymerase gene of HIV-1. Paucity of data regarding potential drug resistance to protease inhibitors (PIs) prompted us to carry out this study. Drug resistance (DR) genotyping of the entire protease gene was performed in 104 HIV-1 ART-naive and first-line ART-experienced patients. The DR pattern was analyzed using the Stanford HIV-DR database, International AIDS Society-USA mutation list and REGA algorithm version 8.0. Subtyping was done using Mega 4 and REGA HIV-1 subtyping tool-v2.01. Majority of our sequences 98 (96%) were subtype C and remaining four (3.92%) were subtype A1. In three (2.9%) DE patients, major DR-associated mutation at D30 N and M46I positions were detected. Approximately 70% polymorphisms as minor mutations were observed in protease gene, of which 14 distinct amino acids changes were linked to partial DR such as G16E, K20R, M36I, D60E, I62V, L63P, I64M, H69K, T74A/S, V77I, V82I, I85V, L89M, and I93L. The two major and several minor mutations detected in this study confer low/intermediate levels of resistance to most PIs independently or together. Our results conclude that resistance testing in HIV-1-infected patients should be performed before the initiation of PI therapy for better therapeutic outcome in this region. This information not only will shed light on the extent of current DR in HIV strains but also will aid in patient treatment and drug designing.


Stroke etiologies in patients with COVID-19: the SVIN COVID-19 multinational registry.
Coronavirus disease 2019 (COVID-19) is associated with a small but clinically significant risk of stroke, the cause of which is frequently cryptogenic. In a large multinational cohort of consecutive COVID-19 patients with stroke, we evaluated clinical predictors of cryptogenic stroke, short-term functional outcomes and in-hospital mortality among patients according to stroke etiology. We explored clinical characteristics and short-term outcomes of consecutively evaluated patients 18 years of age or older with acute ischemic stroke (AIS) and laboratory-confirmed COVID-19 from 31 hospitals in 4 countries (3/1/20-6/16/20). Of the 14.483 laboratory-confirmed patients with COVID-19, 156 (1.1%) were diagnosed with AIS. Sixty-one (39.4%) were female, 84 (67.2%) white, and 88 (61.5%) were between 60 and 79 years of age. The most frequently reported etiology of AIS was cryptogenic (55/129, 42.6%), which was associated with significantly higher white blood cell count, c-reactive protein, and D-dimer levels than non-cryptogenic AIS patients (p</=0.05 for all comparisons). In a multivariable backward stepwise regression model estimating the odds of in-hospital mortality, cryptogenic stroke mechanism was associated with a fivefold greater odds in-hospital mortality than strokes due to any other mechanism (adjusted OR 5.16, 95%CI 1.41-18.87, p = 0.01). In that model, older age (aOR 2.05 per decade, 95%CI 1.35-3.11, p < 0.01) and higher baseline NIHSS (aOR 1.12, 95%CI 1.02-1.21, p = 0.01) were also independently predictive of mortality. Our findings suggest that cryptogenic stroke among COVID-19 patients carries a significant risk of early mortality.


Differences in end-point force trajectories elicited by electrical stimulation of individual human calf muscles.
The purpose of this study was to investigate the end-point force trajectories of the fibularis longus (FIB), lateral gastrocnemius (LG), and medial gastrocnemius (MG) muscles. Most information about individual muscle function has come from studies that use models based on electromyographic (EMG) recordings. In this study (N = 20 subjects) we used electrical stimulation (20 Hz) to elicit activity in individual muscles, recorded the end-point forces at the foot, and verified the selectivity of stimulation by using magnetic resonance imaging. Unexpectedly, no significant differences were found between LG and MG force directions. Stimulation of LG and MG resulted in downward and medial or lateral forces depending on the subject. We found FIB end-point forces to be significantly different from those of LG and MG. In all subjects, stimulation of FIB resulted in downward and lateral forces. Based on our results, we suggest that there are multiple factors determining when and whether LG or MG will produce a medial or lateral force and FIB consistently plays a significant role in eversion/abduction and plantar flexion. We suggest that the intersubject variability we found is not simply an artifact of experimental or technical error but is functionally relevant and should be addressed in future studies and models.


Work Status Reduction and Cost-Related Nonadherence during Cancer Treatment.
Many cancer patients experience a reduction in work status during cancer treatment. Authors analyzed cross-sectional survey data from U.S. cancer patients and survivors to examine the relationship between reduced work status and cost-related nonadherence, defined as skipping or forgoing medical treatments or medications due to cost. Of 381 respondents who were working at the time of diagnosis, 143 reported a reduction in work status during treatment. Age, racial identity, level of education, and treatment type were associated with reductions in work status. Respondents who reduced work status had higher odds of engaging in cost-related nonadherence than those with stable employment. Authors conclude that reduced work status is associated with nonadherence that can undermine treatment benefit and lead to disease progression. This association is troubling given that African American respondents were more likely to report reduced work status during treatment, potentially exacerbating existing cancer health disparities. To reduce treatment nonadherence, social workers should assess for potential employment problems and be prepared to intervene through counseling, community resource referrals, and direct financial assistance. Social workers should be aware of how structural racism is reproduced through inequitable labor policies and practices that have direct implications for health and access to care.


Carbonyl reduction of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cytosol of mouse liver and lung.
The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a strong lung carcinogen in all species tested. To elicit its tumorigenic effects, NNK requires metabolic activation which is supposed to occur via alpha-hydroxylation by cytochrome P450 enzymes. Carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronosylation is considered to be the main detoxification pathway in humans. Therefore, NNK carbonyl reducing activity is crucial for NNK inactivation since it initiates the final excretion of this lung carcinogen. Until the present work, studies on NNK metabolism have focused exclusively on microsomal fractions, and several cytochrome P450 enzymes have been shown to be involved in alpha-hydroxylation of NNK. In addition, 11beta-hydroxysteroid dehydrogenase type 1(11beta-HSD1) which is located in the endoplasmic reticulum of the cell has been identified to catalyze the carbonyl reduction of NNK in microsomes. In this study, we provide evidence that carbonyl reduction of NNK does also take place in the cytosolic fraction of mouse liver and lung, and that cytosolic carbonyl reductase contributes to the detoxification of NNK. At a fixed substrate concentration of 1 mM NNK, the specific activity of cytosolic NNAL formation amounts to 72% (liver) and 28% (lung) compared with that in the respective microsomal fractions. Although considerable NNK carbonyl reduction occurred with NADH, the preferred cosubstrate in cytosol is either NADPH or an NADPH-regenerating system. Due to the inhibitor sensitivity to menadione, ethacrynic acid, dicoumarol and quercitrin, it is concluded that carbonyl reductase (EC 220.127.116.11) is mainly responsible for NNAL formation in liver and lung cytosol. The expression of cytosolic carbonyl reductase and microsomal 11beta-HSD1 was established on the mRNA level by reverse transcription-PCR in both liver and lung. Enzyme kinetic studies revealed a nonsaturable Michaelis-Menten kinetic of NNK carbonyl reduction in cytosol. Possibly some other cytosolic NNK carbonyl reducing enzymes are also involved in NNAL formation. In conclusion, this is the first report to show that carbonyl reduction of NNK does occur in cytosol. Further studies with purified enzyme preparations are needed to explore the detailed contribution of the cytosolic enzymes participating in the final elimination of this lung carcinogen.


Novel B3GALTL mutations in classic Peters plus syndrome and lack of mutations in a large cohort of patients with similar phenotypes.
Peters plus syndrome (PPS) is a rare autosomal-recessive disorder characterized by Peters anomaly of the eye, short stature, brachydactyly, dysmorphic facial features, developmental delay, and variable other systemic abnormalities. In this report, we describe screening of 64 patients affected with PPS, isolated Peters anomaly and PPS-like phenotypes. Mutations in the coding region of B3GALTL were identified in nine patients; six had a documented phenotype of classic PPS and the remaining three had a clinical diagnosis of PPS with incomplete clinical documentation. A total of nine different pathogenic alleles were identified. Five alleles are novel including one frameshift, c.168dupA, p.(Gly57Argfs*11), one nonsense, c.1234C>T, p.(Arg412*), two missense, c.1045G>A, p.(Asp349Asn) and c.1181G>A, p.(Gly394Glu), and one splicing, c.347+5G>T, mutations. Consistent with previous reports, the c.660+1G>A mutation was the most common mutation identified, seen in eight of the nine patients and accounting for 55% of pathogenic alleles in this study and 69% of all reported pathogenic alleles; while two patients were homozygous for this mutation, the majority had a second rare pathogenic allele. We also report the absence of B3GALTL mutations in 55 cases of PPS-like phenotypes or isolated Peters anomaly, further establishing the strong association of B3GALTL mutations with classic PPS only.


An asymptomatic schwannoma of the nasal septum: report of a unique case.
Schwannomas of the nasal septum are extremely rare, and therefore their diagnosis and treatment can pose certain challenges. We describe the case of an incidentally discovered schwannoma of the nasal septum that was unique in that the lesion was completely asymptomatic. In view of our finding, we believe that routine examinations of both nasal fossae should be considered during routine diagnostic laryngeal flexible endoscopy.


A Patient with β-Thalassemia Intermedia Secondary to Homozygosity for a Polyadenylation Signal Mutation (AATAAA > AATAGA) (HBB: C.*112A > G) on the β-Globin Gene.
We describe the clinical presentation and laboratory findings of a Malay man with β-thalassemia intermedia (β-TI), secondary to homozygosity for a polyadenylation (polyA) signal mutation (AATAAA > AATAGA) (HBB: c.*112A > G) on the β-globin gene, and give a brief review of the literature. This is the first report of a homozygous case of this polyA mutation, and highlights the importance of molecular analysis of the globin genes in the diagnosis of thalassemia.


Water Conservation in Kalanchoe blossfeldiana in Relation to Carbon Dioxide Dark Fixation.
The succulent Kalanchoe blossfeldiana v. Poel. var Tom Thumb was treated on long and short photoperiods for 6 weeks during which short day plants developed thicker leaves, flowered prolifically, and exhibited extensive net dark fixation of carbon dioxide. In contrast, long day plants remained vegetative and did not develop thicker leaves or exhibit net carbon dioxide dark fixation. When examined after the photoperiodic state described, long day plants showed approximately three times more water loss over a 10-day period than short day plants. Water loss is similar during light and dark periods for short day plants but long day plants exhibited two times more water loss during the day than at night. The latter plants also lost three and one-half times more water during the light period than short day plants. The water conservation by short day plants is correlated with conditions of high carbon dioxide dark fixation and effects of its related Crassulacean acid metabolism on stomatal behavior.


Comparative kinetics of damage to the plasma and mitochondrial membranes by intra-cellularly synthesized and externally-provided photosensitizers using multi-color FACS.
Photodynamic therapy (PDT) of cancer involves inflicting lethal damage to the cells of malignant tumors, primarily by singlet oxygen that is generated following light-absorption in a photosensitizer molecule. Dysfunction of cells is manifested in many ways, including peroxidation of cellular components, membrane rupture, depolarization of electric potentials, termination of mitochondrial activity, onset of apoptosis and necrosis and eventually cell lysis. These events do not necessarily occur in linear fashion and different types of damage to cell components occur, most probably, in parallel. In this report we measured the relative rates of damage to two cellular membranes: the plasma membrane and the mitochondrial membrane. We employed photosensitizers of diverse hydrophobicities and used different incubation procedures, which lead to their different intra-cellular localizations. We monitored the damage that was inflicted on these membranes, by employing optical probes of membrane integrity, in a multi-color FACS experiment. The potentiometric indicator JC-1 monitored the electric cross-membrane potential of the mitochondria and the fluorometric indicator Draq7 monitored the rupture of the plasma membrane. We show that the electric depolarization of the mitochondrial membrane and the damage to the enveloping plasma membrane proceed with different kinetics that reflect the molecular character and intracellular location of the sensitizer: PpIX that is synthesized in the cells from ALA causes rapid mitochondrial damage and very slow damage to the plasma membrane, while externally added PpIX has an opposite effect. The hydrophilic sensitizer HypS4 can be taken up by the cells by different incubation conditions, and these affect its intracellular location, and as a consequence either the plasma membrane or the mitochondria is damaged first. A similar correlation was found for additional extracellularly-provided photosensitizers HP and PpIX.


Prenatal Hypoxia Affects Foetal Cardiovascular Regulatory Mechanisms in a Sex- and Circadian-Dependent Manner: A Review.
Prenatal hypoxia during the prenatal period can interfere with the developmental trajectory and lead to developing hypertension in adulthood. Prenatal hypoxia is often associated with intrauterine growth restriction that interferes with metabolism and can lead to multilevel changes. Therefore, we analysed the effects of prenatal hypoxia predominantly not associated with intrauterine growth restriction using publications up to September 2021. We focused on: (1) The response of cardiovascular regulatory mechanisms, such as the chemoreflex, adenosine, nitric oxide, and angiotensin II on prenatal hypoxia. (2) The role of the placenta in causing and attenuating the effects of hypoxia. (3) Environmental conditions and the mother's health contribution to the development of prenatal hypoxia. (4) The sex-dependent effects of prenatal hypoxia on cardiovascular regulatory mechanisms and the connection between hypoxia-inducible factors and circadian variability. We identified that the possible relationship between the effects of prenatal hypoxia on the cardiovascular regulatory mechanism may vary depending on circadian variability and phase of the days. In summary, even short-term prenatal hypoxia significantly affects cardiovascular regulatory mechanisms and programs hypertension in adulthood, while prenatal programming effects are not only dependent on the critical period, and sensitivity can change within circadian oscillations.


Blood lipid tests in 2017.
Strong epidemiological evidence supports a causal relationship between dyslipidemia and atherosclerotic cardio-vascular disease, which remains the leading cause of death and morbidity worldwide. A lipid profile (total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides) is recommended at the initial evaluation for the assessment of the cardio-vascular risk. A commentary of the lipid profile for the clinician and mostly for the patient should be stated on the lab report. Quantifying the cardio-vascular risk using the SCORE (systematic coronary risk estimation) system, as recommended by the Haute autorité de santé (HAS), is the starting point to establish therapeutic goals and treatment strategies. It may be important to emphasize therapeutic goals in lipid reports in order to better monitor lipid profiles at appropriate intervals to assess compliance and therapeutic efficacy for patients on lipid lowering therapy.


Using metaphor to clarify emerging roles in patient care management teams.
Difficult economic times, competition for scarce resources and changing organizational paradigms are driving health care institutions to re-examine the ways in which they provide care. They must continually strive to provide excellent patient care and ensure positive patient outcomes while responding to increasing fiscal constraint. At Toronto's Hospital for Sick Children, consistent with current trends, nurse managers are asked to take on broad spans of responsibility. The need to decentralize much of the decision making, problem identification and problem solving functions to the multidisciplinary team is a reality of those changes. This paper describes a process the dialysis staff undertook to better understand new organizational imperatives using an orchestra metaphor as a suggestive tool to help people clarify new roles and relationships in organizations that are evolving from a hierarchical model to a knowledge-based team approach to work. The intervention was successful for some people and not others. An analysis of the outcomes is provided from the nurse manager's perspective.


Glycoproteoform Profiles of Individual Patients' Plasma Alpha-1-Antichymotrypsin are Unique and Extensively Remodeled Following a Septic Episode.
Sepsis and septic shock remain the leading causes of death in intensive care units (ICUs), yet the pathogenesis originating from the inflammatory response during sepsis remains ambiguous. Acute-phase proteins are typically highly glycosylated, and the nature of the glycans have been linked to the incidence and severity of such inflammatory responses. To further build upon these findings we here monitored, the longitudinal changes in the plasma proteome and, in molecular detail, glycoproteoform profiles of alpha-1-antichymotrypsin (AACT) extracted from plasma of ten individual septic patients. For each patient we included four different time-points, including post-operative (before sepsis) and following discharge from the ICU. We isolated AACT from plasma depleted for albumin, IgG and serotransferrin and used high-resolution native mass spectrometry to qualitatively and quantitatively monitor the multifaceted glycan microheterogeneity of desialylated AACT, which allowed us to monitor how changes in the glycoproteoform profiles reflected the patient's physiological state. Although we observed a general trend in the remodeling of the AACT glycoproteoform profiles, e.g. increased fucosylation and branching/LacNAc elongation, each patient exhibited unique features and responses, providing a resilient proof-of-concept for the importance of personalized longitudinal glycoproteoform profiling. Importantly, we observed that the AACT glycoproteoform changes induced by sepsis did not readily subside after discharge from ICU.


Genetically engineered gold-binding polypeptides: structure prediction and molecular dynamics.
The biological control of inorganic crystal formation, morphology, and assembly is of interest to biologists and biotechnologists studying hard tissue growth and regeneration, as well as to materials scientists using biomimetic approaches for the control of inorganic material fabrication and assembly. Biomimetics requires an accurate understanding of natural mechanisms at the molecular level. Such understanding can be derived from the use of metal surfaces to study surface recognition by proteins together with combinatorial genetics techniques for the selection of suitable peptides. Polymerization of these peptides produces engineered polypeptides large enough to encode their own folding information with low structural complexity, while enhancing binding affinity to surfaces. The low complexity of such polypeptides can aid in analyses, leading to modeling and eventual manipulation of the structure of the folded polypeptide. This paper presents structure predictions for gold-binding protein sequences, originally selected by combinatorial techniques. Molecular dynamics simulations lasting 5 ns were carried out using solvated polypeptides at the gold surface to assess the dynamics of the binding process and the effects of surface topography on the specificity of protein binding.


Very-low-density lipoprotein-induced triglyceride accumulation in human mesangial cells is mainly mediated by lipoprotein lipase.
Very-low-density lipoprotein (VLDL) in vitro can induce foam cell formation in human mesangial cells. Lipoprotein lipase (LPL) expressed in the arterial wall plays a key role in atherogenesis by actions of enzymolysis and 'molecular bridge', and, thereby, leads to the formation of lipid-loaded foam cells. It is known that LPL is expressed by glomerular mesangial cells. This study was designed to investigate if LPL plays a role in VLDL-induced lipid accumulation in human mesangial cells and its underlying mechanism. Human wild-type LPL (hLPLwt), catalytically inactive LPL (hLPL194) or control alkaline phosphatase (hAP) were expressed in human mesangial cell line (HMCLs) via adenoviral vectors. Orlistat (tetrahydrolipstatin), a specific inhibitor of the lipoidolytic activity of endogenous LPL, and heparinase, which degrades cell-surface heparan sulfate proteoglycans, were also used to estimate the role of either the enzymolysis or 'molecular bridge' actions of LPL in the uptake of VLDL. Anti-low-density lipoprotein receptor (LDLr) antibody and anti-LDL receptor-related protein antibody were used to evaluate the effect of lipoprotein receptors on VLDL-induced lipid accumulation in HMCLs. Cellular lipid deposition was visualized by Oil Red O staining and analyzed quantitatively by standard enzymatic procedures. LPL protein expression and activity were measured by Western blot and a chemical analysis, respectively. VLDL induced triglyceride accumulation in HMCLs in a time- and dose-dependent manner. Compared with Ad-hAP transfected HMCLs, cellular triglyceride content increased 4.55-fold (p < 0.05) in Ad-hLPLwt-transfected HMCLs and 1.52-fold (p < 0.05) in Ad-hLPL194-transfected HMCLs. Triglyceride accumulation in response to VLDL was mostly blocked by orlistat. Pretreatment of the cells with heparinase slightly reduced cellular triglyceride accumulation in the present of high concentrations of VLDL. The blockade of some lipoprotein receptors, such as LDLr, did not significantly reduce cellular triglyceride accumulation. LPL expression was upregulated by VLDL. VLDL-induced triglyceride accumulation in human mesangial cells is mainly mediated by LPL, and the enzymolysis action of LPL could be a major factor in this process. These results suggest that LPL may be an important factor participating in the initiation and progression of VLDL-mediated lipid renal injury.


Chyloperitoneum associated with chronic severe sarcoidosis.
A 51-year-old black female with sarcoidosis diagnosed 20 yr earlier developed massive chyloperitoneum and chylothorax. Autopsy demonstrated fibrotic and enlarged thoracic and mesenteric lymph nodes. Sarcoidosis can produce chyloperitoneum by producing intrathoracic nodal fibrosis and lymphatic obstruction.


Optimization of Processing Parameters in ECM of Die Tool Steel Using Nanofluid by Multiobjective Genetic Algorithm.
Formation of spikes prevents achievement of the better material removal rate (MRR) and surface finish while using plain NaNO3 aqueous electrolyte in electrochemical machining (ECM) of die tool steel. Hence this research work attempts to minimize the formation of spikes in the selected workpiece of high carbon high chromium die tool steel using copper nanoparticles suspended in NaNO3 aqueous electrolyte, that is, nanofluid. The selected influencing parameters are applied voltage and electrolyte discharge rate with three levels and tool feed rate with four levels. Thirty-six experiments were designed using Design Expert 7.0 software and optimization was done using multiobjective genetic algorithm (MOGA). This tool identified the best possible combination for achieving the better MRR and surface roughness. The results reveal that voltage of 18 V, tool feed rate of 0.54 mm/min, and nanofluid discharge rate of 12 lit/min would be the optimum values in ECM of HCHCr die tool steel. For checking the optimality obtained from the MOGA in MATLAB software, the maximum MRR of 375.78277 mm(3)/min and respective surface roughness Ra of 2.339779 μm were predicted at applied voltage of 17.688986 V, tool feed rate of 0.5399705 mm/min, and nanofluid discharge rate of 11.998816 lit/min. Confirmatory tests showed that the actual performance at the optimum conditions was 361.214 mm(3)/min and 2.41 μm; the deviation from the predicted performance is less than 4% which proves the composite desirability of the developed models.


Tryptophan metabolism in alcoholism.
Studies of tryptophan (Trp) metabolism in relation to the serotonin status in alcoholism are of 2 types: (1) those related to the pharmacological effects of ethanol; (2) those concerning the serotonin status in the absence of alcohol intake. In experimental animals, acute and chronic ethanol administration and subsequent withdrawal exert a variety of effects on brain serotonin synthesis and turnover mediated by corresponding changes in Trp availability to the brain secondarily mainly to modulation of liver Trp pyrrolase (TP) activity. Alcohol-preferring mice and rats exhibit a central serotonin deficiency caused by, or in some cases associated with, a higher TP activity. Liver TP also appears to be a target of ethanol in man and evidence has recently emerged that alcoholics with positive family history are serotonin-deficient because of a lower availability of circulating Trp to the brain. Acutely, ethanol depletes brain serotonin in normal subjects, which may explain alcohol-induced aggression in susceptible individuals and also the incidence of depression in alcoholism. Trp availability to the brain is increased before the appearance of the alcohol-withdrawal syndrome in man, raising the possibility that the associated behavioural disturbances may involve the excitotoxic Trp metabolite quinolinate. Further studies of the Trp and serotonin status in relation to these important clinical features of alcohol dependence and alcoholism may therefore yield fruitful results.


The social, moral, ethical, legal and political implications of today's biological technologies: an Indian point of view.
The last 50 years have seen an increasing emphasis on ethical, moral, social, legal, political and economic implications of science for reasons that are discussed in this article. Biotechnology has been no exception to this trend. Areas of biotechnology where the above implications have been important, are briefly described. Ethical and related issues in today's biology-based technologies are discussed with special reference to India. Examples of technological exploitation within a country, or of one country by another, using modern biology-based technologies are given. The possible implications of one new and emerging biology-based technology are discussed. It is concluded that a well-informed and knowledgeable society is the only assured insurance against possible misuse of biology-based technologies of today and tomorrow, including their use for the exploitation of people. The recent decision of the Prime Minister of India to set up a National Knowledge Commission is mentioned in this context.


Impact of a novel interprofessional dental and pharmacy student tobacco cessation education programme on dental patient outcomes.
The dental setting presents a unique opportunity to assist patients with tobacco cessation. Many dental providers do not feel prepared to provide tobacco cessation, particularly with regard to education on pharmacological treatments. An interprofessional practice experience with dental and pharmacy students provides a novel approach to tobacco cessation in the dental setting, but it is not known whether such methods affect patient outcomes. The goal of the study was to examine the impact of a novel dental and pharmacy student tobacco cessation education programme on patient knowledge gained, barriers to utilising cessation medications, quit intentions, and quit behaviours as compared to standard care. Dental patients who were seen at the dental admissions clinic of a dental school on interprofessional care (IPC) days and received tobacco cessation education from the dental-pharmacy student team (N = 25) were compared with dental patients at the clinic seen on Standard Care (SC) days (N = 25). Patients completed a post-appointment survey and a 4-week follow-up survey. IPC patients reported greater perceived knowledge post-appointment and at follow-up regarding tobacco cessation compared with SC patients and had greater intentions to utilise medication to assist with tobacco cessation. At follow-up there were no differences between groups in terms of quit attempts. Among patients who made a quit attempt those in the IPC group were more likely to have set a quit date and contacted a provider for assistance regarding tobacco cessation. Dental-pharmacy student interprofessional tobacco cessation may be an innovative way to provide tobacco cessation education to dental patients and provide students with interprofessional practice experiences.


Endothelial nitric oxide synthase regulates microvascular hyperpermeability in vivo.
Nitric oxide (NO) is an important regulator of blood flow, but its role in permeability is still challenged. We tested in vivo the hypotheses that: (a) endothelial nitric oxide synthase (eNOS) is not essential for regulation of baseline permeability; (b) eNOS is essential for hyperpermeability responses in inflammation; and (c) molecular inhibition of eNOS with caveolin-1 scaffolding domain (AP-Cav) reduces eNOS-regulated hyperpermeability. We used eNOS-deficient (eNOS-/-) mice and their wild-type control as experimental animals, platelet-activating factor (PAF) at 10(-7) m as the test pro-inflammatory agent, and integrated optical intensity (IOI) as an index of microvascular permeability. PAF increased permeability in wild-type cremaster muscle from a baseline of 2.4 +/- 2.2 to a peak net value of 84.4 +/- 2.7 units, while the corresponding values in cremaster muscle of eNOS-/- mice were 1.0 +/- 0.3 and 15.6 +/- 7.7 units (P < 0.05). Similarly, PAF increased IOI in the mesentery of wild-type mice but much less in the mesentery of eNOS-/- mice. PAF increased IOI to comparable values in the mesenteries of wild-type mice and those lacking the gene for inducible NOS (iNOS). Administration of AP-Cav blocked the microvascular hyperpermeability responses to 10(-7) m PAF. We conclude that: (1) baseline permeability does not depend on eNOS; (2) eNOS and NO are integral elements of the signalling pathway for the hyperpermeability response to PAF; (3) iNOS does not affect either baseline permeability or hyperpermeability responses to PAF; and (4) caveolin-1 inhibits eNOS regulation of microvascular permeability in vivo. Our results establish eNOS as an important regulator of microvascular permeability in inflammation.


TLR8 deficiency leads to autoimmunity in mice.
TLRs play an essential role in the induction of immune responses by detecting conserved molecular products of microorganisms. However, the function of TLR8 is largely unknown. In the current study, we investigated the role of TLR8 signaling in immunity in mice. We found that Tlr8(-/-) DCs overexpressed TLR7, were hyperresponsive to various TLR7 ligands, and showed stronger and faster NF-κB activation upon stimulation with the TLR7 ligand R848. Tlr8(-/-) mice showed splenomegaly, defective development of marginal zone (MZ) and B1 B cells, and increased serum levels of IgM and IgG2a. Furthermore, Tlr8(-/-) mice exhibited increased serum levels of autoantibodies against small nuclear ribonucleoproteins, ribonucleoprotein, and dsDNA and developed glomerulonephritis, whereas neither Tlr7(-/-) nor Tlr8(-/-)Tlr7(-/-) mice showed any of the phenotypes observed in Tlr8(-/-) mice. These data provide evidence for a pivotal role for mouse TLR8 in the regulation of mouse TLR7 expression and prevention of spontaneous autoimmunity.


Development of an interleukin (IL)-33 sandwich ELISA kit specific for mature IL-33.
Interleukin (IL)-33 is an inflammatory cytokine and belongs to the IL-1 family of cytokines. There are eleven members of the IL-1 family of cytokines and all have important roles in host defense against infections. Their levels are increased during infection and in various auto-inflammatory diseases. IL-33 is also associated with autoimmune diseases such as asthma, atopic dermatitis, rheumatoid arthritis, and atherosclerosis. IL-33 receptors consist of IL-1R4 and IL-1R3 to induce both Th1 and Th2 type immune response. Here we present the development of monoclonal antibodies (mAbs) against human mature IL-33. Recombinant human mature IL-33 protein was expressed in E. coli and purified by multi-step affinity chromatography. The human IL-33 activity was examined in HMC-1 and Raw 264.7 cells. Mice were immunized with the biologically active mature IL-33 to generate mAb against IL-33. The anti-IL-33 mAb (clone/4) was used as a capture antibody for a sandwich enzyme-linked immunosorbent assay (ELISA). This assay detects mature IL-33 with a high sensitivity (80 pg/mL) but does not recognize the biologically inactive precursor IL-33. This article describes the methods for a newly developed IL-33 ELISA kit that is specific for mature IL-33 and may be used to analyze bioactive mature IL-33 in various immunological diseases.


Open-cell Stent Deployment across the Wide Neck of a Large Middle Cerebral Aneurysm Using the Stent Anchor Technique.
We describe a case of successful open-cell stent deployment across the wide neck of a large middle cerebral artery aneurysm using the stent anchor technique. A microcatheter was looped through the aneurysm and navigated into a distal vessel across the aneurysm neck. Although the loop of the microcatheter in the aneurysm straightened as it was gently withdrawn, the microcatheter again protruded into the aneurysm by open-cell stent navigation. The stent was partially deployed in a vessel distal to the aneurysm neck, withdrawn slowly to straighten the loop of the microcatheter in the aneurysm, and completely deployed across the aneurysm neck. After successful stent deployment, stent-assisted coil embolization was performed without complications. The stent anchor technique was successfully used to deploy an open-cell stent across the aneurysm neck in this case of microcatheter protrusion into the aneurysm during stent navigation.


Factors Impacting Early Mobilization Following Hip Fracture: An Observational Study.
Hip fracture guidelines emphasize mobilization within 48 hours of surgery. The aims of this audit were to determine the proportion of patients with hip fracture who mobilize within 48 hours, identify factors associated with delayed mobilization, and identify barriers to mobilization. Single-site prospective audit of 100 consecutive patients (age 82 ± 9 years) admitted for surgical management of hip fracture. Data collected included time to mobilization, factors that may impact mobilization (age, weight-bearing status, additional injuries, premorbid mobility status, time to surgery, dementia, delirium, and postoperative complications), and barriers to mobilization as identified by the physical therapist. Mobilization within 48 hours of surgery was achieved by 43% of patients. Multivariate logistic regression demonstrated odds of mobilizing early increased with higher New Mobility Scores, representing better premorbid mobility (odds ratio [OR] = 1.30; 95% confidence interval [CI], 1.06-1.60); odds reduced if delirium was present on day 1 or 2 (OR = 0.25; 95% CI, 0.08-0.79). New Mobility Scores 5 or more, which indicate independent premorbid mobility inside and outside the house, best predicted early mobilization in patients who did not develop delirium. No cutoff score was identified for those with delirium. Identified barriers to mobilization included patient confusion, manual handling risk, patient declined, and hypotension. Less than half of this cohort achieved the guideline of mobilization within 48 hours of surgery. Patients who develop delirium within the first 2 days of surgery or who had premorbid mobility limitation were less likely to mobilize. Identification of patients likely to have delayed mobilization will assist physical therapists with delivering appropriate management to patients with hip fracture during their acute hospital stay.


Sequence conservation in field and experimental isolates of Borna disease virus.
Coding and noncoding sequences were analyzed from field and experimental isolates of Borna disease virus. For a 24-kDa protein, maximum divergence was 1.5% at the predicted amino acid level and 3.1% at the nucleotide level. For a 40-kDa protein, maximum divergence was 1.1% at the predicted amino acid level and 4.1% at the nucleotide level. The highest variability in sequence (10%) was found in a 40-nucleotide stretch of genomic RNA between coding sequences for the 40- and 24-kDa proteins. The degree of sequence conservation in these isolates, passaged in various host species in vivo and in vitro over a period of 64 years, is unusual for negative-strand RNA viruses.


Peritoneal Involvement Is More Common Than Nodal Involvement in Patients With High-Grade Appendix Tumors Who Are Undergoing Prophylactic Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.
Right hemicolectomy is routinely recommended in patients with histologic findings of high-grade appendix tumors after appendicectomy. Undetected peritoneal disease may be encountered at surgery. In high-grade appendix tumors with disease detected radiologically, complete cytoreduction may not be possible and outcomes poor. For these reasons, we adopted a policy of prophylactic cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. The purpose of this study was to quantify the rates of peritoneal and nodal metastatic disease in patients with high-grade appendix tumors without obvious metastatic disease and to report the long-term outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in these patients. Data regarding peritoneal and nodal metastatic disease were extracted from surgical and histologic records. The study was conducted at a high-volume tertiary referral center for peritoneal malignancy. Patients referred with histologically high-grade appendix tumors at appendicectomy, without detectable metastatic spread, between January 1994 and September 2016 were included MAIN OUTCOME MEASURES:: A total of 62 patients with high-grade pathology at appendicectomy, without clinical or radiological peritoneal disease, underwent complete cytoreduction with hyperthermic intraperitoneal chemotherapy. Thirty-five (57%) of 62 patients had peritoneal disease (median peritoneal cancer index 5 (range, 1-28)). Eleven (31%) of 35 had microscopic peritoneal disease. Overall, 23 (37%) of 62 had peritoneal disease beyond the confines of a standard right hemicolectomy. Nine (15%) of 62 had nodal involvement. Mean overall and disease-free survival were 110.9 (95% CI, 94.8-127.0 mo) and 102.1 months (95% CI, 84.3-119.9 mo), with 5-year overall and disease-free survival of 83.2% and 76.0%. The retrospective nature limits the interpretation of these results. Complete cytoreduction was achieved in all of the patients, with excellent long-term survival. The incidence of peritoneal spread (57%) compared with nodal involvement (15%) supports cytoreductive surgery and hyperthermic intraperitoneal chemotherapy as definitive treatment rather than prophylaxis in patients with high-grade appendix tumors, even without radiologically detectable disease. High-grade appendix tumors benefit from early aggressive operative management to deal with potential peritoneal and nodal spread and should be considered for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. See Video Abstract at http://links.lww.com/DCR/A360.


Lay theories of financial well-being predict political and policy message preferences.
People differ in their lay theories about how and why the financial well-being of individuals changes over time or varies between individuals. We introduce a measure of Causal Attributions of Financial Uncertainty-the CAFU scale-and find that such attributions can be described reliably along three distinct dimensions, respectively capturing the extent to which changes in financial well-being are perceived to be: (a) knowable and within individuals' control due to individual factors such as effort ("Rewarding"); (b) knowable and outside of individuals' control due to factors such as favoritism and discrimination ("Rigged"); and (c) inherently unpredictable and determined by chance events ("Random"). In a sample representative of the U.S. population on various demographic characteristics (N = 1,102), we find that differences in these beliefs are associated with political ideology, revealing a predicted pattern: conservatives scored higher on the Rewarding subscale and liberals scored higher on the Rigged and Random subscales, even when controlling for key demographics. Moreover, we find that these three dimensions predict responses to different policy messages, even when controlling for political ideology. In three preregistered experiments (combined N = 2,560), we observe increased support for various social welfare policies when we highlighted aspects of these policies that are compatible with people's beliefs about financial well-being. Likewise, we observe increased support for political candidates when they expressed their positions in a way that is compatible with people's beliefs. Thus, this work can help better understand drivers of political attitudes and guide in crafting more persuasive policy messages. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Candida spp. isolation from critically ill patients' respiratory tract. Does antifungal treatment affect survival?
Isolation of Candida spp. from bronchial samples of patients on mechanical ventilation is common. Even though it may not always reflect infection, it may induce immunological changes that can facilitate bacterial pneumonia. In this case, antifungal treatment is of uncertain value. This study examined the impact of antifungal treatment on the outcome of intensive care unit (ICU)-acquired respiratory tract infection (RTI) of critically ill, immunocompetent patients, with Candida isolation from their respiratory tract. This is a retrospective cohort study of adult patients hospitalized in the ICU of the University Hospital of Heraklion, Greece, from 2014 through 2016 with ICU-acquired RTI and Candida spp. isolated from their bronchial secretions. Data regarding medical history, demographics (gender, age), reason for ICU admission, previous antimicrobial use or hospitalization, SOFA and APACHE II score, clinical outcomes (primary clinical outcome: overall mortality during hospitalization; secondary clinical outcome: mortality during the ICU stay and duration of ICU and hospital stay) at the end of their ICU stay and at the end of their hospital stay were recorded and consequently evaluated. A logistic regression analysis model evaluated the effect of the recorded parameters in association with ICU mortality and overall mortality during hospitalization. A total of 90 individuals were enrolled. Of them, 47 (52.2%) were treated with antifungals during their hospitalization around the time of Candida isolation. Patients treated with antifungals had higher SOFA and APACHE II scores, longer duration of stay in the ICU, more days on ventilator and higher total mortality during hospitalization. Multivariate logistic regression analysis identified antifungal use to be independently associated with total mortality during hospitalization. Antifungal use in patients with ICU-acquired RTI was associated with higher overall mortality as compared to those not receiving such agents.


Extraosseous intra-articular osteochondroma.
Background. Conventional osteochondromas are common bone lesions developing in the metaphyseal region of growing skeleton. Marginal excision is the treatment of choice for such tumours. Extraosseous cartilaginous tumours are rare and their biological potential is poorly characterized. Case Presentation. A-52-year old woman presented with 3-year history of fullness and dull pain and inability to flex her left knee, sit cross-legged, or squat. Clinical and imaging studies revealed a nodular mineralised mass in the anterior portion of the knee displacing the patellar tendon laterally. Excision biopsy confirmed the diagnosis of extraosseous osteochondroma-like soft tissue mass. There is no recurrence at two-year followup. Conclusion. An integrated clinicopathological diagnosis helps to clarify the nature of extraosseous cartilaginous tumour that can arise at an unusual anatomic site. Complete surgical excision is the treatment of choice.


Promoting sensitive parenting in 'at-risk' mothers and fathers: A UK outcome study of Mellow Babies, a group-based early intervention program for parents and their babies.
The objective of this study was to evaluate the effectiveness of Mellow Babies (MB) in the UK. MB is a 14-week early parenting intervention program that is delivered in groups and is targeted at 'at-risk' parents (both mothers and fathers) and their babies up to 18 months old. The study used a pragmatic pre-post intervention design. Outcomes were parental mental health, parenting confidence, quality of life, socio-emotional development of children, and perceived parent-child relationship. Fifteen groups representing n = 91 parent-baby dyads were recruited across the UK between 2017-2018. The sample consisted of 10 Mellow Mums groups (70 mother-baby dyads) and 5 Mellow Dads groups (21 father-baby dyads). Intention-to-treat and 'completer' analyses were performed. Findings suggest short-term positive outcomes for parents attending MB. Completion of the program was associated with significant improvements in anxiety and overall wellbeing, parenting confidence, and perceived closeness of the parent-child relationship. The significance of these improvements, except for parenting confidence, was maintained in the intention-to-treat analysis. MB engaged and retained a high proportion of parents who could be considered 'at-risk' and benefitted fathers and mothers attending the intervention equally. This is the first prospective study to explore MB participation for both mothers and fathers and to indicate engagement and potential benefits specifically for 'at-risk' parents. Findings further demonstrate the effectiveness of MB as an early intervention program for parents experiencing psychosocial difficulties. Replication by studies using a contrast or control group also incorporating follow-up data would further improve the evidence base for MB.


[The social impact of the vaccination against measles in Mexico. Comments during the course of the epidemics of 1988-1990].
A number of issues have arisen concerning the current measles epidemic. In this paper we review: 1) the causes of this cyclic rise; 2) the benefit of a vaccination program sustained during more than 15 years; 3) the vaccine efficacy, as well as 4) the vaccination coverage goal for controlling measles. Immediate causes of the epidemic recurrence are: 1) low vaccination coverage, and 2) an increasing absolute number of newborns enlarges the pool of susceptibles. A strategy to identify now-vaccinated children in a systematic fashion is suggested. As long as measles transmission occurs even if measles vaccination coverage increases, the proportion of vaccinated cases will not decrease. Within optimal values of vaccine efficacy this proportion will increase as the coverage increases. The universal goal for measles vaccination is stressed.


Titanatranes derailed: static and dynamic triethanolamine slippage induced by polyphenoxide chelation.
Aryloxytitanatranes [N(CH(2)CH(2)O)(3)]Ti[OC(6)H(2)-2,4-(t)()Bu(2)-6-CHPh(3)(-)(n)()(C(6)H(2)-3,5-(t)()Bu(2)-2-OH)(n)(-)(1)] (1, n = 1; 2, n = 2; 3, n = 3) containing aryloxides derived from substituted triphenylmethanes are formed in high yield in the reactions of the corresponding phenols with tert-butoxytitanatrane [N(CH(2)CH(2)O)(3)]Ti(O(t)()Bu). The aryloxytitanatranes adopt monomeric, trigonal bipyramidal structures, as confirmed by X-ray crystallography for 1 and 2. The compounds with pendant phenol groups display fluxional behavior due to interchange of the bound phenoxide with the free phenol groups, most likely via a mechanism involving displacement of one arm of the nitrilotriethoxide by the dangling phenol group. The amidotitanatrane [[N(CH(2)CH(2)O)(3)]Ti(NEt(2))](2) reacts with the bisphenol PhCH(C(6)H(2)-3,5-(t)()Bu(2)-2-OH)(2) to give a crystallographically characterized fully metalated cyclic octatitanium complex of the formula [PhCH(C(6)H(2)-3,5-(t)()Bu(2)-2-O)(2)Ti(2)[(OCH(2)CH(2))(3)N](2)](4) (4). The structure of 4 reveals a metallamacrocycle (minimum ring size = 28 members) consisting of four repeating unsymmetrical dititanium units. In each dititanium unit, there is an unprecedented slippage of the nitrilotriethoxide ligand such that both triethanolamine nitrogens coordinate to only one of the two titaniums, while the bisphenoxide is coordinated only to the other titanium. The propensity of the polyphenoxide ligands to chelate is attributed to favorable pi-bonding interactions attainable in the eight-membered chelate rings.


Transcatheter closure of large sized patent ductus arteriosus using the amplatzer duct occluder device.
To assess the results of anterograde transcatheter closure of a large sized patent ductus arteriosus using the Amplatzer Duct Occluder (ADO) device. A case series. Department of Cardiology, Armed Forces Institute of Cardiology and National Institute of Heart Diseases, Rawalpindi, from January 2005 to December 2007. All patients who underwent transcatheter closure of large sized PDA (> or = 4.0 mm), using the Amplatzer Duct Occluder (ADO) device, from January 2005 to December 2007, were included by convenient sampling technique. After the procedure, repeat aortogram was performed to confirm the appropriate position of the ADO and to evaluate for residual shunts. A total of 100 patients had PDA diameter of > or = 4.00 mm. Mean age was 11.73 + 10.31 years and there were 37 males and 63 females. Mean PDA diameter was 6.011 + 2.078 mm. Forty-nine patients had type 'A', 19 had type 'B', 19 patients had type 'C', 5 had type 'D' and 8 patients had type 'E' PDA. Complete closure was achieved in 70 patients, 26 had trace shunt and 4 patients had small residual shunt immediately after the procedure. However, no patient had residual shunt 24 hours after the procedure. ADO is a highly efficient prosthesis that can be safely applied in most patients with PDA particularly in patients with large sized PDA.


Cardiovascular and metabolic characteristics of infertile Chinese women with PCOS diagnosed according to the Rotterdam consensus criteria.
Polycystic ovary syndrome (PCOS) is strongly associated with metabolic abnormalities in Western women. However, data from other populations and geographical regions are scarce. This study evaluated cardiovascular and metabolic risk factors in Chinese infertile women diagnosed with PCOS using the 2003 Rotterdam consensus criteria. A total of 615 women representing the four PCOS phenotypes (oligo- or anovulation (AO)+hyperandrogenism (HA)+polycystic ovaries (PCO), AO+HA, AO+PCO and HA+PCO) underwent standardized metabolic screening including a 75g oral glucose tolerance test. All groups presented with similar reproductive characteristics, with the only difference being a significantly higher Ferriman-Gallwey score for hirsutism (P=0.01) in the subgroup characterized by HA+PCO. Overall, the prevalence of metabolic syndrome was 6.4%, with no difference among the four groups (range of 2.3-12.2%). Metabolic syndrome was associated with body mass index (P<0.001), waist/hip ratio (P=0.002), index of insulin resistance (P=0.005) and fasting insulin (P=0.009) in multivariate analysis. Compared with Caucasians and Chinese women in Westernized societies, mainland Chinese women with PCOS have a low risk of metabolic syndrome and its presence does not vary across the specific PCOS phenotypes.


Enterovirus 71 Suppresses miR-17-92 Cluster Through Up-Regulating Methylation of the miRNA Promoter.
Enterovirus 71 (EV71), the etiological agent of hand-foot-and-mouth disease, has become an increasing public health challenge worldwide. Accumulating evidence suggests that mammalian microRNAs (miRNAs), a class of non-coding RNAs of 18 to 24 nucleotides (nt) with important regulatory roles in cellular processes, participate in host antiviral defense and studies have suggested roles of miRNAs in EV71 replication and pathogenesis. In the current study, we reported that the expression of hsa-miR-17∼92 cluster was significantly downregulated during EV71 infection. Overexpression of hsa-miR-17∼92 inhibited, while inhibition of endogenous hsa-miR-17∼92 facilitated EV71 replication. We identified two sequences located at nt 3024 to 3038 and nt 2838 to 2862 of the EV71 (strain FY0805) genome as potential targets for hsa-miR-17-5p and miR-19a/b, respectively, which were validated by luciferase reporter assays and Western blot. Meanwhile, we identified DNA methylation as a novel mechanism of hsa-miR-17∼92 regulatory roles. The methylation of the miR-17-92 promoter was significantly increased (50%) upon EV71 infection, which appeared to be caused by the increased expression of DNMT3B but not DNMT1 and DNMT3A. Furthermore, we demonstrated that the members of miR-17-92 cluster were decreased in the sera of EV71 infected patients, suggesting the clinical implication and the potential therapeutic application of miR-17-92.


Theoretical and experimental studies of cationized uracil complexes in the gas phase.
Cationized uracil clusters were generated in the gas phase by electrospray ionization (ESI). Mass spectrometry experiments showed that with particular experimental conditions, decameric uracil clusters are magic number clusters. MS/MS experiments demonstrated that the structure of these decameric uracil clusters depends substantially on the size and the charge of the cation. On the basis of the ab initio and density functional theory (DFT) quantum chemistry calculations, structures for these decameric clusters were proposed. These structures are in agreement with the experimental mass spectra of modified nucleobases. Theoretical calculations showed that complexes experimentally observed using ESI-MS techniques, are not naturally the most stable in the gas phase.


Developmental exposure to an environmental PCB mixture delays the propagation of electrical kindling from the amygdala.
Developmental PCB exposure impairs hearing and induces brainstem audiogenic seizures in adult offspring. The degree to which this enhanced susceptibility to seizure is manifest in other brain regions has not been examined. Thus, electrical kindling of the amygdala was used to evaluate the effect of developmental exposure to an environmentally relevant PCB mixture on seizure susceptibility in the rat. Female Long-Evans rats were dosed orally with 0 or 6mg/kg/day of the PCB mixture dissolved in corn oil vehicle 4 weeks prior to mating and continued through gestation and up until postnatal day (PND) 21. On PND 21, pups were weaned, and two males from each litter were randomly selected for the kindling study. As adults, the male rats were implanted bilaterally with electrodes in the basolateral amygdala. For each animal, afterdischarge (AD) thresholds in the amygdala were determined on the first day of testing followed by once daily stimulation at a standard 200μA stimulus intensity until three stage 5 generalized seizures (GS) ensued. Developmental PCB exposure did not affect the AD threshold or total cumulative AD duration, but PCB exposure did increase the latency to behavioral manifestations of seizure propagation. PCB exposed animals required significantly more stimulations to reach stage 2 seizures compared to control animals, indicating attenuated focal (amygdala) excitability. A delay in kindling progression in the amygdala stands in contrast to our previous finding of increased susceptibility to brainstem-mediated audiogenic seizures in PCB-exposed animals in response to a an intense auditory stimulus. These seemingly divergent results are not unexpected given the distinct source, type, and mechanistic underpinnings of these different seizure models. A delay in epileptogenesis following focal amygdala stimulation may reflect a decrease in neuroplasticity following developmental PCB exposure consistent with reductions in use-dependent synaptic plasticity that have been reported in the hippocampus of developmentally PCB exposed animals.


Nanoscale Architecture of Polymer-Organolead Halide Perovskite Films and the Effect of Polymer Chain Mobility on Device Performance.
The integration of polymer chains with organolead halide perovskite (MAPbI3) films, leading to enhanced stability and electro-optical performance, is critically affected by the molecular weight of chains. The molecular weight determines the mobility and volume of the chains, which affects the crystallization kinetics and, hence, perovskite grain size. The insulating nature of the chains is another critical factor that affects both ion migration and conduction of electronic charge. The combined effect of these factors leads to optimal performance with the use of medium-length chains. A simple model integrating the two effects accurately fits the response of the polymer-perovskite composite. Further characterization results show that the polymer-perovskite films have a three-layer architecture consisting of nanoscale polymer-rich top and bottom layers. These combined results show that the optimization of performance in polymer-perovskite devices depends critically on the size of the chains due to their multiple effects on the perovskite matrix.


Low birthweight in Riyadh, Saudi Arabia: incidence and risk factors.
In a multicentre prospective study, we have determined the incidence of low birthweight (LBW) and the main predisposing risk factors. Among 4651 consecutive births over a 5-month period in five hospitals in Riyadh, the overall incidence of LBW was 8.4%. When stillbirths were excluded the incidence of LBW was 7.4% of all live births. Statistical analysis was performed among 638 births (319 LBW infants, i.e. less than or equal to 2499 g and 319 babies weighing 2500 g or more). Of the 28 antenatal risk variables analysed, 13 were found to be significant when studied separately. Of these 13 variables, six were found to be significant predictors of LBW, using stepwise multiple logistic regression. These six variables together correctly predicted 72% and 88% of the LBW babies or normal birthweight babies, respectively. The risk factors thus identified were (i) short gestation, (ii) multiple gestation, (iii) low maternal body mass index, (iv) nulliparity, (v) availability of housework help, and (vi) absence of consanguinity. Measures for reducing these factors are also discussed.


Supervised Learning in a Multilayer, Nonlinear Chemical Neural Network.
The development of programmable or trainable molecular circuits is an important goal in the field of molecular programming. Multilayer, nonlinear, artificial neural networks are a powerful framework for implementing such functionality in a molecular system, as they are provably universal function approximators. Here, we present a design for multilayer chemical neural networks with a nonlinear hyperbolic tangent transfer function. We use a weight perturbation algorithm to train the neural network which uses a simple construction to directly approximate the loss derivatives required for training. We demonstrate the training of this system to learn all 16 two-input binary functions from a common starting point. This work thus introduces new capabilities in the field of adaptive and trainable chemical reaction network (CRN) design. It also opens the door to potential future experimental implementations, including DNA strand displacement reactions.


Acute profound deafness in Ramsay Hunt syndrome. Two case reports.
Two patients with sudden progressive profound hearing loss resulting from Ramsay Hunt syndrome are reported. Case 1: A 63-year-old woman was admitted to Jichi Medical School Hospital with sudden, progressing deafness of the left ear, vertigo, sore throat, and hoarseness. An otoscopic examination revealed the external ear and the tympanic membrane to be normal. Pure-tone audiometry revealed profound deafness in the left ear. A horizontal nystagmus in the non-affected direction was observed by gaze nystagmus test. An endoscopic examination revealed herpetic vesicles and shallow ulcers on the left side of the pharynx and the larynx. There was complete paralysis of the left recurrent nerve. Hearing acuity of the left ear did not recover at all with steroid hormone therapy. Case 2: A 75-year-old man was referred to the ENT Clinic by a dermatologist for hearing evaluation in Ramsay Hunt syndrome. The man had noticed severe otalgia and sudden progressive deafness of the right ear approximately 2 weeks prior to admission. Physical examination revealed herpetic vesicles and ulcers in the right external ear and lateral neck. Complete paralysis of the right facial nerve was noted. Profound hearing loss in the affected ear was observed by pure-tone audiometry. A gaze nystagmus test revealed a horizontal nystagmus in the non-affected direction. No recovery of the cochlear function was noted following administration of antiviral drug. The pertinent literature is briefly reviewed.


Irinotecan (CPT-11) combined with bolus 5-fluorouracil/leucovorin (Saltz regimen) as first-line chemotherapy of patients with advanced colorectal cancer.
Concerns about the safety of irinotecan (CPT-11) plus bolus 5-fluorouracil (5-FU)/leucovorin (LV) (the so-called Saltz regimen) have been previously reported. This prospective, multicenter, non-randomized study evaluated the anti-tumoral effect and toxicity of the Saltz regimen as first-line chemotherapy of 130 patients with advanced colorectal cancer (CRC). The median numbers of treatment cycles and infusions received per patient were 3 and 12, respectively. Eight (6.1) and 37 patients (28.5%) showed complete and partial responses, respectively [overall response rate=34.6% (95% confidence interval=20.7-48.5%)]. After a median follow up period of 9 months, 70 patients had died. The median progression-free survival and overall survival were 6.78 (0.3-33.8) and 8.26 months (range 0.3-33.8), respectively. The combined CPT-11/5-FU/LV treatment was well tolerated and no toxic deaths were reported. The most common grade 3/4 hematological toxicity was neutropenia (28% of patients and 3% of infusions), but no febrile neutropenia was reported. Delayed diarrhea was the most reported grade 3/4 non-hematological toxicity (21% of patients and 2% of infusions). Other non-hematological toxicities showed very low incidences. During the study five patients died due to factors not associated with disease progression. We conclude that the Saltz regimen administered on an outpatient basis was safe and well tolerated in patients with advanced CRC. Close monitoring of external patients together with an early treatment of toxicity was found to be essential to prevent severe and potentially fatal gastrointestinal or thromboembolic events previously reported with this CPT-11 combined regimen.


Factors associated with radiographic progression in patients with Takayasu's arteritis.
To identify the factors related to radiographic progression in patients with Takayasu's arteritis (TAK). A retrospective cohort study was conducted among patients with TAK who underwent computed tomography angiography (CTA) at least twice in a 2-5-year interval. Radiographic progression was defined as newly developed and/or aggravated (more than 20%) characteristic CTA findings. Correlation analysis was performed using a multivariate Cox regression model. The cohort included 153 TAK patients with a mean CTA interval of 3.53 years, and 24 (15.7%) showed radiographic progression. Those with progression showed higher acute-phase reactant levels (erythrocyte sedimentation rate [ESR], 26.06 vs. 35.72 mm/h, p=0.040; C-reactive protein [CRP], 0.45 vs. 1.13 mg/dL, p<0.001), were younger at the initial CTA (43.70 vs. 31.81 years, p<0.001), and were more likely to be receiving immunosuppressants (14 [10.9%] vs. 7 [29.2%] patients, p=0.038). Multivariate Cox regression analysis revealed age at the initial CTA (hazard ratio [HR]=0.945, confidence interval [CI]=0.898-0.995, p=0.030) and area under the curve (AUC) of CRP levels (HR=2.126, CI=1.046-4.319, p=0.037) as significant factors for radiographic progression. In a subgroup of patients with high CRP levels, 30.4% (14/24) showed progression; only age at the initial CTA was significantly different (37.03 vs. 27.10 years, p=0.012) between those with and without progression. Higher CRP levels and younger age were risk factors of radiographic progression in patients with TAK. In the high CRP group, younger patients are more prone to progression and may need aggressive anti-inflammatory treatment.


Violence risk assessment: combining actuarial and clinical information to structure clinical judgements for the formulation and management of risk.
Throughout history most societies have assumed a link between mental disorder and violence to others. In recent times there has been increasing concern in the United Kingdom over law and order, specifically the risk of violence, and these issues are now high on the political and mental health agenda. Nurses and staff working in National Health Service Mental Health Service Trusts are the groups most at risk of violence. Many clinical decisions are based on risk. Mental health nurses play a pivotal role in the assessment and management of risk and it is argued that they need to adopt a clear structured approach to violence risk assessment and management, which is evidence-based. The advantages of clinical and actuarial approaches to risk assessment are briefly reviewed and a structured clinical judgement approach is proposed that combines these approaches. A method of linking the assessment process with the management plan via a risk formulation is discussed.


The world according to homeopathy.
The author, a family nurse practitioner, describes how homeopathic medicines and the homeopathic conceptual framework distinguish her practice from a conventional one. An introduction to homeopathic health care includes a brief history of the discovery of homeopathy, the homeopathic view of the healing process, and the origins of disease. Factors that would influence a person's candidacy for homeopathy are discussed. Case studies are included.


Use of diffusion-weighted MRI to differentiate chronic pancreatitis from pancreatic cancer.
The purpose of this study was to compare diffusion-weighted MRI (DWI) and conventional (non-DWI) MRI sequences in differentiating mass-forming chronic pancreatitis from pancreatic cancer. A retrospective cohort study included 36 patients who underwent pancreatic resection for pancreatic cancer (n = 13) and chronic pancreatitis (n = 23) after preoperative MRI with DWI. Two independent reviewers assessed the DW images for signal intensity and apparent diffusion coefficient (ADC) values. Four weeks later, they reviewed the other MR images for size of mass, double-duct sign, pancreatic duct cutoff, and perivascular soft-tissue cuffing. A score for conventional MRI was given with 1 meaning definitely benign and 5 meaning definitely malignant. Univariate and multivariate analyses and receiver operating characteristic (ROC) curve analysis were performed with surgical pathologic examination as the reference standard. The only finding that differentiated the two groups was the presence of a well-defined mass, favoring the diagnosis of cancer (p = 0.02, p < 0.01). There was no significant difference between the two groups in signal intensity on DW images (p = 0.82, p = 0.85) or ADC (p = 0.51, p = 0.76). Double-duct sign, pancreatic duct cutoff, and perivascular soft-tissue cuffing were not useful in differentiating the two groups. The areas under the ROC curve were 0.873 and 0.878 for the conventional MRI scores, compared with 0.602 and 0.552 for ADC measurements (p = 0.02, p = 0.008). The addition of DWI to conventional MRI does not facilitate differentiation of pancreatic cancer from chronic pancreatitis.


Processes and Outcomes from a Medical Student Research Training Program in Integrative, Complementary, and Alternative Medicine.
In response to the growing need to train a new generation of clinician scientists, a research program was developed to train medical students in integrative, complementary, and alternative medicine (ICAM) research early in their careers. A total of 25 students (100%) successfully completed a 10-week program. Students reported significantly increased levels of knowledge in all 7 integrative, complementary, and alternative medicine topics at the conclusion of the program. All students presented their work at one or more local research symposia. In addition, the average number of quality research outputs, which included manuscripts, awards, and abstracts presented at national and international meetings, was 1.5 per student, which exceeded benchmarks based on prior program outcomes. Results from this program may be useful when planning larger or longer-term projects aimed at attracting physicians who will become our next generation of academicians, researchers, and healers.


Malocclusion characteristics of patients with cleft lip and/or palate.
This study aimed to evaluate the malocclusions of patients with a cleft lip and/or palate (CLP) and to compare malocclusion characteristics between subjects with a pre-foramen incisor cleft (PIC) and a trans-foramen incisor cleft (TIC). A cross-sectional study was conducted of 117 cleft patients (53 per cent male) aged 6-37 years (mean age 14.7 ± 7.4 years) who attended the Dental Specialty Center in the city of Fortaleza, Brazil, between 2004 and 2007. Oral clefts were classified and radiographic examinations and dental casts were analysed to determine malocclusions and facial patterns. Malocclusion measurements were compared between the PIC and TIC groups by Mann-Whitney and Fisher's exact tests. The percentage of subjects with PIC, TIC, post-foramen incisor cleft, and rare cleft were 20.5, 73.5, 5.1, and 0.9 per cent, respectively. The prevalence of malocclusions in subjects with a CLP was 82.1 per cent (molar relationships Classes II and III) in 6- to 12-year-olds, and a severe malocclusion [dental aesthetic index (DAI)] was observed in all patients aged 13 years and above. The frequency of patients with a normal canine relationship, open bite, and anterior crossbite was higher in the PIC group than in the TIC group (6-12 years). Patients aged 13 years and above in the PIC group showed lower means for the largest anterior maxillary irregularity, higher means for positive anterior mandibular overjet, a lower frequency of crowding in the anterior incisal segments, and a normal antero-posterior molar relationship compared with the TIC group. Severe malocclusions were prevalent in subjects with a CLP. Subjects with a TIC have higher prevalence of malocclusions than those with a PIC.


Integrating science and policy in a National Human Exposure Assessment Survey.
Despite tremendous progress in environmental protection over the past two decades, critical gaps remain in our understanding of actual human exposures to environmental chemicals. While the research community and the policy makers share the common goal of reducing environmental risks, it must be recognized that their information needs are often divergent. The design of effective exposure research must consider the needs and practical limitations of regulators and policy-makers and balance the often conflicting needs of policy and science. This paper examines some of the inherent conflicts between exposure research (science) and regulatory (policy) realities, and describes how the needs of policy makers were integrated into the design of a National Human Exposure Assessment Survey (NHEXAS). NHEXAS represents perhaps the most ambitious exposure surveillance effort ever undertaken. Exposure surveillance is presented as a model for bridging the gap between policy and science in the development of risk management approaches. The success of risk-based priority setting will depend upon the quality of information to support the risk assessment process. Environmental exposure surveillance will be essential to the characterization of risks and, ultimately, to the evaluation of the effectiveness of regulatory strategies.


[Delicate transition: Building-up an adult life for young people with developmental chromosomal anomalies].
A qualitative study was performed in the South of France among young people (16-25 years) affected by chromosomal anomalies: Down, velo-cardio-facial, or Williams-Beuren syndromes. We conducted interviews with them and with their parents to understand the obstacles to social participation that they most frequently face when becoming adults. Once their education comes to an end, young adults with developmental anomalies face several difficulties to develop and keep diversified social ties and to find their place in society, be it with a stable job - either in the ordinary working environment or in sheltered employment - or by attending occupational workshops. While parents are mostly concerned with finding a professional place for their children, the latter seem to especially value opportunities for satisfactory relational dynamics outside of the protective frame of the family. Nevertheless, a wish for familial protection keeps coexisting with their wish for independence.


Neuroimaging guidelines in cognitive impairment: lessons from 3 cases of meningiomas presenting as isolated dementia.
We report three cases of large intracranial meningiomas who presented with dementia alone and no accompanying focal neurological deficits. The meningiomas were detected solely as a result of a policy of routinely scanning the brains of patients presenting with early dementia. Dramatic improvements in the cognitive functions were noted following the excision of the tumours in two of the patients (the third passed away in the perioperative period). The implications of these cases with regard to deciding when to order a brain scan for patients presenting with isolated dementia are discussed in this article and a brief review of the relevant medical literature on this topic is also presented.


Asymmetric Ru/Cinchonine Dual Catalysis for the One-Pot Synthesis of Optically Active Phthalides from Benzoic Acids and Acrylates.
Herein, we report the asymmetric Ru/cinchonine dual catalysis that provides straightforward access to enantioselective synthesis of C-3 substituted phthalides via tandem C-H activation/Michael addition cascade. The use of readily accessible and less expensive [RuCl2(p-cym)]2 and cinchonine catalyst for the one-pot assembly of chiral phthalides greatly overcomes the present trend of using highly sophisticated catalysts. The developed method provides access to both enantiomers of a product using pseudoenantiomeric cinchona alkaloids as catalysts streamlining the synthesis of phthalide in both the optically active forms.


Inhibition of E-selectin-, ICAM-1-, and VCAM-1-mediated cell adhesion by benzo[b]thiophene-, benzofuran-, indole-, and naphthalene-2-carboxamides: identification of PD 144795 as an antiinflammatory agent.
It was previously reported that 3-alkoxybenzo[b]thiophene-2-carboxamides exemplified by 1, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide, decreased the adherence of neutrophils to activated endothelial cells by inhibiting the upregulation of the adhesion molecules E-selectin and ICAM-1 on the surface of the endothelium. This finding is extended here to a series of 3-thiobenzo[b]thiophene-2-carboxamides and also heterocyclic analogs of 1, including benzofurans, indoles, and napthalenes. The compounds that inhibited the expression of E-selectin and ICAM-1 had the same effect on the expression of VCAM-1. PD 144795, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxamide 1-oxide (44), the sulfoxide analog of 1, was orally active in several models of inflammation. The in vitro and in vivo activity of PD 144795 resided predominately in the S-enantiomer.


Enhanced production of bovine chymosin by autophagy deficiency in the filamentous fungus Aspergillus oryzae.
Aspergillus oryzae has been utilized as a host for heterologous protein production because of its high protein secretory capacity and food-safety properties. However, A. oryzae often produces lower-than-expected yields of target heterologous proteins due to various underlying mechanisms, including degradation processes such as autophagy, which may be a significant bottleneck for protein production. In the present study, we examined the production of heterologous protein in several autophagy (Aoatg) gene disruptants of A. oryzae. We transformed A. oryzae gene disruptants of Aoatg1, Aoatg13, Aoatg4, Aoatg8, or Aoatg15, with a bovine chymosin (CHY) expression construct and found that the production levels of CHY increased up to three fold compared to the control strain. Notably, however, conidia formation by the Aoatg gene disruptants was significantly reduced. As large amounts of conidia are necessary for inoculating large-scale cultures, we also constructed Aoatg gene-conditional expression strains in which the promoter region of the Aoatg gene was replaced with the thiamine-controllable thiA promoter. Conidiation by the resultant transformants was clearly enhanced in the absence of thiamine, while autophagy remained repressed in the presence of thiamine. Moreover, these transformants displayed increased CHY productivity, which was comparable to that of the Aoatg gene disruptants. Consequently, we succeeded in the construction of A. oryzae strains capable of producing high levels of CHY due to defects in autophagy. Our finding suggests that the conditional regulation of autophagy is an effective method for increasing heterologous protein production in A. oryzae.


Effects of taxol on microtubule organization in mouse splenic lymphocytes and on response to mitogenic stimulation.
We have used immunofluorescence staining with antibodies to tubulin and electron microscopy to examine the effects of microtubule assembly-promoting drug taxol on the organization of microtubules in unstimulated and in mitogen stimulated mouse splenic lymphocytes. A 4-h exposure to 10 microM taxol of unstimulated or stimulated cells results in an extensive reorganization of the microtubule system to form one to a few large bundles of microtubules which extend from the centrosome. Concomitantly, the centrosome is displaced from the normal position near the nucleus to a position near the plasma membrane. The Golgi apparatus is not disrupted by this treatment and also appears to be displaced in association with the centrosome. We then examined the capacity of lymphocytes with taxol-reorganized microtubules to respond to stimulation by the mitogen concanavalin A. The taxol-induced reorganization of microtubules has no effect on the increase in cell size (blastogenesis), the changes in structure of the nucleus and cytoplasm, or on the DNA replication that occurs in response to mitogen. The stimulated cells, however, do not proliferate and appear to accumulate in mitosis with the appearance of multiple asters. We conclude that all of the major events of mitogenic stimulation up to the first mitosis can occur in the presence of a highly reorganized microtubule system. Our results suggest that taxol will be a useful drug in determining those lymphocyte functions that are dependent on the presence of normal microtubule organization.


Escaping free-energy minima.
We introduce a powerful method for exploring the properties of the multidimensional free energy surfaces (FESs) of complex many-body systems by means of coarse-grained non-Markovian dynamics in the space defined by a few collective coordinates. A characteristic feature of these dynamics is the presence of a history-dependent potential term that, in time, fills the minima in the FES, allowing the efficient exploration and accurate determination of the FES as a function of the collective coordinates. We demonstrate the usefulness of this approach in the case of the dissociation of a NaCl molecule in water and in the study of the conformational changes of a dialanine in solution.


Changing cellular location of CheZ predicted by molecular simulations.
In the chemotaxis pathway of the bacterium Escherichia coli, signals are carried from a cluster of receptors to the flagellar motors by the diffusion of the protein CheY-phosphate (CheYp) through the cytoplasm. A second protein, CheZ, which promotes dephosphorylation of CheYp, partially colocalizes with receptors in the plasma membrane. CheZ is normally dimeric in solution but has been suggested to associate into highly active oligomers in the presence of CheYp. A model is presented here and supported by Brownian dynamics simulations, which accounts for these and other experimental data: A minority component of the receptor cluster (dimers of CheA(short)) nucleates CheZ oligomerization and CheZ molecules move from the cytoplasm to a bound state at the receptor cluster depending on the current level of cellular stimulation. The corresponding simulations suggest that dynamic CheZ localization will sharpen cellular responses to chemoeffectors, increase the range of detectable ligand concentrations, and make adaptation more precise and robust. The localization and activation of CheZ constitute a negative feedback loop that provides a second tier of adaptation to the system. Subtle adjustments of this kind are likely to be found in many other signaling pathways.


Quantized heat transport in small systems: a phenomenological approach.
Recent progress in nanoscale materials science has pushed the basic research on physical effects while going to such length scales. Particularly, the study of size effects on heat conductivity has attracted much theoretical and experimental interest. In this work we explore the possibilities to study such kinds of phenomena through the quantization of the dynamic equations of a class of nonlinear heat transport macroscopic models. We develop a quantization procedure to search the energy level structure of one-dimensional nanosystems. The procedure may have applications in other fields of the physics of mesoscopic systems.


[Stereometric characteristics of inflammatory gingival infiltrates].
The aim of this paper was to assess stereometric characteristics of gingival cell infiltrate in regard to intensity of clinical inflammation. Materials used for assessment were 70 specimen of human gingiva removed during periodontal surgery therapy. Just before the surgery in the area where specimen was to be taken, intensity of clinical gingival inflammation was determined by gingival index after Loben. Considering stereometric parameters numerical density of lymphocytes and plasma cells were established. Analyzing results it was established that by increase of intensity of clinical gingival inflammation and increase of cell infiltrate occurs, whereas an increase of numerical plasma cells' density is statistically highly important (p < 0.001), while the numerical density of lymphocytes does not changes significantly (p > 0.05).


Therapeutic advantages of treatment of high-dose curcumin in the ovariectomized rat.
Although curcumin has a protective effect on bone remodeling, appropriate therapeutic concentrations of curcumin are not well known as therapeutic drugs for osteoporosis. The purpose of this study was to compare the bone sparing effect of treatment of low-dose and high-dose curcumin after ovariectomy in rats. Forty female Sprague-Dawley rats underwent either a sham operation (the sham group) or bilateral ovariectomy (OVX). The ovariectomized animals were randomly distributed among three groups; untreated OVX group, low-dose (10 mg/kg) curcumin administered group, and high-dose (50 mg/kg) curcumin group. At 4 and 8 weeks after surgery, serum biochemical markers of bone turnover were analyzed. Bone histomorphometric parameters of the 4th lumbar vertebrae were determined by micro-computed tomography (CT). In addition, mechanical strength was determined by a three-point bending test. High-dose curcumin group showed significantly lower osteocalcin, alkaline phosphatase, and the telopeptide fragment of type I collagen C-terminus concentration at 4 and 8 weeks compared with the untreated OVX group as well as low-dose curcumin group. In the analyses of micro-CT scans of 4th lumbar vertebrae, the high-dose curcumin treated group showed a significant increase in bone mineral densities (p=0.028) and cortical bone mineral densities (p=0.036) compared with the low-dose curcumin treated group. Only high-dose curcumin treated group had a significant increase of mechanical strength compared with the untreated OVX group (p=0.015). The present study results demonstrat that a high-dose curcumin has therapeutic advantages over a low-dose curcumin of an antiresorptive effect on bone remodeling and improving bone mechanical strength.


The subjective brain, identity, and neuroethics.
The human brain is subjective and reflects the life of a being-in-the-world-with-others whose identity reflects that complex engaged reality. Human subjectivity is shaped and in-formed (formed by inner processes) that are adapted to the human life-world and embody meaning and the relatedness of a human being. Questions of identity relate to this complex and dynamic reality to reflect the fact that biology, human ecology, culture, and one's historic-political situation are inscribed in one's neural network and have configured its architecture so that it is a unique and irreplaceable phenomenon. So much is a human individual a relational being whose own understanding and ownership of his or her life is both situated and distinctive that neurophilosophical conceptions of identity and human activity that neglect these features of our being are quite inadequate to ground a robust neuroethics.