"Far-medial" expanded endonasal approach to the inferior third of the clivus: the transcondylar and transjugular tubercle approaches.
The endoscopic endonasal transclival approach is a valid alternative for treatment of lesions in the clivus. The major limitation of this approach is a significant lateral extension of the tumor. We aim to identify a safe corridor through the occipital condyle to provide more lateral exposure of the foramen magnum. Sixteen parameters were measured in 25 adult skulls to analyze the exact extension of a safe corridor through the condyle. Endonasal endoscopic anatomic dissections were carried out in nine colored latex-injected heads. Drilling at the lateral inferior clival area exposed two compartments divided by the hypoglossal canal: the jugular tubercle (superior) and the condylar (inferior). Completion of a unilateral ventromedial condyle resection opens a 3.5 mm (transverse length) * 10 mm (vertical length) lateral surgical corridor, facilitating direct access to the vertebral artery at its dural entry point into the posterior fossa. The supracondylar groove is a reliable landmark for locating the hypoglossal canal in relation to the condyle. The hypoglossal canal is used as the posterior limit of the condyle removal to preserve more than half of the condylar mass. The transjugular tubercle approach is accomplished by drilling above the hypoglossal canal, and increases the vertical length of the lateral surgical corridor by 8 mm, allowing for visualization of the distal cisternal segment of the lower cranial nerves. The transcondylar and transjugular tubercle "far medial" expansions of the endoscopic endonasal approach to the inferior third of the clivus provide a unique surgical corridor to the ventrolateral surface of the ponto- and cervicomedullary junctions.


Endocardial catheter mapping in patients in sinus rhythm: relationship to underlying heart disease and ventricular arrhythmias.
Catheter mapping during sinus rhythm was performed in 132 patients with coronary artery disease and 26 patients with congestive noncoronary cardiomyopathy. Each of the patients had a clinical history of one of the following: no ventricular arrhythmia, nonsustained ventricular tachycardia, cardiac arrest, or sustained ventricular tachycardia. The characteristics of the endocardial electrogram and other measured indexes of slow endocardial conduction were compared between patients with different types of disease and in different arrhythmia groups to determine if differences existed. The cardiomyopathic group had a higher percent of normal endocardial electrograms than the coronary artery disease group, with no evidence of slow endocardial conduction. The sustained ventricular tachycardia group exhibited a greater percent of abnormal endocardial electrograms and more evidence of slow endocardial conduction, distinguishing this group from the three other arrhythmia groups. We conclude the following: The underlying electrophysiologic substrate varies in patients with different ventricular arrhythmias. It is therefore inappropriate to analyze all patients with ventricular arrhythmias as a single group. Patients with congestive noncoronary cardiomyopathy, regardless of the type of their arrhythmia, have a relatively normal endocardium. Those patients with serious ventricular arrhythmias should not be considered candidates for surgery directed at removing abnormal endocardium.


Nickel-Catalyzed C-3 Direct Arylation of Pyridinium Ions for the Synthesis of 1-Azafluorenes.
The direct arylation of pyridine substrates using non-precious catalysts is underdeveloped but highly desirable due to its efficiency to access important motifs while being extremely cost-effective. The first nickel-catalyzed C-3 direct arylation of pyridine derivatives to provide a new approach to valuable 1-azafluorene pharmacophore frameworks was developed. This transformation is accomplished using air-stable nickel catalyst precursors combined with phenanthroline ligands and tolerates a variety of substituents. Computational studies suggest facile oxidative addition via the pyridinium form, deprotonation, and a subsequent carbo-nickelation cyclization. Nickel homolysis/recombination permits isomerization to the stereochemical array needed for the final elimination.


Role of mitogen-activated protein kinase/extracellular signal-regulated kinase cascade in gonadotropin-releasing hormone-induced growth inhibition of a human ovarian cancer cell line.
Although gonadotropin-releasing hormone agonists (GnRHa) have been used in the therapy of the endocrine-dependent cancers, their biological mechanism remained obscure. We have studied the roles of mitogen-activated protein kinase family in the antiproliferative effect of GnRHa on the Caov-3 human ovarian cancer cell line. Reverse transcription-PCR assays confirmed mRNA for GnRH receptor in Caov-3 cells. In the presence of 1 microM GnRHa, the proliferation of cells was significantly reduced to 76% of controls after 24 h, and the effect was sustained up to 4 days. Although GnRHa had no effect on the activation of the Jun N-terminal kinase (JNK), treatment of Caov-3 cells with GnRHa activated extracellular signal-regulated protein kinase (ERK), and its effect was more than that induced by GnRH. Activation of ERK by GnRHa occurred within 5 min, with the maximum occurring at 3 h and sustained until 24 h. GnRHa also activated ERK kinase (mitogen-activated protein/ERK kinase) and resulted in an increase in phosphorylation of son of sevenless (Sos), and Shc. Furthermore, we examined the mechanism by which GnRHa induced ERK activation. Both pertussis toxin (10 ng/ml), which inactivates Gi/Go proteins, and expression of a peptide derived from the carboxyl terminus of the beta-adrenergic receptor kinase I, which specifically blocks signaling mediated by the betagamma subunits of G proteins, blocked the GnRHa-induced ERK activation. Phorbol 12-myristate 13-acetate (PMA) also induced the ERK activity, but pretreatment of the cultured cells with PMA to down-regulate protein kinase C did not abolish the activation of ERK by GnRHa. Elimination of extracellular Ca2+ by EGTA also did not abolish the activation of ERK by GnRHa. To examine the role of ERK cascade in the antiproliferative effect of GnRHa, PD98059, an inhibitor of mitogen-activated protein/ERK kinase, was used. This inhibitor canceled the antiproliferative effect of GnRHa and apparently reversed the GnRH-induced dephosphorylation of the retinoblastoma protein, the hyperphosphorylation of which is a hallmark of G1-S transition in the cell cycle. These results provide evidence that GnRHa stimulation of ERK activity may be mediated by Gbetagamma protein, not by PMA-sensitive protein kinase C nor extracellular Ca2+ in the Caov-3 human ovarian cancer cell line, suggesting that this cascade may play an important role in the antiproliferative effect of GnRHa.


Education for contraceptive use by women after childbirth.
Postpartum education on contraceptive use is a routine component of discharge planning in many different countries with a wide variety of health care systems. This education is based on assumptions concerning women's receptivity to contraceptive education during the postpartum period and their presumed lack of access to such education after that time. The objective of this review is to assess the effects of education about contraceptive use to postpartum mothers. We searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, CINAHL, Psychlit, Popline, citations indexes and reference lists of relevant articles. We contacted subject experts to locate additional research, in addition to the Group's Specialised Register of Controlled Trials. Date of the most recent search: April 1999. Trials using random or quasi-random methods of allocation which evaluated the effectiveness of postpartum education about contraceptive use. Two independent reviewers abstracted data on trial characteristics and results. Three trials were identified with 5438 women. These trials were conducted in Lebanon, Peru and Nepal. None of the trials examined all major prespecified endpoints. Postpartum education about contraceptive use influenced short-term use assessed between 40 days and three months post-partum. Women in the intervention groups were less likely to be non-users than women in the comparison groups (Odds Ratio (OR) = 0.47, 95% Confidence Interval (CI) 0.39 to 0.58). This benefit was not apparent following analysis of data from better quality studies (OR = 0.67, 95% CI 0.41 to 1.13). An apparent benefit on contraceptive use at six months post-partum (OR = 0.52, 95% CI 0.37 to 0.74) was not apparent following sensitivity analyses (OR = 0.59, 95% CI 0.33 to 1.06). Data are inadequate to assess the impact on cessation of breast feeding and non-attendance at family planning clinics. Unplanned pregnancies, knowledge about contraception and satisfaction with care were not assessed in any trial. The effectiveness of postpartum education about contraceptive use has not yet been established in randomised controlled trials. Such education may be effective in increasing the short-term use of contraception. However, there are only limited data examining a more-important longer-term effect on the prevention of unplanned pregnancies. Research needs to be undertaken to assess the effectiveness of the minimalist education provided in more developed countries and the variety of programs provided in less developed regions. Such research should examine the content, timing, range and organisation of postpartum education on contraceptive use, as well as its impact on breast feeding rates.


[Participation of Sphingolipids in the Pathogenesis of Atherosclerosis].
Lipid metabolism disorders are the most significant risk factor of development of cardiovascular diseases (CVD). In the process of diagnosing ischemic heart disease and other cardiovascular pathologies, levels of total cholesterol, low- and high- density lipoprotein cholesterol, triglycerides are determined. However, in recent years, close attention has been paid to the intersection of the metabolic pathways of the biosynthesis of cholesterol and sphingolipids. Sphingolipids - a group of lipids, which include a molecule of aliphatic alcohol sphingosine. This group includes sphingomyelins, cerebrosides, gangliosides and ceramides, sphingosines and sphingosine-1-phosphate (S-1-P). Ceramides and sphingosines have pro-apoptotic properties, and S-1-P protects cells from apoptosis. Particular attention as inducer CVD attracts ceramide. It has been established that aggregated lipoproteins isolated from atherosclerotic zones are enriched with ceramides. The level of ceramide and sphingosine increases with ischemia/reperfusion of the heart, in the infarction zone and in the blood, and also in hypertensive disease. S-1-P has a pronounced cardioprotective properties. Its content sharply decreases with ischemia and myocardial infarction. S-1-P performs a special function in the structure of high-density lipoproteins (HDL), being one of the main lipid components of these lipoproteins, which determines their multiple functions. Recently, work has been underway to create drugs that can correct the metabolism of S-1-P. The most successful drugs are those that use the S-1-P receptor as a target, since all of its actions are carried out through receptors. Increasing ceramide and sphingosine and reducing blood plasma level of S-1-P can be an important factor in the development of atherosclerosis. It is proposed to use the determination of the level of sphingolipids in blood plasma for early diagnosis of cardiac ischemia and in arterial hypertension. Chromatography-mass spectrometry has been suggested as the main method for testing these lipids.


Exercising for life? Energy metabolism, body composition, and longevity in mice exercising at different intensities.
Studies that have found a positive influence of moderate, nonexhaustive exercise on life expectancy contradict the rate-of-living theory, which predicts that high energy expenditure in exercising animals should shorten life. We investigated effects of exercise on energy metabolism and life span in male mice from lines that had been selectively bred for high voluntary wheel-running activity and from the nonselected control lines. Mice were divided into the following three groups (n = 100 per group): active high-runner mice (housed with wheels; HR+), sedentary high-runner mice (no wheels provided; HR-), and active control mice (C+). Sixty animals from each group were left undisturbed throughout their lives to create survival curves. In the remaining 40 animals in each group, energy metabolism and body composition was measured at 2, 10, 18, or 26 mo of age. Wheel-running activity was increased by approximately 50% throughout life in HR+ mice compared with C+ mice, and mass-specific daily energy expenditure was increased by approximately 30% in HR+ mice compared with both C+ mice and HR- mice. Median life span was similar in HR+ mice and HR- mice (740 and 733 d, respectively), and it was significantly shorter in these mice than it was in C+ mice (828 d). Thus, increasing the amount of voluntary aerobic exercise (as a result of selective breeding or housing with wheels) did not result in extended life span in mice, and we found no evidence for a direct link between energy expenditure and life span.


Bulk bismuth anodes for wide-temperature sodium-ion batteries enabled by electrolyte chemistry modulation.
Sodium ion batteries (SIBs) are considered reliable supplies for next-generation energy devices. However, there is a limited understanding of strategies to prevent the performance deterioration of SIBs under extreme temperature conditions. This study aimed to address this challenge by developing modified electrolyte chemistry to achieve stable wide-temperature SIBs. Weakly Na+-solvating solvent 2-methyltetrahydrofuran (MeTHF) was used to promote the kinetics of Na+ de-solvation. Moreover, 1,2-dimethoxyethane (DME) was introduced as a co-solvent because of the high solubility for Na salts and the coupling reaction mechanism with the Bi electrode. The formulated electrolyte not only endows an anion-dominated NaF-rich solid electrolyte interface (SEI) layer, but also reduces the energy required for the Na+ across the SEI layer (from 291.2 to 89.6 meV). Consequently, Na||Bi half batteries achieve stable cycles at 400 mA g-1 at -20, 20 and 60 °C, respectively. Meanwhile, the extreme operating temperature of the batteries can be extended to -40 and 80 °C, which exceeds those of most current lithium/sodium-based batteries. Furthermore, full batteries employing Na3V2(PO4)3 as the cathode material exhibit stable operation over a wide temperature range of -20 to 60 °C. This electrolyte design strategy presented in this study shows significant promise for enabling wide-temperature SIBs with improved performance.


Microtelemetry--the use of integrated circuits in biotelemetry.
Integrated circuits are now in widespread use in such equipment as computers and consumer electronics, where their low cost, high reliability and small size are their principal advantages. In biotelemetry, small size is of particular importance. Here the use of integrated circuits allows systems of considerable complexity to be produced with high reliability in small packages. Commercial integrated circuits with the low power consumption and low voltage operation needed for biotelemetry are now becoming available; some such applications are briefly reviewed. In addition, examples of the use of custom integrated circuits in biotelemetry, and of the use of integrated circuit technology to build unique transducers and assemblies, are described.


A Case of Hashimoto's Thyroiditis with Multiple Drug Resistance and High Expression of Efflux Transporters.
Hashimoto's thyroiditis is the most common cause of hypothyroidism. Patients usually respond well to oral synthetic thyroxine (levothyroxine); however, for unknown reasons some individuals present with treatment-resistant Hashimoto thyroiditis. In cases of cancer and certain infectious diseases, the ATP binding cassette (ABC) transporters have been implicated in multidrug resistance, and we hypothesized and investigated a role of ABC transporters in drug-resistant Hashimoto's thyroiditis. The patient whose case we report had a history of Hashimoto's thyroiditis, immune thrombocytopenia, and refractory hypertension, with varying treatment resistance to the oral medications prescribed for each condition. In order to establish or exclude a genetic basis for her illness, we examined the patient's gene expression profiles using peripheral blood leukocytes, and found that ABCG2/BCRPexpression was significantly high compared with healthy volunteers. Also, the increased daunomycin efflux capacity of our patient's lymphocytes was successfully inhibited by fumitremorgin C, a specific ABCG2/BCRP inhibitor, and the patient's level of thyroid-stimulating hormone increased by 248.6% after administration of intact levothyroxine tablets but decreased by 45.1% when tablets were crushed. Her average blood pressure decreased from 166.3/108.5 mmHg to 125.9/78.8 mmHg when switching from intact to crushed losartan tablets. High expression and accelerated efflux transporter activity of ABCG2/BCRP in the small intestine are expected to contribute to the ineffectiveness of orally administered intact tablets in cases with treatment-resistant Hashimoto's thyroiditis, and crushed tablets can be more effective for some of these patients.


High-throughput 5'P sequencing enables the study of degradation-associated ribosome stalls.
RNA degradation is critical for gene expression and mRNA quality control. mRNA degradation is connected to the translation process up to the degree that 5'-3' mRNA degradation follows the last translating ribosome. Here, we present an improved high-throughput 5'P degradome RNA-sequencing method (HT-5Pseq). HT-5Pseq is easy, scalable, and uses affordable duplex-specific nuclease-based rRNA depletion. We investigate in vivo ribosome stalls focusing on translation termination. By comparing ribosome stalls identified by ribosome profiling, disome-seq and HT-5Pseq, we find that degradation-associated ribosome stalls are often enriched in Arg preceding the stop codon. On the contrary, mRNAs depleted for those stalls use more frequently a TAA stop codon preceded by hydrophobic amino acids. Finally, we show that termination stalls found by HT-5Pseq, and not by other approaches, are associated with decreased mRNA stability. Our work suggests that ribosome stalls associated with mRNA decay can be easily captured by investigating the 5'P degradome.


Mini-interfacial Fracture Toughness of a Multimode Adhesive Bonded to Plasma-treated Dentin.
To investigate the bonding efficacy of a multimode adhesive to plasma-treated and -untreated (control) dentin using a mini-interfacial fracture toughness (mini-iFT) test. Twenty human molars were used in a split-tooth design (n = 10). The adhesive Scotchbond Universal (SBU; 3M ESPE) was applied in etch-and-rinse (E&R) and self-etch (SE) modes. Mid-coronal dentin was exposed and covered with a standardized smear layer ground to 320 grit. One half of each dentin surface received 15 s of non-thermal atmospheric plasma (NTAP), while the other half was covered with a metallic barrier and kept untreated. Following the E&R mode, dentin was plasma treated immediately after phosphoric acid etching. SBU and a resin-based composite were applied to dentin following the manufacturer's instructions. Six mini-iFT specimens were prepared per tooth (1.5 x 2.0 x 16 to 18 mm), and a single notch was prepared at the adhesive-dentin interface using a 150-μm diamond blade under water cooling. Half of the mini-iFT specimens were immediately loaded until failure in a 4-point bending test, while the other half were first stored in distilled water for 6 months. After testing, the exact dimensions of the notch were measured with a measuring optical microscope, from which ΚIc was determined. Three-way ANOVA revealed higher mini-iFT for SBU applied in E&R than SE mode for both storage times, irrespective of NTAP treatment. Overall, mini-iFT did not decrease for any of the experimental groups upon 6-month aging, while plasma treatment did not show a direct beneficial effect on mini-iFT of SBU applied in either E&R or SE mode.


Broad-scale trophic shift in the pelagic North Pacific revealed by an oceanic seabird.
Human-induced ecological change in the open oceans appears to be accelerating. Fisheries, climate change and elevated nutrient inputs are variously blamed, at least in part, for altering oceanic ecosystems. Yet it is challenging to assess the extent of anthropogenic change in the open oceans, where historical records of ecological conditions are sparse, and the geographical scale is immense. We developed millennial-scale amino acid nitrogen isotope records preserved in ancient animal remains to understand changes in food web structure and nutrient regimes in the oceanic realm of the North Pacific Ocean (NPO). Our millennial-scale isotope records of amino acids in bone collagen in a wide-ranging oceanic seabird, the Hawaiian petrel (Pterodroma sandwichensis), showed that trophic level declined over time. The amino acid records do not support a broad-scale increase in nitrogen fixation in the North Pacific subtropical gyre, rejecting an earlier interpretation based on bulk and amino acid specific δ15N chronologies for Hawaiian deep-sea corals and bulk δ15N chronologies for the Hawaiian petrel. Rather, our work suggests that the food web structure in the NPO has shifted at a broad geographical scale, a phenomenon potentially related to industrial fishing.


Creation and Validation of an EMR-based Algorithm for Identifying Major Adverse Cardiac Events while on Statins.
Statin medications are often prescribed to ameliorate a patient's risk of cardiovascular events due in part to cholesterol reduction. We developed and evaluated an algorithm that can accurately identify subjects with major adverse cardiac events (MACE) while on statins using electronic medical record (EMR) data. The algorithm also identifies subjects experiencing their first MACE while on statins for primary prevention. The algorithm achieved 90% to 97% PPVs in identification of MACE cases as compared against physician review. By applying the algorithm to EMR data in BioVU, cases and controls were identified and used subsequently to replicate known associations with eight genetic variants. We replicated 6/8 previously reported genetic associations with cardiovascular diseases or lipid metabolism disorders. Our results demonstrated that the algorithm can be used to accurately identify subjects with MACE and MACE while on statins. Consequently, future e studies can be conducted to investigate and validate the relationship between statins and MACE using real-world clinical data.


Dimethyl fumarate: Regulatory effects on the immune system in the treatment of multiple sclerosis.
Dimethyl fumarate (DMF) is an important oral treatment option for various autoimmune diseases, such as multiple sclerosis (MS) and psoriasis. DMF and its dynamic metabolite, monomethyl fumarate (MMF) are the major compounds that exert therapeutic effects on several pathologic conditions in part, through downregulation of immune responses. The exact mechanism of DMF is yet to be fully understood even though its beneficial effects on the immune system are extensively studied. It has been shown that DMF/MMF can affect various immune cells, which can get involved in both the naive and adaptive immune systems, such as T cells, B cells, dendritic cells, macrophages, neutrophils, and natural killer cells. It is suggested that DMF/MMF may exert their effect on immune cells through inhibition of nuclear factor-κB translocation, upregulation of nuclear factor erythroid-derived 2(E2)-related factor antioxidant pathway, and activation of hydroxyl carboxylic acid receptor 2. In this review, the mechanisms underlying the modulatory functions of DMF or MMF on the main immune cell populations involved in the immunopathogenesis of MS are discussed.


Reconstruction of osteomyelitis defects.
Reconstruction of large skeletal defects secondary to osteomyelitis remains a challenging problem. Osteomyelitis can result from a variety of etiologies; most often, it is a consequence of trauma to a long bone. Despite advances in antibiotic therapy, treatment of chronic osteomyelitis requires adequate surgical debridement, which can often lead to large soft tissue and bone loss. Free vascularized bone can be used to reconstruct large skeletal defects greater than 6 cm or bone defects of smaller size that failed to heal with nonvascularized bone grafting. The length, cortical strength, and anatomic configuration of the free vascular fibular graft make it an ideal bone graft to bridge extremity defects, and it can be transferred with skin, fascia, and muscle to fill soft tissue defects in the recipient site.


Transient Pruritic Erythema as a Forme Fruste of Solar Urticaria.
Solar urticaria (SU) is a rare and disabling photodermatosis. SU typically manifests as urticarial wheals and erythema appearing shortly after sun exposure. SU is often initially diagnosed clinically with subsequent confirmation through photoprovocation tests. Early diagnosis is important for correct management of patients. To present the clinical features of three cases of atypical presentation of SU and to discuss possible underlying mechanisms. We report a series of three patients who presented with transient pruritic erythema without wheals after sun exposure. All patients had photoprovocation tests conducted to confirm SU diagnosis and to determine their action spectra. Treatment outcomes were recorded. All three patients developed classical manifestations of SU during photoprovocation tests within the UVA1 spectrum. Two patients required high-dose irradiation to provoke urticaria. Erythema without urticaria can be the primary manifestation of SU, especially in countries with sunny climates where natural skin hardening is common. Such cases require a high index of suspicion for SU and highlight the importance of photoprovocation testing to confirm the diagnosis.


Enhanced Sampling of Protein Conformational Transitions via Dynamically Optimized Collective Variables.
Protein conformational transitions often involve many slow degrees of freedom. Their knowledge would give distinctive advantages because it provides chemical and mechanistic insight and accelerates the convergence of enhanced sampling techniques that rely on collective variables. In this study, we implemented a recently developed variational approach to conformational dynamics metadynamics to the conformational transition of the moderate size protein, L99A T4 Lysozyme. To find the slow modes of the system, we combined data coming from NMR experiments as well as from short MD simulations. A Metadynamics simulation based on these information reveals the presence of two intermediate states, at an affordable computational cost.


Reducing cancer risk in women through lifestyle-mediated changes in hormone levels.
The major hormone-associated cancers of women, viz. breast, endometrium, and ovary, account for some 40% of all female cancers in the U. S. Variable expression of estrogens and progestins account for major differences in the incidence of breast and endometrial cancer. Identified differences in premenopausal ovarian hormone expression and the known effects of post-menopausal weight on estrogen metabolism now permit an essentially complete hormonal explanation of the epidemiology of endometrial cancer. Recent confirmation of decreased ovarian steroid levels in certain Oriental women now permits a hormonal explanation of the four- to sixfold differences in breast cancer rates between Japanese and U.S. women, and a complete hormonal explanation of the epidemiology of breast cancer is almost at hand. A delay of 2 years in the age at menarche plus a low postmenopausal weight are predicted to lead to a more than 50% lifelong reduction in both breast cancer and endometrial cancer. A 2-year delay in menarche is predicted to lead to an 18% reduction in ovarian cancer. The lifestyle basis of variable premenopausal ovarian hormone expression is poorly understood and should be the focus of a major research effort. Profound effects on estrogen and progestin expression and on cancer rates are obtained from use of hormonal contraceptives and menopausal hormone replacement therapy; it appears possible to use this knowledge to construct a LHRHA-plus-estrogen contraceptive regimen that should produce a major lifelong reduction in current U.S. breast cancer rates (32% reduction from 5 years use; 55% from 10 years use). The proposed regimen should also cause a major lifelong reduction in ovarian cancer rates (40% reduction from 5 years use; 66% from 10 years use). Addition of a progestin-containing IUCD to such a regimen should also cause a major lifelong reduction in endometrial cancer rates (55% reduction from 5 years use; 82% reduction from 10 years use).


Distribution of Serratia marcescens serotypes in cancer patients.
A study of 1314 patients with malignancies was made to determine the prevalence of Serratia marcescens in surveillance, diagnostic, and environmental cultures. Sera obtained from a commercial source were used to determine serotypic distributions of the S. marcescens strains isolated during a 51-month period. S. marcescens was isolated from 19% of patients with haematological neoplasms, from 5% of patients with lymphoma, and from 6% of those with solid tumours. Among carriers, rectal cultures were the commonest source in patients with lymphoma (32%); rectal and gingival cultures in patients with leukaemia (43% and 39%, respectively), and gingival cultures in patients with solid tumours (30%). Bacteraemias (.07%) were infrequent sources. Although seldom isolated from environmental or food samples, S. marcescens may occasionally be abundant in fresh fruit and vegetables. Serotyping of 220 strains of S. marcescens demonstrated 38 distinct antigenic types. The predominant serotype, O14:H12, was present in the upper respiratory tract of half of the persons who carried this serotype. Serotyping is a readily reproducible method of subspeciating S. marcescens; it can be satisfactorily used as an epidemiological tool.


Cancer incidence among short- and long-term workers in the Norwegian silicon carbide industry.
A previous study among workers in the Norwegian silicon carbide industry, followed until 1996, revealed an excess incidence of lung and total cancer. The present study adds nine years of follow-up and focuses on cancer risk among short- and long-term workers, based on the assumption that these two groups have different exposure and lifestyle characteristics. The total cohort for this study comprised 2612 men employed for >6 months between 1913 and 2003. The follow-up period for cancer was 1953-2005. Short-term workers were defined as having <3 years of total employment in the industry. We estimated standardized incidence ratios (SIR) using national rates as the expected values. Among the short-term workers, we observed an overall excess incidence of cancer [SIR 1.4, 95% confidence interval (95% CI) 1.2-1.6], with an excess of lung cancer (SIR 2.6, 95% CI 1.9-3.5) as the most important contributing factor. The long-term workers also had an excess incidence of total cancer (SIR 1.2, 95% CI 1.1-1.3) and lung cancer (SIR 1.7, 95% CI 1.3-2.2). We also observed an increased risk of cancers at other sites, specifically among short-term workers. We observed an increased risk of cancer (especially in the lung but also at other sites) among both short- and long-term workers. Dust exposure in the silicon carbide industry may have contributed to the increased risk among long-term workers, whereas the increased risk among short-term workers may be due to a combination of occupational and lifestyle factors.


The Clinical Outcomes of Immediate Versus Delayed Restoration Procedures on Immediate Implants: A Comparative Cohort Study for Single-Tooth Replacement.
Immediate implant placement into fresh extraction sockets is generally considered a reliable procedure that offers several clinical advantages. The primary aim of this study was to evaluate and compare the overall clinical outcomes of immediate and delayed restoration procedures for implants placed in fresh extraction sockets by means of a flapless technique and resorbable membrane stabilizing a xenograft. Total costs and operating times were also compared. In this prospective cohort study, changes of marginal bone level, facial soft tissue (ΔFST), and width of keratinized gingiva (ΔWKG), in addition to the papilla index, underwent a pairwise comparison; correlations with pristine buccal bone thickness were also investigated. Although similar results were recorded for the two procedures, with a bone loss of -1.0 ± 0.5 mm and -0.9 ± 0.7 mm, respectively, for immediate and delayed restoration, negative remodeling in the delayed restoration procedure was seen to occur from 4 to 12 months after implant placement. No significant differences were recorded between the two procedures in terms of ΔFST and ΔWKG. A loss of the papillary soft tissues before restoration, followed by a reestablishment after restoration, seemed to be verified for the delayed group, for which the papilla index went from the minimum of 0 at 4 months to a value of 2 at 24 months. Moreover, the immediate restoration procedure seemed to be more promising in terms of healing times and costs. Immediate restoration of implants installed in fresh extraction sockets was at least as effective and safe as delayed restoration.


Flexor tendon repair after rupture caused by volar plate fixation of the distal radius.
Volar plate fixation of unstable fractures of the distal radius is preferred by a majority of surgeons today. One known complication is the rupture of flexor tendons. The aim of this paper is to present flexor tendon ruptures after volar plate fixation analysing the clinical outcome after tendon surgery, aetiology, and methods of prevention. Seventeen consecutive ruptures in 14 patients were included. The incidence was 1.4%. Three patients declined tendon surgery. Eleven patients were treated with a free tendon graft. Only two patients showed excellent results regarding mobility in the thumb and/or fingers. Analysis of radiographs demonstrated sub-optimal placement of plate or screws in all cases. Rupture of a flexor tendon is a serious complication where the functional outcome after surgical reconstruction is uncertain. Early removal of the plate when the placement is sub-optimal or when local volar tenderness appears would probably prevent many ruptures.


Gamma knife radiosurgery for medically and surgically refractory prolactinomas.
Experience with gamma knife radiosurgery (GKRS) for prolactinomas is limited because of the efficacy of medical and surgical intervention. Patients who are refractory to medical and/or surgical therapy may be treated with GKRS. We characterize the efficacy of GKRS for medically and surgically refractory prolactinomas. We reviewed our series of patients with prolactinomas who were treated with GKRS after failing medical and surgical intervention who had at least 1 year of follow-up. Twenty-three patients were included in analysis of endocrine outcomes (median and average follow-up of 55 and 58 mo, respectively) and 28 patients were included in analysis of imaging outcomes (median and average follow-up of 48 and 52 mo, respectively). Twenty-six percent of patients achieved a normal serum prolactin (remission) with an average time of 24.5 months. Remission was significantly associated with being off of a dopamine agonist at the time of GKRS and a tumor volume less than 3.0 cm3 (P < 0.05 for both). Long-term image-based volumetric control was achieved in 89% of patients. Complications included new pituitary hormone deficiencies in 28% of patients and cranial nerve palsy in two patients (7%). Clinical remission in 26% of treated patients is a modest result. However, because the GKRS treated tumors were refractory to other therapies and because complication rates were low, GKRS should be part of the armamentarium for treating refractory prolactinomas. Patients with tumors smaller than 3.0 cm3 and who are not receiving dopamine agonist at the time of treatment will likely benefit most.


Postinfarct cytokine therapy regenerates cardiac tissue and improves left ventricular function.
We systematically investigated the comparative efficacy of three different cytokine regimens, administered after a reperfused myocardial infarction, in regenerating cardiac tissue and improving left ventricular (LV) function. Wild-type (WT) mice underwent a 30-minute coronary occlusion followed by reperfusion and received vehicle, granulocyte colony-stimulating factor (G-CSF)+Flt-3 ligand (FL), G-CSF+stem cell factor (SCF), or G-CSF alone starting 4 hours after reperfusion. In separate experiments, chimeric mice generated by reconstitution of radioablated WT mice with bone marrow from enhanced green fluorescent protein (EGFP) transgenic mice underwent identical protocols. Mice were euthanized 5 weeks later. Echocardiographically, LV function was improved in G-CSF+FL- and G-CSF+SCF-treated but not in G-CSF-treated mice, whereas LV end-diastolic dimensions were smaller in all three groups. Morphometrically, cytokine-treated hearts had smaller LV diameter and volume. Numerous EGFP-positive cardiomyocytes, capillaries, and arterioles were noted in the infarcted region in cytokine-treated chimeric mice treated with G-CSF+FL or G-CSF+SCF, but the numbers were much smaller in G-CSF-treated mice. G-CSF+FL therapy mobilized bone marrow-derived cells exhibiting increased expression of surface antigens (CD62L and CD11a) that facilitate homing. We conclude that postinfarct cytokine therapy with G-CSF+FL or G-CSF+SCF limits adverse LV remodeling and improves LV performance by promoting cardiac regeneration and probably also by exerting other beneficial actions unrelated to regeneration, and that G-CSF alone is less effective.


Caffeic acid reduces oxidative stress and microglial activation in the mouse hippocampus.
A number of studies have indicated the benefits of coffee consumption on physical and mental health; however, scientific evidence on these effects, in particular of the benefits to brain function, has not been determined. In the present study, we aimed to determine the benefits of caffeic acid in the nervous system. For this purpose, we administered doses of 0 or 300 mg/kg for 30 days to mice that were not otherwise affected. We analyzed survival of newly born cells, oxidative stress, inflammatory marker expression, and microglial activation in the hippocampus. We found that caffeic acid had no effect on the expression levels of neurotrophic factors and inflammatory or anti-inflammatory cytokines. However, caffeic acid-treated mice exhibited significantly lower levels of 4-hydroxynonenal, an oxidative stress marker, in the hippocampus, as well as significantly fewer activated microglia. Abnormally high oxidative stress, as well as activated microglia accumulation are both considered to relate to the pathophysiology of neurological and psychiatric disorders. The present study demonstrates the physiological effects of caffeic acid and may explain the suggested benefits of coffee consumption on brain health.


Silicon Solar Cells on Glass with Power Conversion Efficiency above 13% at Thickness below 15 Micrometer.
Liquid phase crystallized silicon on glass with a thickness of (10-40) μm has the potential to reduce material costs and the environmental impact of crystalline silicon solar cells. Recently, wafer quality open circuit voltages of over 650 mV and remarkable photocurrent densities of over 30 mA/cm2 have been demonstrated on this material, however, a low fill factor was limiting the performance. In this work we present our latest cell progress on 13 μm thin poly-crystalline silicon fabricated by the liquid phase crystallization directly on glass. The contact system uses passivated back-side silicon hetero-junctions, back-side KOH texture for light-trapping and interdigitated ITO/Ag contacts. The fill factors are up to 74% and efficiencies are 13.2% under AM1.5 g for two different doping densities of 1 · 1017/cm3 and 2 · 1016/cm3. The former is limited by bulk and interface recombination, leading to a reduced saturation current density, the latter by series resistance causing a lower fill factor. Both are additionally limited by electrical shading and losses at grain boundaries and dislocations. A small 1 × 0.1 cm2 test structure circumvents limitations of the contact design reaching an efficiency of 15.9% clearly showing the potential of the technology.


Antibody-dependent cellular cytotoxicity to clinical isolates of HIV-1 and SIVcpz: comparison of human and chimpanzees.
To investigate differences in the antibody-dependent cellular cytotoxicity (ADCC) responses between HIV-1-infected humans and chimpanzees. The breadth of the ADCC responses in the two populations were tested against autologous and heterologous HIV-1 and SIVcpz clinical isolates as well as against reference isolates. ADCC was tested in a 51Cr-release assay using human peripheral blood mononuclear cells as effector cells and infected Jurkat/Tat-cells as target cells. The majority of sera from chronically HIV-1-infected humans and chimpanzees had ADCC responses to HIV-1LAI. Interestingly, vaccinated chimpanzees with a low virus load during the immediate post-challenge period had low ADCC responses 3 years after challenge. In contrast, when ADCC activity to clinical isolates was evaluated, HIV-1-infected chimpanzees had more frequent heterologous (broader) responses than HIV-1-infected humans. ADCC was also tested in consecutive serum samples from two patients and two chimpanzees against autologous isolates, but was only detected to a low degree in one of the animals, although heterologous ADCC was demonstrated in all cases. The naturally infected (SIVcpz) chimpanzee did not have detectable heterologous or autologous ADCC responses. HIV-1-infected chimpanzees had broader ADCC reactivity to heterologous HIV-1 clinical isolates than the HIV-1-infected humans. These findings are consistent with subtle differences in host-virus relationships of these two species.


Pressure signature and evaluation of hammer pulses during underwater implosion in confining environments.
The fluid structure interaction phenomenon occurring in confined implosions is investigated using high-speed three-dimensional digital image correlation (DIC) experiments. Aluminum tubular specimens are placed inside a confining cylindrical structure that is partially open to a pressurized environment. These specimens are hydrostatically loaded until they naturally implode. The implosion event is viewed, and recorded, through an acrylic window on the confining structure. The velocities captured through DIC are synchronized with the pressure histories to understand the effects of confining environment on the implosion process. Experiments show that collapse of the implodable volume inside the confining tube leads to strong oscillating water hammer waves. The study also reveals that the increasing collapse pressure leads to faster implosions. Both peak and average structural velocities increase linearly with increasing collapse pressure. The effects of the confining environment are better seen in relatively lower collapse pressure implosion experiments in which a long deceleration phase is observed following the peak velocity until wall contact initiates. Additionally, the behavior of the confining environment can be viewed and understood through classical water hammer theory. A one-degree-of-freedom theoretical model was created to predict the impulse pressure history for the particular problem studied.


Physiologically-based Pharmacokinetic (PBPK) Modelling of Transporter Mediated Drug Absorption, Clearance and Drug-drug Interactions.
Membrane transporters play an important role in intestinal absorption, distribution and clearance of drugs. Additionally transporters along with enzymes regulate tissue exposures (e.g. liver, kidney and brain), which are important for safety and efficacy considerations. Early identification of transporters involved guides generation of in vitro and in vivo data needed to gain mechanistic understanding on the role of transporters in organ clearance, tissue exposures and enables development of physiological-based pharmacokinetic (PBPK) models. A lot of progress has been made in developing several in vitro assay systems and mechanistic in silico models to determine kinetic parameters for transporters, which are incorporated into PBPK models. Although, intrinsic clearance and inhibition data from in vitro systems generally tend to underpredict in vivo clearance and magnitude of drug-drug interactions (DDIs), empirical scaling factors derived from a sizable dataset are often used to offset underpredictions. PBPK models are increasing used to predict the impact of transporters on intestinal absorption, clearance, victim and perpetrator DDIs prior to first in human clinical trials. The models are often refined when clinical data is available and are used to predict pharmacokinetics in untested scenarios such as the impact of polymorphisms, ontogeny, ethnicity, disease states and DDIs with other perpetrator drugs. The aim of this review is to provide an overview of (i) regulatory requirements around transporters, (ii) in vitro systems and their limitations in predicting transporter mediated drug disposition and DDIs, (iii) PBPK modelling tactics and case studies used for internal decision making and/or for regulatory submissions.


Colloidal Synthesis of Air-Stable Alloyed CsSn1-xPbxI3 Perovskite Nanocrystals for Use in Solar Cells.
Organic-inorganic hybrid perovskite solar cells have demonstrated unprecedented high power conversion efficiencies in the past few years. Now, the universal instability of the perovskites has become the main barrier for this kind of solar cells to realize commercialization. This situation can be even worse for those tin-based perovskites, especially for CsSnI3, because upon exposure to ambient atmosphere the desired black orthorhombic phase CsSnI3 would promptly lose single crystallinity and degrade to the inactive yellow phase, followed by irreversible oxidation into metallic Cs2SnI6. By alloying CsSnI3 with CsPbI3, we herein report the synthesis of alloyed perovskite quantum dot (QD), CsSn1-xPbxI3, which not only can be phase-stable for months in purified colloidal solution but also remains intact even directly exposed to ambient air, far superior to both of its parent CsSnI3 and CsPbI3 QDs. Ultrafast transient absorption spectroscopy studies reveal that the photoexcited electrons in the alloyed QDs can be injected into TiO2 nanocrystals at a fast rate of 1.12 × 1011 s-1, which enables a high photocurrent generation in solar cells.


Lymphocyte subsets at different stages of subacute sclerosing panencephalitis: a study with monoclonal antibodies.
Lymphocyte subsets in cerebrospinal fluid (CSF) and peripheral blood were studied using monoclonal antibodies, in patients with subacute sclerosing panencephalitis, eight of whom were at stage 2 and seven at stage 4. Eighteen subjects affected with non immunological diseases constituted the controls. Regardless of the stage, patients with subacute sclerosing panencephalitis had lower percentages of OKT3+ (pan-T) cells in both CSF and peripheral blood, with an increase of OKIa+ cells (B cells, macrophages and active T cells) in peripheral blood. A difference was found in the proportion of OKT4+ (helper-inducer) and OKT8+ (suppressor/cytotoxic) cells in relation to the stage, the most striking finding being a significant decrease of OKT8+ with an increase of T4/T8 ratio in peripheral blood at an early stage.


Long-term seizure outcome after stereotactic amygdalohippocampectomy.
The aim of the study was to evaluate the long-term seizure outcome and complications after stereotactic radiofrequency amygdalohippocampectomy (SAHE) performed for mesial temporal lobe epilepsy (MTLE). The article describes the cases of 61 patients who were treated at our institution during the period 2004-2010. Mean post-operative follow-up was 5.3 years. At the last postsurgical visit, 43 (70.5 %) patients were Engel Class I, six (9.8 %) Class II, nine (14.8 %) Class III and three (4.9 %) Class IV. The surgery was complicated by four intracranial haematomas. One of them caused acute hydrocephalus and was treated by shunting and resolved without sequelae. After SAHE, we performed open epilepsy surgery and re-thermo lesions in three and two patients, respectively (8.2 %). There were two cases of meningitis which required antibiotic treatment. In six patients psychiatric disorders developed and one of these committed suicide due to postoperative depression. Our results provide preliminary evidence for good long-term seizure outcomes after SAHE. SAHE could be an alternative therapy for MTLE.


Spontaneous neurodegeneration in transgenic mice with prion protein codon 101 proline----leucine substitution.
Gerstmann-Sträussler-Scheinker syndrome (GSS) is an autosomal, dominantly inherited, human neurodegenerative disease that can sometimes be transmitted to non-human primates and rodents through intracerebral inoculation of brain homogenates from patients. Recent studies of GSS demonstrated significant genetic linkage between GSS and a leucine substitution at codon 102 of the human prion protein (PrP) gene. Transgenic mice were created to test the biologic activity of this mutation. Spontaneous neurologic disease with spongiform degeneration developed in one of three lines of transgenic mice containing murine PrP genes with a leucine substitution at codon 101 (homologous to codon 102 in humans). Transmission studies of brain homogenates from affected mice are in progress. These results indicate that some of the clinical and pathologic features of GSS can be reproduced in a transgenic mouse paradigm; this represents the first time a dominantly inherited, neurodegenerative process similar to a human disease has been genetically modeled in an experimental animal (Hsiao and Prusiner 1990).


Colostrinin alleviates amyloid-beta induced toxicity in rat primary hippocampal cultures.
Colostrinin (CLN), a complex mixture of proline-rich polypeptides derived from colostrums, can alleviate cognitive decline in early Alzheimer's disease patients. The molecular basis of the action of CLN has been studied in vitro using human neuroblastoma cell lines. The aim of the present study was to use quantitative immunocytochemistry and immunoblotting to investigate the ability of CLN to relieve amyloid-beta (Abeta)-induced cytotoxicity in rat primary hippocampal neuronal cells. Our data confirm that CLN alleviates the effect of Abeta-induced cytotoxicity and causes a significant reduction in the elevated levels of the antioxidant enzyme SOD1.


Limb salvage using distraction osteogenesis. A classification of the technique.
We report the results of distraction osteogenesis (callotasis) for the reconstruction of extensive defects after the excision of skeletal tumours in the limbs. Bone transport was performed in ten patients (five osteosarcomas and five giant-cell tumours), shortening-distraction in three (two osteosarcomas and one Ewing's sarcoma), and distraction osteogenesis combined with an intramedullary nail to reduce the time of external fixation in six (three osteosarcomas, two chondrosarcomas, and one malignant fibrous histiocytoma). The mean length of the defects after excision of the lesion was 8.4 cm. The mean external fixation index was 39.5 days/cm for the group treated by bone transport, 34.1 days/cm for the shortening-distraction group, and 24.0 days/cm for the group treated by distraction and an intramedullary nail. Functional evaluation gave excellent results in 12 patients, good in five and fair in two. There were ten complications in 19 patients, all of which were successfully treated. We also classified reconstruction using distraction osteogenesis into five types based on the location of the defects after resection of the tumour: type 1, diaphyseal; type 2, metaphyseal; type 3, epiphyseal; type 4, subarticular reconstruction; and type 5, arthrodesis. Our results suggest that reconstruction using distraction osteogenesis provides bone which will develop sufficient biomechanical strength and durability. It is beneficial in patients with an expectation of long-term survival and in growing children.


Successful cesarean section in a gravida with the thrombocytopenia with absent radius syndrome. A case report.
A 20-year-old primigravida with the autosomal recessive thrombocytopenia with absent radius (TAR) syndrome was followed in her third trimester of pregnancy. Although the platelet counts ranged from 8,000 to 30,000/microL, the patient had minimal symptoms of peripatellar ecchymoses. She presented at term with spontaneous rupture of the membranes and a double footling breech presentation. She successfully underwent low vertical cesarean section and delivery of a term, viable female infant. Management of the hemodynamic status was with blood component therapy. Antenatal ultrasonography demonstrated normal fetal extremities. Review of the literature revealed this to be the first report of cesarean section in a TAR syndrome patient. Management of coagulation problems should be individualized according to the severity of the disease.


Prospective study of breast-feeding in relation to wheeze, atopy, and bronchial hyperresponsiveness in the Avon Longitudinal Study of Parents and Children (ALSPAC).
Breast-feeding clearly protects against early wheezing, but recent data suggest that it might increase later risk of atopic disease and asthma. We sought to examine the relationship between breast-feeding and later asthma and allergy outcomes by using data from the Avon Longitudinal Study of Parents and Children, a large birth cohort in the United Kingdom. We used adjusted logistic regression models to evaluate the association between breast-feeding and atopy at age 7 years, bronchial responsiveness to methacholine at age 8 years, and wheeze at ages 3 and 7 1/2 years. Bayesian methods were used to assess the possibility of bias caused by an influence of early wheezing on the duration of breast-feeding, as well as selection bias. Breast-feeding was protective for wheeze in the first 3 years of life (odds ratio [OR] of 0.80 [95% CI, 0.70-0.90] for > or = 6 months relative to never) but not wheeze (OR, 0.98; 95% CI, 0.79-1.22), atopy (OR, 1.12; 95% CI, 0.92-1.35), or bronchial hyperresponsiveness (OR, 1.07; 95% CI, 0.82-1.40) at ages 7 to 8 years. Bayesian models adjusting for the longer duration of breast-feeding among children with wheezing in early infancy produced virtually identical results. We did not find consistent evidence for either a deleterious effect or a protective effect of breast-feeding on later risk of allergic disease in a large prospective birth cohort of children with objective outcome measures and extensive data on potential confounders and effect modifiers. Neither reverse causation nor loss to follow-up appears to have materially biased our results.


Long ECGs reveal rich and robust dynamical regimes in patients with frequent ectopy.
We have analyzed the electrocardiographic data collected during continuous 7-day ambulatory recordings in patients with frequent premature ventricular complexes (PVCs). We analyze the dependence of the frequency and patterns of PVCs on the heart rate and the time of the day. Patients display rhythms of a complex yet consistent structure. In a given patient, the pattern remains robust over different days and particular repetitive patterns appear at specific heart rates, suggesting the appearance of bifurcations in the dynamics. Over the course of 24 h, we find that in some patients, patterns appear to depend only on the heart rate, whereas in others, both the time of the day and the heart rate play a role in controlling the dynamics. Identifying parameter values at which bifurcations occur facilitates the development of dynamical models for arrhythmia. The use of powerful recording and analysis techniques will enable improved analysis of data and better understanding of mechanisms of arrhythmia in individual patients.


Novel signal transducer and activator of transcription 3 (STAT3) mutations, reduced T(H)17 cell numbers, and variably defective STAT3 phosphorylation in hyper-IgE syndrome.
Hyper-IgE syndrome (HIES) is a rare, autosomal-dominant immunodeficiency characterized by eczema, Staphylococcus aureus skin abscesses, pneumonia with pneumatocele formation, Candida infections, and skeletal/connective tissue abnormalities. Recently it was shown that heterozygous signal transducer and activator of transcription 3 (STAT3) mutations cause autosomal-dominant HIES. To determine the spectrum and functional consequences of heterozygous STAT3 mutations in a cohort of patients with HIES. We sequenced the STAT3 gene in 38 patients with HIES (National Institutes of Health score >40 points) from 35 families, quantified T(H)17 cells in peripheral blood, and evaluated tyrosine phosphorylation of STAT3. Most STAT3 mutations in our cohort were in the DNA-binding domain (DBD; 22/35 families) or Src homology 2 (SH2) domain (10/35) and were missense mutations. We identified 2 intronic mutations resulting in exon skipping and in-frame deletions within the DBD. In addition, we identified 2 mutations located in the transactivation domain downstream of the SH2 domain: a 10-amino acid deletion and an amino acid substitution. In 1 patient, we were unable to identify a STAT3 mutation. T(H)17 cells were absent or low in the peripheral blood of all patients who were evaluated (n = 17). IL-6-induced STAT3-phosphorylation was consistently reduced in patients with SH2 domain mutations but comparable to normal controls in patients with mutations in the DBD. Heterozygous STAT3 mutations were identified in 34 of 35 unrelated HIES families. Patients had impaired T(H)17 cell development, and those with SH2 domain mutations had reduced STAT3 phosphorylation.


HIV-1 infected monozygotic twins: a tale of two outcomes.
Replicate experiments are often difficult to find in evolutionary biology, as this field is inherently an historical science. However, viruses, bacteria and phages provide opportunities to study evolution in both natural and experimental contexts, due to their accelerated rates of evolution and short generation times. Here we investigate HIV-1 evolution by using a natural model represented by monozygotic twins infected synchronically at birth with an HIV-1 population from a shared blood transfusion source. We explore the evolutionary processes and population dynamics that shape viral diversity of HIV in these monozygotic twins. Despite the identical host genetic backdrop of monozygotic twins and the identical source and timing of the HIV-1 inoculation, the resulting HIV populations differed in genetic diversity, growth rate, recombination rate, and selection pressure between the two infected twins. Our study shows that the outcome of evolution is strikingly different between these two "replicates" of viral evolution. Given the identical starting points at infection, our results support the impact of random epigenetic selection in early infection dynamics. Our data also emphasize the need for a better understanding of the impact of host-virus interactions in viral evolution.


[Patients in general practice who experienced violence or threats from someone they knew well].
Having been exposed to threats or violence often influences health. We explored the association between such experiences and sociodemographic data among patients in general practice. A questionnaire study was conducted. 89 doctors and their patients during one workday were the informants. The patients completed the questionnaire at home. 1,401 consultations were included; 1,217 (87%) patients responded. 14% of the patients said that they experienced violence or threats from someone they knew well, 2% were uncertain. 38% of adult patients in single-parent household had such experiences. The prevalence was also higher among patients with a difficult housing situation, in need of social welfare, who had been unemployed for more than six months, or assessed themselves as more than 50% permanently disabled. 6% of patients 60 years or older had experienced of violence or threats. In general practice, patients with social problems or living in single-parent households more often have experience of violence or threats. Comparatively few elderly people report such experiences.


The needs for diagnostic imaging in cases of group A streptococcal meningitis in children: a case report and review of the literature.
Group A streptococcus (GAS) is a rare cause of bacterial meningitis in children and is associated with a high cerebral complication rate. In this case report, we present a 9-year-old girl with GAS meningitis complicated with cerebritis. Clear guidelines about choice of treatment and indications of follow-up by imaging tests are lacking, making GAS meningitis unpredictable and difficult to treat. Eventually, we found 25 paediatric cases of GAS meningitis presented in the literature and reviewed their treatment choices, outcomes and follow-up by imaging tests. Penicillin and ceftriaxone are most preferred for the treatment of GAS meningitis and adding rifampicin to the antibiotic treatment could be of potential benefit. When considering the duration of antibiotic treatment and follow-up by imaging tests, no clear recommendations were found. We found that GAS meningitis is associated with higher mortality and cerebral complication rates compared to other, more common, bacterial causes of meningitis in children. This should alert the clinician to consider imaging tests routinely, even if the patient improves clinically. We advise clinicians to routinely evaluate for possible cerebral complications through magnetic resonance imaging (MRI) scans. When cerebral complications are found, antibiotic treatment should be prolonged and adding rifampicin to the antibiotic regime may be considered.


Simplifications of the Lorenz attractor.
The Lorenz attractor was once thought to be the mathematically simplest autonomous dissipative chaotic flow, but it is now known that it is only one member of a very large family of such systems, many of which are even simpler. Even the system originally proposed by Lorenz is not in its simplest possible form. This paper will describe a number of simplifications that can be made to the Lorenz system that preserve its dynamics as well as a number of chaotic systems that are much simpler and hence can serve as alternate models of chaos.


Influence of mutation type on clinical expression of Leber hereditary optic neuropathy.
The aim of this research was to determine the molecular factors of influence on the clinical expression of Leber hereditary optic neuropathy (LHON), which might aid in counseling LHON patients and families. The prevalence of LHON in the Dutch population was determined. Observational, retrospective population cohort study. The clinical characteristics of LHON patients of 25 families, previously described in 1963, were reevaluated. The mutation and haplotype were determined in the DNA of one affected LHON patient per family. The genotype of their relatives could be deducted, enabling us to evaluate retrospectively the genotype-phenotype correlation. The prevalence of LHON was determined on the basis of anamnestic evaluation of patients in 1963 and by using population registers of that period. The LHON mutation does not influence disease penetrance (50% in male subjects; 10% to 20% in female subjects). More than half of the patients with the 14484 mutation exhibit a partial recovery of vision, regardless of the acuteness of disease onset (P = .001), whereas only 22% of the 11778 carriers and 15.4% of the 3460 carriers recovered. The recovery did not take place within the first year after onset and was uncommon after four years. The onset of LHON is in general very acute but might be more gradual in 11778 carriers and in children. The calculated prevalence of LHON in the Dutch population (1/39,000) is very likely an underestimation caused by a selection bias of familial cases in the original study. The LHON genotype influences the recovery of vision and disease onset but is unrelated to age, acuteness of onset, or gender. The genotype does not influence disease penetrance. Children might exhibit a slower onset of disease.


Biochemical and structural studies of A-to-I editing by tRNA:A34 deaminases at the wobble position of transfer RNA.
Initial RNA transcription produces several tRNAs (one in prokaryotes and plant chloroplasts and seven or eight in eukaryotes) that contain an adenosine (A) at the wobble position (position 34). However, in all cases, adenosine at position 34 is post-transcriptionally converted to inosine (I), producing mature tRNAs without adenosine at the wobble position. The enzymes responsible for this A-to-I conversion in tRNA are tadA (acting as a homodimer) in prokaryotes and the heterodimeric ADAT2-ADAT3 complex in eukaryotes. The genes encoding these proteins are essential for cell viability, illustrating the biological importance of A-to-I editing at the wobble position of tRNA. In this study, recombinant tadA proteins from Escherichia coli, Agrobacterium tumefaciens, and Aquifex aeolicus, as well as the ADAT2-ADAT3 proteins from Saccharomyces cerevisiae, were overexpressed in E. coli and purified to homogeneity by chromatography. Crystallization of a proteolytically cleaved A. tumefaciens tadA (missing the last eight amino acids at the C-terminus) produced high-quality crystals, and the structure was determined at 1.6 A resolution. In addition, enzymatic assays of the wild-type proteins as well as several mutants were carried out using both the full-length E. coli tRNA(arg2) and the truncated anticodon stem-loop motif as substrates. Our biochemical and structural studies, in combination with sequence and structural comparisons with other deaminases, allow us to propose a model of tadA-tRNA interaction that explains the molecular basis of tRNA recognition by tadA. In particular, a conserved FFxxxR motif at the C-terminus, which is unique to tadA, has been identified, and its critical role in tRNA substrate recognition is proposed. Furthermore, the structural study of prokaryotic tadA presented here also sheds light on tRNA substrate recognition and the possible evolutionary origin of the eukaryotic ADAT2-ADAT3 heterodimer.


Genetic association studies: discovery of the genetic basis of renal disease.
Genetic association studies are a means to investigate the causal role of genes in diseases in order to unravel pathways involved in the etiology of disease. There are two types of genetic association studies: hypothesis-driven studies, i.e. candidate gene studies, targeting genes with a known or presumed role in pathways or diseases of interest, and non-hypothesis-driven studies, i.e. genome-wide association studies, aiming for the discovery of new genetic associations. This educational article is an introduction to genetic association studies for nephrologists and researchers in the domain of kidney disease.


Prevention of doxorubicin myocardial toxicity in mice by reduced glutathione.
The effect of reduced glutathione (GSH) on acute myocardial toxicity due to doxorubicin (DXR) was investigated. At 20 mg/kg i.p. DXR was 100% lethal to BALB/c X DBA/2 F1 mice. At 500 or 1000 mg/kg i.p. GSH significantly decreased the lethality (P less than 0.01). Electron micrographs of the myocardium from DXR-treated mice showed narrowing of myofibrils, edematous cytoplasm, and mitochondrial swelling which were detectable at day 2, was strongest at day 14, but had disappeared by day 56. Light microscopic examination revealed that intercellular spaces between myocardial cells were widened at day 56, indicating shrinking of myocardial cells. These changes were significantly decreased by treatment with GSH (500 mg/kg i.p.). Treatment with DXR (14 mg/kg) significantly decreased myocardial non-protein sulfhydryl content (P less than 0.02) and administration of GSH (500 mg/kg) prevented the drop of non-protein sulfhydryl levels due to DXR treatment. Thus it was considered that administration of exogenous GSH contributes to prevention of the acute myocardial toxicity of DXR by increasing extracellular GSH levels and intracellular GSH synthesis, which detoxifies DXR-oxygen metabolites. The administration of GSH did not interfere with the antineoplastic effect of DXR against L1210 mouse leukemia.


Tissue engineering for cutaneous wounds: selecting the proper time and space for growth factors, cells and the extracellular matrix.
Currently, autografts are the best treatment to any substantial cutaneous injury, and their success is well known as a burn therapy. However, autografts have been less successful in the treatment of chronic ulcers, and are usually a last-resort therapy because of infection at the injured site, high surgical expense, additional morbidity and engraftment failure. In addition, patients with burns covering more than 50% of their skin have limited donor sites for autograft harvest. Therefore, there is a great need for a cost-effective, user-friendly, tissue-engineered construct (TEC) that can provide successful treatments to both acute and chronic wounds in a wider repertoire of patients, including diabetics and the elderly. One approach to the challenge is to create a substitute for skin in vitro that can integrate into the engraftment site in vivo. An alternative is to engineer a biocompatible, resorbable matrix that can recruit the proper, native tissue cells to the injured site and induce them to heal the wound without scarring. This chapter reviews the 3 essential components of cutaneous wound healing, that is, cells, extracellular matrix molecules and bioactive molecules, that must be considered for designing TECs to potentially enhance the healing process. In nature, a 'dynamic reciprocity' exists amongst cells and extracellular matrix that is mediated by bioactive molecules at the site of injury. Thus, it is important to examine the interplay of all 3 components when engineering a TEC. This chapter also includes examples of commercially available products to highlight how researchers have already begun to find success in tissue engineering.


Family therapy for Dutch drug abusers: replication of an American study.
This paper presents the results of an evaluation study conducted in The Netherlands in which an attempt was made to determine the efficacy of family therapy treatment for drug abusers in that country. The theory underlying the approach, as formulated most prominently by Stanton and Todd, is outlined. This study is an attempt to replicate Stanton and Todd's finding that significantly more drug abusers who underwent family therapy would abstain than would clients who received methadone treatment. Stanton and Todd's findings were partly confirmed. As in their study, nearly two-thirds of the clients abstained from heroin and 75% of the clients abstained from illegal use of nonopiates. No significant differences were found, however, between the experimental and the control group in the Dutch study.


The structure of HIV-1 genomic RNA in the gp120 gene determines a recombination hot spot in vivo.
By frequently rearranging large regions of the genome, genetic recombination is a major determinant in the plasticity of the human immunodeficiency virus type I (HIV-1) population. In retroviruses, recombination mostly occurs by template switching during reverse transcription. The generation of retroviral vectors provides a means to study this process after a single cycle of infection of cells in culture. Using HIV-1-derived vectors, we present here the first characterization and estimate of the strength of a recombination hot spot in HIV-1 in vivo. In the hot spot region, located within the C2 portion of the gp120 envelope gene, the rate of recombination is up to ten times higher than in the surrounding regions. The hot region corresponds to a previously identified RNA hairpin structure. Although recombination breakpoints in vivo cluster in the top portion of the hairpin, the bias for template switching in this same region appears less marked in a cell-free system. By modulating the stability of this hairpin we were able to affect the local recombination rate both in vitro and in infected cells, indicating that the local folding of the genomic RNA is a major parameter in the recombination process. This characterization of reverse transcription products generated after a single cycle of infection provides insights in the understanding of the mechanism of recombination in vivo and suggests that specific regions of the genome might be prompted to yield different rates of evolution due to the presence of circumscribed recombination hot spots.


[Biochemical characteristics of traditional Chinese medicine syndromes and their elements in patients with hepatitis B cirrhosis].
To investigate the characteristics of traditional Chinese medicine (TCM) syndromes and their elements in patients with post hepatitic cirrhosis by analyzing the relationships between signs and symptoms and biochemical parameters. A total of 440 patients with hepatitis B cirrhosis treated in Shanghai Public Health Center and Shuguang Hospital, Longhua Hospital and Central Hospital of Putuo District Affiliated to Shanghai University of Traditional Chinese Medicine during January 2002 to January 2006 were enrolled in this study. Signs and symptoms and biochemical information of patients were collected by using a self-designed questionnaire regarding the four examinations of TCM. Signs and symptoms were firstly analyzed to find the frequency of occurrence. Then, the patients were divided into two groups according to non-existent or existent sign and symptom and the correlations between the signs and symptoms which occurred most frequently and their biochemical parameters were analyzed. Sixteen symptoms which occurred most frequently were fatigue, colored urine, liver palms, opaque complexion, string-like pulse, weakness at waist and knees, dry month and bitter taste in the mouth, profuse dreaminess and poor sleepiness, heaviness of limbs, abdominal distention, yellow eyes, fine pulse, impetuosity and susceptibility to rage, splenomegaly, poor appetite, and distension and fullness in the chest and hypochondrium. A previous study on syndrome differentiation of 900 patients with post hepatitic cirrhosis showed 4 syndrome patterns: internal accumulation of dampness-heat, liver-kidney yin deficiency, internal accumulation of blood stasis-heat, and liver depression and spleen deficiency. Further analysis showed that internal accumulation of dampness-heat syndrome was characterized by obvious hepatic inflammation, poor synthesis function and more ascites. Liver-kidney yin deficiency syndrome was characterized by low-level hepatic inflammation, poor synthesis function and more ascites. Internal accumulation of blood stasis-heat syndrome was characterized by low-level hepatic inflammation, poorer synthesis function, ascites and splenomegalia, and liver depression and spleen deficiency syndrome was characterized by slight hepatic inflammation, synthesis function injury, decreased internal portal vein diameter and less ascites. Different syndrome patterns have different pathological features, showing the complexity and polymorphism of syndrome construction.


An intelligent control strategy for computer consultation.
Expert consultant systems often perform computations on a directed graph of associated propositions. Each proposition is represented by a node. Edges connecting these nodes are associated with rules which organize the propositions into antecedent/consequent relationships. A node may be assigned a value through the edges that bind it to its antecedents. Various strategies are employed to determine assignment sequences that result in efficient computer consultation. One such strategy, the merit system, has been successfully implemented in Battle, an expert consultant system for the Marine Corps. The merit strategy enables Battle to focus the consultation process on the most appropriate questions. The merit system, originally defined for logical functions in the Multiple program, has been extended to the Mycin style of propagation and to the method of subjective Bayesian assignments used by Prospector. A procedure for merit calculations with any differentiable, real-valued assignment function is presented. Our experience has shown that merit values provide an efficient flow of control for expert consultation.


A decade of sustained geographic spread of HIV infections among women in Durban, South Africa.
Fine scale geospatial analysis of HIV infection patterns can be used to facilitate geographically targeted interventions. Our objective was to use the geospatial technology to map age and time standardized HIV incidence rates over a period of 10 years to identify communities at high risk of HIV in the greater Durban area. HIV incidence rates from 7557 South African women enrolled in five community-based HIV prevention trials (2002-2012) were mapped using participant household global positioning system (GPS) coordinates. Age and period standardized HIV incidence rates were calculated for 43 recruitment clusters across greater Durban. Bayesian conditional autoregressive areal spatial regression (CAR) was used to identify significant patterns and clustering of new HIV infections in recruitment communities. The total person-time in the cohort was 9093.93 years and 613 seroconversions were observed. The overall crude HIV incidence rate across all communities was 6·74 per 100PY (95% CI: 6·22-7·30). 95% of the clusters had HIV incidence rates greater than 3 per 100PY. The CAR analysis identified six communities with significantly high HIV incidence. Estimated relative risks for these clusters ranged from 1.34 to 1.70. Consistent with these results, age standardized HIV incidence rates were also highest in these clusters and estimated to be 10 or more per 100 PY. Compared to women 35+ years old younger women were more likely to reside in the highest incidence areas (aOR: 1·51, 95% CI: 1·06-2·15; aOR: 1.59, 95% CI: 1·19-2·14 and aOR: 1·62, 95% CI: 1·2-2·18 for < 20, 20-24, 25-29 years old respectively). Partnership factors (2+ sex partners and being unmarried/not cohabiting) were also more common in the highest incidence clusters (aOR 1.48, 95% CI: 1.25-1.75 and aOR 1.54, 95% CI: 1.28-1.84 respectively). Fine geospatial analysis showed a continuous, unrelenting, hyper HIV epidemic in most of the greater Durban region with six communities characterised by particularly high levels of HIV incidence. The results motivate for comprehensive community-based HIV prevention approaches including expanded access to PrEP. In addition, a higher concentration of HIV related services is required in the highest risk communities to effectively reach the most vulnerable populations.


Clinical features, etiology and outcomes of community-acquired pneumonia in patients with chronic obstructive pulmonary disease.
Community-acquired pneumonia (CAP) is a frequent complication of chronic obstructive pulmonary disease (COPD), but previous studies are often contradictory. We aimed to ascertain the characteristics and outcomes of CAP in patients with COPD as well as to determine the risk factors for mortality and Pseudomonas aeruginosa pneumonia in COPD patients with CAP. We also describe the etiology and outcomes of CAP in COPD patients receiving chronic oxygen therapy at home and those receiving inhaled steroids. An observational analysis of a prospective cohort of hospitalized adults with CAP (1995-2011) was performed. We documented 4121 CAP episodes, of which 983 (23.9%) occurred in patients with COPD; the median FEV1 value was 50%, and 57.8% were classified as stage III or IV in the GOLD classification. Fifty-eight per cent of patients were receiving inhaled steroids, and 14.6% chronic oxygen therapy at home. Patients with COPD presented specific clinical features. S. pneumoniae was the leading causative organism overall, but P. aeruginosa was more frequent in COPD (3.4 vs. 0.5%; p<0.001). Independent risk factors for case-fatality rate in patients with COPD were multilobar pneumonia, P. aeruginosa pneumonia, and high-risk PSI classes. Prior pneumococcal vaccination was found to be protective. FEV1 was an independent risk factor for P. aeruginosa pneumonia. CAP in patients with COPD presents specific characteristics and risk factors for mortality. Prior pneumococcal vaccine has a beneficial effect on outcomes. P. aeruginosa pneumonia is associated with low FEV1 values and poor prognosis.


Indocyanine green-sulfobromophthalein pharmacokinetics for diagnosing primary biliary cirrhosis and assessing histological severity.
Primary biliary cirrhosis (PBC) is a chronic cholestatic disease in which there is a crucial need for quantitative liver-function tests. We have developed a mixed sulfobromophthalein (BSP)-indocyanine green (ICG) test and have applied it to 15 healthy subjects and 50 patients with PBC to determine its relevance to the histological severity of the disease. The two dyes were administered intravenously and sequentially as boluses. Plasma concentrations were measured over 60 min. Pharmacokinetic analysis of the plasma elimination curve permitted the calculation of clearance, constants k1 and k2, and the retention percentage at 45 min. In PBC patients, ICG kinetics were within the normal range except for those with stage IV disease (cirrhosis). BSP clearance and the k2 constant were reduced in all the patients, whereas the k1 constant was reduced only in stage III and IV disease. The BSP retention percentage at 45 min was highly correlated with histological stage (r = 0.89, P less than 0.001). The BSP-ICG mixed test may thus prove useful in the diagnosis and follow-up of patients with PBC.


Alcohol-induced impairment of behavioral control: effects on the alteration and suppression of prepotent responses.
Alcohol use in humans is associated with aggression and other socially inappropriate behaviors. These adverse effects have been attributed to an acute impairment of behavioral control, and research findings indicate that inhibitory aspects of behavioral control might be particularly vulnerable to the effects of alcohol. The present study tested the degree to which alcohol-induced impairment of behavioral control is due to a specific impairment of inhibitory mechanisms or due to a general information processing deficit. Forty subjects (29 men) performed a cued reaction time task before and after receiving 0.65 g/kg alcohol or a placebo. Subjects performed the task under conditions that differed in the type of response needed to maintain behavioral control: response-suppression and response-alteration. Alcohol impairment was observed when behavioral controlwas dependent on response-suppression, but no impairment was observed when control relied on response-alteration. The findings point to the susceptibility of inhibitory processes by showing that alcohol can be particularly detrimental to behavioral control in situations where prepotent responses must be completely suppressed. Evidence for alcohol-induced impairment of inhibitory functions could provide important clues about basic behavioral mechanisms by which alcohol disrupts such higher order cognitive processes as working memory, learning and decision making.


Arsenic exposure and the induction of human cancers.
Arsenic is a metalloid, that is, considered to be a human carcinogen. Millions of individuals worldwide are chronically exposed through drinking water, with consequences ranging from acute toxicities to development of malignancies, such as skin and lung cancer. Despite well-known arsenic-related health effects, the molecular mechanisms involved are not fully understood; however, the arsenic biotransformation process, which includes methylation changes, is thought to play a key role. This paper explores the relationship of arsenic exposure with cancer development and summarizes current knowledge of the potential mechanisms that may contribute to the neoplastic processes observed in arsenic exposed human populations.


DNA damage predicts prognosis and treatment response in colorectal liver metastases superior to immunogenic cell death and T cells.
Preclinical models indicate that DNA damage induces type I interferon (IFN), which is crucial for the induction of an anti-tumor immune response. In human cancers, however, the association between DNA damage and an immunogenic cell death (ICD), including the release and sensing of danger signals, the subsequent ER stress response and a functional IFN system, is less clear. Methods: Neoadjuvant-treated colorectal liver metastases (CLM) patients, undergoing liver resection in with a curative intent, were retrospectively enrolled in this study (n=33). DNA damage (γH2AX), RNA and DNA sensors (RIG-I, DDX41, cGAS, STING), ER stress response (p-PKR, p-eIF2α, CALR), type I and type II IFN- induced proteins (MxA, GBP1), mature dendritic cells (CD208), and cytotoxic and memory T cells (CD3, CD8, CD45RO) were investigated by an immunohistochemistry whole-slide tissue scanning approach and further correlated with recurrence-free survival (RFS), overall survival (OS), radiographic and pathologic therapy response. Results: γH2AX is a negative prognostic marker for RFS (HR 1.32, 95% CI 1.04-1.69, p=0.023) and OS (HR 1.61, 95% CI 1.23-2.11, p<0.001). A model comprising of DDX41, STING and p-PKR predicts radiographic therapy response (AUC=0.785, p=0.002). γH2AX predicts prognosis superior to the prognostic value of CD8. CALR positively correlates with GBP1, CD8 and cGAS. A model consisting of γH2AX, p-eIF2α, DDX41, cGAS, CD208 and CD45RO predicts pathological therapy response (AUC=0.944, p<0.001). Conclusion: In contrast to preclinical models, DNA damage inversely correlated with ICD and its associated T cell infiltrate and potentially serves as a therapeutic target in CLM.


What can we learn from synaptic weight distributions?
Much research effort into synaptic plasticity has been motivated by the idea that modifications of synaptic weights (or strengths or efficacies) underlie learning and memory. Here, we examine the possibility of exploiting the statistics of experimentally measured synaptic weights to deduce information about the learning process. Analysing distributions of synaptic weights requires a theoretical framework to interpret the experimental measurements, but the results can be unexpectedly powerful, yielding strong constraints on possible learning theories as well as information that is difficult to obtain by other means, such as the information storage capacity of a cell. We review the available experimental and theoretical techniques as well as important open issues.


Using expert knowledge for test linking.
Linking and equating procedures are used to make the results of different test forms comparable. In the cases where no assumption of random equivalent groups can be made some form of linking design is used. In practice the amount of data available to link the two tests is often very limited due to logistic and security reasons, which affects the precision of linking procedures. This study proposes to enhance the quality of linking procedures based on sparse data by using Bayesian methods which combine the information in the linking data with background information captured in informative prior distributions. We propose two methods for the elicitation of prior knowledge about the difference in difficulty of two tests from subject-matter experts and explain how these results can be used in the specification of priors. To illustrate the proposed methods and evaluate the quality of linking with and without informative priors, an empirical example of linking primary school mathematics tests is presented. The results suggest that informative priors can increase the precision of linking without decreasing the accuracy. (PsycINFO Database Record


The demographic basis of population regulation in columbian ground squirrels.
Environmental factors influence the dynamics and regulation of biological populations through their influences on demographic variables, but demographic mechanisms of population regulation have received little attention. We investigated the demographic basis of regulation of Columbian ground squirrel (Spermophilus columbianus) populations under natural and experimentally food-supplemented conditions. Food supplementation caused substantial increases in population density, and population densities returned to pretreatment levels when the supplementation ended. Control (untreated) populations remained relatively stable throughout the study period (1981-1986). Because food resources regulated the size of the ground squirrel populations, we used life-table response experiment (LTRE) analyses to examine the demographic basis of changes in population growth rate and thus also demographic influences on population regulation. LTRE analyses of two food-manipulated populations revealed that changes in age at maturity and fertility rate of females generally made the largest contributions to observed changes in population growth rate. Thus, our results suggested that abundance of food resources regulated the size of our study populations through the effects of food resources on age at maturity and fertility rates. Our results also indicated that different demographic mechanisms can underlie population regulation under different environmental conditions, because lower juvenile survival substantially contributed to population decline, but in only one of the populations. Demographic analyses of experimental data, such as those presented here, offer a rigorous and unambiguous means to elucidate the demographic basis of population regulation and to help identify environmental factors that underlie dynamics and regulation of biological populations.


Heterogeneous distribution of a basement membrane heparan sulfate proteoglycan in rat tissues.
A heparan sulfate proteoglycan (HSPG) synthesized by murine parietal yolk sac (PYS-2) cells has been characterized and purified from culture supernatants. A monospecific polyclonal antiserum was raised against it which showed activity against the HSPG core protein and basement membrane specificity in immunohistochemical studies on frozen tissue sections from many rat organs. However, there was no reactivity with some basement membranes, notably those of several smooth muscle types and cardiac muscle. In addition, it was found that pancreatic acinar basement membranes also lacked the HSPG type recognized by this antiserum. Those basement membranes that lacked the HSPG strongly stained with antisera against laminin and type IV collagen. The striking distribution pattern is possibly indicative of multiple species of basement membrane HSPGs of which one type is recognized by this antiserum. Further evidence for multiple HSPGs was derived from the finding that skeletal neuromuscular junction and liver epithelia also did not contain this type of HSPG, though previous reports have indicated the presence of HSPGs at these sites. The PYS-2 HSPG was shown to be antigenically related to the large, low buoyant density HSPG from the murine Engelbreth-Holm swarm tumor. It was, however, confirmed that only a single population of antibodies was present in the serum. Despite the presence of similar epitopes on these two proteoglycans of different hydrodynamic properties, it was apparent that the PYS-2 HSPG represents a basement membrane proteoglycan of distinct properties reflected in its restricted distribution in vivo.


Progress in Brain Computer Interface: Challenges and Opportunities.
Brain computer interfaces (BCI) provide a direct communication link between the brain and a computer or other external devices. They offer an extended degree of freedom either by strengthening or by substituting human peripheral working capacity and have potential applications in various fields such as rehabilitation, affective computing, robotics, gaming, and neuroscience. Significant research efforts on a global scale have delivered common platforms for technology standardization and help tackle highly complex and non-linear brain dynamics and related feature extraction and classification challenges. Time-variant psycho-neurophysiological fluctuations and their impact on brain signals impose another challenge for BCI researchers to transform the technology from laboratory experiments to plug-and-play daily life. This review summarizes state-of-the-art progress in the BCI field over the last decades and highlights critical challenges.


Room-Temperature Magnetic Bistability in Organic Radical Crystals.
A large first-order magnetic phase transition in an organic radical, 1,3,5-trithia-2,4,6-triazapentalenyl, is described. The transition occurs with a wide thermal hysteresis loop over the temperature range 230 to 305 kelvin. The high-temperature phase is paramagnetic, and its structure consists of a uniform one-dimensional stacking of the radical. The low-temperature phase is diamagnetic because of strong dimerization along the stacking direction. The results may have applications in thermal sensors, switching units, and information storage media based on organic radical crystals.


Dose-dependent exacerbation of ventilation-induced lung injury by erythropoietin in preterm newborn lambs.
Erythropoietin (EPO) is being trialled in preterm infants to reduce brain injury, but high doses increase lung injury in ventilated preterm lambs. We aimed to determine whether early administration of lower doses of EPO could reduce ventilation-induced lung injury and systemic inflammation in preterm lambs. Ventilation was initiated in anaesthetized preterm lambs [125 ± 1 (SD) days gestation] using an injurious strategy for the first 15 min. Lambs were subsequently ventilated with a protective strategy for a total of 2 h. Lambs were randomized to receive either intravenous saline (Vent; n = 7) or intravenous 300 ( n = 5), 1,000 (EPO1000; n = 5), or 3,000 (EPO3000; n = 5) IU/kg of human recombinant EPO via an umbilical vein. Lung tissue was collected for molecular and histological assessment of inflammation and injury and compared with unventilated control lambs (UVC; n = 8). All ventilated groups had similar blood gas and ventilation parameters, but EPO1000 lambs had a lower fraction of inspired oxygen requirement and lower alveolar-arterial difference in oxygen. Vent and EPO lambs had increased lung interleukin (IL)-1β, IL-6, and IL-8 mRNA, early lung injury genes connective tissue growth factor, early growth response protein 1, and cysteine-rich 61, and liver serum amyloid A3 mRNA compared with UVCs; no difference was observed between Vent and EPO groups. Histological lung injury was increased in Vent and EPO groups compared with UVCs, but EPO3000 lambs had increased lung injury scores compared with VENT only. Early low-doses of EPO do not exacerbate ventilation-induced lung inflammation and injury and do not provide any short-term respiratory benefit. High doses (≥3,000 IU/kg) likely exacerbate lung inflammation and injury in ventilated preterm lambs. NEW & NOTEWORTHY Trials are ongoing to assess the efficacy of erythropoietin (EPO) to provide neuroprotection for preterm infants. However, high doses of EPO increase ventilation-induced lung injury (VILI) in preterm lambs. We investigated whether early lower doses of EPO may reduce VILI. We found that lower doses did not reduce, but did not increase, VILI, while high doses (≥3,000 IU/kg) increase VILI. Therefore, lower doses of EPO should be used in preterm infants, particularly those receiving respiratory support.


Tolerance and efficacy of polyethylene glycol 3350/electrolyte solution versus lactulose in relieving opiate induced constipation: a double-blinded placebo-controlled trial.
Chronicity and high therapeutic cost prompted this study to determine a cost-effective and efficacious regimen in treating narcotic-induced constipation. The efficacy of lactulose was compared with polyethylene glycol 3350/electrolyte solution for relief of methadone-induced constipation. This was a randomized, triple cross-over after control run-in (no treatment) study conducted at a methadone maintenance program in Baltimore, Maryland in 57 patients who are affected by opiate-induced constipation. The study was measured by self-reported frequencies, consistency, and ease of defecation during a 1 week run-in control period, followed by 3 treatment phases of 2 weeks each. Polyethylene glycol 3350/electrolyte solution and lactulose produced more "nonhard" stools than the placebo (P < 0.01) and control (P < 0.003). Polyethylene glycol 3350/electrolyte solution produced the loosest stool (P < 0.0001) compared with the control, whereas lactulose had the most adverse effects. There were no significant differences in reducing hard stool formation in either experimental group, but both were better than having nothing or just the placebo. Polyethylene glycol/electrolyte solution resulted in the loosest (diarrheal) stool. It is also likely that polyethylene glycol/electrolyte solution is the most cost effective.