Synthesis of fluorescent Molecularly Imprinted Polymer Nanoparticles Sensing Small Neurotransmitters with High Selectivity Using Immobilized Templates with Regulated Surface Density.
To develop nanosensors to probe neurotransmitters, we synthesized fluorescent-functionalized molecularly imprinted polymeric nanoparticles (fMIP-NPs) using monoamine neurotransmitters (serotonin and dopamine) immobilized on glass beads as templates. The size and fluorescence intensity of the fMIP-NPs synthesized with blended silane couplers increased with the presence of the target but were insensitive to the target analogs (L-tryptophan and L-dopa, respectively). However, when the template is anchored by a pure silane agent, both the fluorescence intensity and particle size of the fMIP-NPs were sensitive to the structural analog of the template. Another fMIP-NP was synthesized in the presence of poly([2-(methacryloyloxy)ethyl] trimethylammonium chloride (METMAC)-co-methacrylamide) grafted onto glass beads as a dummy template for acetylcholine. Acetylcholine increased the diameter and fluorescence intensity of the fMIP-NP, but choline had no effect. When the homopolymer of METMAC was used as a template, the fluorescence intensity and size of the resulting nanoparticles were not responsive to either acetylcholine or choline. The principle of increased fluorescence intensity due to specific interaction with the target substance is probably due to the increased distance between the fluorescent functional groups and decreased self-quenching due to the swelling caused by the specific interaction with the template. The results also indicate that MIP nanoparticles prepared by solid-phase synthesis can be used for targeting small molecules, such as the neurotransmitters addressed in this study, by adjusting the surface density of the template.


Low-Profile Visualized Intraluminal Support Junior Flow-Diversion Properties Used for Stabilization of a Superior Cerebellar Artery Pseudoaneurysm.
Pseudoaneurysms of the posterior circulation pose a unique management challenge. The fragile nature of the pseudoaneurysm wall presents a high risk of rupture and demands treatment. Small vasculature, particularly distal in the posterior circulation, can preclude management with traditional flow diverters, where the alternative of vessel sacrifice is unacceptable. Small stents can have flow-diversion properties and can be used in these high-risk, difficult-to-access aneurysms. We describe a 40-year-old woman presenting with a ruptured dissecting right superior cerebellar artery pseudoaneurysm after minor trauma. Given the aneurysm's small size and morphology, it was not amenable to coiling and parent vessel sacrifice was potentially morbid. The pseudoaneurysm was initially stabilized with a Low-Profile Visualized Intraluminal Support Junior (LVIS Jr.) stent due to its reported flow-diverting properties. At six-month follow-up the pseudoaneurysm was stable and the vasospasm had resolved. At this point, definitive treatment with a "FRED Jr." (Flow Re-Direction Endoluminal Device Junior) flow diverter was pursued. Complete obliteration of the pseudoaneurysm was seen at 12 months' follow-up after staged treatment. Due to the unique challenges associated with ruptured pseudoaneurysms located on small-caliber vessels, the options for definitive treatment are limited. The small size of the LVIS Jr. stent and its flow-diverting properties make it a practical treatment option in a difficult situation. This case report provides further support for the flow-diverting properties of the LVIS Jr. and its potential application in the treatment of ruptured pseudoaneurysms in small-caliber intracranial vessels.


Utility of intra-operative capnogram to detect branch pulmonary artery obstruction following total correction of tetralogy of Fallot.
Branch pulmonary artery obstruction is one of the prime reasons for re-operation in patients who have undergone repair for tetralogy of Fallot. Branch pulmonary artery obstruction may develop over a period of time due to dilation of right ventricular outflow tract or it may be caused by residual stenosis after inadequate repair. This may lead to differential lung perfusion causing morbidity. Intra-operative capnogram monitoring reveals ventilation-perfusion relationship. We report two cases where the capnogram helped the diagnosis and management of branch pulmonary artery obstruction. We found a redundant patch in the first and an extra length of the homograft in second case which led to the obstruction. However, but for the changes in the intraoperative capnogram, this condition may by far remain undiagnosed considering the fact that it does not produce hemodynamic changes but can lead to postoperative morbidity.


[Overdose statistics--a complicated account].
Norwegian media often claim that a disproportionately high number of deaths in Norway are caused by overdoses. The police statistics in 2007 showed an increase in the number of overdose deaths, and many media postings focused on this in autumn 2008. In this paper we investigate the basis for those police statistics and discuss problems associated with calculating deaths caused by use of illegal substances. The police registries of overdose deaths were anonymized in the period 2005-2007. The deaths were coded according to type of substance involved. In 2007, 62 deaths were coded as overdose deaths without any use of illegal substances; in 2005 this was the case for 24 deaths and in 2006 for 25. The maximum proportions of deaths in Oslo that can be related to heroine were 91.7 % in 2006 and 57.8 % in 2007. In the rest of the country the corresponding numbers were 68.8 % and 62.2 %. A considerable number of deaths without use of illegal drugs are counted as overdose deaths. The increase found in Norway in 2007 is largely explained by changes in registration routines in Oslo. The high number of overdose deaths can partly be explained by methodological problems with registration. Nevertheless, the number of overdose deaths is high and of major concern. Causes of deaths should be discriminated better in the overdose statistics in order to improve the preventive strategies.


Structural relationship between DNA polymerases epsilon and epsilon* and their occurrence in eukaryotic cells.
Monoclonal antibodies raised against the N-terminal half of human DNA polymerase epsilon bind both to a large > 200 kDa form of DNA polymerase epsilon from HeLa cells and to a small 140 kDa form (DNA polymerase epsilon*) from calf thymus, while antibody against the C-terminal half binds to DNA polymerase epsilon but does not bind to DNA polymerase epsilon*. These results indicate that the two enzymes have common structural motifs in their N-terminal halves, and that DNA polymerase epsilon* is very likely derived from DNA polymerase epsilon by removal of its C-terminal half. DNA polymerase epsilon as well as DNA polymerase epsilon* was detected in extracts from cells of numerous eukaryotic species from yeast to human. The results indicate that DNA polymerase epsilon and its tendency to occur in a smaller form, DNA polymerase epsilon*, are evolutionarily highly conserved and that DNA polymerase epsilon may occur universally in proliferating eukaryotic cells.


Ketamine and the arrhythmogenic dose of epinephrine in cats anesthetized with halothane and isoflurane.
Epinephrine-induced arrhythmias were studied in 4 cats (group A), using a 4 X 4 Latin square design. Each cat was anesthetized 4 times, 1 week apart, with halothane (1.5% end expired), isoflurane (2.0% end expired), and halothane or isoflurane preceded by ketamine administered IM (8.8 mg/kg). Lead II of the ECG and femoral artery pressure were recorded. Epinephrine was infused in progressively doubled rates (initial rate = 0.125 micrograms/kg/min) for a maximum of 2.5 minutes or until at least 4 ventricular premature depolarizations occurred within 15 s of each other. The arrhythmogenic dose of epinephrine (ADE; micrograms/kg) was calculated as the product of infusion rate and time to arrhythmia. The ADE (means +/- SD) during anesthesia with halothane alone and with ketamine-halothane anesthesia were 1.33 +/- 0.65 and 1.37 +/- 0.59 micrograms/kg, respectively; during anesthesia with isoflurane alone and ketamine-isoflurane anesthesia, the ADE were 9.34 +/- 1.29 and 16.16 +/- 3.63 micrograms/kg, respectively. The ADE was significantly greater (P less than 0.05) during isoflurane anesthesia and ketamine-isoflurane anesthesia than during halothane anesthesia. The percentages of change in systolic blood pressure (means +/- SD) at the ADE during halothane, ketamine-halothane, isoflurane, and ketamine-isoflurane were 31 +/- 34, 41 +/- 17, 127 +/- 27, and 148 +/- 57, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Women's experiences of lymphedema.
To explore women's experiences of lymphedema. Qualitative descriptive. An urban community in the midwestern United States. Ten women who experienced lymphedema after breast cancer treatment and who had (a) completed their treatment for stage I or stage II breast cancer at least one year before the study, (b) experienced an onset of lymphedema at least two months after surgery, (c) no current evidence of cancer disease or cancer recurrence, (d) lymphedema not caused by cancer in the brachial plexus, and (e) no history of hospitalization for alcoholism, substance abuse, or psychiatric conditions. The women ranged in age from 36-75 years. Mean survival time was seven years, and the mean time since onset of lymphedema was four years. Two in-depth interviews per participant. Most women were able to continue living their normal lives. Some women experienced depression, anxiety, and impairments related to their intimate, work, and social relationships. Physicians' limited knowledge about lymphedema, conflicting treatment information, and the limited number of available treatment centers caused distress for the participants. Their experiences can be categorized into three predominant themes: Abandonment by Medicine, Concealing the imperfect image, and Living the Interrupted Life. Research efforts to expand the knowledge base regarding the epidemiology, prevention, and treatment of lymphedema are needed. Also needed is research that explores the impact of lymphedema on quality of life and functional ability as well as the psychosocial impact of lymphedema on body image, self esteem, and social support. Care providers and breast cancer survivors should be educated about the prevention and treatment of lympedema. Nurses should refer patients to advocacy hot lines and support groups for information and support when appropriate. Women with lymphedema should be assessed periodically for psychosocial distress and referred for care as needed.


Phospholipid transfer protein activity and incident type 2 diabetes mellitus.
The plasma activity of phospholipid transfer protein (PLTP), which has multifaceted functions in lipoprotein metabolism and in inflammatory responses, is elevated in insulin resistant conditions. We determined the association of plasma PLTP activity with incident type 2 diabetes mellitus (T2DM). Plasma PLTP activity was determined using a liposome vesicle-HDL system in 218 men without T2DM at baseline. We used logistic regression models to establish odds ratios (ORs) for incident T2DM. Twenty four men developed T2DM over 9.4-year follow-up. Plasma PLTP activity was higher in incident T2DM cases (p=0.009). We observed 82% higher odds for T2DM per 1-SD increase in PLTP activity. Multivariable modeling showed that the association of PLTP activity with T2DM was independent of clinical risk factors including age, and either the metabolic syndrome, individual metabolic syndrome components, total cholesterol, HOMA-IR or albuminuria (ORs ranging from 1.64 (95% CI 1.03-2.66) to 1.87 (1.19-3.010)). Elevated plasma PLTP activity may predict an increased risk of T2DM in men.


Cavum septum pellucidum in schizophrenia: a case report.
Different structural alterations of the central nervous system (CNS), such as an increase in ventricular size, decrease in hippocampus and amygdala volume, and other abnormalities that are probably secondary to a loss of neuronal mass and neuropili (axons and dendrite ramifications) linked to a precocious alteration in neurodevelopment are described in patients with schizophrenia in greater proportion than in the general population. The cavum septum pellucidum is among the alterations whose role in the disease is more unknown, since the cavity between the two septum laminae draws attention in very few cases. According to several studies, this alteration is more frequent in patients with schizophrenia than in healthy subjects and currently its association to the disease is being studied. In the following, we present the case of a 37 year old patient with no outstanding background, who was admitted to our psychiatry department due to psychotic symptoms.


Chair design and the anesthesia provider.
Anesthesia providers spend a considerable amount of time sitting in poorly designed chairs. In the majority of hospitals, anesthesia providers are reluctant to request ergonomically designed chairs for the operating room. Multiple studies have given conclusive evidence that properly designed chairs reduce low back pain, improve lower extremity circulation, and relieve muscle tension, thus increasing overall comfort. Continual use of poorly designed chairs and stools in the operating room will cause eventual health complaints. Ergonomically designed chairs will be a wise purchase for the anesthesia provider, especially those who are aging or have physical complaints related to the back, muscle tension, and other lower extremity problems.


Oxcarbazepine in bipolar disorder: a critical review of the literature.
Oxcarbazepine (OXC) is a keto-congener of carbamazepine, which has fewer side effects and drug interactions. However, the efficacy of OXC in treating bipolar disorder is not as well established as that of carbamazepine. This article is a systematic literature review of all studies regarding OXC and bipolar disorders, with particular attention to papers published in the last 6 years. Using the terms 'oxcarbazepine and bipolar disorder', 'oxcarbazepine and mania' or 'oxcarbazepine and bipolar depression', a computer-aided search of MEDLINE for the years 2000-2006 has been conducted. Since its introduction as an antiepileptic drug in early 2000, clinical research regarding the potential role of OXC in the treatment of bipolar disorder remains limited. There is a lack of double-blind, placebo-controlled studies. Studies recently published have small samples of patients, with insufficient follow-up periods and other methodological weaknesses. The efficacy of OXC in bipolar disorder has not been widely studied. Some authors recommend using OXC as monotherapy or as add-on therapy in refractory mania, although results are not conclusive. It is unknown whether OXC has efficacy in the maintenance treatment of bipolar disorder. OXC can be particularly useful as an add-on treatment in bipolar disorder patients for whom previous treatments have failed, or in patients who have difficulty tolerating adequate dosages of standard approved treatments.


Circadian and estrous cycle-dependent variations in blood pressure and heart rate in female rats.
To determine whether cardiovascular functions are controlled by the endogenous circadian system and whether they change with the estrous cycle in female rats, we measured mean arterial pressure (MAP), heart rate (HR), and spontaneous activity (ACT) of female rats using an implantable radiotelemetry device and a computerized data-collecting system. Under a 12:12-h light-dark (LD) cycle, these parameters exhibited daily rhythms that were entrained to the photic cycle. The patterns of the daily rhythms varied with estrous cycles, and variations were particularly marked in the proestrous stage. During the dark period of this stage, ACT levels were significantly higher, but HR was significantly lower than in other stages. Although the peak MAP occurred within 2 h after the onset of the dark phase in three of the estrous stages, it occurred around midnight in the proestrous stage. Such estrous cycle-dependent variations were eliminated by ovariectomy. The implantation of 17 beta-estradiol produced a gradual increase in MAP and an abrupt decrease in HR. During constant darkness, all three parameters were free running, maintaining the same internal phase relationships with each other as during LD cycles. These results indicate that daily variations in these parameters were controlled by the endogenous circadian oscillating system, that they vary with the estrous cycle in female rats, and that estrogen may be responsible for these estrous cycle-dependent variations.


Glial cells and chronic pain.
Over the past few years, the control of pain exerted by glial cells has emerged as a promising target against pathological pain. Indeed, changes in glial phenotypes have been reported throughout the entire nociceptive pathway, from peripheral nerves to higher integrative brain regions, and pharmacological inhibition of such glial reactions reduces the manifestation of pain in animal models. This complex interplay between glia and neurons relies on various mechanisms depending both on glial cell types considered (astrocytes, microglia, satellite cells, or Schwann cells), the anatomical location of the regulatory process (peripheral nerve, spinal cord, or brain), and the nature of the chronic pain paradigm. Intracellularly, recent advances have pointed to the activation of specific cascades, such as mitogen-associated protein kinases (MAPKs) in the underlying processes behind glial activation. In addition, given the large number of functions accomplished by glial cells, various mechanisms might sensitize nociceptive neurons including a release of pronociceptive cytokines and neurotrophins or changes in neurotransmitter-scavenging capacity. The authors review the conceptual advances made in the recent years about the implication of central and peripheral glia in animal models of chronic pain and discuss the possibility to translate it into human therapies in the future.


Simple modifications in operating room processes to reduce the times and costs associated with robot-assisted laparoscopic radical prostatectomy.
Robot-assisted laparoscopic radical prostatectomy (RALRP) is the most expensive, yet most common, surgical treatment for patients with prostate cancer. Furthermore, its popularity continues to grow despite the lack of evidence for functional and oncologic superiority over other treatments. As a result, we modified operating room (OR) processes to determine if the times and costs that are associated with RALRP in an academic setting could be reduced. Four modifications in OR processes were implemented: Trainee adherence to time-oriented surgical goals; use of a dedicated anesthesia team; simultaneous processing by nursing and urology house staff during case turnover; and identification and elimination of unused disposable instruments. Total surgical, anesthesia, and OR turnover times were measured. Payroll, surgical supply, OR time, and anesthesia costs were also measured. One hundred RALRP cases before and after the modifications were implemented were compared. Patients undergoing RALRP were similar both before and after the modifications were implemented. Total surgical, anesthesia, and turnover times were reduced by 17.4 (6.8%, P=0.041), 4.5 (19.1%, P=0.006), and 12.1 (28.1%, P=0.005) minutes, respectively. Payroll, surgical supply, and OR costs were reduced by $330 (25%), $609 (15.7%), and $1638 (27.7%), respectively. There was no fiscally significant change in anesthesia costs. Using simple modifications, it is possible that RALRP efficiency can be improved by decreasing its associated times and costs. These modifications were implemented in an academic setting but may be used in any institution. These modifications represent an initial attempt to improve RALRP cost-competitiveness with other treatment modalities.


Use of physiologically relevant biopharmaceutics tools within the pharmaceutical industry and in regulatory sciences: Where are we now and what are the gaps?
Regulatory interactions are an important part of the drug development and licensing process. A survey on the use of biopharmaceutical tools for regulatory purposes has been carried out within the industry community of the EU project OrBiTo within Innovative Medicines Initiative (IMI). The aim was to capture current practice and experience in using in vitro and in silico biopharmaceutics tools at various stages of development, what barriers exist or are perceived, and to understand the current gaps in regulatory biopharmaceutics. The survey indicated that biorelevant dissolution testing and physiologically based modelling and simulation are widely applied throughout development to address a number of biopharmaceutics issues. However, data from these in vitro and in silico predictive biopharmaceutics tools are submitted to regulatory authorities far less often than they are used for internal risk assessment and decision making. This may prevent regulators from becoming familiar with these tools and how they are applied in industry, and limits the opportunities for biopharmaceutics scientists working in industry to understand the acceptability of these tools in the regulatory environment. It is anticipated that the advanced biopharmaceutics tools and understanding delivered in the next years by OrBiTo and other initiatives in the area of predictive tools will also be of value in the regulatory setting, and provide a basis for more informed and confident biopharmaceutics risk assessment and regulatory decision making. To enable the regulatory potential of predictive biopharmaceutics tools to be realized, further scientific dialogue is needed between industry, regulators and scientists in academia, and more examples need to be published to demonstrate the applicability of these tools.


Acute toxicity study of a simian immunodeficiency virus-based lentiviral vector for retinal gene transfer in nonhuman primates.
A phase 1 clinical trial evaluating the safety of gene therapy for patients with wet age-related macular degeneration (AMD) or retinoblastoma has been completed without problems. The efficacy of gene therapy for Leber's congenital amaurosis (LCA) was reported by three groups. Gene therapy may thus hold promise as a therapeutic method for the treatment of intractable ocular diseases. However, it will first be important to precisely evaluate the efficiency and safety of alternative gene transfer vectors in a preclinical study using large animals. In the present study, we evaluated the acute local (ophthalmic) and systemic toxicity of our simian immunodeficiency virus from African green monkeys (SIVagm)-based lentiviral vectors carrying human pigment epithelium-derived factor (SIV-hPEDF) for transferring genes into nonhuman primate retinas. Transient inflammation and elevation of intraocular pressure were observed in some animals, but these effects were not dose dependent. Electroretinograms (ERGs), including multifocal ERGs, revealed no remarkable change in retinal function. Histopathologically, SIV-hPEDF administration resulted in a certain degree of inflammatory reaction and no apparent structural destruction in retinal tissue. Regarding systemic toxicity, none of the animals died, and none showed any serious side effects during the experimental course. No vector leakage was detected in serum or urine samples. We thus propose that SIVagm-mediated stable gene transfer might be useful and safe for ocular gene transfer in a clinical setting.


Auditory steady-state EEG response across the schizo-bipolar spectrum.
Deviant auditory steady-state responses (aSSRs) in the gamma range (30-90 Hz) may be translational biomarkers for schizophrenia (SZ). This study tests whether aSSR deviations are (i) specific to SZ across the psychosis dimension, (ii) specific to particular frequency bands, and (iii) present in bipolar I disorder without psychosis (BDNP). Beta (20-), low- (40-), and high-gamma (80-Hz) aSSRs were measured with EEG and compared across 113 SZ, 105 schizoaffective disorder (SAD), 99 bipolar disorder with psychosis (BDP), 68 BDNP, and 137 healthy comparison subjects (HC). Standard aSSR measures (single-trial power [STP] and inter-trial phase coherence [ITC]), as well as evoked responses to stimulus onsets/offsets and pre-stimulus power, were quantified. Multivariate canonical discriminant analysis was used to summarize variables that efficiently and maximally differentiated groups. (i) Psychosis groups showed reduced responses on ITC 20 Hz, STP/ITC 40 Hz, STP/ITC 80 Hz, indicating dimensional reductions in aSSR across the psychosis spectrum not specific to aSSR frequency. For the 40- and 80-Hz ITCs there was greater reduction in SZ compared to SAD, possibly indexing cortical disruptions linked to psychosis without mood symptoms. (ii) All probands had elevated pre-stimulus power, possibly compromising neural entrainment to the steady-state stimuli. (iii) Onset/Offset and 80 Hz ITC responses were most important for group discrimination and showed dimensional reduction across the schizo-bipolar spectrum. Deviant aSSRs were found across the schizo-bipolar spectrum at multiple frequencies with psychosis status and severity linked to greatest reductions at low and high gamma.


[Usefulness of the Laser FLare Cell Meter (LFCM, Kowa FC-1000) for evaluating inflammation of the anterior chamber in clinical practice].
The Laser Flare Cell Meter (LFCM, Kowa FC-1000), an instrument measuring aqueous flare and cells in a quantitative, objective and non-invasive way, has been mainly used so far to measure inflammation in clinical and experimental research. In the light of some illustrative examples, its practical clinical usefulness is presented; the LFCM was found to be specially helpful in 3 types of situations. 1. In acute anterior uveitis (AAU) patients, precise LFCM monitoring of inflammation made it possible to avoid excessive corticosteroid therapy, mainly by more rapid and controlled tapering at the end of an inflammatory episode, so possibly minimizing steroid side effects in a group of patients prone to numerous uveitis recurrences. In a steroid-responder patient it allowed successful treatment of a flare-up of AAU with a combination of systemic and topical diclofenac (Voltaren), a potent nonsteroidal antiinflammatory drug. 2. LFCM monitoring of inflammation in patients undergoing laser treatments allowed optimal adjustment of antiinflammatory therapy. Diclofenac drops (Voltarene Ophta), were sufficient to treat inflammation in all patients, undergoing Nd-YAG laser posterior capsulotomy or Argon laser trabeculoplasty. 3. In patients with acyclovir treated herpes simplex or herpes zoster uveitis corticosteroid treatment should be avoided whenever possible, because of the tendency to develop steroid dependency. LFCM monitoring of this group of patients gave a precise evolutionary pattern of inflammation and permitted to avoid steroid treatment in many patients.


[Importance of detection of hypertensive reaction to physical loading in patients with or without left ventricular hypertrophy and arterial hypertension].
Clinical implications of elevated arterial pressure (AP) in exercise tests were considered in 129 patients with arterial hypertension (AH) and "physiological" left ventricular hypertrophy (LVH). AP changes during veloergometry were compared with results of echocardiography. A rise in systolic AP was identical in "physiological" and pathological LVH while changes of diastolic pressure were greater in the absence of AH. Moreover, AH patients more frequently experienced reduced diastolic AP at a maximum load. These variations positively correlated with thickening of left ventricular (LV) wall and interventricular septum and with enlargement of left atrium, hence with increased myocardial size and greater LVH in patients with AH. All examined cases, with and without AH, suffered diastolic LV dysfunction of myocardial relaxation type associated with a significant 1.2-1.3-fold rise in wave A speed and a 1.3-fold decrease of the E/A ratio. It is concluded that exercise induces hypertensive response even in patients with "physiological" LVH.


Patterns of childhood medical spending.
To provide data on childhood medical spending. This article is based on data released in 1991 through 1993 from the 1987 National Medical Expenditure Survey. The data were analyzed for 14 diagnostic categories. They excluded spending on nursing home and dental care. We inflated the National Medical Expenditure Survey expenditures to December 1993 dollars by means of annual medical spending per capita as a price index. Medical spending on children aged 0 to 21 years totaled $86 billion per year, 15% of all US medical care spending. The largest source of child medical spending was on live birth and pregnancy, at $19 billion, followed by injury, at $12 billion, and respiratory conditions, at $10 billion. Live birth and pregnancy were the largest contributor of hospital inpatient spending for children 0 to 21 years old. Injury accounted for more than half of the spending in emergency departments. One quarter of prescription spending was the result of respiratory conditions. Childhood medical spending for the three largest categories can be reduced through proved preventive measures. These analyses also show that prevention priorities differ by age group.


[Estimation of the minimum infective doses of HIV in the prevalence of its infection].
Estimation of the minimum human infective doses of HIV is essential to the prediction of its infection prevalence, including in bioterrorism. Information on the epidemiology and pathogenesis of HIV infection and on the biological properties of the pathogen may serve as reference data for the theoretical determination of a rough infective dose of HIV. The most common route of virus infection is parenteral transmission. The likelihood of HIV transmission through blood depends on the frequency of transfusions, the stage of HIV infection in a donor and the amount of blood given to a recipient. The author has analyzed the data available in the literature on the epidemiology and pathogenesis of the infection, on the properties of the pathogen, and on the risks of HIV infection in different groups and summarized information on the infection among injecting drug users, which could roughly estimate the level of sensitivity in man as a biological species to this virus.


Modeling the Treatment of Glioblastoma Multiforme and Cancer Stem Cells with Ordinary Differential Equations.
Despite improvements in cancer therapy and treatments, tumor recurrence is a common event in cancer patients. One explanation of recurrence is that cancer therapy focuses on treatment of tumor cells and does not eradicate cancer stem cells (CSCs). CSCs are postulated to behave similar to normal stem cells in that their role is to maintain homeostasis. That is, when the population of tumor cells is reduced or depleted by treatment, CSCs will repopulate the tumor, causing recurrence. In this paper, we study the application of the CSC Hypothesis to the treatment of glioblastoma multiforme by immunotherapy. We extend the work of Kogan et al. (2008) to incorporate the dynamics of CSCs, prove the existence of a recurrence state, and provide an analysis of possible cancerous states and their dependence on treatment levels.


The effect of the PREMIER interventions on insulin sensitivity.
This ancillary study of PREMIER sought to determine the effects on insulin sensitivity of a comprehensive behavioral intervention for hypertension with and without the Dietary Approaches to Stop Hypertension (DASH) dietary pattern. Participants were assigned to one of three nonpharmacologic interventions for blood pressure (group A, advice only; group B, established; and group C, established plus DASH). The established intervention included weight loss, reduced sodium intake, increased physical activity, and moderate alcohol intake; the DASH dietary pattern was added to the established intervention for those in group C. The DASH dietary pattern is high in fruits, vegetables, and low-fat dairy products while being lower in total fat, saturated fat, and cholesterol. It is abundant in nutrients such as magnesium, calcium, and protein, which have been associated with improved insulin sensitivity. Insulin sensitivity was measured at baseline and at 6 months using the frequently sampled intravenous glucose tolerance test with minimal model analysis. Both intervention groups decreased total calories, percentage of calories from fat, and sodium intake to similar levels, with similar amounts of energy expenditure and weight loss. Covariate differences seen only in group C included increased intake of protein, potassium, calcium, and magnesium. Compared with control subjects, insulin sensitivity improved significantly only in group C, from 1.96 to 2.95 (P = 0.047). Group B did have a significant decrease in fasting insulin and glucose, but the changes in insulin sensitivity did not reach statistical significance when compared with control subjects. These results suggest that including the DASH dietary pattern as part of a comprehensive intervention for blood pressure control enhances insulin action beyond the effects of a comprehensive intervention that does not include DASH.


Effect of ring size on conformations of aromatic amine-DNA adducts: the aniline-C8 guanine adduct resides in the B-DNA major groove.
While the one-ring amine aniline (AN) has only slight genetic activity, the polycyclic aromatic amines 2-aminofluorene (AF) and 1-aminopyrene (AP) are significant mutagens and carcinogens. Moreover, the bulkier AP is more mutagenic per adduct than AF in the tetracycline-resistance gene of plasmid pBR322 [Melchior et al. (1994) Carcinogenesis 15, 889]. To elucidate possible conformational origins of the differing mutagenic effects of these three adducts, which may stem from their differing ring sizes, we have examined their conformations in two mutation-susceptible sequences from the above gene: TTGAG*GCCG (sequence I) and GAATG*GTGC (sequence II), where G* = C8-modified guanine. No experimental high-resolution NMR data are yet available for the aniline adduct in a DNA duplex. Minimized potential energy calculations were carried out, using the molecular mechanics program DUPLEX to explore the conformation space of these adducts. In the case of AN, a relatively unperturbed B-DNA helix with the amine in the major groove was strongly favored in both sequences. In the case of AF- and AP-modified DNA, however, several differing conformations were competitive in energy. They included major groove structures, as well as conformations with syn-modified guanine and the polycyclic amine in the minor groove, or the amine rings intercalated into the helix with displacement of the modified guanine, in overall harmony with high-resolution NMR solution structures. Thus, aniline distorts DNA structure to a lesser extent than larger aromatic amine ring systems, since a number of different conformations are energetically feasible and have been observed for the larger systems. This result may be relevant to their enhanced mutagenicity and their repair propensity, in contrast to aniline's low mutagenic effect.


Thermodynamic studies of the solvent effects in chromatography on molecularly imprinted polymers. 3. Nature of the organic mobile phase.
Experimental isotherm data of the Fmoc-tryptophan (Fmoc-Trp) enantiomers were measured by frontal analysis on a Fmoc-L-Trp imprinted polymer, using different organic mobile phases, in a wide concentration range. The nonlinear regression of the data and the independent calculation of the affinity energy distributions of the two enantiomers allowed the selection of the isotherm model and the determination of the isotherm parameters. The organic solvents studied were acetonitrile (MeCN), methylene chloride, chloroform, and tetrahydrofuran (THF), all in the presence of the same concentration of acetic acid, used as an organic modifier. It was found that the highest overall affinity and enantiomeric selectivity were obtained in MeCN, which is also the solvent used in the polymerization. In the other solvents, the overall affinity decreases with increasing hydrogen-bonding ability of the solvents but not the enantiomer selectivity. In MeCN, three types of adsorption sites coexist for the two enantiomers on the MIP. The highest energy sites for Fmoc-L-Trp in MeCN are inactive in CH(2)Cl(2), CHCl(3), and THF, and only two types of sites were identified in these solvents. Increasing the acetic acid concentration from 0.2 to 0.9 M causes a large decrease in the association constant of the highest energy sites in CH(2)Cl(2), CHCl(3), and THF but not in MeCN. The overall affinity of Fmoc-L-trp in CH(2)Cl(2), CHCl(3), and THF is dominated by adsorption on the lowest energy sites, the most abundant ones. In contrast, in MeCN, the overall affinity of Fmoc-L-Trp is dominated by adsorption on the highest energy sites, the least abundant sites. In CH(2)Cl(2), CHCl(3), and THF, the number of each type of sites increases with decreasing hydrogen-bonding ability of the solvents while the association constant of the corresponding sites does not change significantly.


Toward an Attentive Robotic Architecture: Learning-Based Mutual Gaze Estimation in Human-Robot Interaction.
Social robotics is an emerging field that is expected to grow rapidly in the near future. In fact, it is increasingly more frequent to have robots that operate in close proximity with humans or even collaborate with them in joint tasks. In this context, the investigation of how to endow a humanoid robot with social behavioral skills typical of human-human interactions is still an open problem. Among the countless social cues needed to establish a natural social attunement, this article reports our research toward the implementation of a mechanism for estimating the gaze direction, focusing in particular on mutual gaze as a fundamental social cue in face-to-face interactions. We propose a learning-based framework to automatically detect eye contact events in online interactions with human partners. The proposed solution achieved high performance both in silico and in experimental scenarios. Our work is expected to be the first step toward an attentive architecture able to endorse scenarios in which the robots are perceived as social partners.


Expression and effects of glial cell line-derived neurotrophic factor on periodontal ligament cells.
To investigate Glial cell line-derived neurotrophic factor (GDNF) expression in normal and wounded rat periodontal ligament (PDL) and the effects of GDNF on human PDL cells (HPDLCs) migration and extracellular matrix expression in HPDLCs. The expression of GDNF and GDNF receptors was examined by immunocyto/histochemical analyses. Gene expression in HPDLCs treated with GDNF, interleukin-1 beta (IL-1β), or tumour necrosis factor-alpha (TNF-α) was quantified by quantitative RT-PCR (qRT-PCR). In addition, we examined the migratory effect of GDNF on HPDLCs. GDNF was expressed in normal rat PDL and cultured HPDLCs. HPDLCs also expressed GDNF receptors. In wounded rat PDL, GDNF expression was up-regulated. QRT-PCR analysis revealed that IL-1β and TNF-α significantly increased the expression of GDNF in HPDLCs. Furthermore, GDNF induced migration of HPDLCs, which was blocked by pre-treatment with the peptide including Arg-Gly-Asp (RGD) sequence, or neutralizing antibodies against integrin αVβ3 or GDNF. Also, GDNF up-regulated expression of bone sialoprotein (BSP) and fibronectin in HPDLCs. GDNF expression is increased in rat wounded PDL tissue and HPDLCs treated with pro-inflammatory cytokines. GDNF enhances the expression of BSP and fibronectin, and migration in an RGD-dependent manner via the integrin αVβ3. These findings suggest that GDNF may contribute to wound healing in PDL tissue.


[Acute post-traumatic tetraparesis: a developmental complication of cervical arthrosis. Physiopathology, clinical study, prognosis. Apropos of 6 cases].
After dealing with the anatomo-pathology of arthrosis, and then the physio-pathology of cervico-arthrotic myelopathy, the authors describe just now six cases of acute post-traumatic tetraplegia happening as a complication of cervical arthrosis. They do insist on the circumstances of that unexpected coming of such neurologic accidents, on their prognosis very often pejorative, on the necessity of a preventive surgical treatment at the stage of cervico-arthrosis myelopathy not very evolved, which is the only one accurate device to avoid the acute decompensation, insisting at last on the functional sequela most often severe of these complications.


Protective effect of astaxanthin on acute cerebral infarction in rats.
The aim of the study was to investigate the effect of astaxanthin and its possible mechanisms on acute cerebral infarction (ACI) in rat model. Male Sprague Dawley rats were randomly divided into sham group, model group, and astaxanthin-treated groups (20, 40, and 80 mg/kg). Neurological examination, the ratio of cerebral edema, and histopathology changes were assessed. Moreover, some oxidative stress markers were obtained for biochemical analysis, and the expression of neurotrophic factors gene was detected by real-time polymerase chain reaction (RT-PCR) method. The results showed that treatment with astaxanthin notably reduced neurological deficit scores and the ratio of cerebral edema compared with the model group. Meanwhile, astaxanthin increased the activity of catalase, superoxide dismutase, and glutathioneperoxidase as well as decreased the content of malondialdehyde in brain tissue. RT-PCR results showed that the expression of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) mRNA were increased with astaxanthin treatment. The results indicated that astaxanthin could ameliorate ACI followed by suppressing oxidative stress and upregulating the expression of BDNF and NGF mRNA.


Illicit Upregulation of Serotonin Signaling Pathway in Adrenals of Patients With High Plasma or Intra-Adrenal ACTH Levels.
In the human adrenal, serotonin (5-HT), released by mast cells stimulates corticosteroid secretion through activation of type 4 serotonin receptors (5-HT4R). In primary pigmented nodular adrenocortical disease cells, activation of the cAMP/protein kinase A (PKA) pathway by PRKAR1A mutations triggers upregulation of the 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and the 5-HT4, 5-HT6, and 5-HT7 receptors. Because ACTH stimulates cortisol secretion through activation of PKA, adrenocortical tissues exposed to sustained stimulation by ACTH may harbor increased expression of TPH and 5-HT4/6/7 receptors. To investigate the effects of long-term ACTH stimulation on the serotonergic pathway in adrenals of patients with high plasma or intra-adrenal ACTH levels. Adrenal tissues were obtained from patients with Cushing disease, ectopic secretion of ACTH [paraneoplastic Cushing syndrome; (paraCS)], 21-hydroxylase deficiency (21-OHD), primary bilateral macronodular adrenal hyperplasia with intra-adrenal ACTH presence, or cortisol-producing adenomas. TPH and 5-HT4/6/7 receptor expression was investigated using RT-PCR and immunochemistry in comparison with normal adrenals. Primary cultured adrenocortical cells originating from a patient with paraCS were incubated with 5-HT and 5-HTR agonists/antagonists. TPH and/or 5-HT4/6/7 receptors were overexpressed in the different types of tissues. In paraCS cultured cells, the cortisol response to 5-HT was exaggerated compared with normal adrenal cells and the stimulatory action of 5-HT was reduced by 5-HT4R antagonist. Our results indicate that prolonged activation of the cAMP/PKA pathway by ACTH induces an aberrant serotonergic stimulatory loop in the adrenal cortex that likely participates in the pathogenesis of corticosteroid hypersecretion.


Quantifying and monitoring functional photosystem II and the stoichiometry of the two photosystems in leaf segments: approaches and approximations.
Given its unique function in light-induced water oxidation and its susceptibility to photoinactivation during photosynthesis, photosystem II (PS II) is often the focus of studies of photosynthetic structure and function, particularly in environmental stress conditions. Here we review four approaches for quantifying or monitoring PS II functionality or the stoichiometry of the two photosystems in leaf segments, scrutinizing the approximations in each approach. (1) Chlorophyll fluorescence parameters are convenient to derive, but the information-rich signal suffers from the localized nature of its detection in leaf tissue. (2) The gross O(2) yield per single-turnover flash in CO(2)-enriched air is a more direct measurement of the functional content, assuming that each functional PS II evolves one O(2) molecule after four flashes. However, the gross O(2) yield per single-turnover flash (multiplied by four) could over-estimate the content of functional PS II if mitochondrial respiration is lower in flash illumination than in darkness. (3) The cumulative delivery of electrons from PS II to P700(+) (oxidized primary donor in PS I) after a flash is added to steady background far-red light is a whole-tissue measurement, such that a single linear correlation with functional PS II applies to leaves of all plant species investigated so far. However, the magnitude obtained in a simple analysis (with the signal normalized to the maximum photo-oxidizable P700 signal), which should equal the ratio of PS II to PS I centers, was too small to match the independently-obtained photosystem stoichiometry. Further, an under-estimation of functional PS II content could occur if some electrons were intercepted before reaching PS I. (4) The electrochromic signal from leaf segments appears to reliably quantify the photosystem stoichiometry, either by progressively photoinactivating PS II or suppressing PS I via photo-oxidation of a known fraction of the P700 with steady far-red light. Together, these approaches have the potential for quantitatively probing PS II in vivo in leaf segments, with prospects for application of the latter two approaches in the field.


[Contralateral vesicoureteral reflux after endoscopic treatment of primary unilateral reflux].
The endoscopic treatment (ET) of vesicoureteral reflux (VUR) is considered by many urologic and pediatric surgeons as the first treatment option in the event of being required, because it is a minimally invasive procedure, of short duration, ambulatory in many cases, with good results and few complications. Ureteral obstruction is the most serious but less frequent complication. The objective is know the incidence, treatment and evolution of patients with ureteral obstruction as complication of the ET of VUR. Evaluation of the medical literature using Pubmed and Ovid. Revision of the clinical report of children (CH) under ET of VUR between March of 1998 and July of 2007, to find those cases that presented ureteral obstruction after ET. A total of 377 children (CH) with VUR in 598 ureters (U), were treated with TE, during the mentioned period of 9 years, between March 1998 and July 2007. Only 2 U (0.33%), in 2 CH (0.5%) presented Ureteral Obstruction with dilatation of the upper urinary tract that need open surgical ureteral reimplantation, with good results in both patients. The risk of ureteral obstruction after ET of VUR is low, less than 0.5% of U. The treatment of this complication can be endoscópic or by open surgery both of them with good results.


Evaluation of a tobacco prevention program on knowledge, attitudes, intention and behavior of tobacco use among fourth grade students--a preliminary study.
This was a preliminary study to evaluate the effectiveness of a tobacco prevention program on knowledge, attitude, intention, and behavior of tobacco use among fourth-grade students in four north central Florida counties. The results suggest that the program was effective in improving students' knowledge, attitudes, and intention toward not using tobacco products. Data analysis showed that students in the education group had a greater improvement in knowledge than the comparison group. Students in the education group also improved their attitude and intention scores while the comparison group did not show any improvement. The results also indicated positive responses from the students. In addition, teachers also gave a very positive response to the program.


Efficient curing of vinyl carbonates by thiol-ene polymerization.
Vinyl carbonates have recently been identified as a suitable alternative to (meth)acrylates, especially due to the low irritancy and cytotoxicity of these monomers. The drawback of some vinyl carbonates containing abstractable hydrogens arises through their moderate reactivity compared with acrylates. Within this paper, we use the thiol-ene concept to enhance the photoreactivity of vinyl carbonates to a large extent to reach the level of those of similar acrylates. Mechanical properties of the final thiol-ene polymers were determined by nanoindentation. Furthermore, low toxicity of all components was confirmed by osteoblast cell culture experiments.


Screening as an application of decision theory.
We develop a decision-theoretical approach to setting the threshold for a screening procedure that declares each examined subject as a positive or a negative. It is fundamentally different from maximising the Youden index. The method incorporates the consequences of the two kinds of bad decisions (false positives and false negatives) by means of a set of plausible loss functions elicited from a subject-matter expert or committee. We present details for several classes of loss functions and within-group distributions of the outcomes. We outline extensions related to mixture distributions and compositions of loss functions. We illustrate the method on simulated examples and apply it to real datasets.


The genetic factor in acute myocardial infarction with hypertension.
This study assessed the contribution of polymorphisms of angiotensin II (AngII) receptors and bradykinin B2 (BK-B2) receptor to hypertension and acute myocardial infarction (AMI) in a Japanese population: 150 subjects with essential hypertension, 150 subjects with AMI with/without hypertension, and 150 healthy, age- and sex-matched controls. Polymorphisms of the AngII type 1 receptor (1166 A/C) and type 2 receptor (3123 C/A), and the BK-B2 receptor (-58T/C, exon 1) were analyzed and significant differences of genotypes and allelic frequencies in the AngII type 2 receptor C/A and BK-B2 receptor -58T/C were found between the essential hypertension and control subjects. Further, a significantly higher incidence of the C allele of the BK-B2 receptor was seen in AMI subjects with hypertension compared with those without hypertension. Genetic variations in the AngII and BK-B2 receptors could prove to be significant pathophysiological mechanisms affecting essential hypertension and AMI, and genetic differences appear to be a new risk factor for these conditions.


Differing field methods and site conditions lead to varying bias in suspended sediment concentrations in the Lower Mississippi and Atchafalaya Rivers.
At sites that have been sampled for decades, changes in field and laboratory methods happen over time as instrumentation and protocols improve. Here, we compare the influence of depth- and point-integrated sampling on total, fine (< 0.0625 mm), and coarse (≥ 0.0625 mm) suspended sediment (SS) concentrations in the Lower Mississippi and Atchafalaya Rivers. Using historical field method information, we identified seven sites to test such differences. We found SS samples collected using point-integration tended to have higher concentrations than those collected using depth-integration. However, the presence and magnitude of the bias were inconsistent across sites. Bias was present at the site with less-than-ideal conditions (i.e., non-trapezoidal channel, non-uniform flow) and non-existent at the ideal site location, indicating the bias between sampling methods depends on site sampling conditions. When present, the bias is greater at higher concentrations and at moderate to high flows. At the less-than-ideal site, point-integrated samples can have 16% (total) and 34% (coarse) higher concentrations than depth-integrated samples. When flow effects are removed, this translates to a bias of 19, 9, and 8 mg per liter for total, fine, and coarse SS. When a change in field methods occurs, comparison samples and a rigorous evaluation of those samples are warranted to determine the proper course of action for a particular site. Often, the effect and solution will not be known until several years of comparison samples have been collected under a variety of hydrologic conditions.


Body proportionality and head and length 'sparing' in growth-retarded neonates: a critical reappraisal.
Despite the popular current distinction between "proportional" and "disproportional" intrauterine growth retardation, it has never been shown that variation in body proportions is greater among growth-retarded than nongrowth-retarded infants of the same birth weight, nor that proportionality is distributed bimodally among growth-retarded infants. Based on a cohort of 8719 neonates born between 1980 and 1986 of mothers with concordant (+/- 7 days) menstrual dating and early ultrasound estimates of gestational age, we used a continuous measure of birth weight for gestational age to define four study groups: nongrowth retarded (n = 5163) and mild (n = 411), moderate (n = 226), and severe (n = 147) intrauterine growth retardation. Compared with non-growth-retarded infants of the same gestational age, growth-retarded infants had substantially lower lengths, head circumferences, and proportionality ratios, and the magnitude of the deficits increased significantly with increasing degrees of growth retardation. When the comparison was based on birth weight rather than gestational age, however, growth-retarded infants had slightly but significantly greater lengths and head circumferences, with increased variability in body proportions, but no evidence of the bimodality that would characterize two distinct subtypes. The analysis suggests that proportionality among intrauterine growth-retarded infants represents a continuum, with progressive disproportionality as severity of growth retardation increases. Moreover, despite evidence of some "sparing," the absolute magnitudes of the deficits in length and head growth remain substantial.


The influence of geographic isolation on late preterm infant and mother outcomes.
Risk of adverse outcome in late-preterm infants (born between 34 and 36 weeks and 6 days' gestation) is heightened for those living in geographic isolation (GI). We examined the relationships between GI and several mother and infant outcomes. This was a tricenter cross-sectional study of 38 English-speaking late-preterm infant/mother dyads admitted to neonatal intensive care in a predominately rural Midwestern state. Eligibility for the study included English-speaking mothers and their biologically born late-preterm infants with no known anomalies. METHODS AND MAIN OUTCOME: Outcomes included maternal knowledge of infant development (Knowledge of Infant Development Inventory) and competence (Competence in Preterm Infant Care questionnaire), maternal perception of vulnerability (Vulnerable Baby Scale ([VBS]), risk, and temperament (Pictorial Assessment of Temperament ([PAT]). Infant readmission and follow-up data were also examined. Potential covariates included any use of the Internet for healthcare information, demographic data, and mother and infant health history and were obtained from medical records and from the mother. Level of GI was determined by time and distance traveled (minutes) from the mother's primary residence to the closest regional healthcare center. Study participants traveled 61 ± 58 miles and 72 ± 62 minutes on average. The Mean ± SD scores on assessment were as follows: Knowledge of Infant Development Inventory 77 ± 10, and Competence in Preterm Infant Care questionnaire 90 ± 14, VBS 27.5 ± 3.5, and PAT 17.5 ± 3. Bivariate associations were observed between distance and time and VBS scores (P = .03 for both). Multiple regression analysis showed significant relationship between time (P = .02) and PAT scores when maternal education (0.09) and the number of hours spent in the NICU (P = .01) were entered into the model. The association between time traveled and VBS scores became marginally significant when maternal age and Internet use were entered into the regression models. The odds for a mother to perceive her infant at risk for suboptimal outcomes were 6 times greater for each 1-hour additional travel time (odds ratio = 6.0; 95% confidence interval: 1.3-36; P = .001). There was no association between GI and readmission rate and follow-up care. Readmission rate was 8%, and anticipatory guidance was found to be inadequate. Remote access to appropriate healthcare services elicits more than legitimate concerns for the late preterm infant and warrants further investigation with consideration for how services might be more easily accessed for this at-risk group.


The changing context of advanced practice nursing within the UK community care setting.
Advanced practice nursing (APN) roles have developed partly to address demand and workforce issues. In community care settings and general practice, an advanced nursing practitioner is generally understood to mean a nurse who has undertaken additional education and training in clinical assessment, including history-taking and physical examination, clinical reasoning and independent prescribing, so they can safely manage patients presenting with undifferentiated and undiagnosed conditions. Capabilities in the Skills for Health framework cover everything from communication and consultation skills, practising holistically and personalised care, to working with colleagues and in teams. The framework is intended to ensure advanced nursing practitioners work to an advanced level. It is also designed to support them to demonstrate and evidence their capabilities to service commissioners, employers, people accessing healthcare and the public.


Acceptability of self-testing for trichomoniasis increases with experience.
Self-testing and point-of-care (POC) tests could improve the detection of sexually transmitted infections (STIs) in adolescents. This study aimed to (1) validate a scale measuring acceptability of self-testing for trichomoniasis, (2) compare acceptability of self versus clinician testing using a POC test for trichomoniasis, (3) examine changes in acceptability after experience and review of results, and (4) examine predictors of acceptability. Women (14-22 years old) performed the POC test and completed surveys assessing acceptability of self and clinician testing at baseline, after testing, and after discussion of results. Factor analysis examined scale structure; changes in mean scale scores were assessed with mixed models. Generalised linear models examined predictors of acceptability. Of 247 participants, 54 (22%) had a positive POC test for trichomoniasis. Factor analysis confirmed four acceptability subscales: trust of results, confidence, comfort, and effects of testing. At baseline, trust and confidence were higher, and comfort was lower, for clinician versus self testing. For self-testing, all subscale scores increased from baseline to after testing, and trust increased from after testing to after discussion. Trust of self and clinician results was not significantly different after discussion. A positive attitude towards home testing predicted higher self-test acceptability on all subscales. Tampon use was associated with increased self-test comfort at baseline. Concordance between self and clinician results predicted increased trust of self testing after discussion. Many young women lack confidence in their ability to self-test for trichomoniasis. Allowing women to try a POC test and review the results with a clinician increases acceptability of self-testing.


aNMJ-morph: a simple macro for rapid analysis of neuromuscular junction morphology.
Large-scale data analysis of synaptic morphology is becoming increasingly important to the field of neurobiological research (e.g. 'connectomics'). In particular, a detailed knowledge of neuromuscular junction (NMJ) morphology has proven to be important for understanding the form and function of synapses in both health and disease. The recent introduction of a standardized approach to the morphometric analysis of the NMJ-'NMJ-morph'-has provided the first common software platform with which to analyse and integrate NMJ data from different research laboratories. Here, we describe the design and development of a novel macro-'automated NMJ-morph' or 'aNMJ-morph'-to update and streamline the original NMJ-morph methodology. ImageJ macro language was used to encode the complete NMJ-morph workflow into seven navigation windows that generate robust data for 19 individual pre-/post-synaptic variables. The aNMJ-morph scripting was first validated against reference data generated by the parent workflow to confirm data reproducibility. aNMJ-morph was then compared with the parent workflow in large-scale data analysis of original NMJ images (240 NMJs) by multiple independent investigators. aNMJ-morph conferred a fourfold increase in data acquisition rate compared with the parent workflow, with average analysis times reduced to approximately 1 min per NMJ. Strong concordance was demonstrated between the two approaches for all 19 morphological variables, confirming the robust nature of aNMJ-morph. aNMJ-morph is a freely available and easy-to-use macro for the rapid and robust analysis of NMJ morphology and offers significant improvements in data acquisition and learning curve compared to the original NMJ-morph workflow.


Androgen receptor in human foreskin. II. Characterization of the receptor from hypospadiac tissue.
Hypospadias represents a spectrum of disorders known as androgen insensitivity syndromes, which are characterized by a nonresponsiveness of an androgen target tissue to the steroid. The basic defect in this disorder is unknown. This article presents results of studies of the androgen receptor with use of human foreskin from normal neonates undergoing circumcision and from patients undergoing urethroplasty necessitated by hypospadias. It is speculated that a defect in receptor level or function might explain this disorder. The androgen receptors from both normal and hypospadiac tissue were stabilized with a buffer containing 50 mM Tris hydrochloride, 1 mM ethylenediaminetetraacetic acid, 12 mM monothioglycerol, 10% (v/v) glycerol, and 10 mM sodium molybdate plus 1 mM phenylmethylsulfonylfluoride (pH 7.5). The receptors were characterized by Scatchard analysis, competitive binding assays, sedimentation analysis, molecular sieve chromatography, and isoelectric focusing techniques. Specific R 1881 binding to soluble proteins from normal human foreskin was shown to be high affinity (dissociation constant = 0.5 nM), low capacity (6 fmol/mg of protein), and steroid specific. Sedimentation analysis by sucrose density gradients demonstrated the 8S-to-4S shift from low- to high-salt treatments. The receptor from the foreskins of hypospadiac patients also contained androgen receptor in a concentration similar to that in the foreskins of normal persons. The affinity for steroid binding and sedimentation profiles or sucrose gradients of the androgen receptor between normal persons and hypospadiac patients were also similar. However, the androgen receptor from hypospadiac patients displayed different patterns of molecular sieve chromatography from those displayed by the receptor of normal persons. The reason for this difference is not known but may reflect a defective receptor and explain the basic mechanism of this disorder.


A rare variant in the visfatin gene (NAMPT/PBEF1) is associated with protection from obesity.
Visfatin was recently reported as a novel adipokine encoded by the NAMPT (PBEF1) gene. This study was aimed at investigation of the possibility that single-nucleotide polymorphisms (SNPs) in the visfatin gene are associated with either obesity or type 2 diabetes (T2D). A set of eight "tag-SNPs" were selected and ABI SNPlex assays designed for genotyping purposes. A total of 1,709 severely obese subjects were typed (896 class III obese adults and 813 children) together with 2,367 T2D individuals and 2,850 controls. For quantitative trait analysis, an additional 2,362 subjects were typed for rs10487818 from a general population sample. One rare SNP, rs10487818, located in intron 4 of NAMPT was associated with severe obesity, with a minor allele frequency of 1.6% in controls, 0.4% in the class III obese adults and, remarkably, 0% in the severely obese children. A highly significant association was observed for the presence or absence of the rare allele, i.e., (A,A) vs. (A,T + T,T) genotypes, in children (P = 6 x 10(-9)) and in adults (P = 8 x 10(-5)). No other significant (P < 0.05) association was observed with obesity or T2D for this or any other SNP. No association with BMI or waist-to-hip ratio was observed in a general population sample (n = 5,212). This is one of the first rare SNPs shown to be protective against a common polygenic disease and provides further evidence that rare alleles of strong effect can contribute to complex diseases such as severe obesity.


A comparison of human chorionic gonadotropin and luteinizing hormone releasing hormone on the induction of spermiation and amplexus in the American toad (Anaxyrus americanus).
Captive breeding programs for endangered amphibian species often utilize exogenous hormones for species that are difficult to breed. The purpose of our study was to compare the efficacy of two different hormones at various concentrations on sperm production, quantity and quality over time in order to optimize assisted breeding. Male American toads (Anaxyrus americanus) were divided into three separate treatment groups, with animals in each group rotated through different concentrations of luteinizing hormone releasing hormone analog (LHRH; 0.1, 1.0, 4.0 and 32 micrograms/toad), human chorionic gonadotropin (hCG; 50, 100, 200, and 300 IU), or the control over 24 hours. We evaluated the number of males that respond by producing spermic urine, the sperm concentration, percent motility, and quality of forward progression. We also evaluated the effects of hCG and LHRH on reproductive behavior as assessed by amplexus. Data were analyzed using the Generalized Estimating Equations incorporating repeated measures over time and including the main effects of treatment and time, and the treatment by time interaction. The hormone hCG was significantly more effective at stimulating spermiation in male Anaxyrus americanus than LHRH and showed a dose-dependent response in the number of animals producing sperm. At the most effective hCG dose (300 IU), 100% of the male toads produced sperm, compared to only 35% for the best LHRH dose tested (4.0 micrograms). In addition to having a greater number of responders (P < 0.05), the 300 IU hCG treatment group had a much higher average sperm concentration (P < 0.05) than the treatment group receiving 4.0 micrograms LHRH. In contrast, these two treatments did not result in significant differences in sperm motility or quality of forward progressive motility. However, more males went into amplexus when treated with LHRH vs. hCG (90% vs. 75%) by nine hours post-administration. There is a clear dichotomy between the two hormones' physiological responses on gamete production and stimulation of amplexus. Understanding how these two hormones influence physiology and reproductive behaviors in amphibians will have direct bearing on establishing similar breeding protocols for endangered species.


Intrathoracic meningocele associated with neurofibromatosis Type 1 and a novel technique for surgical repair: case report.
Neurofibromatosis Type 1 (NF1) is a neurocutaneous disorder that can have associated spinal abnormalities related to both bone and dural dysplasia. Thoracic meningoceles are one spine anomaly associated with NF1, although they are a fairly uncommon pathology. Surgical techniques to treat these meningoceles, usually undertaken only when the patient is symptomatic, are targeted at decreasing the size of the protrusion and improving lung capacity. Surgical interventions discussed in the literature include shunting the pseudomeningocele, primary repair with laminectomy, thoracoscopic plication, and reinforcement of the closure with cement, muscle, or fascia. Authors here report the case of a 43-year-old woman with NF1 with worsening pulmonary function tests and in whom shunting of the pseudomeningocele failed. Subsequently, a posterolateral thoracotomy was performed. The dura mater was reconstructed and primarily closed. On this closure a Gore-Tex soft-tissue patch was placed along with polypropylene mesh and Evicel fibrin sealant, followed by titanium mesh. At the end of the procedure, a chest tube was left in place and therapeutic pneumoperitoneum was performed to decrease the dead space as the lung did not fully expand with positive-pressure ventilation. The patient's pulmonary function tests improved after the procedure. Thoracic meningoceles are uncommon and difficult pathologies to treat surgically. Although shunting is arguably the least invasive surgical option, it can fail in some patients. When it does fail, there are other options that require a multidisciplinary approach and careful attention to the dural closure and reinforcing layers.


Beliefs About Linear Social Progress.
Society changes, but the degree to which it has changed can be difficult to evaluate. We propose that people possess beliefs that society has made, and will make, progress in a linear fashion toward social justice. Five sets of studies (13 studies in total) demonstrate that American participants consistently estimated that over time, society has made positive, linear progress toward social issues, such as gender equality, racial diversity, and environmental protection. These estimates were often not aligned with reality, where much progress has been made in a nonlinear fashion. We also ruled out some potential alternative explanations (Study 3) and explored the potential correlates of linear progress beliefs (Study 4). We further showed that these beliefs reduced the perceived urgency and effort needed to make further progress on social issues (Study 5), which may ultimately inhibit people's willingness to act.


ALCAM is indirectly modulated by miR-125b in MCF7 cells.
MicroRNA (miRNA) deregulation is associated with various cancers. Among an expanding list of cancer-related miRNAs, deregulation of miR-125b has been well documented in many cancers including breast. Based on current knowledge, miR-125b is considered to be a tumor suppressor in breast cancers. While important messenger RNA (mRNA) targets have been defined for miR-125b, here, we aimed to further investigate direct/indirect consequences of miR-125b expression in breast cancer cells by using a transcriptome approach. Upon miR-125b expression, a total of 138 cancer-related genes were found to be differentially expressed in breast cancer cells. While only a few of these were predicted to be direct mRNA targets, majority of the gene expression changes were potentially downstream and indirect effects of miR-125b expression. Among these, activated leukocyte antigen molecule (ALCAM) mRNA and protein levels were found to be highly significantly increased upon miR-125b expression. Given the tumor suppressor role of miR-125b in our model system, upon silencing of ALCAM expression, cell proliferation rate re-increased in miR-125b-expressing cells. While ALCAM's possible context-dependent roles are not clear in breast cancer, a diverse expression pattern of ALCAM mRNA was detected in a panel of breast cancer patient samples. Differentially expressed/regulated cancer-related genes upon miR-125b expression along with the significant increase of ALCAM are of future interest to understand how deregulated expression of miR-125b may have a tumor suppressor role in breast and other cancers.


S-adenosyl L-methionine inhibits azoxymethane-induced colonic aberrant crypt foci in F344 rats and suppresses human colon cancer Caco-2 cell growth in 3D culture.
S-adenosyl L-methionine (SAM) is a universal methyl group donor to various intermediary metabolites, hormones, proteins, neurotransmitters, phospholipids and nucleic acids. Deficiency of folate, which plays a role in the synthesis of SAM leads to increased risk for colon cancer. This study tested the effectiveness of SAM supplementation in protecting against azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. We also tested the effect of SAM on cyclooxygenase-2 (COX-2) in a macrophage cell line. Further, we developed a 3-D culture model using Caco-2 cells to test the effect of SAM on tumor spheroid size and number. Groups of rats were given the experimental diet containing either 0-, 400- or 800-ppm SAM, 1 week before the first AOM injection and continued until 8 weeks. In the control group, AOM produced a substantial number of aberrant crypt foci (ACF) (96 +/- 8). Dietary administration of SAM significantly reduced the number of total ACF (400 ppm SAM, 68 +/- 7.3, p < 0.01 and 800 ppm SAM, 57 +/- 7.1, p < 0.001). SAM significantly decreased AOM-induced colonic multicrypt foci in a dose-dependent manner. Suppression of Lipopolysaccharide (LPS) induced COX-2 protein expression was observed in a RAW264.7 cell line. We established growth of Caco-2 cells as spheroids, in a 3D matrix of collagen and matrigel. Treatment with SAM decreased both size and number of spheroids in a dose-dependent manner (p < 0.0001). These observations demonstrate for the first time that SAM can reduce the occurrence of ACF in AOM treated male F344 rats and suppress formation of human tumor spheroids and expression of COX-2.


The unification of European optometry: how the profession will change after 1992.
The economic integration of the European Community (EC) targeted for 1992 has the potential to change the course of the development of the optometric profession in Europe. One of the goals of this integration is to create within Europe an environment free of professional barriers, such that European professionals will be able to practice their skill anywhere within the Community. Because optometry is practiced so differently among the 12 EC countries, the development of a system of reciprocity for optometric credentials in Europe will be a difficult task. Currently, there exists a strong movement, headed by the Association of European Schools and Colleges of Optometry (AESCO), to unify the profession by creating a European-wide examination for optometry. The implications of such an examination are tremendous in that it will establish a standard for the delivery of optometric care not only for the 320 million people within the EC, but also world-wide. The purpose of this paper is to examine the current status of optometry in Europe, to review efforts by both the EC and AESCO to unify the profession, and to discuss the impact of recent developments on the future of optometry not only in Europe, but throughout the world.


Divalproex therapy in medication-naive and mood-stabilizer-naive bipolar II depression.
There have been few systematic studies of the treatment of bipolar II depression. While divalproex sodium (DVPX) is effective in acute mania, there are few data on the antidepressant effects of DVPX. Similarly, little is known regarding the use of DVPX administered in a single daily dose. We performed a 12-week open trial of DVPX monotherapy (mean dose 882 mg qhs, mean level 80.7 mug/ml) in nineteen (thirteen women, six men, mean age 29) bipolar II depressed outpatients. Eleven patients (six women, five men) were medication-naive (MN) and eight (seven women, one man) were mood stabilizer-naive (MSN), having had prior trials of antidepressants or stimulants. Mean illness and current depressive episode duration were 15.4 years and 11.8 weeks, respectively. DVPX was given as a single dose each evening starting with 250 mg at bedtime and increased by 250 mg at bedtime every 4 days until symptom relief or adverse effects were noted. Weekly prospective Hamilton Depression, Young Mania and Clinical Global Impression ratings were obtained. DVPX therapy was generally well tolerated. Twelve of nineteen patients (63%) responded (>50% decrease in Hamilton Depression ratings). MN patients compared to MSN patients tended to have a higher response rate (9/11 versus 3/8, P<0.08). Mean Hamilton scores decreased from 22.2 to 9.6 (P<0.0001) in the entire group, from 20.6 to 6.6 (P<0.0003) in MN patients, and from 24.2 to 14.7 (P=0.008) in MSN patients. Single daily dose DVPX monotherapy appeared to be well tolerated and substantially benefited 63% of patients with bipolar II depression. The trend towards a higher rate of antidepressant response to DVPX in MN patients (82%) compared to MSN patients (38%) could be due to a milder form or earlier phase of illness and the lack of prior medication exposure or failures. This uncontrolled open pilot study must be viewed with caution, and randomized double-blind placebo controlled studies of DVPX in bipolar II depression are warranted to confirm the possibility that single daily dose DVPX is an effective, well-tolerated, first-line monotherapy in this population.


Reliability and complications of 500 consecutive cochlear implantations.
To assess device failures as well as early postoperative, late postoperative, and medical complications occurring after cochlear implantation and to discuss their causes and treatments. Retrospective study of 500 consecutive cochlear implantations. Tertiary referral center. All patients receiving cochlear implants at our institution between 1989 and 2006. All complications and treatments were systematically reviewed with a maximum follow-up of 18 years. The number of reimplantations was calculated according to follow-up duration to determine the cochlear implant survival rate. Specific risks of reimplantation were calculated for groups with differing durations of implantation. The overall rate of complications was 16.0% (79 of 500), with minor complications accounting for 5.6%; major complications, 3.2%; and reimplantations, 7.2%. Reasons for revision surgery were device failure, infection, trauma, and "soft device failure" (failure despite normal results from integrity testing). Revision surgery was performed in 51 of the 500 cases (10.2%), and other complications were managed medically (28 of 500; 5.6%). The rate of hard and soft device failures was 6% (30 of 500). Seventy-two percent of reimplantations occurred within 5 years. The risk of severe infection (eventually requiring explantation) was 1.4% (7 of 500). There was 1 case of transient facial palsy following surgery (0.2%), and the incidence of postsurgical meningitis was 0. Cochlear implantation is a safe technique with a relatively low complication rate; however, certain complications may require specific attention to prevent or correct them.


Pediatric en bloc kidney transplantation into pediatric recipients.
As a result of the ongoing shortage in organ supply, en bloc renal transplantation from small donors has become more common for adult recipients with ESRD. However, because of concern for higher complication rates and sub-optimal outcomes, it is not being performed in every center, and data describing its use in pediatric recipients are even more limited. We retrospectively studied three patients who have undergone en bloc renal transplantation at our center. Median age at transplantation was 16.7 yr with a median follow-up of 1.2 yr. Donor age ranged from nine to 49 months with weight ranging from 10 to 22 kg. There were no post-operative thrombotic complications. All grafts showed increased renal size at follow-up by ultrasound. There was no clinical or histological rejection at last follow-up. To the best of our knowledge, this is the first report on the outcomes of en bloc kidney transplantation from pediatric donors into pediatric recipients. Based on our experience, albeit very limited, we feel that en bloc renal transplantation from young donors is an acceptable and safe procedure with low complication rates in pediatric recipients and should be given consideration to minimize wait times on the wait list and to improve quality of life.


Perindopril inhibits myocardial apoptosis in mice with acute myocardial infarction through TLR4/NF-κB pathway.
To explore the anti-apoptotic effect of perindopril on myocardial cells in mice with acute myocardial infarction (AMI). A total of 48 mice were randomly divided into 4 groups before intervention, namely sham operation group (Sham group, n=12), AMI group (n=12), 1.5 mg/kg perindopril treatment group (Perindopril group, n=12), and 1.5 mg/kg perindopril treatment and Toll-like receptor-4 (TLR4) knockout group (TLR4-/-Perindopril group, n=12). Mice in the control group and AMI group were gavaged with normal saline, and those in the Perindopril group and TLR4-/-Perindopril group were gavaged with perindopril for 7 d. On the 4th day after drug administration, mice in the AMI group, Perindopril group and TLR4-/-Perindopril group were subjected to the ligation of the anterior descending coronary artery to induce AMI, and those in the Sham group underwent the same operation, but had a loose knot at the anterior descending coronary artery. At 24 h after the above operation, color echocardiography was performed on mice to observe changes in cardiac function. Then, the mice were sacrificed. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) assay was carried out to determine myocardial apoptosis. Immunohistochemistry and Western blotting technique were employed to detect the protein expression levels of B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p50 in infarction zones. The messenger ribonucleic acid (mRNA) expression levels of TLR4 and NF-κB p50 in infarction zones were measured via Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Perindopril could significantly reduce the number of apoptotic myocardial cells after AMI. Mouse echocardiography showed that ejection fraction (EF), left ventricular fractional shortening (FS), left ventricular end-systolic diameter (LVESD) and left ventricular end-diastolic diameter (LVEDD) of AMI mice in the Perindopril groups were markedly superior to those in the AMI group. AMI mice in the Perindopril group had decreased expression levels of Bax protein and TLR4 and NF-κB p50 mRNA and protein, as well as the Bax/Bcl-2 ratio. Knockout of TLR4 attenuated the effect of perindopril in alleviating myocardial apoptosis after AMI. Perindopril inhibits myocardial apoptosis in mice with AMI through the TLR4/NF-κB pathway.


Rapid melatonin transients.
Two normal male subjects exhibited rapid pulses of melatonin concentration in plasma, apparently unrelated to stages of sleep and undisturbed with spontaneous waking during the night. Pulse intervals of approximately 8 and 12 min., respectively, for subjects 1 and 2, were associated with excursions of 35% and 33% of the nadir or 28% and 26% of the mean value. The pulses were detected with a 2.5 min. sampling interval.


129I and 127I transport in the Mississippi River.
The watershed processes which control 129I/127I ratios, 129I and 127I concentrations, and speciation of iodine isotopes were studied through an investigation into the variability of these parameters in the Mississippi River near New Orleans, undertaken in 1996-1998. Analyses of suspended particulate matter (SPM) revealed a greater percent association of 127I than of 129I, resulting in lower 129I/127I ratios in SPM than in surrounding water. Furthermore, crossflow ultrafiltration showed that organo-iodine was the dominant form for both isotopes, with 70-85% of these isotopes found in the 0.45 microm filter-passing fraction associated with colloidal macromolecular organic matter. 129I showed a weak correlation, 127I no correlation, and 129I/127I ratios a strong inverse correlation with river flow rate. Inverse correlations between 129I/127I ratios and river flow rates can be best explained by rainwater and evapotranspiration dominated ratios at base flow and a lowering of the isotope ratios during higher flow due to extra inputs of 127I from soil weathering. We postulate that different equilibration times for 127I and 129I as well as for bomb-produced 129I and reprocessing-produced 129I are responsible for these fractionation effects and the differential mobilities of these isotopes in the Mississippi River watershed.


Membrane cholesterol and cell fusion of hen and guinea-pig erythrocytes.
1. The cholesterol content of hen erythrocytes was modified by treating the cells with phospholipid liposomes. 2. Depletion of cellular cholesterol, by using liposomes of dipalmitoylglycerophosphocholine or phosphatidylcholine from hen erythrocytes, had no effect on the susceptibility of the cells to fusion induced by oleoylglycerol, but markedly decreased fusion induced by Sendai virus. 3. By contrast, enrichment of cellular cholesterol by using liposomes of dipalmitoylglycerophosphocholine and cholesterol increased cell fusion induced by oleoylglycerol, poly(ethylene glycol) and Sendai virus. 4. Virus-induced cell fusion of guinea-pig erythrocytes, which were enriched in cholesterol by feeding a cholesterol-rich diet to the animals, was also enhanced. 5. Hen erythrocytes that were treated with liposomes prepared from egg phosphatidylcholine contained increased quantities of phospholipid phosphorus and fused readily on incubation with retinol, independently of their cholesterol content. 6. It is suggested that cholesterol may enhance cell fusion by acting to facilitate a phase separation of protein-free areas of lipid bilayer, which subsequently provide the sites for cell fusion.


TLX3 repressed SNAI1-induced epithelial-mesenchymal transition by directly constraining STAT3 phosphorylation and functionally sensitized 5-FU chemotherapy in hepatocellular carcinoma.
TLX3 has an established role as a sequence-specific transcription factor with vital functions in the nervous system. Although several studies have shown that TLX3 is aberrantly up-regulated in leukemia, its expression and function in hepatocellular carcinoma (HCC) remain unknown. We found that TLX3 expression was decreased in 68/100 (68%) HCC cases and negatively correlated with the expression of p-STAT3, SNAI1, and Vimentin, while it was positively associated with E-cadherin expression. ITRAQ proteomic profiling revealed significantly less TLX3 expression in primary HCC tumors than in portal vein tumor thrombi. Comparison of Kaplan-Meier curves showed that down-regulation of TLX3 in HCC was associated with poor post-surgical survival. TLX3 over-expression inhibited HCC cell viability, proliferation, migration, invasion and enhanced 5-FU treatment, whereas silencing TLX3 produced the opposite results. Further experiments showed that TLX3 attenuated the EMT phenotype. In vivo experiments showed that knockdown of TLX3 promoted the growth of HCC xenografts and attenuated the anti-tumor effects of 5-FU treatment. Gene expression microarray analysis revealed that TLX3 inhibited IL-6/STAT3 signaling. In additional mechanistic studies TLX3 reversed the EMT phenotype of HCC cells by binding to STAT3, inhibiting STAT3 phosphorylation, and down-regulating SNAI1 expression. Taken together, loss of expression of TLX3 induces EMT by enhancing IL-6/STAT3/SNAI1 signaling, and accelerates HCC progression while also attenuated the effect of 5-FU on HCCs.


De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.


Unilateral coronal synostosis: can we trust the sagittal suture as a landmark for the underlying superior sagittal sinus?
OBJECTIVE The sagittal suture is usually considered an external anatomical landmark, indicating the location of the superior sagittal sinus (SSS) for surgical approaches. Children with unilateral coronal synostosis (UCS) often present with an important deviation of the sagittal suture. Because these patients usually undergo frontal reconstruction or even endoscope-assisted minimally invasive procedures, it is imperative to know the location of the SSS. The aim of this investigation was to study the anatomical relationship between the SSS and the sagittal suture in children with anterior plagiocephaly. METHODS The authors retrospectively studied the relationship between the sagittal sinus and the sagittal suture at 5 points: nasion, midpoint nasion-bregma, bregma, midpoint bregma-lambda, and lambda. The study analyzed CT scans of 50 children with UCS admitted to the craniofacial unit of Necker Enfants Malades Hospital between March 2006 and March 2013 and compared them with 50 control children with no evidence of craniosynostosis, bone disease, or genetic syndromes. The authors also analyzed the presence of extracerebral fluid collection and ventricular asymmetry in children with UCS. RESULTS Fifty-six percent of patients had anterior right UCS and 44% had left-sided UCS. Type I UCS was seen in 1 patient, Type IIA in 20 patients, Type IIB in 20 patients, and Type III in 9 patients. The authors found that the nasion is usually deviated to the ipsilateral side of the synostosis, the bregma contralaterally, and the lambda ipsilaterally. The gap distances between the reference point and the SSS were 0-7.3 mm (mean 1.4 mm) at the nasion; 0-16.7 mm (mean 3.8 mm) at the midpoint nasion-bregma; 0-12 mm (mean 5.8 mm) at the bregma; 0-9.5 mm (mean 3 mm) at the midpoint bregma-lambda; and 0-11.6 mm (mean 5.5 mm) at the lambda. Conversely, a discrepancy of more than 1 mm between the SSS and the position of the suture was found only in 7 control cases (14%). Of patients with UCS, 38% presented with an extracerebral fluid collection contralateral to the fused coronal suture. Fifty-two percent had a ventricular asymmetry, which was characterized by reduced ventricular volume ipsilateral to the synostosis in all but 1 patient. CONCLUSIONS In this study, the SSS was usually deviated contralaterally to the closed coronal suture. It tended to be in the midline of the cranial vault and could be projected virtually along an imaginary line passing through the midline of the cranial base. The authors recommend a distance of 37 mm from the sagittal suture as a safety margin during surgery.


Use of middle infrared radiation to estimate the leaf area index of a boreal forest.
The leaf area index (LAI) of boreal forest can be estimated using reflected radiation recorded by satellite sensors. Measurements of visible and near infrared radiation are commonly used in the normalized difference vegetation index (NDVI) to estimate LAI. However, research, mainly in tropical forest, has demonstrated that LAI is related more closely to radiation of middle infrared wavelengths than of visible wavelengths. This paper derives a vegetation index, VI3, based on radiation from vegetation recorded at near and middle infrared wavelengths. For a boreal forest canopy, the relationship between VI3 and LAI was observed to be much stronger than that between NDVI and LAI. In addition, the LAI estimated using VI3 accounted for about 76% of the variation in field estimates of LAI, compared with about 46% when using the NDVI. We conclude that information provided by middle infrared radiation should be considered when estimating the leaf area index of boreal forest.


Mycophenolate mofetil, together with cyclosporin A, prevents anti-OKT3 antibody response in kidney transplant recipients.
OKT3 monoclonal antibody, a murine IgG2a monoclonal antibody targeting the T cell CD3 antigen, elicits a neutralizing humoral response in 20 to 50% of kidney transplant recipients when the concomitant immunosuppression consists of CsA-Sandimmun (SAND) and azathioprine (AZA). In the present study, we investigated the impact of the newer agents, CsA-Neoral (NEO) and mycophenolate mofetil (MMF) on OKT3 sensitization. Sixty-two consecutive kidney transplant recipients received prophylactic OKT3 (5 mg/d) from days 0 to 13, together with steroids. Concomitant immunosuppression consisted of either AZA + SAND (n=20), AZA + NEO (n=31), or MMF + NEO (n=11). The following doses were used: AZA, 2 mg/kg per d from days 0 to 13, then 1 mg/kg per d; MMF, 2 g/d starting on day 1; and CsA, either SAND or NEO, 6 mg/kg per d from day 6. At least two serum samples per month were available during the initial 3 mo for each patient. IgG anti-OKT3 antibodies were first evaluated by enzyme-linked immunosorbent assay. Patients were considered sensitized if their serum scored positive at a dilution > or = 1/1000. Peak titers of IgG anti-OKT3 antibodies and the incidence of patients harboring neutralizing anti-idiotypic antibodies were also determined. A first reduction in OKT3 sensitization was seen in patients receiving Neoral instead of Sandimmun (AZA + SAND: 10 of 20 [50%] patients sensitized versus 6 of 31 [19%] in the AZA + NEO group; P=0.03). This was probably related to the achievement of higher mean CsA trough blood levels in the NEO group during the first month (253+/-44 versus 186+/-49 ng/ml in SAND patients). Peak antibody titers and the proportion of patients with anti-idiotypic antibodies were similar in the AZA + SAND and AZA + NEO groups. A further reduction in the sensitization rate was observed with the replacement of AZA by MMF (MMF + NEO: 0% sensitized patients; P=0.0013). It is concluded that the combination of CsA-Neoral and MMF efficiently prevents sensitization against OKT3.


Allele-specific DNA methylation of disease susceptibility genes in Japanese patients with inflammatory bowel disease.
Inflammatory bowel disease (IBD) has an unknown etiology; however, accumulating evidence suggests that IBD is a multifactorial disease influenced by a combination of genetic and environmental factors. The influence of genetic variants on DNA methylation in cis and cis effects on expression have been demonstrated. We hypothesized that IBD susceptibility single-nucleotide polymorphisms (SNPs) regulate susceptibility gene expressions in cis by regulating DNA methylation around SNPs. For this, we determined cis-regulated allele-specific DNA methylation (ASM) around IBD susceptibility genes in CD4+ effector/memory T cells (Tem) in lamina propria mononuclear cells (LPMCs) in patients with IBD and examined the association between the ASM SNP genotype and neighboring susceptibility gene expressions. CD4+ effector/memory T cells (Tem) were isolated from LPMCs in 15 Japanese IBD patients (ten Crohn's disease [CD] and five ulcerative colitis [UC] patients). ASM analysis was performed by methylation-sensitive SNP array analysis. We defined ASM as a changing average relative allele score ([Formula: see text]) >0.1 after digestion by methylation-sensitive restriction enzymes. Among SNPs showing [Formula: see text] >0.1, we extracted the probes located on tag-SNPs of 200 IBD susceptibility loci and around IBD susceptibility genes as candidate ASM SNPs. To validate ASM, bisulfite-pyrosequencing was performed. Transcriptome analysis was examined in 11 IBD patients (seven CD and four UC patients). The relation between rs36221701 genotype and neighboring gene expressions were analyzed. We extracted six candidate ASM SNPs around IBD susceptibility genes. The top of [Formula: see text] (0.23) was rs1130368 located on HLA-DQB1. ASM around rs36221701 ([Formula: see text] = 0.14) located near SMAD3 was validated using bisulfite pyrosequencing. The SMAD3 expression was significantly associated with the rs36221701 genotype (p = 0.016). We confirmed the existence of cis-regulated ASM around IBD susceptibility genes and the association between ASM SNP (rs36221701) genotype and SMAD3 expression, a susceptibility gene for IBD. These results give us supporting evidence that DNA methylation mediates genetic effects on disease susceptibility.