Low prevalence of DHFR and DHPS mutations in Pneumocystis jirovecii strains obtained from a German cohort.
Pneumocystis pneumonia (PCP) is an opportunistic and potentially life-threatening infection of immunocompromised individuals. A combination of trimethoprim-sulfamethoxazole is widely used for prophylaxis and treatment of PCP. Polymorphisms in the drug targets, the dihydropteroate synthase (DHPS) or the dihydrofolate reductase (DHFR) are presumably a reason for treatment failure. We retrospectively examined the prevalence of DHPS and DHFR mutations in Pneumocystis jirovecii isolates obtained from HIV-infected and non-HIV-infected PCP patients. DHFR and DHPS genes were amplified using semi-nested PCR followed by sequencing. Obtained data were correlated with clinical findings. Sequencing of the DHPS gene was achieved in 81 out of 128 isolates (63%), the DHFR-gene was successfully sequenced in 96 isolates (75%). The vast majority of DHFR and DHPS sequences were either wild-type or showed synonymous single nucleotide polymorphisms. Only one sample contained a double mutation at DHPS codon 55 and codon 57 which was associated with treatment failure in some studies. No linkage of treatment failure to a DHFR or DHPS genotype was observed. In our cohort, 35 of 95 Patients (37%) were HIV-positive and 60 (63%) were HIV-negative. The overall mortality rate was 24% with a much higher rate among non-HIV patients. DHPS and DHFR mutations exist but are infrequent in our cohort. The contribution of gene polymorphisms to treatment failure needs further research. In immunocompromised HIV-negative patients PCP is associated with high mortality rates. Prophylactic treatment is warranted in this patient subset.


UNESCO conference on human rights and bioethics.
UNESCO's Division of Human Rights and Peace, together with the USSR Academy of Science and the USSR Academy of Medicine, held an international bioethics conference in Moscow May 13-15, 1991. Twenty participants from the United States, Europe, Asia, and South America participated....The Moscow conference, which took place on the new campus of the USSR Academy of Social Sciences, addressed four topics: (1) organ transplantation; (2) informed consent; (3) bioethics and the law; and (4) institutionalization of bioethics....


Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines for Occipital Nerve Stimulation for the Treatment of Patients With Medically Refractory Occipital Neuralgia: Update.
The Guidelines Task Force conducted a systematic review of the relevant literature on occipital nerve stimulation (ONS) for occipital neuralgia (ON) to update the original 2015 guidelines to ensure timeliness and accuracy for clinical practice. To conduct a systematic review of the literature and update the evidence-based guidelines on ONS for ON. The Guidelines Task Force conducted another systematic review of the relevant literature, using the same search terms and strategies used to search PubMed and Embase for relevant literature. The updated search included studies published between 1966 and January 2023. The same inclusion/exclusion criteria as the original guideline were also applied. Abstracts were reviewed, and relevant full text articles were retrieved and graded. Of 307 articles, 18 were retrieved for full-text review and analysis. Recommendations were updated according to new evidence yielded by this update . Nine studies were included in the original guideline, reporting the use of ONS as an effective treatment option for patients with medically refractory ON. An additional 6 studies were included in this update. All studies in the original guideline and this current update provide Class III evidence. Based on the availability of new literature, the current article is a minor update only that does not result in modification of the prior recommendations: Clinicians may use ONS as a treatment option for patients with medically refractory ON.


Biocompatibility property of 100% strontium-substituted SiO2 -Al2 O3 -P2 O5 -CaO-CaF2 glass ceramics over 26 weeks implantation in rabbit model: Histology and micro-Computed Tomography analysis.
One of the desired properties for any new biomaterial composition is its long-term stability in a suitable animal model and such property cannot be appropriately assessed by performing short-term implantation studies. While hydroxyapatite (HA) or bioglass coated metallic biomaterials are being investigated for in vivo biocompatibility properties, such study is not extensively being pursued for bulk glass ceramics. In view of their inherent brittle nature, the implant stability as well as impact of long-term release of metallic ions on bone regeneration have been a major concern. In this perspective, the present article reports the results of the in vivo implantation experiments carried out using 100% strontium (Sr)-substituted glass ceramics with the nominal composition of 4.5 SiO2 -3Al2 O3 -1.5P2 O5 -3SrO-2SrF2 for 26 weeks in cylindrical bone defects in rabbit model. The combination of histological and micro-computed tomography analysis provided a qualitative and quantitative understanding of the bone regeneration around the glass ceramic implants in comparison to the highly bioactive HA bioglass implants (control). The sequential polychrome labeling of bone during in vivo osseointegration using three fluorochromes followed by fluorescence microscopy observation confirmed homogeneous bone formation around the test implants. The results of the present study unequivocally confirm the long-term implant stability as well as osteoconductive property of 100% Sr-substituted glass ceramics, which is comparable to that of a known bioactive implant, that is, HA-based bioglass.


Experience of registered nurses in assessing postoperative pain in hip fracture patients with dementia.
Aim To explore the experience of registered nurses in assessing pain in hip fracture in patients with dementia in the postoperative setting. Methods The study questionnaire contained 23 items mainly addressing demographic and social data, information about communication and pain assessment, attention and awareness of the health-care professionals on the ward and suggestions for improving nursing. Results The nurses claimed that they began their assessment of pain in patients with dementia first by observing the patient and making a visual assessment of pain, after which they began to communicate with these patients; majority of dementia patients with hip fractures displayed more facial expressions of pain than patients without dementia. All the nurses agreed that the more severe the patient's dementia was, the less clear the facial expressions and that this in turn made it difficult for the nurses to take care of such patients. Body language was the most common way the patients with dementia and hip fractures expressed their pain. Assessing the pain of a dementia patient with hip fracture and interpreting a non-verbally communicative patient was experienced as very difficult by all the nurses. Conclusion The nurses found that the fact that they had not attended any courses on dementia and pain assessment in those patients made their work more difficult; they need to know more and to have more information about those patients and their needs for a more comprehensive exchange of information between the hospital wards and the patients' care homes.


Optical Detection of Copper Ions via Structural Dissociation of Plasmonic Sugar Nanoprobes.
Heavy metal ions are known to cause environmental pollution and several human diseases because of their inherent toxicity. Among them, Cu2+ is an essential element for the human body, but its continuous exposure and accumulation may cause adverse effects. Thus, copper ion levels in aquatic environments are strictly regulated by international standards. Herein, we demonstrate a simple optical method for detecting Cu2+ using plasmonic sugar nanoprobes (PSNs) composed of gold nanoparticles and polysaccharides. Gold precursors were reduced to nanoparticles and spontaneously embedded in the sugar-based polymeric network with the sulfated residues of carrageenan during the polymerization procedure. Owing to the abundant functional residues of PSNs and their affinity toward Cu2+, we observed the Cu2+-mediated preferential dissociation of the PSNs, resulting in absorbance spectral shifts and scattering shifts of the PSNs. Based on these plasmon band shifts, Cu2+ below the EPA regulation level of 20 μM can be easily detected by the optimized experimental condition. Additionally, the reaction mechanism between the PSNs and Cu2+ was elucidated by indepth spectroscopic analyses, which revealed that the increased binding of Cu2+ to the sulfate groups in the PSNs induces the eventual decomposition of the PSNs.


Interaction of protein tyrosine phosphatase (PTP) 1B with its substrates is influenced by two distinct binding domains.
We have shown previously that protein tyrosine phosphatase (PTP) 1B interacts with insulin receptor and negatively regulates insulin signalling by an N-terminal binding domain [Dadke, Kusari and Chernoff (2000) J. Biol. Chem. 275, 23642-23647] and it also negatively regulates integrin signalling through a proline-rich region present in the C-terminus [Liu, Hill and Chernoff (1996) J. Biol. Chem. 271, 31290-31295; Liu, Sells and Chernoff (1998) Curr. Biol. 8, 173-176]. Here we show that PTP1B mutants that are defective in Src homology 3 domain binding fully retain the ability to inhibit insulin signalling, whereas mutants defective in insulin-receptor binding fully retain the ability to inhibit integrin signalling. In contrast, both the C-terminal proline-rich region and the tandem tyrosine residues present in the N-terminal region are required for the activation of Src family kinases. These data show that PTP1B can independently regulate insulin and integrin signals, and that Src might represent a convergence point for regulating signal transduction by this phosphatase.


Open 1.0-T versus closed 1.5-T cardiac MR: Image quality assessment.
The aim of this paper was to compare the open 1-T (O-1T) versus the closed 1.5-T (C-1.5T) cardiac magnetic resonance (MR). The MR examinations of two concurrent cohorts (each including 100 subjects) of patients with suspected or known cardiac disease were reviewed. Such examinations were obtained using O-1T or C-1.5T MRI. The bright-blood cine, T1-weighted (T1), T2-weighed short-tau inversion recovery (T2-STIR), late gadolinium enhancement (LGE) sequences were performed. Signal-to-noise ratio of blood (SNRb) or myocardium (SNRm), and contrast-to-noise ratio of myocardium (CNRm) were calculated. Subjective image quality (SIQ) of each sequence was graded as 0 = poor, 1 = intermediate, or 2 = optimal. Each examination was considered as diagnostic when the report answered the clinical question. C-1.5T was better than O-1T on cine for SNRb(median 172 versus 452), SNRm(71 versus 160) and CNRm (107 versus 265) and on T2-STIR for SNRb(10 versus 29), SNRm(74 versus 261) and CNRm(-67 versus -233)(P < 0.001). On LGE, SNRm was higher with O-1T than for C-1.5T (312 versus 79, P < 0.001) while CNR was lower (158 versus 389; P < 0.001). No significant differences were found for SNRb on LGE and both SNRm and CNRm on T1 (P ≥ 0.215). SIQ of O-1T was not significantly different from that of C-1.5T for both R1 and R2 for cine, T1, and LGE (P ≥ 0.157); for T2-STIR, SIQ of O-1T was significantly lower (P = 0.003). R1-R2 concordance was almost perfect (κ = 0.816-0.894), and all examinations were diagnostic. Even though quantitative measurements mostly favored C-1.5T, the SIQ of O-1T was not significantly different for any sequence, with the only exception of T2-STIR.


[Early detection and initial treatment of depression].
Clinical interaction between primary care physicians and psychiatrists is important in the treatment of depression. Most depressive patients first visit to primary care physicians. In this paper, we explain early detection and initial treatment of depression to primary care physicians. They first should have a question about insomnia to their patients to detect depression. And we show seven principles in the initial treatment of depression to primary care physicians.


Dielectric chiral metasurfaces for enhanced circular dichroism spectroscopy at near infrared regime.
Numerous applications of chiro-optical effects can be found in nanophotonics, including imaging and spin-selective absorption, particularly in sensing for separating and detecting chiral enantiomers. Flat single-layer metasurfaces composed of chiral or achiral sub-wavelength structures offer unique properties to manipulate the light due to their extraordinary light-matter interaction. However, at optical wavelengths, the generation of strong chirality is found to be challenging via conventional chiral metasurface approaches. This work intends to design and optimize a dielectric chiral meta-nano-surface based on a diatomic design strategy to comprehend giant chiro-optical effects in the near-infrared (NIR) regime for potential application in circular dichroism (CD) spectroscopy. Instead of using a single chiral structure that limits the CD value at optical wavelengths, the proposed metasurface used a diatomic (two meta-atoms with distinct geometric parameters) chiral structure as a building block to significantly enhance the chiro-optical effect. Combining both meta-atoms in a single periodicity of the building block introduces constructive and destructive interferences to attain the maximum circular dichroism value exceeding 75%. Moreover, using multipolar resonance theory, the physics behind the generation of giant chiro-optical effects have also been investigated. The proposed dielectric chiral meta-platform based on the extra degree of freedom can find application in compact integrated optical setups for CD spectroscopy, enantiomer separation and detection, spin-dependent color filters, and beam splitters.


Axially Chiral Enamides: Substituent Effects, Rotation Barriers, and Implications for their Cyclization Reactions.
The barrier to rotation around the N-alkenyl bond of 38 N-alkenyl-N-alkylacetamide derivatives was measured (ΔG(⧧) rotation varied between <8.0 and 31.0 kcal mol(-1)). The most important factor in controlling the rate of rotation was the level of alkene substitution, followed by the size of the nitrogen substituent and, finally, the size of the acyl substituent. Tertiary enamides with four alkenyl substituents exhibited half-lives for rotation between 5.5 days and 99 years at 298 K, sufficient to isolate enantiomerically enriched atropisomers. The radical cyclizations of a subset of N-alkenyl-N-benzyl-α-haloacetamides exhibiting relatively high barriers to rotation round the N-alkenyl bond (ΔG(⧧) rotation >20 kcal mol(-1)) were studied to determine the regiochemistry of cyclization. Those with high barriers (>27 kcal mol(-1)) did not lead to cyclization, but those with lower values produced highly functionalized γ-lactams via a 5-endo-trig radical-polar crossover process that was terminated by reduction, an unusual cyclopropanation sequence, or trapping with H2O, depending upon the reaction conditions. Because elevated temperatures were necessary for cyclization, this precluded study of the asymmetric transfer in the reaction of individual atropisomers. However, enantiomerically enriched atropsiomeric enamides should be regarded as potential asymmetric building blocks for reactions that can be accomplished at room temperature.


Is Workload Associated With Internal Impingement in Professional Baseball Pitchers? An Analysis of Days of Rest, Innings Pitched, and Batters Faced.
Internal impingement is a common cause of shoulder pain and dysfunction in baseball pitchers. The purpose of this study was to determine if the amount of rest days between outings, the number of innings pitched in each outing, and the number of batters faced in each outing are risk factors for internal impingement in professional baseball pitchers. It was hypothesized that a higher workload would significantly increase a pitcher's risk of developing internal impingement. Case-control study; Level of evidence, 3. All professional (Major and Minor League) baseball pitchers who were diagnosed with internal impingement between 2011 and 2017 were identified using the Major League Baseball's Health and Injury Tracking System. A separate player usage data set was used to determine workload. The authors compared workload variables (days of rest, innings pitched, and batters faced per game) between each of 4 injury-exposure groups (pitchers with documented internal impingement <2, <6, <12, and >12 weeks after a game) and a control group of pitchers with no internal impingement using Student t tests or Mann-Whitney U tests. In a within-pitcher paired analysis of the injury groups, the workload variables during 3 acute periods (<2, <6, and <12 weeks preinjury) were compared with the baseline values (>12 weeks preinjury). Overall, there were 624 professional baseball pitchers diagnosed with internal impingement during the study period. Compared with pitcher games (n = 213,964), pitchers in all 4 injury-exposure groups had significantly more innings pitched per game (P ≤ .003 for all) and faced significantly more batters per game (P < .001 for all). There were significantly more starting pitchers in each of the injury-exposure groups when compared with the controls (P < .001 for all). However, when comparing acute and baseline workloads in the pitchers diagnosed with internal impingement, there were no significant differences in the number of innings pitched, batters faced, or days of rest. This analysis revealed significantly greater pitcher workload and percentage of starting pitchers in professional baseball players diagnosed with internal impingement when compared with healthy controls. However, this injury did not seem to be associated with an acute increase in workload.


Overexpression of OsZHD1, a zinc finger homeodomain class homeobox transcription factor, induces abaxially curled and drooping leaf in rice.
Leaf rolling is receiving considerable attention as an important agronomic trait in rice (Oryza sativa L.). However, little has been known on the molecular mechanism of rice leaf rolling, especially the abaxial rolling. We identified a novel abaxially curled and drooping leaf-dominant mutant from a T₁ transgenic rice line. The abaxially curled leaf phenotypes, co-segregating with the inserted transferred DNA, were caused by overexpression of a zinc finger homeodomain class homeobox transcription factor (OsZHD1). OsZHD1 exhibited a constitutive expression pattern in wild-type plants and accumulated in the developing leaves and panicles. Artificial overexpression of OsZHD1 or its closest homolog OsZHD2 induced the abaxial leaf curling. Histological analysis indicated that both the increased number and the abnormal arrangement of bulliform cells in leaf were responsible for the abaxially curled leaves. We herein reported OsZHD1 with key roles in rice morphogenesis, especially in the modulating of leaf rolling, which provided a novel insight into the molecular mechanism of leaf development in rice.


The lncRNA CASC9 alleviates lipopolysaccharide-induced acute kidney injury by regulating the miR-424-5p/TXNIP pathway.
This study aimed to clarify the mechanism by which the long non-coding RNA cancer susceptibility candidate 9 (CASC9) alleviates sepsis-related acute kidney injury (S-AKI). A lipopolysaccharide (LPS)-induced AKI model was established to simulate S-AKI. HK-2 human renal tubular epithelial cells were treated with LPS to establish an in vitro model, and mice were intraperitoneally injected with LPS to generate an in vivo model. Subsequently, the mRNA expression of inflammatory and antioxidant factors was validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Reactive oxygen species (ROS) production was assessed using an assay kit. Apoptosis was detected by western blotting and fluorescence-activated cell sorting. CASC9 was significantly downregulated in the LPS-induced AKI model. CASC9 attenuated cell inflammation and apoptosis and enhanced the antioxidant capacity of cells. Regarding the mechanism, miR-424-5p was identified as the downstream target of CASC9, and the interaction between CASC9 and miR-424-5p promoted thioredoxin-interacting protein (TXNIP) expression. CASC9 alleviates LPS-induced AKI in vivo and in vitro, and CASC9 directly targets miR-424-5p and further promotes the expression of TXNIP. We have provided a possible reference strategy for the treatment of S-AKI.


Doppler changes as the earliest parameter in fetal surveillance to detect fetal compromise in intrauterine growth-restricted fetuses.
It is estimated that 3-10% of infants are growth restricted. Growth disturbances may have long-term issues. Doppler allows insight into the fetal response to intrauterine stress. The aim of this study was to detect fetal compromise in intrauterine growth-restricted (IUGR) fetuses by means of biophysical profile (BPP) vis-à-vis Doppler velocimetry studies of the fetal umbilical artery, and to find out which of the two is a better and earlier predictor of fetal compromise. A prospective study was conducted on a total of 50 singleton pregnancies with IUGR between 28 and 42 weeks of gestation. Study patients were managed expectantly with nonstress testing and amniotic fluid assessment, BPP and Doppler velocimetry studies of the fetal umbilical artery. Fetal outcome was poor in 5/50 (10%) of the fetuses, defined as presence of all of the following: poor Apgar test score, neonatal intensive care unit stay, necrotizing enterocolitis, and low birth weight. Of the four with abnormal BPP, 50% had poor fetal outcomes. Out of 46 with normal BPP, 6.5% had poor fetal outcomes. Inference drawn from the study is that the Doppler technology provides us the opportunity for repetitive noninvasive hemodynamic monitoring in IUGR pregnancies.


Cronkhite-Canada syndrome: report of two cases, biopsy findings in the associated alopecia, and a new treatment option.
Two patients with Cronkhite-Canada syndrome (CCS) are reported, both of whom had diffuse alopecia, nail and skin changes, gastrointestinal polyposis, diarrhea, and wasting. A scalp biopsy was performed in one patient, and the specimen showed a marked noninflammatory loss of follicular units, miniaturization of the hair shafts, markedly dilated follicles, and a heavy deposition of glycosaminoglycans in the reticular dermis. This patient responded to prednisone therapy. The other patient was found to have elevated gastric acid levels and responded to ranitidine therapy. The conditions of both patients are now in remission two and six years later, respectively. Our patients have shown a temporally related remission of disease during treatment with prednisone and ranitidine, suggesting that each agent may be effective in CCS. However, randomized placebo-controlled trials are needed to prove the efficacy of these therapies. Further investigation of the histopathologic features of the associated alopecia may determine its cause.


Early life development in a multiethnic sample and the relation to late life cognition.
Poor quality of early life conditions has been associated with poorer late life cognition and increased risk of dementia. Early life physical development can be captured using adult measures of height and head circumference. Availability of resources may be reflected by socioeconomic indicators, such as parental education and family size. We sought to determine the association between early life development and experience and late life semantic memory, episodic memory, and executive functioning abilities, as well as rate of cognitive decline. This study was conducted using the UC Davis Aging Diversity cohort, an ethnically diverse sample of Caucasian, African American, and Hispanic individuals from northern California. We used latent variable modeling to measure growth and childhood socioeconomic environment (SES) and examine their associations with longitudinal cognitive outcomes using mixed effects modeling. Growth was positively related to higher childhood SES. Higher childhood SES was associated with better semantic memory. Both low growth and low SES were associated with increased rate of cognitive decline. These findings demonstrate that early life experiences influence the trajectory of cognitive aging. Early life development and experience appears to provide a distal basis upon which additional risk and protective factors interact in the development of dementia.


Personality and life satisfaction: a facet-level analysis.
At the global level of the Big Five, Extraversion and Neuroticism are the strongest predictors of life satisfaction. However, Extraversion and Neuroticism are multifaceted constructs that combine more specific traits. This article examined the contribution of facets of Extraversion and Neuroticism to life satisfaction in four studies. The depression facet of Neuroticism and the positive emotions/cheerfulness facet of Extraversion were the strongest and most consistent predictors of life satisfaction. These two facets often accounted for more variance in life satisfaction than Neuroticism and Extraversion. The findings suggest that measures of depression and positive emotions/cheerfulness are necessary and sufficient to predict life satisfaction from personality traits. The results also lead to a more refined understanding of the specific personality traits that influence life satisfaction: Depression is more important than anxiety or anger and a cheerful temperament is more important than being active or sociable.


Separating bias and sensitivity in judgments of associative memory.
Ratings of the degree of association between words are linearly related to normed associative strengths, but the intercept is high, and the slope is shallow (the judgments of associative memory [JAM] function). Two experiments included manipulations intended to decrease the intercept and increase the slope. Discrimination training on many pairs of words and constraining ratings to sum to a constant both reduced the intercept but failed to change the slope. The intercept of the JAM function appears to contain a bias component that can be manipulated independently of the slope, which reflects sensitivity to associative strengths.


The Inheritance Angle: A Determinant for the Number of Members in the Substituted Cucurbit[n]uril Family.
Two new glycoluril diethers have been prepared, bearing strained cyclobutene and cyclobutane rings at the fused junction of the two imidazolidinone rings. The wide angle of the concave face of the cyclobutano derivative enabled the synthesis of cyclobutanocucurbit[5-8]uril, the largest member being the most significant achievement. A limited binding affinity study compared the new substituted family to classical cucurbit[5-8]uril. Surprisingly lower affinities were found, except for cyclobutanocucurbit[6]uril, which was 3.3-fold higher.


A theory of international bioethics: multiculturalism, postmodernism, and the bankruptcy of fundamentalism.
The first of two articles analyzing the justifiability of international bioethical codes and of cross-cultural moral judgments reviews "moral fundamentalism," the theory that cross-cultural moral judgments and international bioethical codes are justified by certain "basic" or "fundamental" moral priniciples that are universally accepted in all cultures and eras. Initially propounded by the judges at the 1947 Nuremberg Tribunal, moral fundamentalism has become the received justification of international bioethics, and of cross-temporal and cross-cultural moral judgments. Yet today we are said to live in a multicultural and postmodern world. This article assesses the challenges that multiculturalism and postmodernism pose to fundamentalism and concludes that these challenges render the position philosophically untenable, thereby undermining the received conception of the foundations of international bioethics. The second article, which follows, offers an alternative model -- a model of negotiated moral order -- as a viable justification for international bioethics and for transcultural and transtemporal moral judgments.


The use of geographical information systems in examining variations in sociodemographic profiles of dental practice catchments: a case study of a Swansea practice.
The aim of this paper is to use a case study approach to illustrate the potential for using geographical information systems (GIS) to examine the provision of dental services in the UK. A major benefit of using GIS to examine sociodemographic profiles of patients on a dental register is to inform policy makers. We illustrate the advantages of such an approach by using a postcoded list of registered patients for a dental practice in Swansea. To be of value in this context, the maintenance of up-to-date and fully postcoded information by practitioners is vital. We draw attention to the advantages (and current limitations) of using deprivation indices in conjunction with such lists. GIS has significant potential in analysing patterns of registration, and utilisation, of such services but, to date, there has been a relative dearth of studies that have developed such systems. We conclude by drawing attention to wider benefits of such software tools in the dental profession and outline a research agenda to take these issues further.


Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome.
Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission. We conducted a prospective open-label 10-week trial of acamprosate in 12 youth aged 6-17 years (mean age: 11.9 years) with FXS. Acamprosate use (mean dose: 1,054 ± 422 mg/day) was associated with treatment response (defined by a Clinical Global Impressions Improvement (CGI-I) scale score of "very much improved" or "much improved") in nine of 12 (75 %) subjects. Improvement was noted in social behavior and inattention/hyperactivity using multiple standard behavioral outcome measures. No significant adverse effects or changes in vital signs, including weight or laboratory measures, occurred during treatment with acamprosate. Additionally, pre- and post-treatment blood biomarker analyses looking at brain-derived neurotrophic factor (BDNF) levels found a significant increase in BDNF with treatment. In our pilot sample, treatment response did not correlate with change in BDNF with treatment. Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted.


Effect of evening exposure to dim or bright light on the digestion of carbohydrate in the supper meal.
In a previous study we found that daytime exposure to bright as compared to dim light exerted a beneficial effect on the digestion of the evening meal. This finding prompted us to examine whether the digestion of the evening meal is also affected by evening light intensity. Subjects lived in light of 200 lux during the daytime (08:00-17:00 h) and took their evening meal at 17:00 h under 20 lux (evening dim-light condition: 17:00-02:00 h) or 2000 lux (evening bright-light condition: 17:00-02:00 h) until retiring at 02:00 h. Assessment of carbohydrate digestion of the evening meal was accomplished by a breath hydrogen test that is indicative of the malabsorption of dietary carbohydrate. Hydrogen excretion in the breath in the evening under the dim-light condition was significantly less than under the bright-light condition (p < 0.05). This finding is the opposite to that obtained in previous experiments in which subjects were exposed to the different intensities of light during the daytime, and indicates that the exposure to dim light in the evening exerts a better effect on carbohydrate digestion in the evening meal than does the exposure to bright light.


Recent Advances in Breast Reconstruction.
The incidence of breast cancer in the United States is high and appears to be increasing. The American cancer Society has estimated that one in nine American women (11 percent) will eventually develop breast carcinoma. Recently there has been a dramatic shift away from mastectomy and toward breast-conserving therapy (Iumpectomy, axillary node dissection and whole breast irradiation). In some centres the majority of breast cancer patients are now treated with conservation therapy. Some patients, however, are not candidates for radiation, because of the size, location or histology of their tumour and are still best treated by mastectomy and reconstruction. Women who develop local recurrence following radiation therapy are likewise candidates for mastectomy with reconstruction. Additionally, there is a large group of women who had mastectomies in years past who have not had reconstruction. Thus many patients may potentially benefit from breast reconstruction.


Citrate content of liver and kidney of rat in various metabolic states and in fluoroacetate poisoning.
The citrate content of rat liver changes little when normal rats are starved, when starved rats are re-fed with various diets and when normal animals are made diabetic with alloxan. The citrate content of rat kidney changes little on starvation, but it doubles on induction of diabetes. Fluoroacetate poisoning has relatively little effect on the citrate content of liver under a variety of conditions except that normal female rats show a 2.4-fold increase. Fluoroacetate poisoning leads to increases in the citrate content of kidney under all conditions. The relevance of these observations to the regulation of fatty acid synthesis is discussed. The acetic anhydride-pyridine method and the pentabromoacetone method for the estimation of citrate are compared.


Heart failure: ivabradine is no better than optimised beta-blocker therapy.
In a double-blind randomised placebo-controlled trial including about 6500 heart failure patients, ivabradine did not reduce overall mortality or cardiovascular mortality. Ivabradine reduced mortality due to heart failure, but not in the subgroup of patients receiving at least half the recommended dose of a beta-blocker. In a double-blind randomised placebo-controlled trial in about 10 000 patients with coronary artery disease and heart failure, ivabradine had no tangible efficacy. Treatment withdrawals were more frequent with ivabradine than in the placebo arms of these trials. Adverse effects included bradycardia and visual disorders. In practice, beta-blockers used at optimal doses have documented efficacy in heart failure patients. This is not the case for ivabradine, and its adverse effects have been confirmed.


5alpha-reductase type 1 immunostaining is enhanced in some prostate cancers compared with benign prostatic hyperplasia epithelium.
In the prostate testosterone is converted to the more potent androgen dihydrotestosterone by the enzymes 5alpha-reductase (5alphaR) types 1 (5alphaR1) and 2 (5alphaR2). Since 5alphaR2 is the dominant prostatic enzyme, the 5alphaR2 selective inhibitor finasteride has been widely used to treat benign prostatic hyperplasia (BPH). However, inhibition of both 5alphaR enzymes provides a greater decrease in serum dihydrotestosterone. We developed a specific antibody to 5alphaR1 and assessed expression in BPH and prostate cancer (pCa) tissue. The presence of this isoenzyme in localized prostate cancer would provide a rationale for assessing the efficacy of dual inhibition for prostate cancer prevention. A polyclonal antibody to 5alphaR1 was developed and validated using 5alphaR1 and 5alphaR2 transfected COS-1 cells. A total of 26 BPH and 53 pCa specimens were assessed for 5alphaR1 protein expression using immunocytochemical methods. Also, 29 BPH and 37 pCa specimens were assayed for 5alphaR1 and 5alphaR2 enzyme activity. Specificity of the 5alphaR1 antibody was confirmed using transfected COS-1 cells. Cells transfected with 5alphaR1 showed specific staining in immunocytochemistry experiments and on Western blotting of cell lysates the expected 24 kDa band was observed. High intensity immunoreactivity for 5alphaR1 was observed in the tumor epithelium of 28% of pCa specimens. No high intensity epithelial staining was observed in BPH specimens. In 19% of pCa and 7% of BPH specimens 5alphaR1 enzyme activity was detected. The presence of increased 5alphaR1 in some prostatic malignancies suggests that it is worthwhile to investigate the use of a dual 5alphaR inhibitor to prevent or treat early stage prostate cancer.


Analysis of volatile organic compounds in the exhaled breath for the diagnosis of lung cancer.
Volatile organic compounds are able to be detected in the exhaled breath by a variety of sensing techniques. These volatiles may be produced by cellular metabolic processes, or inhaled/absorbed from exogenous sources. Lung cancer cells may produce and process these compounds different than normal cells. The differences may be detectable in the breath. The following manuscript will review the evidence supporting the premise that a unique chemical signature can be detected in the breath of patients with lung cancer, discuss the results of studies using mass spectrometry and nonspecific chemical sensing techniques to detect the unique lung cancer signature, and speculate on the advancements that must occur to develop a breath test accurate enough to be clinically useful.


Nutrition and interference competition have interactive effects on the behavior and performance of Argentine ants.
Food availability often influences competitive outcomes through effects on consumer growth. Although it has received less attention, food availability may also affect competition through nutritional effects on behavior. One hypothesis linking nutrition and competition in ants posits that increased access to carbohydrates favors greater investment in worker traits that underlie behavioral dominance. We tested this hypothesis by varying dietary protein:carbohydrate (P:C) ratios and levels of interspecific interference for Argentine ants (Linepithema humile), a widespread invasive species. As predicted, colonies facing interference increased patrolling more when reared on low P:C diets; this result is the first demonstration of an interactive effect of nutrition and interference on ant colonies. Several results suggest that this dietary effect on patrolling was due primarily to changes in colony size rather than worker behavior. Colonies on lower P:C diets had lower worker mortality and larger final colony sizes. Diet had little effect on per capita patrolling, and worker behavior in performance assays depended more on previous exposure to interference than on diet. Our findings indicate that dietary P:C ratios can influence Argentine ant performance in a competitive environment and suggest a mechanism by which monopolization of carbohydrate-rich resources can help invasive ants displace native ant competitors.


Cocaine enhances HIV-1 infectivity in monocyte derived dendritic cells by suppressing microRNA-155.
Cocaine and other drugs of abuse increase HIV-induced immunopathogenesis; and neurobiological mechanisms of cocaine addiction implicate a key role for microRNAs (miRNAs), single-stranded non-coding RNAs that regulate gene expression and defend against viruses. In fact, HIV defends against miRNAs by actively suppressing the expression of polycistronic miRNA cluster miRNA-17/92, which encodes miRNAs including miR-20a. IFN-g production by natural killer cells is regulated by miR-155 and this miRNA is also critical to dendritic cell (DC) maturation. However, the impact of cocaine on miR-155 expression and subsequent HIV replication is unknown. We examined the impact of cocaine on two miRNAs, miR-20a and miR-155, which are integral to HIV replication, and immune activation. Using miRNA isolation and analysis, RNA interference, quantitative real time PCR, and reporter assays we explored the effects of cocaine on miR-155 and miR-20 in the context of HIV infection. Here we demonstrate using monocyte-derived dendritic cells (MDCCs) that cocaine significantly inhibited miR-155 and miR-20a expression in a dose dependent manner. Cocaine and HIV synergized to lower miR-155 and miR-20a in MDDCs by 90%. Cocaine treatment elevated LTR-mediated transcription and PU.1 levels in MDCCs. But in context of HIV infection, PU.1 was reduced in MDDCs regardless of cocaine presence. Cocaine increased DC-SIGN and and decreased CD83 expression in MDDC, respectively. Overall, we show that cocaine inhibited miR-155 and prevented maturation of MDDCs; potentially, resulting in increased susceptibility to HIV-1. Our findings could lead to the development of novel miRNA-based therapeutic strategies targeting HIV infected cocaine abusers.


Discovery of new open-air Paleolithic localities in Central Alborz, Northern Iran.
The cooperative French-Iranian Paleoanthropological Project (FIPP) discovered three Paleolithic localities in Central Alborz, Northern Iran during its 2005 field mission. In the northern foothills near Baliran in Mazandârân province, Garm Roud yielded an open-air site with an archaeological layer attributable to the last glacial period that dates from the end of OIS 3 (28,486+/-190 cal BP). These geochronological data and the typo-technical observations converge to place the Garm Roud 2 assemblage in the Upper Paleolithic. Garm Roud 2 is thus the first site of this kind discovered in the area. In the southern foothills near Damâvand in Tehran province, Moghanak and Otchounak represent two open-air surface localities with lithic assemblages of Mousterian to Ante-Mousterian affinity. Garm Roud, Moghanak, and Otchounak provide some of the first direct field evidence of early human settlements in this central area of the Middle East.


In vitro translation of the intermediate filament proteins desmin and vimentin.
Polyadenylated ribonucleic acid (RNA) was isolated from chicken skeletal and smooth muscle and translated in a cell-free rabbit reticulocyte system. Both types of muscle tissue contain messenger RNAs that code for the intermediate filament proteins desmin and vimentin, and the relative concentrations of the two translation products reflect the prevalence of the two proteins in vivo. Desmin synthesis represents a greater proportion of the total protein synthesis from smooth muscle RNA than from skeletal muscle RNA, whereas the converse is true of vimentin synthesis. Fractionation of the RNA on formamide-containing sucrose gradients before translation indicates that the desmin messenger RNA is larger than the vimentin messenger RNA and contains an extensive noncoding segment. The desmin and vimentin messages code predominantly for the non-phosphorylated forms of desmin and vimentin. However, the ratio of phosphorylated to unphosphorylated forms of the proteins could be increased by adding cyclic adenosine monophosphate-dependent kinase activity to the translation mixtures. These results suggest that desmin and vimentin are each synthesized from a single messenger RNA species and that posttranslational phosphorylation generates the additional isoelectric variants of each which are observed in vivo.


Transcription factor EGR1 promotes differentiation of bovine skeletal muscle satellite cells by regulating MyoG gene expression.
The transcription factor, early growth response 1 (EGR1), has important roles in various cell types in response to different stimuli. EGR1 is thought to be involved in differentiation of bovine skeletal muscle-derived satellite cells (MDSCs); however, the precise effects of EGR1 on differentiation of MDSCs and its mechanism of action remain unknown. In the present study, a time course of EGR1 expression and the effects of EGR1 on MDSC differentiation were determined. The results demonstrated that the expression of EGR1 mRNA and protein increased significantly in differentiating MDSCs relative to that in proliferating cells. Over-expression of the EGR1 gene in MDSCs promoted their differentiation and inhibited proliferation. Conversely, knock-down of EGR1 inhibited differentiation of MDSCs and promoted their proliferation, indicating that EGR1 promotes MDSC differentiation. Moreover, over-expression of EGR1 in MDSCs increased the expression of MyoG mRNA and protein, whereas its knock-down had the opposite effect. Furthermore, ChIP-PCR analyses demonstrated that EGR1 could bind directly to its putative binding site within the promoter region of MyoG, and determination of ERG1 subcellular localization in MDSCs demonstrated that it could relocate to the nucleus, indicating MyoG is likely an EGR1 target gene whose expression is positively regulated by this transcription factor. In conclusion, EGR1 can promote MDSC differentiation through positive regulation of MyoG gene expression.


Correspondence: A combination of sectional micro-anatomy and micro-stereoscopic anatomy is an improved micro-dissection method.
It is easy to make errors in estimating the exact size and positioning of neural structures, especially when only using tomographic methods, as a lot of imagination and little precision is required. We found that combining the use of sectional micro-anatomy and micro-stereoscopic anatomy is much more accurate. We believe that our study makes a significant contribution to the literature because we believe that using improved methods to examine the neural structure is vital in future research on the micro-stereoscopic anatomy of the brain.


Late-onset posttraumatic stress disorder.
Posttraumatic stress disorder (PTSD) is a complex psychological response to a perceived life-threatening trauma that includes re-experiencing the trauma, avoidance, intrusive thoughts, hyperarousal, and dissociation. Exposure to trauma in early adulthood increases the potential for further psychological threats throughout life. In older adult populations, PTSD is an underrecognized and undertreated disorder that can result in psychosocial disability, substance use, and other negative health outcomes. This article examines the range of symptoms related to PTSD in older adults and expands on health care provider sensitivity to the interrelationship of mental and physical health when addressing the needs of older adults with this disorder.


Drastic reduction in time to controlled viral load in people with HIV in France (2009-2019): a longitudinal cohort study.
Aspirational targets to end AIDS by 2030 include 95% of PWH diagnosed, 95% treated, and 95% with controlled viral load (VL). Our objective was to describe, using a large French prospective cohort, the median transition times through the cascade of care, between 2009 and 2019, taking into account patients' characteristics. We analyzed patients whose first HIV diagnosis was made between 2009/01/01 and 2019/12/31. Using Kaplan-Meier method we estimated time to linkage to care (from HIV diagnosis to first biological assessment), to treatment (using the date of first ART prescription), and to controlled VL (first value below 200 copies/ml). Analyses were disaggregated by time periods and patients' characteristics. Censoring date was 2021/12/31. Among the 16 864 patients linked to care since 2009, the median [Q1;Q3] time from HIV diagnosis to controlled VL decreased from 254 [127-745] to 73 [48-132] days in 2009-2011 and 2018-2019, respectively. Transition times from linkage to care to first ART decreased from 67 [17;414] in 2009-2011 to 13 [5;26] days in 2018-2019, and from ART to controlled VL from 83 [35;130] in 2009-2011 to 38 [28;90] days in 2018-2019. Differences were observed depending on patients' characteristics. We describe drastic reductions in transition time through the cascade of care, allowing to reduce the transmission period following each new infection. Delayed diagnosis remains the main obstacle to end AIDS in the next decade.


Exercise-induced anaphylaxis.
A 23-year-old man presented with acute flushing, pruritus and warmth followed by collapse after vigorous exercise in a gymnasium. After resting for 30 min and receiving a rapid infusion of 0.9% sodium chloride, he was finally stable. He admitted that he had a similar experience 5 years earlier during exercise. Based on the patient's history, his symptoms were attributed to exercise-induced anaphylaxis. None of his episodes was associated with any suspicious co-triggers of anaphylaxis. He was successfully discharged from hospital without any complications after receiving guidance on how to prevent this condition.


[Traditional prescription rules of Aconitum herbs in treatment of Bi syndrome].
The application of Aconitum herbs in the treatment of Bi syndrome has a long history and exact effects.By taking Aconiti Radix(Chuanwu), Aconiti Kusnezoffii Radix(Caowu) and Aconiti Lateralis Radix Preparata(Fuzi) as example, this study was aimed to mine the prescription rules of Aconitum herbs in the treatment of Bi syndrome, and provide thoughts and bases for modern clinical medication. 1 106 prescriptions were obtained in more than 20 classic books including medical, pharmacy, and synthesized books from Eastern Han dynasty to Qing dynasty. Based on the methods of frequency statistics, percentile statistics and Apriori algorithm of association rules, the characteristics of syndrome classification, dosage and compatibility of Aconitum herbs in the treatment of Bi syndrome were analyzed. The data-mining results indicated that 60.76% prescriptions contained Fuzi, which was obviously higher than Chuanwu or Caowu, and 17.63% contained two or more kinds of Aconitum herbs. 70.34% prescriptions were used mainly to treat Bi syndrome with wind-cold-wetness, others were for the syndrome with the deficiency of liver and kidney, blockage of phlegm and blood stasis, and wind-heat-wetness Bi. In the prescriptions with definite dose, 80% dosage of Fuzi was in the range from 0.29-2.14 g·d⁻¹, while the dosage of Chuanwu and Caowu was from 0.14-1.01g·d⁻¹, which was also affected by patterns, formulations and processing. The dose of Aconitum herbs was highest in the Bi syndrome with wind-cold-wetness, and its dose in the decoction and vinum was significantly higher than that in the pills and powders. The processed products were used in 93.11% prescriptions, and their dosage was higher than the raw ones. In the clinical treatment of Bi syndrome, Chuanwu and Caowu were often used with Saposhnikoviae Radix(Fangfeng), Liquiritiae Radix et Rhizoma(Gancao), Myrrha(Moyao) and Ephedrae Herba(Mahuang), while Fuzi was often used with Cinnamomi Cortex(Rougui), Achyranthis Bidentatae Radix(Niuxi), Fangfeng and Chuanxiong Rhizoma(Chuanxiong), which can both expel wind-dampness and relieve pain. All in all, Aconitum herbs are widely used in the treatment of Bi syndrome, which can relieve arthralgia and pain.


Detection of antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific interstitial pneumonia.
It has been suggested that the humoral immune system plays a role in the pathogenesis of non-specific interstitial pneumonia (NSIP). Although some circulating autoantibodies to cytoskeletal protein(s) have been suggested, the antimyofibroblast antibody has not been investigated in patients with idiopathic pulmonary fibrosis (IPF) and NSIP. The purpose of this study is to evaluate the existence of antimyofibroblast antibody in the sera of patients with IPF and NSIP. The MRC5 cell line was used as a model of myofibroblast. The anti-MRC5 cell antibody was characterized in a patient with NSIP using Western blotting. Since we found that one of the anti-MRC5 antibodies was an antivimentin antibody, we established an enzyme-linked immunosorbent assay (ELISA) to measure the levels of antivimentin antibody in the sera of patients with IPF (n = 12) and NSIP (n = 23). Initially, two anti-MRC5 cell antibodies were detected in the sera of patients with NSIP, one of which was characterized as the antivimentin antibody by Western blotting. The other was characterized as an antivimentin fragment antibody. We established an ELISA to measure the antivimentin antibody and found significantly higher levels in patients with IPF and NSIP than in normal volunteers. One of the anti-MRC5 cell antibodies in the serum of a patient with NSIP was against vimentin. The serum levels of antivimentin antibody were increased in patients with IPF and NSIP compared with that of normal volunteers. These results suggest that the antivimentin antibody may be involved in the process of lung injury in IPF and NSIP.


Clinical features of pediatric patients with coronavirus disease (COVID-19).
Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 has spread around the world, and reports of children with COVID-19 are increasing. To assess clinical profiles of pediatric COVID-19. A retrospective analysis was undertaken using clinical data of sixteen children (11 months-14 years) diagnosed with COVID-19 between January 1, 2020 and March 17, 2020 at Xiangyang Central Hospital, Hubei province, China. All children had positive epidemiologic histories, 12 (12/16, 75 %) involving family units. The illnesses were either mild (5/16, 31.3 %) or ordinary (11/16, 68.8 %), presenting as follows: asymptomatic (8/16, 50 %), fever and/or cough (8/16, 50 %). Four asymptomatic patients (4/16, 25 %) in ordinary cases had chest computed tomography (CT) abnormalities. Leukocyte counts were normal in 14 cases(88 %), but 2 patients (12.5 %) had leukopenia, and 1 (6.3 %) was lymphopenic. There were 11 patients with chest CT abnormalities, some nodular, others small patchy and others ground-glass opacities. In asymptomatic children, the median time to SRAS-CoV-2 nucleic acid test(NAT) positivity once exposed to a family member with confirmed infection was 15.5 days (range, 10-26 days). The median time to first NAT-negative conversion was 5.5 days (range, 1-23 days). COVID-19 in children of Xiangyang city is often family acquired and not serious, with favorable outcomes. Asymptomatic children can be diagnosed as pneumonia because of chest CT abnormalities. It is essential to actively screen this segment of the population.


Implementing a hybrid approach to select patients for care management: variations across practices.
Appropriate selection of patients is key to the success of care management programs (CMPs). Hybrid patient selection approaches, in which large data assets are culled to develop a list of patients for more targeted clinical review, are increasingly common. We sought to describe the patient and practice characteristics associated with high-risk patient identification and selection for a CMP during clinical review, and to explore variation across primary care practices. Retrospective cohort study. Standardized estimates of Medicare beneficiaries identified as high risk for poor outcomes and high medical expense, and appropriate for a CMP within a large Pioneer Accountable Care Organization, were developed using mixed effects logistic models. Study subjects were 2685 Medicare beneficiaries aged over 18 (includes individuals eligible for Medicare due to a disability) aligned to 35 primary care practices in 2013. Independent predictors of patient identification as high risk include older age; higher risk score; recent increases in medical conditions; higher numbers of medical hospitalizations, skilled nursing facility days, and primary care physician visits; and shorter relationships with the primary care physician. Older age, and lower income, but no prior hospice use were independently associated with patient selection for a CMP among the subset of patients identified as being high risk. Adjusted predicted percents of high-risk patients varied significantly across practices overall and for 5 of the 6 patient characteristics that were independently associated with identification as high risk. Inconsistency in high-risk patient identification and selection for a CMP may reflect differences in practice resources, but also highlight the need for continual training and feedback in order to protect against unintentional biases.


Electronic mail: an imperative for healthcare epidemiologists.
Electronic mail (e-mail) offers the potential for near-instantaneous transfer of messages and files across thousands of miles. The same message can be sent simultaneously to multiple recipients and forwarded without retyping. Messages can be sent or read at any time, eliminating "telephone tag," and, because the system is paperless, lost, blurred, and incomplete, facsimile transmissions can be minimized. Additionally, e-mail is less expensive than overnight letter services or long-distance faxes. All healthcare epidemiologists should enter the information superhighway using e-mail. This article provides basic information needed to understand and begin using e-mail.


Advanced Glycation End-Products Downregulate HoxA9EC through Activation of Nuclear Factor Kappa B by Reciprocal Interaction.
Advanced glycation end-products (AGEs) have been recognized as an important pathophysiological mechanism in endothelial dysfunction during diabetic atherogenesis. Homeobox (Hox) genes have been identified as playing a regulatory role in the adult cardiovascular system. Regulation of HoxA9EC is involved in diabetic endothelial dysfunction, but the mechanism of HoxA9EC regulation has remained undefined. Here, we sought to investigate how HoxA9EC is regulated in AGE-induced endothelial dysfunction and to explore the mechanism involved. We used human umbilical venous endothelial cells (HUVECs) cocultured with AGEs, and examined endothelial nitric oxide synthase (eNOS) activation, nitric oxide (NO) release, cell migration, and the expression of HoxA9EC and nuclear factor kappa B (NF-κB). AGEs suppressed eNOS activation, NO release, and the migration of HUVECs. Knockout of HoxA9EC also reduced eNOS activation, NO release, and the migration of HUVECs, and the enhancement of HoxA9EC improved the function of HUVECs. Furthermore, AGEs downregulated HoxA9EC expression and activated NF-κB, and the depression of HoxA9EC was significantly attenuated by the NF-κB inhibitor. On the other hand, knockout of HoxA9EC activated NF-κB and the enhancement of HoxA9EC suppressed NF-κB activation. In conclusion, AGEs could induce endothelial dysfunction through NF-κB-dependent HoxA9EC downregulation by reciprocal interaction, and the enhancement of HoxA9EC expression could attenuate the impairment.


Montmorillonite-supported Ag/TiO(2) nanoparticles: an efficient visible-light bacteria photodegradation material.
Montmorillonite (MMT)-supported Ag/TiO(2) composite (Ag/TiO(2)/MMT) has been prepared through a one-step, low-temperature solvothermal technique. Powder X-ray diffraction (XRD) and transmission electron microscopy (TEM) reveal that the Ag particles coated with TiO(2) nanoparticles are well-dispersed on the surface of MMT in the composite. As a support for the Ag/TiO(2) composite, the MMT prevents the loss of the catalyst during recycling test. This Ag/TiO(2)/MMT composite exhibits high photocatalytic activity and good recycling performance in the degradation of E. coli under visible light. The high visible-light photocatalytic activity of the Ag/TiO(2)/MMT composite is ascribed to the increase in surface active centers and the localized surface plasmon effect of the Ag nanoparticles. The Ag/TiO(2)/MMT materials with excellent stability, recyclability, and bactericidal activities are promising photocatalysts for application in decontamination.


[Paratuberculosis in cattle. Reflections on the interactions with Crohn disease in humans. A literature review].
Based on more than 30 literature references, the author tries to explain the phenomena of paratuberculosis in cattle. He gives a short description of the origin of the infection, the disease categories, the diagnostic problems and eradication. Also the human infection with the Mycobacterium known as Mycobacterium avium supspecies paratuberculosis (MAP)--a recognized pathogen in animals causing some or possibly all cases of Crohn's disease will be discussed. The conclusion is that until now no study gives evidence that MAP may be transmitted to humans through foods derived from cattle with MAP infection.


Prevention and control strategies for ticks and pathogen transmission.
Ticks and tick-borne pathogens have evolved together, resulting in a complex relationship in which the pathogen's life cycle is perfectly coordinated with the tick's feeding cycle, and the tick can harbour high pathogen levels without affecting its biology. Tick-borne diseases (TBDs) continue to emerge and/or spread, and pose an increasing threatto human and animal health. The disruptive impacts of global change have resulted in ecosystem instability and the future outcomes of management and control programmes for ticks and TBDs are difficult to predict. In particular, the selection of acaricide-resistant ticks has reduced the value of acaricides as a sole means of tick control. Vaccines provide an alternative control method, but the use of tick vaccines has not advanced since the first vaccines were registered in the early 1990s. An understanding of the complex molecular relationship between hosts, ticks and pathogens and the use of systems biology and vaccinomics approaches are needed to discover proteins with the relevant biological function in tick feeding, reproduction, development, immune response, the subversion of host immunity and pathogen transmission, all of which mediate tick and pathogen success. The same approaches will also be required to characterise candidate protective antigens and to validate vaccine formulations. Tick vaccines with a dual effect on tick infestations and pathogen transmission could reduce both tick infestations and their vector capacity for humans, animals and reservoir hosts. The development of integrated tick control strategies, including vaccines and synthetic and botanical acaricides, in combination with managing drug resistance and educating producers, should lead to the sustainable control of ticks and TBDs.


Poison center funding--who should pay?
To illustrate costs associated with poison center closure a survey of lay callers to the poison center and emergency department costs was conducted. For 21 days all callers to a Regional Poison Information Center receiving home treatment were asked the type of health insurance coverage the patient had. This information was documented on the medical record and tabulated. Health care costs were determined by surveying local hospitals. Of the callers, 1,276 (43%) provided insurance information: 928 (73%) of the patients were covered by private insurers; 258 (20%) received state medical assistance and 90 (7%) had no medical coverage. The average emergency department cost of an ingestion exposure was $210.75, ocular $172.22, and inhalation $298.03. In the absence of a Regional Poison Information Center responding to 61,000 calls annually, the state would incur a debt ranging from 1.27 to 2.20 million dollars if 60% of those covered under state assistance went to the emergency department. Private insurers would forfeit 4.58 to 7.93 million dollars per year. These cost estimates consider only the emergency department charges, not unnecessary admissions. State government and private insurers clearly are the financial beneficiaries of poison center services which save several times their operating costs.


Switchable Access to Different Spirocyclopentane Oxindoles by N-Heterocyclic Carbene Catalyzed Reactions of Isatin-Derived Enals and N-Sulfonyl Ketimines.
A novel NHC-catalyzed annulation protocol for the asymmetric synthesis of biologically important β-lactam fused spirocyclopentane oxindoles with four contiguous stereocenters, including two quaternary carbon centers, was developed. Alternatively, spirocyclopentane oxindoles containing an enaminone moiety can be achieved using the same starting materials, isatin-derived enals, and N-sulfonyl ketimines, in the presence of a slightly different NHC catalytic system. This switchable annulation strategy enables the selective assembly of both heterocyclic scaffolds with good yields and excellent enantioselectivities for a broad range of substrates.


miR-522-3p Promotes Tumorigenesis in Human Colorectal Cancer via Targeting Bloom Syndrome Protein.
miR-522-3p is known to degrade bloom syndrome protein (BLM) and enhance expression of other proto-oncogenes, leading to tumorigenesis. This study aimed to investigate the molecular mechanisms of miR-522-3p in human colorectal cancer (CRC) cells. Expressions of miR-522-3p in CRC and adjacent tissues, as well as in normal human colon epithelial cell line (FHC) and five CRC cell lines, were detected. Human CRC cell lines, HCT-116 and HT29, were transfected with miR-522-3p mimic, inhibitor, or scrambled controls. Then cell viability, apoptosis, cell cycle progression, and the expressions of c-myc, cyclin E, CDK2, and BLM were assessed. It was found that miR-522-3p was highly expressed in CRC tissues when compared to adjacent nontumor tissues and was highly expressed in CRC cell lines when compared to FHC cells. miR-522-3p overexpression promoted cell viability, reduced apoptotic cell rate, arrested more cells in the S phase, and upregulated c-myc, cyclin E, and CDK2 expression. BLM was a target gene of miR-522-3p, and miR-522-3p suppression did not exert antiproliferative and proapoptotic activities when BLM was silenced. These findings demonstrate that miR-522-3p upregulation negatively regulates the expression of BLM, with upregulation of c-myc, CDK2, and cyclin E, and thereby promoting the proliferation of human CRC cells.


Endovascular Management of Long-Segmental Petrocavernous Internal Carotid Artery (Carotid S) Occlusion.
Long-segmental thrombotic occlusion of the distal internal carotid artery (ICA) sparing the cervical segment proximally and the supraclinoid segment distally, which could be termed 'Carotid S occlusion', has an unusual clinical presentation. However, endovascular management of this lesion is challenging. The purpose of our study is to report our endovascular treatment clinical experience of the disease. From March 2008 to June 2013, we could identify 14 patients (average age: 62.1, median age: 62, range: 50-79) with 'Carotid S occlusion', who underwent endovascular recanalization procedures. Patient's clinical presentations were collected and the imaging findings also analyzed. The technical success rate, 24-hour and follow-up imaging outcome, and the clinical outcome using the 90-day mRS (modified Rankin scale) score were evaluated. Patients presented with gradually progressing (n = 8), fluctuating (n = 3), transient ischemic attack (n = 2) and stationary (n = 1) symptoms. DWI showed internal and external border-zone lesions in six patients, only internal ICA border-zone lesions in three patients, and only external border-zone lesions in two patients. Underlying distal ICA stenosis was noted in 12 patients. The technical success rate was 92.8% (13/14). Luminal patency was noted in all patients (100%) after 24 hours and in nine of 10 (90%) on long-term follow-up (median: 6.5, average: 15.1, range: 1-39 months). A 90-day, good functional outcome (mRS ≤ 2) was noted in 13 of 14 patients (92.8%). 'Carotid S occlusion' usually presented with border-zone infarction and endovascular management of the lesions was feasible. A relatively successful clinical outcome could be achieved after successful revascularization.


An oncogenic form of p53 confers a dominant, gain-of-function phenotype that disrupts spindle checkpoint control.
Although it is well-established that p53 functions as a tumor suppressor gene, certain mutations exhibit gain-of-function activities that increase oncogenic transformation. We have found a common class of p53 missense mutation that exhibits a dominant, gain-of-function activity that generates genomic instability. Fibroblasts from Li-Fraumeni syndrome heterozygotes with such mutations generate polyploid cells when exposed to spindle depolymerizing agents. Expression of such mutant alleles in normal fibroblasts yields the same phenotype. This class of dominant, gain-of-function p53 mutation (p53(RSC), relaxed spindle checkpoint allele) does not require the transcriptional activation function of p53 for this behavior. Thus p53 mutations can contribute to progression of a cancer cell not only by absence of p53 tumor suppressor activity but also by the presence of an activity that promotes genetic instability.


[Urinary diversion following radical cystectomy: ileal conduit or ileal replacement bladder?].
Among those patients who have undergone radical cystoprostatectomy in the Department of Urology at the Municipal Hospital of Kassel (FRG) since 1985, 57 received a continent ileal bladder anastomosed to the membranous urethra. In a retrospective study intra- and postoperative complications, late complications and prognosis of the tumor disease of these patients were compared with those who had an ileum conduit from 1983 to 1988 (n = 44). The intra- and postoperative complications were nearly identical. During the further postoperative course, patients with a continent ileal bladder may present with strictures at the anastomosis of the ileal bladder and urethra, incomplete voiding with residual urine, secretion of water by the mucosa, and metabolic disturbances because of absorption of substances usually eliminated with the urine. The latter decreases with time as the glandular epithelium of the ileal mucosa changes into mucigenous cells with villous atrophy. The danger of local tumor recurrence and metastasis is the same in patients with an ileal bladder and an ileal conduit.


The role of mutations affecting gonadotrophin secretion and action in disorders of pubertal development.
A number of mutations that disturb the development and function of the hypothalamic-pituitary-gonadal (HPG) axis and cause disturbances in pubertal development are known today. These mutations have effects at all levels of the HPG axis, from the migration of gonadotrophin releasing hormone (GnRH) neurones from the nasal cavity to the hypothalamus, GnRH secretion, GnRH action, pituitary gonadotroph differentiation, gonadotrophin synthesis and secretion, right through to gonadotrophin action. Most of the mutations are inactivating, thus causing hypogonadism and arrest or delay of pubertal development. One exception is the activating mutations of the LH receptor, which causes the male-limited gonadotrophin-independent precocious puberty. The human mutations and animal models with disrupted function of orthologous genes have clarified the molecular pathogenesis of hypogonadism and disturbances of pubertal development. The correct diagnosis of these disorders using molecular biological techniques is now possible. This allows the selection of specific treatments and correct counselling of the patients and their families.


Good grief: exploring the dimensionality of grief experiences and social work support.
This study explored the dimensionality of grief with a sample (n = 180) of caregivers of deceased loved ones; utilizing a positive grief scale, additional data were collected about perceptions of social worker practice behaviors in end-of-life care. Results revealed the presence of both positive and negative aspects of grief. Supportive social work practice behaviors at the end of life were present at least 52.2% of the time and specific practices were analyzed as to their association with positive or negative grief reactions. Results from this study suggest that grief is a multidimensional process and that social work practice behaviors can support positive aspects of grief with clients in all fields of practice.


Molecular evidence for a recent demographic expansion in the puma (Puma concolor) (Mammalia, Felidae).
The puma is an iconic predator that ranges throughout the Americas, occupying diverse habitats. Previous phylogeographic analyses have revealed that it exhibits moderate levels of genetic structure across its range, with few of the classically recognized subspecies being supported as distinct demographic units. Moreover, most of the species' molecular diversity was found to be in South America. To further investigate the phylogeographic structure and demographic history of pumas we analyzed mtDNA sequences from 186 individuals sampled throughout their range, with emphasis on South America. Our objectives were to refine the phylogeographic assessment within South America and to investigate the demographic history of pumas using a coalescent approach. Our results extend previous phylogeographic findings, reassessing the delimitation of historical population units in South America and demonstrating that this species experienced a considerable demographic expansion in the Holocene, ca. 8,000 years ago. Our analyses indicate that this expansion occurred in South America, prior to the hypothesized re-colonization of North America, which was therefore inferred to be even more recent. The estimated demographic history supports the interpretation that pumas suffered a severe demographic decline in the Late Pleistocene throughout their distribution, followed by population expansion and re-colonization of the range, initiating from South America.


Global changes explain the long-term demographic trend of the Eurasian common lizard (Squamata: Lacertidae).
The demographic trend of a species depends on the dynamics of its local populations, which can be compromised by local or by global phenomena. However, the relevance of local and global phenomena has rarely been investigated simultaneously. Here, we tested whether local phenomena compromised a species' demographic trend using the Eurasian common lizard Zootoca vivipara, the terrestrial reptile exhibiting the widest geographic distribution, as a model species. We analyzed the species' ancient demographic trend using genetic data from its 6 allopatric genetic clades and tested whether its demographic trend mainly depended on single clades or on global phenomena. Zootoca vivipara's effective population size increased since 2.3 million years ago and started to increase steeply and continuously from 0.531 million years ago. Population growth rate exhibited 2 maxima, both occurring during global climatic changes and important vegetation changes on the northern hemisphere. Effective population size and growth rate were negatively correlated with global surface temperatures, in line with global parameters driving long-term demographic trends. Zootoca vivipara's ancient demography was neither driven by a single clade, nor by the 2 clades that colonized huge geographic areas after the last glaciation. The low importance of local phenomena, suggests that the experimentally demonstrated high sensitivity of this species to short-term ecological changes is a response in order to cope with short-term and local changes. This suggests that what affected its long-term demographic trend the most, were not these local changes/responses, but rather the important and prolonged global climatic changes and important vegetation changes on the northern hemisphere, including the opening up of the forest by humans.


Effectiveness of Psychosocial and Educational Prenatal and Postnatal Care Interventions for Married Immigrant Women in Korea: Systematic Review and Meta-analysis.
The rapid influx of married immigrant women from low-income Asian countries is a concern in South Korea, Japan, and Taiwan. In South Korea, 1 in 10 couples includes a Korean man and a migrant woman, increasing the need for prenatal and postnatal care interventions. Studies published in English or Korean after 2000 were retrieved from 8 databases and reviewed via a systematic review and meta-analysis of the effectiveness of prenatal and postnatal psychosocial and educational interventions in Korea. Of 3583 records, 10 studies (1 randomized controlled trial [RCT] and 9 non-RCTs) involving 408 married immigrant women fulfilled the inclusion criteria. A meta-analysis of the non-RCTs showed that prenatal and postnatal care interventions were effective in improving family support, knowledge regarding self-care management and infant rearing, and self-efficacy regarding self-care management and infant rearing. Subgroup analysis showed that interventions involving husbands and individualized care were most effective. This study illustrated the extent to which strategies are needed for developing prenatal and postnatal care interventions for married immigrant women. Further studies should explore other factors and identify the most important factor for improving the effectiveness of such interventions. Robust study designs published in peer-reviewed journals are required for examining the effectiveness of these interventions.


The effect of co-trimoxazole on antitoxin response to tetanus toxoid.
The effect of a 4-day course of co-trimoxazole (Septrin) on antitoxin response to tetanus vaccine was assessed in a double-blind study involving 22 healthy adults. The tetanus antitoxin levels were measured by in vivo and in vitro methods for up to 8 weeks after the first of two injections of tetanus vaccine, given 4 weeks apart. No sigificant difference was observed in the level of tetanus antitoxin produced in subjects who received co-trimoxazole (Septrin) in recommended therapeutic dosage during the first 4 days of the trial from that in subjects who received placebo tablets. The results indicate that a 4-day course of co-trimoxazole (Septrin) does not affect antibody production.


Effect of dietary protein deprivation on insulin-like growth factor (IGF)-I and -II, IGF binding protein-2, and serum albumin gene expression in rat.
Circulating levels of insulin-like growth factor I (IGF-I) and serum albumin are decreased under conditions of chronic dietary protein limitation. To investigate the biochemical mechanism(s) involved in the regulation of IGF-I and serum albumin synthesis by dietary protein, we studied the effects of protein limitation on IGF-I and serum albumin gene expression in young growing rats maintained on isocaloric diets containing 20%, 12%, 8%, or 4% protein. Animals maintained on the 12%, 8%, or 4% protein diets exhibited slight, moderate, or severe growth deficiency, respectively, and a decreased abundance of hepatic IGF-I messenger RNA (mRNA). The decrease in IGF-I mRNA was most pronounced for the largest [7.7 kilobase (kb)] species, which was decreased by 87% in animals maintained on the 4% protein diet compared with animals on the 20% protein diet. The 0.9 kb species of IGF-I mRNA exhibited a smaller (46%) reduction in abundance in animals maintained on the 4% protein diet. The differential regulation of the 7.7 kb IGF-I mRNA species compared with the shorter IGF-I mRNA species suggests that a sequence or sequences within the long 3'-untranslated region of this mRNA species may play a role in regulating its abundance under conditions of protein limitation. Serum albumin mRNA was also decreased (by 62%) in the animals maintained on the 4% protein diet. The level of serum albumin gene transcription was not decreased in animals on the low protein diets, suggesting that nutrition regulates albumin mRNA at a posttranscriptional step. There was considerable animal-to-animal variability in the level of IGF-I gene transcription within each dietary group. The mean level of IGF-I gene transcription was decreased by 46% in the animals on the 4% protein diet compared with animals on the 20% protein diet, although this decrease was not statistically significant because of the animal-to-animal variability in IGF-I gene transcription within the dietary groups. Additional studies of brain RNA from animals on the four diets indicated that brain IGF-II mRNA was decreased by 57% in animals on the 4% protein diet. It has been demonstrated recently that expression of the gene for IGF binding protein-2 (IGFBP-2) is strongly induced in the liver of fasting animals. To investigate the possible regulation of the IGFBP-2 gene in the protein-limited animals, the abundance of liver and brain IGFBP-2 mRNA was analyzed in animals on the four diets.(ABSTRACT TRUNCATED AT 400 WORDS)


Bleb needling with subconjunctival ologen insertion using IOL cartridge.
We describe a novel technique to bleb needling by injecting subconjunctival ologen through an intraocular lens (IOL) delivery system to modulate wound healing in a failing filter. Bleb needling with 26G needle was performed, followed by subconjunctival injection of a biodegradable collagen implant using an IOL delivery system with cartridge in two eyes with a failing filter and high intraocular pressure (IOP). Postoperatively, the bleb was diffusely elevated, and the IOP was maintained between 10 and 14 mmHg at 6 weeks, 3 and 6 months follow-up. Therefore, bleb needling augmented with a biodegradable collagen implant inserted through an IOL injector system is a useful option in the management of failing filter posttrabeculectomy.


The safety of antituberculosis medications during breastfeeding.
Most antituberculosis drugs appear to be safe for use with breastfeeding. These agents are excreted in breast milk at relatively small concentrations. No adverse effects have been reported to date. The percentages of the therapeutic dose of antituberculosis agents that potentially may be delivered to the nursing infants range from 0.05% to 28%. Currently isoniazid, rifampin, ethambutol, streptomycin (first-line agents), kanamycin and cycloserine (second-line agents) are the only agents considered by the AAP to be compatible with breastfeeding. Unfortunately, there are still no clear data on the safety of pyrazinamide, ethionamide, and capreomycin during breastfeeding. If the mother chooses to breastfeed, it may be prudent to examine the infant for signs and symptoms of toxicity. In infants requiring treatment with antituberculosis agents, it is important to use therapeutic doses since drug concentrations in breast milk are not adequate as effective therapy for treatment or prevention. However, dosing at the lower end of the therapeutic range should be prescribed (i.e., 10 mg/kg/day of isoniazid) to decrease the risk of toxicity.


Intraorbital metastasis from solitary fibrous tumor.
Solitary fibrous tumor (SFT) is a rare spindle cell tumor of mesenchymal origin that usually arises from pleura or pericardium but can also arise from many extraserosal sites. Although more than 50 cases of primary SFT of the orbit have been reported, there are no reports to date of a malignant nonophthalmic SFT metastasizing in the orbital soft tissues (although sphenoid wing bony involvement has been reported). The authors report here the first case of a patient with intraorbital metastasis of a CD34-positive malignant SFT. The patient was a 57-year-old man with a history of malignant pleural SFT and a prior kidney metastasis. He presented with the rapid appearance of proptosis and massive conjunctival chemosis preventing eyelid closure, and he was found to have a well-circumscribed metastasis to his lateral rectus muscle. Surgical excision cured his ocular symptoms, although he died 3 months later from brain and widespread metastases.


Characterisation of the genomic structure of chick Fgf8.
The Fgf8 gene encodes a series of secreted signalling molecules important in the normal development of the face, brain and limbs. The genomic structure of the chick Fgf8 gene has been analysed and compared to the human and mouse sequences. Divergence between the chick, human and mouse genomic structure was observed. Data indicates that the long alternatively spliced form of exon 1b observed in mouse and exon 1c observed in human and mouse do not exist in the chick Fgf8 gene. RT-PCR analysis indicates that chick Fgf8, like its mouse and human counterpart is alternatively spliced. This data along with the genomic structure data indicates that in the chick there are only two isoforms of Fgf8. This is in contrast to the human and mouse, where evidence suggests that there are 4 and 8 isoforms, respectively. Approximately 400 bp of intron 1d is highly conserved between chick, human and mouse genomic sequences. Using TRANSFAC possible conserved regulatory element binding sites within this domain were identified.


pAUL: a gateway-based vector system for adaptive expression and flexible tagging of proteins in Arabidopsis.
Determination of protein function requires tools that allow its detection and/or purification. As generation of specific antibodies often is laborious and insufficient, protein tagging using epitopes that are recognized by commercially available antibodies and matrices appears more promising. Also, proper spatial and temporal expression of tagged proteins is required to prevent falsification of results. We developed a new series of binary Gateway cloning vectors named pAUL1-20 for C- and N-terminal in-frame fusion of proteins to four different tags: a single (i) HA epitope and (ii) Strep-tagIII, (iii) both epitopes combined to a double tag, and (iv) a triple tag consisting of the double tag extended by a Protein A tag possessing a 3C protease cleavage site. Expression can be driven by either the 35 S CaMV promoter or, for C-terminal fusions, promoters from genes encoding the chloroplast biogenesis factors HCF107, HCF136, or HCF173. Fusions of the four promoters to the GUS gene showed that endogenous promoter sequences are functional and drive expression more moderately and consistently throughout different transgenic lines when compared to the 35 S CaMV promoter. By testing complementation of mutations affected in chloroplast biogenesis factors HCF107 and HCF208, we found that the effect of different promoters and tags on protein function strongly depends on the protein itself. Single-step and tandem affinity purification of HCF208 via different tags confirmed the integrity of the cloned tags.


Ceramide signaling in cancer and stem cells.
Most of the previous work on the sphingolipid ceramide has been devoted to its function as an apoptosis inducer. Recent studies, however, have shown that in stem cells, ceramide has additional nonapoptotic functions. In this article, ceramide signaling will be reviewed in light of 'systems interface biology': as an interconnection of sphingolipid metabolism, membrane biophysics and cell signaling. The focus will be on the metabolic interconversion of ceramide and sphingomyelin or sphingosine-1-phosphate. Lipid rafts and sphingolipid-induced protein scaffolds will be discussed as a membrane interface for lipid-controlled cell signaling. Ceramide/sphingomyelin and ceramide/sphingosine-1-phosphate-interdependent cell-signaling pathways are significant for the regulation of cell polarity, apoptosis and/or proliferation, and as novel pharmacologic targets in cancer and stem cells.


Scale-free correlations in the dynamics of a small (N∼10000) cortical network.
The advent of novel optogenetics technology allows the recording of brain activity with a resolution never seen before. The characterization of these very large data sets offers new challenges as well as unique theory-testing opportunities. Here we discuss whether the spatial and temporal correlations of the collective activity of thousands of neurons are tangled as predicted by the theory of critical phenomena. The analysis shows that both the correlation length ξ and the correlation time τ scale as predicted as a function of the system size. With some peculiarities that we discuss, the analysis uncovers evidence consistent with the view that the large-scale brain cortical dynamics corresponds to critical phenomena.


Sustainability.
This review on Sustainability covers selected 2014 publications on the focus of the following sections: • Sustainable water and wastewater utilities • Sustainable water resources management • Stormwater and green infrastructure • Sustainability in wastewater treatment • Life cycle assessment (LCA) applications • Sustainability and energy in wastewater industry, • Sustainability and asset management.


Constitutively active canonical NF-κB pathway induces severe bone loss in mice.
Physiologic osteoclastogenesis entails activation of multiple signal transduction pathways distal to the cell membrane receptor RANK. However, atypical osteoclastogenesis driven by pro-inflammatory stimuli has been described. We have reported recently a novel mechanism whereby endogenous mutational activation of the classical NF-κB pathway is sufficient to induce RANKL/RANK-independent osteoclastogenesis. Here we investigate the physiologic relevance of this phenomenon in vivo. Using a knock-in approach, the active form of IKK2, namely IKK2SSEE, was introduced into the myeloid lineage with the aid of CD11b-cre mice. Phenotypic assessment revealed that expression of IKK2SSEE in the myeloid compartment induced significant bone loss in vivo. This observation was supported by a dramatic increase in the number and size of osteoclasts in trabecular regions, elevated levels of circulating TRACP-5b, and reduced bone volume. Mechanistically, we observed that IKK2SSEE induced high expression of not only p65 but also p52 and RelB; the latter two molecules are considered exclusive members of the alternative NF-κB pathway. Intriguingly, RelB and P52 were both required to mediate the osteoclastogenic effect of IKK2SSEE and co-expression of these two proteins was sufficient to recapitulate osteoclastogenesis in the absence of RANKL or IKK2SSEE. Furthermore, we found that NF-κB2/p100 is a potent inhibitor of IKK2SSEE-induced osteoclastogenesis. Deletion of p52 enabled more robust osteoclast formation by the active kinase. In summary, molecular activation of IKK2 may play a role in conditions of pathologic bone destruction, which may be refractory to therapeutic interventions targeting the proximal RANKL/RANK signal.


Familial Kallmann syndrome: a novel splice acceptor mutation in the KAL gene.
Kallmann syndrome is an inherited disease which is characterised by anosmia (inability to smell) and hypogonadotropic hypogonadism both of which are thought to occur as a result of a failure of correct neuronal migration. To date the only genetic lesions identified are mutations in the X-linked gene, KAL. We conducted a mutation screen of the KAL gene in a family with Kallmann syndrome. This identified a new mutation in the KAL gene which removed an acceptor site at the junction of exon 6/intron 5. Exon 6 of the KAL gene encodes the C-terminal portion of a fibronectin type III domain may be involved in axonal pathfinding. We presume that the described mutation would result in the removal of exon 6 resulting in a frame shift which terminates the protein prematurely. It has been proposed that both mental illness and vesico-ureteric reflux are associated with mutations in the KAL gene. However, results from the family presented here do not show an association between either trait and the KAL gene mutation.


Employment and adolescent alcohol and drug treatment and recovery: an exploratory study.
Studies of adolescents in the general population show that most high school students are employed and that there is a positive linear relationship between hours worked and increases in alcohol and other drug use. Mixed methods are used to examine the relationship of employment for adolescents who are in outpatient substance abuse treatment to their use, treatment experiences, and recovery. Several theories offered to explain the relationship between adolescent employment and substance use were examined. Most adolescents were employed, often during treatment, with increasing numbers reporting employment over the year-long follow-up period. Adolescents reported frequent alcohol and other drug use after work and with coworkers and indicated that income from work often was used to purchase alcohol and other drugs. Most parents did not provide monitoring of work-related income. Balancing employment and treatment was often logistically difficult and stressful for the adolescents. Employment situations are a critical aspect of adolescents' recovery environment, and more research is needed to learn how to create support for recovery in this aspect of an adolescent's life.


A new alpha 2HS-glycoprotein typing by isoelectric focusing.
Isoelectric focusing (pH 4.0-5.0) of serum alpha 2HS-glycoprotein on polyacrylamide gels has been found to be a useful tool in population genetics and forensic science. Using this method, we isolated three common types, alpha 2HS 1-1, alpha 2HS 2-1 and alpha 2HS 2-2, and showed that alpha 2HS types are determined by two autosomal codominant alleles, alpha 2HS1 and alpha 2HS2. The method is simple, fast and easy to perform. Results of typing for the two alleles, alpha 2HS1 and alpha 2HS2, are described for a Japanese population sample (n = 1003).


Human leukocyte antigen-specific polymorphisms in HIV-1 Gag and their association with viral load in chronic untreated infection.
Selection of specific human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) escape mutations in key Gag epitopes has been associated with loss of HIV immune control on an individual basis. Here we undertake a population-based identification of HLA-associated polymorphisms in Gag and investigate their relationship with plasma viral load. Cross-sectional analysis of 567 chronically HIV subtype B-infected, treatment-naive individuals. HLA class I-associated Gag substitutions were identified using phylogenetically corrected analysis methods featuring a multivariate adjustment for HLA linkage disequilibrium and a q-value correction for multiple tests. Presence of HLA-associated substitutions and markers of HIV disease status were correlated using Spearman's rank test. We have created a gene-wide map of HLA class I-associated substitutions in HIV-1 subtype B Gag. This features 111 HLA-associated substitutions occurring at 51 of 500 Gag codons, more than 50% of which occur within published and/or putative HLA-restricted CTL epitopes. A modest inverse correlation was observed between the total number of HLA-associated Gag polymorphic sites within each individual and plasma viral load in chronic untreated infection (R = -0.17, P < 0.0001), supporting the hypothesis that a broad ability to target Gag in vivo contributes to viral control. A modest positive correlation was observed between the proportion of these sites exhibiting HLA-associated substitutions and plasma viral load (R = 0.09, P = 0.03), consistent with a loss of viremia control with the accumulation of CTL escape mutations. Results contribute to our understanding of immune-driven viral adaptation and suggest that the accumulation of CTL escape mutations in Gag results in clinically detectable consequences at the population level. These data have implications for HIV vaccines.


Chemical doping to control the in-situ formed doping structure in light-emitting electrochemical cells.
The initial operation of a light-emitting electrochemical cell (LEC) constitutes the in-situ formation of a p-n junction doping structure in the active material by electrochemical doping. It has been firmly established that the spatial position of the emissive p-n junction in the interelectrode gap has a profound influence on the LEC performance because of exciton quenching and microcavity effects. Hence, practical strategies for a control of the position of the p-n junction in LEC devices are highly desired. Here, we introduce a "chemical pre-doping" approach for the rational shifting of the p-n junction for improved performance. Specifically, we demonstrate, by combined experiments and simulations, that the addition of a strong chemical reductant termed "reduced benzyl viologen" to a common active-material ink during LEC fabrication results in a filling of deep electron traps and an associated shifting of the emissive p-n junction from the center of the active material towards the positive anode. We finally demonstrate that this chemical pre-doping approach can improve the emission efficiency and stability of a common LEC device.


Regulatory volume decrease in Leishmania mexicana: effect of anti-microtubule drugs.
The trypanosomatid cytoskeleton is responsible for the parasite's shape and it is modulated throughout the different stages of the parasite's life cycle. When parasites are exposed to media with reduced osmolarity, they initially swell, but subsequently undergo compensatory shrinking referred to as regulatory volume decrease (RVD). We studied the effects of anti-microtubule (Mt) drugs on the proliferation of Leishmania mexicana promastigotes and their capacity to undergo RVD. All of the drugs tested exerted antiproliferative effects of varying magnitudes [ansamitocin P3 (AP3)> trifluoperazine > taxol > rhizoxin > chlorpromazine]. No direct relationship was found between antiproliferative drug treatment and RVD. Similarly, Mt stability was not affected by drug treatment. Ansamitocin P3, which is effective at nanomolar concentrations, blocked amastigote-promastigote differentiation and was the only drug that impeded RVD, as measured by light dispersion. AP3 induced 2 kinetoplasts (Kt) 1 nucleus cells that had numerous flagella-associated Kts throughout the cell. These results suggest that the dramatic morphological changes induced by AP3 alter the spatial organisation and directionality of the Mts that are necessary for the parasite's hypotonic stress-induced shape change, as well as its recovery.


Auto bias control and bias hold circuit for IQ-modulator in flexible optical QAM transmitter with Nyquist filtering.
An Auto Bias Control (ABC) technique for the IQ-modulator of a flexible optical QAM transmitter is described. This technique can support various optical QAM signal formats with Nyquist filtering and electronic dispersion pre-compensation. 16, 32 and 64-QAM signals (21 Gbaud) are successfully generated, and all bias voltages are held to their optimum value even when signal format is changed.