Elucidating the impact of microbial community biodiversity on pharmaceutical biotransformation during wastewater treatment.
In addition to removing organics and other nutrients, the microorganisms in wastewater treatment plants (WWTPs) biotransform many pharmaceuticals present in wastewater. The objective of this study was to examine the relationship between pharmaceutical biotransformation and biodiversity in WWTP bioreactor microbial communities and identify taxa and functional genes that were strongly associated with biotransformation. Dilution-to-extinction of an activated sludge microbial community was performed to establish cultures with a gradient of microbial biodiversity. Batch experiments were performed using the dilution cultures to determine biotransformation extents of several environmentally relevant pharmaceuticals. With this approach, because the communities were all established from the same original community, and using sequencing of the 16S rRNA and metatranscriptome, we identified candidate taxa and genes whose activity and transcript abundances associated with the extent of individual pharmaceutical biotransformation and were lost across the biodiversity gradient. Metabolic genes such as dehydrogenases, amidases and monooxygenases were significantly associated with pharmaceutical biotransformation, and five genera were identified whose activity significantly associated with pharmaceutical biotransformation. Understanding how biotransformation relates to biodiversity will inform the design of biological WWTPs for enhanced removal of chemicals that negatively impact environmental health.


Attachment, uncoating and blockage of cell protein synthesis by Sabin derivatives of poliovirus in HeLa and Vero cells.
Virulent Mah type 1 poliovirus and the attenuated Sab types 1, 2 and 3 poliovirus do not efficiently produce plaques or grow as efficiently with Vero cells as with HeLa cells. All viruses attach poorly to simian cells on monolayer and, except for Mah and Sab1, eclipse poorly. Additionally, all three attenuated viruses block initiation of Vero cell protein synthesis less effectively than HeLa cell protein synthesis. The lower rates of attachment and eclipse of these viruses with Vero cells and their limited capacities to block cellular protein synthesis and thereby provide ribosomes for translation of viral RNA probably contribute to their more restricted growth in Vero cells.


Trehalose provisioning in Daphnia resting stages reflects local adaptation to the harshness of diapause conditions.
Environmental fluctuations often select for adaptations such as diapause states, allowing species to outlive harsh conditions. The natural sugar trehalose which provides both cryo- and desiccation-protection, has been found in diapause stages of diverse taxa. Here, we hypothesize that trehalose deposition in resting stages is a locally adapted trait, with higher concentrations produced in harsher habitats. We used resting stages, produced under standardized conditions, by 37 genotypes of Daphnia magna collected from Western Palaearctic habitats varying in their propensity to dry in summer and freeze in winter. Resting eggs produced by D. magna from populations from summer-dry habitats showed significantly higher trehalose than those from summer-wet habitats, suggesting that trehalose has a protective function during desiccation. By contrast, winter-freezing did not explain variation in trehalose content. Adaptations to droughts are important, as summer dryness of water bodies is foreseen to increase with ongoing climate change.


Measurement of Cu/Zn SOD in placenta, cultured cells, various fetal tissues, decidua and semen by ELISA.
The concentration of copper/zinc-containing superoxide dismutase (Cu/Zn SOD) was measured in placental villous tissues (8-20 weeks' gestation), decidual tissues, cultured cells from chorionic villi and amniotic fluid cells, various fetal tissues (8-11 weeks' gestation), spermatozoa, seminal plasma and ovarian follicular fluid using a sensitive enzyme-linked immunosorbent assay (ELISA). The isoenzyme was expressed in all samples expect ovarian follicular fluid. Cu/Zn SOD was also detected in hydatidiform mole and choriocarcinoma. In placental villous tissues the concentration of the enzyme increased with gestation between 8 and 20 weeks of pregnancy (n = 69, r = 0.34, P < 0.005).


Probing selectivity in recognition-mediated dynamic covalent processes.
[reaction: see text] Two simple recognition-mediated dynamic Diels-Alder systems are used to probe the role of kinetics and thermodynamics in determining the equilibrium position in exchanging libraries and the time taken to reach that equilibrium. The selectivity expressed by recognition-driven dynamic processes is demonstrated to be less than the free-energy difference between the components as a result of compensatory effects arising from the extent of conversion to products within the library.


Effectiveness of Zinc Supplementation on Lithium-Induced Alterations in Thyroid Functions.
Lithium is an integral drug used in the management of acute mania, unipolar and bipolar depression, and prophylaxis of bipolar disorders. Thyroid abnormalities have been associated with treatment with lithium. Zinc is an essential trace element that plays a role in several biological activities. Therefore, the present study was aimed at investigating the potential role of zinc in the thyroid gland following lithium administration to explore the role of zinc under such conditions. To achieve this goal, male Wistar rats (150-195 g) were divided into four groups: Group 1 animals were fed standard pellet feed and tap water ad lib; Group 2 rats were fed lithium in the form of lithium carbonate through diet at a concentration of 1.1 g/kg body weight; Group 3 animals received zinc treatment in the form of zinc sulfate (ZnSO4·7H2O) at a dose level of 227 mg/L mixed with drinking water of the animals; and Group 4 animals were given lithium and zinc in a similar manner as was given to the animals belonging to groups 2 and 4 respectively. The role of zinc on thyroid functions in lithium-treated rats was studied after 2, 4, and 8 weeks of different treatments. Zinc has been observed to have the capability to nearly normalize the altered 2-h uptake of 131I, biological and effective half-lives of 131I, and circulating T4 levels that were altered after lithium treatment. The present study concludes that zinc may be an effective agent in normalizing the adverse effects caused by lithium on thyroid functions.


Extending the infoway benefits evaluation framework for health information systems.
A proposal is made that extends the current Canada Health Infoway Benefits Evaluation (BE) Framework for Health Information Systems (HIS) being deployed in Canada. The current BE framework takes a micro view of HIS quality, use and impact at the local level whereas the extended framework takes into account the broader socio-organizational and contextual aspects known as the meso and macro views of HIS deployment. The meso view addresses the people, organization, network and implementation dimensions. The macro view focuses on the contextual dimensions of technology standard, funding/incentive, legislation/policy and professional practice. Validation of this extended BE framework is being planned through a comparative review of recent HIS evaluation literature, a Delphi-consensus process with HIS experts and users, and multiple validation studies with recent HIS implementation projects in British Columbia.


[Ultraconservative treatment in stage I and II breast carcinoma. Results of a long-term follow-up on 500 operated breasts].
Several randomized trials on conservative surgery compared with mastectomy in early-stage breast cancer have validated this technique in terms of local and distant relapse and survival of patients. Standard conservative approach includes surgical removal of the cancer with adequate cancer-free margins, axillary dissection, postoperative breast irradiation and adjuvant treatments when required. From 1987 to 2003, 500 early stage breast carcinoma were treated on 494 patients with conservative surgery and postoperative radiotherapy. Surgery consisted in a wide tumorectomy, with intraoperative control of R0 margins. The total postoperative radiation dosage was 50 Gy on the whole breast, associated with a boost of 10 Gy on tumor bed (20 Gy in T2 neoplasms). Before 1997 node-positive patients were treated with axillary irradiation with 50 Gy. Postoperative chemotherapy and/or hormonal therapy were administered to patients according with node-involvement, age and menopausal status. AJCC-stage was T1N0 in 44%, T2N0 in 15%, T1N1 in 19% and T2N1 in 22% of the patients. In a postoperative setting, we observed 9% of axillary seromas or hematomas and 7% of oedema of the arm. At a median follow-up of 150 months (range 48-248 months), actuarial local recurrence rates were 7% at 5 years and 14% at 10 years. The actuarial rates of distant metastases were 18% at 5 years and 33% at 10 years. Ten-year overall and disease-free survival rates were 81% and 60%, respectively. Cosmetic results were good/excellent in 80%, satisfactory in 10% and poor in 10% of patients. Recurrence and survival rates in breast-conserving surgery are consistent with indexed literature on conservative treatment of early breast cancer. Women eligible for conservative treatment should be offered the choice of either wide tumorectomy or quadrantectomy with axillary lymph nodes removal and postoperative radiotherapy, or modified radical mastectomy.


Second meeting of the French CEIP (Centres d'Evaluation et d'Information sur la Pharmacodépendance). Part I: how to evaluate and prevent the abuse and dependence on hypnotic/anxiolytic drugs?
The second meeting of the French CEIP (Centres d'Evaluation et d'Information sur la Pharmacodépendance) was organized during the annual congress of the French Society of Pharmacology Therapeutics and Physiology in 2008. The aim of this meeting was to update the knowledge on abuse and dependence of the anxiolytics and hypnotics from different points of view (pharmacoepidemiology, epidemiology and treatment). The first part of this meeting summarized the pharmacological data obtained by the pharmacoepidemiological tools developed by the CEIP network. Even if the abuse liability of these agents is not a new problem, it remains always present and characterized by differences of misuse between drugs in real-life settings. The second part targeted to a subtype of consumers, the elderly population, because older patients are more likely to be prescribed with multiple prescriptions and also more at risk for prescription abuse. Despite this evidence, there is a scarcity of information on the factors associated with a such behaviour and its screening, assessment, diagnosis and treatment.


Ce6-Conjugated and polydopamine-coated gold nanostars with enhanced photoacoustic imaging and photothermal/photodynamic therapy to inhibit lung metastasis of breast cancer.
Metastasis is the main cause of treatment failure in breast cancer, and integrated phototheranostics is a promising strategy to achieve both precision theranostics and metastasis inhibition. In this work, a multifunctional phototheranostic nanoprobe composed of chlorin e6 (Ce6)-conjugated and polydopamine (PDA)-coated gold nanostars (AuNSs) was synthesized for simultaneous photoacoustic (PA) imaging, photothermal therapy (PTT) and photodynamic therapy (PDT). Under the irradiation of near infrared laser, AuNSs@PDA showed enhanced photothermal conversion and amplified PA imaging performance, compared with single AuNSs. By the covalent conjugation of Ce6, the AuNSs@PDA-Ce6 nanoprobe showed robust stability and excellent singlet oxygen (1O2) generation ability. Under the combination of PTT/PDT, the AuNSs@PDA-Ce6 nanoprobes significantly reduced the growth of 4T1 tumors and suppressed their lung metastasis. All the results demonstrated the considerable potential of AuNSs@PDA-Ce6 phototheranostic nanoprobes for precision theranostics and metastasis inhibition of breast cancer.


An uncommon cause of headache after headbanging at a party.
Subdural haematomas can result from bridging vein rupture. Rotational acceleration in the sagittal plane and in a forward direction, as in falls, is very likely the 'mechanical' cause of subdural haematoma, as shown in cadaveric studies. Some recreational activities, for example roller-coaster rides and bungee jumping, have been associated with subdural haematoma, owing to acceleration/deceleration or repetitive head movements. We report a case of chronic subdural haemorrhage in a male teenager without precipitating factors and no history of head trauma. This case shows the value of good history-taking in medical diagnosis and that one should be aware of the risks of violent sports or dancing and the minimal clinical signs encountered.


Genetic characteristics and antibiotic resistance of Haemophilus influenzae isolates from pediatric patients with acute otitis media after introduction of 13-valent pneumococcal conjugate vaccine in Japan.
Acute otitis media (AOM) occurs commonly in pediatric populations. We examined resistance genotype, antibiotic susceptibility, quinolone (QL) resistance, and multilocus sequence type (MLST) among Haemophilus influenzae isolates causing AOM following introduction of pneumococcal conjugate vaccines in Japan. The AOM surveillance group included 69 participating otolaryngologists. Causative pathogens isolated from middle ear fluid (MEF) samples collected from 582 children with AOM were identified using both bacterial culture and real-time PCR. H. influenzae isolates among these pathogens were characterized by capsular type, resistance genotype, antibiotic susceptibility, QL resistance, and MLST. In 2016, H. influenzae was identified in 319 samples (54.8%), among which 72.4% (n = 231) tested positive by both culture and PCR; remaining H. influenzae cases were only PCR-positive. This proportion of H. influenzae positivity has increased significantly from 41.2% in 2006 (p < 0.001). Among culture-positive strains, genotypic β-lactamase-nonproducing ampicillin (AMP)-resistant (gBLNAR) strains were frequent (63.2%), with β-lactamase-nonproducing AMP-susceptible (gBLNAS) strains accounting for only 24.2%. Susceptibilities of gBLNAR to oral antimicrobials were best for tosufloxacin, followed by cefditoren and tebipenem; MIC90s were 0.031 μg/mL, 0.5 μg/mL, and 1 μg/mL, respectively. In 7 gBLNAR isolates (3.0%), QL susceptibility was low, owing to amino acid substitutions in GyrA and/or ParC. Sequence types identified numbered 107, including 28 that were new. Prevention of further increases in resistance to antimicrobial agents will require antibiotic selection based on characterization of causative pathogens in clinical practice.


Urinary tract infections in children: clinical and antimicrobial resistance data from Bucharest area, Romania.
Urinary tract infections (UTIs) are among the most common bacterial diseases of childhood with an increased frequency in infants and young children. We conducted a retrospective study of children diagnosed with UTI in the Alessandrescu-Rusescu National Institute for Mother and Child Health, Bucharest, Romania between January 2017 and December 2019. We evaluated the patients' clinical characteristics, laboratory parameters and the resistance profile of the identified uropathogens. A total of 264 children were included in the analysis. Females (71.6%, n=186) and infants (52.7%, n=139) were more commonly affected. The recurrence rate was 27.7% and was positively associated with the presence of renal malformations. Age under 1-year, increased leukocyte and neutrophil counts, and elevated C-reactive protein were associated with hospitalization. E. coli (80.3%, n=212) was the main etiological agent isolated, followed by Proteus mirabilis (9.8%, n=26) and Klebsiella spp. (6.4%, n=17). We identified increased resistance for all germs to common antibiotics used in pediatrics: ampicillin, amoxicillin/clavulanate, cefuroxime, ceftriaxone, and trimethoprim/sulfamethoxazole. We identified an increased resistance of uropathogens to antimicrobials commonly used in children. Reporting antimicrobial resistance from real-world clinical practice is necessary for accurate mapping and continuous updating of initial treatment recommendations until antibiogram results are received. In Romania and other countries, extensive studies are needed to follow up uropathogen resistance in both children and adults.


The development of a measure of job satisfaction for use in monitoring the morale of community nurses in four trusts.
The development of the Measure of Job Satisfaction (MJS) for use in a longitudinal study of the morale of community nurses in four trusts is described. The review of previous studies focuses on the use of principal component analysis or factor analysis in the development of measures. The MJS was developed from a bank of items culled from the literature and from discussions with key informants. It was mailed to a one in three sample of 723 members of the community nursing forums of the Royal College of Nursing. A 72% response rate was obtained from those eligible for inclusion. Principal component analysis with varimax rotation led to the identification of five dimensions of job satisfaction; Personal Satisfaction, Satisfaction with Workload, Satisfaction with Professional Support, Satisfaction with Pay and Prospects and Satisfaction with Training. These factors form the basis of five subscales of satisfaction which summate to give an Overall Job Satisfaction score. Internal consistency, test-retest reliability, concurrent and discriminatory validity were assessed and were found to be satisfactory. The factor structure was replicated using data obtained from the first three of the community trusts involved in the main study. The limitations of the study and issues which require further exploration are identified and discussed.


UV laser interaction with a fluorescent dye solution studied using pulsed digital holography.
A frequency tripled Q-switched Nd-YAG laser (wavelength 355 nm, pulse duration 12 ns) has been used to pump Coumarin 153 dye solved in ethanol. Simultaneously, a frequency doubled pulse (532 nm) from the same laser is used to probe the solvent perpendicularly resulting in a gain through stimulated laser induced fluorescence (LIF) emission. The resulting gain of the probe beam is recorded using digital holography by blending it with a reference beam on the detector. Two digital holograms without and with the pump beam were recorded. Intensity maps were calculated from the recorded digital holograms and used to calculate the gain of the probe beam due to the stimulated LIF. In addition numerical data of the local temperature rise was calculated from the corresponding phase maps using Radon inversion. It was concluded that about 15% of the pump beam energy is transferred to the dye solution as heat while the rest is consumed in the radiative process. The results show that pulsed digital holography is a promising technique for quantitative study of fluorescent species.


Prognostic Significance of Size, Location, and Number of Lymph Node Metastases in Endometrial Carcinoma.
Regional lymph node metastasis is a well-established negative predictive prognostic factor in endometrial carcinomas. Recently, our approach to the pathologic evaluation of lymph nodes in endometrial carcinomas has changed, mainly due to the utilization of immunohistochemical stains in the assessment of sentinel lymph nodes, which may result in the identification of previously unrecognized disease [particularly isolated tumor cells (ITCs)] on hematoxylin and eosin stained slides. However, the clinical significance of this finding is not entirely clear. Following the experience in other organs systems such as breast, the Eight Edition of the American Joint Committee on Cancer's Cancer Staging Manual has recommended utilizing the N0(i+) terminology for this finding, without impact in the final tumor stage. We performed a comparative retrospective multi-institutional survival analysis of 247 patients with endometrial carcinoma with regional lymph node metastasis of various sizes identified in nonsentinel lymphadenectomy, demonstrating that the cumulative survival of patients with isolated tumor cells in regional lymph nodes is not statistically different from patient with negative lymph nodes, and is statistically different from those with lymph nodes showing micrometastasis or larger metastatic deposits. In addition, we evaluated the prognostic implications of the number of involved regional lymph nodes, demonstrating a worsening prognosis as the number of involved lymph nodes increases from none to one, and from one to more than one. Our data suggests that regional lymph nodes with isolated tumor cells in patients with endometrial carcinoma should likely be considered, for staging purposes, as negative lymph nodes, simply indicating their presence with the (i+) terminology.


COVID-19 Vaccination In Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: A USIDNET Report.
The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI and whether vaccination attenuates infection severity in IEI. To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. We built a secure registry database in conjunction with the United States Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022 and closed on August 19, 2022. Physicians entered data on 1,245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least 1 COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p<0.001), ICU admission (2.8% versus 7.6%, p=0.013), and death (2.3% versus 4.3%, p=0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity.


Calpain activation and progression of inflammatory cycles in Parkinson's disease.
Parkinson's disease (PD) is a progressive, neurodegenerative condition of the central nervous system (CNS) affecting 6.3 million people worldwide with no curative treatments. Current therapies aim to mitigate PD's effects and offer symptomatic relief for patients. Multiple pathways are involved in the pathogenesis of PD, leading to neuroinflammation and the destruction of dopaminergic neurons in the CNS. This review focuses on PD pathology and the role of calpain, a neutral protease, as a regulator of various immune cells such as T-cells, microglia and astrocytes which lead to persistent neuroinflammatory responses and neuronal loss in both the brain and spinal cord (SC). Calpain plays a significant role in the cleavage and aggregation of toxic α-synuclein (α-syn), a presynaptic neural protein, and other organelles, contributing to mitochondrial dysfunction and oxidative stress. α-Syn aggregation results in the formation of Lewy bodies (LB) that further contribute to neuronal damage through lipid bilayer penetration, calcium ion (Ca2+) influx, oxidative stress and damage to the blood brain barrier (BBB). Dysfunctional mitochondria destabilize cytosolic Ca2+ concentrations, raising intracellular Ca2+; this leads to excessive calpain activation and persistent inflammatory responses. α-Syn aggregation also results in the disruption of dopamine synthesis through phosphorylation of tyrosine hydroxylase (TH), a key enzyme involved in the conversion of tyrosine to levodopa (L-DOPA), the amino acid precursor to dopamine. Decreased dopamine levels result in altered dopamine receptor (DR) signaling, ultimately activating pro-inflammatory T-cells to further contribute to the inflammatory response. All of these processes, together, result in neuroinflammation, degeneration and ultimately neuronal death seen in PD. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-a prodrug to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+)), rotenone (an environmental neurotoxin), and 6-hydroxydopamine (6-OHDA - a neurotoxic synthetic organic compound) induce PD-like conditions when injected into rodents. All three agents work through similar mechanisms and lead to degeneration of dopaminergic neurons in the substantia nigra (SN) and more recently discovered in motor neurons of the spinal cord (SC). These neurotoxins also increase calpain activity, furthering the neuroinflammatory response. Hence, calpain inhibitors have been posited as potential therapeutics for PD to prevent calpain-related inflammation and neurodegenerative responses in not only the SN but the SC as well.


Antihypertensive effects of 12 beta adrenoceptor antagonists in conscious spontaneously hypertensive rats: relationship to changes in plasma renin activity, heart rate and sympathetic nerve function.
Twelve beta adrenoceptor antagonists were examined for their effects on mean blood pressure (MBP), heart rate (HR), plasma renin activity (PRA) and sympathetic nerve function in spontaneously hypertensive rats (SHR). The selected drugs included cardioselective agents (acebutolol, atenolol and metoprolol), agents with intrinsic sympathomimetic activity (oxprenolol, acebutolol, alprenolol and pindolol) and agents with local anesthetic activity (propranolol, oxprenolol, acebutolol, alprenolol and labetalol). All 12 beta adrenoceptor antagonists, administered once daily for 4 days (30 mg/kg p.o.), significantly decreased MBP of SHR. This reduction in MBP was dissociable from both reductions in HR as well as peripheral beta adrenoceptor blockade. In addition, the onset of MBP reduction was slower than the onset of beta adrenoceptor blockade and became greater with duration of treatment. PRA activity was significantly and markedly reduced by both bunolol and metoprolol shortly after dosing at a time when HR was significantly reduced but MBP was not. Conversely, at a time when MBP was significantly reduced by both bunolol and metoprolol, PRA and HR were found to be normal. The changes in HR and PRA were correlated with peripheral beta adrenoceptor blockade but changes in MBP were not. Bunolol, metoprolol and propranolol had no consistent inhibitory effect on pressor responses to nerve stimulation in pithed SHR, although positive chronotropic responses to norepinephrine, tyramine, dimethylphenylpiperazinium and angiotensin I and II were significantly and markedly reduced. It is concluded that beta adrenoceptor antagonists, as a class, reduce MBP of conscious SHR, provided that sufficient time is allowed for this observation to occur. Furthermore, the reduction in MBP caused by beta adrenoceptor antagonists is unrelated to acute beta adrenoceptor blockade, changes in HR, reductions in PRA or inhibition of sympathetic nerve function. Finally, cardioselectivity, intrinsic sympathomimetric activity and local anesthetic activity are not required for the antihypertensive activity of these agents.


Non-iron porphyrins cause tumbling to blue light by an Escherichia coli mutant defective in hemG.
Previously we showed that an Escherichia coli hemH mutant, defective in the ultimate step of heme synthesis, ferrochelatase, is somewhat better than 100-fold more sensitive than its wild-type parent in tumbling to blue light. Here we explore the effect of a hemG mutant, defective in the penultimate step, protoporphyrinogen oxidase. We found that a hemG mutant also is somewhat better than 100-fold more sensitive in tumbling to blue light compared to its wild-type parent. The amount of non-iron porphyrins accumulated in hemG or hemH mutants was more than 100-fold greater than in wild type. The nature of these accumulated porphyrins is described. When heme was present, as in the wild type, the non-iron (non-heme) porphyrins were maintained at a relatively low concentration and tumbling to blue light at an intensity effective for hemG or hemH did not occur. The function of tumbling to light is most likely to allow escape from the lethality of intense light.


Reliability and validity of the Myotest® for measuring running stride kinematics.
Accelerometer-based systems are often used to quantify human movement. This study's aim was to assess the reliability and validity of the Myotest® accelerometer-based system for measuring running stride kinematics. Twenty habitual runners ran two 60 m trials at 12, 15, 18 and 21 km·h(-1). Contact time, aerial time and step frequency parameters from six consecutive running steps of each trial were extracted using Myotest® data. Between-trial reproducibility of measures was determined by comparing kinematic parameters from the two runs performed at the same speed. Myotest® measures were compared against photocell-based (Optojump Next®) and high-frequency video data to establish concurrent validity. The Myotest®-derived parameters were highly reproducible between trials at all running speeds (intra-class correlation coefficient (ICC): 0.886 to 0.974). Compared to the photo-cell and high-speed video-based measures, the mean contact times from the Myotest® were 34% shorter and aerial times were 64% longer. Only step frequency was comparable between systems and demonstrated high between-system correlation (ICC ≥ 0.857). The Myotest® is a practical portable device that is reliable for measuring contact time, aerial time and step frequency during running. In terms of validity, it provides accurate step frequency measures but underestimates contact time and overestimates aerial time compared to photocell- and optical-based systems.


Histone deacetylase inhibitors enhance endothelial cell sprouting angiogenesis in vitro.
Treatment with histone deacetylases inhibitors (HDACi) such as valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) has been shown to improve survival after lethal insults through mechanisms that are incompletely understood. Cell survival under adverse conditions requires a healthy network of capillaries to ensure adequate oxygen delivery. Angiogenic activation of endothelial cells to migrate and form sprouts is associated with characteristic changes in gene expression profiles. Because HDACi can modulate expression of various genes involved in angiogenic activity, we investigated the effect of these agents on capillary-like sprout formation in this study. Human umbilical vein endothelial cells (HUVECs) were cultured as multicellular spheroids within a type I collagen matrix, which promotes formation of sprouts resembling angiogenesis in vitro. HUVECs were cultured as multicellular spheroids within a type I collagen matrix, which promotes formation of sprouts (in vitro angiogenesis). Cells were cultured under the following conditions: Control (no growth factors); VPA (1 mmol/L); vascular endothelial growth factor (VEGF; 10 ng/mL); VPA + VEGF; SAHA (5 mmol/L), and SAHA + VEGF. After 24 hours of treatment, the length of spheroid sprouting and cell migration was assessed quantitatively. The levels of acetylated histone H3, phosphor-extracellular signal-regulated kinase (ERK)1/2, and β-catenin in HUVECs were measured by Western blotting at 6 hours after treatment. High levels of acetylated histone H3 were detected in VPA and SAHA treated-groups. Compared with the VEGF-alone treated group (2379 ± 147.1 μm), the spheroid sprouting was 1.7 times increased with VPA and VEGF combined treatment (3996 ± 192.5 μm; P < .01). Cell migrations did not show a significant difference after addition of VPA, whereas SAHA suppressed migration. Expression of β-catenin was significantly increased by VPA and SAHA treatments. Addition of VPA greatly enhanced expression of phosphor-ERK1/2. Exposure of HUVECs to VPA and SAHA increased the expression of β-catenin and enhanced spheroid sprout formation in vitro. Modulation of HDAC-dependent pathways may offer a novel approach to alter angiogenic processes and provide a useful therapeutic target.


Articular Findings on Chest Computed Tomography: An Algorithmic Approach for Radiologists.
Chest computed tomography (CT) is one of the most frequently performed imaging studies. Incidental osseous and articular findings are commonly encountered in chest CTs in daily practice. The spectrum of findings is broad, varying from benign to malignant, and interpretation of these incidental musculoskeletal findings could be challenging for radiologists. In this review, we provide a systematic algorithmic approach for the diagnosis of common articular findings seen on chest CT with recommendations for appropriate follow-up evaluation.


[Internet addiction? A new form of behavioral dependence?].
The speed of development of new technologies of information and communication (I.C.T.) modified the mode of our intersubjective relations leading certain individuals to develop new forms of behavioral dependence. If the majority of the users consume the Internet with moderation, 1 to 2% of the general population would suffer from "problematic use of the Internet" and /or of "lnternet addiction". These figures are to be taken with caution because of the lack of reliable epidemiologic data. If, beside the classical forms of addictions to the psychoactive substances, the concept of "addictions without drugs" is more and more the subject of scientific works, it is appropriate, however, not to call pathological all these new behaviours. We will approach in this article the clinical reality related to the problematic or abusive use of new technologies with or without the Internet. We will then describe the possible therapeutic approaches that is ambulatory or in the form of day-hospitalization. Lastly, we will conclude with some recommendations to the attention of the relatives or the close friends.


A 4D x-ray computer microtomography for high-temperature electrochemistry.
High-temperature electrochemistry is widely used in many fields. However, real-time observations and an in-depth understanding of the inside evolution of this system from an experimental perspective remain limited because of harsh reaction conditions and multiphysics fields. Here, we tackled this challenge with a high-temperature electrolysis facility developed in-house. This facility permits in situ x-ray computer microtomography (μ-CT) for nondestructive and quantitative three-dimensional (3D) imaging. In an electrorefining system, the μ-CT probed the dynamic evolution of 3D morphology and components of electrodes (4D). Subsequently, this 4D process was visually presented via reconstructed images. The results monitor the efficiency of the process, explore the dynamic mechanisms, and even offer real-time optimization. This 4D analysis platform is notable for in-depth combinations of traditional electrochemistry with digital twin technologies owing to its multiscale visualization and high efficiency of data extraction.


Clinical features of patients with a myocardial infarction during acute management of an ischemic stroke.
Ischemic stroke and myocardial infarction (MI) share some common risk factors and pathophysiological mechanisms. In addition, brain injury has been associated with abnormalities of heart function such as increased cardiac enzymes and EKG changes. However, there is little information on patients with post-stroke MI. In this study, we investigated the characteristics of ischemic stroke patients who had a MI during the acute stroke period. One thousand three hundred fifty-seven patients with acute ischemic stroke were studied by retrospective review of the stroke registry and inpatient charts. Among these patients, 12 that developed a post-stroke MI, during acute stroke management, were included in this study. The stroke subtype, pattern of arterial stenosis, and lesional dominance were analyzed. The overall frequency of a post-stroke MI during hospitalization was 0.9% (12 of 1,357 patients initially studied). Eight of the 12 patients included had a painless MI. Significant intracranial arterial stenosis was observed in 10 patients (83%). According to the TOAST classification, seven patients (58.3%) had large artery atherosclerosis, three patients were classified as undetermined etiology and two patients were divided into the lacunar and cardioembolic group. Acute ischemia of the insular region was noted in six patients. Five patients died from their cardiac complications during the hospital stay. Post-stroke MI can be a potential complication of acute ischemic stroke; these events have a high mortality. Routine EKG monitoring, during the acute stroke period, may improve patient outcome due to the possibility of a painless post-stroke MI.


A self-consistent approach for determining pairwise interactions that underlie channel activation.
Signaling proteins such as ion channels largely exist in two functional forms, corresponding to the active and resting states, connected by multiple intermediates. Multiparametric kinetic models based on sophisticated electrophysiological experiments have been devised to identify molecular interactions of these conformational transitions. However, this approach is arduous and is not suitable for large-scale perturbation analysis of interaction pathways. Recently, we described a model-free method to obtain the net free energy of activation in voltage- and ligand-activated ion channels. Here we extend this approach to estimate pairwise interaction energies of side chains that contribute to gating transitions. Our approach, which we call generalized interaction-energy analysis (GIA), combines median voltage estimates obtained from charge-voltage curves with mutant cycle analysis to ascertain the strengths of pairwise interactions. We show that, for a system with an arbitrary gating scheme, the nonadditive contributions of amino acid pairs to the net free energy of activation can be computed in a self-consistent manner. Numerical analyses of sequential and allosteric models of channel activation also show that this approach can measure energetic nonadditivities even when perturbations affect multiple transitions. To demonstrate the experimental application of this method, we reevaluated the interaction energies of six previously described long-range interactors in the Shaker potassium channel. Our approach offers the ability to generate detailed interaction energy maps in voltage- and ligand-activated ion channels and can be extended to any force-driven system as long as associated "displacement" can be measured.


Investigating the Role of BATF3 in Grass Carp (Ctenopharyngodon idella) Immune Modulation: A Fundamental Functional Analysis.
Basic leucine zipper transcription factor ATF-like (BATF)-3, belonging to activator protein 1 (AP-1) superfamily transcription factors, is essential for homeostatic development of CD8α⁺ classical dendritic cells activating CD8 T-cell responses to intracellular pathogens. In this study, the characteristics and cDNA cloning of the CiBATF3 molecule were described in grass carp (Ctenopharyngodon idella). CiBATF3 had abundant expression in immune-related organizations, including liver, spleen and gill, and grass carp reovirus (GCRV) infection had significantly changed its expression level. After Ctenopharyngodon idella kidney (CIK) cells were challenged with pathogen-associated molecular patterns (PAMPs), polyinosinic:polycytidylic acid (poly(I:C)) stimulation induced higher mRNA levels of CiBATF3 than that of lipopolysaccharide (LPS). Subcellular localization showed that CiBATF3-GFP was entirely distributed throughout cells and nuclear translocation of CiBATF3 was found after poly(I:C) treatment. Additionally, the interaction between CiBATF3 and interleukin 10 (IL-10) was proven by bimolecular fluorescence complementation (BiFC) system. The small interfering RNA (siRNA)-mediated CiBATF3 silencing showed that the mRNA of CiBATF3 and its downstream genes were down-regulated in vitro and in vivo. CiBATF3 played a negative regulatory role in the transcriptional activities of AP-1 and NF-κB reporter gene. In summary, the results may provide valuable information on fundamental functional mechanisms of CiBATF3.


[Study on the polymorphism of killer cell immunoglobulin like receptor (KIR) gene with systemic lupus erythematosus of North population in China].
To investigate the polymorphism of KIR genes in systemic lupus erythematosus (SLE) patients, and to study the correlation between KIR genes and susceptibility of SLE. The polymorphism of KIR genes were detected by PCR-SSP technique in 62 patients with SLE and 61 healthy persons as controls from North of China. The differences of KIR frequency between the SLE group and the control were tested by statistical analysis. The most frequent genotype was KIR 3DP1, 2DL1, 2DP1, 3DL1, 2DL3, 1D, followed by 2DS4, 2DL5, 3DS1, 2DS2, 2DS5 and 2DL2. KIR 2DS1, 2DS3 and 3DP1v were lower in frequency compared with others. The frequency of KIR 3DS1, 2DL2, 2DL5 and 2DL3 were significantly lower in SLE group than that in the control èP<0.01é. There may be a association between the polymorphism of KIR genes with SLE in North of China should be investigated further.


Weak Interaction-Tailored Catalytic Interface of Ultrasmall Gold Nanoclusters as Enzyme Mimics for Enhanced Colorimetric Biosensing.
Gold nanoclusters (AuNCs) represent an emerging type of engineered nanomaterials with intrinsic enzymatic activity for both chemical and biological applications, but the catalytic activity of most reported AuNCs remains rather limited. Herein, we report a new, efficient strategy of promoting the peroxidase-mimic activity of AuNCs by tailoring their catalytic interfaces via small molecule-mediated weak interactions. Inspired by the presence of imidazole structures in many biocatalytic centers, we screened a series of imidazole-containing small molecules to evaluate their impact on the enzymatic activity of AuNCs. Through monitoring the absorbance change of 3,3',5,5'-tetramethylbenzidine, 1-methyl-2-imidazolecarboxaldehyde (MCA) was identified to possess the most significant effect on enhancing the peroxidase-mimic activity of glutathione-stabilized AuNCs (GSH-AuNCs) among all the examined molecules. Interestingly, the enhancement effect of MCA on the catalytic activity of these AuNCs was found to be highly reversible and can be switched on/off by simply adding MCA/dialysis treatment. Molecular dynamics simulations and further experimental analysis confirmed that these MCA molecules were adsorbed on the surface of GSH-AuNCs through weak non-covalent interactions. The underlying mechanism analysis suggested that the presence of MCA can efficiently promote the production of •OH in the GSH-AuNC system. As a proof of example, we then demonstrated that the presence of MCA can greatly increase the bioanalytical performance of AuNC-based peroxidase mimics, as evidenced by a 65-fold lower LOD for glucose detection of AuNCs@MCA than that using AuNCs only. Finally, the present system has been successfully applied for sensing the blood glucose level of both healthy people and diabetics with promising results.


Inhaled sodium nitroprusside. Non-selective reduction of thromboxane analogue-induced pulmonary vasoconstriction in healthy sheep.
Both inhaled nitric oxide (NO) and inhaled prostacyclin have been shown to selectively decrease pulmonary hypertension of various origin. The aim of the present study was to assess the potential of the NO donor sodium nitroprusside (SNP) to elicit selective pulmonary vasodilation. SNP spontaneously liberates nitric oxide in the presence of reducing substances like cysteine or glutathione, ubiquitous in many different tissues. Inhaled as an aerosol in 3 healthy lambs presenting pulmonary hypertension induced by infusion of a thromboxane analogue, low concentrations of SNP (0.02-0.6 mg/ml) revealed no effect at all. In contrast, high concentrations of SNP (1.0-20.0 mg/ml) lowered pulmonary artery pressure in conjunction with systemic arterial hypotension, suggesting systemic resorption of SNP with subsequent release of its nitroso-group. Selective pulmonary vasodilation was never observed. In conclusion, the present results do not support a selective effect of inhaled SNP in the pulmonary circulation.


Silent cardiac ischemia.
Between the extremes of those who have no coronary disease and those limited by it are those with documented ischemia but no symptoms. Treating these patients in the "murky middle" generates some important questions. Should we treat patients with no symptoms solely on the basis of test abnormalities? Can we make the asymptomatic person better? What interventions would we use to treat such a disorder? How do we justify the risk, inconvenience, and cost of these interventions? How do we measure the efficacy of our intervention? Treating the asymptomatic person can only be justified if we prevent future events through our intervention. The management of silent ischemia can serve as a model for handling other preventative measures. The following article describes the issues around silent cardiac ischemia and some of the insights obtained in the Asymptomatic Cardiac Ischemia Pilot (ACIP) Study.


Avidin and streptavidin ligands based on the glycoluril bicyclic system.
Glycoluril derivatives with a carboxylic acid side chain have been synthesized and shown to bind to both avidin and streptavidin. Introduction of a valerate side chain in glycoluril led to an increased binding to both proteins only when the valerate group was bound to a N atom and with the proper stereochemistry [(+)-enantiomer]. On the other hand, introduction of the valerate side chain either on the bridgehead carbon or on the N atom with the opposite stereochemistry [(-)-enantiomer] led to a decrease in binding constant compared with unsubstituted glycoluril. Direct spectrophotometric competitive titration of each protein with a racemic ligand allowed measurement of the enantioselectivity of the ligand-protein complexation, together with the binding constant of the two enantiomers. In the case of the N-substituted glycoluril, the extension of the side chain by one methylene group, from valerate to caproate, led to an increase in the binding constant to both proteins. Docking studies using AutoDock 3.05 have been performed in order to predict the binding modes of these ligands to streptavidin. The effect of the stereochemistry and the position of the side chain on the binding constant to streptavidin is discussed in view of the predicted binding modes.


A Review on Recent Innovations of Pretreatment and Analysis Methods for Sulfonylurea Herbicides.
Sulfonylurea herbicides (SUHs) are widely used in agriculture because of their low dosage, low cost, and high selectivity. However, due to improper use and lack of effective management, their residues pose a threat to the human health through environment and food pollution. Therefore, there is a need for simple, quick, economical, and effective methods to analyze SUHs in plant-derived foods, crops, and environmental samples. The present article presents a comprehensive review of the pretreatment and analytical technologies used for SUHs in various sample matrices, focusing on the developments since 2010. The main pretreatment methods include liquid-liquid extraction, solid-phase extraction, QuEChERS, and different microextraction methods, whereas analytical methods mainly include liquid chromatography coupled with different detectors, capillary electrophoresis, among others. In addition, the present study also compared the advantages and disadvantages of the methods and the future development is prospected.


Private sector initiatives in case management.
Case management for high-cost patients is offered by virtually all private insurers and many health management firms. Despite the proliferation of the service, little is known about the process of case management, how it varies among vendors, what its impact is on short- and long-run patient costs, and what its effects are on quality. In this article, the authors present the results of a survey of insurance-based programs that reveal some process variations that could lead to differences in program effectiveness and cost.


Long-term determinants of muscle strength decline: prospective evidence from the 22-year mini-Finland follow-up survey.
To examine long-term changes in handgrip strength and the factors predicting handgrip strength decline. Longitudinal cohort study with 22 years of follow-up. Population-based Mini-Finland Health Examination Survey in Finland. Nine hundred sixty-three men and women aged 30 to 73 at baseline. Handgrip strength was measured using a handheld dynamometer at baseline and follow-up. Information on potential risk factors, namely lifestyle and chronic conditions, and their changes throughout the follow-up were based on health interviews. Based on linear mixed-effect models, midlife physically strenuous work, excess body weight, smoking, cardiovascular disease, hypertension, diabetes mellitus, and asthma predicted muscle strength decline over 22 years of follow-up (P < .05 for all). In addition, pronounced weight loss, becoming physically sedentary, persistent smoking, incident coronary heart disease, other cardiovascular disease, diabetes mellitus, chronic bronchitis, chronic back syndrome, long-lasting cardiovascular disease, hypertension, and asthma were associated with accelerated handgrip strength decline (P < .05 for all). Lifestyle and physical health earlier in life determine rate of muscle strength decline in old age. Efforts should be made to recognize persons at risk in a timely manner and target early interventions to middle-aged persons to slow down muscle strength decline and prevent future functional limitations and disability.


Sexual Modesty in Sexual Expression and Experience: A Scoping Review, 2000 - 2021.
Sexual modesty is the social, cultural, interpersonal, and psychological systems - defined by the tenets of Script Theory - that regulate individuals' sexual expression and experience at the social, legal, and interpersonal boundaries of acceptable/not-acceptable, private/public, and personal/social. Almost all aspects of sexual expression and experience are touched by the pervasive modesty standards for sexual communication, sexual display, sexual relations, and sexual behaviors. Sexual modesty influences an array of sexual and reproductive health outcomes. Many aspects of sexual modesty are enforced by legal as well as social, cultural, and religious proscriptions, including social shaming and ostracism as well as corporal and capital punishments. The purpose of this paper is to summarize a diverse literature related to sexual modesty from the years 2000 to 2021 in order to clarify its role in sexual health and sexual wellbeing and to identify directions for new research.


Pearls: neurologic complications of HIV/AIDS.
Clinically apparent and frequently debilitating neurologic disease is common with infection by HIV type 1. Approximately one half of all HIV-infected patients will develop clinically significant neurologic disease, and the frequency with which neuropathologic abnormalities are detected at autopsy in some series exceeds 90%, suggesting that neurologic findings are often overlooked. Not surprisingly, careful neurologic examination, even in the absence of specific complaints by the HIV-infected patient, often reveals evidence of central or peripheral nervous system dysfunction. Although neurologic disease typically occurs with advanced disease and profound immunosuppression, it may also occur during early stages of the infection. In as many as 20% of individuals, neurologic disease is the harbinger of AIDS. The spectrum of neurologic disorders that complicate HIV infection is extremely broad; any part of the neuraxis may be affected. Additionally, the complexity of evaluating the HIV-infected person with neurologic disease is increased by the relatively high frequency with which more than one disease concurrently affects the nervous system.


The chloride-stimulated K(+)-secretion by insect midgut and its modification in the presence of osmotic gradients: a short-circuit current and noise-analysis study.
K(+)-secretion in the midgut of the larval moth, Manduca sexta, was studied by measuring the kinetics of the lumen-directed short-circuit current (Isc) and the conduction noise from basolateral K+ channel block by Ba2+. Hemolymph chloride as well as hypotonicity both stimulate this K+ current (IK). The kinetic nature of the stimulation is, however, different in each case. Analysis of blocker noise supports, to a large degree, the interpretation obtained from kinetics, namely: chloride ions do not act via changes in cell volume but influence ion turnover and channel number.


Retroperitoneal Bronchogenic Cyst Mimicking a Pancreatic Cystic Lesion with Extremely High Level of Intralesional Fluid CA-19.9 Antigen: Benign in Disguise.
Bronchogenic cysts are congenital benign tumors resulting from abnormal budding of the primitive foregut. Usually presented on the posterior mediastinum, its presence on the retroperitoneum is extremely rare. We present an asymptomatic lady patient with a retroperitoneal cystic lesion that was submitted to endoscopic ultrasound-guided biopsies and intracystic fluid aspiration with histology excluding malignance despite intracystic fluid biochemical analysis that disclosed extremely high carbohydrate antigen 19-9. Definite diagnosis of bronchogenic cyst was only possible after complete surgical resection of the lesion. Furthermore, we discuss the use of this antigen as a tumor marker in this situation and its relevance to the preoperative diagnosis of such lesions.


Vertical distraction osteogenesis of a free vascularized fibula flap in a reconstructed hemimandible for mandibular reconstruction and optimization of the implant prosthetic rehabilitation. Report of a case.
Free vascularized fibular flap is considered the treatment of choice in mandibular reconstruction for extensive bone defects (over 6 centimeters) resulting from trauma, infections or tumor resections. But, when the reconstruction involves a dentate mandible, the fibula has the limit as it does not offer sufficient bone height to restore the alveolar arch up to the occlusal plane. Therefore, the deficiency in bone height makes implant placement impractical. We report a case of vertical distraction osteogenesis of a free vascularized fibula flap used to reconstruct a hemimandible after resection of an odontogenic myxoma, for optimization of the implant prosthetic rehabilitation. The distraction device was applied intraorally. After 10 days of latency period, distraction protocol was performed at a distraction rate of 0.5 mm per day. A consolidation period of 3 months followed. Afterwards the distraction device was removed and 3 osseointegrated dental implants were placed in the distracted area. As a result, the vertical discrepancy between the fibula and the native hemimandible was corrected. The amount of vertical height achieved after distraction was 17 milimeters. The increase of vertical bone height was stable and enabled placement of dental implants without any complications. In conclusion, we consider that vertical distraction osteogenesis of free vascularized flaps is a reliable technique that optimizes implant positioning for ideal prosthetic rehabilitation, after mandibular reconstruction following tumor surgery.


Galanin and vasoactive intestinal polypeptide: coexistence and corelease from the vascularly perfused pig ileum during distension and chemical stimulation of the mucosa.
By immunohistochemistry and double staining technique, almost complete coexistence of galanin-like immunoreactivity (GAL-LI) and vasoactive intestinal polypeptide-like immunoreactivity (VIP-LI) was demonstrated in submucosal ganglionic cells and mucosal nerve fibers of the porcine ileum. The release of the two neuropeptides was studied in isolated, vascularly perfused pig ileum. Distension (increasing intraluminal pressure by 10 mm Hg) and intraluminal instillation of homologous gallbladder bile, amino acids, 0.1 M HCl, hypertonic NaCl (3,400 mosm x kg-1) and hypertonic glucose (1,100 mosm x kg-1) all increased the release of GAL-LI and VIP-LI into the venous effluent in parallel. Being the most potent stimulus, bile increased the output of GAL-LI from 0.74 +/- 0.12 to 2.44 +/- 0.81 pmol/min (mean +/- SE, p = 0.018) and the output of VIP-LI from 3.29 +/- 0.19 to 12.68 +/- 4.01 pmol/min (p less than 0.001), respectively. In conclusion, the coexistence and parallel release of GAL and VIP suggest that GAL/VIP neurons may be involved in intramural secretory and motor reflexes.


Update on assessment activities. United States perspective.
The purpose of this paper is to present an update on biomedical technology assessment activities from a United States perspective. In 1985, I described in detail (a) a primary vehicle for technology assessment--the Consensus Development Program (CDP) of the National Institutes of Health (NIH)--and also discussed, in a second paper, (b) the transfer of consensus-enhanced scientific information and some of its impact on U.S. medical practice. Here, I focus on what has transpired during the past year: the changes in the climate in which U.S. technology assessment efforts are being conducted, the consequences of these changes, and the challenges that they pose for all concerned with the provision of quality health care. The first part of this paper centers on the broader framework within which technology assessment plays a role in the United States. Later, it addresses the specific technology assessment and transfer activities in which the NIH is engaged.


Extracting surface diffusion coefficients from batch adsorption measurement data: application of the classic Langmuir kinetics model.
Surface diffusion coefficients may be estimated by fitting solutions of a diffusion model to batch kinetic data. For non-linear systems, a numerical solution of the diffusion model's governing equations is generally required. We report here the application of the classic Langmuir kinetics model to extract surface diffusion coefficients from batch kinetic data. The use of the Langmuir kinetics model in lieu of the conventional surface diffusion model allows derivation of an analytical expression. The parameter estimation procedure requires determining the Langmuir rate coefficient from which the pertinent surface diffusion coefficient is calculated. Surface diffusion coefficients within the 10-9 to 10-6 cm2/s range obtained by fitting the Langmuir kinetics model to experimental kinetic data taken from the literature are found to be consistent with the corresponding values obtained from the traditional surface diffusion model. The virtue of this simplified parameter estimation method is that it reduces the computational complexity as the analytical expression involves only an algebraic equation in closed form which is easily evaluated by spreadsheet computation.


Small nonpolypoid colorectal carcinoma.
The objective of this study was to characterize and assess the presence and frequency of small nonpolypoid colorectal adenocarcinomas among patients with colorectal cancer referred for surgery. The medical, endoscopic, and surgical reports and the histopathologic slides of all patients operated on for colorectal cancer were retrospectively reviewed. Small nonpolypoid colorectal cancer (SNPCC) was defined as a malignant, nonpolypoid lesion smaller than 15 mm. SNPCC was classified according to the Japanese macroscopic classification of colorectal carcinoma. The frequency of SNPCC among patients referred for operation was 1.8%. Most of these patients were asymptomatic and were diagnosed by the same endoscopist using a high-resolution video-endoscope without the assistance of enhancement techniques. These lesions had a mean size of 10.8 mm, were mainly of the flat or flat elevated type, and were located in the distal colon. Among patients with colorectal cancer referred for surgery, 1.8% had SNPCC. These lesions can be detected using high-resolution video-endoscopy equipment without the need for enhancement techniques, as reported in Japanese series. Increased awareness of the existence of such SNPCC lesions may help the average endoscopist detect such lesions. As SNPCC represents colorectal cancer, all the cases in our series were treated by typical oncologic surgical resection.


Anorectal injuries in children: a 20-year experience in two centers.
Anorectal injuries in children are not frequently reported and their management is challenging. This report reviews the experience in managing this type of injuries in two medical centers over 20 years. An institutional database search for patients who were treated for anorectal injuries between 1994 and 2015 was undertaken. Twenty cases were located and medical records reviewed. This study was conducted with institutional review board approval (#572-14). There were 6 girls and 14 boys with ages ranging between 1 and 15 years (mean 7 years). Eleven patients sustained penetrating trauma, while nine sustained blunt trauma. The mechanism of injury was variable and associated injuries were more common in blunt trauma. Most common presenting symptoms were rectal bleeding (n = 12) and anal pain (n = 11), followed by abdominal pain in six patients. Eighteen anorectal injuries were extraperitoneal and two intraperitoneal. Among patients with extraperitoneal injuries, 12/18 were managed by primary repair with (6) or without (6) fecal diversion and 2/18 by wound irrigation and drainage with fecal diversion and delayed repair. Four patients had superficial anal and perineal injuries that were irrigated and left to heal by secondary intention. Two patients with intraperitoneal rectal injuries underwent primary repair with fecal diversion. Follow-up period ranged from 2 weeks to 8 years (mean 2 years). There were three cases of wound infection, one case of suture line leak requiring reoperation and one case of vesicorectal fistula in a patient with combined trauma of the rectum and urinary bladder. There was no mortality. Fecal continence was preserved in all patients available for follow-up evaluation. Primary repair of the perineal wound and anal sphincters can be performed safely in most cases given hemodynamic stability. Fecal diversion should be saved for cases with severe perineal involvement or cases with substantial associated injuries and concern of gross contamination.


LIM homeodomain transcription factor Isl-1 enhances follicle stimulating hormone-beta and luteinizing hormone-beta gene expression and mediates the activation of leptin on gonadotropin synthesis.
The Lin-11, Isl-1, and Mec-3 (LIM) homeodomain transcription factor Isl-1 has been reported to be involved in pituitary development in the early stages of mouse embryogenesis. Our recent studies have shown that Isl-1 is mainly located in the pituitary gonadotropes throughout pituitary development and persists to adulthood. We still do not know the physiological functions of Isl-1 expression and its related mechanisms in the pituitary gland. The aim of the present study was to examine the hypothesis that Isl-1 is involved in regulating pituitary gonadotropin hormone (FSH/LH) production by activating FSHβ and LHβ gene expressions. We have shown that Isl-1 activates FSHβ and LHβ subunit promoters and endogenous gene transcription in LβT2 cells. In addition, Isl-1 overexpression significantly increased FSH synthesis and secretion but not LH. The actions of Isl-1 were not observed when the homeodomain or LIM1 domains are mutated. This demonstrates that Isl-1 induction of FSHβ and LHβ is by both direct and indirect binding of Isl-1 to DNA sequences. Furthermore, Isl-1 expressional level was up-regulated in LβT2 cells after exposure to GnRH, activin, and leptin. However, RNA interference-induced knockdown of Isl-1 significantly reduced the effect of leptin but did not obviously influence the stimulating effects of GnRH and activin on LH and FSH production. In conclusion, the results demonstrate that the LIM-homeodomain transcription factor Isl-1 functions to increase FSHβ/LHβ gene transcription, and mediates the effects of leptin on gonadotropin synthesis.


Evaluation of independent-living programs.
The program report that states must submit to the federal government under the federal Title IV-E Independent-Living Initiative is, in essence, a program evaluation report and will require comprehensive program and evaluation data to complete. Because the program report will be a key factor in determining the future of this federal initiative, it is important that states improve their information system capability to generate the range of necessary data. This article offers detailed suggestions for ways in which states could establish their independent-living program information systems to produce program and evaluation data; and presented two examples of approaches to evaluating the Title IV-E independent-living program, one in Pennsylvania and another in Texas. These states were selected for the purpose of illustrating two different approaches and not necessarily for the presentation of exemplary evaluation practices.


Biochemical composition, antimicrobial activities,and anti-quorum-sensing activities of ethanol and ethyl acetate extracts from Hypericum connatum Lam. (Guttiferae).
We studied the polyphenol composition and antioxidant activity of the ethanolic and ethyl acetate extracts of Hypericum connatum (Guttiferae), in addition to their antimicrobial and antiquorum-sensing (AQS) properties. The extracts exhibited a similar polyphenol content and a notable antioxidant activity, which was stronger in the ethanolic extract (EC50=3.2 μg/mL). Ultrahigh-performance liquid chromatography analyses revealed different polyphenol profiles, with rutin and apigen being the main components of the ethanolic extract and caffeic acid, (-)-epicatechin and p-coumaric acid being abundant in the ethyl acetate extract. The ethyl acetate extract exhibited a more effective antimicrobial activity than the ethanolic extract against the pathogens Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa. For the first time, AQS activity was detected in H. connatum: the ethanolic extract inhibited the production of violacein, a quorum-sensing-regulated pigment, in a Chromobacterium violaceum tester strain, without interfering with its growth.


Efficient bioremediation of tannery wastewater by monostrains and consortium of marine Chlorella sp. and Phormidium sp.
This study evaluated the bioremediation potential of two marine microalgae Chlorella sp. and Phormidium sp., both individually and in consortium, to reduce various pollutants in tannery wastewater (TW). The microalgae were grown in hazardous 100% TW for 20 days, and the reductions in biochemical oxygen demand (BOD), chemical oxygen demand (COD), total nitrogen (TN), total phosphorous (TP), chromium (Cr) and total dissolved solids (TDS) of the wastewater monitored periodically. Both marine isolates reduced the BOD and COD by ≥90% in the consortium and by over 80% individually. Concentrations of TN and TP were reduced by 91.16% and 88%, respectively, by the consortium. Removal/biosorption efficiencies for chromium ranged from 90.17-94.45%. Notably, the TDS, the most difficult to deal with, were reduced by >50% within 20 days by the consortium. The novel consortium developed in this study reduced most of the ecologically harmful components in the TW to within the permissible limits of discharge in about 5 to 15 days of treatment. Thus, both the tested marine strains of Chlorella and Phormidium sp. are promising for bioremediating/detoxifying TW and adequately improve the water quality for safe discharge into open water bodies, in particular when used as a consortium.


A family caregiving model for public health nursing.
The absence of clear definitions of public health nursing competency have plagued efforts to demonstrate the need for public health nursing programs. This article describes a model that can be used to explain why public health nursing services should be integral to the public agenda.


Down-regulation of murine contact sensitivity by hapten-amino acid derivatives.
The low responsiveness of contact sensitivity (CS) in sensitized and challenged mice was induced by using hapten-amino acid derivatives. Subcutaneous injection of trinitrophenyl (TNP)-lysine or oxazolone-glycine inhibited ear swelling responses in mice that received rechallenge. The inhibitory effect was long-lasting and antigen-specific. TNP-lysine blocked the transfer of CS in vivo and the binding of immune lymph node cells to antigen in vitro. Thus, the suppression was mediated by inhibition of effector cells, but not associated with the generation of efferent limb-acting suppressor cells. The tool reported herein seems to be quite useful for controlling ongoing murine CS to simple chemicals.


Staging of regional lymph nodes in melanoma: a case for including nonsentinel lymph node positivity in the American Joint Committee on Cancer staging system.
Survival varies widely in patients with stage III melanoma. The existence of clinical significance for positive nonsentinel lymph node (NSLN) status would warrant consideration for incorporation into the American Joint Committee on Cancer staging system and better prediction of survival. To evaluate whether disease limited to sentinel lymph nodes (SLNs) represents different clinical significance than disease spread into NSLNs. The database of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, California, was queried for all patients with SLNs positive for cutaneous melanoma who subsequently underwent completion lymph node dissection. Disease-free survival, melanoma-specific survival (MSS), and overall survival. A total of 4223 patients underwent SLN biopsy from 1986 to 2012. Of these patients, 329 had a tumor-positive SLN. Of the 329, 250 patients (76.0%) had no additional positive nodes and 79 (24.0%) had a tumor-positive NSLN. Factors predictive of NSLN positivity included older age (P = .04), greater Breslow thickness (P < .001), and ulceration (P < .02). Median overall survival was 178 months for the SLN-only positive group and 42.2 months for the NSLN positive group (5-year overall survival, 72.3% and 46.4%, respectively). Median MSS was not reached for the SLN-only positive group and was 60 months for the NSLN positive group (5-year MSS, 77.8% and 49.5%, respectively). On multivariate analysis, NSLN positivity had a strong association with recurrence (hazard ratio [HR], 1.75; 95% CI, 1.23-2.50; P = .002), shorter overall survival (HR, 2.24; 95% CI, 1.48-3.40; P < .001), and shorter MSS (HR, 2.23; 95% CI, 1.46-3.07; P < .001). To further control for the effects of total positive lymph nodes, comparison was done for patients with only N2 disease (2-3 total positive lymph nodes); the results of this comparison confirmed the independent effect of NSLN status (MSS; P = .04). Nonsentinel lymph node positivity is one of the most significant prognostic factors in patients with stage III melanoma. Subclassification of melanoma by NSLN tumor status should be considered for the American Joint Committee on Cancer staging system.


Hierarchical integration of agency and communion: a study of influential moral figures.
The purpose of this research is to (a) identify which of recent history's influential figures did and which did not personify moral excellence, and (b) to examine the motives that drove these individuals along such divergent paths. In Study 1, 102 social scientists evaluated the moral qualities of influential figures from Time Magazine's lists. In Study 2, we selected the 15 top ranking of these figures to comprise a moral exemplar group and the bottom 15 to comprise a comparison group of similarly influential people. We measured the motivational aspects of their personality (agency and communion) by content-analyzing extant speeches and interviews. Moral exemplars exhibited the hierarchical integration of agency and communion by treating agentic motives as a means to an end of communal motives. Comparison subjects, by contrast, personified unmitigated agency by treating motives of agency as both a means to an end and an end unto itself. These results imply that both the strength and structure of a person's motives account for moral behavior.


Daytime colour preference in Drosophila depends on the circadian clock and TRP channels.
Light discrimination according to colour can confer survival advantages by guiding animals towards food and shelter and away from potentially harmful situations1,2. Such colour-dependent behaviour can be learned or innate. Data on innate colour preference in mammals remain controversial3 and there are limited data for simpler organisms4-7. Here we show that, when given a choice among blue, green and dim light, fruit flies exhibit an unexpectedly complex pattern of colour preference that changes according to the time of day. Flies show a strong preference for green in the early morning and late afternoon, a reduced green preference at midday and a robust avoidance of blue throughout the day. Genetic manipulations reveal that the peaks in green preference require rhodopsin-based visual photoreceptors and are controlled by the circadian clock. The midday reduction in green preference in favour of dim light depends on the transient receptor potential (TRP) channels dTRPA1 and Pyrexia, and is also timed by the clock. By contrast, avoidance of blue light is primarily mediated by multidendritic neurons, requires rhodopsin 7 and the TRP channel Painless, and is independent of the clock. Our findings show that several TRP channels are involved in colour-driven behaviour in Drosophila, and reveal distinct pathways of innate colour preference that coordinate the behavioural dynamics of flies in ambient light.


[Recurrent fever, nocturnal sweating, weight loss].
A 69-year-old woman was admitted to the hospital for fever of unknown origin with nightsweats and weight loss. Diagnosis of endocarditis lenta with streptococcus viridans and a preexisting mitral-valve prolapse with small regurgitation jet was established. Signs and symptoms of endocarditis lenta are stressed in the discussion. Special attention is given to transesophageal echocardiography and to the connection of endocarditis with mitral-valve prolapse.


Heparin induced thrombocytopenia with thrombosis: a two step process?
Heparin induced thrombocytopaenia is an increasingly recognised prothrombotic disorder, where platelet activation by immunoglobulin G, heparin and platelet factor 4 complexes has been proposed to result in the activation of coagulation, and thrombus formation. However, this pathophysiological mechanism will not explain the predilection of patients, undergoing surgical procedures, especially orthopaedic surgeries, for the development of thrombosis secondary to heparin induced thrombocytopaenia. The article describes a two-step process, where a quantitative role for platelet factor 4 in activating monocytes at the tissue injury sites may play a role in the pathogenesis of heparin induced thrombocytopenia with thrombosis.


A Randomized Crossover Comparison of Airway Sealing with the Laryngeal Mask Airway Ambu AuraFlex at Three Intracuff Pressures in Pediatric Laparoscopic Surgery.
An adequate intracuff pressure is important to ensure sufficient sealing function when using supraglottic airway devices to protect the airway from secretions and achieve adequate positive pressure ventilation. The aim of this study is to analyze a feasible and effective alternative Ambu AuraFlex intracuff pressure in child's laparoscopic surgery. Seventy-two children were included in this study. After insertion of the laryngeal mask airway AuraFlex, oropharyngeal leak pressure (OLP) was measured at intracuff pressures of 10, 30, and 60-cmH2O according to one of six sequences produced on the basis of 3 × 6 Williams crossover design. During the intraoperative period, AuraFlex was maintained using the last intracuff pressure of the allocated sequence. Oropharyngeal leak pressure, peak airway pressure, the fiberoptic view, mucosal change, and complications were assessed at three intracuff pressures. The OLP at the intracuff pressure of 10 cmH2O was significantly lower than that of 30 cmH2O (2# 18.1 ± 1.5 vs. 19.5 ± 1.4 cmH2O, p = 0.001; 2.5# 17.7 ± 1.2 vs. 20.2 ± 1.4, p = 0.001) and 60 cmH2O (2# 18.1 ± 1.5 vs. 20.0 ± 1.3 cmH2O, p = 0.002; 2.5# 17.7 ± 1.2 vs. 20.8 ± 1.1, p = 0.003). Compared with the peak airway pressure in pre-and postpneumoperitoneum, the OLP was significantly higher. Subgroup analysis showed no differences in mucosal change and complications. Intracuff pressures of 30 may be sufficient for the Ambu AuraFlex in child's laparoscopic surgery, and there may be no added benefit of an intracuff pressure of 60 cmH2O, as oropharyngeal leak pressures were similar.


Evaluation of the human fragile X mental retardation 1 polymerase chain reaction reagents to amplify the FMR1 gene: testing in a clinical diagnostic laboratory.
Fragile X syndrome (FXS) is caused by the absence of a functional fragile X mental retardation protein (FMRP). In most cases, the molecular mutation is an expansion and consequent methylation of the CGG trinucleotide repeat in the 5' end of the FMR1 gene. Polymerase chain reaction (PCR)-based assays that overcome the limitations of amplifying >100-150 CGG repeats have been designed. One such product, Human FMR1 PCR Reagents, can detect expanded mutation alleles without determining methylation status. We used this assay to amplify 70 clinical samples previously tested in three clinical laboratories, including 28 full mutation alleles, 17 premutation alleles, 6 gray zone alleles, and 21 normal samples (51 normal alleles including 5 homozygous females). The results were concordant with previously reported results. All full and premutation alleles were identifiable: repeat sizes are not assigned when the CGG repeat number is >200 and all full and premutation alleles were scored in the same category using this assay. All normal and gray zone alleles were within 0-1 repeat of their previously reported allele sizes. This method identified a mosaic premutation/full mutation pattern in 12/21 samples previously identified as full mutation only and in 5/7 samples previously reported as mosaic premutation/full mutation. These results demonstrate that this assay provides comparable results to the combination of PCR/Southern blot methodologies. Additional issues such as technologist time, reagent costs, turnaround times, and sample requirements are comparable to the PCR/Southern blotting assays currently utilized; however, methylation status cannot be determined using this assay. It is likely that PCR-only based assays will eventually replace previous methods for FXS and that Southern blotting or another methylation assay will only be utilized when determination of methylation status is necessary. This type of assay may also be utilized for other nucleotide expansion disorders.


Chiral helicity induced by hydrogen bonding and chirality of podand histidyl moieties.
[structure: see text] The single-crystal X-ray structure determination of N,N'-bis[(S)-(+)-1-methoxycarbonyl-2-(4-imidazolyl)ethyl]-2,6-pyridinedicarboxamide (L-BHisPA) and the D-isomer (D-BHisPA) derived from the corresponding chiral histidine revealed a left- and right-handed helical conformation, respectively, through intramolecular hydrogen bonding and chirality of the podand histidyl moieties. Furthermore, each helical molecule is connected by continuous intermolecular hydrogen bonds to afford a left- or right-handed helical assembly, respectively, in the crystal packing.


Is the Sardinian Blue Zone the New Shangri-La for mental health? Evidence on depressive symptoms and its correlates in late adult life span.
An area of extraordinary longevity (i.e., Sardinian Blue Zone) characterized by a very high prevalence of long-lived successful agers has been validated in Sardinia, an Italian island located in the Mediterranean Sea. This study was primarily aimed at examining whether dietary habits (intake of vegetables and fruit, animal-derived proteins, and carbohydrates-rich food), time spent on hobbies, subjective physical health, and socio-cultural context (Sardinian Blue Zone vs. another Sardinian rural area) predicted self-reported depressive symptoms in older adults recruited in the Sardinian Blue Zone and another Sardinian rural area not being characterized by a higher prevalence of long-lived individuals. Three hundred and eighteen community-dwellers, age 65 years and older, 188 females and 130 males (Mage = 79.1 years, SD = 6.9 years) were recruited from the Sardinian Blue Zone and another Sardinian rural area. Each participant individually completed a battery of instruments to assess lifestyle, food habits, perceived physical health, and depressive symptoms through the CES-D inventory. Significant associations were found between depressive signs, perceived physical health, time spent gardening, proteins, and carbohydrates intake, respectively. Approximately 17% of the variance in the CES-D condition was predicted by socio-cultural context, perceived physical health, and gardening. Participants recruited in the Sardinian Blue Zone spent more time gardening and self-reported better physical health. current results suggest that a socio-cultural context where people age well (i.e., the Sardinian Blue Zone), and a healthy and physically active lifestyle are crucial for promoting well-being in late adulthood.


Retargeted Foamy Virus Vectors Integrate Less Frequently Near Proto-oncogenes.
Retroviral gene therapy offers immense potential to treat many genetic diseases and has already shown efficacy in clinical trials. However, retroviral vector mediated genotoxicity remains a major challenge and clinically relevant approaches to reduce integration near genes and proto-oncogenes are needed. Foamy retroviral vectors have several advantages over gammaretroviral and lentiviral vectors including a potentially safer integration profile and a lower propensity to activate nearby genes. Here we successfully retargeted foamy retroviral vectors away from genes and into satellite regions enriched for trimethylated histone H3 at lysine 9 by modifying the foamy virus Gag and Pol proteins. Retargeted foamy retroviral vectors integrated near genes and proto-oncogenes less often (p < 0.001) than controls. Importantly, retargeted foamy retroviral vectors can be produced at high, clinically relevant titers (>107 transducing units/ml), and unlike other reported retargeting approaches engineered target cells are not needed to achieve retargeting. As proof of principle for use in the clinic we show efficient transduction and retargeting in human cord blood CD34+ cells. The modified Gag and Pol helper constructs we describe will allow any investigator to simply use these helper plasmids during vector production to retarget therapeutic foamy retroviral vectors.


Simvastatin attenuates renal ischemia/reperfusion injury from oxidative stress via targeting Nrf2/HO-1 pathway.
Ischemia-reperfusion (I/R) injury of the kidneys is commonly encountered in the clinic. The present study assessed the efficacy of simvastatin in preventing I/R-induced renal injury in a rat model and investigated the corresponding molecular mechanisms. Rats were divided into 3 groups, including a sham, I/R and I/R + simvastatin group. The results revealed that in the I/R group, the levels of blood urea nitrogen, serum creatinine and lactate dehydrogenase were significantly higher than those in the sham group, which was significantly inhibited by simvastatin pre-treatment. I/R significantly decreased superoxide dismutase activity compared with that in the sham group, which was largely rescued by simvastatin. Furthermore, I/R significantly increased the malondialdehyde content compared with that in the sham group, which was reduced by simvastatin. Hematoxylin-eosin staining revealed no obvious morphological abnormalities in the sham group, while I/R led to notable tubular cell swelling, vacuolization, cast formation and tubular necrosis, which was rescued by simvastatin. A terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay demonstrated that I/R significantly increased the number of apoptotic cells compared with that in the sham group, which was significantly inhibited by simvastatin. Western blot analysis demonstrated that simvastatin upregulated I/R-induced increases of nuclear factor erythroid-2-related factor 2 (Nrf2) and anti-oxidant enzyme heme oxygenase-1 (HO-1). Reverse-transcription quantitative PCR indicated that changes in the mRNA levels of Nrf2 and HO-1 were consistent with the western blot results. It was concluded that simvastatin treatment led to upregulation of HO-1 protein levels through activating the Nrf2 signaling pathway to ultimately protect the kidneys from I/R-associated oxidative damage.


Collagenous spherulosis in chondroid syringomas.
We report a case of collagenous spherulosis (CS) incidentally found in a chondroid syringoma of the facial skin. The lesion was studied by routine light microscopy, special stains, immunohistochemical methods, x-ray spectrophotometry, and electron microscopy. Light microscopy revealed solitary and confluent eosinophilic globules with radiating fibrillary structures within and around the lumina of the tubuloglandular components of chondroid syringoma. The fibrillary structures stained strongly for collagen and reticulin and less intensely for acidic mucopolysaccharides. Immunohistochemically, the globules were focally positive only for collagen type IV. Electron microscopy revealed radiating collagen fibers surrounded by basal lamina-like material. No inorganic crystals were identified by x-ray spectrophotometry. We conclude that (a) CS is not specific to breast but also occurs in chondroid syringomas; (b) the term collagenous spherulosis is appropriate because collagen fibers were demonstrated histochemically and ultrastructurally in the spherules; (c) CS appears to be associated with tubular epithelial structures; (d) there was no immunohistochemical evidence of myoepithelial differentiation. The etiology and significance of CS remain obscure.


Perilipin-1 immunostaining improves semi-automated digital quantitation of bone marrow adipocytes in histological bone sections.
Bone marrow adipocytes (BMAds) are not just passive fillers inside the bone marrow compartment but respond to various metabolic changes. Assessment of those responses requires evaluation of the number of BMAds and their morphology for which laborious and error-prone manual histological analysis remains the most widely used method. Here, we report an alternative image analysis strategy to semi-automatically quantitate and analyse the morphology of BMAds in histological bone sections. Decalcified, formalin-fixed paraffin-embedded histological sections of long bones of Sprague-Dawley rats were stained with either haematoxylin and eosin (HE) or by immunofluorescent staining for adipocyte-specific protein perilipin-1 (PLIN1). ImageJ-based commands were constructed to detect BMAds sized 200 µm2 or larger from standardized 1 mm2 analysis regions by either classifying the background colour (HE) or the positive and circular PLIN1 fluorescent signal. Semi-automated quantitation strongly correlated with independent, single-blinded manual counts regardless of the staining method (HE-based: r=0.85, p<0.001; PLIN1 based: r=0.95, p<0.001). The detection error was higher in HE-stained sections than in PLIN1-stained sections (14% versus 5%, respectively; p<0.001), which was due to false-positive detections of unstained adipocyte-like circular structures. In our dataset, the total adiposity area from standardised ROIs in PLIN-1-stained sections correlated with that in whole-bone sections (r=0.60, p=0.02).


Behavior of haloperidol and various phenothiazines on several alkyl bonded phases.
Haloperidol and phenothiazines are present in psychiatrical treatments. An analysis in body fluids is tedious because of the presence of demethylated (DM) derivatives of phenothiazines. The behavior of some interfering solutes on alkyl bonded phases has been studied. Phenothiazines and DM derivatives exhibit a very similar behavior with a binary eluent (phosphate buffer-acetonitrile), which precludes an optimization with this system. When a ternary phase is used (phosphate buffer-acetonitrile-methanol), haloperidol and reduced haloperidol behave differently as compared with phenothiazines. In this mode it is possible to unambiguously detect haloperidol that would otherwise interfere. Phenothiazine peaks are characterized by a large tailing. An interesting feature is the comparison between cyclohexyl bonded and octadecyl bonded phases, the former being much more efficient.


Actin turnover is required to prevent axon retraction driven by endogenous actomyosin contractility.
Growth cone motility and guidance depend on the dynamic reorganization of filamentous actin (F-actin). In the growth cone, F-actin undergoes turnover, which is the exchange of actin subunits from existing filaments. However, the function of F-actin turnover is not clear. We used jasplakinolide (jasp), a cell-permeable macrocyclic peptide that inhibits F-actin turnover, to study the role of F-actin turnover in axon extension. Treatment with jasp caused axon retraction, demonstrating that axon extension requires F-actin turnover. The retraction of axons in response to the inhibition of F-actin turnover was dependent on myosin activity and regulated by RhoA and myosin light chain kinase. Significantly, the endogenous myosin-based contractility was sufficient to cause axon retraction, because jasp did not alter myosin activity. Based on these observations, we asked whether guidance cues that cause axon retraction (ephrin-A2) inhibit F-actin turnover. Axon retraction in response to ephrin-A2 correlated with decreased F-actin turnover and required RhoA activity. These observations demonstrate that axon extension depends on an interaction between endogenous myosin-driven contractility and F-actin turnover, and that guidance cues that cause axon retraction inhibit F-actin turnover.


Revascularization of the ischemic diabetic foot using popliteal artery inflow.
Between March 1988 and June 1994, 35 popliteal to distal artery vein bypasses were done in 32 diabetic patients. There were 16 males and 16 females with an average age of 60 years. Eighteen patients (56%) had insulin dependent diabetes mellitus. Medical risk factors included coronary artery disease (CAD) in 15 (47%), hypertension in 15 (47%), chronic renal failure (CRF) in 9 (28%), and cigarette smoking in 10 (31%). Indications for revascularization were: non-healing ulcerations in 18 (51%), gangrene in 15 (43%), and rest pain in 2 (6%). The distal anastomosis was to the posterior tibial artery in 9, anterior tibial artery in 8, dorsalis pedis artery in 10 and peroneal artery in 8 cases. All the bypasses were done with autogenous saphenous veins (in-situ 11, reversed 17, and free non-reversed 7). The limbs were graded into three groups based on the preoperative angiographic evaluation of their pedal arch: patent arch (Grade "0"), partial occlusion of the arch (grade "1.5") and little or no arch visualized (Grade "3"). Eight limbs had Grade "0", 16 had Grade "1.5" and 11 had Grade "3" pedal circulation. Bypass follow up was done by clinical exam and color duplex surveillance (CDS) for a mean duration of 24 months. CDS identified 4 failing bypasses which were surgically revised and have subsequently remained patent. There were 3 bypass occlusions which resulted in a major amputation in 2 patients. Three additional major amputations were performed for persisting infection despite a patent bypass. By life table analysis the cumulative primary & secondary patency and limb salvage rates for this group of diabetic patients were 75% at 2 years, 89% at 3 years and 82% at 3 years respectively (S.E. < 10%). The 3 bypass occlusions, which occurred at 1 week, 5 weeks, and 20 months, were in patients with both CRF and Grade "3" foot circulation (significantly different outcome compared to the rest of the group, by chi 2 test, p < 0.05). Good results can be achieved in the majority of diabetic patients undergoing short popliteal-distal bypasses. However, the combination of chronic renal failure and very limited foot circulation (Grade "3") has a significant adverse outcome.


Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade.
Hereditary angioedema (HAE) is a rare, chronic, genetic disease that presents with nonpruritic angioedema of the face, extremities, airway (can be life-threatening), genitourinary system, and abdomen. These symptoms can significantly impair daily activities. Hereditary angioedema is classified into HAE owing to a deficiency of functional C1INH (HAE-C1INH) or HAE with normal C1INH (HAE-nl-C1INH). Both type I and II HAE-C1INH result from inherited or spontaneous mutations in the SERPING1 gene, which encodes for C1INH. These mutations result in C1INH dysfunction, leading to uncontrolled plasma kallikrein activity with excessive bradykinin production. Bradykinin receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in submucosal angioedema through fluid extravasation. Hereditary angioedema nl-C1INH is caused by either a known or unknown genetic mutation. The underlying mechanism of HAE-nl-C1INH is less well understood but is thought to be related to bradykinin signaling. Plasma kallikrein inhibitors have been developed to inhibit the kallikrein-kinin pathway to prevent (prophylactic) and treat on-demand (acute) HAE attacks. Several of these medications are delivered through subcutaneous or intravenous injection, although new and emerging therapies include oral formulations. This article provides a historical review and describes the evolving landscape of available kallikrein inhibitors to treat HAE-C1INH.


Plasticity of synapses and reward circuit function in the genesis and treatment of depression.
What changes in brain function cause the debilitating symptoms of depression? Can we use the answers to this question to invent more effective, faster acting antidepressant drug therapies? This review provides an overview and update of the converging human and preclinical evidence supporting the hypothesis that changes in the function of excitatory synapses impair the function of the circuits they are embedded in to give rise to the pathological changes in mood, hedonic state, and thought processes that characterize depression. The review also highlights complementary human and preclinical findings that classical and novel antidepressant drugs relieve the symptoms of depression by restoring the functions of these same synapses and circuits. These findings offer a useful path forward for designing better antidepressant compounds.


[Effects of drugs on the adrenal cortex and its tumors].
The structure of the normal adrenal cortex is changed by stimulating hormones (ACTH) and inhibiting hormonal drugs (especially glucocorticoids). ACTH induces hyperplasia and lipid depletion in the fascicular and reticular zones, whereas glucocorticoids lead to atrophy and lipid accumulation in both zones. In animal experiments, the adrenostatic drug mitotane causes shrinkage of the cells of the fascicular and reticular zones, whereas metyrapone induces a decrease in the steroid producing organelle system and aminoglutethimide leads to an increase in lipids. In the therapy of patients with adrenocortical cancer, mitotane can cause an increase in of necrosis and fibrosis, but also in intracellular lipid. The ultrastructure shows increased liposomes, more pigment-rich lysosomes and laminated bodies.


The combination of dimethoxycurcumin with DNA methylation inhibitor enhances gene re-expression of promoter-methylated genes and antagonizes their cytotoxic effect.
Curcumin and its analogs exhibited antileukemic activity either as single agent or in combination therapy. Dimethoxycurcumin (DMC) is a more metabolically stable curcumin analog that was shown to induce the expression of promoter-methylated genes without reversing DNA methylation. Accordingly, co-treatment with DMC and DNA methyltransferase (DNMT) inhibitors could hypothetically enhance the re-expression of promoter-methylated tumor suppressor genes. In this study, we investigated the cytotoxic effects and epigenetic changes associated with the combination of DMC and the DNMT inhibitor decitabine (DAC) in primary leukemia samples and cell lines. The combination demonstrated antagonistic cytotoxic effects and was minimally cytotoxic to primary leukemia cells. The combination did not affect the metabolic stability of DMC. Although the combination enhanced the downregulation of nuclear DNMT proteins, the hypomethylating activity of the combination was not increased significantly compared to DAC alone. On the other hand, the combination significantly increased H3K27 acetylation (H3K27Ac) compared to the single agents near the promoter region of promoter-methylated genes. Furthermore, sequential chromatin immunoprecipitation (ChIP) and DNA pyrosequencing of the chromatin-enriched H3K27Ac did not show any significant decrease in DNA methylation compared to other regions. Consequently, the enhanced induction of promoter-methylated genes by the combination compared to DAC alone is mediated by a mechanism that involves increased histone acetylation and not through potentiation of the DNA hypomethylating activity of DAC. Collectively, our results provide the mechanistic basis for further characterization of this combination in leukemia animal models and early phase clinical trials.