Accurate prediction of calving in dairy cows by applying feature engineering and machine learning.
Prediction of calving is key to dairy cow management. Current trends of increasing herd sizes globally can directly impact the time that farmers spend monitoring individual animals. Automated monitoring on behavioural and physiological changes prior to parturition can be used to develop machine learning solutions for calving prediction. In this study, we developed a machine learning algorithm for the prediction of calving in dairy cows. We demonstrated that temperature and activity index information retrieved from a commercial reticuloruminal bolus sensor can accurately predict calving from 1-day to 5-days in advance. The best prediction solution using data from 82 dairy cows, achieved up to 87.81 % in accuracy, 92.99 % in specificity, 75.84 % in sensitivity, 82.99 % in positive predictive value (PPV), 78.85 % in F-score, and 90.02 % in negative predictive value (NPV) on the test dataset when using information from 2-days in advance and all the subsets of feature characteristics (temperature + drinking + activity). The performance only decreased by 2.45 % points in accuracy, 0.74 % points in specificity, 6.41 % points in sensitivity, 2.45 % points in positive predictive value, 4.91 % points in F-score, and 2.44 % points in negative predictive value on the test dataset when using all feature characteristics and 5-days in advance information compared to using all features and information from 2-days in advance. Full evaluation of the performance of the prediction showed an improvement when using all the different subsets of feature characteristics together (temperature, activity, and drinking) compared to using temperature features only. When adding activity and drinking to the subset of temperature features, an average increase of 2.70, 1.52, 5.40, 4.39, 5.02, 2.13 % points in accuracy, specificity, sensitivity, PPV, F-score, and NPV, respectively, was obtained. Notably, evaluation of feature importance (i.e., relative weight of any given feature in relation to model prediction) showed that 3-5 (depending on the selected days in advance model) of the top ten features were derived from drinking behaviour, showing the relevance that this behaviour can have in the prediction of calving. This algorithm can provide a useful tool for automated calving prediction in dairy cows which has potential for improvement of health, welfare, and productivity in the dairy industry.


A multimethod study of needs for physician assessment: implications for education and regulation.
Deficiencies in physician competence play an important role in medical errors and poor-quality health care. National trends toward implementation of continuous assessment of physicians hold potential for significant impact on patient care because minor deficiencies can be identified before patient safety is threatened. However, the availability of assessment methods and the quality of existing tools vary, and a better understanding of the types of deficiencies seen in physicians is required to prioritize the development and enhancement of assessment and remediation methods. Surveys of physicians and licensing authorities and analysis of the Federation of State Medical Boards (FSMB) Board Action Data Bank were used to collect information describing the nature and types of problems seen in practicing physicians. Focus groups, depth interviews with key professional stakeholders, and state medical board site visits provided additional information about deficiencies in physician competence. Quantitative and qualitative analyses identified (1) communication skills as a priority target for assessment approaches that also should focus on professional behaviors, knowledge, clinical judgment, and health-care quality; and (2) differences between regulatory approaches of licensing and certifying bodies contribute to a culture that limits effective self-assessment and continuous quality improvement. System problems impacting physician performance emerged as an important theme in the qualitative analysis. Considering alternative perspectives from the regulatory, education, and practice communities helps to define assessment priorities for physicians, facilitating development of a coherent and defensible approach to assessment and continuing professional development that promises to provide a more comprehensive solution to problems of health-care quality in the United States.


Airborne infection. Theoretical limits of protection achievable by building ventilation.
Of 67 office workers 27 (40%) had documented tuberculin skin test conversions after an estimated 4-wk exposure to a coworker with cavitary tuberculosis. Worker complaints for more than 2 yr before the tuberculosis exposure prompted investigations of air quality in the building before and after the tuberculosis exposure. Carbon dioxide concentrations in many parts of the building were found to be above recommended levels, indicating suboptimal ventilation with outdoor air. We applied a mathematical model of airborne transmission to the data to assess the role of building ventilation and other transmission factors. We estimated that ventilation with outside air averaged about 15 feet 3/min (cfm) per occupant, the low end of acceptable ventilation, corresponding to CO2 levels of about 1,000 ppm. The model predicted that at 25 cfm per person 18 workers would have been infected (a 33% reduction) and at 35 cfm, a level considered optimal for comfort, that 13 workers would have been infected (an additional 19% reduction). Further increases in outdoor air ventilation would be impractical and would have resulted in progressively smaller increments in protection. According to the model, the index case added approximately 13 infectious doses (quanta) per hour (qph) to the office air during the exposure period, 10 times the average infectiousness reported in a large series of tuberculosis cases. Further modeling predicted that as infectiousness rises, ventilation would offer progressively less protection. We conclude that outdoor air ventilation that is inadequate for comfort may contribute to airborne infection but that the protection afforded to building occupants by ventilation above comfort levels may be inherently limited, especially when the level of exposure to infection is high.


Punctured Two-Dimensional Sheets for Harvesting Blue Energy.
The challenges of global climate change and the world's growing demand for energy have brought the need for new renewable energy sources to the top of the international community's agenda. We have known for many centuries that energy is released upon mixing seawater and freshwater, yet it was just a few decades ago that it became clear how this energy can be converted into electricity instead of heat. As a result, the blue energy rush has raised and set new strategies in different science and technology sectors, leading to the construction of a new generation of plants and other technological investments. Among many approaches, pressure-retarded osmosis has emerged as a promising method to collect the largest amount of produced blue energy. In this Perspective, we highlight the advances in the development of ultrathin membranes based on two-dimensional materials. We discuss the most relevant synthetic methods devised to generate atomically thin membranes for pressure-retarded osmosis and retarded electrodialysis applications, and we provide some critical views on the greatest challenges in this thrilling research area.


[Childhood cancer epidemiology and available evidence on case clustering].
This paper introduces a Monograph on childhood cancer clusters addressed to Italian public health workers, paediatricians and paediatric oncologists, and the general public. Two issues have been underlined in most definitions of cancer clusters reported in the literature over the last 30 years. The first is the need for an unbiased methodological approach for the detection and the interpretation of clustering and of individual clusters. The other is the responsibility for scientists and public health workers to unravel suspicious events and to interact with the population in circumstances which may turn out to be false alarms. The relative weight given to epidemiological methods and to risk perception has varied between definitions of clusters given in different periods. In the field of childhood cancer clusters, epidemiological research has produced very little fresh knowledge. However, it is recognized that this is not a sufficient reason for refusing to pay attention to reports of perceived clusters. Models of spatio-temporal interactions according to Birch et al. (2000) are taken in consideration: the literature offers a very limited number of circumstances fitting such models. In Italy, over the years, only two childhood cancer clusters have been reported in the indexed literature, both of them regarded cases of acute lymphatic leukaemia and occurred in Sardinia in the Eighties and in the area of Roma in the Nineties. A possible reason for the paucity of reports (compared, for instance, to the UK scenario) is the limited availability of health statistics.


[The Brånemark implant in the lower jaw. Experiences of edentate patients with a complete implant-supported bridge].
The Brånemark system for implant supported bridges has been carried out in Amsterdam since 1982. One hundred patients with a maxillary conventional full denture and a mandibular fixed tissue-integrated prosthesis were selected for this study. Before and long after the treatment, questionnaires were sent to these patients in order to gain information of their experiences. The treatment had greatly benefitted the patients, in spite of the problem of the loose lower denture in some cases was shifted to the upper jaw.


Automatic Epileptic Seizure Detection Using Graph-Regularized Non-Negative Matrix Factorization and Kernel-Based Robust Probabilistic Collaborative Representation.
Automatic seizure detection system can serve as a meaningful clinical tool for the treatment and analysis of epilepsy using electroencephalogram (EEG) and has obtained rapid development. An automatic detection of epileptic seizure method based on kernel-based robust probabilistic collaborative representation (ProCRC) combined with graph-regularized non-negative matrix factorization (GNMF) is proposed in this work. The raw EEG signals are pre-processed through the wavelet transform to obtain time-frequency distribution of EEG signals as preliminary feature information and GNMF is further employed for dimension reduction, retaining and enhancing the productive feature information of EEG signals. Then, the test sample is represented using robust ProCRC that can decide whether the testing sample belongs to each class (seizure or non-seizure) by jointly maximizing the likelihood. In addition, the kernel trick is applied to improve the separability of non-linear high dimensional EEG signals in robust ProCRC. Finally, post-processing techniques are introduced to generate more accurate and reliable results. The average epoch-based sensitivity of 96.48%, event-based sensitivity of 93.65% and specificity of 98.55% are acquired in this method, which is evaluated on the public Freiburg EEG database.


Blood glucose variability is associated with mortality in the surgical intensive care unit.
Intensive insulin therapy has widely and rapidly been adopted as the standard of care for the treatment of hyperglycemia in the intensive care unit (ICU). Variability in blood glucose is increasingly recognized as an important factor in outcomes in the chronic diabetic in addition to hemoglobin A1C. We tested the hypothesis that measures of blood glucose variability would be associated with mortality in the surgical ICU. A retrospective analysis of a cohort of ventilated, critically ill surgical and trauma ICU patients placed on an automated insulin protocol was performed. Blood glucose (BG) variability was measured by comparing standard deviation, percentile values, successive changes in blood glucose, and by calculating the triangular index for various glucose-related indices. Eight hundred and fifty-eight patients had 46,474 blood glucose and insulin dose data points. One hundred and twenty-one patients died for an overall mortality rate of 14 per cent. Several measures of blood glucose variability (maximum successive change in BG and the triangular index) were different between the groups despite similar mean BG between survivors (117 mg/dL) and nonsurvivors (118 mg/dL). Increased blood glucose variability is associated with mortality in the surgical ICU. Further studies should focus on the demographic, clinical, and genetic factors responsible for this observation and identify strategies to minimize BG variability.


Corneal Epithelial Removal with a Newly Designed Epithelial Brush.
This study aimed to evaluate and compare the effectiveness of a newly developed epithelial removal brush with conventional methods in a rabbit model of corneal epithelial defects. The corneal epithelia of thirty-seven rabbits were removed by three different methods including blades (blade group), newly developed epithelial brushes (Ocu group), and conventional rotating brushes (Amo group). The defect area was measured with light microscopy immediately and at 4, 18, 24, and 50 hours after removal. Corneas were obtained immediately and at 24 and 50 hours and subjected to hematoxylin and eosin (H&E) and immunofluorescence staining using proliferating cell nuclear antigen (PCNA) and phosphorylated heat shock protein 27 (pHSP27) antibodies. The residual stromal surface was observed by scanning electron microscopy (SEM). In the Ocu group, epithelia were significantly recovered at 18, 24, and 50 hours compared with immediately after removal, and in the blade and Amo groups, epithelia were significantly recovered only at 50 hours after epithelial removal. The expression levels of PCNA and pHSP27 did not differ among three groups. There was significantly more inflammatory cell infiltration in the blade group than in the other groups. SEM showed a more regular and uniform residual stromal surface in the Ocu group than in the other groups. The newly developed epithelial brush showed better polishing ability and led to earlier significant epithelial recovery and a more regular and uniform stromal surface than conventional methods in this rabbit model of epithelial defects. Accumulation of clinical data is expected to expand the scope of application of new brushes for laser surface ablation.


Use and barriers to use of screening and brief interventions for alcohol problems among Norwegian general practitioners.
To investigate the use and the obstacles to use of screening and brief interventions (SBI) for alcohol misuse among Norwegian general practitioners (GP). A questionnaire with 68 questions about the use and barriers to use of SBI in general practice was mailed to 2000 randomly selected Norwegian GPs. The survey response rate was 45%. There was a much higher prevalence of using interventions (mean = 4.47 on a seven-point Likert scale) than of screening for alcohol problems (mean = 2.10 on a seven-point Likert scale). Regression models showed that knowledge and self-efficacy were the main predictors for GPs' use of screening instruments and use of interventions, respectively, in particular with regard to use of screening. However, GPs' views of their relationship with their patients, and structural factors were significant predictors. (i) Norwegian GPs do not necessarily see the link between screening for alcohol problems and conducting interventions. (ii) Factors on at least three levels, i.e. personal, social and structural, play significant roles for understanding the problems related to implementing the use of SBI in general practice. (iii) Training GPs in the use of SBI is important but may not increase GPs' use of SBI due to social and structural barriers.


Total hydrolyzable glycerol in amniotic fluid, and its relationship to fetal lung maturity.
We describe an enzymic quantification of total hydrolyzable glycerol in amniotic fluid. An extract of amniotic fluid is hydrolyzed in mild alkali, without pretreatment with lipase. The resulting glycerol (some of which may be derived from trace amounts of triglyceride) is then enzymatically phosphorylated with adenosine 5'-[gamma 32P]triphosphate to yield glycerol [gamma 32P]phosphate. After removal of excess [gamma 32P]ATP by charcoal, the radioactivity of the glycerophosphate is measured in a liquid scintillation counter. The close correlation (r = 0.96) we found between total hydrolyzable glycerol and phosphatidylglycerol indicates that the contribution of triglyceride to the value for total glycerol is inconsequential. This method is less time consuming and more precise than the method for phosphatidylglycerol.


Systematic Review on the Impact of Guidelines Adherence on Antibiotic Prescription in Respiratory Infections.
Overuse and inappropriate antibiotic prescription for respiratory tract infections (RTI) are one of the major contributors to the current antibiotic resistance problem. Guidelines provide support to prescribers for proper decision-making. Our purpose is to review the impact of prescribers' exposure to guidelines in antibiotic prescription for RTIs. A systematic review was performed searching in the scientific databases MEDLINE PubMed and EMBASE for studies which exposed prescribers to guidelines for RTI and compared antibiotic prescription rates/quality before and after the implementation, with thirty-four articles included in the review. The selected studies consisted on a simple intervention in the form of guideline implementation while others involved multifaceted interventions, and varied in population, designs, and settings. Prescription rate was shown to be reduced in the majority of the studies, along with an improvement in appropriateness, defined mainly by the prescription of narrow-spectrum rather than broad-spectrum antibiotics. Intending to ascertain if this implementation could decrease prescription costs, 7 articles accessed it, of which 6 showed the intended reduction. Overall interventions to improve guidelines adherence can be effective in reducing antibiotic prescriptions and inappropriate antibiotic selection for RTIs, supporting the importance of implementing guidelines in order to decrease the high levels of antibiotic prescriptions, and consequently reduce antimicrobial resistance.


Gingival and dentofacial changes in adolescents and adults 2 to 10 years after orthodontic treatment.
Information about long-term changes of the shape of the gingival margin is missing. To monitor 8 year changes of the gingival contour occurring in adolescents and adults and relate these changes to dentofacial growth. Forty adolescents (mean age 16.3), and 14 adults (mean age 29.7) were included in the study with photographs, radiographs and casts taken 2 and 10 years after orthodontic treatment. The gingival contour of upper central incisors and the midline passing through the contact surface of both teeth were traced digitally using calibrated photographs. Changes were measured on seven standardized lines of the gingival contour. Lower facial height changes and tooth eruption were measured using lateral cephalograms. Adolescents and adults showed a central mean apical displacement of the gingival margin of 0.51 mm (SD 0.4 mm) and 0.13 mm (SD 0.17 mm), respectively. This displacement decreased by moving away from the centre. The gingival displacement was associated to the individual's lower facial height augmentation, r=0.63 (p<0.001). Apical displacement of the gingival contour of the upper central incisors takes place during adolescence following a semi-lunar shape. Growth explains parts of these changes.


Monitoring evoked potentials during surgery to assess the level of anaesthesia.
The hypnotic and analgesic components of anaesthesia can be assessed using middle latency auditory evoked potentials (MLAEPs) and somatosensory evoked potentials (SEPs). To monitor these potentials reliably during clinical anaesthesia, we have developed an evoked potential (EP) system based around a portable personal computer, a DSP board and an isolated pre-amplifier unit. Unlike many currently available systems, this amplifier is largely immune to diathermy interference due to excellent isolation via a digital fibre optical link, small size and RF screening and filtering. The pre-amplifier unit has integral auditory and somatosensory stimulators, and automatic calibration and impedance checking. Stimulus intensity and profile are under software control and SEP stimulus level is constantly monitored. The unit is powered by two AA cells and battery status continuously monitored by the PC software. Up to eight channels of EEG may be recorded and displayed in a smoothly scrolling window and as moving average MLAEPs and SEPs.


TIDE: an intelligent home-based healthcare information & diagnostic environment.
The 21st century promises to usher in an era of Internet based healthcare services--Tele-Healthcare. Such services augur well with the on-going paradigm shift in healthcare delivery patterns, i.e. patient centred services as opposed to provider centred services and wellness maintenance as opposed to illness management. This paper presents a Tele-Healthcare info-structure TIDE--an 'intelligent' wellness-oriented healthcare delivery environment. TIDE incorporates two WWW-based healthcare systems: (1) AIMS (Automated Health Monitoring System) for wellness maintenance and (2) IDEAS (Illness Diagnostic & Advisory System) for illness management. Our proposal comes from an attempt to rethink the sources of possible leverage in improving healthcare; vis-à-vis the provision of a continuum of personalised home-based healthcare services that emphasise the role of the individual in self health maintenance.


Analysis of the V1V2 region of the SIV envelope in the brains of morphine-dependent and control SIV/SHIV-infected macaques.
Six morphine-dependent and three control macaques were infected with a mixture of SIV/SHIV. Half of the animals in the morphine group developed accelerated disease (rapid progressor) and died within 20 weeks postinfection. The evolution of the envelope gene in the brain of the rapid progressor and morphine-dependent group along with that in the control group was assessed. Six to 10 clones from the brain of each macaque were sequenced and were compared against each other as well as against a challenge virus. Analysis of the sequences revealed that the diversity and divergence of the clones were higher in the control group as compared to the morphine-dependent macaques, although this difference was not statistically significant.


Cervical malignant teratoma masquerading as a hematoma: a case report.
Post-pubertal teratomas, which mostly occur at 20 to 40 years old, are more likely to be found at a metastatic site in up to 20% of cases and may be inadvertently overlooked. We present a case of cervical malignant teratoma that masqueraded as a hematoma.Case presentation: A 24-year-old man presented to our institution with a 4-month history of a progressively relapsing painless mass in the neck, despite conservative treatments with oral medications. A huge space-occupying mass was identified with almost total occlusion of the left internal jugular vein. The likely diagnosis was an organized hematoma or congenital cystic tumor with internal hemorrhage. Surgical excisional biopsy of the mass lesion was conducted and a malignant teratoma was found. A whole-body positron emission tomography scan showed a left inguinal mass, bilateral intra-abdominal lymphadenopathies, and abdominal metastases. Histopathology further suggested the diagnosis of an immature testicular teratoma with multiple lymph node metastases. The patient received adjuvant chemotherapy with a bleomycin, etoposide, and cisplatin regimen. During follow-up, salvage second-line chemotherapy was required with a paclitaxel, ifosfamide, and cisplatin regimen. Although uncommon, cervical teratoma should be taken into consideration once a painless and non-remitting mass lesion is found in a young adult.


Cannabinoid receptor 2 as a novel target for promotion of renal cell carcinoma prognosis and progression.
Renal cell carcinoma (RCC) is the most common malignancy of urogenital system, and patients with RCC may face a poor prognosis. However, limited curable therapeutic options are currently available. The aim of this study is to investigate the role of Cannabinoid receptor 2 (CB2) in RCC progression. Immunohistochemistry was to investigate the expression pattern of CB2 in 418 RCC tissues and explore its prognostic function in RCC patients. Furthermore, the role of used CB2 si-RNA knockdown and inhibited by AM630, a CB2 inverse agonist, on cell proliferation, migration, and cell cycle of RCC cell lines in vitro was also investigated. We observed that CB2 was up-regulated in RCC tissues, and presented as an independent prognostic factor for overall survival of RCC patients and higher CB2 expression tends to have poor clinical outcomes in survival analyses. Moreover, we also observed that CB2, incorporated with pN stage, pathological grade, and recurrence or distant metastasis after surgery, could obviously enhance their prognostic accuracy in a predictive nomogram analysis. In addition, knockdown or inhibition by AM630 for the expression of CB2 in vitro could significantly decreased cell proliferation and migration, and obviously induced cell cycle arrest in G2/M of RCC cells. CB2 expression is functionally related to cellular proliferation, migration, and cell cycle of RCC cells. Our data suggest that CB2 might be a potential therapeutic target for RCC.


Identification of rehabilitation problems after head injury.
We have reported a large study of patients admitted to hospital following head injury in the city of Glasgow over one calendar year. This showed 1000 patients still to be disabled one year after their injury. In order to see whether the difficulties reported by these patients represented needs for rehabilitation services, we undertook a parallel study in which a separate group of 26 patients were assessed by the same methods as in the main group, but also had a clinical review by an experienced rehabilitation medicine physician, to determine the patient's rehabilitation needs. The physician was unaware of the results of the first assessment. Both the extent and the nature of the services as needed were reported remarkably similarly by each form of assessment. In addition, the Glasgow Outcome Scale categories were closely related to the need for services. We conclude that the data reported by Thornhill et al. can be used to estimate the volume and type of rehabilitation services required by head injured patients in the early months after injury.


Acute respiratory distress syndrome with miliary tuberculosis.
A 71-year-old man was admitted to the hospital complaining of productive cough and weight loss. Physical examination showed fine bilateral basal crackles. Laboratory findings showed elevated liver enzymes. Tuberculin skin test and sputum smear for acid-fast bacilli were negative. On the fifth day of admission, he deteriorated and developed severe respiratory distress. A chest radiograph demonstrated worsening pulmonary infiltrates. He was electively intubated and was put on a mechanical ventilator. The chest CT scan revealed diffuse bilateral pulmonary nodules and airspace disease. Based upon the clinical suspicion of acute respiratory distress syndrome associated with miliary tuberculosis (TB), empiric treatment with antituberculosis and systemic steroids was started. He was extubated after 6 days. The diagnosis of miliary TB was confirmed by a thoracoscopic lung biopsy. He was discharged with a near normal chest radiograph and was followed up as an outpatient.


Identification of a pancreatic stellate cell population with properties of progenitor cells: new role for stellate cells in the pancreas.
Numerous studies conducted in a diversity of adult tissues have shown that certain stem cells are characterized by the expression of a protein known as the ABCG2 transporter (where ABC is ATP- binding cassette). In the adult pancreas, although various multipotent progenitors have been proposed, the ABCG2 marker has only been detected in the so-called 'side population' (a primitive haematopoietic cell population with a multipotential capacity). In the present study we sought to identify new ABCG2+ pancreatic cell populations and to explore whether they exhibit the properties of progenitor cells. We isolated and expanded mitoxantrone-resistant cells from pancreata of lactating rats by drug selection. These cells were characterized and maintained in different stages of differentiation using several media 'cocktails' plus Matrigel (BD Biosciences). Differentiation was assessed by RT-PCR (reverse transcription-PCR), immunocytochemistry, electron microscopy and ELISA. The expanded cell population demonstrated a phenotype of PaSCs (pancreatic stellate cells). Spontaneous cell clusters occurred during cell expansion and they showed weak expression of the transcription factor Pdx1 (pancreatic and duodenal homeobox 1). Moreover, the presence of inductive factors in the Matrigel plus exendin-4 led to an increase in Pdx1 and endocrine genes, such as insulin, islet amyloid polypeptide, glucagon, the glucose transporter GLUT2, chromogranin A and the convertases PC1/3 and PC2 were also detected. Immunocytochemical analysis showed co-localization of insulin and C-peptide, whereas ultrastructural studies revealed the presence of granules. Insulin secretion from cell clusters was detected in the cell culture medium. We identified a population of PaSCs that express the ABCG2+ transporter and have the capacity to transdifferentiate into insulin-producing cells. Although the potential therapeutic application remains to be tested, PaSCs could represent a future option for insulin replacement in diabetes research.


Tandem nucleophilic addition/fragmentation reactions and synthetic versatility of vinylogous acyl triflates.
A thorough analysis of the chemistry of vinylogous acyl triflates provides insight into important chemical processes and opens new directions in synthetic technology. Tandem nucleophilic addition/C-C bond cleaving fragmentation reactions of cyclic vinylogous acyl triflates 1 yield a variety of acyclic acetylenic compounds. Full details are disclosed herein. A wide array of nucleophiles, such as organolithium and Grignard reagents, lithium enolates and their analogues, hydride reagents, and lithium amides, are applied. The respective reactions produce ketones 2, 1,3-diketones and their analogues 3, alcohols 4, and amides 5. The present reactions are proposed to proceed through a 1,2-addition of the nucleophile to the carbonyl group of starting triflates 1 to form tetrahedral alkoxide intermediates C, followed by Grob-type fragmentation, which effects C-C bond cleavage to yield acyclic acetylenic compounds 2-5 and 7. The potent nucleofugacity of the triflate moiety is channeled through the sigma-bond framework of 1, providing direct access to the fragmentation pathway without denying other typical reactions of cyclic vinylogous esters. The synthetic versatility of vinylogous acyl triflates, including functionalization reactions of the cyclic enone core (1 --> 6 or 8), is also illustrated.


[Old and new tasks in social pediatrics].
Social pediatrics has been highly successful in transmitting basic pediatric knowledge into the last family so that it has been possible by the measures of prevention and prophylaxis to reduce the infant mortality rate from 30% to less than 2% and to eradicate some infectious diseases completely. The importance of social pediatrics can be noted with the misery of children in the developing countries where morbidity and mortality in childhood are as high as ever although the knowledge in clinical pediatrics is on the same level. In the industrial nations psychosocial diseases have replaced infectious diseases. The fight against these requires special social pediatric efforts in order to meet the threat of e.g. juvenile delinquency and the drug scene together with pedopsychology and pedagogics.


Fingerprinting of Cretaceous higher plant resins by infrared spectroscopy and gas chromatography coupled to mass spectrometry.
Ambers from Peñacerrada (Basque Country, North Spain) have been analysed by IR spectroscopy and GC-MS in order to study the polymeric and solvent-soluble GC-amenable fractions, respectively. All samples showed branched monoalkybenzenes, bicyclic sesquiterpenoids and tricyclic diterpenoids related to pimaric acids precursors, suggesting a paleobotanic origin from araucarian species. Molecules containing oxygenated polar functionalities were not found, which is in agreement with the Cretaceous origin of the samples and in good correspondence with the IR spectra and with the low oxygen content estimated from elemental composition analysis. In addition, no IR bands for exocyclic double bonds and very few GC-amenable monounsaturated molecules were found, which provides further evidence of the loss of olefinic groups. These features show that the age-dependent loss of oxygenated and olefinic functions is a general process affecting the whole amber structure, not only the solvent soluble fraction.


Unmet treatment needs in patients with chronic pelvic pain in a New Zealand gynaecology service.
Chronic pelvic pain, which carries a high burden of disability and distress, is a common presentation to gynaecology clinics. While there is increasing acknowledgment of the complexity of chronic pelvic pain, and the benefits of providing management from a multidisciplinary team within a sociopsychobiomedical framework, the mainstay of management in gynaecology outpatient clinics remains within a single clinician biomedical-focused model. This model of care is only sufficient for women who present with minimal psychosocial complexity to their pain. To estimate the proportion of women attending the gynaecology outpatient clinic at a public women's hospital in New Zealand referred with chronic pelvic pain who have needs unmet by the current biomedical model of care. Informed by international research, pain catastrophising was used as a psychosocial correlate of this complexity. An audit was undertaken of 100 consecutive pre-appointment questionnaires of women, referred to a gynaecology outpatient clinic for review of pelvic pain of duration over six months, with no red flags in their referral history. An unexpectedly high level of catastrophic thoughts about pain was reported. Seventy-seven percent of the women scored in the high or severe range, with 55% endorsing clinically significant scores for helpless catastrophising. The Pain Catastrophising Scores in this cohort were found to be higher than those in similar groups in the published international literature and also than in patients referred to the local tertiary level pain management centre, further reinforcing the need for investment into appropriate services for women with chronic pelvic pain.


Hidden chaos factors inducing random walks which reduce hospital operative efficiency.
Operative parameters of La Fuenfría Hospital such as: hospitalized patients; daily admissions and discharges were studies for the hospital as a whole, and for each hospital's service unit (henceforth called 'services'). Conventional statistical analyzes and fractal dimension analyzes were performed on daily In-Patient series. The sequence of daily admissions and patients staying on each service were found to be a kind of random series known as random walks (Rw), sequences where what happens next, depends on what happens now plus a random variable. Rw analyzed with parametric or nonparametric statistics may simulate cycles and drifts which resemble seasonal variations or fake trends which reduce the Hospital's efficiency. Globally, inpatients Rw s in LFH, were found to be determined by the time elapsed between daily discharges and admissions. The factors determining LFH R were found to be the difference between daily admissions and discharges. The discharges are replaced by admissions with some random delay and the random difference determines LFH Rw s. These findings show that if the daily difference between admissions and discharges is minimized, the number of inpatients would fluctuate less and the number of unoccupied beds would be reduced, thus optimizing the Hospital service.


Sexual dysfunction, social maladjustment, and psychiatric disorders in women seeking treatment in a premenstrual syndrome clinic.
The NIMH Diagnostic Interview Schedule (n = 43), and the Hopkins Symptom Checklist and Weissman Social Adjustment Scale (n = 35) was administered to assess the prevalence of psychiatric disorders and psychosocial maladjustment present in women seeking treatment in a multidisciplinary Premenstrual Syndrome Clinic. We found a 67 percent lifetime prevalence of DIS/DSM-III psychiatric disorders: 50 percent Major Affective Disorder (primarily Depression), 53 percent Anxiety Disorder (primarily Phobias or Generalized Anxiety Disorder), and 40 percent Psychosexual Dysfunction (notably Inhibited Sexual Desire or Excitement). Our group had significantly greater Major Depression, Dysthymia, and any one psychiatric disorder compared with female general population samples. Two-thirds of women with premenstrual symptoms had true Premenstrual Syndrome. In our sample, social maladjustment as well as psychiatric symptomatology was significantly greater than in normals and closer to that in psychiatric out-patient norms, and was independent of cycle phase. Presence or absence of PMS, social maladjustment and sexual dysfunction was each not significantly different in women with or without psychiatric disorder.


What is emptiness? Clarifying the 7th criterion for borderline personality disorder.
The present study aims to clarify the 7th DSM-IV criterion for Borderline Personality Disorder: "chronic feelings of emptiness." Emptiness has been the subject of little empirical investigation. The relationship of emptiness to boredom and other affect-states is uncertain, and patients and clinicians can find it difficult to generate verbal descriptions of emptiness. In the present study, two sets of analyses address the meaning and clinical implications of feeling empty. First, affect-states that co-occur with emptiness are identified in 45 young adults who exhibit a prominent feature of Borderline Personality Disorder (i.e., self-injury). Second, the relationship of chronic emptiness to key psychiatric variables is examined in a large nonclinical sample (n = 274). Results indicate that emptiness is negligibly related to boredom, is closely related to feeling hopeless, lonely, and isolated, and is a robust predictor of depression and suicidal ideation (but not anxiety or suicide attempts). Findings are consistent with DSM-IV revisions regarding the 7th criterion for Borderline Personality Disorder. In addition, findings suggest that emptiness reflects pathologically low positive affect and significant psychiatric distress.


First molecules, biological chirality, origin(s) of life.
Origin(s) of biological chirality appear(s) to be intimately connected to origin(s) of life. Prebiotic evolution toward these important turning points can be traced back to single chiral molecules. These can be small (monomeric) units as amino acids or monosaccharides or oligomers as oligo-RNA type molecules. Earlier speculations about these two kinds of entries to biological chirality are critically reviewed.


[Increasing waiting lists for cataract surgery in the county of Vejle].
For several years the waiting list for cataract surgery has increased in the county of Vejle, Denmark. To reveal any change of indications for cataract surgery accounting for this increase, we analyzed referral notes and files in two samples of 86 and 72 patients examined preoperatively in 1991 and 1993. No significant difference was found between the groups regarding age, visual acuity, other eye diseases than cataract, diabetes, treatment with steroids, anisometropia or occupational disability due to poor vision. Thus no signs of changed indications for cataract surgery were found comparing the two samples. Median waiting time from referral to surgery had increased highly significantly from 1991 to 1993 (p << 0.01). The number of cataract operations per year was unchanged in the period. We propose that the increasing waiting time could be attributed to more people wanting cataract surgery, reflecting growing demands for good visual functioning and better expectations of the outcome after surgery.


Presynaptic group II mGluR inhibition of short-term depression in the medial perforant path of the dentate gyrus in vitro.
Inhibition of short-term plasticity by activation of presynaptic group II metabotropic glutamate receptors (group II mGluR) was investigated in the medial perforant path of the dentate gyrus in the hippocampus in vitro. Brief trains of stimulation (10 stimuli at 1--200 Hz) evoked short-term depression of field excitatory postsynaptic potentials (EPSPs). The steady-state level of depression, measured after 10 stimuli, was frequency dependent, increasing between 1 and 200 Hz. Activation of group II mGluR by the selective agonist LY354740 did not alter short-term depression evoked by frequencies up to 10 Hz, but did inhibit short-term depression evoked at higher frequencies in a frequency- and concentration-dependent manner. The time-averaged postsynaptic response (EPSP per unit time) was found to increase linearly with frequency up to approximately 20 Hz. At higher frequencies, the response plateaued, thereby becoming independent of frequency. Frequencies above this were differentiated only during the transient postsynaptic response that accompanies changes in firing rates. Activation of presynaptically located group II mGluR increased the frequency at which the EPSP per unit time plateaued up to 30-50 Hz.


Possibilities of See5 software in forecasting of life expectancy not achieving.
Results of application of See5 to epidemiological domain were presented. The aim of this paper is to find out if See5 can be used for forecasting whether life expectancy will be achieved or not. The basis for forecasting are data-attributes, predictors (anthropological data, living habits, laboratory data, blood pressure measured in years 1970/71, and the status of examinee--class (alive or dead) in 1990. Data were split at random into 10 blocks with approximately the same number of cases and the same distribution of classes. Results were given in the form of decision trees and rulesets, and tested through crossvalidation. The most interesting question--what are prediction-candidates for not achieving life expectancy estimated in the year of examination--did not give a satisfactory result: the accuracy of classification was about 70%. However, a very interesting fact is that each rule consists of at least one candidate predictor, usually considered as risk factor (e.g. high diastolic blood pressure and animal fat consumption).


Intracellular autoantigens: diagnostic fingerprints but aetiological dilemmas.
Autoimmune diseases such as systemic lupus erythematosus, scleroderma, Sjögren's syndrome, mixed connective tissue disease and dermato/polymyositis are each characterized by distinct sets of autoantigens and antibodies which confer on each disease a specific immune profile or fingerprint. These immune fingerprints have advanced our management of this group of diseases, as aids in differential diagnosis and earlier recognition. In lupus and scleroderma, multiple antigen/antibody systems characterize these fingerprints and the autoantigens appear to be located in separate cell compartments of the nucleus, nucleolus and cytoplasm. Because these antibodies are so distinctive for each disease, the response must be antigen driven or at least antigen directed. However, the apparent multi-focus location of the autoantigens poses a problem. It now appears that in scleroderma this dilemma may be explained by the consideration that at a certain time point in cell metabolism all the known autoantigens may be assembled at one location to form a single structural entity. It is possible that this assembly of antigens may be required for a specific cellular function. An autoimmune response to this transiently assembled structure comprising several different proteins and nucleic acids could result in the complex immune response seen in this disease.


Enteroendocrine secretion of gut hormones in diabetes, obesity and after bariatric surgery.
Gastric bypass surgery is associated with a major weight loss and often causes remission in patients with type 2 diabetes. Surgery is also associated with dramatic increases in the secretion of the gut hormones, glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), both of which regulate appetite and food intake, while GLP-1 in addition functions as an incretin hormone, stimulating insulin secretion. It has been possible to probe the role of GLP-1 for the diabetes resolution after gastric bypass using a GLP-1 receptor antagonist, and it is clear that the enhanced beta cell sensitivity to glucose which underlies the enhanced insulin secretion in the patients after the operation depends critically on the increased GLP-1 secretion. Both hormones seem to contribute importantly to the reduction in food intake after bypass and, therefore, to the weight loss. Currently, there are no data to indicate that decreased secretion of the hormones is involved in the pathogenesis of obesity and/or diabetes, but impaired secretion generally observed in obesity (and hence also in diabetes) may contribute to the development. Because of these effects receptor agonists for both hormones are currently being developed for the treatment of obesity and diabetes.


Team-based strategies to prevent heart failure.
The burden of heart failure (HF) in the United States and worldwide is projected to rise. Prevention of HF can curb the burden of this chronic syndrome, but current approaches are limited. This review discusses team-based strategies aimed to prevent HF. Individuals at high risk for developing HF can be identified using HF risk scores, biomarkers, and cardiac imaging. Electronic medical records (EMR) can integrate clinical data to estimate HF risk and identify individuals who may benefit most from preventive therapies. Team-based interventions can lead to enhanced adherence to medications, optimization of medical management, and control of risk factors. Multifaceted interventions involve EMR-based strategies, pharmacist- and nurse-led initiatives, involvement of community personnel, polypills, and digital solutions. Team-based strategies aimed to prevent HF incorporate a broad group of personnel and tools. Despite implementation challenges, existing resources can be efficiently utilized to facilitate team-based approaches to potentially reduce the burden of HF.


Effects of dietary enrichment with n-3 fatty acids on the quality of raw and processed breast meat of high and low growth rate chickens.
1. The enrichment of raw poultry meat with n-3 fatty acids (n-3 FA) has been investigated in detail, particularly in high growth rate genotype standard broiler chickens, whereas low growth rate genotype Label Rouge chickens have received less attention. With the increased development of processed poultry products, it is necessary to ensure that the nutritional and sensory quality of meat enriched with n-3 FA is not affected by processing. 2. Two experiments were undertaken for this purpose. In the first experiment, 696 male Ross 708 chickens were reared under standard conditions, and in the second, 750 male JA 657 chickens were reared under Label Rouge conditions. All birds received the same starting and growing diets containing palm and soya oils in each experiment. Birds were distributed into three groups from 21 or 57 d of age for standard and Label Rouge chickens, respectively, and given a control, linseed oil or extruded linseed diet. Diets were also supplemented with vitamin E (100-200 mg/kg). Birds were slaughtered at 56 or 84 d of age for standard and Label Rouge chickens, respectively. A total amount of 60 kg of breast meat from each group was processed into white cured-cooked meat. 3. The dietary treatment had no effect on the growth performance of chickens or meat yield. The use of extruded linseed or linseed oil only decreased the carcass fatness of the standard chickens but had no effect on the carcass fatness of Label Rouge chickens. The nutritional quality of raw and cured-cooked meat was improved (increased concentration of n-3 FA), whereas the technological quality of the meat (pH, juice loss after cold storage, susceptibility to oxidation, colour, processing yield and shear force value) and sensory quality of the processed products were not or slightly affected. 4. Linked to lower breast yield, to lower lipid content in breast meat and to higher slaughter age, Label Rouge chickens seemed to be less efficient for n-3 FA deposition in breast muscles than standard chickens.


Resident neuroelectrochemical interfacing using carbon nanofiber arrays.
Carbon nanofiber electrode architectures are used to provide for long-term, neuroelectroanalytical measurements of the dynamic processes of intercellular communication between excitable cells. Individually addressed, vertically aligned carbon nanofibers are incorporated into multielement electrode arrays upon which excitable cell matrixes of both neuronal-like derived cell lines (rat pheochromocytoma, PC-12) and primary cells (dissociated cells from embryonic rat hippocampus) are cultured over extended periods (days to weeks). Electrode arrays are characterized with respect to their response to easily oxidized neurotransmitters, including dopamine, norepinephrine, and 5-hydroxytyramide. Electroanalysis at discrete electrodes following long-term cell culture demonstrates that this platform remains responsive for the detection of easily oxidized species generated by the cultured cells. Preliminary data also suggests that quantal release of easily oxidized transmitters can be observed at nanofiber electrodes following direct culture and differentiation on the arrays for periods of at least 16 days.


Identification and characterization of SirA, an iron-regulated protein from Staphylococcus aureus.
The acquisition of iron by pathogenic bacteria is often a crucial step in establishing infection. To accomplish this, many bacteria, including Staphylococcus aureus, produce low-molecular-weight iron-chelating siderophores. However, the secretion and transport of these molecules in gram-positive organisms are poorly understood. The sequence, organization, and regulation of genes involved in siderophore transport are conserved among gram-negative bacteria. We used this information to identify a putative siderophore transport locus from an S. aureus genomic sequence database. This locus contains three predicted open reading frames with a high degree of homology to genes involved in siderophore uptake in several bacterial species, in particular the cbr locus of the plant pathogen Erwinia chrysanthemi. The first gene in the locus, which we have designated sir for staphylococcal iron regulated, encodes a putative lipoprotein with a molecular mass of 37 kDa. The open reading frame is preceded by a 19-bp region of dyad symmetry with homology for operator sequences controlling iron-regulated expression of genes in other bacteria. Fur titration experiments indicate that this region of dyad symmetry is sufficient for Fur-dependent regulation in Escherichia coli. The expression of this gene was repressed, in a dose-dependent manner, by the addition of iron to the S. aureus culture medium. sir-encoded proteins may be involved in iron acquisition in vivo and therefore may be targets for antimicrobial agents.


CLE peptides can negatively regulate protoxylem vessel formation via cytokinin signaling.
Cell-cell communication is critical for tissue and organ development. In plants, secretory CLAVATA3/EMBRYO SURROUNDING REGION-related (CLE) peptides function as intercellular signaling molecules in various aspects of tissue development including vascular development. However, little is known about intracellular signaling pathways functioning in vascular development downstream of the CLE ligands. We show that CLE peptides including CLE10, which is preferentially expressed in the root vascular system, inhibit protoxylem vessel formation in Arabidopsis roots. GeneChip analysis displayed that CLE10 peptides repressed specifically the expression of two type-A Arabidopsis Response Regulators (ARRs), ARR5 and ARR6, whose products act as negative regulators of cytokinin signaling. The arr5 arr6 roots exhibited defective protoxylem vessel formation. These results indicate that CLE10 inhibits protoxylem vessel formation by suppressing the expression of type-A ARR genes including ARR5 and ARR6. This was supported by the finding that CLE10 did not suppress protoxylem vessel formation in a background of arr10 arr12, a double mutant of type-B ARR genes. Thus, our results revealed cross-talk between CLE signaling and cytokinin signaling in protoxylem vessel formation in roots. Taken together with the indication that cytokinin signaling functions downstream of the CLV3/WUS signaling pathway in the shoot apical meristem, the cross-talk between CLE and cytokinin signaling pathways may be a common feature in plant development.


Androgens in women - critical evaluation of the methods for their determination in diagnostics of endocrine disorders.
The androgens dehydroepiandrosterone sulfate, dehydro-epiandrosterone, androstenedione and testosterone are routinely assessed in women, and circulating levels of these androgens reflect their production. These androgens are measured in most laboratories using various immuno-analytical methods. Recently, however, androgen assays have begun to be performed using gas or liquid chromatography combined with mass spectrometry. To better understand the difficulties and issues of androgen laboratory diagnostics, it is important to assess each of the methods used, how and why they were introduced into practice, and their advantages, limits, historic milestones and current status. It is also necessary to understand how reference ranges are determined and specifics arising from the physiology of individual androgens. Here we present a summary and discussion of these issues.


Preventing child abuse and neglect: a national evaluation of Parents Anonymous groups.
This evaluation assessed whether participation in Parents Anonymous mutual support groups was associated with child maltreatment prevention. Parents new to groups across the United States were interviewed at baseline, one month, and six months. Using standardized scales, all parents showed improvements in some child maltreatment outcomes, risk factors, and protective factors. Parents starting out with particularly serious needs showed statistically significant improvement on every scale. Results indicated that Parents Anonymous participation contributes to child maltreatment reduction.


Expression of matrix metalloproteinase 2 and heat shock protein-72 in immobilized muscle in rats.
Metalloproteinases (MMPs) are proteolytic enzymes that function in the extracellular matrix to degrade connective tissues. While it is clear that certain induced skeletal muscle pathologies promote increased expression of MMP-2 and heat shock protein- 72 (HSP-72), the relationship between muscle disuse and expression of MMP-2 and HSP-72 in muscles is unknown. These experiments tested the hypothesis that knee immobilization induced expression of MMP-2 and HSP-72 is disuse-dependent in a way that short-term joint immobilization increases HSP-72 expression, whereas long-term joint immobilization increases MMP-2 expression in skeletal muscles. Male rats (8 months old) completed 1, 2, 3, and 4 weeks of knee joint immobilization. Muscle mRNA and protein levels of MMP-2 and HSP-72 were assessed in Gastrocnemius (Gast), Superficial and Deep Quadriceps, and Soleus (Sol) muscles by reverse transcriptase-polymerase chain reaction and western blotting, respectively. Results reveal that during the first two weeks of immobilization there is increased protein levels of HSP-72 and expression of mRNA of HSP-72 mainly in slow twitch muscle fibers. However, 3 and 4 weeks of joint immobilization increased both mRNA and protein levels of MMP-2 in skeletal muscles containing a high percentage of fast type II fibers (i.e., Gast and superficial quadriceps). These results support the hypothesis that different periods of muscle disuse induced different proteins expression, and that the influence of joint immobilization on the expression of HSP-72 in the short-term, and MMP-2 in the long ran is associated to fiber types.


Birth and Resuscitation of (p)ppGpp Induced Antibiotic Tolerant Persister Cells.
Transient antibiotic treatment typically eradicates most sensitive bacteria except a few survivors called persisters. The second messenger (p)ppGpp plays a key role in persister formation in Escherichia coli populations but the underlying mechanisms have remained elusive. In this study we induced (p)ppGpp synthesis by modulating tRNA charging and then directly observed the stochastic appearance, antibiotic tolerance, and resuscitation of persister cells using live microscopy. Different physiological parameters of persister cells as well as their regularly growing ancestors and sisters were continuously monitored using fluorescent reporters. Our results confirmed previous findings that high (p)ppGpp levels are critical for persister formation, but the phenomenon remained strikingly stochastic without any correlation between (p)ppGpp levels and antibiotic tolerance on the single-cell level. We could not confirm previous notions that persisters exhibit markedly low concentrations of intracellular ATP or were linked to post-transcriptional effects of (p)ppGpp through the activation of small genetic elements known as toxin-antitoxin (TA) modules. Instead, we suggest that persister cell formation under regular conditions is driven by the transcriptional response to increased (p)ppGpp levels.


Multi-drug approaches to NASH: what's in the development pipeline?
Introduction: The pandemic of obesity over the last two decades has triggered a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD is associated with liver-related and cardiovascular complications. Despite this, the first licensed drug for NAFLD is yet to be approved. Given the scale of the problem and unmet needs, there is a myriad of agents in the development pipeline.Areas covered: We discuss promising agents in early phase clinical trials and categorize these agents based on their action on steatosis, steatohepatitis, and fibrosis. Furthermore, given the multisystemic nature of NAFLD, we consider the effects of these agents on the liver, their cardiometabolic effects, and the potential future strategies of combination therapies.Expert opinion: The paradigm for the ideal drug is the targeting of both steatohepatitis and fibrosis and the amelioration of cardiometabolic risk factors. New drugs that confer benefit in nonalcoholic steatohepatitis (NASH) must also be tested for their effects on type 2 diabetes mellitus and cardiovascular disease. The treatment of NASH will become analogous to the treatment of hypertension; it is very likely that multiple classes of drugs targeting different mechanistic pathways will be necessary because no single agent is likely to control all aspects of this complex liver disease.


An unusual clinical course of adenoid cystic carcinoma of the lacrimal gland.
The case of a 25-year-old woman with adenoid cystic carcinoma of the lacrimal gland is reported. Her complaints, including pain and localized swelling, first started six years earlier. She was diagnosed elsewhere as orbital pseudotumor based on clinical and computed tomographic features and was prescribed oral corticosteroids. The regimen completely relieved her signs and symptoms, which regularly recurred in the ensuing years. When she finally presented with rapidly worsening proptosis and pain, she underwent incisional biopsy followed by exenteration and 6000 cGy of radiotherapy. This patient is a rare example of adenoid cystic carcinoma of the lacrimal gland with an atypical clinical course of long duration during which corticosteroids completely suppressed the clinical signs and symptoms.


Computational imaging reveals mitochondrial morphology as a biomarker of cancer phenotype and drug response.
Mitochondria, which are essential organelles in resting and replicating cells, can vary in number, mass and shape. Past research has primarily focused on short-term molecular mechanisms underlying fission/fusion. Less is known about longer-term mitochondrial behavior such as the overall makeup of cell populations' morphological patterns and whether these patterns can be used as biomarkers of drug response in human cells. We developed an image-based analytical technique to phenotype mitochondrial morphology in different cancers, including cancer cell lines and patient-derived cancer cells. We demonstrate that (i) cancer cells of different origins, including patient-derived xenografts, express highly diverse mitochondrial phenotypes; (ii) a given phenotype is characteristic of a cell population and fairly constant over time; (iii) mitochondrial patterns correlate with cell metabolic measurements and (iv) therapeutic interventions can alter mitochondrial phenotypes in drug-sensitive cancers as measured in pre- versus post-treatment fine needle aspirates in mice. These observations shed light on the role of mitochondrial dynamics in the biology and drug response of cancer cells. On the basis of these findings, we propose that image-based mitochondrial phenotyping can provide biomarkers for assessing cancer phenotype and drug response.


Long-Term Outcomes of Post Dural Puncture Headache Treated With Epidural Blood Patch: A Pilot Study.
Post dural puncture headache (PDPH) is a known complication which may occur in the setting of patients undergoing lumbar punctures (LP) for diagnostic or therapeutic purposes. The gold standard for treating a PDPH is an epidural blood patch (EBP). There have been few publications evaluating the long-term outcomes of PDPH treated with EBP. The aim of this pilot study was to examine the incidence of chronic headaches in dural puncture patients who received EBP versus those who did not. A retrospective case control study was performed at a single large center institution. Forty-nine patients who had intentional dural puncture were identified on chart review and completed a survey questionnaire via phone interview: twenty-six of these patients required a subsequent EBP, while twenty-three did not. The primary outcomes were the development and prevalence of chronic headaches after the procedures. There was no statistically significant difference in the prevalence of current headaches between the EBP group and Non-EBP group (54% vs. 52% p = 0.91). There were no significant differences in the rates of severity and descriptive qualities of headache between the EBP and non-EBP groups. There was higher incidence of tinnitus in the PDPH patients. This pilot study demonstrates that patients who received an EBP for treatment of a PDPH following LP are no more likely to experience chronic headaches compared to patients who do not receive an EBP. However, both the EBP group and Non-EBP group had high incidence of chronic headaches which may be related to dural puncture or a baseline trait of this cohort given the recall bias. There is a suggestion that tinnitus could be a long-term residual symptom of PDPH treated with EBP.


Flight and hearing: ultrasound sensitivity differs between flight-capable and flight-incapable morphs of a wing-dimorphic cricket species.
We studied frequency sensitivity of flight-capable and flight-incapable forms of the wing-dimorphic cricket Gryllus texensis, using both behavioral and neurophysiological measurements. Behavioral thresholds for negative phonotaxis in response to ultrasound stimuli are lower for long-winged (i.e. flight-capable) crickets than for short-winged (flight-incapable) individuals, whereas thresholds for positive phonotaxis in response to a calling-song model do not differ. Similarly, thresholds of the identified interneurons ON1 and AN2 differ between flight morphs for high sound frequencies but not for the frequency of calling song. Our results show that sensitivity to ultrasound is closely linked to flight ability, and thus to the risk of predation from aerially hawking bats. We suggest that sensitivity to ultrasound is one of a suite of flight-associated characteristics, the development of which may be under common hormonal regulation.


Poly-l-lysine/Laminin Surface Coating Reverses Glial Cell Mechanosensitivity on Stiffness-Patterned Hydrogels.
Brain tissues demonstrate heterogeneous mechanical properties, which evolve with aging and pathologies. The observation in these tissues of smooth to sharp rigidity gradients raises the question of brain cell responses to both different values of rigidity and their spatial variations, in dependence on the surface chemistry they are exposed to. Here, we used recent techniques of hydrogel photopolymerization to achieve stiffness texturing down to micrometer resolution in polyacrylamide hydrogels. We investigated primary neuron adhesion and orientation as well as glial cell proliferative properties on these rigidity-textured hydrogels for two adhesive coatings: fibronectin or poly-l-lysine/laminin. Our main observation is that glial cell adhesion and proliferation is favored on the stiffer regions when the adhesive coating is fibronectin and on the softer ones when it consists of poly-l-lysine/laminin. This behavior was unchanged by the presence or the absence of neuronal cells. In addition, glial cells were not confined by sharp, micron-scaled gradients of rigidity. Our observations suggest that rigidity sensing could involve adhesion-related pathways that profoundly depend on surface chemistry.


Kinetic peculiarities of human tissue kallikrein: 1--substrate activation in the catalyzed hydrolysis of H-D-valyl-L-leucyl-L-arginine 4-nitroanilide and H-D-valyl-L-leucyl-L-lysine 4-nitroanilide; 2--substrate inhibition in the catalyzed hydrolysis of N alpha-p-tosyl-L-arginine methyl ester.
Hydrolysis of D-valyl-L-leucyl-L-lysine 4-nitroanilide (1), D-valyl-L-leucyl-L-arginine 4-nitroanilide (2), and N alpha-p-tosyl-L-arginine methyl ester (3) by human tissue kallikrein was studied throughout a wide range of substrate concentrations. At low substrate concentrations, the hydrolysis followed Michaelis-Menten kinetics but, at higher substrate concentrations, a deviation from Michaelis-Menten behavior was observed. With the nitroanilides, a significant increase in hydrolysis rates was observed, while with the ester, a significant decrease in hydrolysis rates was observed. The results for substrates (1) and (3) can be accounted for by a model based on the hypothesis that a second substrate molecule binds to the ES complex to produce a more active or an inactive SES complex. The deviation observed for substrate (2) can be explained as a bimolecular reaction between the enzyme-substrate complex and a free substrate molecule.


Bacterial synthesis of copper/copper oxide nanoparticles.
A bacterial mediated synthesis of copper/copper oxide nanoparticle composite is reported. A Gram-negative bacterium belonging to the genus Serratia was isolated from the midgut of Stibara sp., an insect of the Cerambycidae family of beetles found in the Northwestern Ghats of India. This is a unique bacterium that is quite specific for the synthesis of copper oxide nanoparticles as several other strains isolated from the same insect and common Indian mosquitoes did not result in nanoparticle formation. By following the reaction systematically, we could delineate that the nanoparticle formation occurs intracellularly. However, the process results in the killing of bacterial cells. Subsequently the nanoparticles leak out as the cell wall disintegrates. The nanoparticles formed are thoroughly characterized by UV-Vis, TEM, XRD, XPS and FTIR studies.


Effect of submicron polyethylene particles on an osseointegrated implant: an experimental study with a rabbit patello-femoral prosthesis.
In a rabbit model of a weight bearing, articulating prosthetic joint we repeatedly injected submicron particles of Ultra-High-Molecular-Weight-Polyethylene (UHMWPE) produced in a hip simulator. The contralateral knee with the same prosthesis was injected with carrier (NaCl) without UHMWPE. Histomorphometrical studies on undecalcified cut and ground sections at 26 and 42 weeks involved quantifications of the entire bone to metal contact and the bone area around each implant. We found no statistically significant differences between test and control groups, and the UHMWPE debris did not induce any significant osteolysis, indicating that an osseointegrated implant with a sealed interface may not be affected by UHMWPE debris or progress to aseptic loosening.


The Teratogenic Effects of Flurazepam Intake during Organogenesis of the Rat Fetus.
ABSTRACT Flurazepam is a long acting drug with sedative, hypnotic, anxiolytic, relaxant, and anti-epileptic properties. The drug is a benzodiazepine and is commonly used by adults, including pregnant women, intentionally or sometimes unintentionally during their pregnancy. It is increasingly used these days, and therefore, it seems a special problem to the clinician treating anxiety disorders in women. It should be noticed that flurazepam exposure during pregnancy may have teratogenic effects on the fetus. Until now, many studies have been conducted on drug side-effects in poisonings, behavioral disorder, and anxiety reactions, but there is no accurate report about the teratogenic effect of flurazepam. In this study, teratogenicity flurazepam intake during pregnancy and its effects on fetus development was investigated. About 30 virgin rats of known age and weight were used. After being pregnant, they were divided into three groups: Negative and positive control group, case groups exposed for 1 to 6 mg/kg/day. The fetuses were first studied macroscopically regarding anomalies, and then histological and histochemically to inspect the defects of tissue organogenesis. Our results show that there was significant difference in the weight and length of the cases compared to the control group. The statistical results indicate that flurazepam intake during the second half of pregnancy can lead to irreversible anomalies. It seems that benzodiazepine therapy among pregnant woman would be better to avoid during the first trimester and multidrug regimens.


Combined Adipose Tissue-Derived Mesenchymal Stem Cell Therapy and Rehabilitation in Experimental Stroke.
Background/Objective: Stroke is a leading global cause of adult disability. As the population ages as well as suffers co-morbidities, it is expected that the stroke burden will increase further. There are no established safe and effective restorative treatments to facilitate a good functional outcome in stroke patients. Cell-based therapies, which have a wide therapeutic window, might benefit a large percentage of patients, especially if combined with different restorative strategies. In this study, we tested whether the therapeutic effect of human adipose tissue-derived mesenchymal stem cells (ADMSCs) could be further enhanced by rehabilitation in an experimental model of stroke. Methods: Focal cerebral ischemia was induced in adult male Sprague Dawley rats by permanently occluding the distal middle cerebral artery (MCAO). After the intravenous infusion of vehicle (n = 46) or ADMSCs (2 × 106) either at 2 (n = 37) or 7 (n = 7) days after the operation, half of the animals were housed in an enriched environment mimicking rehabilitation. Subsequently, their behavioral recovery was assessed by a neurological score, and performance in the cylinder and sticky label tests during a 42-day behavioral follow-up. At the end of the follow-up, rats were perfused for histology to assess the extent of angiogenesis (RECA-1), gliosis (GFAP), and glial scar formation. Results: No adverse effects were observed during the follow-up. Combined ADMSC therapy and rehabilitation improved forelimb use in the cylinder test in comparison to MCAO controls on post-operative days 21 and 42 (P < 0.01). In the sticky label test, ADMSCs and rehabilitation alone or together, significantly decreased the removal time as compared to MCAO controls on post-operative days 21 and 42. An early initiation of combined therapy seemed to be more effective. Infarct size, measured by MRI on post-operative days 1 and 43, did not differ between the experimental groups. Stereological counting revealed an ischemia-induced increase both in the density of blood vessels and the numbers of glial cells in the perilesional cortex, but there were no differences among MCAO groups. Glial scar volume was also similar in MCAO groups. Conclusion: Early delivery of ADMSCs and combined rehabilitation enhanced behavioral recovery in an experimental stroke model. The mechanisms underlying these treatment effects remain unknown.


The role of gene products of non-H-2 loci and M locus in secondary MLC response.
The response in the secondary MLC after priming in vivo was studied in combinations of mouse strains H-2 identical and differing at genetic loci that segregate independently of the H-2 system (non H-2 loci including M locus). After priming with gene products of non-H-2 loci and M locus the response in secondary MLC in H-2-identical strains is influenced by the H-2 genotype (combinations compatible for H-2b and H-2k haplotypes were compared). With the H-2k compatibility, the type of secondary MLC response depends on the non-H-2 genotype of the responder strain. The same gene products of the M locus activate a cell suppressor mechanism, which suppresses the blastic response of lymphocytes, in some responder strains and an early proliferative response in others.


Adequacy of tissue oxygenation in cardiac surgery: regional measurements.
The aim of the study was to measure visceral and peripheral perfusion and oxygenation during and immediately after cardiac surgery. Central hemodynamics, blood gases, core temperature, visceral and peripheral tissue perfusion, and oxygenation were studied in eight patients undergoing coronary artery bypass grafting and in the early postoperative period in another group of ten coronary artery bypass grafting patients. The variables were measured after induction of anesthesia, after sternotomy, during cardiopulmonary bypass, after rewarming and after closing the wounds. Postoperatively, the measurements were carried out hourly up to 8 hrs after the arrival of patients in the ICU. The patients were operated on under moderate hemodilution and systemic hypothermia. The inspired oxygen concentration was maintained at 30 volumes percent during the postoperative study. Visceral perfusion was indirectly assessed by determining the gastric intramucosal pH. Peripheral tissue perfusion was assessed in the upper extremity by continuous recording of subcutaneous tissue PO2, laser-Doppler skin erythrocyte flux, transcutaneous PO2, and fingertip temperature. Transcutaneous PO2 index (transcutaneous PO2/PaO2) was calculated. Gastric intramucosal pH, PaO2, and transcutaneous PO2 reached maximum values during cardiopulmonary bypass at the deepest level of hypothermia, and gastric intramucosal pH reached its minimum at the end of the operation. During the first 3 hrs after admission of patients to the ICU, gastric intramucosal pH decreased progressively, reached its minimum value at 5 hrs, and increased slowly thereafter. Subcutaneous tissue PO2, laser-Doppler skin erythrocyte flux, and fingertip temperature decreased markedly during cardiopulmonary bypass, increased during rewarming, and decreased again at the end of surgery. The peripheral vascular bed was vasoconstricted on ICU admission, as indicated by the low values of subcutaneous tissue PO2, transcutaneous PO2, transcutaneous PO2 index, laser-Doppler skin erythrocyte flux, and fingertip temperature. These variables began to increase over the next 2 to 4 hrs and reached their maximum value by the end of the 8-hr postoperative study period, indicating complete vasodilation of the peripheral vascular bed. These data suggest that the visceral perfusion of patients is well maintained during cardiopulmonary bypass, while, at the same time, these patients develop hypoperfusion and hypoxia of peripheral tissues. After closing the wounds, gastric intramucosal pH, transcutaneous PO2 index (transcutaneous PO2/PaO2), and other peripheral tissue perfusion variables were at the lowest values, indicating impending residual hypothermia and tissue hypoperfusion after rewarming. During the first few hours in the ICU, both the visceral and peripheral oxygenation and perfusion variables reflected hypoperfusion of tissues coinciding in time with the period most vulnerable for hemodynamic disasters and cardiac arrhythmias.


Fitting computational models to fMRI.
Many computational models in psychology predict how neural activation in specific brain regions should change during certain cognitive tasks. The emergence of fMRI as a research tool provides an ideal vehicle totest these predictions. Before such tests are possible, however, significant methodological problems must be solved. These problems include transforming the neural activations predicted by the model into predicted BOLD responses, identifying the voxels within each region of interest against which to test the model, and comparing the observed and predicted BOLD responses in each of these regions. In the present article, methods are described for solving each of these problems.


Phosphorus-Rich Copper Phosphide Nanowires for Field-Effect Transistors and Lithium-Ion Batteries.
Phosphorus-rich transition metal phosphide CuP2 nanowires were synthesized with high quality and high yield (∼60%) via the supercritical fluid-liquid-solid (SFLS) growth at 410 °C and 10.2 MPa. The obtained CuP2 nanowires have a high aspect ratio and exhibit a single crystal structure of monoclinic CuP2 without any impurity phase. CuP2 nanowires have progressive improvement for semiconductors and energy storages compared with bulk CuP2. Being utilized for back-gate field effect transistor (FET) measurement, CuP2 nanowires possess a p-type behavior intrinsically with an on/off ratio larger than 10(4) and its single nanowire electrical transport property exhibits a hole mobility of 147 cm(2) V(-1) s(-1), representing the example of a CuP2 transistor. In addition, CuP2 nanowires can serve as an appealing anode material for a lithium-ion battery electrode. The discharge capacity remained at 945 mA h g(-1) after 100 cycles, showing a good capacity retention of 88% based on the first discharge capacity. Even at a high rate of 6 C, the electrode still exhibited an outstanding result with a capacity of ∼600 mA h g(-1). Ex-situ transmission electron microscopy and CV tests demonstrate that the stability of capacity retention and remarkable rate capability of the CuP2 nanowires electrode are attributed to the role of the metal phosphide conversion-type lithium storage mechanism. Finally, CuP2 nanowire anodes and LiFePO4 cathodes were assembled into pouch-type lithium batteries offering a capacity over 60 mA h. The full cell shows high capacity and stable capacity retention and can be used as an energy supply to operate electronic devices such as mobile phones and mini 4WD cars.


Comparison of ramipril against atenolol in controlling mild-to-moderate hypertension.
This trial was a multicenter, double-blind, randomized, parallel-group, variable-dose study comparing ramipril with atenolol, and incorporating a 4-week run-in period on placebo. A total of 92 patients suffering from mild to moderate hypertension were randomized to the trial. Following a 4-week run-in period on placebo, newly diagnosed patients were only continued if their blood pressure remained within the defined range throughout the placebo run-in period. Known hypertensive patients who were safely switched to the trial therapy were only continued if their blood pressure was within the defined range at the end of this placebo washout period. An analysis of the data at baseline showed no statistical differences between treatment groups. Both systolic and diastolic blood pressures were significantly reduced from baseline in each group, but there were no differences between treatments. The study showed that ramipril and atenolol were both successful at reducing and controlling mild-to-moderate hypertension, but it showed no difference between treatments.


A qualitative study to investigate the psychosocial effects of operational deployments on Medical Emergency Response Team personnel.
The stressors associated with emergency medical teams responding to critical incidents are well documented; however, the impact of such duties on the UK military personnel had never been investigated. This study explored the psychosocial effects of Medical Emergency Response Teams (MERT) operating in Afghanistan to inform the development of a Resilience Model. A structured and contextually relevant process could then be applied for a team's preparation for, delivery of and recovery from, their duties. A qualitative cross-sectional design used semi-structured interviews and 15 multidisciplinary team members participated. Interviews were transcribed verbatim and data were systematically analysed using grounded theory. Emergent theory poses that developing resilience against the demands of this role is dependent upon personnel having a realistic understanding of the deployed environment by phased immersion within it. This preparatory training generates situational awareness, trust and strong team cohesion, which together with peer and organizational support are necessary factors to effectively cope with the role. To limit the costs of caring, there is a need for MERT personnel to segregate the physiological and emotional aspects of delivering care to the injured; those unable to do so may be at greater risk of poor mental health outcomes. The preparatory training of MERT personnel must be further developed to provide an immersive environment that more closely matches the reality of the role. A period of stability is required post deployment with the support of peers to enable personnel to more efficiently transition back to their home life.


Overlapping region of p53/wrap53 transcripts: mutational analysis and sequence similarity with microRNA-4732-5p.
Although the majority of investigations concerned with TP53 and its protein have focused on coding regions, recently a set of studies highlighted significant roles of regulatory elements located in p53 mRNA, especially 5 ? UTR. The wrap53α transcript is one of those that acts as a natural antisense agent, forming RNA-RNA hybrids with p53 mRNA and protecting it from degradation. In this study, we focused on the mutation status of exon 1α of the WRAP53 gene (according to exon 1 of p53) in 160 breast tumor tissue samples and conducted a bioinformatics search for probable miRNA binding site in the p53/wrap53 overlapping region. Mutations were detected, using single stranded conformation polymorphism (SSCP) and sequencing. We applied the miRBase database for prediction of miRNAs which target overlapping region of p53/wrap53 transcripts. Our results showed all samples to have wild type alleles in exon 1 of TP53 gene. We could detect a novel and unreported intronic mutation (IVS1+ +56, G>C) outside overlapping regions of p53/wrap53 genes in breast cancer tissues and also predict the presence of a binding site for miR-4732-5p in the 5' UTR of Wrap53 mRNA. From our findings we propose designing further studies focused on overexpression of miRNA-4732-5p and introducing different mutations in the overlapping region of wrap53 and p53 genes in order to study their effects on p53 and its δN isoform (δ40p53) expression. The results may provide new pieces in the p53 targeting puzzle for cancer therapy.


[Osteonecrosis].
In orthopedic pathology, the pathologist is most commonly faced with the study of resected femoral heads for osteonecrosis. Such a study necessitates a knowledge of clinical findings, of physiopathology and chiefly of radiological findings. Osteonecrosis of the femoral head following fracture has been reported with four morphological stages which are very precisely described. In the same way, idiopathic, non traumatic, or primary osteonecrosis is covered, stressing the putative etiological factors and the most important findings of imaging. The review includes also the skeletal manifestations of decompression sickness as well as bone infarctions not associated with caisson disease, and spontaneous osteonecrosis of the knee. From the recruitment of the Hospital for Special Surgery, NY, it has been recently reported that a significant number of patients regarded as cases of osteonecrosis, either in the femoral head or in the knee, are actually cases of subchondral insufficiency fractures.


Investigating insecticide resistance and knock-down resistance (kdr) mutation in Dielmo, Senegal, an area under long lasting insecticidal-treated nets universal coverage for 10 years.
The use of insecticides, through indoor residual spraying and long-lasting insecticide-treated nets (LLINs), is essential to control malaria vectors. However, the sustainability of these tools is challenged by the spread of insecticide resistance in Anopheles mosquitoes. This study was conducted to assess the susceptibility to insecticides and to determine the resistance mechanisms in malaria vectors in Dielmo, a rural area of western Senegal where LLINs were introduced a decade ago. CDC bottle bioassays were used to determine the susceptibility of 2-5 day-old unfed Anopheles gambiae s.l. females to alphacypermethrin (12.5 µg/bottle), deltamethrin (12.5 µg/bottle), etofenprox (12.5 µg/bottle), lambdacyhalothrin (12.5 µg/bottle), permethrin (21.5 µg/bottle), DDT (100 µg/bottle), bendiocarb (12.5 µg/bottle), pirimiphos-methyl (20 µg/bottle) and fenitrothion (50 µg/bottle). The involvement of glutathione-S-transferases (GSTs) in insecticide resistance was assessed using a synergist, etacrynic acid (EA, 80 µg/bottle). Polymerase chain reaction (PCR) was used to investigate the presence of 'knock-down resistance (kdr)' mutation and to identify sibling species within the An. gambiae complex. CDC bottle bioassays showed that mosquitoes were fully susceptible to lambdacyhalothrin, bendiocarb and fenitrothion. Overall, mortality rates of 97, 94.6, 93.5, 92.1, and 90.1% were, respectively, observed for permethrin, deltamethrin, pirimiphos-methyl, etofenprox and alphacypermethrin. Resistance to DDT was observed, with a mortality rate of 62%. The use of EA significantly improved the susceptibility of An. gambiae s.l. to DDT by inhibiting GSTs (p = 0.03). PCR revealed that Anopheles arabiensis was the predominant species (91.3%; IC 95 86.6-94%) within An. gambiae complex from Dielmo, followed by Anopheles coluzzii (5.4%; IC 95 2.7-8.1%) and Anopheles gambiae s.s. (3.3%; IC 95 0.6-5.9%). Both 1014F and 1014S alleles were found in An. arabiensis population with frequencies of 0.08 and 0.361, respectively, and 0.233 and 0.133, respectively in An. coluzzii. In An. gambiae s.s. population, only kdr L1014F mutation was detected, with a frequency of 0.167. It was observed that some individual mosquitoes carried both alleles, with 19 specimens recorded for An. arabiensis and 2 for An. coluzzii. The presence of L1014F and L1014S alleles were not associated with resistance to pyrethroids and DDT in An. arabiensis. The co-occurrence of 1014F and 1014S alleles and the probable involvement of GSTs enzymes in insecticide resistance in An. gambiae s.l. should prompt the local vector programme to implement non-pyrethroid/DDT insecticides alternatives.


Actions of nipecotic acid and SKF89976A on GABA transporter in cone-driven horizontal cells dissociated from the catfish retina.
Whole-cell voltage-clamp recordings were made from dissociated horizontal cells of the catfish retina. In the presence of picrotoxin (PTX, 100 microM), GABA evoked a sustained inward current at negative holding potentials. Dose-response measurements were well fitted by a logistic curve with a Hill coefficient of 1.11 and EC50 of 9.76 microM. When external Na+ was replaced with Li+, this GABA-induced current was eliminated. The substitution of methanesulfonate for Cl- also suppressed the current. This current was blocked by either nipecotic acid or SKF89976A. However, the mechanisms by which these drugs suppress the GABA-induced current differ. Intracellularly applied SKF89976A blocked the GABA-induced current, while nipecotic acid intracellularly had no effect. beta-Alanine at concentrations greater than 1 mM exerted a slight inhibitory effect. Extracellularly applied SKF89976A produced no current by itself but suppressed GABA-induced currents. Dose-response curves showed that SKF89976A has an IC50 of 0.93 microM and a Hill coefficient of 2.68. Nipecotic acid evoked a current response, like GABA. A Hill coefficient was 1.64 and an EC50 was 7.69 microM. This nipecotic acid-induced current was blocked by substituting Li+ for Na+ or by the addition of SKF89976A. This result is consistent with other studies indicating that nipecotic acid is transported in place of GABA. Extracellular Na+ was required for the prolonged suppression by extracellularly applied SKF89976A, while the extracellular Cl- depletion has no influence on the suppression. The pharmacological profile of this GABA transporter fits the neuronal rather than the glial type of cloned transporters.


Understanding the effects of a myocardial infarction on sexual functioning: a basis for sexual counseling.
Sexual counseling is an integral component of the rehabilitative process for clients who have experienced a myocardial infarction (MI). This article describes myths and fears concerning the dangers of resuming sexual intercourse after a heart attack, positions for intercourse, and the effects of intercourse on arrhythmias, angina, and blood pressure. The purpose is to provide the results of empirical research to dispel myths and fears and to consider the causes of sexual dysfunction, the changes MI brings about in sexual activity for men and women, and the effects of age, exercise, and antihypertensive drugs on the resumption of sexual activity. Guidelines are provided for conducting a sexual/cardiac history as part of the counseling model with specific information for the post-MI client.


Thin Film and Nanostructured Pd-Based Materials for Optical H2 Sensors: A Review.
In this review paper, we provide an overview of state-of-the-art Pd-based materials for optical H2 sensors. The first part of the manuscript introduces the operating principles, providing background information on the thermodynamics and the primary mechanisms of optical detection. Optical H2 sensors using thin films (i.e., films without any nanostructuring) are discussed first, followed by those employing nanostructured materials based on aggregated or isolated nanoparticles (ANPs and INPs, respectively), as well as complex nanostructured (CN) architectures. The different material types are discussed on the basis of the properties they can attribute to the resulting sensors, including their limit of detection, sensitivity, and response time. Limitations induced by cracking and the hysteresis effect, which reduce the repeatability and reliability of the sensors, as well as by CO poisoning that deteriorates their performance in the long run, are also discussed together with an overview of manufacturing approaches (e.g., tailoring the composition and/or applying functionalizing coatings) for addressing these issues.


Gremlin and renal diseases: ready to jump the fence to clinical utility?
The current therapeutic strategy for the treatment of chronic kidney diseases only ameliorates disease progression. During renal injury, developmental genes are re-expressed and could be potential therapeutic targets. Among those genes reactivated in the adult damaged kidney, Gremlin is of particular relevance since recent data suggest that it could be a mediator of diabetic nephropathy and other progressive renal diseases. Earlier studies have shown that Gremlin is upregulated in trans-differentiated renal proximal tubular cells and in several chronic kidney diseases associated with fibrosis. However, not much was known about the mechanisms by which Gremlin acts in renal pathophysiology. The role of Gremlin as a bone morphogenetic protein antagonist has clearly been demonstrated in organogenesis and in fibrotic-related disorders. Gremlin binds to vascular endothelial growth factor receptor 2 (VEGFR2) in endothelial and tubular epithelial cells. Activation of the Gremlin-VEGFR2 axis was found in several human nephropathies. We have recently described that Gremlin activates the VEGFR2 signaling pathway in the kidney, eliciting a downstream mechanism linked to renal inflammatory response. Gremlin deletion improves experimental renal damage, diminishing fibrosis. Overall, the available data identify the Gremlin-VEGFR2 axis as a novel therapeutic target for kidney inflammation and fibrosis and provide a rationale for unveiling new concepts to investigate in several clinical conditions.


Coronary flow stimulates auricular-ventricular transmission in the isolated perfused guinea pig heart.
In the heart in situ coronary flow stimulates oxygen consumption, glycolytic flux, myocardial contractility, and the release of bioactive substances. Studies have indicated that the coronary flow-enhanced contraction is similar to a hormonelike effect because the enhanced contraction results from an elevation in intracellular free calcium. In fact, if extracellular calcium is raised sufficiently, the contraction amplitude rises and remains constant and independent of coronary flow. We hypothesized that coronary flow could also stimulate other calcium-dependent cardiac functions such as auricular-ventricular (A-V) transmission. This hypothesis was tested in isolated guinea pig hearts perfused at constant flow. Our results show that increases in coronary flow (6-25 ml/min range) decrease the A-V delay solely as a result of reduced propagation time in the A-V node and not in atrial or ventricular propagation. When coronary vascular resistance was altered by dilation (nitroglycerin, bradykinin, nitroprusside, and adenosine) or by constriction (angiotensin II), this dromotropic effect of flow remained the same despite wide changes in perfusing pressure. Also, this dromotropic effect of flow was not altered by energy-altering substrates in the perfusate or by perfusion of adenosine receptor blockers. Furthermore, the effectiveness of flow as a dromotropic stimulus varied inversely with changes in calcium entry caused either by elevation or reduction of extracellular calcium. In addition, enhanced viscosity of the perfusing medium amplifies the positive dromotropic effect of flow. These results suggest that coronary flow is a stimulus that exerts a positive dromotropic effect mediated by shear stress.


Cytosolic Calcium Oscillations in Smooth Muscle Cells.
In a variety of smooth muscle cells, agonists activating membrane receptors induce oscillations in the cytoplasmic Ca(2+) concentration via an inositol trisphosphate-activated mechanism. Ca(2+) oscillations participate in the control of cell membrane potential and the tone of smooth muscle. There is evidence that alterations in Ca(2+) oscillations modulate smooth muscle responsiveness.


Kinetic investigation of myeloperoxidase upon interaction with copper, cadmium, and lead ions.
Myeloperoxidase (MPO), which is abundantly expressed in neutrophils, catalyzes the formation of a number of reactive oxidant species. However, evidence has emerged that MPO-derived oxidants contribute to tissue damage and initiation and propagation of inflammatory diseases, particularly, cardiovascular diseases. Therefore, studying the regulatory mechanisms of the enzyme activity is of great importance. For clarifying some possible mechanism of the enzyme activity, kinetic investigations of MPO in the presence of Copper (Cu), Cadmium (Cd), and Lead (Pb) ions were carried out in vitro. MPO was partially purified from human white blood cells using ion-exchange and gel-filtration chromatography techniques. Its activity was measured spectrophotometrically by using tetramethyl benzidine (TMB) as substrate. Purified enzyme had a specific activity of 21.7 U/mg protein with a purity index of about 0.71. Cu inhibited MPO activity progressively up to a concentration of 60 mM at which about 80% of inhibition achieved. The inhibition was non-competitive with respect to TMB. An inhibitory constant (Ki) of about 19 mM was calculated from the slope of repot. Cd and Pb did not show any significant inhibitory effect on the enzyme activity. The results of the present study may indicate that there are some places on the enzyme and enzyme-substrate complex for Cu ions. Binding of Cu ions to these places result in conformational changes of the enzyme and thus, enzyme inhibition. This inhibitory effect of Cu on the enzyme activity might be considered as a regulatory mechanism on MPO activity.