Standardization approaches in absolute quantitative proteomics with mass spectrometry.
Mass spectrometry-based approaches have enabled important breakthroughs in quantitative proteomics in the last decades. This development is reflected in the better quantitative assessment of protein levels as well as to understand post-translational modifications and protein complexes and networks. Nowadays, the focus of quantitative proteomics shifted from the relative determination of proteins (ie, differential expression between two or more cellular states) to absolute quantity determination, required for a more-thorough characterization of biological models and comprehension of the proteome dynamism, as well as for the search and validation of novel protein biomarkers. However, the physico-chemical environment of the analyte species affects strongly the ionization efficiency in most mass spectrometry (MS) types, which thereby require the use of specially designed standardization approaches to provide absolute quantifications. Most common of such approaches nowadays include (i) the use of stable isotope-labeled peptide standards, isotopologues to the target proteotypic peptides expected after tryptic digestion of the target protein; (ii) use of stable isotope-labeled protein standards to compensate for sample preparation, sample loss, and proteolysis steps; (iii) isobaric reagents, which after fragmentation in the MS/MS analysis provide a final detectable mass shift, can be used to tag both analyte and standard samples; (iv) label-free approaches in which the absolute quantitative data are not obtained through the use of any kind of labeling, but from computational normalization of the raw data and adequate standards; (v) elemental mass spectrometry-based workflows able to provide directly absolute quantification of peptides/proteins that contain an ICP-detectable element. A critical insight from the Analytical Chemistry perspective of the different standardization approaches and their combinations used so far for absolute quantitative MS-based (molecular and elemental) proteomics is provided in this review.


[Prolonged paravertebral analgesia in therapy of chronic pain syndrome in critical lower-limb ischaemia].
Chronic pain syndrome in patients presenting with lower-limb critical ischaemia may have considerable significance in progression of the degree of limb ischaemia, and quality of life of patients appears to be largely determined by adequate analgesia. Currently, there is no 'gold standard' of therapy for chronic pain syndrome in critical lower-limb ischaemia, which makes it necessary to search for new effective and safe methods of analgesia. The purpose of this study was to evaluate efficacy and safety of paravertebral analgesia compared with epidural analgesia in therapy of chronic pain syndrome in critical lower-limb ischaemia. Our prospective randomized double-centre study included a total of 40 patients suffering from atherosclerotic-genesis critical lower-limb ischaemia and pronounced unilateral pain syndrome. The patients were randomized into two equal groups comprising 20 patients each. They were comparable by the main clinical and demographic parameters, as well as by the scope of the comprehensive treatment performed. In the study group, therapy of chronic pain syndrome was provided by the method of paravertebral analgesia, with the comparison group patients receiving epidural analgesia. Paravertebral analgesia was performed with the use of ultrasound navigation, in the prolonged mode by means of using microinfusion elastomeric pumps, epidural analgesia - according to the standard technique. The use of various methods of analgesia was accompanied by a decrease in chronic pain syndrome according to the visual analogue scale by 60% within the first 24 hours, and by 65% at 72 hours thereafter, with the differences being statistically insignificant. The use of prolonged paravertebral analgesia was accompanied by neither considerable haemodynamic reactions nor the development of the motor block, however requiring significant expenditure of a local anaesthetic. The conclusion was drawn that paravertebral analgesia in lower-limb critical ischaemia turned out to be a safe and efficient method of comprehensive therapy of chronic pain syndrome.


Reduced masticatory function is related to lower satellite cell numbers in masseter muscle.
The physiology of masseter muscles is known to change in response to functional demands, but the effect on the satellite cell (SC) population is not known. In this study, the hypothesis is tested that a decreased functional demand of the masseter muscle causes a reduction of SCs. To this end, twelve 5-week-old male Sprague-Dawley rats were put on a soft diet (SD, n = 6) or a hard diet (HD, n = 6) and sacrificed after 14 days. Paraffin sections of the superficial masseter and the m. digastricus (control muscle) were stained with haematoxylin and eosin for tissue survey and with anti-myosin heavy chain (MHC) for slow and fast fibres. Frozen sections of both muscles were double-stained for collagen type IV and Pax7. Slow MHC fibres were equally distributed in the m. digastricus but only localized in a small area of the m. masseter. No differences between HD or SD for the m. digastricus were found. The m. masseter had more SCs per fibre in HD than in SD (0.093 ± 0.007 and 0.081 ± 0.008, respectively; P = 0.027). The m. masseter had more fibres per surface area than the m. digastricus in rats with an SD group (758.1 ± 101.6 and 568.4 ± 85.6, P = 0.047) and a HD group (737.7 ± 32.6 and 592.2 ± 82.2; P = 0.007). The m. digastricus had more SCs per fibre than the m. masseter in the SD group (0.094 ± 0.01 and 0.081 ± 0.008; P = 0.039). These results suggest that reduced masseter muscle function is related to a lower number of SCs. Reduced muscle function might decrease microdamage and hence the requirement of SCs in the muscle fibres.


Calpain 3: a key regulator of the sarcomere?
Calpain 3 is a 94-kDa calcium-dependent cysteine protease mainly expressed in skeletal muscle. In this tissue, it localizes at several regions of the sarcomere through binding to the giant protein, titin. Loss-of-function mutations in the calpain 3 gene have been associated with limb-girdle muscular dystrophy type 2A (LGMD2A), a common form of muscular dystrophy found world wide. Recently, significant progress has been made in understanding the mode of regulation and the possible function of calpain 3 in muscle. It is now well accepted that it has an unusual zymogenic activation and that cytoskeletal proteins are one class of its substrates. Through the absence of cleavage of these substrates, calpain 3 deficiency leads to abnormal sarcomeres, impairment of muscle contractile capacity, and death of the muscle fibers. These data indicate a role for calpain 3 as a chef d'orchestre in sarcomere remodeling and suggest a new category of LGMD2 pathological mechanisms.


How Will Machine Learning Inform the Clinical Care of Atrial Fibrillation?
Machine learning applications in cardiology have rapidly evolved in the past decade. With the availability of machine learning tools coupled with vast data sources, the management of atrial fibrillation (AF), a common chronic disease with significant associated morbidity and socioeconomic impact, is undergoing a knowledge and practice transformation in the increasingly complex healthcare environment. Among other advances, deep-learning machine learning methods, including convolutional neural networks, have enabled the development of AF screening pathways using the ubiquitous 12-lead ECG to detect asymptomatic paroxysmal AF in at-risk populations (such as those with cryptogenic stroke), the refinement of AF and stroke prediction schemes through comprehensive digital phenotyping using structured and unstructured data abstraction from the electronic health record or wearable monitoring technologies, and the optimization of treatment strategies, ranging from stroke prophylaxis to monitoring of antiarrhythmic drug (AAD) therapy. Although the clinical and population-wide impact of these tools continues to be elucidated, such transformative progress does not come without challenges, such as the concerns about adopting black box technologies, assessing input data quality for training such models, and the risk of perpetuating rather than alleviating health disparities. This review critically appraises the advances of machine learning related to the care of AF thus far, their potential future directions, and its potential limitations and challenges.


Phase III study, V-15-32, of gefitinib versus docetaxel in previously treated Japanese patients with non-small-cell lung cancer.
This phase III study (V-15-32) compared gefitinib (250 mg/d) with docetaxel (60 mg/m(2)) in patients (N = 489) with advanced/metastatic non-small-cell lung cancer (NSCLC) who had failed one or two chemotherapy regimens. The primary objective was to compare overall survival to demonstrate noninferiority for gefitinib relative to docetaxel. An unadjusted Cox regression model was used for the primary analysis. Noninferiority in overall survival was not achieved (hazard ratio [HR], 1.12; 95.24% CI, 0.89 to 1.40) according to the predefined criterion (upper CI limit for HR <or= 1.25); however, no significant difference in overall survival (P = .330) was apparent between treatments. Poststudy, 36% of gefitinib-treated patients received subsequent docetaxel, and 53% of docetaxel-treated patients received subsequent gefitinib. Gefitinib significantly improved objective response rate and quality of life versus docetaxel; progression-free survival, disease control rates, and symptom improvement were similar for the two treatments. Grades 3 to 4 adverse events occurred in 40.6% (gefitinib) and 81.6% (docetaxel) of patients. Incidence of interstitial lung disease was 5.7% (gefitinib) and 2.9% (docetaxel). Four deaths occurred due to adverse events in the gefitinib arm (three deaths as a result of interstitial lung disease, judged to be treatment related; one as a result of pneumonia, not treatment related), and none occurred in the docetaxel arm. Noninferiority in overall survival between gefitinib and docetaxel was not demonstrated according to predefined criteria; however, there was no statistically significant difference in overall survival. Secondary end points showed similar or superior efficacy for gefitinib compared with docetaxel. Gefitinib remains an effective treatment option for previously treated Japanese patients with NSCLC.


Trifloxystrobin blocks the growth of Theileria parasites and is a promising drug to treat Buparvaquone resistance.
Theileria parasites are responsible for devastating cattle diseases, causing major economic losses across Africa and Asia. Theileria spp. stand apart from other apicomplexa parasites by their ability to transform host leukocytes into immortalized, hyperproliferating, invasive cells that rapidly kill infected animals. The emergence of resistance to the theilericidal drug Buparvaquone raises the need for new anti-Theileria drugs. We developed a microscopy-based screen to reposition drugs from the open-access Medicines for Malaria Venture (MMV) Pathogen Box. We show that Trifloxystrobin (MMV688754) selectively kills lymphocytes or macrophages infected with Theileria annulata or Theileria parva parasites. Trifloxystrobin treatment reduced parasite load in vitro as effectively as Buparvaquone, with similar effects on host gene expression, cell proliferation and cell cycle. Trifloxystrobin also inhibited parasite differentiation to merozoites (merogony). Trifloxystrobin inhibition of parasite survival is independent of the parasite TaPin1 prolyl isomerase pathway. Furthermore, modeling studies predicted that Trifloxystrobin and Buparvaquone could interact distinctly with parasite Cytochrome B and we show that Trifloxystrobin was still effective against Buparvaquone-resistant cells harboring TaCytB mutations. Our study suggests that Trifloxystrobin could provide an effective alternative to Buparvaquone treatment and represents a promising candidate for future drug development against Theileria spp.


Obstructive sleep apnea syndrome affects liver histology and inflammatory cell activation in pediatric nonalcoholic fatty liver disease, regardless of obesity/insulin resistance.
Obstructive sleep apnea syndrome (OSAS) and nonalcoholic fatty liver disease (NAFLD) are frequently encountered in obese children. Whether OSAS and intermittent hypoxia are associated with liver injury in pediatric NAFLD is unknown. To assess the relationship of OSAS with liver injury in pediatric NAFLD. Sixty-five consecutive children with biopsy-proven NAFLD (age, mean ± SD, 11.7 ± 2.1 yr; 58% boys; body mass index z score, 1.93 ± 0.61) underwent a clinical-biochemical assessment and a standard polysomnography. Insulin sensitivity, circulating proinflammatory cytokines, markers of hepatocyte apoptosis (cytokeratin-18 fragments), and hepatic fibrogenesis (hyaluronic acid) were measured. Liver inflammatory infiltrate was characterized by immunohistochemistry for CD45, CD3, and CD163, surface markers of leukocytes, T cells, and activated macrophage/Kupffer cells, respectively. OSAS was defined by an apnea/hypopnea index (AHI) greater than or equal to 1 event/h, and severe OSAS was defined by an AHI greater than or equal to 5 events/h. Fifty-five percent of children with NAFLD had nonalcoholic steatohepatitis (NASH), and 34% had significant (stage F ≥ 2) fibrosis. OSAS affected 60% of children with NAFLD; the presence and severity of OSAS were associated with the presence of NASH (odds ratio, 4.89; 95% confidence interval, 3.08-5.98; P = 0.0001), significant fibrosis (odds ratio, 5.91; 95% confidence interval, 3.23-7.42; P = 0.0001), and NAFLD activity score (β, 0.347; P = 0.029), independently of body mass index, abdominal adiposity, metabolic syndrome, and insulin resistance. This relationship held also in nonobese children with NAFLD. The duration of hemoglobin desaturation (Sa(O2) < 90%) correlated with increased intrahepatic leukocytes and activated macrophages/Kupffer cells and with circulating markers of hepatocyte apoptosis and fibrogenesis. In pediatric NAFLD, OSAS is associated with biochemical, immunohistochemical, and histological features of NASH and fibrosis. The impact of hypoxemia correction on liver disease severity warrants evaluation in future trials.


Spiroplasma corruscae sp. nov., from a firefly beetle (Coleoptera: Lampyridae) and tabanid flies (Diptera: Tabanidae).
Spiroplasma strain EC-1T (T = type strain), which was isolated from the gut of a lampyrid beetle (Ellychnia corrusca) in Maryland, was serologically distinct from other spiroplasma species and groups. Similar strains were obtained from other E. corrusca specimens, and, later, numerous isolates of similar or partially related strains were obtained from several species of tabanid files. Cells of strain EC-1T were helical, motile filaments that were bound by a single cytoplasmic membrane, and there was no evidence of a cell wall. The cells were filterable through 220-nm-pore-size membrane filters but not through 100-nm-pore-size membrane filters. The organism was absolutely resistant to penicillin (1,000 U/ml) and required sterol for growth. Strain EC-1T grew well in M1D and SP-4 liquid media and could be cultivated in the Edward formulation of conventional mycoplasma medium and in 1% serum fraction medium. Optimal growth occurred at 32 degrees C (doubling time, 1.5 h). Strain EC-1T multiplied at 10 to 41 degrees C, but not at 5 or 43 degrees C. This organism produced acid from glucose, but did not hydrolyze arginine or utilize urea. The guanine-plus-cytosine content of the DNA was determined to be 26.3 mol% by the melting temperature method and 27.0 mol% by the buoyant density method. As a result of our studies, strain EC-1 (= ATCC 43212) is designated the type strain of a new species, Spiroplasma corruscae.


The impact of practice guidelines on opioid utilization for injured workers.
Opioid use is rising in the US and may cause special problems in workers compensation cases, including addiction and preventing a return to work after an injury. This study evaluates a physician-level intervention to curb opioid usage. An insurer identified patients with out-of-guideline opioid utilization and called the prescribing physician to discuss the patient's treatment protocol. This study uses a differences-in-differences study design with a propensity-score-matched control group. Medical and pharmaceutical claims data from 2005 to 2011 were used for analyses. Following the intervention, the use of opioids increased for the intervention group and there is little impact on medical spending. Counseling physicians about patients with high opioid utilization may focus more attention on their care, but did not impact short-term outcomes. More robust interventions may be needed to manage opioid use. While the increasing use of opioids is of growing concern around the world, curbing the utilization of these powerfully addictive narcotics has proved elusive. This study examines a prescribing guidelines intervention designed to reduce the prescription of opioids following an injury. The study finds that there was little change in the opioid utilization after the intervention, suggesting interventions along other parts of the prescribing pathway may be needed.


Psychologic, relational, and sexual functioning in women after surgical treatment of vulvar malignancy: a prospective controlled study.
Vulvectomy for vulvar malignancy can affect sexual functioning based on anatomic, physiologic, psychologic, and relational mechanisms. The aims of this study were to prospectively investigate sexual adjustment of women with vulvar malignancy during a follow-up period of 1 year after vulvectomy and to compare the results with healthy control women. In this prospective controlled study, participants completed the Beck Depression Inventory scale, World Health Organization-5 Well-being scale, Dyadic Adjustment Scale, Short Sexual Functioning Scale, and Specific Sexual Problems Questionnaire to assess various aspects of psychosocial and sexual functioning just before surgery, 6 months, and 1 year after treatment. Twenty-nine women with vulvar malignancy and 29 healthy controls completed the survey. Compared with the presurgery status, no significant differences were found in psychologic, relational, and sexual functioning in women after surgery for vulvar malignancy. Compared with healthy control women, women with vulvar malignancy reported significantly lower psychologic well-being and quality of partner relationship, both before and after treatment. Moreover, significantly more patients with vulvar malignancy reported preoperative and postoperatively sexual dysfunctions than healthy controls, including entry and deep dyspareunia, abdominal pain during intercourse, reduced ability to achieve orgasm, and reduced intensity of orgasm. This prospective study yielded no differences in psychosocial and sexual functioning for women with vulvar malignancy before and after vulvectomy. However, when compared with healthy controls, patients with vulvar malignancy are at high risk for sexual dysfunctions, both before and after surgical treatment.


Effect of Autologous Platelet-Rich Plasma Drops in the Treatment of Ocular Surface Disease.
Platelet rich plasma (PRP) is an autologous preparation that concentrates platelets in a small volume of plasma. The purpose of this study was to determine if PRP eye drops improved the symptoms and signs of ocular surface disease. A retrospective case series was conducted of patients who were prescribed PRP eye drops. Subjects were excluded if they did not have follow-up, underwent intraocular surgery prior to follow-up, received nerve growth factor treatments, or did not have a baseline examination with photography. Symptoms were assessed using the Ocular Surface Disease Index (OSDI). Patients also underwent a slit lamp exam, ocular surface staining with fluorescein and lissamine green, and Schirmer testing. The charts of 47 patients treated with PRP drops for ocular surface disease were reviewed. Sixty-four eyes of 32 patients were included in the study who had photographs of lissamine green staining taken at baseline and at follow-up. Thirteen patients (28%) had ocular graft-versus-host disease, 16 patients (34%) had Sjögren's syndrome, and 4 patients (8.5%) had rheumatoid arthritis. There was a statistically significant decrease in OSDI score from baseline to follow-up (39.5 vs 30.8 points, p = 0.02). Among the 64 eyes included, 9 (14%) had an improvement in conjunctival lissamine green staining, while 6 (9%) had an increase in staining at follow-up. Among the 20 eyes with Schirmer testing, there was a borderline significant increase in score from baseline to follow-up (5.9 vs 9.7, p = 0.06). Among the 44 eyes that had corneal fluorescein staining (CFS) reported, 8 (18.2%) had decreased staining and 2 (4.5%) had increased staining at follow-up. Treatment with PRP drops was associated with a significant improvement in symptoms in patients with ocular surface disease. Future larger prospective studies are needed to further evaluate the efficacy of PRP drops for treating ocular surface disease.


Pyridine versus acetonitrile coordination in rhodium-N-heterocyclic carbene square-planar complexes.
Experimental and theoretical studies on the factors that control the coordination chemistry of N-donor ligands in square-planar complexes of the type RhCl(NHC)L(1)L(2) (NHC = N-heterocyclic carbene) are presented. The dinuclear complexes [Rh(μ-Cl)(IPr)(η(2)-olefin)]2 {IPr = 1,3-bis-(2,6-diisopropylphenyl)imidazol-2-carbene} have been reacted with different combinations of ligands including pyridine, acetonitrile, 2-pyridylacetonitrile, triphenylphosphine, tricyclohexylphosphine, carbon monoxide or molecular oxygen. In addition, the reactivity of RhCl(IPr)(PPh3)2 has also been studied. Pyridine preferentially coordinates trans to the carbene ligand whereas π-acceptor ligands (olefin, CO or PPh3) are prone to bind cis to IPr and trans to chlorido, unless steric bulk hinders the coordination of the ligand (PCy3). In contrast, acetonitrile is more labile than pyridine but is able to form complexes coordinated cis-to-IPr. Molecular dioxygen also displaces the labile cyclooctene ligand in RhCl(IPr)(η(2)-coe)(py) to give a square-planar dioxygen adduct which can be transformed into a peroxo derivative by additional coordination of pyridine. Charge decomposition analysis (CDA) shows that σ-donation values are similar for coordination at cis- or trans-IPr positions, whereas efficient π-backbonding is significantly observed at cis position being the favoured coordination site for π-acceptor ligands. The Rh-IPr rotational barrier in a series of square-planar complexes has been analysed. It has been found that the main contribution is the steric hindrance of the ancillary ligand. The presence of a π-donor ligand such as chlorido slows down the dynamic process.


Deep learning tackles single-cell analysis-a survey of deep learning for scRNA-seq analysis.
Since its selection as the method of the year in 2013, single-cell technologies have become mature enough to provide answers to complex research questions. With the growth of single-cell profiling technologies, there has also been a significant increase in data collected from single-cell profilings, resulting in computational challenges to process these massive and complicated datasets. To address these challenges, deep learning (DL) is positioned as a competitive alternative for single-cell analyses besides the traditional machine learning approaches. Here, we survey a total of 25 DL algorithms and their applicability for a specific step in the single cell RNA-seq processing pipeline. Specifically, we establish a unified mathematical representation of variational autoencoder, autoencoder, generative adversarial network and supervised DL models, compare the training strategies and loss functions for these models, and relate the loss functions of these models to specific objectives of the data processing step. Such a presentation will allow readers to choose suitable algorithms for their particular objective at each step in the pipeline. We envision that this survey will serve as an important information portal for learning the application of DL for scRNA-seq analysis and inspire innovative uses of DL to address a broader range of new challenges in emerging multi-omics and spatial single-cell sequencing.


Autologous Chondrocyte Implantation to Isolated Patella Cartilage Defects.
Background Autologous chondrocyte implantation (ACI) is a durable treatment for patients with chondral defects. This study presents the comprehensive evaluation of patients with patella defects treated with ACI at medium- to long-term follow-up. Methods Thirty consecutive patients with isolated chondral lesions of the patella were enrolled prospectively. Primary outcome measures were validated patient reported outcome measures and objective magnetic resonance imaging. Results Nineteen of 30 patients underwent tibial tubercle osteotomy (TTO) to correct lateral maltracking in combination with soft tissue balancing. The defect sizes were large, averaging 4.7 ± 2.1 cm2 (range 2.2-30.0 cm2). Pidoriano/Fulkerson classification revealed that 3 defects were type II (lateral), 9 were type III (medial), and 18 were type IV (central/panpatella). Age at the time of surgery was 32 ± 10 years. At follow-up of 2 to 14 years, knee function was rated good to excellent in 25 (83%) patients, fair in 4 (13%) patients, and poor in 1 (3%) patient. Three patients failed treatment after a mean of 75 months (6.25 years). All 3 failures were Workers Compensation (WC) cases. They were older than the non-WC patients, 42 ± 6 years compared with the non-WC 28 ± 9 years ( P = 0.0019). Significant increases in all clinical and health utility outcome scores were seen. Magnetic resonance imaging demonstrated that the fill grade, surface and integrity of the repair tissue correlated with clinical scores. Conclusion ACI to isolated patella defects results in significant functional improvement at a minimum of 24 months, with the results remaining durable at latest follow-up of 15 years. Level of evidence Level 4.


Stealthy Secret Key Generation.
In order to make a warden, Willie, unaware of the existence of meaningful communications, there have been different schemes proposed including covert and stealth communications. When legitimate users have no channel advantage over Willie, the legitimate users may need additional secret keys to confuse Willie, if the stealth or covert communication is still possible. However, secret key generation (SKG) may raise Willie's attention since it has a public discussion, which is observable by Willie. To prevent Willie's attention, we consider the source model for SKG under a strong secrecy constraint, which has further to fulfill a stealth constraint. Our first contribution is that, if the stochastic dependence between the observations at Alice and Bob fulfills the strict more capable criterion with respect to the stochastic dependence between the observations at Alice and Willie or between Bob and Willie, then a positive stealthy secret key rate is identical to the one without the stealth constraint. Our second contribution is that, if the random variables observed at Alice, Bob, and Willie induced by the common random source form a Markov chain, then the key capacity of the source model SKG with the strong secrecy constraint and the stealth constraint is equal to the key capacity with the strong secrecy constraint, but without the stealth constraint. For the case of fast fading models, a sufficient condition for the existence of an equivalent model, which is degraded, is provided, based on stochastic orders. Furthermore, we present an example to illustrate our results.


[Effects of teriparatide and alendronate on bone mineral density of osteoporotic rats].
To investigate the effects of teriparatide (hPTH1-34, PTH) and alendronate (Alen) on bone turnover rate and bone mineral density (BMD) of ovariectomized (OVX) osteoporotic rats. 70 female 6-month-old Wistar rats were randomly divided into 7 groups: (1) baseline group: killed immediately as baseline controls; (2) sham operation group: injected subcutaneously with normal saline (NS) as normal controls; (3) OVXb group: underwent ovarietomy (OVX) and killed 6 weeks after OVX as pre-therapeutic controls; (4) OVXe group: injected with NS subcutaneously and then sacrificed 14 weeks after OVX as controls by the end of treatment; (5) PTH group: PTH 40 microg.kg(-1).d(-1) was administered; (6) Alen group: Alen 100 microg.kg(-1).d(-1) was administered; (7) A + P group: PTH 40 microg.kg(-1).d(-1) and Alen 100microg.kg(-1).d(-1) were administered. In groups 4 approximately 7, different medicines were injected subcutaneously QD 5 times per week from the 6th week to the 14th week after OVX and then the rats were killed and their right femurs, lumbar vertebrae, and samples of blood and urine were collected. Absorptometry was used to measure the BMD of the right femur and lumbar vertebrae. The serum calcium, phosphate, creatinine, alanine transaminase, and alkaline phosphatase (ALP) activity were measured by automatic biochemical analysis. The bone resorption marker urine deoxypyridinoline/creatinine (UDpd/Cr) level was measured by enzyme-linked immuosorbent assay. Six weeks after OVX the ALP and UDpd/Cr levels in the OVXb group were 101 U/L +/- 59 U/L and (118 +/- 32) x 10(-6) respectively, both significantly higher than those of the baseline group (58 U/L +/- 10 U/L and (48 +/- 34) x 10(-6) respectively, both P < 0.01) and the BMD results of the OVXb group were all significantly lower than those in the baseline group (all P < 0.01), which indicated that an OVX osteoporotic rat model was established successfully. The ALP and UDpd/Cr levels of the Alen group were 61 U/L +/- 28 U/L and (17 +/- 39) x 10(-6), significantly lower than those of the PTH group 120 U/L +/- 36 U/L and (111 +/- 26) x 10(-6) respectively, both P < 0.01) and the UDpd/Cr levels of the A + P group were between those of the Alen group and those of the PTH group. The BMD levels of the femur and lumbar vertebrae of the PTH, Alen, and A + P groups were all significantly higher than those of the control groups (all P < 0.01), and were similar to or higher than those of the sham operation group without significant differences between the PTH and Alen groups. The BMD level of the lumber vertebrae of the A + P group were significantly higher than those in the PTH group (all P < 0.05), and the femoral BMD results of the A + P group were significantly higher than those in the PTH and Alen groups (all P < 0.01). PTH and Alen are all effective on osteoporosis. In particular, the combination of PTH and Alen is more effective on increasing the BMD level.


Contributions of long-term research and time-series observations to marine ecology and biogeochemistry.
Time-series observations form a critical element of oceanography. New interdisciplinary efforts launched in the past two decades complement the few earlier, longer-running time series to build a better, though still poorly resolved, picture of lower-frequency ocean variability, the climate processes that drive variability, and the implications for food web dynamics, carbon storage, and climate feedbacks. Time series also enlarge our understanding of ecological processes and are integral for improving models of physical-biogeochemical-ecological ocean dynamics. The major time-series observatories go well beyond simple monitoring of core ocean properties, although that important activity forms the critical center of all time-series efforts. Modern ocean time series have major process and experimental components, entrain ancillary programs, and have integrated modeling programs for deriving a better understanding of the observations and the changing, three-dimensional ocean in which the observatories are embedded.


Human phagocytic cell responses to Scedosporium apiospermum (Pseudallescheria boydii): variable susceptibility to oxidative injury.
Scedosporium apiospermum (Pseudallescheria boydii) is an emerging opportunistic filamentous fungus that causes serious infections in both immunocompetent and immunocompromised patients. To gain insight into the immunopathogenesis of infections due to S. apiospermum, the antifungal activities of human polymorphonuclear leukocytes (PMNs), mononuclear leukocytes (MNCs), and monocyte-derived macrophages (MDMs) against two clinical isolates of S. apiospermum were evaluated. Isolate SA54A was amphotericin B resistant and was the cause of a fatal disseminated infection. Isolate SA1216 (cultured from a successfully treated localized subcutaneous infection) was susceptible to amphotericin B. MDMs exhibited similar phagocytic activities against conidia of both isolates. However, PMNs and MNCs responded differently to the hyphae of these two isolates. Serum opsonization of hyphae resulted in a higher level of superoxide anion (O(2)(-)) release by PMNs in response to SA54A (amphotericin B resistant) than that seen in response to SA1216 (amphotericin B susceptible; P < 0.001). Despite this increased O(2)(-) production, PMNs and MNCs induced less hyphal damage to SA54A than to SA1216 (P < 0.001). To investigate the potential mechanisms responsible for these differences, hyphal damage was evaluated in the presence of antifungal oxidative metabolites as well as in the presence of a series of inhibitors and scavengers of antifungal PMN function. Mannose, catalase, superoxide dismutase, dimethyl sulfoxide, and heparin had no effect on PMN-induced hyphal damage to either of the two isolates. However, azide, which inhibits PMN myeloperoxidase activity, significantly reduced hyphal damage to SA1216 (P < 0.01) but not to SA54A. Hyphae of SA1216 were slightly more susceptible to oxidative pathway products, particularly HOCl, than those of SA54A. Thus, S. apiospermum is susceptible to antifungal phagocytic function to various degrees. The selective inhibitory pattern of azide with respect to hyphal damage and the parallel susceptibility to HOCl suggests an important difference in susceptibilities to myeloperoxidase products that may be related to the various levels of pathogenicity and amphotericin B resistance of S. apiospermum.


Functional polymorphisms in two pre-microRNAs and cancer risk: a meta-analysis.
Since the identification of two functional polymorphisms in pre-miRNAs ﹛miR-146a rs2910164 and miR-196a2 rsll614913), a number of studies were published in the past several years to evaluate the associations between the two SNPs and cancer risk. However, the findings remain conflicting rather than conclusive. This meta-analysis included 12 published case-control studies, 5,916 cancer patients and 6,869 control subjects for SNP rs2910164, and 6,574 cases and 7,601 controls for SNP rsll614913. The allele C of rsll614913 was associated with a significantly increased risk of overall cancers (CC vs. TT: OR=1.18; 95%CI: 1.02-1.37; CT vs. TT: OR=1.11; 95% CI: 1.02-1.21; CC/CT vs. TT: OR=1.13; 95%CI: 1.04-1.23). However, we failed to find main effects for rs2910164 on overall cancer risk in different genetic models tested, while significantly increased risk was evident among cancers other than breast (GG/GC vs. CC: OR=1.30, 95%CI: 1.03-1.64; between study heterogeneity test: P = 0.007). The two functional SNPs may represent tissue specific effect on cancer susceptibility; however, additional well-designed large studies are required for the validation of the associations.


Molecular characterization of pigmented and nonpigmented isolates of Mycobacterium avium subsp. paratuberculosis.
Five pigmented isolates of Mycobacterium avium subsp. paratuberculosis were examined by pulsed-field gel electrophoresis (PFGE), IS900 restriction fragment length polymorphism (IS900-RFLP), and IS1311 polymorphism analysis using PCR. All of the pigmented isolates exhibited one of three distinct PFGE profiles with SnaBI, designated 9, 10, and 11, and with SpeI, designated 7, 8, and 9, which generated three multiplex profiles designated [9-7], [10-8], and [11-9]. All of the pigmented isolates had the same IS900-RFLP BstEII and PvuII profiles. The IS900-RFLP BstEII profile was new, but the IS900-RFLP PvuII profile corresponded to PvuII type 6 of a sheep strain described by Cousins and colleagues (D. V. Cousins, S. N. Williams, A. Hope, and G. J. Eamens, Aust. Vet. J. 78:184-190, 2000). IS1311-PCR analysis typed all of the pigmented isolates as sheep (S) strains. The genetic relationship between pigmented and nonpigmented isolates was investigated by using multiplex PFGE data from the analysis of both the 5 pigmented isolates and 88 nonpigmented isolates of M. avium subsp. paratuberculosis from a variety of host species and geographic locations. It was possible to classify the isolates into two distinct types designated type I, comprising the pigmented isolates, and type II, comprising the nonpigmented isolates, which exhibit a very broad host range.


Weight-depression association in a high-risk maternal population.
Both maternal depression and overweight carry potential adverse effects on perinatal health and are inter-related. We explored the relationship between weight and depressive symptoms in a high-risk maternal population. We administered the Edinburgh Postnatal Depression Scale (EPDS) to all women attending the Motherisk Clinic at The Hospital for Sick Children between October 2007 and April 2010. We explored possible associations between the EPDS scores, maternal weight and other characteristics. The study population consisted of 352 women, 43.7% of whom were pregnant, with a variety of exposures. Twenty seven percent of the study population had diagnosed depression. Depressed women had a significantly higher body weight compared to non-depressed women (p = 0.016). The same finding remained significant in the pregnant sub-group. The EPDS score, for the entire study population, was significantly correlated with body weight (p = 0.027). Use of antidepressants was an independent predictor of maternal weight in a multivariate regression analysis. There is a strong association between maternal weight and depressive symptoms, whether diagnosed or not. Antidepressant therapy is an independent predictor of maternal weight. Since both depression and maternal overweight may adversely affect pregnancy outcome, and are treatable, addressing both is essential for optimal pregnancy management.


[Neuropsychiatric disorders in multiple sclerosis].
A comprehensive randomized study involved 138 patients with multiple sclerosis (MS). Clinical follow-up of the patients was supplemented by computer-aided tomography in 40 cases and electroencephalo-, rheoencephalo- and echoencephalography in 25 cases. Twenty-five patients were subjected to experimental and psychological examination. Follow-up for as long as 4 years was conducted in 56 patients. The main syndromes of psychic disorders in MS patients were as follows: neurosis-like disturbances (asthenic, hysteriform and obsessive syndromes), affective disturbances (apathic and anxiety depression, euphoria without decreased intellect), as well as organic oligophrenia, psychotic states and epileptiform syndrome in the initial status. Structural changes in the brain were found to be the principal factor in the genesis of the described disorders. The authors propose a differential approach to the treatment of the identified disorders including the use of tranquilizers, antidepressants, neuroleptics and nootropic drugs, as well as methods of rational psychotherapy.


[New developments in pediatric abdominal MRI].
Ultrasound is the first choice imaging modality in pediatric abdominal pathologies. In recent years, MRI is being increasingly used for complimentary information in the domain of GI and GU imaging as well as in biliary tract imaging. In the radiological workup of children, radiation issues as well as noninvasive techniques are important to consider in particular in young infants. A pediatric setting with specialized practitioners (to reassure the child and to sedate him if necessary) should be helpful in acquiring satisfying MR images even in small children.


The impact of cardiovascular risk factors on aortic stiffness and wave reflections depends on age: the Anglo-Cardiff Collaborative Trial (ACCT III).
Ageing exerts differential effects on arterial stiffness and wave reflections. However, the impact of cardiovascular risk factors on arterial stiffness and wave reflections and, particularly, how such effects are influenced by ageing has not been assessed within a single large population, covering a sufficiently wide age range. Therefore, we determined the extent to which age alters the impact of traditional cardiovascular risk factors on arterial stiffness and wave reflections. Aortic stiffness and wave reflections were assessed in 4421 individuals (age range 18 to 92 years). When treated as continuous variables, clinic systolic, diastolic, and pulse pressures and glucose levels were independently associated with stiffness, and, with the exception of diastolic pressure, these associations were more marked in older individuals. In contrast, clinic systolic and diastolic pressures and smoking were independently associated with wave reflections, with stronger associations observed in younger individuals. The impact of traditional cardiovascular risk factors on arterial stiffness and wave reflections is strongly dependent on age and is largely driven by blood pressure. Additional studies are required to assess the impact of these arterial measures on cardiovascular outcome within a single population.


Alcohol exposure during adulthood induces neuronal and astroglial alterations in the hippocampal CA-1 area.
Ethanol (ETOH) exposure can result in neuronal damage. Astrocytes are morphologic and functionally related to neurons, and astrocyte-neuron interactions provide strategic sites for the actions of many chemical compounds. The aim of the present work was to study the morphologic alterations of glial cells and neurons on the hippocampus after long-term ETOH exposure using GFAP and S-100 beta protein, neurofilaments of 200 kDa (Nf200), MAP2, and serotonin transporter (5HT-T) immunocytochemical staining. Adult Wistar male rats (200-250 g) were orally exposed to ETOH (6.6% v/v ad libitum) for 6 weeks. Control rats received water ad libitum. Brain sections from control and exposed rats were processed by immunocytochemistry. After ETOH exposure we observed in the CA1 area of the hippocampus: (1) an important astroglial reaction evidenced by the presence of GFAP(+) reactive astrocytes; (2) an increase in S-100 beta immunostaining in astroglial cells; and (3) a decrease in Nf200, 5HT-T, and MAP2 immunoreactivity. The current study provides evidence that long-term ETOH exposure induces alterations in the neuronal cytoskeleton and an astroglial reaction, which is a common response to brain injury and may promote functional recovery of the nervous system, as by the release of glial-derived trophic factors (such as S-100 beta) that promote cell survival and neurite growth.


Impact of the MLC on the MRI field distortion of a prototype MRI-linac.
To cope with intrafraction tumor motion, integrated MRI-linac systems for real-time image guidance are currently under development. The multileaf collimator (MLC) is a key component in every state-of-the-art radiotherapy treatment system, allowing for accurate field shaping and tumor tracking. This work quantifies the magnetic impact of a widely used MLC on the MRI field homogeneity for such a modality. The finite element method was employed to model a MRI-linac assembly comprised of a 1.0 T split-bore MRI magnet and the key ferromagnetic components of a Varian Millennium 120 MLC, namely, the leaves and motors. Full 3D magnetic field maps of the system were generated. From these field maps, the peak-to-peak distortion within the MRI imaging volume was evaluated over a 30 cm diameter sphere volume (DSV) around the isocenter and compared to a maximum preshim inhomogeneity of 300 μT. Five parametric studies were performed: (1) The source-to-isocenter distance (SID) was varied from 100 to 200 cm, to span the range of a compact system to that with lower magnetic coupling. (2) The MLC model was changed from leaves only to leaves with motors, to determine the contribution to the total distortion caused by MLC leaves and motors separately. (3) The system was configured in the inline or perpendicular orientation, i.e., the linac treatment beam was oriented parallel or perpendicular to the magnetic field direction. (4) The treatment field size was varied from 0 × 0 to 20×20 cm(2), to span the range of clinical treatment fields. (5) The coil currents were scaled linearly to produce magnetic field strengths B0 of 0.5, 1.0, and 1.5 T, to estimate how the MLC impact changes with B0. (1) The MLC-induced MRI field distortion fell continuously with increasing SID. (2) MLC leaves and motors were found to contribute to the distortion in approximately equal measure. (3) Due to faster falloff of the fringe field, the field distortion was generally smaller in the perpendicular beam orientation. The peak-to-peak DSV distortion was below 300 μT at SID≥130 cm (perpendicular) and SID≥140 cm (inline) for the 1.0 T design. (4) The simulation of different treatment fields was identified to cause dynamic changes in the field distribution. However, the estimated residual distortion was below 1.2 mm geometric distortion at SID≥120 cm (perpendicular) and SID≥130 cm (inline) for a 10 mT/m frequency-encoding gradient. (5) Due to magnetic saturation of the MLC materials, the field distortion remained constant at B0>1.0 T. This work shows that the MRI field distortions caused by the MLC cannot be ignored and must be thoroughly investigated for any MRI-linac system. The numeric distortion values obtained for our 1.0 T magnet may vary for other magnet designs with substantially different fringe fields, however the concept of modest increases in the SID to reduce the distortion to a shimmable level is generally applicable.


Carbolong Chemistry: A Story of Carbon Chain Ligands and Transition Metals.
The construction of metal-carbon bonds is one of the most important issues of organometallic chemistry. However, the chelation of polydentate ligands to a metal via several metal-carbon bonds is rare. Metallapentalyne, which can be viewed as a 7-carbon (7C) chain coordinated to a metal via three metal-carbon bonds, was first reported in 2013. Although metallapentalyne contains a metal-carbon triple bond in a five-membered ring (5MR) and the bond angle around the carbyne carbon is only 129.5°, metallapentalyne exhibits excellent stability to air, moisture, and heat. Metallapentalyne possesses the rare planar Möbius aromaticity, which is in sharp contrast to the Hückel antiaromaticity in pentalyne. The metal fragment not only relieves the large ring strain present in pentalyne but also results in the transformation of the antiaromaticity in pentalyne to aromaticity in metallapentalyne. With the extension of the carbon chain from 7 to 12 carbon atoms, a series of novel polycyclic frameworks were constructed via the formation of several metal-carbon bonds. Some interesting phenomena were observed for these complexes. For instance, (1) the carbyne carbon of the 7C framework could react with both nucleophilic and electrophilic reagents, leading to the formation of 16- and 18-electron metallapentalenes; (2) σ aromaticity was first observed in an unsaturated system in the 8C framework; (3) two classical antiaromatic frameworks, cyclobutadiene and pentalene, were simultaneously stabilized in the 9C framework for the first time; (4) three fused 5MRs bridged by a metal are coplanar in the 10C framework; (5) the first [2 + 2 + 2] cycloaddition of a late transition metal carbyne complex with alkynes was realized during the construction of an 11C framework; (6) the largest number of carbon atoms coordinated to a metal atom in the equatorial plane was observed in the 12C framework; and (7) sharing of the transition metal by multiple aromatic units has seldom been observed in the metalla-aromatics. Therefore, the term carbolong chemistry has been used to describe the chemistry of these novel frameworks. More interestingly, carbolong complexes exhibit diverse properties, which could lead to potential future applications. As the discovery and creation of molecular fragments lead to advancements in chemistry, medical science, and materials chemistry, these novel polydentate carbon chain chelates might have important influences in these fields due to their facile synthesis, high stability, and unique properties.


Heterogeneous Treatment Effects of Intensive Glycemic Control on Kidney Microvascular Outcomes and Mortality in ACCORD.
Clear criteria to individualize glycemic targets in patients with type II diabetes are lacking. In this post-hoc analysis of the Action to Control Cardiovascular Risk in Diabetes trial (ACCORD), we evaluate whether the kidney failure risk equation (KFRE) can identify patients for whom intensive glycemic control confers more benefit in preventing kidney microvascular outcomes. We divided the ACCORD trial population into quartiles based on 5-year kidney failure risk using the KFRE. We estimated conditional treatment effects within each quartile and compared them to the average treatment effect in the trial. The treatment effects of interest were the 7-year restricted-mean-survival-time (RMST) differences between intensive and standard glycemic control arms on (1) time-to-first development of severely elevated albuminuria or kidney failure and (2) all-cause mortality. We found evidence that the effect of intensive glycemic control on kidney microvascular outcomes and all-cause mortality varies with baseline risk of kidney failure. Patients with elevated baseline risk of kidney failure derived the most from intensive glycemic control in reducing kidney microvascular outcomes (7-year RMST difference of 114.8 (95% CI 58.1, 176.4)v. 48.4 (25.3, 69.6) days in the entire trial population) However, this same patient group also experienced a shorter time to death (7-year RMST difference of -56.7 (-100.2, -17.5) v. -23.6 (-42.2, -6.6)days). We found evidence of heterogenous treatment effects of intensive glycemic control on kidney microvascular outcomes in ACCORD as a function of predicted baseline risk of kidney failure. Patients with higher kidney failure risk experienced the most pronounced reduction in kidney microvascular outcomes but also experienced the highest risk of all-cause mortality.


Evaluation of Peripheral Perfusion in the Presence of Plantar Heel Ulcerations Status After Transmetatarsal Amputation With Achilles Tendon Lengthening.
The objective of this study is to evaluate peripheral perfusion in patients who developed plantar heel ulcerations status after transmetatarsal amputation and Achilles tendon lengthening. Peripheral perfusion was assessed via contrast angiography of the 3 crural vessels (anterior tibial, posterior tibial, and peroneal arteries), as well as intact heel blush and plantar arch. The secondary objective is to correlate the arterial flow to time to develop heel ulceration and incidence of minor and major lower-extremity amputation. Diagnostic angiography without intervention was performed on 40% of patients (4/10), and interventional angiography was performed on 60% of patients (6/10). In-line flow was present in 0% (0/10) of the peroneal arteries, 60% (6/10) of the anterior tibial arteries, and 70% (7/10) of the posterior tibial arteries. Heel angiographic contrast blush was present in 60% (6/10), and intact plantar arch was present in 60% (6/10). Patients developed heel ulcerations at a mean time of 7.6 months (range 0.7 to 41.2) postoperatively. The incidence of major lower-extremity amputation was 30% (3/10), with a mean time of 5.2 months (range 3.5 to 8.3) from time of heel wound development. No amputation occurred in 6 patients (60%). Among them, intact anterior tibial inline arterial flow was present in 3, intact posterior tibial inline arterial flow was present in 6, and heel blush was present in 5. Our results demonstrate that an open calcaneal branch of the posterior tibial artery is sufficient to heal plantar heel ulcerations to potentially increase rates of limb salvage.


Outcomes of surgical aortic valve replacement in moderate risk patients: implications for determination of equipoise in the transcatheter era.
To determine the contemporary outcomes of surgical aortic valve replacement (SAVR) in a moderate surgical risk population. We studied 502 consecutive adults who had undergone isolated SAVR from January 2002 to June 2011 for severe aortic valve stenosis with a Society of Thoracic Surgery predicted risk of mortality of 4% to 8%. We included concomitant coronary artery bypass and aortic annular enlargement but not other concomitant procedures. The updated Valve Academic Research Consortium definitions were used, as appropriate. The median age was 80 years (range, 49-96), 323 (64.3%) had New York Heart Association class III-IV symptoms, and 101 (20.1%) had undergone previous coronary artery bypass grafting. The mean predicted risk of mortality was 5.6%. Concomitant coronary artery bypass grafting was performed in 270 (53.8%). Re-exploration for bleeding occurred in 29 (5.8%), stroke in 9 (1.8%), and vascular complications in 2 (0.4%). In the cohort, 14 early deaths (2.8%) occurred. During follow-up (1174 days), 175 patients died. Using multivariate logistic regression analysis, the significant independent predictors of mid-term death included chronic pulmonary disease (hazard ratio, 2.00, 95% confidence interval, 1.41-2.84; P < .001), peripheral vascular disease (hazard ratio, 1.58; 95% confidence interval, 1.05-2.37; P = .029), and atrial fibrillation (hazard ratio, 1.75; 95% confidence interval, 1.16-2.65; P = .008). SAVR in moderate-risk patients is currently performed with one half of the early predicted risk (2.8%) and a low likelihood of complications, including a 1.8% incidence of stroke. Patients counseled for randomization to transcatheter aortic valve insertion should be informed of the excellent early to mid-term outcomes of SAVR, particularly those without pulmonary impairment, peripheral vascular disease, or atrial fibrillation.


Handgrip Strength Is Associated With Treatment Modifications During Neoadjuvant Chemoradiation in Patients With Esophageal Cancer.
It has been shown that early nutrition intervention improves nutrition status (NS) and treatment tolerance in patients with esophageal cancer. However, it remains unknown whether pretreatment parameters of NS are associated with treatment modifications (TMs) during neoadjuvant chemoradiation (CR) in patients who are intensively nutritionally supervised during treatment. All outpatients with esophageal cancer who were scheduled for CR in the VU medical center from 2006-2015 were included. NS was assessed by body mass index (BMI), weight loss in the past 6 months (WL), fat mass index (FMI) and fat-free mass index (FFMI), handgrip strength (HGS), and energy/protein intake. Logistic regression analyses, adjusted for age, sex, previous tumor, tumor stage, and physical status, were applied. TMs were defined as delay, dose reduction or discontinuation of chemotherapy and/or radiotherapy, hospitalization, or mortality (yes/no). In total, 162 patients were included (73% male; mean age 65 ± 9 years). Mean BMI was 25.1 ± 4.5 kg/m2, and WL was 4.8 ± 5.1 kg. HGS and FFMI were below the 10th percentile of reference values in 21 and 37 patients, respectively. Thirty-five (22%) patients experienced at least 1 TM during CR; unplanned hospitalization (n = 18, 11%) was the most prevalent. After adjustments for confounders, only HGS was statistically significantly associated with TMs (odds ratio, 0.93; 95% confidence interval, 0.88-1.00). In this group of intensively supervised patients with esophageal cancer, pretreatment parameters of NS had little influence on TMs during CR. Only a lower HGS was associated with TMs.


Statin therapy in patients with atypical chest pain and mild-to-moderate coronary stenosis on 64-slice multidetector coronary computed tomography; a retrospective propensity score matching analysis.
The effect of computed tomography (CT)-guided statin therapy on patients with atypical chest pain and mild-to-moderate coronary artery disease has not been elucidated yet. A total of 1,952 patients who had 1-69 % stenosis on CT were reviewed retrospectively. After propensity score matching, 643 patients who were prescribed statins after CT (statin users) and 643 patients without statin therapy (statin non-users) were compared. Major cardiovascular events included all-cause death, acute coronary syndrome and stroke. During a median of 42 months' follow-up, all-cause death was reported in 17 patients (1.3 %), of whom 6 (0.9 %) were statin users and 11 (1.7 %) statin nonusers. Major cardiovascular events developed in 6.1 % in the statin user group and 5.6 % in the statin non-users (P = 0.812). When evaluated according to plaque subtypes, statins showed significant benefit in patients who had non-calcified or mixed plaque (HR 0.47, 95 % CI 0.22-1.01, P = 0.047). However, in patients with calcified plaques, statins had no benefit in reducing adverse events (P = 0.620). In most patients with mild-to-moderate coronary artery stenosis on CT, statin therapy has no beneficial effect on reducing adverse events. However, in patients with non-calcified or mixed plaques, statin therapy showed a significant benefit. • Multidetector CT now identifies numerous subjects with mild-to-moderate coronary stenosis. • Statin therapy has little beneficial effect on patients with calcified plaques. • However, statins reduce adverse events in those with non-calcified or mixed plaques.


Advances in pharmacokinetic-pharmacodynamic modelling for pediatric drug development: extrapolations and exposure-response analyses.
Pharmacokinetic (PK)-Pharmacodynamic (PD) and exposure-response (E-R) modeling are critical parts of pediatric drug development. By integrating available knowledge and supportive data to support the design of future studies and pediatric dose selection, these techniques increase the efficiency of pediatric drug development and lowers the risk of exposing pediatric study participants to suboptimal or unsafe dose regimens. The role of PK, PK-PD and E-R modeling within pediatric drug development and pediatric dose selection is discussed. These models allow investigation of the impact of age and bodyweight on PK and PD in children, despite the often sparse data on the pediatric population. Also discussed is how E-R analyses strengthen the evidence basis to support (full or partial) extrapolation of drug efficacy from adults to children, and between different pediatric age groups. Accelerated pediatric drug development and optimized pediatric dosing guidelines are expected from three future developments: (1) Increased focus on E-R modeling of currently approved drugs in children resulting in (novel) E-R modeling techniques and best practices, (2) increased use of real-world data for E-R (3) increased implementation of available population PK and E-R information in pediatric drug dosing guidelines.


Interictal Spike and Loss of Hippocampal Theta Rhythm Recorded by Deep Brain Electrodes during Epileptogenesis.
Epileptogenesis is the gradual dynamic process that progressively led to epilepsy, going through the latent stage to the chronic stage. During epileptogenesis, how the abnormal discharges make theta rhythm loss in the deep brain remains not clear. In this paper, a loss of theta rhythm was estimated based on time-frequency power using the longitudinal electroencephalography (EEG), recorded by deep brain electrodes (e.g., the intracortical microelectrodes such as stereo-EEG electrodes) with monitored epileptic spikes in a rat from the first region in the hippocampal circuit. Deep-brain EEG was collected from the period between adjacent sporadic interictal spikes (lasting 3.56 s-35.38 s) to the recovery period without spikes by videos while the rats were performing exploration. We found that loss of theta rhythm became more serious during the period between adjacent interictal spikes than during the recovery period without spike, and during epileptogenesis, more loss was observed at the acute stage than the chronic stage. We concluded that the emergence of the interictal spike was the direct cause of loss of theta rhythm, and the inhibitory effect of the interictal spike on ongoing theta rhythm was persistent as well as time dependent during epileptogenesis. With the help of the intracortical microelectrodes, this study provides a temporary proof of interictal spikes to produce ongoing theta rhythm loss, suggesting that the interictal spikes could correlate with the epileptogenesis process, display a time-dependent feature, and might be a potential biomarker to evaluate the deficits in theta-related memory in the brain.


Fat Infiltration of Multifidus Muscle Is Correlated with Neck Disability in Patients with Non-Specific Chronic Neck Pain.
Background: Chronic non-specific neck pain (CINP) is common, but the etiology remains unclear. This study aimed to examine the relationship between cervical muscle composition (cervical multifidus and longus capitis/longus colli), morphometry, range of movement, muscle function, and disability severity (Neck Disability Index) in patients with CINP. Methods: From September 2020 to July 2021, subjects underwent cervical MRI and clinical tests (cervical range of motion, cranio-cervical flexion test, neck flexor, and extensor muscle endurance). MRI analysis comprised muscle cross-sectional area, volume, and fat infiltration of multifidus and longus colli between C4 and C7 levels. Results: Twenty-five participants were included. Multiple linear regression analysis indicated that NDI was positively correlated with the volume percentage of fat infiltration of the multifidus (B = 0.496), negatively correlated with fat-free muscle volume of the multifidus normalized by subject height (B = −0.230), and accounted for 32% of the variance. There was no relationship between neck disability and longus capitis/longus colli morphology. We also found no relationship between neck disability scores, neck flexor or extensor muscle endurance, or the outcome motor control test of craniocervical flexion (p > 0.05). Conclusions: Neck disability was moderately correlated with the percentage of fat volume in the multifidus muscle and fat-free volume of the multifidus. There was no relationship between NDI scores and muscle function test outcomes or any fat or volume measures pertaining to the longus colli muscle.


[Pituitary macroadenoma associated with pulmonary and cutaneous sarcoidosis--a clinical case].
Sarcoidosis is a granulomatous disease of unknown etiology that can affect all organs and systems, including the central nervous system in approximately 5% of patients. Although the hypothalamo-hypophyseal system may be one of the areas affected by neurosarcoidosis, pseudotumoral lesions are very rare. This paper reports the case of a 42-year-old male Caucasian patient followed by the Pneumology and Dermatology services for pulmonary and cutaneous sarcoidosis. Corticotherapy was initiated five months from diagnosis and the patient showed clear clinical and imagiological signs of improvement. In the following two months, the patient experienced visual disturbances and a slight decrease in libido, but denied having other symptoms associated with hypothalamo-hypophyseal hypofunction. Laboratorial evaluation (basal determinations and stimulation tests) revealed panhypopituitarism. The EC-NMR showed a bulky intrasellar lesion extending into the suprasellar and right parasellar regions, with evidence of optic chiasm compression, erosion of the floor of the sella and cavernous sinus invasion. Campimetry showed a bitemporal hemianopsia. For the purposes of chiasmatic decompression and histological study of the lesion the patient underwent a right frontal craniotomy, with a subtotal resection of the hypophyseal lesion. The histological diagnosis revealed a pituitary adenoma with no immunohistochemical expression. The patient began radiotherapy six months after surgery. Although today's diagnostic tools allow for a high degree of accuracy, hypophyseal lesions still present problems to the endocrinologist as their identification is essential for determining the appropriate treatment. At times the final diagnosis is only achieved after a histological identification of the lesion (biopsy/surgery). It should be noted that the described cases of association between sarcoidosis and hypophyseal adenoma are very rare, making the differential diagnosis with neurosarcoidosis difficult--a condition which has a preferential medical approach and a different prognosis.


Neurogram recording during acute inflammation in the rat hind paw.
Electrophysiological recording was conducted using the intact tibiotarsal nerve of the left hind leg of adult male rats before and after subplantar injections of three different phlogistic agents or saline vehicle in the left hind paw. In three-hour recordings, peak neural activity as activated by 5 g of pressure to the injected paw was reached in 90 min (dextran), 120 min (brewer's yeast) and 150 min (carrageenan). The least neural hyperactivity was seen with dextran, while yeast and carrageenan produced comparably high degrees of hyperactivity. Neurograms were also studied in rats receiving orally administered prototype anti-inflammatory agents or chlorpromazine 1 hr before carrageenan was injected pedally. Chlorpromazine HCl pretreatment (100 mg/kg) exerted the greatest protective effect with the nadir of neural activity seen at 90-120 min. The nadir for phenylbutazone (100 mg/kg) was at 60-120 min, indomethacin (10 mg/kg) at 60-90 min and aspirin (300 mg/kg) at 45-90 min. Despite these temporal differences, the protective effects of these three anti-inflammatory agents were statistically equivalent at the doses tested. Hydrocortisone alcohol (20 mg/kg) provided a significant reduction in hyperactivity at 30-60 min but the duration was much shorter than the other agents which showed protective effects through to the end of the 180-min observation period.


Tree frog adhesion biomimetics: opportunities for the development of new, smart adhesives that adhere under wet conditions.
Enlarged adhesive toe pads on the tip of each digit allow tree frogs to climb smooth vertical and overhanging surfaces, and are effective in generating reversible adhesion under both dry and wet conditions. In this review, we discuss the complexities of the structure of tree frog toe pads in relation to their function and review their biomimetic potential. Of particular importance are the (largely) hexagonal epithelial cells surrounded by deep channels that cover the surface of each toe pad and the array of nanopillars on their surface. Fluid secreted by the pads covers the surface of each pad, so the pads adhere by wet adhesion, involving both capillarity and viscosity-dependent forces. The fabrication and testing of toe pad mimics are challenging, but valuable both for testing hypotheses concerning tree frog toe pad function and for developing toe pad mimics. Initial mimics involved the fabrication of hexagonal pillars mimicking the toe pad epithelial structure. More recent ones additionally replicate the nanostructures on their surface. Finally we describe some of the biomimetic applications that have been developed from toe pad mimics, which include both bioinspired adhesives and friction-generating devices. This article is part of the theme issue 'Bioinspired materials and surfaces for green science and technology (part 2)'.


Comparison of full- and partial-thickness autogenous skin transplantation in dogs: a pilot study.
Thin partial-thickness (0.063 cm), medium (0.127 cm) partial-thickness, and full-thickness skin autografts were transplanted to surgically created granulating foreleg wounds of dogs. Thin partial-thickness grafts had an 89% survival, medium partial-thickness grafts had 47% survival, and full-thickness grafts had a 58% survival. Of the successful grafts, only the thin partial-thickness grafts did not grow adequate hair after transplantation.


Computer Analysis of the Nuclear Test Ban Treaty.
Experiments were undertaken to determine the applicability of a computer program for automatic syntactic analysis to the systematic discovery of ambiguities in textual material. Specific application of this program was made to portions of the Nuclear Test Ban Treaty. Results, though promising, indicate that such applications are not now economically feasible for large volumes of text.


Quantification by Ultrafiltration and Immunofixation Electrophoresis Testing for Monoclonal Serum Free Light Chains.
Measurement of monoclonal immunoglobulins is a reliable estimate of the plasma cell tumor mass. About 15% of plasma cell myelomas secrete light chains only. The concentration of serum free light chains is insufficient evidence of the monoclonal light chain burden. A sensitive quantitative estimate of serum free monoclonal light chains could be useful for monitoring patients with light chain myeloma. We describe such an assay that does not require mass-spectrometry equipment or expertise. Serum specimens from patients with known light chain myelomas and controls were subjected to ultrafiltration through a membrane with pore size of 50 kDa. The filtrate was concentrated and tested by immunofixation electrophoresis. The relative area under the monoclonal peak, compared to that of the total involved light chain composition, was estimated by densitometric scanning of immunofixation gels. The proportion of the area occupied by the monoclonal peak in representative densitometric scans was used to arrive at the total serum concentration of the monoclonal serum free light chains. Using an ultracentrifugation and concentration process, monoclonal serum free light chains were detectable, along with polyclonal light chains, in all 10 patients with active light chain myelomas. Monoclonal light chains were identified in serum specimens that did not reveal monoclonal light chains by conventional immunofixation electrophoresis. The limit of detection by this method was 1.0 mg/L of monoclonal serum free light chains. The method described here is simple enough to be implemented in academic medical center clinical laboratories and does not require special reagents, equipment, or expertise. Even though urine examination is the preferred method for the diagnosis of light chain plasma cell myelomas, measurement of the concentration of serum free light chains provides a convenient, albeit inadequate, way to monitor the course of disease. The method described here allows effective electrophoretic differentiation of monoclonal serum free light chain from polyclonal serum free light chains and provides a quantitation of the monoclonal serum free light chains in monitoring light chain monoclonal gammopathies.


Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.
The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. In a multicentre, placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea. Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.


Human Papilloma Viruses and Breast Cancer.
Human papillomaviruses (HPV) may have a role in some breast cancers. The purpose of this study is to fill important gaps in the evidence. These gaps are: (i) confirmation of the presence of high risk for cancer HPVs in breast cancers, (ii) evidence of HPV infections in benign breast tissues prior to the development of HPV-positive breast cancer in the same patients, (iii) evidence that HPVs are biologically active and not harmless passengers in breast cancer. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to identify HPV RNA sequences in breast cancers. We also conducted a retrospective cohort study based on polymerase chain reaction (PCR) analyses to identify HPVs in archival specimens from Australian women with benign breast biopsies who later developed breast cancer. To assess whether HPVs in breast cancer were biologically active, the expression of the oncogenic protein HPV E7 was assessed by immunohistochemistry (IHC). Thirty (3.5%) low-risk and 20 (2.3%) high-risk HPV types were identified in 855 breast cancers from the TCGA database. The high risk types were HPV 18 (48%), HPV 113 (24%), HPV 16 (10%), HPV 52 (10%). Data from the PCR cohort study indicated that HPV type 18 was the most common type identified in breast cancer specimens (55% of 40 breast cancer specimens) followed by HPV 16 (13%). The same HPV type was identified in both the benign and subsequent breast cancer in 15 patients. HPV E7 proteins were identified in 72% of benign breast specimens and 59% of invasive breast cancer specimens. There were four observations of particular interest: (i) confirmation by both NGS and PCR of the presence of high-risk HPV gene sequences in breast cancers, (ii) a correlation between high-risk HPV in benign breast specimens and subsequent HPV-positive breast cancer in the same patient, (iii) HPVs in breast cancer are likely to be biologically active (as shown by transcription of HPV DNA to RNA plus the expression of HPV E7 proteins), (iv) HPV oncogenic influences may occur early in the development of breast cancer.


[Study on the surgical treatment for pulmonary metastasis from renal cell carcinoma].
Pulmonary resection for metastatic renal cell carcinoma were studied to assess the indication of surgical management. Between January, 1981 and December 1994, 17 consecutive patients (14 men and 3 women) underwent complete pulmonary resection for metastatic renal carcinoma. Median age was 61 years (range, 45 to 73 years). Eleven were appeared lung metastasis after resection of primary tumor. Median time between nephrectomy and pulmonary resection was 32 months (range, 0 to 127 months). There were no operative deaths. One patient had solitary metastasis, 4 had two, 2 had three, 2 had four, one had seven, one had eight and 6 had more than twenty-two. Segmental resection was performed in 12 patients, lobectomy in 2, lobectomy and segmentectomy in 3 and segmentectomy for total lobes in 3. Four patients had another site operation of renal metastasis, brain tumor resection, chest wall and ribs resection, contra-lateral adrenalectomy and contralateral partial nephrectomy. Median follow-up was 44 months (range, 10 to 129 months). The cause specific survival rate and disease free survival after pulmonary resection was 55 and 48 percent at 5 years and 27 and 14 percent at 10 years, respectively. Pulmonary resection for metastatic renal cell carcinoma was considered effective in some selected slow-growing cases. Multiple and both lungs metastases is not contraindication and the patients under 10 metastatic focuses had good prognosis.


Medications (NSAIDs, statins, proton pump inhibitors) and the risk of esophageal adenocarcinoma in patients with Barrett's esophagus.
Limited evidence suggests that proton pump inhibitors (PPI), nonsteroidal anti-inflammatory drugs (NSAID)/aspirin, and statins may be associated with a low risk of esophageal neoplasia. However, the possible effect these medications may have on the risk of esophageal adenocarcinoma (EAC) in patients with existing Barrett's esophagus (BE) is unclear. We conducted a nested case-control study in a cohort of patients with BE identified in the national Department of Veterans' Affairs computerized databases. Cases with incident EAC were matched by incidence density sampling to controls with BE who remained without EAC at the date of the EAC diagnosis for the corresponding case. We identified prescriptions for PPI, NSAIDs/aspirin, and statins that were filled between BE diagnosis and EAC diagnosis. Incidence density ratios were calculated using conditional logistic regression models that adjusted for race, outpatient encounters, a disease comorbidity index, and socioeconomic status. In a cohort of 11,823 patients with first-time BE diagnosis, we examined 116 EAC cases and 696 matched controls. Most cases and controls had at least one filled PPI prescription (95% vs 94%; P = .5). In this setting of almost universal PPI use, filled NSAID/aspirin prescriptions were associated with a reduced risk of EAC (adjusted incidence density ratio, 0.64; 95% confidence interval, 0.42-0.97). Filled statin prescriptions also were associated with a reduction in EAC risk (0.55; 95% confidence interval, 0.36-0.86), with a significant trend toward greater risk reduction with longer duration of statin use. However, the strong inverse associations with even short periods of use raise concerns of uncontrolled confounding. This observational study indicates that in patients with BE using PPI, NSAID/aspirin, or statin therapy might reduce the risk of developing EAC.


Cancer incidence among physicians in Israel.
Physicians' occupational environment includes exposures to potential carcinogenic factors on a regular basis. The prevalence of specific tumor types and subsequent mortality are reported to be elevated in physicians. To assess the incidence of various cancer types among Israeli physicians of various specialties, as compared with the general population, and to determine the role, if any, of gender and ethnicity. This historical retrospective cohort analysis incorporated data on Israeli officially licensed physicians and information retrieved from the Israel National Cancer Registry database (INCR). Physicians were divided into five groups: non-specialists, internists, pediatricians, surgeons, and potentially at-risk specialties. Data were collected retrospectively for the years 1980-2007. The study cohort comprised 37,789 physicians, of whom 33,393 (88.37%) were Jews and 4396 (11.63%) were Arabs. Comparing Jewish physicians to the general population revealed higher rates of: a) breast cancer among female specialized physicians, and b) melanoma among specialized male and female physicians. All cancer types were more prevalent in the Arab physicians than in the general Arab population. This study revealed incidences of specific cancer types among different medical specialties as compared to the general population. Hopefully, these findings will prompt changes in the occupational environment of physicians of particular specialties in order to reduce their high risk for cancer occurrence.


Point-and-shoot memories: the influence of taking photos on memory for a museum tour.
Two studies examined whether photographing objects impacts what is remembered about them. Participants were led on a guided tour of an art museum and were directed to observe some objects and to photograph others. Results showed a photo-taking-impairment effect: If participants took a photo of each object as a whole, they remembered fewer objects and remembered fewer details about the objects and the objects' locations in the museum than if they instead only observed the objects and did not photograph them. However, when participants zoomed in to photograph a specific part of the object, their subsequent recognition and detail memory was not impaired, and, in fact, memory for features that were not zoomed in on was just as strong as memory for features that were zoomed in on. This finding highlights key differences between people's memory and the camera's "memory" and suggests that the additional attentional and cognitive processes engaged by this focused activity can eliminate the photo-taking-impairment effect.


Endoscopic retrograde cholangiopancreatography outcome from a single referral center in Iran.
Endoscopic retrograde cholangiopancreatography (ERCP) is the first choice for diagnostic evaluation of the pancreatic and biliary tree and can be accompanied by a high diagnostic sensitivity and a poor therapeutic outcome. In the current study, we described our experiences in the indications, findings, and technical success of ERCP in a sample of the Iranian population admitted to a referral center in Iran. In a retrospective review database-based study, 780 patients (393 males and 387 females; mean age 57.5 years) who had undergone diagnostic and therapeutic ERCP with the primary diagnosis of hepatobiliary disorder between 2006 and 2008 at Taleghani Hospital in Tehran were reviewed. The key data were demographic characteristics, clinical information, laboratory parameters, as well as post-ERCP complications. A history of cholecystectomy was found in about one-third (36.3%) of participants and 80 (10.3%) out of 780 patients had a previous history of biliary stone. A minority (1.4%) of the patients suffered from hepatobiliary carcinomas, and 11 patients had cirrhosis. The most common clinical manifestations in the patients undergoing diagnostic ERCP were icterus (47.3%), weight loss (31.2%), and dark urine (26.9%). Selective biliary cannulation was technically successful in 87.0% of the patients; however, cannulation failed in 13.0%. The most frequent final diagnosis of ERCP was common bile duct stone that was detected in 40.1% of the patients. The ERCP results in 11.0% of the patients were normal. Regarding appropriate treatment, successful stenting was performed in 43 patients (15.2%). Among post-ERCP complications, pancreatitis was the most adverse event with an incidence rate of 3.3%. Other complications including local bleeding, cholangitis and gastrointestinal perforation, rarely occurred. Post-ERCP pancreatitis was reported in 1.8% of men and 3.6% of women (P=0.120). Pancreatitis was more common in women below 70 years than in those who were older than 70 years (3.6% versus 0.5%; OR: 8.216, P=0.015). This might be due to the more functionally active pancreas in younger women than in the older ones. However, other complications were similar in the two age groups. Based on our experience, ERCP indications, final diagnosis and related complications are comparatively consistent with those reported in other countries. The most common post-ERCP complication is pancreatitis that is more often observed in younger patients.


Characterization and spontaneous induction of urinary tract Streptococcus anginosus prophages.
Streptococcus anginosus is an often overlooked and understudied emerging pathogen inhabiting many areas of the human body. Through our sequencing of S. anginosus strains isolated from the female bladder microbiota, we detected numerous prophage sequences. Bioinformatic analysis of these sequences identified 17 distinct groups of S. anginosus prophages. The majority of these phages exhibit no sequence homology to previously characterized temperate or virulent phage sequences, indicating an unexplored diversity of Streptococcus phages. By culturing these bacterial isolates, we confirmed that the prophages of five of these groups are capable of induction. One of these putative phages was imaged, the first such evidence of an S. anginosus virus-like particle; it exhibits morphological characteristics of siphoviruses.


Evidence-Based Medicine in Aesthetic Surgery: The Significance of Level to Aesthetic Surgery.
Since its popularization in the 1980s, evidence-based medicine has become the cornerstone of American health care. Many specialties rapidly adapted to the paradigm shift of health care by delivering treatment using the evidence-based guidelines. However, the field of plastic surgery has been slow to implement evidence-based medicine compared with the other specialties because of the challenges of performing randomized controlled trials, such as funding, variability in surgical skills, and difficulty with standardization of techniques. To date, aesthetic surgery has been at the forefront of evidence-based medicine in plastic surgery by having the most randomized controlled trials. Nevertheless, a detailed analysis of these studies has not been previously performed. In this article, the level I and II articles of aesthetic surgery are discussed to increase awareness of high-quality evidence-based medicine in aesthetic surgery.


Gene specific therapy for cardiac disease: the case of long QT syndrome.
Molecular genetics is progressively entering clinical practice. This new approach is modifying medical thinking as it becomes possible to diagnose diseases in their presymptomatic phase. It is therefore important for physicians to become acquainted with the "language" and the "methodology" of molecular biologists in order to balance opposite attitudes of the novice, i.e. skepticism and over-expectation, and to establish a fruitful interaction with the molecular diagnostic laboratories. Long QT syndrome is an inherited disease that few years ago was still called "idiopathic" as the underlying causes were unknown. Clinicians are now becoming aware that what was considered as one disease is actually the common phenotype of defects in at least five different LQT-related genes and that therefore clinical heterogeneity is likely to parallel genetic heterogeneity. The first steps have been undertaken to define the relative prevalence of the molecular variants of LQTS, to develop gene-specific therapy and to perform risk stratification based on the molecular defect. In this article, current knowledge of the molecular bases of LQTS is reviewed and criteria are proposed to help defining 1) when it is appropriate to attempt molecular diagnosis, 2) how to interpret results of the diagnostic laboratory and 3) how molecular diagnosis may affect patients management.


Triplet pregnancy: changes in morbidity and mortality.
The outcome of 13 sets of triplet infants delivered between January 1, 1981, and December 31, 1988, is analyzed with specific regard to immediate neonatal morbidity. Thirty-nine viable infants were born with no perinatal deaths. Overall, 80% of triplet infants incurred some morbidity, including hyperbilirubinemia (51.3%), hypoglycemia (30.8%), respiratory distress syndrome (28.2%), respiratory compromise (23.1%), anemia (17.9%), patent ductus arteriosus (15.4%), and intraventricular hemorrhage (10.3%). All morbidities occurred in infants who averaged less than 2,000 g and 35 weeks' gestation at birth. As a background to understanding these observations, a review of reports of triplet morbidity and mortality in the United States and Europe is presented. Over the past 80 years, a continual decline in triplet perinatal mortality has occurred despite no change in the average gestational age at delivery over the past 40 years. The triplet perinatal mortality rate is now less than 10%, and prematurity is no longer as influential on perinatal mortality as it is on morbidity. Improvement in neonatal resuscitation and care and delivery by cesarean section are felt to be responsible for lower mortality rates. We believe that the optimum level of care for triplet gestations includes antenatal and neonatal care at tertiary perinatal centers and, except for special circumstances, delivery by cesarean section.


Conflict, cultural marginalization, and personal costs of filial caregiving.
This study investigated the role of cultural marginalization as factor mediating the relationship between family conflict and the perceived personal costs associated with caring for an elderly parent. Participants included forty-seven Mexican American filial caregivers residing in Colorado. Using data from structured interviews, the results of regression analysis indicated that family conflict is a significant predictor of the personal costs of caregiving. Adding the variable of cultural marginalization to the regression equation increased the amount of explained variance; supporting an hypothesis that marginalization mediates the influence of family conflict on the perceived costs of caregiving. Practice implications for mental health professionals working with Mexican American caregivers are presented, as are study limitations and suggestions for future research.


Analysis of the interaction of antibodies with immunoglobulin idiotypes on neoplastic B lymphocytes: implications for immunotherapy.
We have examined the reactions of a panel of nine monoclonal anti-idiotype antibodies with the surface immunoglobulin in situ on guinea pig L2C leukemic lymphocytes. Equilibrium binding constants were shown to range between 10(7) and 10(8) M-1 for univalent Fab' gamma fragments and between 10(8) and 10(9) M-1 for intact IgG. Saturation of the cell surface binding sites was achieved with 2.9 X 10(5) Fab' gamma molecules/cell and 1.2 X 10(5) IgG molecules/cell for each antibody, a result that is consistent with a bivalent mode of interaction for the IgG. Despite these overall similarities in binding characteristics antibodies showed striking differences in their ability to clear Ig from the cell surface by antigenic modulation in vitro. This suggested differences in the readiness with which the antibodies cross-linked neighboring surface Ig molecules. Such an interpretation was supported by differences in the times required to achieve bivalent binding at 0 degree C, and in the rates at which labeled antibody dissociated from the cell surface in the presence or absence of an excess of unlabeled antibody. The data are consistent with there being two functionally distinct types of anti-idiotype antibody: those that form predominantly intra-Ig bridges, with each antibody Fab being linked to an Fab on one target molecule ("monogamous" binding) and not favoring modulation; and those that form predominantly inter-Ig bridges ("bigamous" binding) and favor modulation. The nature of interaction is presumably dictated by the orientation of the particular idiotope concerned. This distinction could be of great importance in the therapeutic use of anti-idiotype to ablate B cell neoplasms.


Type IV hypersensitivity reactions following Dermabond adhesive utilization in knee surgery: A Report of Three Cases.
We retrospectively reviewed the records of 3 patients (3 knees) with a delayed type hypersensitivity reaction following Dermabond exposure after an orthopaedic knee procedure. Delayed hypersensitivity reactions are mediated by CD4+ helper T cells. The use of skin adhesives in place of traditional sutures is increasing in popularity given Dermabond's potential benefits of decreased wound infection rate and better wound approximation. However, hypersensitivity reactions to the cyanoacrylate material in Dermabond have been described. Differentiating hypersensitivity reactions from post-operative infections is important as septic arthritis is a potentially devastating complication. This case series presents the challenge of properly diagnosing and managing hypersensitivity reactions. Consultation with allergists and dermatologists may be appropriate for ascertaining the nature of the surgical site complication and proper management. The recommended management of hypersensitivity-type reactions is a course of topical steroids and infection work up if needed.


Identification of proliferating human anterior pituitary adenoma cells in vitro.
A method to determine whether dispersed human anterior pituitary adenoma cells proliferate in mixed culture was developed. Fifteen pituitary adenomas were dispersed enzymatically to single cells, following which twelve were double immunostained after eight days. Proliferating cells were identified immunologically following one hour of bromo-deoxyuridine incorporation. Adenoma cells were subsequently identified with an anti-neuron-specific enolase antibody system. A time course of bromo-deoxyuridine labelling was performed on three nonfunctional adenomas over a four day period, with bromo-deoxyuridine being added to cultures at one hour, 24 hours and four days prior to immunostaining. Double immunolabelled cells were unambiguously identified by a dark brown nucleus surrounded by red cytoplasm. Eight out of 12 pituitary adenomas (two prolactinomas, three nonfunctional, three growth hormone secreting) showed an increased bromo-deoxyuridine labelling index (range 0.1%-1.4%). Bromo-deoxyuridine incorporation over four days showed an increase in bromo-deoxyuridine from 0.02%, 0.03% and 3.3% at one hour to 10.1%, 1.3% and 5.0% at four days, respectively, but evidence of mitosis was scant. This study shows that pituitary adenomas may proliferate in vitro and that this double immunostaining method may be used as an in vitro proliferation assay in a mixed cell population.


Cyclooxygenase as a target for colorectal cancer chemoprevention.
Colorectal cancer (CRC) is one of the most common neoplasia in Western countries and the second leading cause of cancer-related death. The vast majority of cases belong to sporadic forms, whereas a small but relevant proportion of them corresponds to inherited disorders, i.e. familial adenomatous polyposis and Lynch syndrome. These individuals with germline mutations in cancer-promoting genes, along with those who had already developed a colorectal neoplasm, either adenoma or carcinoma, stand to benefit from chemopreventive interventions. A large body of evidence indicates that the use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) can reduce the risk of CRC. Experimental studies have demonstrated that these drugs decrease the incidence of carcinogen-induced colon tumors in rodents, and several epidemiological investigations and therapeutic trials have also shown a 40-50% reduction in the risk of colorectal adenoma and cancer in individuals taking NSAIDs. Moreover, patients with familial adenomatous polyposis taking sulindac or celecoxib experience a reduction in adenoma size and number. The chemopreventive effects of NSAID are largely related to inhibition of cyclooxygenase-2 (COX-2), the inducible isoform of cyclooxygenase that catalyzes the conversion of arachidonic acid to prostaglandins. COX-2 overexpression is a frequent, but not universal event in colorectal neoplasms. Indeed, approximately 50% of adenomas and 80% of CRC express high levels of COX-2 mRNA and protein in neoplastic tissue. In this article, we will review the role of cyclooxygenase as a target for CRC chemoprevention, with special attention to the use of selective and non-selective COX-2 inhibitors in both individuals genetically predisposed and those who have already developed a colorectal neoplasm.


Evidence-based dietary guidance and the role of dairy products for appropriate nutrition in the elderly.
Food consumption surveys in the elderly come to the general conclusions that most elderly people outside institutions eat reasonably well. There is, however, tremendous variation in health status between older adults. The aging process is complex and influenced not only by factors intrinsic to the individual but also by extrinsic factors. The latter includes nutrition. In the various phases in the aging process, nutritional status and thus appropriate nutrition differ. Undernutrition is a great concern. In community-dwelling people older than 70 years, 5%-10% are undernourished, and for institutionalized elderly, this is up to 30%-65%. The cause is often inappropriate food consumption, and treatment is not always evidence based. National evidence-based dietary guidelines are mainly for healthy elderly people and vary between regions and even between institutes within the same region. To understand these differences, insight is required into the paradigm applied for nutritional science and the designs, selection of the older population, methodology, and endpoints of studies supplying the science behind the guidelines. A European project (Eurecca) compiles and harmonizes dietary guidelines. These activities underpin the need for sound evidence to improve the nutrition of older adults in different health phases. For frail elderly, there is also a plea to take into account results of studies on food satisfaction. First studies in this field show the effectiveness of an adapted social context for meals, appropriate nutritional care, and availability of tasty drinks and foods for selected groups of older adults. Because of the nutrient richness of dairy products and their good taste, these foods are helpful in the diet of healthy as well as frail elderly people. Key teaching points: Most elderly people eat reasonably well. There are, however, large differences in health status between elderly people and therefore also in nutrient requirements. Undernutrition is a main concern. In community-dwelling people older than 70 years, 5%-10% are undernourished, and for institutionalized elderly, this is up to 30%-65%. Evidence-based dietary guidelines are developed mainly for healthy elderly people and vary between regions. Harmonization will improve public health as well as clinical nutritional strategies. Given the nutrient density of dairy products, these products are included in balanced dietary advice for older adults.