The adenovirus DNA binding protein and adenovirus DNA polymerase interact to catalyze elongation of primed DNA templates.
The adenovirus-encoded 140-kDa DNA polymerase (Ad Pol) and the 59-kDa DNA binding protein (Ad DBP) are both required for the replication of viral DNA in vivo and in vitro. Previous studies demonstrated that, when poly(dT).oligo(dA) was used as a template-primer, both proteins were required for poly(dA) synthesis. In this report, the interaction between the Ad Pol and Ad DBP was further investigated using poly(dT).oligo(dA) as well as a linear duplex molecule containing 3' poly(dT) tails. DNA synthesis with the tailed template required Ad Pol, Ad DBP, and an oligo(dA) primer hydrogen bonded to the poly(dT) tails. Incorporation was stimulated 8-10-fold by ATP; however, no evidence of ATP hydrolysis to ADP was observed. Synthesis was initiated at either end of the tailed molecule and proceeded through the duplex region to the end of the molecule. This ability to translocate through duplex DNA and to synthesize long poly(dA) chains suggests that the Ad Pol.Ad DBP complex can act efficiently in the elongation reactions involved in the replication of Ad DNA (both type I and type II). During the replication reaction, substantial hydrolysis of deoxynucleoside triphosphates to the corresponding deoxynucleoside monophosphates occurred. This reaction required DNA synthesis and most likely reflects an idling reaction similar to that observed with other DNA polymerases containing 3'----5' exonuclease activity in which the polymerase first incorporates and then hydrolyzes a dNMP.


Highways of the emotional intellect: white matter microstructural correlates of an ability-based measure of emotional intelligence.
Individuals differ in their ability to understand emotional information and apply that understanding to make decisions and solve problems effectively - a construct known as Emotional Intelligence (EI). While considerable evidence supports the importance of EI in social and occupational functioning, the neural underpinnings of this capacity are relatively unexplored. We used Tract-Based Spatial Statistics (TBSS) to determine the white matter correlates of EI as measured by the ability-based Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Participants included 32 healthy adults (16 men; 16 women), aged 18-45 years. White matter integrity in key tracts was positively correlated with the Strategic Area branches of the MSCEIT (Understanding Emotions and Managing Emotions), but not the Experiential branches (Perceiving and Facilitating Emotions). Specifically, the Understanding Emotions branch was associated with greater fractional anisotropy (FA) within somatosensory and sensory-motor fiber bundles, particularly those of the left superior longitudinal fasciculus and corticospinal tract. Managing Emotions was associated with greater FA within frontal-affective association tracts including the anterior forceps and right uncinate fasciculus, along with frontal-parietal cingulum and interhemispheric corpus callosum tracts. These findings suggest that specific components of EI are directly related to the structural microarchitecture of major axonal pathways.


[Regulation of the efficacy of adrenergic synaptic transmission by autoadrenoreceptors in rat brain slices].
A hypothesis of the role of autoadrenoreceptors in the processes of synaptic depression, facilitation, PSP amplitude stabilization and amplitude increase with the stimulation frequency growth is described by means of a mathematical model. Synaptic depression is realized by activation of alpha-autoadrenoreceptors, synaptic facilitation--by beta-autoadrenoreceptors activation. A "stable secretion zone" is formed between the autoadrenoreceptor activation curves at which noradrenaline secretion is stabilized. Experimental studies of H3-NA secretion from rats cerebral cortex slices showed that autoadrenoreceptors really form a stable secretion zone. The presence of stable secretion zone provides for self-facilitation and stabilization of H3-NA secretion elicited by 5-fold consecutive K+-depolarizations of slices with time interval 30 min. The absence of the stable secretion zone leads to destabilization of H3-NA secretion. With an increase of the stimulation intensity the curves of autoadrenoreceptors activity and stable secretion zone shift toward high noradrenaline concentrations.


Of brain and bone: the unusual case of Dr. A.
Frontotemporal dementia (FTD) is a clinical syndrome characterized by progressive decline in social conduct and a focal pattern of frontal and temporal lobe damage. Its biological basis is still poorly understood but the focality of the brain degeneration provides a powerful model to study the cognitive and anatomical basis of social cognition. Here, we present Dr. A, a patient with a rare hereditary bone disease (hereditary multiple exostoses) and FTD (pathologically characterized as Pick's disease), who presented with a profound behavioral disturbance characterized by acquired sociopathy. We conducted a detailed genetic, pathological, neuroimaging and cognitive study, including a battery of tests designed to investigate Dr. A's abilities to understand emotional cues and to infer mental states and intentions to others (theory of mind). Dr. A's genetic profile suggests the possibility that a mutation causing hereditary multiple exostoses, Ext2, may play a role in the pattern of neurodegeneration in frontotemporal dementia since knockout mice deficient in the Ext gene family member, Ext1, show severe CNS defects including loss of olfactory bulbs and abnormally small cerebral cortex. Dr. A showed significant impairment in emotion comprehension, second order theory of mind, attribution of intentions, and empathy despite preserved general cognitive abilities. Voxel-based morphometry on structural MRI images showed significant atrophy in the medial and right orbital frontal and anterior temporal regions with sparing of dorsolateral frontal cortex. This case demonstrates that social and emotional dysfunction in FTD can be dissociated from preserved performance on classic executive functioning tasks. The specific pattern of anatomical damage shown by VBM emphasizes the importance of the network including the superior medial frontal gyrus as well as temporal polar areas, in regulation of social cognition and theory of mind. This case provides new evidence regarding the neural basis of social cognition and suggests a possible genetic link between bone disease and FTD.


DNA adenine methylase mutants of Salmonella typhimurium and a novel dam-regulated locus.
Mutants of Salmonella typhimurium lacking DNA adenine methylase were isolated; they include insertion and deletion alleles. The dam locus maps at 75 min between cysG and aroB, similar to the Escherichia coli dam gene. Dam- mutants of S. typhimurium resemble those of E coli in the following phenotypes: (1) increased spontaneous mutations, (2) moderate SOS induction, (3) enhancement of duplication segregation, (4) inviability of dam recA and dam recB mutants, and (5) suppression of the inviability of the dam recA and dam recB combinations by mutations that eliminate mismatch repair. However, differences between S. typhimurium and E. coli dam mutants are also found: (1) S. typhimurium dam mutants do not show increased UV sensitivity, suggesting that methyl-directed mismatch repair does not participate in the repair of UV-induced DNA damage in Salmonella. (2) S. typhimurium dam recJ mutants are viable, suggesting that the Salmonella RecJ function does not participate in the repair of DNA strand breaks formed in the absence of Dam methylation. We also describe a genetic screen for detecting novel genes regulated by Dam methylation and a locus repressed by Dam methylation in the S. typhimurium virulence (or "cryptic") plasmid.


The diversity and evolution of ecological and environmental citizen science.
Citizen science-the involvement of volunteers in data collection, analysis and interpretation-simultaneously supports research and public engagement with science, and its profile is rapidly rising. Citizen science represents a diverse range of approaches, but until now this diversity has not been quantitatively explored. We conducted a systematic internet search and discovered 509 environmental and ecological citizen science projects. We scored each project for 32 attributes based on publicly obtainable information and used multiple factor analysis to summarise this variation to assess citizen science approaches. We found that projects varied according to their methodological approach from 'mass participation' (e.g. easy participation by anyone anywhere) to 'systematic monitoring' (e.g. trained volunteers repeatedly sampling at specific locations). They also varied in complexity from approaches that are 'simple' to those that are 'elaborate' (e.g. provide lots of support to gather rich, detailed datasets). There was a separate cluster of entirely computer-based projects but, in general, we found that the range of citizen science projects in ecology and the environment showed continuous variation and cannot be neatly categorised into distinct types of activity. While the diversity of projects begun in each time period (pre 1990, 1990-99, 2000-09 and 2010-13) has not increased, we found that projects tended to have become increasingly different from each other as time progressed (possibly due to changing opportunities, including technological innovation). Most projects were still active so consequently we found that the overall diversity of active projects (available for participation) increased as time progressed. Overall, understanding the landscape of citizen science in ecology and the environment (and its change over time) is valuable because it informs the comparative evaluation of the 'success' of different citizen science approaches. Comparative evaluation provides an evidence-base to inform the future development of citizen science activities.


Adhesions and pelvic pain: a retrospective study.
Retrospective review of 100 consecutive laparoscopies for chronic pelvic pain and 88 for infertility was undertaken. Twenty-six of the 100 (26%) chronic pelvic pain patients and 34 of the 88 (39%) infertility patients exhibited pelvic adhesions as the only abnormal finding. Patients in each group with findings of pelvic adhesions were compared with respect to symptomatology, density of adhesions, and locations of adhesions. Only four of the 34 infertility patients in whom pelvic adhesions were found complained of pain. Comparison of the chronic pelvic pain patients and the asymptomatic infertility patients did not reveal a significant difference in the density or the location of adhesions. These findings question the role of pelvic adhesions as a cause of chronic pelvic pain.


Comparing the Health of Canadian Hospitals: Paying Attention to the Mix of Planned and Unplanned Admissions.
Canadian hospitals are being placed under increasing scrutiny for both performance and safety in some cases with a threat of financial consequences for failure. However, there are no accepted standards for comparing the relative context in which hospitals must operate; the unstated assumption being that all are starting from the same place and have equal opportunities for success. A "healthy hospital" should be able to meet the needs of its community with a mix of both planned (scheduled) and unplanned (emergency) services. The proportion of admissions that are planned has been falling in most Canadian hospitals and unplanned admissions have been rising, creating an unhealthy state with added costs. Canadian Institute for Health Information's databases give us a way to monitor these changes, but it is not routinely done. Making this information more available would help to identify hospitals most in need of support.


Issues surrounding spinal cord protection.
In summary, paraplegia following procedures on the thoracic and thoraco-abdominal aorta is an unpredictable and dreadful complication of multifactorial origin. However, it appears that the major causes of immediate post-operative paraplegia are the depth and duration of ischemia during the period of aortic cross-clamping and failure to identify and reimplant critical vessels that supply blood to the spinal cord. Delayed paraplegia, which has been reported to occur from 1 to 21 days after surgery, is most commonly caused by postoperative hypotension. We believe that the final approach to the prevention of paraplegia following procedures on the thoracic aorta will be one that involves the use of a technique to assure oxygenation of the spinal cord during aortic cross-clamping, through an alternate vascular tree, along with a method that can uniformly depict critical vessels that must be reimplanted at the time of surgery.


Early diagnosis and management of esophageal leakage after peroral endoscopic myotomy for achalasia.
To improve the understanding of esophageal leakage after peroral endoscopic myotomy (POEM). From August 2010 to April 2013, patients with postoperative esophageal leakage were identified from the database of cases with achalasia who had undergone POEM and their medical records were reviewed. Three patients (0.4%, 3/679) developed esophageal leakage after POEM. All three patients had non-severe chest or upper abdominal pain within 3 days after the procedure. Infections were observed, and computed tomography scans showed pleural effusion in all three patients. Pneumonia occurred in two of the three patients. Esophageal leakage was confirmed by gastroscopy. Incision rupture due to an early breaking-off of the clips at the tunnel entry was revealed in two cases. When detected, the entry was immediately closed using metal clips. A thoracic drain was placed in all cases. An enteric feeding tube was also placed to help correct nutrition deficiencies. Successful leakage closure was achieved in all three cases and no surgical intervention was needed. Early diagnosis and treatment can improve the status of patients with esophageal leakage after POEM and can shorten the recovery time.


Association between physical, psychological and social frailty and health-related quality of life among older people.
Studies on the association between frailty and health-related quality of life (HRQoL) are scarce and show contradictory results. This study aimed to evaluate the association between physical, psychological and social frailty and HRQoL among community-dwelling older people. A cross-sectional study was performed with baseline data collected in 2015 from the Urban Health Centers Europe (UHCE) project in five European countries, the United Kingdom, Greece, Croatia, The Netherlands and Spain. A total of 2325 participants were included in the baseline measurements of the Urban Health Centers Europe project; 2167 participants (mean age = 79.7; SD=5.6) were included in the analyses after excluding participants with missing data. The Tilburg Frailty Indicator measured overall frailty as well as physical, psychological and social frailty. The 12-Item Short-Form Health Survey was used to measured physical and mental HRQoL. Regarding physical HRQoL, a large difference (d=1.29) between physically and not physically frail participants was observed. Regarding mental HRQoL, a large difference (d=1.20) between psychologically and not psychologically frail participants was observed. In the full model with all three domains of frailty and the covariates to explain physical HRQoL, physical (P <0.001) and social frailty (P <0.001) remained significant. In the full model to explain mental HRQoL, all three domains of frailty remained significant (P <0.001). Physical frailty had the strongest association with physical HRQoL, and psychological frailty had the strongest association with mental HRQoL. The associations between social frailty and both physical and mental HRQoL remain significant when controlling for physical and psychological frailty.


The dental amalgam toxicity fear: a myth or actuality.
Amalgam has been used in dentistry since about 150 years and is still being used due to its low cost, ease of application, strength, durability, and bacteriostatic effect. When aesthetics is not a concern it can be used in individuals of all ages, in stress bearing areas, foundation for cast-metal and ceramic restorations and poor oral hygiene conditions. Besides all, it has other advantages like if placed under ideal conditions, it is more durable and long lasting and least technique sensitive of all restorative materials, but, concern has been raised that amalgam causes mercury toxicity. Mercury is found in the earth's crust and is ubiquitous in the environment, so even without amalgam restorations everyone is exposed to small but measurable amount of mercury in blood and urine. Dental amalgam restorations may raise these levels slightly, but this has no practical or clinical significance. The main exposure to mercury from dental amalgam occurs during placement or removal of restoration in the tooth. Once the reaction is complete less amount of mercury is released, and that is far below the current health standard. Though amalgam is capable of producing delayed hypersensitivity reactions in some individuals, if the recommended mercury hygiene procedures are followed the risks of adverse health effects could be minimized. For this review the electronic databases and PubMed were used as data sources and have been evaluated to produce the facts regarding amalgam's safety and toxicity.


[Histochemical studies of the secretory capability of myometrial cells during pregnancy].
Investigations of many authors carried out on animals have shown the ability of myometrium cells to synthesize and secrete proteins and glycoproteid products in the period of pregnancy. The author's own studies have been carried out on human and animal material. In the muscles slices of gravid uterus as markers of appropriate cytoplasmatic structures were found out: S-nucleotidase, TPP-ase, succinat dehydrogenase, acid phopshatase and additionally glycogen. On the basis of the results obtained it may be concluded that in myometrium cells of gravid uterus morphological features of Golgi Apparatus (bacilliform, crescent, vesicular and granular structures) and mitochondria as well as the amount of glycogen manifest metabolic activity of these cells. Considering heterogenity of morphological forms of Golgi Apparatus and frequent charateristic polar localization round the nucleus it may be supposed that the cells charakterized by these features may possess the ability of secreting synthesized proteins or other products.


Understanding the Outcomes Measures used in Huntington Disease Pharmacological Trials: A Systematic Review.
The identification of the gene mutation causing Huntington disease has raised hopes for new treatments to ease symptoms and slow functional decline. As such, there has been a push towards designing efficient pharmacological trials (i.e., drug trials), especially with regard to selecting outcomes measures that are both brief and sensitive to changes across the course of the disease, from subtle prodromal changes, to more severe end-stage changes. Recently, to aid in efficient development of new HD research studies, the National Institute of Neurological Disorders and Stroke (NINDS) published recommendations for measurement selection in HD. While these recommendations are helpful, many of the recommended measures have little published data in HD. As such, we conducted a systematic review of the literature to identify the most common outcomes measures used in HD clinical trials. Major medical databases, including PubMed, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials, were used to identify peer-reviewed journal articles in English from 2001 through April 2013; 151 pharmacological trials were identified. The majority of HD clinical trials employed clinician-reported outcomes measures (93%); patient reported outcome measures (11%) and observer reported outcome measures (3%) were used with much less frequency. We provide a review of the most commonly used measures across these trials, compare these measures to the clinical recommendations made by the NINDS working groups, and provide recommendations for selecting measures for future clinical trials that meet the Food and Drug Administration standards.


Pre-operative coagulopathy management of a neonate with complex congenital heart disease: a case study.
Severe coagulation defects often develop in neonates undergoing cardiac surgery, both as a result of the surgical intervention, and as pre-existing defects in the hemostatic mechanisms. The following case report describes a newborn patient with complex congenital heart disease and respiratory failure whose pre-operative coagulopathy was aggressively managed prior to surgical correction. A 5-day-old, 2.5 kg child presented with interrupted aortic arch, ventricular septal defect, atrial septal defect, and patent ductus arteriosus. On admission, he was in respiratory arrest suffering from profound acidemia. In addition, the child was hypothermic (30.1 degrees C), septic (Streptococcus viridans), and coagulopathic (disseminated intravascular coagulation-DIC). The patient was immediately intubated and initial coagulation assessment revealed the following: prothrombin time (PT) 48.9 s (international normalized ratio (INR) 15.7), activated partial thromboplastin time (aPTT) >106 s, platelet count 30,000 mm(3), fibrinogen 15 mg dL(-1) and antithrombin III (AT-III) 10%. Before cardiac surgery could be performed, the patient's DIC was corrected with the administration of cryoprecipitate (15 ml), fresh frozen plasma (300 ml), and platelets (195 ml). In spite of the large transfusion of fresh frozen plasma, the AT-III activity, measured as a percentage, remained depressed at 33. Initial thromboelastographic (TEG) determination revealed an index of +2.02, and following 100 IU administration of an AT-III concentrate, declined to -2.32. Sequential TEG profiles were performed over several days, with the results used to guide both transfusion and medical therapy. The congenital heart defect correction was subsequently performed with satisfactory initial results, but the patient developed a fungal infection and expired on the 16th post-operative day. The present case describes techniques of coagulation management for a newborn with both a severe hemostatic defect and congenital heart disease.


Human and animal skin identified by palaeoproteomics in Scythian leather objects from Ukraine.
Leather was one of the most important materials of nomadic Scythians, used for clothing, shoes, and quivers, amongst other objects. However, our knowledge regarding the specific animal species used in Scythian leather production remains limited. In this first systematic study, we used palaeoproteomics methods to analyse the species in 45 samples of leather and two fur objects recovered from 18 burials excavated at 14 different Scythian sites in southern Ukraine. Our results demonstrate that Scythians primarily used domesticated species such as sheep, goat, cattle, and horse for the production of leather, while the furs were made of wild animals such as fox, squirrel and feline species. The surprise discovery is the presence of two human skin samples, which for the first time provide direct evidence of the ancient Greek historian Herodotus' claim that Scythians used the skin of their dead enemies to manufacture leather trophy items, such as quiver covers. We argue that leather manufacture is not incompatible with a nomadic lifestyle and that Scythians possessed sophisticated leather production technologies that ensured stable supply of this essential material.


Understanding vulnerability and resilience in Somalia.
In the recent years, Somalia witnessed a heightened frequency of droughts and conflicts. This article explores the experiences of Somalis during the 2011 and 2016 crises, examining the link between vulnerability and resilience, and the role played by international humanitarian responders in resilience building. The aim of this study is to provide information on how different population groups responded to and managed to survive recurrent shocks; the prevailing drivers of marginalisation and exclusion, and mechanisms through which these are maintained; and the role of external stakeholders. A review of literature was combined with field consultations in four study sites: Kismayo Urban, Kismayo Rural, Baidoa and Beledweyne, and complemented by consultations with the Somali diaspora community in Kampala, Uganda. Participatory research methods were used, including participant observation, focus group discussions, household dialogues, livelihood analysis, well-being analysis and gender analysis. The findings of the study revealed an inextricable link between vulnerability, conflict and disasters, with the major challenge facing the most vulnerable Somalis being uncertain about the future. Somali households adopted different coping strategies depending on their resource endowments, including the social and organisational coping strategies, divesting of non-essential domestic assets, and diversification of income generation and food production strategies. Thus, different population groups survived the shocks through social connectedness, which aligned with the effective use of remittances to create robust mechanisms for sharing risk. That notwithstanding, groups that had the backing of more powerful clans seemed to have the edge over those who did not.


The role of Arp2/3 in growth cone actin dynamics and guidance is substrate dependent.
During development extrinsic guidance cues modulate the peripheral actin network in growth cones to direct axons to their targets. We wanted to understand the role of the actin nucleator Arp2/3 in growth cone actin dynamics and guidance. Since growth cones migrate in association with diverse adhesive substrates during development, we probed the hypothesis that the functional significance of Arp2/3 is substrate dependent. We report that Arp2/3 inhibition led to a reduction in the number of filopodia and growth cone F-actin content on laminin and L1. However, we found substrate-dependent differences in growth cone motility, actin retrograde flow, and guidance after Arp2/3 inhibition, suggesting that its role, and perhaps that of other actin binding proteins, in growth cone motility is substrate dependent.


The synaptonemal complex, recombination nodules and chiasmata in human spermatocytes.
Reconstruction from serial sections of 120 human spermatocyte nuclei, ranging in stage from leptotene to anaphase I, has led to the following conclusions. The reconstructed nuclei form a continuous sequence of developmental stages. With few exceptions, all of the bivalents are identifiable by length, centromere index and morphological markers. Crossing over is accompanied by a transformation of the recombination nodule (RN) into a fusiform bar lying across the synaptonemal complex (SC). The evolution of the crossover distribution at late pachytene is regulated at two levels both involving the SC. Each bivalent displays a pattern of SC regions - domains - with high affinity for RNs in the middle and low affinity at the ends. The occurrence of crossing over in a domain reduces the probability of attachment of new RNs and causes RNs not yet involved in crossing over to be released from that domain. Positive interference between crossovers is a consequence of these phenomena. At diplotene the degradation of the SC is initiated in regions with low affinity for RNs and small segments of the SC are retained at the crossover sites until late diakinesis. The site of crossing over is only identifiable by an RN for a certain period of time during pachytene. The distribution of total crossovers in a nucleus is similar but not identical to the distribution of chiasmata as seen in the light microscope. The number of crossovers has been estimated to be 70 and exceeds the number of chiasmata determined by light microscopy by a factor of 1.4.


Fly ash-based geopolymer lightweight concrete using foaming agent.
In this paper, we report the results of our investigation on the possibility of producing foam concrete by using a geopolymer system. Class C fly ash was mixed with an alkaline activator solution (a mixture of sodium silicate and NaOH), and foam was added to the geopolymeric mixture to produce lightweight concrete. The NaOH solution was prepared by dilute NaOH pellets with distilled water. The reactives were mixed to produce a homogeneous mixture, which was placed into a 50 mm mold and cured at two different curing temperatures (60 °C and room temperature), for 24 hours. After the curing process, the strengths of the samples were tested on days 1, 7, and 28. The water absorption, porosity, chemical composition, microstructure, XRD and FTIR analyses were studied. The results showed that the sample which was cured at 60 °C (LW2) produced the maximum compressive strength for all tests, (11.03 MPa, 17.59 MPa, and 18.19 MPa) for days 1, 7, and 28, respectively. Also, the water absorption and porosity of LW2 were reduced by 6.78% and 1.22% after 28 days, respectively. The SEM showed that the LW2 sample had a denser matrix than LW1. This was because LW2 was heat cured, which caused the geopolymerization rate to increase, producing a denser matrix. However for LW1, microcracks were present on the surface, which reduced the compressive strength and increased water absorption and porosity.


Characterization of alpha1-antitrypsin as a heme oxygenase-1 suppressor in Alzheimer plasma.
Heme oxygenase-1 (HO-1) mRNA and protein levels are diminished in Alzheimer disease (AD) blood, cerebrospinal fluid (CSF) and choroid plexus. Herein, the presence of a heme oxygenase-1 suppressor (HOS) factor was ascertained by astroglial bioassay, biochemical techniques and immunofluorescence confocal microscopy. We report significantly augmented plasma HOS activity in AD patients relative to healthy elderly and neurological controls. The HOS factor was determined to be a 50-100 kDa heat-labile, heparin-binding glycoprotein that is unrelated to antioxidant ingestion, plasma total antioxidant capacity, circulating cortisol levels or apolipoprotein E epsilon4 carrier status. HOS bioactivity was recapitulated by exogenous alpha(1)-antitrypsin. alpha(1)-antitrypsin levels were significantly increased in AD plasma and correlated with HOS activity and MMSE scores. alpha(1)-antitrypsin immunodepletion attenuated HOS activity of AD plasma. In AD brain, alpha(1)-antitrypsin immunoreactivity was augmented and co-distributed with HO-1. HOS activity of alpha(1)-antitrypsin may curtail HO-1-dependent derangement of cerebral iron homeostasis and account for diminished HO-1 expression in AD peripheral tissues.


Symmetrical craniofacial hypertrophy in patients with tertiary hyperparathyroidism and high-dose cinacalcet exposure.
We are reporting on a series of two patients with end-stage renal disease on hemodialysis, presented for surgical parathyroidectomy secondary refractory hyperparathyroidism. Both patients had failed maximized medical managements, including higher-than-usual doses of the calcimimetic cinacalcet (270 and 180 mg/day, respectively). On physical exam, both patients had marked symmetrical craniofacial hypertrophy with coarse distortion of facial features, similar in appearance to past reports of Sagliker syndrome. On X-ray and computed tomographic exam, they had peculiar areas of bone absorption on the skull, imitating the radiologic appearance of multiple myeloma. Bone biopsy of the maxilla, however, did not show the expected brown tumor, but rather described only fibrosis and reactive bone formations. This phenotype developed while being on cinacalcet, progressed despite escalation of therapy, and improved only after parathyroidectomy. Both patients developed massive "hungry bone syndrome" after parathyroidectomy necessitating prolonged i.v. calcium infusion. This pattern of severe facial distortion likely represented an adverse consequence of severe tertiary hyperparathyroidism, along with supraphysiologic dose of cinacalcet administration and 25-hydroxy vitamin D deficiency in sensitive individuals. The genetic base of this observation remained unexplained.


The role of routine magnetic resonance imaging in the preoperative evaluation of adolescent idiopathic scoliosis.
The routine use of magnetic resonance imaging (MRI) in adolescent idiopathic scoliosis remains controversial, and current indications for MRI in idiopathic scoliosis vary from study to study. The purpose of this study was to demonstrate the prevalence of neural axis malformations and the clinical relevance of routine MRI studies in the evaluation of patients with adolescent idiopathic scoliosis undergoing surgical intervention without any neurological findings. A total of 249 patients with a diagnosis of idiopathic scoliosis were treated surgically between the years 2002 and 2007. A routine whole spine MRI analysis was performed in all patients. On the preoperative clinical examination, all patients were neurologically intact. There were 20 (8%) patients (3 males and 17 females) who had neural axis abnormalities on MRI. Three of those 20 patients needed additional neurosurgical procedures before corrective surgery; the remaining underwent corrective spinal surgery without any neurosurgical operations. Magnetic resonance imaging may be beneficial for patients with presumed idiopathic scoliosis even in the absence of neurological findings and it is ideally performed from the level of the brainstem to the sacrum.


Potential Prognostic Role of SPARC Methylation in Non-Small-Cell Lung Cancer.
The silencing of SPARC (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is frequently associated with tumor progression and an aggressive clinical outcome. Anyhow, the data concerning the epigenetic mechanism of SPARC deregulation and its prognostic value in lung cancer are still incomplete. We explored the aberrant methylation of SPARC and its effects in 4 non-small cell lung cancer (NSCLC) cell lines and 59 NSCLC tissues and correlated the methylation levels with clinical-pathological features and disease outcome of patients. In 3 out of 4 tumor cell lines high SPARC methylation levels were observed. An inverse correlation between the epigenetic silencing and SPARC expression was confirmed by 5-Aza-2'-deoxycytidine ((5-Aza-CdR) treatment that also significantly induced a reduction in cell viability, proliferation and tumor cell migration. In tissues, the DNA methylation levels of the SPARC gene were significantly lower in paired non-neoplastic lungs (NLs) and normal lungs distant from tumor (NLDTs) than in NSCLCs (p = 0.002 and p = 0.0034 respectively). A promoter hypermethylation was detected in 68% of squamous cell carcinoma (SqCCs, 17/25) and 56% of adenocarcinoma (ADCs, 19/34), with SqCC showing the highest levels of methylation. Higher SPARC methylation levels were significantly associated with higher mortality risk both in all NSCLCs early stage patients (Hazard Ratio, HR = 1.97; 95% Confidence Interval, CI: 1.32-2.93; p = 0.001) and in those with SqCC (HR = 2.96; 95% CI: 1.43-6.12; p = 0.003). Promoter methylation of SPARC gene should represent an interesting prognostic biomarker in NSCLC, with potential application in the squamous early-stage context. Further research in this setting on larger independent cohorts of lung patients with different histologies and stages of disease are warranted.


Symptoms of eating disorders in patients with obsessive-compulsive disorder.
This study was designed to explore potential overlap of the symptoms of obsessive-compulsive disorder and eating disorders. The authors administered a structured, self-rating scale, the Eating Disorder Inventory, to 59 outpatients at an obsessive-compulsive disorder clinic and to 60 sex-matched normal volunteers. The Eating Disorder Inventory has been previously validated as a reliable measure of the specific cognitive and behavioral dimensions of the psychopathology typical of patients with eating disorders. The scores of the patients with obsessive-compulsive disorder and of the healthy comparison subjects were compared with those of 32 female inpatients with anorexia nervosa (N = 10) or bulimia nervosa (N = 22) who had also been given the inventory. The patients with obsessive-compulsive disorder scored significantly higher than the healthy comparison subjects on all eight subscales of the Eating Disorder Inventory: drive for thinness, bulimia, body dissatisfaction, ineffectiveness, perfectionism, interpersonal distrust, interoceptive awareness, and maturity fears. Relative to the healthy subjects, male patients with obsessive-compulsive disorder had more symptoms than female patients with obsessive-compulsive disorder. The scores of the female patients with obsessive-compulsive disorder were midway between those of the 32 female patients with eating disorders and those of the 35 female normal subjects. These results suggest that patients with obsessive-compulsive disorder display significantly more disturbed eating attitudes and behavior than healthy comparison subjects and that they share some of the psychopathological eating attitudes and behavior that are common to patients with eating disorders.


Integrating identities.
Lesbians and gays who become step parents undergo a series of identity transitions. Previous models typically used to describe gay and lesbian identity formation lack attention to later life transitions. I argue that these models provide little understanding of the experiences of lesbians and gays who integrate their lesbian/gay identity with a step parent status. This transition is more complex than that experienced by either their partners (previously married biological parents) or by heterosexual step parents.


Urinary benzylmercapturic acid as a marker of occupational exposure to toluene.
To examine if benzylmercapturic acid (or N-acetyl- S-benzyl cysteine) in urine can be used as a marker of occupational exposure to toluene. A factory survey was conducted in the latter half of a working week. A group of 46 men, who volunteered for the study, was engaged in ink preparation, surface coating or printing work. Diffusive samplers were used to measure average solvent exposure in an 8-h shift. End-of-shift urine samples were analyzed for benzylmercapturic acid (BMA) by a modification of an HPLC method originally developed for phenylmercapturic acid determination. The workers were exposed primarily to toluene [TOL; 13 ppm as the geometric mean (GM) and 86 ppm at the maximum] together with isopropyl alcohol (<1 and 4 ppm), ethyl acetate (2 and 127 ppm) and methyl ethyl ketone (2 and 142 ppm). BMA in urine correlated closely [correlation coefficient ( r) =0.7] with TOL in air, irrespective of correction for urine density. The lowest TOL concentration at which urinary BMA increased to a measurable level was approximately 10 ppm, and urinary BMA could separate the exposed from the non-exposed when TOL exposure was 15 ppm or higher. BMA in end-of-shift urine samples is a good marker of occupational TOL exposure. Urinalysis for BMA is sensitive enough to detect TOL exposure at 15 ppm, and therefore BMA appears to be more sensitive than hippuric acid and possibly o-cresol as a urinary marker of TOL exposure.


Bioreactor maintained living skin matrix.
Numerous reconstructive procedures result in wounds that require skin grafting. Often, the amount of tissue available from donor sites is limited. In vivo tissue expanders have been used clinically to generate larger sections of skin, and other methods exist to cover large wounds, but all have significant limitations. We investigated whether these difficulties could be overcome by increasing the surface area of skin in vitro while maintaining tissue viability. Human foreskin was incrementally expanded in a computer-controlled bioreactor system over 6 days to increase its surface dimensions under culture conditions. Morphological, ultrastructural, and mechanical properties of the foreskin were evaluated before and after expansion using histology, scanning electron microscopy, mercury porosimetry, and tensile testing. The surface area of the tissue was 110.7% +/- 12.2% greater, with maintenance of cell viability and proliferative potential. Histomorphological and ultrastructural analyses showed that dermal structural integrity was preserved. The pore diameter of the expanded skin was 64.49% +/- 32.8% greater. The mechanical properties were not adversely affected. These findings show that expansion of living skin matrices can be achieved using a computer-controlled bioreactor system. This technique provides an opportunity to generate large amounts of skin for reconstructive procedures.


Mitochondrial regulation of the cytosolic Ca2+ concentration and the InsP3-sensitive Ca2+ store in guinea-pig colonic smooth muscle.
1. Mitochondrial regulation of the cytosolic Ca2+ concentration ([Ca2+]c) in guinea-pig single colonic myocytes has been examined, using whole-cell recording, flash photolysis of caged InsP3 and microfluorimetry. 2. Depolarization increased [Ca2+]c and triggered contraction. Resting [Ca2+]c was virtually restored some 4 s after the end of depolarization, a time when the muscle had shortened to 50 % of its fully relaxed length. The muscle then slowly relaxed (t = 17 s). 3. The decline in the Ca2+ transient was monophasic but often undershot or overshot resting levels, depending on resting [Ca2+]c. The extent of the overshoot or undershoot increased with increasing peak [Ca2+]c. 4. Carbonyl cyanide m-chlorophenyl hydrazone (CCCP; 5 microM), which dissipates the mitochondrial proton electrochemical gradient and therefore prevents mitochondrial Ca2+ accumulation, slowed Ca2+ removal at high ( > 300 nM) but not at lower [Ca2+]c and abolished [Ca2+]c overshoots. Oligomycin B (5 microM), which prevents mitchondrial ATP production, affected neither the rate of decline nor the magnitude of the overshoot. 5. During depolarization, the global rhod-2 signal (which represents the mitochondrial matrix Ca2+ concentration, [Ca2+]m) rose slowly in a CCCP-sensitive manner during and for about 3 s after depolarization had ended. [Ca2+]m then slowly decreased over tens of seconds. 6. Inhibition of sarcoplasmic reticulum Ca2+ uptake with thapsigargin (100 nM) reduced the undershoot and increased the overshoot. 7. Flash photolysis of caged InsP3 (20 microM) evoked reproducible increases in [Ca2+]c. CCCP (5 microM) reduced the magnitude of the [Ca2+]c transients evoked by flash photolysis of caged InsP3. Oligomycin B (5 microM) did not reduce the inhibition of the InsP3-induced Ca2+ transient by CCCP thus minimizing the possibility that CCCP lowered ATP levels by reversing the mitochondrial ATP synthase and so reducing SR Ca2+ refilling. 8. While CCCP reduced the magnitude of the InsP3-evoked Ca2+ signal, the internal Ca2+ store content, as assessed by the magnitude of ionomycin-evoked Ca2+ release, did not decrease significantly. 9. [Ca2+]c decline in smooth muscle, following depolarization, may involve mitochondrial Ca2+ uptake. Following InsP3-evoked Ca2+ release, mitochondrial uptake of Ca2+ may regulate the local [Ca2+]c near the InsP3 receptor so maintaining the sensitivity of the InsP3 receptor to release Ca2+ from the SR.


Modified mesenchymal stem cells using miRNA transduction alter lung injury in a bleomycin model.
Although different preclinical models have demonstrated a favorable role for bone marrow-derived mesenchymal stem cells (B-MSC) in preventing fibrosis, this protective effect is not observed with late administration of these cells, when fibrotic changes are consolidated. We sought to investigate whether the late administration of B-MSCs overexpressing microRNAs (miRNAs) let-7d (antifibrotic) or miR-154 (profibrotic) could alter lung fibrosis in a murine bleomycin model. Using lentiviral vectors, we transduced miRNAs (let-7d or miR-154) or a control sequence into human B-MSCs. Overexpression of let-7d or miR-154 was associated with changes in the mesenchymal properties of B-MSCs and in their cytokine expression. Modified B-MSCs were intravenously administered to mice at day 7 after bleomycin instillation, and the mice were euthanized at day 14 Bleomycin-injured animals that were treated with let-7d cells were found to recover quicker from the initial weight loss compared with the other treatment groups. Interestingly, animals treated with miR-154 cells had the lowest survival rate. Although a slight reduction in collagen mRNA levels was observed in lung tissue from let-7d mice, no significant differences were observed in Ashcroft score and OH-proline. However, the distinctive expression in cytokines and CD45-positive cells in the lung suggests that the differential effects observed in both miRNA mice groups were related to an effect on the immunomodulation function. Our results establish the use of miRNA-modified mesenchymal stem cells as a potential future research in lung fibrosis.


Essential immunogens in human pertussis: the role of fimbriae.
After the decline in pertussis vaccination in Britain from the mid-1970s, isolates possessing agglutinogen 2 (types 1.2.3 and 1.2) have replaced type 1.3 as the predominant serotypes. These agglutinogen-2 strains are fimbriate, and their predominance in non-vaccinated communities may result from enhanced attachment to mucosal cells. However, type 1.3 cells are not fimbriate; and, because agglutinogen 3 is essential in fully effective whole-cell vaccine, a subcellular vaccine prepared from fimbriae alone (agglutinogen 2) would probably be inadequate. The mouse can be killed with type 1 strains, devoid of agglutinogens 2 and 3, and is therefore not a suitable model for ensuring that pertussis vaccine contains these essential immunogens.


Flexible TiVCTx MXene film for high-performance magnesium-ion storage device.
Magnesium-based battery system has emerged as the potential candidate to beyond Li-ion battery system due to the numerous advantageous of magnesium anode, such as natural abundance, high capacity and dendrites free. However, the selection of cathode materials and the intercalation of magnesium-ions in the cathode host material remains a challenge due to the strong interaction of highly polar divalent magnesium ions with the cathode material, making the diffusion of magnesium ions relatively difficult. Herein, the flexible TiVCTx MXene film was developed via a facile and economical approach. As the cathode host material for magnesium-ion storage, the freestanding TiVCTx MXene film displays a high specific capacity of 111 and 135 mAh g-1 at a current density of 0.05 A g-1 for magnesium-ion batteries (MIB) and Mg/Li hybrid batteries (MLHB). Furthermore, a long-term cycling stability over 1000 cycles was demonstrated and a detailed investigation of the unique long activation phenomenon of MXene films during cycling. More importantly, the reaction mechanism of magnesium-ion storage was validated, i.e., the MXene interlayer spacing variation with the reversible Mg2+ diffusion behavior. This work reveals the magnesium storage mechanism of MXene materials and provides a new pathway for high-performance storage of magnesium-ion cathode materials.


Bcl-2 is a key regulator for the retinoic acid-induced apoptotic cell death in neuroblastoma.
Retinoic acid (RA) has been shown to induce neuronal differentiation and/or apoptosis, and is widely used as a chemotherapeutic agent for treating the patients with neuroblastoma. However, the therapeutic effect of RA is still limited. To unveil the molecular mechanism(s) inducing differentiation and apoptosis in neuroblastoma cells, we compared CHP134 and NB-39-nu cell lines, in which all-trans-RA (ATRA) induces apoptosis, with LA-N-5 and RTBM1 cell lines, in which it induces neuronal differentiation. Here, we found that Bcl-2 was strongly downregulated in CHP134 and NB-39-nu cells, whereas it was abundantly expressed in LA-N-5 and RTBM1 cells. ATRA-mediated apoptosis in CHP134 and NB-39-nu cells was associated with a significant activation of caspase-9 and caspase-3 as well as cytoplasmic release of cytochrome c from mitochondria in a p53-independent manner. Enforced expression of Bcl-2 significantly inhibited ATRA-mediated apoptosis in CHP134 cells. In addition, treatment of RTBM1 cells with a Bcl-2 inhibitor, HA14-1, enhanced apoptotic response induced by ATRA. Of note, two out of 10 sporadic neuroblastomas expressed bcl-2 at undetectable levels and underwent cell death in response to ATRA in primary cultures. Thus, our present results suggest that overexpression of Bcl-2 is one of the key mechanisms to give neuroblastoma cells the resistance against ATRA-mediated apoptosis. This may provide a new therapeutic strategy against the ATRA-resistant and aggressive neuroblastomas by combining treatment with ATRA and a Bcl-2 inhibitor.


Males are overrepresented among life science researchers committing scientific misconduct.
A review of the United States Office of Research Integrity annual reports identified 228 individuals who have committed misconduct, of which 94% involved fraud. Analysis of the data by career stage and gender revealed that misconduct occurred across the entire career spectrum from trainee to senior scientist and that two-thirds of the individuals found to have committed misconduct were male. This exceeds the overall proportion of males among life science trainees and faculty. These observations underscore the need for additional efforts to understand scientific misconduct and to ensure the responsible conduct of research. As many of humanity's greatest problems require scientific solutions, it is critical for the scientific enterprise to function optimally. Misconduct threatens the scientific enterprise by undermining trust in the validity of scientific findings. We have examined specific demographic characteristics of individuals found to have committed research misconduct in the life sciences. Our finding that misconduct occurs across all stages of career development suggests that attention to ethical aspects of the conduct of science should not be limited to those in training. The observation that males are overrepresented among those who commit misconduct implies a gender difference that needs to be better understood in any effort to promote research integrity.


Inhibition of lipoprotein lipase activity by sphingomyelin: role of membrane surface structure.
We have recently shown that sphingomyelin (SM) strongly inhibits lipoprotein lipase (LPL)-mediated lipolysis in monolayers and emulsion particles. To further evaluate how SM modulates LPL activity on the emulsion surface, the relationship between membrane surface structure and LPL activity was investigated. We measured fluorescence anisotropy of 1-palmitoyl-2-[3-(diphenylhexatrienyl)propionyl]-sn-3-phosphati dylcho line, probing surface acyl chain fluidity, and fluorescence lifetime of N-(5-dimethylaminonaphthalene-1-sulfonyl)dipalmitoylphosphatidylethan olamine in H(2)O and D(2)O buffer, assessing the degree of hydration in the head group region. The results revealed that incorporation of egg SM into triolein-egg phosphatidylcholine emulsions markedly increased acyl chain order and decreased head group hydration of the surface monolayers. In contrast, cholesterol was shown to increase head group hydration despite a strong increase in acyl chain order. The close correlation between the apparent K(m) values of LPL and the degree of head group hydration indicated that LPL interacts with the head group region rather than with the hydrophobic interior of the surface monolayers. However, apparent V(max) did not show a simple correlation with any surface structure, and the finding in which SM had no effect on apparent V(max) of medium-chain triglyceride emulsions suggested that the hydrophobic interaction between acyl chains of SM and triglyceride at the emulsion surface is important for determining the apparent V(max). These results showed conclusively that SM inhibits LPL activity mainly by changing the emulsion surface structure and not by a specific interaction between SM and LPL.


Evaluation of clinical and laboratory findings of pediatric and adult patients with oropharyngeal tularemia in Turkey: a combination of surgical drainage and antibiotic therapy increases treatment success.
We analyzed the clinical and laboratory findings of both pediatric and adult patients with oropharyngeal tularemia. We also compared the therapeutic outcomes of patients who underwent surgical drainage of lymph nodes early or late during antibiotic therapy. A total of 68 patients with oropharyngeal tularemia, including 26 children and 42 adults, were enrolled in this study. The average duration between symptom onset and hospital admission was 20.8 days (4-60 days) in the pediatric group and 32.6 days (4-90 days) in the adult group (P = 0.009). The most frequently observed clinical symptoms were sore throat (100% and 100%), fever (96.2% and 90.5%), tonsillitis (69.2% and 78.6%), and rash (15.4% and 11.9%) in the pediatric and adult groups, respectively. However, the frequencies of erythema, tenderness, and fluctuant of enlarged lymph nodes were significantly higher in the adult group than in the pediatric group (P = 0.005, P = 0.029, and P = 0.041, respectively). Treatment failure was observed in 2 (7.7%) pediatric patients and 4 (9.5%) adult patients, for a total of 6 (8.8%) treatment failures in the study group. Similar clinical findings and treatment outcomes were observed in both groups. We concluded that a combination of surgical drainage and antibiotic therapy increases treatment success for patients diagnosed with oropharyngeal tularemia.


[Osteoporosis at high remodeling and parathyroid function. Histo-biological confrontations (author's transl)].
In order to evaluate the relationship between apparently idiopathic osteoporosis and parathyroid hormone secretion, plasma immunoreactive parathyroid hormone (iPTH) was measured in 57 untreated osteoporotic patients using a carboxyl-terminal specific antiserum, and sections of undecalcified iliac bone biopsies from these subjects, who had been previously doubly labelled with tetracycline, were quantitatively analysed. Twenty-one patients (36%) exhibited histological signs of a high remodeling similar to that which is present in primary hyperparathyroidism, but their osteoplastic appositional rate values were lower. Among these 21 cases 8 had an increase of their iPTH levels. These data and those of the literature indicate that in a few cases high remodeling osteoporosis may be associated with parathyroid hypersecretion, but do not bring out the evidence that the increased circulating iPTH is the cause of osteoporosis. The authors draw from their results some practical consequences for the treatment of high remodeling osteoporosis.


Morpho-physiological responses of tall wheatgrass populations to different levels of water stress.
Tall wheatgrass [Elymus elongatus subsp. ponticus (Podp.) Melderis] is a perennial forage grass cultivated in dry, saline or alkaline environments. The morpho-physiological characteristics of four populations of tall wheatgrass from different climatic-edaphic origins were evaluated under three conditions of water stress (100%-50%-30% of field capacity). The trial was analyzed with three replicates and two-factor ANOVA in pots within the greenhouse during 35 days. Only dry matter and tiller number showed interaction between populations and water conditions. The most relevant changes in morpho-physiological parameters under strong water stress were reduced dry matter production (48-32% differing among populations), smaller leaf and tiller size (46% and 28%), together with higher water use efficiency (74%), and increased proline and protein contents (144% and 71%), smaller tiller number (30-11% differing among populations) and a slight decrease in leaf water content (3%). The populations differed in growth strategies and morpho-physiological mechanisms to survive water stress, which could be related to their habitat background. The study shows the stability in dry matter production under all levels of water stress, which can be related to the higher tiller number. Due to this plasticity, tall wheatgrass should be studied as a species with great potential to adapt to drought stress.


A rare cause of parastomal hernia: stomach herniation.
Our case of a parastomal hernia is rare because the stomach became incarcerated in the hernial sac. The diagnosis of parastomal hernia is not a difficult one, but one must be aware of the possible complications of the colostomy and the rare occurrence of the parastomal hernia containing the stomach.


Could an optimized joint pharmacokinetic/pharmacodynamic target attainment of continuous infusion ceftazidime-avibactam be a way to avoid the need for combo therapy in the targeted treatment of deep-seated DTR Gram-negative infections?
The objective of this study was to assess the relationship between joint pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous infusion (CI) ceftazidime-avibactam and the microbiological outcome of documented difficult-to-treat resistant (DTR) Gram-negative infections. A 2-year retrospective cohort study was performed in patients receiving CI ceftazidime-avibactam mono- or combo therapy for documented DTR Gram-negative infections and undergoing therapeutic drug monitoring of both ceftazidime and avibactam. The free fractions of steady-state concentrations (fCss) of ceftazidime and avibactam were calculated. The joint PK/PD target was considered optimal when both the fCss/MIC ratio for ceftazidime ≥4 (equivalent to 100% fT>4xMIC) and the fCss/CT ratio for avibactam >1 (equivalent to 100% fT >CT of 4.0 mg/L) were simultaneously achieved (quasi-optimal if only one of the two and suboptimal if neither of the two was achieved). Multivariate logistic regression analysis was applied for testing potential variables associated with microbiological failure. Fifty-eight patients were treated with CI ceftazidime-avibactam mono- (36) or combo therapy (22) for documented DTR Gram-negative infections [74.2% for primary or secondary bloodstream infections (BSIs)]. Combo therapy was administered more frequently to intensive care unit (ICU) patients (P = 0.023) or for pneumonia (P = 0.001) and less frequently for intra-abdominal infections and BSIs (P = 0.04). Microbiological failure occurred in five cases (8.6%, three in mono- and two in combo therapy). In the multivariate analysis, the suboptimal/quasi-optimal joint PK/PD target emerged as the only independent predictor of microbiological failure (odds ratio [OR] 11.11; 95% confidence interval [CI] 1.31-93.98; P = 0.023), whereas monotherapy was not (P = 0.99). Optimized joint PK/PD target attainment of CI ceftazidime-avibactam monotherapy could represent a way forward for allowing microbiological eradication of DTR Gram-negative infections and could render unnecessary combo therapy.


Bioequivalence evaluation of rilmenidine in healthy volunteers.
The bioavailability of two rilmenidine tablet formulations was compared in healthy male (17) and female (8) subjects, aged 18 to 36 years, during a laboratory-blind, randomized, two-treatment, two-period, cross-over study under fasting conditions. In each treatment phase subjects received a single dose of 1.544 mg rilmenidine dihydrogen phosphate (CAS 85409-38-7), equivalent to 1 mg rilmenidine (CAS 54187-04-1). Consecutive dosing was separated by a drug-free wash-out period of 7 d. Following each dosing, serial venous blood samples were collected over a period of 48 h for the determination of plasma rilmenidine concentrations by means of a validated LCMS/MS method. The most frequently reported drug-related adverse events were dizziness and headache ranging from mild to moderate in intensity. The geometric mean C(max) of rilmenidine for the reference and test products was 3.73 and 3.97 ng/ml, respectively. The corresponding geometric mean AUC(0-infinity)) was 34.0 and 35.1 ng x h/ml. T(max) for both products under investigation appeared at 1.33 h. The test product was shown to be bioequivalent to the reference product with respect to all pharmacokinetic variables investigated.


Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer.
A major clinical hurdle for the management of advanced prostate cancer (PCa) in patients is the resistance of tumors to androgen deprivation therapy (ADT) and their subsequent development into castration-resistant prostate cancer (CRPC). While recent studies have identified potential pathways involved in CRPC development, the drivers of CRPC remain largely undefined. Here we determined that nuclear receptor coactivator 2 (NCoA2, also known as SRC-2), which is frequently amplified or overexpressed in patients with metastatic PCa, mediates development of CRPC. In a murine model, overexpression of NCoA2 in the prostate epithelium resulted in neoplasia and, in combination with Pten deletion, promoted the development of metastasis-prone cancer. Moreover, depletion of NCoA2 in PTEN-deficient mice prevented the development of CRPC. In human androgen-sensitive prostate cancer cells, androgen signaling suppressed NCoA2 expression, and NCoA2 overexpression in murine prostate tumors resulted in hyperactivation of PI3K/AKT and MAPK signaling, promoting tumor malignance. Analysis of PCa patient samples revealed a strong correlation among NCoA2-mediated signaling, disease progression, and PCa recurrence. Taken together, our findings indicate that androgen deprivation induces NCoA2, which in turn mediates activation of PI3K signaling and promotes PCa metastasis and CRPC development. Moreover, these results suggest that the inhibition of NCoA2 has potential for PCa therapy.


Delayed diagnosis of hypopituitarism following severe traumatic brain injury.
The following case illustrates a 10-year delay in the diagnosis of hypopituitarism after severe traumatic brain injury in a 22-year-old man crushed by a forklift truck. His symptoms of mood changes, headaches and sleep pattern disturbances were attributed to post traumatic brain injury syndrome resulting in a delay in diagnosing the underlying pathology. Following recurrent episodes of symptomatic hyponatraemia, hypopituitarism was diagnosed. When pituitary hormone replacement treatment was given, there was clinical and biochemical improvement. There is currently very limited evidence in the literature to routinely screen patients post traumatic brain injury for pituitary dysfunction.


Insertion of the total artificial heart in the Fontan circulation.
Though the Fontan circulation provides long-term palliation for patients with univentricular hearts, failure of the circulation may ensue, leaving heart transplantation as the only definitive treatment. For Fontan patients awaiting transplant, both "right-sided" and "left-sided" symptoms may be present and severe, hence, biventricular mechanical circulatory support may be indicated. This can be provided by implantation of the total artificial heart (TAH), a procedure which is performed slightly differently than in patients with biventricular hearts. In this article, the unique aspects of implantation of this device in a patient with a Fontan operation are reviewed, with specific attention to the most commonly encountered anatomic variants of importance to the implanting surgeon.


[Immunologic disorders and their significance in the treatment of cervical cancer].
The study is concerned with immunologic status (cell-mediated and humoral immunity) as a factor influencing the choice of scheme of treatment for carcinoma of cervix uteri. The indexes of immunocompetence should be taken into account in planning the differential treatment of precancer and early forms of carcinoma of cervix uteri. Radiation treatment exerts an immunosuppressive effect. However, immunologic indexes are not affected considerably by laser destruction or surgery. Cryodestruction has a beneficial effect on cell-mediated immunity. Considering these effects as well as the long-term results of different procedures of treatment, laser coagulation, cryogenic destruction or diathermoconization should be recommended for management of carcinoma in situ of cervix uteri, and extensive extirpation of the uterus, unattended by radiation, for Tla.


Absence of testicular DAZ gene expression in idiopathic severe testiculopathies.
Deletions of the DAZ (deleted in azoospermia) gene family are frequently responsible for male infertility and are generally assessed by analyses of genomic DNA extracted from peripheral leukocytes. The multicopy nature of this gene prevents the distinction of intragenic deletions or deletions not involving the whole DAZ gene cluster. Thus it is still unclear whether each DAZ copy is effectively expressed in the testis. We analysed, by reverse transcription-polymerase chain reaction (RT-PCR), the expression of DAZ, RBM and SRY genes, in testicular cells from infertile men affected by idiopathic severe hypospermatogenesis, obstructive azoospermia and Sertoli cell-only syndrome. Normal mRNA for DAZ, RBM and SRY were observed in obstructive azoospermia, whereas only SRY transcripts were detected when only Sertoli cells were present. Nine out of 10 patients affected by idiopathic severe hypospermatogenesis had normal expression of SRY, RBM and DAZ, while in one patient no DAZ transcript was detected, suggesting that his testiculopathy was related to the absence of DAZ expression. The lack of DAZ mRNA in testicular cells with an apparently normal DAZ gene constitution on DNA extracted from leukocytes may be explained by different hypotheses: (i) not all the copies of the DAZ gene cluster are transcribed in the germ cells and the reported patient had a small deletion involving only the active ones; (ii) the patient may be mosaic for the DAZ gene having a normal constitution in leukocytes and be deleted for DAZ gene in the testis; (iii) abnormalities of DAZ transcription may exist. These findings highlight the intrinsic interpretative difficulties of normal PCR analysis for DAZ and RBM on leukocytes and suggest caution in the use of germ cells for assisted reproductive techniques in these cases to avoid transmission of genetic abnormalities to male offspring.


Documenting and validating metrological traceability of serum alanine aminotransferase measurements: a priority for medical laboratory community for providing high quality service in hepatology.
Alanine aminotransferase (ALT) represents the first-level test to detect individuals with hepatocellular damage of any etiology. However, it has been highlighted that the lack of assay harmonization may lead to overdiagnosis and unnecessary further testing if guideline-recommended fixed cut-offs are uncritically employed. To solve the issue of ALT (dis)harmonization and improve the interpretation of its values, a series of urgent actions for documenting and validating metrological traceability of serum ALT measurements, as described in this paper, are no longer postponeable. It is time that all medical laboratory stakeholders (in vitro diagnostic manufacturers, laboratorians, external quality assessment scheme organizers) actively co-operate to implement the ALT standardization in a concerted action following well-established theoretical assumptions and applying experimental approaches described in literature.


Flavopiridol suppresses tumor necrosis factor-induced activation of activator protein-1, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase (MAPK), p44/p42 MAPK, and Akt, inhibits expression of antiapoptotic gene products, and enhances apoptosis through cytochrome c release and caspase activation in human myeloid cells.
Although flavopiridol, a semisynthetic flavone, was initially thought to be a specific inhibitor of cyclin-dependent kinases, it has now been shown that flavopiridol mediates antitumor responses through mechanism(s) yet to be defined. We have shown previously that flavopiridol abrogates tumor necrosis factor (TNF)-induced nuclear factor-kappaB (NF-kappaB) activation. In this report, we examined whether this flavone affects other cellular responses activated by TNF. TNF is a potent inducer of activator protein-1 (AP-1), and flavopiridol abrogated this activation in a dose- and time-dependent manner. Flavopiridol also suppressed AP-1 activation induced by various carcinogens and inflammatory stimuli. When examined for its effect on other signaling pathways, flavopiridol inhibited TNF-induced activation of various mitogen-activated protein kinases, including c-Jun NH(2)-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and p44/p42 MAPK. It is noteworthy that this flavone also suppressed TNF-induced activation of Akt, a cell survival kinase, and expression of various antiapoptotic proteins, such as IAP-1, IAP-2, XIAP, Bcl-2, Bcl-xL, and TRAF-1. Flavopiridol also inhibited the TNF-induced induction of intercellular adhesion molecule-1, c-Myc, and c-Fos, all known to mediate tumorigenesis. Moreover, TNF-induced apoptosis was enhanced by flavopiridol through activation of the bid-cytochrome-caspase-9-caspase-3 pathway. Overall, our results clearly suggest that flavopiridol interferes with the TNF cell-signaling pathway, leading to suppression of antiapoptotic mechanisms and enhancement of apoptosis.


Ado-Mediated Depletion of Taurine Impairs Mitochondrial Respiratory Capacity and Alters the Chromatin Landscape of Inguinal Adipose Tissue.
Non-shivering thermogenesis (NST) has strong potential to combat obesity; however, a safe molecular approach to activate this process has not yet been identified. The sulfur amino acid taurine has the ability to safely activate NST and confer protection against obesity and metabolic disease in both mice and humans, but the mechanism of this action is unknown. In this study, we discover that a suite of taurine biosynthetic enzymes, especially that of cysteamine dioxygenase (ADO), significantly increases in response to β3 adrenergic signaling in inguinal adipose tissue (IWAT) in order to increase intracellular concentrations of taurine. We further show that ADO is critical for thermogenic mitochondrial respiratory function as its ablation in adipocytes significantly reduces taurine levels, which leads to declines in mitochondrial oxygen consumption rates. Finally, we demonstrate via assay for transposase-accessible chromatin with sequencing (ATAC-seq) that taurine supplementation in beige adipocytes has the ability to remodel the chromatin landscape to increase the chromatin accessibility and transcription of genes, such as glucose-6-phosphate isomerase 1 (Gpi1), which are critical for NST. Taken together, our studies highlight a potential mechanism for taurine in the activation of NST that can be leveraged toward the treatment of obesity and metabolic disease.


Diagnosis of left ventricular systolic dysfunction (LVSD): development and validation of a clinical prediction rule in primary care.
Diagnosing suspected left ventricular systolic dysfunction (LVSD) in the community is a challenge for GPs. We developed and validated a clinical prediction rule (CPR) for LVSD based on history, examination and electrocardiogram (ECG). Prospective cohort studies of 458 symptomatic patients (derivation cohort) and 535 patients (validation cohort) in 26 general practices in Tayside and Fife, Scotland. All patients underwent a structured clinical examination and ECG and the 'reference standard' investigation of echocardiography to establish the presence of LVSD. Four elements from the clinical history and examination were all independently associated with LVSD--male sex [adjusted odds ratio (OR) 2.5; 95% CI 1.1, 5.0], presence of orthopnoea (OR 5.4; 1.9, 13.8) history of myocardial infarction (OR 5.6; 2.3, 13.6) and elevated jugular venous pulsations (OR 15.1; 4.6, 49.3). Addition of ECG (OR 20.6; 2.7, 158.6) provides important diagnostic information in terms of probability of LVSD. A CPR based on the presence or absence of these five elements will generate probabilities ranging from 1% to 97% for LVSD when applied to an individual patient. In the validation cohort, the model under-predicted the probability of LVSD, particularly at lower levels of expected risk, reflecting differences in the risk-factor profiles of the derivation and validation cohorts. The derived CPR provides quantitative estimates of post-test probability for LVSD. This rule requires further validation in other populations and settings because of the difficulties encountered in the validation cohort.


Retention and response rates in 14 261 PsA patients starting TNF inhibitor treatment-results from 12 countries in EuroSpA.
To investigate TNF inhibitor (TNFi) retention and response rates in European biologic-naïve patients with PsA. Prospectively collected data on PsA patients in routine care from 12 European registries were pooled. Heterogeneity in baseline characteristics between registries were explored (analysis of variance and pairwise comparison). Retention rates (Kaplan-Meier), clinical remission [28-joint count DAS (DAS28) <2.6; 28 joint Disease Activity index for Psoriatic Arthritis ⩽4] and ACR criteria for 20% improvement (ACR20)/ACR50/ACR70 were calculated, including LUNDEX adjustment. Overall, 14 261 patients with PsA initiated a first TNFi. Considerable heterogeneity of baseline characteristics between registries was observed. The median 12-month retention rate (95% CI) was 77% (76, 78%), ranging from 68 to 90% across registries. Overall, DAS28/28 joint Disease Activity index for Psoriatic Arthritis remission rates at 6 months were 56%/27% (LUNDEX: 45%/22%). Six-month ACR20/50/70 responses were 53%/38%/22%, respectively. In patients initiating a first TNFi after 2009 with registered fulfilment of ClASsification for Psoriatic ARthritis (CASPAR) criteria (n = 1980) or registered one or more swollen joint at baseline (n = 5803), the retention rates and response rates were similar to those found overall. Approximately half of >14 000 patients with PsA who initiated first TNFi treatment in routine care were in DAS28 remission after 6 months, and three-quarters were still on the drug after 1 year. Considerable heterogeneity in baseline characteristics and outcomes across registries was observed. The feasibility of creating a large European database of PsA patients treated in routine care was demonstrated, offering unique opportunities for research with real-world data.


Molecular-dynamics simulations of insertion of chemically modified DNA nanostructures into a water-chloroform interface.
DNA-based two-dimensional and three-dimensional arrays have been used as templates for the synthesis of functional polymers and proteins. Hydrophobic or amphiphilic DNA arrays would be useful for the synthesis of hydrophobic molecules. The objective of this study was to design a modified amphiphilic double crossover DNA molecule that would insert into a water-chloroform interface, thus showing an amphiphilic character. Since experiments for such designs are tedious, we used molecular-dynamics simulations to identify and optimize the functional groups to modify the DNA backbone that would enable insertion into the water-chloroform interface before synthesis. By methylating the phosphates of the backbone to make phosphonates, in combination with placing a benzyl group at the 2' position of the deoxyribose rings in the backbone, we observed that the simple B-DNA structure was able to insert into the water-chloroform interface. We find that the transfer free energy of methylated benzylated DNA is better than that of either just methylated or benzylated DNA. The driving force for this insertion comes from the entropic contribution to the free energy and the favorable van der Waals interaction of the chloroform molecules with the methyl and benzyl groups of the DNA.


A psychophysiological investigation of the effects of driving longer-combination vehicles.
Fatigue contributes to driving-related accidents and fatalities. Cardiovascular measures such as heart rate and heart rate variability may serve as early indicators of fatigue. In the current investigation, 24 professional truck drivers drove three truck configurations: single trailer, triple trailer A-dolly, and triple trailer C-dolly on a standard route that lasted between 8 and 10 h. During the driving session, continuous measures of heart rate were quantified on-line. In addition to heart rate, two measures of heart rate variability (i.e. respiratory sinus arrhythmia and the Traube-Hering-Mayer wave or 0.1 Hz oscillation) were derived from the beat-to-beat heart rate. Independent of configuration, heart rate increased and the measures of heart rate variability decreased during the driving route. Only heart rate statistically differed among the configurations. Since heart rate is physiologically linked to metabolic output, the results suggest that the observed effect may be due to the physical demands required to drive each truck configuration. In support of this conclusion, the heart rate effect was consistent with the subjective report of task demand. The slowest heart rates were observed while driving the least demanding configuration (i.e. single trailer). The fastest heart rates were observed while driving the most demanding configuration (i.e. triple trailer A-dolly).


[Pregnant and mentally incompetent].
Two women, aged 31 and 36 years, under treatment for schizophrenia and psychotic episodes, respectively, became pregnant and decided to discontinue their medication. Thereupon the psychiatric disorder recurred and they refused--i.e. they were unable--to consent to a proposed treatment or investigation regarding their pregnancies. The necessary consent had to be obtained from a legal guardian. This was the husband in the first, urgent case. In the second case approval from the judge was obtained for the patient to be admitted against her will to protect her life and that of the foetus. In the Netherlands obstetric intervention to protect the life of the mother or her unborn child is legally regulated by the Wet Bijzondere Opnemingen in Psychiatrische Ziekenhuizen (Act on Compulsory Admissions to Psychiatric Hospitals) and the Wet op de Geneeskundige Behandelingsovereenkomst (Act on Agreement Concerning Medical Treatment).


DNA profiling from heroin street dose packages.
A large amount of heroin street doses are seized and examined for drug content by the Israel police. These are generally wrapped in heat-sealed plastic. Occasionally it is possible to visualize latent fingerprints on the plastic wrap itself, but the small size of the plastic item and the sealing process makes the success rate very low. In this study, the possibility of extracting and profiling DNA from the burnt edge of the plastic wrap was investigated. The idea was based on the assumption that epithelial cells might be trapped during the sealing process. The results show that there are sufficient quantities of DNA deposited at the "amorphic" burnt edges of sealed street doses for DNA profiling to be carried out. A controlled experiment using a known donor was performed. This subject carried out sealing of "street drug" packages and consequent DNA extractions were performed to show that known DNA profiles could be recovered from such packages, as a result of handling by the "packer." "Square-like" burnt edges did not yield DNA profiles, probably because of differences in the sealing process. It was also shown that DNA could be recovered from the plastic wrap itself and not only from the amorphic burnt edges. As heroin dealers and drug users are often involved in other crimes and run-ins with the law, the effective extraction and addition of their DNA profiles from such items of evidence to the newly established DNA database in Israel provides new avenues in the continued fight against crime and drug traffickers.


[Surgical treatment of multiple heart valve defects].
The article deals with the study of problems of the surgical treatment of patients with multivalvular heart diseases. Problems of myocardial protection, the methods for correcting tricuspid disease, and the attitude towards attendant valvular diseases depending on their severity are discussed on the grounds of the analysis of hospital fatality rate in a group fo 505 patients who underwent one-stage correction of two or three defective heart valves and the appraisal of late results. Analysis of the late results indicates that a more radical approach to the surgical treatment of mitral valvular disease is necessary and that marked relative insufficiency and all forms of organic tricuspid disease must be corrected without fail.


Reflections on Patient-Centered Care: From the Perspective of a Young Otolaryngologist.
It is now well recognized that patient engagement in health care is a key factor in improving satisfaction; however, it is also critical if we are to improve the health outcomes of our patients, as well as the economic and quality outcomes of our health system. Medicine, though, has traditionally resisted a culture of patient-centered or patient-controlled care. What follow are the reflections of one otolaryngologist on the importance and challenges of making the transition to patient-centered care.


Decreased spinothalamic and dorsal column medial lemniscus-mediated function is associated with neuropathic pain after spinal cord injury.
Neuropathic pain (NP) after spinal cord injury (SCI) can significantly and negatively affect quality of life and is often refractory to currently available treatments. In order to find more effective therapeutic avenues, it would be helpful to identify the primary underlying pathophysiological mechanisms in each individual. The aim of the present study was to assess the relationship between the presence and severity of NP after SCI and measures of somatosensory function mediated via the dorsal column medial lemniscal (DCML) pathway and the spinothalamic tract (STT). Vibratory, mechanical, thermal, and pain thresholds measured in areas at and below the neurological level of injury (LOI) in persons with SCI and NP (SCI-NP, n=47) and in persons with SCI without NP (SCI-noNP, n=18) were normalized to data obtained from able-bodied pain-free control subjects (A-B, n=30). STT-mediated function at and below the LOI was significantly impaired in both SCI groups compared with A-B controls (p<0.001), but not significantly different between the two SCI groups (NP vs. no-NP). In contrast, the SCI-NP group had significantly greater impairment of DCML-mediated function at the LOI, as reflected by greater vibratory detection deficits (z=-3.89±0.5), compared with the SCI-noNP group (z=-1.95±0.7, p=0.034). Within the SCI-NP group, NP severity was significantly associated with increased thermal sensitivity below the LOI (r=0.50, p=0.038). Our results suggest that both impaired STT and DCML-mediated function are necessary for the development of NP after SCI. However, within the SCI-NP group, greater NP severity was associated with greater sensitivity to thermal stimuli below the LOI. This finding concurs with other studies suggesting that STT damage with some sparing is associated with NP.


Treatment of alveolar macrophages with cytochalasin D inhibits uptake and subsequent growth of Legionella pneumophila.
Legionella pneumophila multiplied rapidly in guinea pig and rat alveolar macrophages but failed to grow when phagocytic activity was inhibited by pretreatment with 0.5 or 1.0 microgram of cytochalasin D per ml. Attachment was not inhibited by cytochalasin D. No extracellular multiplication occurred when L. pneumophila were in close proximity to viable functional macrophages or even when the bacteria were attached to plasma membranes of the macrophages. Nonopsonized L. pneumophila were avidly phagocytized by alveolar macrophages. When bacteria were centrifuged onto a cell pellet, more than 85% of the phagocytes contained one or more bacteria within 15 min. In contrast, under the same conditions only approximately 15% of the macrophages contained nonopsonized Escherichia coli or Staphylococcus aureus. Phagocytosis of L. pneumophila by untreated guinea pig macrophages occurred by extension of pseudopodia around the bacteria in a classical manner. The failure of the bacteria to actively penetrate the phagocyte suggests that their intracellular survival must not depend on avoidance of a phagosome but rather on an inhibition of or resistance to subsequent microbicidal functions of the macrophage.


NMR and X-ray structural characterization of a cisplatin analogue able to slow down the Pt-N7 rotation of a coordinated guanine base by a billion-fold times: 2,2'-bipiperidine(dimethylmalonato)platinum(II) complex.
The synthesis and the NMR and X-ray structural characterization of a cisplatin analogue designed to reduce the Pt-N7 rotation of a coordinated guanine base by a billion times are reported. The [Pt(dmm){(+/-)-bip}] (dmm=dimethylmalonato; bip=2,2'-bipiperidine) complex crystallizes in the C2/m space group, which contemplates a mirror plane bisecting the bip and dmm ligands. Because the bip moiety (R, R or S, S configuration at the 2,2'-carbon atoms) does not have planes of symmetry, the requirements of the crystal symmetry are satisfied by a statistical disorder made of bip molecules of R, R or S, S configurations alternating at the same crystallographic site. Such an unexpected arrangement has been permitted by a "quasi planarity" of the bip ligand [maximum deviation from the mean plane through the C and N atoms of 0.2927(9) A], which allows bip molecules of different chiralities to fit in the same space. The bip array of heavy atoms is overlaid, from both sides, by a layer of "quasi axial" (C)H and (N)H atoms (six per side). Those on one side are hydrogen-bonded to the dmm oxygen atoms of another complex molecule joined in a pair. The distance between the average platinum coordination planes is as short as 3.498(1) A, comparable to those found in crystals of the [PtCl 2(bipy)] complex (bipy=2,2'-bipyridine) and of graphite, in which, however, all atoms of each unit are rigorously coplanar and there are no out-of-plane hydrogen atoms. The NMR data show a net chemical shift separation between geminal methylene protons, with the "quasi axial" protons being always at higher field with respect to the "quasi equatorial" ones. This is in accordance with a rigid bip ligand frame and the inability of the bip methylene protons adjacent to the coordinated nitrogen to rotate away from a cis-G base (G=guanine) during G rotation around the Pt-N7 bond.


Real-world challenges for hepatitis C virus medications: a critical overview.
From 2010, the landscape of hepatitis C therapeutics has been changed rapidly, and today we are standing at a cusp of a pharmacological revolution where highly effective and interferon (IFN)-free direct acting antivirals (DAAs) are already on the market. Such treatment paradigms attain 90-95% sustained virologic response (SVR; undetectable viral load at week 12 or 24 at the end of therapy) rates in treated individuals compared to 50-70% with treatment completion of dual-therapy-pegylated interferon (PEG-IFN) and ribavirin (RBV). As the major goal now for the hepatologists, clinicians, physicians, and health care workers is likely to eradicate hepatitis C infection in parallel to treatment, the demand is for a one-size-fits-all pill that could be prescribed beyond the limitations of hepatitis C genotype, viral load, previous treatment history, advanced hepatic manifestations (fibrosis, cirrhosis) and antiviral drug resistance. Although the new treatment strategies have shown high cure rates in clinical trials, such treatment paradigms are posing dilemmas too in real-world clinical practice. Therapy cost, treatment access to low and middle-income countries, treatment-emergent adverse events, lack of effective viral screening and disease progression simulation models are potential challenges in this prospect. This review article deeply overviews the challenges encountered while surmounting the burden of hepatitis C around the world.


Projections for primary hip and knee replacement surgery up to the year 2060: an analysis based on data from The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.
We estimated the number of primary total hip and knee replacements (THR and TKR) that will need to be performed up to the year 2060. We used data from The National Joint Registry for England, Wales, Northern Ireland and the Isle of Man on the volume of primary THRs (n=94,936) and TKRs (n=100,547) performed in 2018. We projected future numbers of THR and TKR using a static estimated rate from 2018 applied to population growth forecast data from the UK Office for National Statistics up to 2060. By 2060, THR and TKR volume would increase from 2018 levels by an estimated 37.7% (n=130,766) and 36.6% (n=137,341), respectively. For both males and females demand for surgery was also higher for patients aged 70 and over, with older patients having the biggest relative increase in volume over time: 70-79 years (44.6% males, 41.2% females); 80-89 years (112.4% males, 85.6% females); 90 years and older (348.0% males, 198.2% females). By 2060 demand for hip and knee joint replacement is estimated to increase by almost 40%. Demand will be greatest in older patients (70+ years), which will have significant implications for the health service requiring forward planning given that morbidity and resource use is higher in this population. These issues, coupled with two waves of COVID-19, will impact the ability of health services to deliver timely joint replacement to many patients for a number of years, requiring urgent planning.


Unlocking Pb2+ Sensing Potential in a DNA G-Quadruplex via Loop Modification with Fluorescent Chalcone Surrogates.
The ability of guanine (G)-rich DNA to bind toxic lead (Pb2+) ions within a G-quadruplex (GQ) motif is a leading DNA biosensor strategy. A major analytical hurdle for GQ detection of Pb2+ is competitive GQ templating by potassium (K+) ions. We employ the on-strand DNA synthesis of internal fluorescent chalcone surrogates within the 15-mer thrombin binding aptamer (TBA15) to address this challenge. Replacement of thymidine at the 3-position (T3) within TBA15 with an indole-4-hydroxy-indanone (Ind4HI) chalcone strongly decreases K+-GQ stability while enhancing Pb2+-GQ stability to increase Pb2+ binding specificity. The new T3-Ind4HI probe exhibits a 15-fold increase in fluorescence intensity upon binding of Pb2+ by the modified TBA15 and can detect 6.4 nM Pb2+ in the presence of 10 mM K+. Thus, replacement of the T3 residue of TBA15 with the new Ind4HI probe modulates metal ion affinity by native TBA15 to solve the analytical challenge posed by K+ in real water samples for detecting Pb2+ to meet regulatory guidelines by using a GQ biosensor.


Studying the organization of genes encoding plant cell wall degrading enzymes in Chrysomela tremula provides insights into a leaf beetle genome.
The ability of herbivorous beetles from the superfamilies Chrysomeloidea and Curculionoidea to degrade plant cell wall polysaccharides has only recently begun to be appreciated. The presence of plant cell wall degrading enzymes (PCWDEs) in the beetle's digestive tract makes this degradation possible. Sequences encoding these beetle-derived PCWDEs were originally identified from transcriptomes and strikingly resemble those of saprophytic and phytopathogenic microorganisms, raising questions about their origin; e.g. are they insect- or microorganism-derived? To demonstrate unambiguously that the genes encoding PCWDEs found in beetle transcriptomes are indeed of insect origin, we generated a bacterial artificial chromosome library from the genome of the leaf beetle Chrysomela tremula, containing 18 432 clones with an average size of 143 kb. After hybridizing this library with probes derived from 12 C. tremula PCWDE-encoding genes and sequencing the positive clones, we demonstrated that the latter genes are encoded by the insect's genome and are surrounded by genes possessing orthologues in the genome of Tribolium castaneum as well as in three other beetle genomes. Our analyses showed that although the level of overall synteny between C. tremula and T. castaneum seems high, the degree of microsynteny between both species is relatively low, in contrast to the more closely related Colorado potato beetle.


What does the left atrial v wave signify during balloon commissurotomy of mitral stenosis?
Left atrial v-wave amplitude has been associated with the presence and severity of chronic mitral regurgitation (MR) but it has not been evaluated for the detection of acute MR. We evaluated the left atrial v-wave amplitude of 205 consecutive patients with mitral stenosis immediately before and after stepwise, incremental balloon mitral commissurotomy to determine predictors of large v waves at baseline and an increase in v-wave amplitude after balloon commissurotomy. The sensitivity and specificity of an increase in v-wave amplitude for detecting worsening and severe MR were determined. A large v wave was present in 44% of patients before balloon commissurotomy and was predicted by age, mean left atrial pressure, mean transmitral gradient, mean pulmonary artery pressure, and angiographic severity of MR. There was a strong inverse correlation between v-wave amplitude and calculated left atrial compliance (r = -0.92). An increase in v-wave amplitude after balloon commissurotomy was associated with an increasing probability of worsening or severe MR. This indicator had a sensitivity, specificity, and positive and negative predictive values of 35%, 91%, 64%, 75%, respectively, for detecting any increase in MR. For the detection of severe MR, the sensitivity was 79%, specificity 89%, positive predictive value 42%, and negative predictive value 98%. Thus, left atrial v-wave amplitude reflects left atrial compliance and severity of mitral stenosis before balloon commissurotomy. An increase in v-wave amplitude is an insensitive but very specific indicator of worsening or severe MR during stepwise, incremental balloon mitral commissurotomy.


Increase in the Prevalence of Atrophic Gastritis Among Adults Age 35 to 44 Years Old in Northern Sweden Between 1990 and 2009.
Atrophic corpus gastritis (ACG) is believed to be an early precursor of gastric adenocarcinoma. We aimed to investigate trends of ACG in Northern Sweden, from 1990 through 2009, and to identify possible risk factors. We randomly selected serum samples collected from 5284 participants in 1990, 1994, 1999, 2004, and 2009, as part of the population-based, cross-sectional Northern Sweden Multinational Monitoring of Trends and Determinants in Cardiovascular Disease study (ages, 35-64 y). Information was collected on sociodemographic, anthropometric, lifestyle, and medical factors using questionnaires. Serum samples were analyzed for levels of pepsinogen I to identify participants with functional ACG; data from participants with ACG were compared with those from frequency-matched individuals without ACG (controls). Blood samples were analyzed for antibodies against Helicobacter pylori and Cag pathogenicity island protein A. Associations were estimated with unconditional logistic regression models. Overall, 305 subjects tested positive for functional ACG, based on their level of pepsinogen I. The prevalence of ACG in participants age 55 to 64 years old decreased from 124 per 1000 to 49 per 1000 individuals between 1990 and 2009. However, the prevalence of ACG increased from 22 per 1000 to 64 per 1000 individuals among participants age 35 to 44 years old during this time period. Cag pathogenicity island protein A seropositivity was associated with risk for ACG (odds ratio, 2.29; 95% confidence interval, 1.69-3.12). Other risk factors included diabetes, low level of education, and high body mass index. The association between body mass index and ACG was confined to individuals age 35 to 44 years old; in this group, overweight and obesity were associated with a 2.8-fold and a 4.7-fold increased risk of ACG, respectively. Among residents of Northern Sweden, the prevalence of ACG increased from 1990 through 2009, specifically among adults age 35 to 44 years old. The stabilizing seroprevalence of H pylori and the increasing prevalence of overweight and obesity might contribute to this unexpected trend. Studies are needed to determine whether these changes have affected the incidence of gastric cancer.