Safety of Anticoagulant Therapy Including Direct Oral Anticoagulants in Patients With Acute Spontaneous Intracerebral Hemorrhage.
Because the efficacy and safety of anticoagulant therapy in patients with acute intracerebral hemorrhage (ICH) are not fully known, present study aimed to elucidate the current status and the safety of anticoagulant therapy, mainly direct oral anticoagulants (DOACs), for acute ICH and anticoagulant-indicated patients. Methods and Results: From September 2014 through March 2017, consecutive patients with acute (<7 days from onset), spontaneous ICH were retrospectively enrolled from a prospective registry. Whether to start anticoagulation was at the attending physicians' discretion, and thromboembolic or hemorrhagic events during hospitalization were analyzed. A total of 236 patients (80 women [34%]; median age 69 [interquartile range 61-79] years; National Institutes of Health stroke scale score 7 [3-16]) were enrolled. Of them, 47 patients (20%) had an indication for anticoagulant therapy (33 had atrial fibrillation, 14 developed deep vein thrombosis), and 41 of 47 patients (87%) were actually treated with anticoagulant therapy (DOACs were used in 34 patients) after a median of 7 days from ICH onset. There was neither hematoma expansion nor excessive hemorrhagic complications during hospitalization after starting anticoagulant therapy. Anticoagulant therapy was conducted for approximately 90% of anticoagulation-indicated patients after a median of 7 days from ICH onset. The predominant anticoagulant medications were DOACs. Anticoagulant therapy started from the acute phase of ICH should be safe.


Could an increase in vigilance for spinal tuberculosis at primary health care level, enable earlier diagnosis at district level in a tuberculosis endemic country?
Expert clinicians and researchers in the field of spinal tuberculosis (STB) advocate for early identification and diagnosis as a key to reducing disability, severity of disease, expensive surgery and death, especially in tuberculosis (TB) endemic countries like South Africa. South Africa has the highest incidence per capita of tuberculosis in the world, and a conservative estimate of the incidence of STB in South Africa is 8-16:100 000. People living with STB may initially present to primary health care (PHC) centres, where the opportunity exists for early identification. Spinal pain is the most common presentation of STB, but even this symptom may not be present. Occasionally the only symptoms are neurological injury, dysphagia or referred pain. Computerised tomography-guided biopsy remains the diagnostic gold standard for STB. A narrative review was undertaken to investigate the evidence available that could assist with the early diagnosis of STB. Articles were searched for and retrieved from three databases and assessed for quality and relevance to primary settings in a TB endemic country. The following evidence-based, affordable and available tools could facilitate early diagnosis of STB at PHC and district hospital levels: (1) back pain screening questions, undressed spinal physical examination, HIV and antiretroviral therapy history, (2) erythrocyte sedimentation rate, C-reactive protein, platelets, haemoglobin, white cell count (WCC), sputum for GeneXpert and accurate weight measurement, (3) physiotherapy and/or medical and/or speech therapy assessment, (4) full spinal radiograph, chest radiograph, abdominal ultrasound, urine lipoarabinomannan (LAM) if CD4 < 200 and ultrasound-guided biopsy of superficial abscesses, (5) clear referral guidelines at all levels, (6) a positive response to treatment to confirm the diagnosis. These affordable and simple actions at PHC and district levels could facilitate earlier diagnosis of STB.


Modulation of the extracellular matrix patterning of thrombospondins by actin dynamics and thrombospondin oligomer state.
Thrombospondins (TSPs) are evolutionarily-conserved, secreted glycoproteins that interact with cell surfaces and extracellular matrix (ECM) and have complex roles in cell interactions. Unlike the structural components of the ECM that form networks or fibrils, TSPs are deposited into ECM as arrays of nanoscale puncta. The cellular and molecular mechanisms for the patterning of TSPs in ECM are poorly understood. In the present study, we investigated whether the mechanisms of TSP patterning in cell-derived ECM involves actin cytoskeletal pathways or TSP oligomer state. From tests of a suite of pharmacological inhibitors of small GTPases, actomyosin-based contractility, or actin microfilament integrity and dynamics, cytochalasin D and jasplakinolide treatment of cells were identified to result in altered ECM patterning of a model TSP1 trimer. The strong effect of cytochalasin D indicated that mechanisms controlling puncta patterning depend on global F-actin dynamics. Similar spatial changes were obtained with endogenous TSPs after cytochalasin D treatment, implicating physiological relevance. Under matched experimental conditions with ectopically-expressed TSPs, the magnitude of the effect was markedly lower for pentameric TSP5 and Drosophila TSP, than for trimeric TSP1 or dimeric Ciona TSPA. To distinguish between the variables of protein sequence or oligomer state, we generated novel, chimeric pentamers of TSP1. These proteins accumulated within ECM at higher levels than TSP1 trimers, yet the effect of cytochalasin D on the spatial distribution of puncta was reduced. These findings introduce a novel concept that F-actin dynamics modulate the patterning of TSPs in ECM and that TSP oligomer state is a key determinant of this process.


Evaluation of the carcinogenicity of chemicals: a review of the Monograph Program of the International Agency for Research on Cancer (1971 to 1977).
In 1971 the International Agency for Research on Cancer initiated a program on the evaluation of the carcinogenic risk of chemicals to humans, which concentrated on the production of monographs on individual chemicals. A review of this ongoing program is presented here as a contribution to the discussion of primary prevention of cancer. A total of 368 chemicals were evaluated in the first 16 volumes of the International Agency for Research on Cancer monographs. For 26 chemicals (or industrial processes), a positive association between exposure and the occurrence of cancer in humans was observed. For 221 chemicals, some evidence of carcinogenicity was found in at least one species of experimental animals. However, no evaluation of the carcinogenic risk of these chemicals to humans was made, either because no epidemiological studies or case reports were available or because the results of available human studies were inconclusive. For the remaining 121 chemicals, the available data were inadequate for an evaluation of the presence or absence of a carcinogenic effect in experimental animals or humans. The criteria on which the carcinogenicity of chemicals to humans and/or experimental animals was assessed, from the initiation of this program in 1971 until 1977, have recently been revised and are briefly discussed.


Effect of noble gas doping in single-bubble sonoluminescence.
The trillionfold concentration of sound energy by a trapped gas bubble, so as to emit picosecond flashes of ultraviolet light, is found to be extremely sensitive to doping with a noble gas. Increasing the noble gas content of a nitrogen bubble to about 1% dramatically stabilizes the bubble motion and increases the light emission by over an order of magnitude to a value that exceeds the sonoluminescence of either gas alone. The spectrum also strongly depends on the nature of the gas inside the bubble: Xenon yields a spectral peak at about 300 nanometers, whereas the helium spectrum is so strongly ultraviolet that its peak is obscured by the cutoff of water.


Stimulation of the growth of cutaneous strains of Peptococcus saccharolyticus by iron, haematin and blood.
The growth of nine strains of Peptococcus saccharolyticus was assessed quantitatively by culture Trypticase Soy/yeast extract/Tween 80 agar (TSY-TW) with and without supplementation with iron or haematin and on blood agar, in aerobic, reduced 02 (3% O2 with 8% CO2, 8% H2 and 81% N2) and anaerobic atmospheres. All strains grew better anaerobically and under reduced O2 conditions than aerobically on supplemented or unsupplemented TSY-TW. Supplementation of TSY-TW with iron or haematin resulted in an average 4.4-fold increase in bacterial count in a reduced O2 atmosphere and an average 4.2-fold increase under anaerobic conditions. Under aerobic conditions the increase in count ranged from O to greater than 5000-fold, as some strains failed to grow on unsupplemented TSY-TW but responded well to the supplements of iron or haematin. The highest bacterial counts were obtained on Columbia blood agar incubated anaerobically. However, P. saccharolyticus failed to grow aerobically on plain or heated Columbia blood agar with or without supplements. TSY-TW blood agar supported the growth of the one strain tested under all three atmospheric conditions. The type strain (ATCC 14953) differed from all others in its failure to grow aerobically or in a reduced O2 atmosphere on supplement or unsupplemented media. Colony size varied greatly on different media, in different atmospheres and from strain to strain, being greatest in a reduced O2 atmosphere on Columbia blood agar. There was no correlation between the viable bacterial count and colony size.


Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis.
Metabolic changes are associated with cancer, but whether they are just bystander effects of deregulated oncogenic signaling pathways or characterize early phases of tumorigenesis remains unclear. Here we show in a rat model of hepatocarcinogenesis that early preneoplastic foci and nodules that progress towards hepatocellular carcinoma (HCC) are characterized both by inhibition of oxidative phosphorylation (OXPHOS) and by enhanced glucose utilization to fuel the pentose phosphate pathway (PPP). These changes respectively require increased expression of the mitochondrial chaperone TRAP1 and of the transcription factor NRF2 that induces the expression of the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase (G6PD), following miR-1 inhibition. Such metabolic rewiring exclusively identifies a subset of aggressive cytokeratin-19 positive preneoplastic hepatocytes and not slowly growing lesions. No such metabolic changes were observed during non-neoplastic liver regeneration occurring after two/third partial hepatectomy. TRAP1 silencing inhibited the colony forming ability of HCC cells while NRF2 silencing decreased G6PD expression and concomitantly increased miR-1; conversely, transfection with miR-1 mimic abolished G6PD expression. Finally, in human HCC patients increased G6PD expression levels correlates with grading, metastasis and poor prognosis. Our results demonstrate that the metabolic deregulation orchestrated by TRAP1 and NRF2 is an early event restricted to the more aggressive preneoplastic lesions.


Cost-effectiveness of screening for anal precancers in HIV-positive men.
To assess the cost-effectiveness of high-resolution anoscopy (HRA), anal cytology, and anal human papillomavirus (HPV) detection in screening for histologic high-grade anal intraepithelial neoplasia (AIN 2/3) in HIV-positive MSM. Participants were 401 HIV-positive MSM who were screened for anal cancer in a tertiary care HIV clinic. A decision analytical model was used to determine the cost-effectiveness of three anal cancer screening strategies: the direct use of HRA; HRA only if anal cytology was abnormal; and HRA only if oncogenic HPV was present. The model included the use of different thresholds for abnormal cytology and also combined cytology and HPV testing. The outcome was the number of AIN 2/3 cases detected. Costs were estimated from institutional data and sensitivity/specificity of cytology and HPV tests were obtained from the screening study. The costs ($ US) per procedure for HRA, cytology, and HPV testing were $193, $90, and $95, respectively. The direct use of HRA was the most cost-effective strategy. It detected 98 individuals with AIN 2/3 and had a cost-effectiveness of $809 per AIN 2/3 case detected. Using probabilistic sensitivity analysis, three other strategies had similar costs per case detected and might be as cost-effective as HRA. In HIV-infected MSM, the direct use of HRA is the most cost-effective strategy for detecting AIN 2/3. The higher cost per use for HRA was offset by the high sensitivity and low specificity of HPV and cytology testing.


Serum procalcitonin levels in patients with primary pulmonary coccidioidomycosis.
The serum procalcitonin assay has emerged as a promising biomarker to distinguish between bacterial and viral respiratory tract infections but has not been used to differentiate coccidioidomycosis from bacterial infection. A correlation between procalcitonin serum levels and coccidioidomycosis has never been reported. To determine any association between serum procalcitonin levels and primary pulmonary coccidioidomycosis. We identified and enrolled 20 immunocompetent patients with symptomatic primary pulmonary coccidioidomycosis of < 8 weeks' duration and performed a one-time procalcitonin assay, with a cutoff of < 0.25 μg/L indicating a nonbacterial infection. Nineteen of 20 patients (95%) had serum procalcitonin of < 0.25 μg/L. The median procalcitonin level was 0.05 μg/L (range, < 0.05-0.87 μg/L; interquartile range, 0.05-0.05 μg/L). Sixteen of 20 patients (80%) had undetectable procalcitonin of < 0.05 μg/L. The four patients with detectable procalcitonin had a median value of 0.2 μg/L (range, 0.09-0.87 μg/L). In this pilot study, procalcitonin was not elevated in immunocompetent patients with primary pulmonary coccidioidomycosis at a median of 32 days after symptom onset. Larger prospective studies are needed to confirm this finding.


A mixed methods pilot randomised controlled trial to develop and evaluate the feasibility of a Mediterranean diet and lifestyle education intervention 'THINK-MED' among people with cognitive impairment.
Accumulating evidence supports the role of a Mediterranean diet (MD) in cognition, with a greater adherence to a MD associated with reduced dementia risk. It is important to understand how best to achieve behaviour change towards a MD, particularly in non-Mediterranean and high-risk populations. The aim of this study was to evaluate the feasibility of a MD and lifestyle education intervention (THINK-MED) among older adults with cognitive impairment. Qualitative interviews (Phase I), conducted with mild cognitive impairment (MCI) participants, evaluated the intervention materials to allow refinement before pilot testing. THINK-MED was a 12-month, pilot RCT (Phase II) whereby MCI participants were randomised into one of three groups: education on one occasion vs education staged and supported by a dietitian vs control. The primary outcome was a change in MD score. Secondary outcome measurements were collected to gather data on variability of the outcomes to inform a full trial power calculation and to test their acceptability. Slower recruitment rates necessitated a change in primary outcome to a revised focus primarily on feasibility. A sub-study of the same THINK-MED intervention and data collection measures was also conducted among community-dwelling participants with subjective cognitive impairment (SCI) (NCT03569319). A total of 20 participants (n = 15 MCI; n = 5 SCI) were enrolled in the THINK-MED study. However, there were 10 (50%) participants (n = 9 MCI; n = 1 SCI) who withdrew from the study. Although, those who remained in the intervention rated and evaluated their experience as generally positive, recruitment and retention, especially from a MCI population, was extremely challenging. This highlights the complex needs of this heterogeneous clinical cohort. Recruiting participants from a community-based sample with SCI was more feasible, reaching a wider audience in a shorter time period. There were challenges relating to data collection and incompleteness, with the occurrence of missing data particularly among the questionnaire-based assessments. Owing to the challenges with recruitment and retention of older adults with cognitive impairment in this study, it is difficult to confirm if this intervention is feasible. This research has highlighted considerations for a future trial, including a review of the recruitment strategies used and prioritisation of the outcome measures assessed. Clinical trials registration NCT03265522 / NCT03569319.


Diagnostic criteria for late-onset (childhood and adult) Pompe disease.
The diagnosis of late-onset (childhood and adult) Pompe disease can often be challenging, as it is a rare disease and the heterogeneous clinical presentation can mimic the presentation of other neuromuscular disorders. The objective was to develop a consensus-based algorithm for the diagnosis of late-onset Pompe disease. A systematic literature search was conducted, and an expert panel composed of neuromuscular specialists and individuals with expertise in Pompe disease reviewed the literature and convened for consensus development. An algorithm for the diagnosis of late-onset Pompe disease was created. Patients presenting with either a limb-girdle syndrome or dyspnea secondary to diaphragm weakness should undergo further testing, including evaluations of muscle strength, motor function, and pulmonary function. A blood-based acid alpha-glucosidase (GAA) enzyme activity assay is the recommended tool to screen for GAA enzyme deficiency. The diagnosis should be confirmed by a second test: either a second GAA enzyme activity assay in another tissue or GAA gene sequencing.


Alpha-enolase regulates the malignant phenotype of pulmonary artery smooth muscle cells via the AMPK-Akt pathway.
The molecular mechanisms underlying the metabolic shift toward increased glycolysis observed in pulmonary artery smooth muscle cells (PASMC) during the pathogenesis of pulmonary arterial hypertension (PAH) are not fully understood. Here we show that the glycolytic enzyme α-enolase (ENO1) regulates the metabolic reprogramming and malignant phenotype of PASMC. We show that ENO1 levels are elevated in patients with associated PAH and in animal models of hypoxic pulmonary hypertension (HPH). The silencing or inhibition of ENO1 decreases PASMC proliferation and de-differentiation, and induces PASMC apoptosis, whereas the overexpression of ENO1 promotes a synthetic, de- differentiated, and apoptotic-resistant phenotype via the AMPK-Akt pathway. The suppression of ENO1 prevents the hypoxia-induced metabolic shift from mitochondrial respiration to glycolysis in PASMC. Finally, we find that pharmacological inhibition of ENO1 reverses HPH in mice and rats, suggesting ENO1 as a regulator of pathogenic metabolic reprogramming in HPH.


Efficient Distalization of Maxillary Molars with Temporary Anchorage Devices for the Treatment of Class II Malocclusion.
Treatment of Class II malocclusion often requires maxillary molar distalization. However, when applying distalization forces on the maxillary molars, anchorage loss may occur in different degrees not only during molar distalization (such as distal tipping of maxillary molars and mesial movement and proclination of the anterior teeth) but also during the subsequent stage of anterior teeth retraction (such as mesial movement of maxillary molars). All these movements are considered as unwanted side effects, which diminish the clinical effectiveness of distalization. Miniscrew implants can be used as temporary anchorage devices (TADs) to enhance anchorage and, if properly used, to counterbalance the side effects. Among the different available systems, the TAD-supported amda® can be considered as a simple, noncompliant, minimally invasive, and very efficient approach that can be used for the comprehensive treatment of patients with Class II malocclusion not only to distalize the maxillary molars bodily without or with minimal distal tipping and without proclination of the anterior teeth but also in combination with full-fixed appliances to retract and intrude the anterior teeth.


[Effect of antioxidants on the status of the antioxidative system in cerebral ischemia and reperfusion injury].
Protective effects of ionol, o-benzoquinone-2 and ascorbic acid, their influence on the activity of antioxidative enzymes, the level of diene conjugates (DC) and of recovered glutathione in the mitochondrial fraction in the case of ischemic and reperfusion injury of the brain have been investigated. An increase in the activity of the antioxidative system enzymes during the post-ischemic period induced probably by the accumulated products of lipid peroxidation is shown: glutathione peroxidase (EC 18.104.22.168)--by 159%, glutathione reductase (EC 184.108.40.206)--by 26%, catalase (EC 184.108.40.206)--by 79%. This effect was not observed after introduction of antioxidants lowering the DC-level. It is concluded that antihypoxic action of the investigated antioxidants providing the survival of animals not only after the 5 min total circulatory ischemia but also after the 15 min one is caused by their antiradical properties and is not connected with stimulation of activity of enzymes supporting peroxidative homeostasis.


[Prevalence of allergic reactions to implant materials in total hip and knee arthroplasty].
Several case reports have been published on allergic reactions like eczema, urticaria, persistent swelling, sterile osteomyelitis or aseptic implant loosening in the context of orthopaedic implants. There is, however, a lack of data concerning incidence or prevalence of allergies in this special group of patients. The aim of this study was to analyse a consecutive series of patients with a total hip or knee arthroplasty to gain information about prevalence of allergic reactions to constituents of the alloys or bone cement. Between February and September 2005, a consecutive series of 300 patients after total hip (THA) or total knee (TKA) arthoplasty were interviewed during regular follow-up using the standardised questionnaire of the working group 20 "Implant and Allergy" of the DGOOC with respect to allergies, especially to different metals or constituents of bone cement. In this study 100 males and 200 females with 214 THA and 86 TKA were included. The mean follow-up time was 33.3 months (min: 3, max: 174). Different allergies were found in 39 patients. In 12 cases (4 %) allergic reactions against nickel, in 4 cases (1.3 %) against cobalt, in 2 cases (0.7 %) against chromium and in 2 cases (0.7 %) against benzoyl peroxide were detected by means of epicutaneous testing. One patient each suffering from a nickel allergy showed signs of osteolysis or recurrent effusion after THA with a metal-on-metal bearing. One patient each suffering from recurrent effusion or eczema following TKA showed allergic reactions to benzoyl peroxide. In all the other patients with allergies to the alloy constituents, the follow-up was uneventful. The prevalence of allergic reactions in an unselected group of orthopaedic patients is significantly lower in comparison to that in dermatological studies. Most patients suffering from allergies tolerated the implant uneventfully. Further studies are needed to identify those groups of patients with allergies who may not tolerate the implant in order to provide better care or use special implants.


Noninvasive in vivo measurement of venous blood pH during exercise using near-infrared reflectance spectroscopy.
Blood pH is an important indicator of anaerobic metabolism in exercising muscle. This paper demonstrates multivariate calibration techniques that can be used to produce a general pH model that can be applied to spectra from any new subject without significant prediction error. Tissue spectra (725 approximately 880 nm) were acquired through the skin overlying the flexor digitorum profundus muscle on the forearms of eight healthy subjects during repetitive hand-grip exercise and referenced to the pH of venous blood drawn from a catheter placed in a vein close to the muscle. Calibration models were developed using multi-subject partial least squares (PLS) and validated using subject-out cross-validation after the subject-to-subject spectral variations were corrected by mathematical preprocessing methods. A combination of standard normal variate (SNV) scaling and principal component analysis loading correction (PCALC) successfully removed most of the subject-to-subject variations and provided the most accurate prediction results.


The role of sport-fish consumption advisories in mercury risk communication: a 1998-1999 12-state survey of women age 18-45.
In 2002, in the United States, 48 states issued advisories for sport-fish consumers that included 39 chemical contaminants. The most commonly identified chemical was methyl mercury, which is linked to reproductive and developmental effects. Advisories to reduce consumption of contaminated fish have been issued by states since the early 1970s. Advisories are being integrated to include both sport and commercial fish. As part of a comprehensive risk-communication project, from December 1998 through August 1999 the Wisconsin Division of Public Health and the State of Maine Bureau of Health conducted a 12-state random-digit-dial telephone survey of 3015 women of childbearing age (ages 18-45). The goal was to assess the prevalence of fish consumption, understanding of mercury toxicity, and awareness of state sport-fish consumption advisories for mercury. We gathered information concerning respondents' demographic characteristics, understanding of mercury toxicity, fish consumption during the preceding 12 months, and sport-fish consumption advisory awareness. The overall survey completion rate was 57% with a Council of American Survey Research Organizations (CASRO)-calculated response rate of 50%. Completion rates varied from 37% in New Jersey to 73% in Minnesota. Fish consumption during the previous 12 months was reported by 87% of respondents (range by state of 82-90%). Nearly 10% of women reported consuming two or more fish-meals per week over the prior 12 months. Twenty-nine percent reported sport-fish consumption during the same time period, with a greater state-to-state variability (14-43%). Most women (71%) were aware of mercury's toxicity to a developing child (87% among those aware of an advisory and 67% among those unaware of an advisory). However, awareness of state advisories was only 20%, ranging by state from 8% to 32%. Women who were older, had more than a high school education, and had a household member with a fishing license were the most informed about mercury and fish-consumption advisories. Most women of childbearing age consume commercial fish and a substantial number also consume sport-caught fish. Despite this potential exposure to dietary mercury, most are unfamiliar with their state's mercury fish-consumption advisory. Most women were aware of the most toxic effects of mercury but less informed about mercury and its relationship to types of fish and fish characteristics. Minorities, women over age 30, family incomes above 25,000 US dollars, and those with some collage education were more likely to be consuming two or more fish-meals per week. Until source control and environmental remediation efforts can reduce the environmental burden of mercury below levels of concern, combined sport and commercial fish consumption advisories will remain the primary means of reducing human exposure to methylmercury. Assuring and assessing the effectiveness of such advisories is paramount. Our survey documents that current efforts to inform vulnerable populations are far from optimal.


The SKI proto-oncogene enhances the in vivo repopulation of hematopoietic stem cells and causes myeloproliferative disease.
The proto-oncogene SKI is highly expressed in human myeloid leukemia and also in murine hematopoietic stem cells. However, its operative relevance in these cells remains elusive. We have over-expressed SKI to define its intrinsic role in hematopoiesis and myeloid neoplasms, which resulted in a robust competitive advantage upon transplantation, a complete dominance of the stem and progenitor compartments, and a marked enhancement of myeloid differentiation at the expense of other lineages. Accordingly, enforced expression of SKI induced a gene signature associated with hematopoietic stem cells and myeloid differentiation, as well as hepatocyte growth factor signaling. Here we demonstrate that, in contrast to what has generally been assumed, the significant impact of SKI on hematopoiesis is independent of its ability to inhibit TGF-beta signaling. Instead, myeloid progenitors expressing SKI are partially dependent on functional hepatocyte growth factor signaling. Collectively our results demonstrate that SKI is an important regulator of hematopoietic stem cell activity and its overexpression leads to myeloproliferative disease.


Can the Market Economy Deal with Sustainability?
The central question in this paper is whether a market economy can theoretically and empirically deal with sustainability. A system analysis of the current neoclassical theory shows that the system components (goal function, interaction mechanisms, actors and outcomes) are predominantly defined in terms of economic growth and facilitated by market exchange. This fosters (over)production and consumption of private goods, crowding out public goods and preservation of the commons. The one size fits all 'economic mechanism design' cannot deliver social outcomes regarding sustainability. The explicit recognition that an economy has different domains (ecological, social, economic) broadens the options for incorporating sustainability within the economic system. This richer framework allows us to analyse the economic problem at hand: an efficient economic system in an inclusive society within biophysical boundaries. We show that the alternative for market economics does not only have to be government intervention but can also include private forms of collective decision-making.


Dual function of Zika virus NS2B-NS3 protease.
Zika virus (ZIKV) serine protease, indispensable for viral polyprotein processing and replication, is composed of the membrane-anchored NS2B polypeptide and the N-terminal domain of the NS3 polypeptide (NS3pro). The C-terminal domain of the NS3 polypeptide (NS3hel) is necessary for helicase activity and contains an ATP-binding site. We discovered that ZIKV NS2B-NS3pro binds single-stranded RNA with a Kd of ~0.3 μM, suggesting a novel function. We tested various structural modifications of NS2B-NS3pro and observed that constructs stabilized in the recently discovered "super-open" conformation do not bind RNA. Likewise, stabilizing NS2B-NS3pro in the "closed" (proteolytically active) conformation using substrate inhibitors abolished RNA binding. We posit that RNA binding occurs when ZIKV NS2B-NS3pro adopts the "open" conformation, which we modeled using highly homologous dengue NS2B-NS3pro crystallized in the open conformation. We identified two positively charged fork-like structures present only in the open conformation of NS3pro. These forks are conserved across Flaviviridae family and could be aligned with the positively charged grove on NS3hel, providing a contiguous binding surface for the negative RNA strand exiting helicase. We propose a "reverse inchworm" model for a tightly intertwined NS2B-NS3 helicase-protease machinery, which suggests that NS2B-NS3pro cycles between open and super-open conformations to bind and release RNA enabling long-range NS3hel processivity. The transition to the closed conformation, likely induced by the substrate, enables the classical protease activity of NS2B-NS3pro.


Natural genital herpesvirus hominis infection in chimpanzees (Pan troglodytes and Pan paniscus).
Type 2 Herpesvirus hominis was isolated from pustulovesicular lesions on the external genitalia of two chimpanzees. Histopathologic examination of biopsy specimens from both animals revealed typical herpetic changes which included necrosis, superficial ulceration acute inflammatory cell infiltration, multinucleated syncytial giant cells, and intranuclear inclusions. Large numbers of herpes-type viruses were demonstrated by electron microscopy in biopsy specimens from both animals. Serologic studies also demonstrated infection of these animals with Herpesvirus hominis.


Statistical coil model of the unfolded state: resolving the reconciliation problem.
An unfolded state ensemble is generated by using a self-avoiding statistical coil model that is based on backbone conformational frequencies in a coil library, a subset of the Protein Data Bank. The model reproduces two apparently contradicting behaviors observed in the chemically denatured state for a variety of proteins, random coil scaling of the radius of gyration and the presence of significant amounts of local backbone structure (NMR residual dipolar couplings). The most stretched members of our unfolded ensemble dominate the residual dipolar coupling signal, whereas the uniformity of the sign of the couplings follows from the preponderance of polyproline II and beta conformers in the coil library. Agreement with the NMR data substantially improves when the backbone conformational preferences include correlations arising from the chemical and conformational identity of neighboring residues. Although the unfolded ensembles match the experimental observables, they do not display evidence of native-like topology. By providing an accurate representation of the unfolded state, our statistical coil model can be used to improve thermodynamic and kinetic modeling of protein folding.


Separation Anxiety and Measures of Suicide Risk Among Patients With Mood and Anxiety Disorders.
Separation anxiety disorder may be important when considering risk of suicide. The aim of this study was to examine the association between both childhood and adult separation anxiety (disorder) and measures of suicide risk in a large cohort of outpatients with anxiety and mood disorders. The sample included 509 consecutive adult psychiatric outpatients with DSM-IV mood disorders or anxiety disorders as a principal diagnosis recruited at the Department of Psychiatry, University of Pisa, Italy, between 2015 and 2018. Suicide risk was evaluated by the Hamilton Depression Rating Scale (HDRS) item 3. Patients were classified in 2 groups: those with a score ≥ 1 and those with a score of 0 on HDRS item 3. Suicide risk was also evaluated by specific items within the Mood Spectrum, Self-Report (MOODS-SR), a questionnaire evaluating lifetime suicidal symptoms. Separation anxiety (disorder) was assessed based on the Structured Interview for Separation Anxiety Symptoms in Adulthood/Childhood (SCI-SAS-A/C), the Separation Anxiety Symptom Inventory (SASI), and the Adult Separation Anxiety Scale (ASA-27). Of the 509 patients, 97 had an HDRS item 3 score ≥ 1, and 412 had a score of 0. Adult separation anxiety disorder was more frequent among individuals who had suicidal thoughts (53.6%) than those who did not (39.6%) (P = .01). Dimensional separation anxiety symptoms on all scales were elevated in patients with suicidality when compared to patients without (SASI: P = .02; SCI-SAS-C: P < .001; SCI-SAS-A: P < .001; ASA-27: P = .002). Logistic regression found that adult separation anxiety disorder (odds ratio [OR] = 1.86, 95% CI = 1.16-2.97), major depression (OR = 7.13, 95% CI = 3.18-15.97), bipolar I disorder (8.15, 95% CI = 3.34-19.90), and bipolar II disorder (OR = 8.16, 95% CI = 3.50-19.05) predicted suicidal thoughts. Linear regression found that depression (P = .001) and ASA-27 separation anxiety (P = .001) significantly predicted lifetime suicide risk. Mediation analysis found that separation anxiety significantly mediated the association between depression and suicide risk. This study indicates a substantial role of separation anxiety in predicting suicidal thoughts, both as state-related symptoms (evaluated by HDRS item 3) and as longitudinal dimensional symptoms (as evaluated by MOODS-SR). Greater understanding of the influence of separation anxiety in patients with affective disorders may encourage personalized interventions for reducing suicide risk.


Experiences of women with breast cancer: exchanging social support over the CHESS computer network.
Using an existential-phenomenological approach, this paper describes how women with breast cancer experience the giving and receiving of social support in a computer-mediated context. Women viewed their experiences with the computer-mediated support group as an additional and unique source of support in facing their illness. Anonymity within the support group fostered equalized participation and allowed women to communicate in ways that would have been more difficult in a face-to-face context. The asynchronous communication was a frustration to some participants, but some indicated that the format allowed for more thoughtful interaction. Motivations for seeking social support appeared to be a dynamic process, with a consistent progression from a position of receiving support to that of giving support. The primary benefits women received from participation in the group were communicating with other people who shared similar problems and helping others, which allowed them to change their focus from a preoccupation with their own sickness to thinking of others. Consistent with past research is the finding that women in this study expressed that social support is a multidimensional phenomenon and that their computer-mediated support group provided abundant emotional support, encouragement, and informational support. Excerpts from the phenomenological interviews are used to review and highlight key theoretical concepts from the research literatures on computer-mediated communication, social support, and the psychosocial needs of women with breast cancer.


Impaired vitamin K recycling in uremia is rescued by vitamin K supplementation.
In chronic kidney disease, vitamin K-dependent proteins, including the calcification inhibitor matrix Gla protein, are largely uncarboxylated indicating that functional vitamin K deficiency may contribute to uremic vascular calcification. Since the effects of uremia on the vitamin K cycle are unknown, we investigated the influence of uremia and vitamin K supplementation on the activity of the vitamin K cycle and extraosseous calcification. Uremia was induced in rats by an adenine-supplemented diet and vitamin K1 or K2 was administered over 4 and 7 weeks. After 4 weeks of adenine diet, the activity of the vitamin K cycle enzyme γ-carboxylase but not the activities of DT-diaphorase or vitamin K epoxide reductase were reduced. Serum levels of undercarboxylated matrix Gla protein increased, indicating functional vitamin K deficiency. There was no light microscopy-detectable calcification at this stage but chemically determined aortic and renal calcium content was increased. Vitamin K treatment reduced aortic and renal calcium content after 4 weeks. Seven weeks of uremia induced overt calcification in the aorta, heart, and kidneys; however, addition of vitamin K restored intrarenal γ-carboxylase activity and overstimulated it in the liver along with reducing heart and kidney calcification. Thus, uremic vitamin K deficiency may partially result from a reduction of the γ-carboxylase activity which possibly contributes to calcification. Pharmacological vitamin K supplementation restored the vitamin K cycle and slowed development of soft tissue calcification in experimental uremia.


A case of thyroid hormone resistance: a rare mutation.
Reduced sensitivity to thyroid hormones (RSTH) is a rare disease that affects about 3,000 individuals, belonging to about 1,000 families. It results from reduced intracellular action of thyroid hormones (TH) genetically determined and manifests as persistent hyperthyroxinemia with non-suppressed thyroid-stimulating hormone (TSH). We describe a 67-years old, Caucasian woman, with past history of subtotal thyroidectomy due to diffuse goiter, who presents with a recurrence of goiter. Although she is clinically euthyroid, laboratory evaluation shows persistent hyperthyroxinemia with non-suppressed TSH. Response to thyrotropin releasing hormone (TRH) test was normal and TSH concentrations were not suppressed during oral administration of suprafisiologic doses of levothyroxine (L-T4). Peripheral blood DNA was extracted from the patient and a mutation was found localized in cluster one, at codon 346 of the ligand binding domain of the THRB gene. The patient's son underwent thyroid function testing (TFT) and genetic study, both negative, suggesting a sporadic mutation. RSTH should be considered in all hyperthyroxinemic patients who are clinically euthyroid. Mutations interfering with three major steps required for TH action on target tissues have been, so far, identified (TR-β, TR-α, MCT8, SPB2). Each mutation is associated with a distinctive syndrome. Goal of management is to maintain a normal serum TSH level and a eumetabolic state and offer appropriate genetic counselling and prenatal diagnosis. Inappropriate treatment of eumetabolic patients results in hypothyroidism and need for TH replacement.


Changing trends in bariatric surgery.
Bariatric surgery is considered the only long-lasting treatment for morbid obesity. Techniques and procedures have changed dramatically. We report on some of the major changes in the field. We reviewed some of the major changes in trends in bariatric surgery based on some landmark paper published in the literature. We identified three major phases in the evolution of bariatric surgery. The pioneer phase was mostly characterized by discovery of weight loss procedures serendipitously from procedures done for other purposes. The second phase can be identified with the advent of laparoscopic techniques. This is considered the phase of greatest expansion of bariatric surgery. The metabolic phase derives from the improved understanding of the mechanisms of actions of the bariatric operations at the hormonal and molecular level. Bariatric surgery has changed significantly over the years. The safety of the laparoscopic approach, along with the better understanding of the metabolic changes obtained postoperatively, has led to a more individualized approach and also an attempt to expand the indications for these procedures.


EMG profiles during normal human walking: stride-to-stride and inter-subject variability.
The EMG patterns for 16 muscles involved in human walking are reported along with stride-to-stride and inter-subject variability measures. These profiles and measures were developed for basic researchers and clinical investigators as a baseline reference of motor patterns and for use in the diagnosis of gait pathologies. Evident from a comparison of these patterns were some fundamental aspects of the neuromuscular control and the mechanical demands of walking. These comparisons can be summarized as follows: (1) The distal support muscles (soleus, tibialis anterior, gastrocnemii) are the most active muscles, the more proximal muscles are least active. (2) The least variable EMG patterns, as quantified by the normalized inter-subject variability measures, are seen in the most distal single joint muscles, the most variable are the more proximal muscles. The EMGs of the biarticulate muscles, both proximal and distal, exhibit higher variability than the EMGs of the single joint muscles. (3) The detailed patterns and levels of EMG activity demonstrate the different mechanical tasks of each muscle over the gait cycle.


Dual task impairments in vascular dementia.
Several studies have shown that people with Alzheimer's disease (AD) demonstrate difficulties in doing two things at once or 'dual-tasking' and that this dual task impairment is insensitive to normal ageing, chronic depression or prodromal conditions like Mild Cognitive Impairment. It is not known, however, if this impairment is specific to AD, or also present in other dementias, such as vascular dementia (VaD). In this study 15 people with VaD, 25 healthy age-matched and 25 healthy young controls were assessed using a paper and pencil dual tasking paradigm and several measures of working and episodic memory. Age had no effect on dual task performance, but the VaD patients demonstrated a significant impairment in dual tasking ability. Performance on the memory measures was instead affected by age with a further deterioration in the VaD patients. Both dual tasking and memory ability were significantly correlated with disease severity, as assessed by the MMSE. These results indicate that performance on the dual task could be a specific indicator of pathological ageing.


Large cell neuroendocrine carcinoma originating in the subglottic larynx.
Large cell neuroendocrine carcinoma (LCNEC) of the larynx is an exceedingly rare cancer of the head and neck that is difficult to diagnose. Few case reports of laryngeal LCNEC exist within the literature, and it was not until recently that LCNEC was recognized as a discrete subtype of neuroendocrine carcinoma. Given its recent recognition as a distinct subtype, histologic characteristics distinguishing LCNEC from other poorly differentiated carcinomas remain under investigation. Various reports have shown genetic alterations such as p53 and/or p16 overexpression, which are typically associated with infection by human papilloma virus (HPV). However, some reports have shown p53 and/or p16 overexpression in HPV negative samples. In this case, we discuss a 67-year-old patient with a history of extensive alcohol and tobacco use with a newly diagnosed T4N0M0, high grade, LCNEC of the subglottic larynx. Tumor pathology demonstrated positive staining for typical neuroendocrine (NE) markers like synaptophysin and chromogranin A; however, there was diffuse CK34βE12 and p16 expression. LCNEC is a newly classified subtype of poorly differentiated neuroendocrine (NE) tumors, and the diagnosis requires consideration of the clinical presentation, microscopic features, and immunostaining markers.


Psychometric properties of Watson-Glaser Critical Thinking Appraisal for a sample of education majors.
Psychometric properties of the Watson-Glaser Critical Thinking Appraisal, Form A, were computed for 135 education majors. Analyses of reliability (internal consistency and split-half) and validity (concurrent and predictive) showed that the scale was reliable and valid measuring critical thinking abilities for students majoring in education. The best predictors of the Educational Psychology course grades were the Inference and Deduction subscale scores.


Effect of bidispersity in grafted chain length on grafted chain conformations and potential of mean force between polymer grafted nanoparticles in a homopolymer matrix.
In efforts to produce polymeric materials with tailored physical properties, significant interest has grown around the ability to control the spatial organization of nanoparticles in polymer nanocomposites. One way to achieve controlled particle arrangement is by grafting the nanoparticle surface with polymers that are compatible with the matrix, thus manipulating the interfacial interactions between the nanoparticles and the polymer matrix. Previous work has shown that the molecular weight of the grafted polymer, both at high grafting density and low grafting density, plays a key role in dictating the effective inter-particle interactions in a polymer matrix. At high grafting density nanoparticles disperse (aggregate) if the graft molecular weight is higher (lower) than the matrix molecular weight. At low grafting density the longer grafts can better shield the nanoparticle surface from direct particle-particle contacts than the shorter grafts and lead to the dispersion of the grafted particles in the matrix. Despite the importance of graft molecular weight, and evidence of non-trivial effects of polydispersity of chains grafted on flat surfaces, most theoretical work on polymer grafted nanoparticles has only focused on monodisperse grafted chains. In this paper, we focus on how bidispersity in grafted chain lengths affects the grafted chain conformations and inter-particle interactions in an implicit solvent and in a dense homopolymer polymer matrix. We first present the effects of bidispersity on grafted chain conformations in a single polymer grafted particle using purely Monte Carlo (MC) simulations. This is followed by calculations of the potential of mean force (PMF) between two grafted particles in a polymer matrix using a self-consistent Polymer Reference Interaction Site Model theory-Monte Carlo simulation approach. Monte Carlo simulations of a single polymer grafted particle in an implicit solvent show that in the bidisperse polymer grafted particles with an equal number of short and long grafts at low to medium grafting density, the short grafts are in a more coiled up conformation (lower radius of gyration) than their monodisperse counterparts to provide a larger free volume to the longer grafts so they can gain conformational entropy. The longer grafts do not show much difference in conformation from their monodisperse counterparts at low grafting density, but at medium grafting density the longer grafts exhibit less stretched conformations (lower radius of gyration) as compared to their monodisperse counterparts. In the presence of an explicit homopolymer matrix, the longer grafts are more compressed by the matrix homopolymer chains than the short grafts. We observe that the potential of mean force between bidisperse grafted particles has features of the PMF of monodisperse grafted particles with short grafts and monodisperse grafted particles with long grafts. The value of the PMF at contact is governed by the short grafts and values at large inter-particle distances are governed by the longer grafts. Further comparison of the PMF for bidisperse and monodisperse polymer grafted particles in a homopolymer matrix at varying parameters shows that the effects of matrix chain length, matrix packing fraction, grafting density, and particle curvature on the PMF between bidisperse polymer grafted particles are similar to those seen between monodisperse polymer grafted particles.


Characterization of Escherichia coli chemotaxis receptor mutants with null phenotypes.
Hydroxylamine mutagenesis was used to alter the tar gene that encodes the transmembrane Tar protein required for chemotaxis. Mutants defective in chemotaxis were selected, and the mutation was characterized by DNA sequencing. Two classes of mutations were found: nonsense and missense. The nonsense mutations were distributed throughout the gene, while the missense mutations were found to cluster in a region that includes 185 amino acids at the C-terminal end of the Tar protein. Partial characterization of mutant phenotypes suggested that some are completely defective in signaling while responding to attractants and repellents by differential methylation. Other mutants are undermethylated and constantly tumble, while yet another class of mutants is overmethylated and biased toward constant swimming with little or no tumbling. These mutants will be useful in experiments designed to understand the mechanism of chemotaxis.


Loss of the group A Streptococcus regulator Srv decreases biofilm formation in vivo in an otitis media model of infection.
Group A Streptococcus (GAS) is a common causative agent of pharyngitis, but the role of GAS in otitis media is underappreciated. In this study, we sought to test the hypothesis that GAS colonizes the middle ear and establishes itself in localized, three-dimensional communities representative of biofilms. To test this hypothesis, the middle ears of chinchillas were infected with either a strain of GAS capable of forming biofilms in vitro (MGAS5005) or a strain deficient in biofilm formation due to the lack of the transcriptional regulator Srv (MGAS5005 Δsrv). Infection resulted in the formation of large, macroscopic structures within the middle ears of MGAS5005- and MGAS5005 Δsrv-infected animals. Plate counts, scanning electron microscopy, LIVE/DEAD staining, and Gram staining revealed a difference in the distributions of MGAS5005 versus MGAS5005 Δsrv in the infected samples. High numbers of CFU of MGAS5005 Δsrv were isolated from the middle ear effusion, and MGAS5005 Δsrv was found randomly distributed throughout the excised macroscopic structure. In contrast, MGAS5005 was found in densely packed microcolonies indicative of biofilms within the excised material from the middle ear. CFU levels of MGAS5005 from the effusion were significantly lower than that of MGAS5005 Δsrv early during the course of infection. Allelic replacement of the chromosomally encoded streptococcal cysteine protease (speB) in the MGAS5005 Δsrv background restored biofilm formation in vivo. Interestingly, our results suggest that GAS naturally forms a biofilm during otitis media but that biofilm formation is not required to establish infection following transbullar inoculation of chinchillas.


Enhanced functional response to CXCL12/SDF-1 through retroviral overexpression of CXCR4 on M07e cells: implications for hematopoietic stem cell transplantation.
The chemokine CXCL12 (stromal cell derived factor-1/SDF-1) stimulates hematopoietic stem and progenitor cells (HSCs/HPCs) through the corresponding chemokine receptor CXCR4. CXCL12 is thought to be important for both proper HSC homing, retention, and engraftment into the bone marrow (BM) and mobilization out of the BM. Previous studies suggest that breaking the CXCL12-CXCR4 interaction mobilizes HPCs, blocking CXCR4 inhibits HSC homing, and overexpression increases HSC/HPC repopulation. The efficiency of mobilization and engraftment therefore appears to be dependent on the response of HSCs/HPCs to CXCL12, which is in turn dependent upon levels of CXCR4 expressed on HSCs/HPCs. However, expression of CXCR4 on the surface of HSCs/HPCs appears to be variable. To study the function of CXCR4 on HSCs/HPCs, we used the MSCV-based bicistronic (EGFP) retroviral vector MIEG3 to overexpress CXCR4 on M07e cells, an established model of human HPC. CXCR4 overexpression resulted in significant increases in CXCL12-induced chemotaxis and cell survival. Most importantly, cells overexpressing CXCR4 responded to CXCL12 at levels typically too low induce a response. These data suggest that an increased transplant efficiency resulting from CXCR4 overexpression is likely a function of increased HSC/HPC homing and increased HSC/HPC survival in the recipient's BM. These experiments also validate the ability of the MIEG3-CXCR4 retroviral construct to overexpress CXCR4 efficiently and the use of MIEG3-CXCR4 M07e cells for further study. Finally, this information may have future potential therapeutic implications for improvements in transplant efficiency.


Potato snakin-1 gene silencing affects cell division, primary metabolism, and cell wall composition.
Snakin-1 (SN1) is an antimicrobial cysteine-rich peptide isolated from potato (Solanum tuberosum) that was classified as a member of the Snakin/Gibberellic Acid Stimulated in Arabidopsis protein family. In this work, a transgenic approach was used to study the role of SN1 in planta. Even when overexpressing SN1, potato lines did not show remarkable morphological differences from the wild type; SN1 silencing resulted in reduced height, which was accompanied by an overall reduction in leaf size and severe alterations of leaf shape. Analysis of the adaxial epidermis of mature leaves revealed that silenced lines had 70% to 90% increases in mean cell size with respect to wild-type leaves. Consequently, the number of epidermal cells was significantly reduced in these lines. Confocal microscopy analysis after agroinfiltration of Nicotiana benthamiana leaves showed that SN1-green fluorescent protein fusion protein was localized in plasma membrane, and bimolecular fluorescence complementation assays revealed that SN1 self-interacted in vivo. We further focused our study on leaf metabolism by applying a combination of gas chromatography coupled to mass spectrometry, Fourier transform infrared spectroscopy, and spectrophotometric techniques. These targeted analyses allowed a detailed examination of the changes occurring in 46 intermediate compounds from primary metabolic pathways and in seven cell wall constituents. We demonstrated that SN1 silencing affects cell division, leaf primary metabolism, and cell wall composition in potato plants, suggesting that SN1 has additional roles in growth and development beyond its previously assigned role in plant defense.


[Electric thermometers and transducers for measuring human body temperature].
The use of digital and analogous electric thermometers with aximer transducers of special design which have low specific mass per area unit and optimal sizes and shape is promising in the measurement of human body temperature. To develop a quick-response transducer, it should be taken into account that the baseline body surface temperature and thermal resistance, internal heat sources, such as skin surface, have a substantial impact on measuring time.


[Antiarrhythmic effects of DHA-As on ventricular arrhythmias in rat and dog hearts].
DHA-Ascorbic acid (DHA-As), a new derivative of docosahexaenoic acid (DHA) was tested for its possible antiarrhythmic effects on coronary artery ligation/reperfusion arrhythmias in rat hearts, and adrenaline-induced arrhythmias in canine hearts. DHA-As (3 mg/kg i.v.) did not change the total duration of VT, and tended to suppress the incidence of VT, VF and mortality of reperfusion in rat hearts. The heart rate, QT90 and systolic blood pressure did not change, and the diastolic blood pressure was decreased by DHA-As in the rat hearts. DHA-As significantly decreased the arrhythmic ratio only at two time points (14 and 15 min after injection), and also decreased the heart rate and mean blood pressure in canine hearts. In conclusion, DHA-As tended to suppress the reperfusion-induced arrhythmias in rat hearts. However, the change was not statistically significant. In addition, DHA-As has a weak suppressing effect on adrenaline-induced arrhythmia.


Chikungunya virus evolution following a large 3'UTR deletion results in host-specific molecular changes in protein-coding regions.
The 3'untranslated region (UTR) in alphavirus genomes functions in virus replication and plays a role in determining virus host range. However, the molecular evolution of virus UTRs is understudied compared to the evolution of protein-coding regions. Chikungunya virus (CHIKV) has the longest 3'UTR among the alphaviruses (500-700 nt), and 3'UTR length and sequence structure vary substantially among different CHIKV lineages. Previous studies showed that genomic deletions and insertions are key drivers of CHIKV 3'UTR evolution. Inspired by hypothesized deletion events in the evolutionary history of CHIKV, we used experimental evolution to examine CHIKV adaptation in response to a large 3'UTR deletion. We engineered a CHIKV mutant with a 258 nt deletion in the 3'UTR (ΔDR1/2). This deletion reduced viral replication on mosquito cells, but did not reduce replication on mammalian cells. To examine how selective pressures from vertebrate and invertebrate hosts shape CHIKV evolution after a deletion in the 3'UTR, we passaged ΔDR1/2 virus populations strictly on primate cells, strictly on mosquito cells, or with alternating primate/mosquito cell passages. We found that virus populations passaged on a single host cell line increased in fitness relative to the ancestral deletion mutant on their selected host, and viruses that were alternately passaged improved on both hosts. Surprisingly, whole genome sequencing revealed few changes in the 3'UTR of passaged populations. Rather, virus populations evolved improved fitness through mutations in protein coding regions that were associated with specific hosts.


Directed evolution induces tributyrin hydrolysis in a virulence factor of Xylella fastidiosa using a duplicated gene as a template.
Duplication of genes is one of the preferred ways for natural selection to add advantageous functionality to the genome without having to reinvent the wheel with respect to catalytic efficiency and protein stability. The duplicated secretory virulence factors of Xylella fastidiosa (LesA, LesB and LesC), implicated in Pierce's disease of grape and citrus variegated chlorosis of citrus species, epitomizes the positive selection pressures exerted on advantageous genes in such pathogens. A deeper insight into the evolution of these lipases/esterases is essential to develop resistance mechanisms in transgenic plants. Directed evolution, an attempt to accelerate the evolutionary steps in the laboratory, is inherently simple when targeted for loss of function. A bigger challenge is to specify mutations that endow a new function, such as a lost functionality in a duplicated gene. Previously, we have proposed a method for enumerating candidates for mutations intended to transfer the functionality of one protein into another related protein based on the spatial and electrostatic properties of the active site residues (DECAAF). In the current work, we present in vivo validation of DECAAF by inducing tributyrin hydrolysis in LesB based on the active site similarity to LesA. The structures of these proteins have been modeled using RaptorX based on the closely related LipA protein from Xanthomonas oryzae. These mutations replicate the spatial and electrostatic conformation of LesA in the modeled structure of the mutant LesB as well, providing in silico validation before proceeding to the laborious in vivo work. Such focused mutations allows one to dissect the relevance of the duplicated genes in finer detail as compared to gene knockouts, since they do not interfere with other moonlighting functions, protein expression levels or protein-protein interaction.


Health and illness in Pilipino immigrants.
Immigrants from the Philippines and their descendants have tripled in number in the United States in the past 18 years. They will soon surpass 1 million and will be the largest Asian-American minority. Pilipinos in the United States are diverse ethnolinguistically and in important socioeconomic and demographic dimensions, one notable feature being the high level of education and professional status of many recent immigrants. Nevertheless, the health and disease circumstances of Pilipinos and their views of health and illness have been surprisingly neglected to date. A generic principle fundamental to their view of health is that concerning the maintenance of balance. Proper social and cultural conduct is believed to help avoid health problems. Imbalances in social relations, infringements of cultural norms or adverse interaction with the supernatural are linked, in the cultural logic of Pilipinos, to illness.


Influence of organic surface coatings on the sorption of anticonvulsants on mineral surfaces.
Here, we explore the role that sorption to mineral surfaces plays in the fate of two commonly encountered effluent-derived pharmaceuticals, the anticonvulsants phenytoin and carbamazepine. Adsorption isotherms and pH-edge experiments are consistent with electrostatics governing anticonvulsant uptake on metal oxides typically found in soil and aquifer material (e.g., Si, Al, Fe, Mn, and Ti). Appreciable, albeit limited, adsorption was observed only for phenytoin, which is anionic above pH 8.3, on the iron oxides hematite and ferrihydrite. Adsorption increased substantially in the presence of cationic and anionic surfactants, species also commonly encountered in wastewater effluent. For carbamazepine, we propose the enhanced uptake results entirely from hydrophobic interactions with apolar tails of surfactant surface coatings. For phenytoin, adsorption also arises from the ability of surfactants to alter the net charge of the mineral surface and thereby further enhance favorable electrostatic interactions with its anionic form. Collectively, our results demonstrate that although pristine mineral surfaces are likely not major sinks for phenytoin and carbamazepine in the environment, their alteration with organic matter, particularly surfactants, can considerably increase their ability to retain these emerging pollutants in subsurface systems.


Proteome of Methanosarcina acetivorans Part II: comparison of protein levels in acetate- and methanol-grown cells.
Methanosarcina acetivorans is an archaeon isolated from marine sediments which utilizes a diversity of substrates for growth and methanogenesis. Part I of a two-part investigation has profiled proteins of this microorganism cultured with both methanol and acetate as growth substrates, utilizing two-dimensional gel electrophoresis and MALDI-TOF-TOF mass spectrometry. In this report, Part II, the analyses were extended to identify 34 proteins found to be present in different amounts between methanol- and acetate-grown M. acetivorans. Among these proteins are enzymes which function in pathways for methanogenesis from either acetate or methanol. Several of the 34 proteins were determined to have redundant functions based on annotations of the genomic sequence. Enzymes which function in ATP synthesis and steps common to both methanogenic pathways were elevated in acetate- versus methanol-grown cells, whereas enzymes that have a more general function in protein synthesis were in greater amounts in methanol- compared to acetate-grown cells. Several group I chaperonins were present in greater amounts in methanol- versus acetate-grown cells, whereas lower amounts of several stress related proteins were found in methanol- versus acetate-grown cells. The potential physiological basis for these novel patterns of protein synthesis are discussed.


Multiple sclerosis and peripheral multifocal demyelinating neuropathies occurring in a same patient.
The co-occurrence of multiple sclerosis and peripheral demyelinating neuropathy is rare. It has been disputed whether these are pathologically related or coincidental findings. We report a 36-year-old woman who presented with diplopia, right facial palsy and left-sided weakness. Brain magnetic resonance imaging showed a lesion indicative of central demyelinating disease. Nerve conduction studies revealed peripheral multifocal demyelinating neuropathies. We suggest that the central and the peripheral lesions may be continua of a demyelinating process.


Deep Learning for the Automatic Diagnosis and Analysis of Bone Metastasis on Bone Scintigrams.
To develop an approach for automatically analyzing bone metastases (BMs) on bone scintigrams based on deep learning technology. This research included a bone scan classification model, a regional segmentation model, an assessment model for tumor burden and a diagnostic report generation model. Two hundred eighty patients with BMs and 341 patients with non-BMs were involved. Eighty percent of cases were randomly extracted from two groups as training set. Remaining cases were as testing set. A deep residual convolutional neural network with different structures was used to determine whether metastatic bone lesions existed, regions of lesions were automatically segmented. Bone scan tumor burden index (BSTBI) was calculated; finally, diagnostic report could be automatically generated. The sensitivity, specificity and accuracy of classification model were compared with three physicians with different clinical experience. The Dice coefficient evaluated the effect of segmentation model and compared to the result of nnU-Net model. The correlation between BSTBI and blood alkaline phosphatase (ALP) level was analyzed to verify the efficiency of BSTBI. The performance of report generation model was evaluated by the accuracy of interpretation of report. In testing set, the sensitivity, specificity and accuracy of classification model were 92.59%, 85.51% and 88.62%, respectively. The accuracy showed no statistical difference with moderately and experienced physicians and obviously outperformed the inexperienced. The Dice coefficient of BMs area was 0.7387 in segmentation stage. Based on the whole model frame, our segmentation model outperformed the nnU-Net. BSTBI value changed as the BMs changed. There was a positive correlation between BSTBI and ALP level. The accuracy of report generation model was 78.05%. Deep learning based on automatic analysis frameworks for BMs can accurately identify BMs, preliminarily realize a fully automatic analysis process from raw data to report generation. BSTBI can be used as a quantitative evaluation indicator to assess the effect of therapy on BMs in different patients or in the same patient before and after treatment.


Detection of luminescence of radicals from TiO2 plate during alpha particle irradiation.
A significant amount of radical related luminescence is observed from the titanium dioxide (TiO2) plate during irradiation of alpha particles although alpha particles do not emit Cerenkov-light. TiO2 is a promising material for application to photodynamic therapy in combination with positron radionuclides that emit Cerenkov light. However, it is not clear that radicals are produced by the irradiation of alpha particles, since although Cerenkov light is required to produce radicals, alpha particles do not produce Cerenkov light. To clarify this point, the author irradiates alpha particles to a TiO2 plate and measured the produced luminescence of the plate, which indicates the radical production in TiO2. A significant amount of luminescence was observed from the TiO2 plate during irradiation of alpha particles. The spectrum of luminescence from the TiO2 plate during this irradiation was the same as that emitted by ultraviolet (UV) light irradiated luminescence, which actually showed radical production in a TiO2 plate. This luminescence was not attributed to the UV light from the air scintillation by alpha particles but to the direct irradiation of alpha particles to the TiO2 plate. A significant amount of luminescence from TiO2 plate was detected during irradiation of alpha particles. The luminescence is thought to be emitted from the radicals produced by the direct alpha particle irradiation to the TiO2 plate.


Solving large-scale general phase retrieval problems via a sequence of convex relaxations.
We present a convex relaxation-based algorithm for large-scale general phase retrieval problems. General phase retrieval problems include, e.g., the estimation of the phase of the optical field in the pupil plane based on intensity measurements of a point source recorded in the image (focal) plane. The non-convex problem of finding the complex field that generates the correct intensity is reformulated into a rank constraint problem. The nuclear norm is used to obtain the convex relaxation of the phase retrieval problem. A new iterative method referred to as convex optimization-based phase retrieval (COPR) is presented, with each iteration consisting of solving a convex problem. In the noise-free case and for a class of phase retrieval problems, the solutions of the minimization problems converge linearly or faster towards a correct solution. Since the solutions to nuclear norm minimization problems can be computed using semidefinite programming, and this tends to be an expensive optimization in terms of scalability, we provide a fast algorithm called alternating direction method of multipliers (ADMM) that exploits the problem structure. The performance of the COPR algorithm is demonstrated in a realistic numerical simulation study, demonstrating its improvements in reliability and speed with respect to state-of-the-art methods.


Phosphorylation of the beta-adrenergic receptor in intact cells: relationship to heterologous and homologous mechanisms of adenylate cyclase desensitization.
We have recently shown that both heterologous and homologous forms of adenylate cyclase desensitization involve phosphorylation of beta-adrenergic receptors. In order to compare these two reactions, we wished to identify a single cell system in which both processes could be studied. Using the frog erythrocyte, which has been previously shown to exhibit cAMP-independent homologous desensitization, we have found that under appropriate conditions cAMP-dependent heterologous desensitization can be elicited. Incubation of intact cells with the membrane-permeable cAMP analogs dibutyryl cAMP or 8-bromo cAMP promotes about a 50% desensitization of isoproterenol- and prostaglandin E1-stimulated adenylate cyclase activity in a time-, temperature-, and dose-dependent fashion. There is also a 20% desensitization in the abilities of guanine nucleotides (GTP and guanyl-5'-yl-imidodiphosphate) and NaF to stimulate adenylate cyclase maximally. In contrast, there is no effect on forskolin- or MnCl2-stimulated enzyme activities. The desensitization response is specific for cAMP as dibutyryl cGMP, 8-bromo cGMP, or 8-bromo AMP produce little or no desensitization. Incubation of the cells with dibutyryl cAMP does not affect the number of cell surface beta-adrenergic receptors. In contrast, incubation with isoproterenol promotes homologous desensitization and sequestration of the receptors. Incubation of 32P-labeled erythrocytes with either dibutyryl cAMP or isoproterenol promotes a stoichiometric threefold increase in the phosphorylation state of the beta-adrenergic receptor which occurs predominantly on serine residues. However, if the cells are coincubated with both dibutyryl cAMP and isoproterenol then the desensitization of isoproterenol-stimulated enzyme activity and phosphorylation of the beta-adrenergic receptor are greater than those observed with either agent alone. These results indicate that heterologous and homologous desensitization of adenylate cyclase-coupled beta-adrenergic receptors are mediated by different biochemical pathways involving phosphorylation of the receptor protein on distinct sites.


Effects of Multi-Shell Free Water Correction on Glioma Characterization.
Diffusion MRI is a useful tool to investigate the microstructure of brain tumors. However, the presence of fast diffusing isotropic signals originating from non-restricted edematous fluids, within and surrounding tumors, may obscure estimation of the underlying tissue characteristics, complicating the radiological interpretation and quantitative evaluation of diffusion MRI. A multi-shell regularized free water (FW) elimination model was therefore applied to separate free water from tissue-related diffusion components from the diffusion MRI of 26 treatment-naïve glioma patients. We then investigated the diagnostic value of the derived measures of FW maps as well as FW-corrected tensor-derived maps of fractional anisotropy (FA). Presumed necrotic tumor regions display greater mean and variance of FW content than other parts of the tumor. On average, the area under the receiver operating characteristic (ROC) for the classification of necrotic and enhancing tumor volumes increased by 5% in corrected data compared to non-corrected data. FW elimination shifts the FA distribution in non-enhancing tumor parts toward higher values and significantly increases its entropy (p ≤ 0.003), whereas skewness is decreased (p ≤ 0.004). Kurtosis is significantly decreased (p < 0.001) in high-grade tumors. In conclusion, eliminating FW contributions improved quantitative estimations of FA, which helps to disentangle the cancer heterogeneity.


The effects of creatine loading and gender on anaerobic running capacity.
Creatine (Cr) loading consists of short-term, high-dosage Cr supplementation and has been shown to increase intramuscular total Cr content. Increases in body weight (BW) have been shown to result from Cr loading, with differences by gender, and increased BW may impact weight-bearing exercise. The critical velocity (CV) test is used to quantify the relationship between total running distance and time to exhaustion. The CV test provides the variable, anaerobic running capacity (ARC), which is an estimate of the anaerobic energy reserves in muscle. The purpose of this study was to examine the effects of gender and Cr loading on ARC. Fifty moderately trained men and women volunteered to participate in this randomized, double-blinded, placebo (PL)-controlled, repeated-measures study. After a familiarization session, a 3-day testing procedure was conducted. A maximal oxygen consumption test VO(2)max) on a treadmill was performed on day 1 to establish the maximum velocity (Vmax) at VO(2)max and to record BW. Days 2 and 3 involved treadmill running at varying percentages of Vmax. Participants were randomly assigned to either the Cr or PL group and received 20 packets of the Cr supplement (1 packet = 5 g Cr citrate, 18 g dextrose) or 20 packets of the PL (1 packet = 18 g dextrose). After consuming 4 packets daily for 5 consecutive days, the 3-day testing procedure was repeated. The male Cr loading group exhibited a 23% higher (p = 0.003) ARC compared to the PL group. Nonsignificant BW increases were found for the Cr groups. These findings suggest that Cr loading may be an effective strategy for improving ARC in men, but not in women, and revealed only nonsignificant increases in BW. Creatine loading may be used before competition by athletes to provide improvements in high-intensity, short-duration activities.


Comparative cardiovascular outcomes of novel drugs as an addition to conventional triple therapy for heart failure with reduced ejection fraction (HFrEF): a network meta-analysis of randomised controlled trials.
Currently, there is no head-to-head comparison of novel pharmacological treatments for heart failure with reduced ejection fraction (HFrEF). A network meta-analysis aimed to compare effects of both conventional and alternative drug combinations on time to develop primary composite outcome of cardiovascular death or heart failure hospitalisation (PCO). Randomised controlled trials (RCTs) were identified from Medline, Scopus up to June 2021. The RCTs were included if comparing any single or combination of drugs, that is, ACE inhibitors (ACEI), angiotensin receptor blockers, beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), ivabradine (IVA), angiotensin receptor blocker/neprilysin inhibitors (ARNI) and sodium-glucose cotransporter-2 inhibitors (SGLT2i), soluble guanylyl cyclase and omecamtiv mecarbil and reporting PCO. Data were extracted from Kaplan-Meier curves, individual patient data were generated. A mixed-effect Weibull regression was applied. Median time to PCO, HRs with 95% CI were estimated accordingly. Our findings suggested that ACEI+BB+MRA+SGLT2i, BB+MRA+ARNI, and ACEI+BB+MRA+IVA had lower probability of PCOs than the conventional triple therapy (ACEI+BB+MRA). Median time to PCOs of ACEI+BB+MRA was 57.7 months whereas median times to those new combinations were longer than 57.7 months. In addition, the three new regimens had a significantly lower PCO risks than ACEI+BB+MRA, with the HRs (95% CI) of 0.51 (0.43 to 0.61), 0.55 (0.46 to 0.65) and 0.56 (0.47 to 0.67), accordingly. This study suggested that SGLT2i, ARNI and IVA in addition to ACEI+BB+MRA may be better in prolonging time to develop PCO in HFrEF patients.


Metal-free C-C bond formation via coupling of nitrile imines and boronic acids.
The challenges of developing sustainable methods of carbon-carbon bond formation remains a topic of considerable importance in synthetic chemistry. Capitalizing on the highly reactive nature of the nitrile imine 1,3-dipole, we have developed a novel metal-free coupling of this species with aryl boronic acids. Photochemical generation of a nitrile imine intermediate and trapping with a palette of boronic acids enabled rapid and facile access to a broad library of more than 25 hydrazone derivatives in up to 92% yield, forming a carbon-carbon bond in a metal free fashion. This represents the first reported example of direct reaction between boronic acids and a 1,3-dipole.


MicroRNAs: master regulators of ethanol abuse and toxicity?
Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol's deleterious effects leading to the suggestion that ethanol is a "dirty drug." An important question is, are there cellular "master-switches" that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol's effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders.


Differential titin isoform expression in human skeletal muscle.
Mammalian skeletal muscle expresses at least two isoforms of the cytoskeletal protein titin (connectin; MW approximately 3000 kDa). These isoforms are associated with different passive force curves, and thus may affect physical performance. To study the distribution of titin and its possible influence on performance in humans, muscle biopsies were obtained from 15 males (mean +/- SE; age = 25.4 +/- 2.9 years, height = 177.7 +/- 1.8 cm, weight = 76.5 +/- 2.2 kg). Two biopsies were obtained on separate occasions from both the right and left vastus lateralis, and one biopsy each from the lateral head of the right gastrocnemius and the right soleus, with all biopsies handled identically. Fibre type analyses were performed via mATPase histochemistry. Expression of titin and myosin heavy chain isoforms were determined by SDS-PAGE. Titin bands in the resulting gels were highly repeatable and were verified by migration patterns, as well as Western blot analysis. Two groups of subjects were identified: group 1 (n = 10) expressed only one titin isoform (titin-1) in all biopsies, and group 2 (n = 5) expressed two titin isoforms (titin-1 and titin-2) in all biopsies. No significant differences (P > 0.05) between groups were observed for percentage fibre types, percentage fibre type areas, fibre type cross-sectional areas, and percentage myosin heavy chain expression when comparing individual muscles, sampling times or bilateral comparisons. This is the first report of differential titin isoform expression in healthy, mature human skeletal muscle, but it is not clear why this occurs or what influence this may have on performance.


Structural definition of a conserved neutralization epitope on HIV-1 gp120.
The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 A resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1.


A retrospective study of peritonsillar abscess in Riyadh Medical Complex [corrected].
To investigate and study the management pattern of peritonsillar abscess, the male to female ratio and incidence. Also, to evaluate the causative organism isolated from abscess and reported by culture/sensitivity (C/S). This study has been designed as a single centered retrospective hospital based study. We carried out this study in the Department of ENT, Riyadh Medical Complex, Saudi Arabia from 2000 to 2004. We gathered the data via survey (5 years). There were 81 patients admitted for the management of peritonsillar abscess. Mean age of patients was 22 years (range 10 to 60 years; 44 male, 37 female). The hospital stay varies from 1-8 days with a mean of 4 days. The left side is more involved. Treatment consisted mainly incision/drainage under local anesthetic in 47 patients (58%), while 5 cases (6%) were carried out under general anesthetic. Aspiration and conservative treatment was noted in 25 (31%) cases, abscess tonsillectomy was carried out in 3 (4%) cases. The most common microorganisms isolated from C/S is Group A beta hemolytic streptococcus (17/81 [21%]). Penicillin G + Flagyl (49/81 [60%]) were the most common antibiotics used. No case of bilateral peritonsillar abscess was found and there is no consensus regarding the best technique. Options include needle aspiration, incision and drainage and immediate tonsillectomy. Peritonsillar abscess remain one of the acute admission in the Department of Otolaryngology at Riyadh Medical Complex, Riyadh. Incision/drainage remains the gold standard treatment, Penicillin G + Flagyl combinations are the cornerstones.


Constructing families and kinship through donor insemination.
This paper presents some central findings of an exploratory qualitative study of New Zealand families with children conceived by donor insemination (DI). Drawing on social anthropological and sociological theorising about kinship and contemporary Western families, the paper explores the ways in which parents and their kin actively construct parent-child relationships and kin connections through the notions of biological and social ties, nature and nurture. The paper discusses three major themes emerging from the data: the social construction of the 'natural facts' of procreation, physical resemblance, and the construction of families through choice, not biology. Whilst the primacy of biological or genetic connection is a powerful cultural theme, particularly evident in the ambiguities and uncertainties for social fathers and their kin, these families also deconstruct this notion. Drawing simultaneously on the power of social and biological connection, using biology as a metaphor for social relations, or by privileging social ties and the formation of families through choice, over time these families strategically establish themselves as the sole parents and kin of their children conceived by DI.


Primary ligament repair for elbow dislocation.
Few have been reported on the role of early primary ligament repair for acute unstable elbow dislocation. The purpose of this study is to evaluate the clinical outcome of early primary ligament repair for unstable elbow dislocation followed by protected early joint mobilization exercise. Thirteen patients who underwent operative treatment due to unstable elbow dislocation without associated fracture were retrospectively reviewed. There were 11 male and 2 female with average age of 37 years (range; 18-72 years). Surgical indications of the unstable elbow were subluxation or non-congruent elbow joint on the radiographs following closed reduction. Elbow dislocation which required extension block splint over 45 degrees to maintain reduction was considered as unstable elbow dislocation. In ten patients, full stability was restored only after both medial and lateral structures were re-attached. In two patients, only lateral structure (LCLC and common extensor tendon) was repaired and in one patient, only medial structure (MCL and flexor pronator tendon) was repaired for stability. Overall mean functional Mayo Elbow Performance Score was 93.5 (range; 70-100). No elbow was dislocated or subluxated after operation. All ten patients returned to previous work level in average of 3.5 months. Heterotopic calcification was noted in six patients and three had mild ulnar nerve symptoms after operation. In conclusion, primary ligament repair in acute unstable elbow dislocation were successful, because surgery achieved sufficient stability to allow early exercise.


Biomimetic material systems for neural progenitor cell-based therapy.
Reconstruction and regeneration of the central nervous system (CNS) following injury is a formidable task. However, cell replacement with transplanted neural progenitor cells (NPC) is a promising technique that has resulted in various levels of functional recovery in animals that had experienced an experimental injury of the brain or spinal cord. Unfortunately, CNS injury often leads to significant tissue damage and loss, limiting the survival and integration of transplanted NPC. In response, researchers have developed many biomaterial substrates that have been used to culture, transplant, and influence the differentiation and integration of transplanted NPC. Biomaterial scaffolds are a three-dimensional lattice that can be engineered to support NPC in vitro as well as serving as a temporary extracellular matrix (ECM) after transplantation. Scaffold modification with bioactive components, such as proteins, adhesive peptide sequences, and growth factors, allow researchers to modulate NPC responses as well as the local environment of the transplantation site. Biomimetic approaches also can include materials that recapitulate the structural dimensions of the ECM, namely self-assembling nanofibers. These materials can be useful for altering the tissue microenvironment by reducing inflammation and glial scarring, which may further enhance NPC survival and integration into functional neural circuitry. This review describes various biomaterial constructs, with a focus on biomimetic systems that have been used in modulating NPC behavior in culture and/or in transplanting NPC to the CNS.


Ankle taping can reduce external ankle joint moments during drop landings on a tilted surface.
Ankle taping is commonly used to prevent ankle sprains. However, kinematic assessments investigating the biomechanical effects of ankle taping have provided inconclusive results. This study aimed to determine the effect of ankle taping on the external ankle joint moments during a drop landing on a tilted surface at 25°. Twenty-five participants performed landings on a tilted force platform that caused ankle inversion with and without ankle taping. Landing kinematics were captured using a motion capture system. External ankle inversion moment, the angular impulse due to the medio-lateral and vertical components of ground reaction force (GRF) and their moment arm lengths about the ankle joint were analysed. The foot plantar inclination relative to the ground was assessed. In the taping condition, the foot plantar inclination and ankle inversion angular impulse were reduced significantly compared to that of the control. The only component of the external inversion moment to change significantly in the taped condition was a shortened medio-lateral GRF moment arm length. It can be assumed that the ankle taping altered the foot plantar inclination relative to the ground, thereby shortening the moment arm of medio-lateral GRF that resulted in the reduced ankle inversion angular impulse.


Open lung biopsy for diffuse interstitial lung disease in children.
The aim of the study was to investigate the contribution that open lung biopsy makes to the management of children with diffuse interstitial lung disease and to review the procedure-related morbidity in comparison with published literature on other biopsy techniques. The authors reviewed the case notes and histology of patients under 18 yrs who had had an open lung biopsy in 1991-1998 for investigation of diffuse interstitial lung disease. The majority of patients returned from theatre breathing spontaneously and without an intercostal drain. Three out of 27 suffered a complication related to the biopsy that required intervention. A clear histological diagnosis was reached in 25/27 patients resulting in a change of management in 15/27. The most common histological patterns were nonspecific interstitial pneumonitis which generally had a favourable prognosis and follicular bronchiolitis/lymphocytic interstitial pneumonitis where prognosis was largely dependent on that of an underlying systemic disorder. It is concluded that open lung biopsy makes a substantial contribution to the management of diffuse interstitial lung disease in children and considering both diagnostic yield and safety, remains the biopsy technique of choice.


Ultrasound findings in ectopic gestation.
To study the diagnostic accuracy of real-time ultrasonography in the evaluation of ectopic pregnancy, the case records and preoperative sonograms of 57 patients with surgically proven ectopic pregnancy were reviewed. Some 81% of these patients had abnormal sonograms. However, the ultrasonographic findings were often nonspecific and in only 8.7% of the cases was an ectopic fetal heart beat demonstrated. Two patients in this series had coexistent intrauterine and extrauterine gestations. Other findings such as an adnexal mass, an empty uterus, fluid in the cul-de-sac, and a decidual reaction in the uterus are all suggestive of an ectopic pregnancy but can be seen in other conditions. The presence of a normal intrauterine gestation practically rules out the possibility of ectopic pregnancy.


Ammonia-regulated expression of a soybean gene encoding cytosolic glutamine synthetase in transgenic Lotus corniculatus.
A full-length cDNA clone encoding cytosolic glutamine synthetase (GS), expressed in roots and root nodules of soybean, was isolated by direct complementation of an Escherichia coli gln A- mutant. This sequence is induced in roots by the availability of ammonia. A 3.5-kilobase promoter fragment of a genomic clone (lambda GS15) corresponding to this cDNA was isolated and fused with a reporter [beta-glucuronidase (GUS)] gene. The GS-GUS fusion was introduced into a legume (Lotus corniculatus) and a nonlegume (tobacco) plant by way of Agrobacterium-mediated transformations. This chimeric gene was found to be expressed in a root-specific manner in both tobacco and L. corniculatus, the expression being restricted to the growing root apices and the vascular bundles of the mature root. Treatment with ammonia increased the expression of this chimeric gene in the legume background (i.e., L. corniculatus); however, no induction was observed in tobacco roots. Histochemical localization of GUS activity in ammonia-treated transgenic L. corniculatus roots showed a uniform distribution across all cell types. These data suggest that the tissue specificity of the soybean cytosolic GS gene is conserved in both tobacco and L. corniculatus; however, in the latter case, this gene is ammonia inducible. Furthermore, the ammonia-enhanced GS gene expression in L. corniculatus is due to an increase in transcription. That this gene is directly regulated by externally supplied or symbiotically fixed nitrogen is also evident from the expression of GS-GUS in the infection zone, including the uninfected cells, and the inner cortex of transgenic L. corniculatus nodules, where a flux of ammonia is encountered by this tissue. The lack of expression of GS-GUS in the outer cortex of the nodules suggests that ammonia may not be able to diffuse outside the endodermis.


[Bilateral pleurisy revealing a myelome with free light chains complicated with an osseous amylose].
The osseous amyloidosis associated with a pleural effusion in a myeloma is a rare situation. We report a case of an association of these three disease entities for discussion. A 75-year-old man was admitted for chest pain and dyspnea with left sacred bone pain. The radiological assessment reported pleurisy and bilateral lytic images of the sacrum with soft tissue invasion, the biochemical tests showed a lambda free light chain myeloma and bone biopsy reported amyloidosis. The occurrence of systemic amyloidosis in myeloma is well documented, but the osseous location is rare and rarely revealed. Pleural effusion is a known complication of myeloma but is exceptionally revealing; it is usually seen in the myeloma IgG and IgA but very rarely in free light chain myeloma. We reported here a case that represents an exceptional situation of complications of light chains myeloma to remember their possible occurrence and to insist for the clinician sensitizing to carry out investigations on time and avoid complications or at minimum to retard them.