Cholestatic Liver Injury After Biliary Reconstruction Impairs Transplanted Islet Viability and Function.
Islet autotransplantation following total pancreatectomy differs from allograft transplantation with respect to the requirement of biliary reconstruction. Although it is known that careful consideration should be given to postoperative cholestatic liver injury after biliary reconstruction, its direct effects on transplanted islets have not been completely elucidated. In this study, we developed a murine model of postoperative cholestatic liver injury after biliary reconstruction with islet autotransplantation that involved syngeneic intraportal islet transplantation into chemically induced diabetic mice and common bile duct ligation. We assessed the viability and function of the transplanted islets. The impaired viability of transplanted islets and increased blood glucose levels indicated restoration of the diabetic state after common bile duct ligation in this murine model. Furthermore, impaired islet viability and function occurred earlier in the transplanted islets than in the surrounding liver tissues, which was consistent with the faster and higher expression of oxidative stress markers in the transplanted islets. Transplanted islets may be more vulnerable to oxidative stress caused by cholestatic liver injury than the surrounding liver tissue. Therefore, patients should be intensively managed after total pancreatectomy with islet autotransplantation to preserve viability and function of the transplanted islets.


[Anaemia in two infants due to fetomaternal transfusion].
In two neonates, a boy suffering from persistent pulmonary hypertension of the newborn and a girl with fetal distress, massive fetomaternal haemorrhage was diagnosed (290 ml). In both cases fetal monitoring showed a sinusoidal heart rate pattern and the Kleihauer-Betke test was positive. Both children were intubated and ventilated and were given an erythrocyte transfusion. They both recovered. Differentiation between acute and chronic fetomaternal haemorrhage is essential when deciding on treatment: blood transfusion in acute fetomaternal haemorrhage and exchange transfusion in chronic fetomaternal haemorrhage with normoor hypervolemia. Differentiation is difficult. Little is known about the prognosis of fetomaternal haemorrhage. Because of the nature of perinatal problems and the possibility of neurological damage, long-term follow-up is recommended.


Incidence and relevance of proteinuria in bevacizumab-treated patients: pooled analysis from randomized controlled trials.
This analysis evaluated the incidence of and risk factors for bevacizumab-related proteinuria and assessed for any associated clinical sequelae, including renal function changes. Patient-level adverse event and laboratory data from a pooled safety database were used to characterize alterations in urine protein excretion following interventional therapy ± bevacizumab in 17 randomized trials across multiple tumor types. Severity of renal function change was assessed using changes in serum creatinine concentration from baseline values. Potential predictors of proteinuria and the association between proteinuria and other adverse events were also investigated. Among 14,548 patients, the incidence of any-grade proteinuria was 8.2% (733/8,917) and 4.6% (257/5,631) in the bevacizumab and control groups, respectively; rates of grade ≥3 proteinuria were 1.4 and 0.2%. Post-baseline proteinuria grade and bevacizumab were associated with increased rates of renal dysfunction. Patients developing proteinuria had an increased rate of any-grade infection but not thromboembolic events. History of diabetes was the only examined risk factor that appeared to have a significant association with proteinuria development. This analysis confirmed a significant increase in the development of proteinuria during bevacizumab treatment. We also observed an increased rate of renal dysfunction associated with bevacizumab treatment and among subjects with proteinuria, although the dysfunction was generally mild. The development of proteinuria was also associated with a modest increase in risk of infection.


Interpreting the estimated timing of migration events between hybridizing species.
The question of whether speciation can occur in the presence of gene flow has long been a contentious one. However, measuring the amount and timing of gene flow remains challenging. The computer program IMa2 allows researchers to estimate the timing of migration events for each locus during analyses, and these estimates have been used to infer the timing of introgression and mode of speciation. We use simulated data sets to examine the degree to which gene-flow timing estimates can be used for these purposes, and what demographic conditions and data sets may be most amenable to gene-flow timing estimation. We find that the 90% highest posterior density (HPD) interval of gene-flow timing is almost always substantially wider than the actual window of gene flow, and increasing the information content of the data set in terms of number of loci, number of sequences sampled or locus length (and thus number of variable sites) has little impact on the posterior distribution over the range of values we tested. Even when simulated gene flow only occurred over the most recent 0.01% of the species' history, the HPD interval usually encompasses the inferred divergence time. Our results indicate that gene-flow timing estimates made using the method currently implemented in IMa2 cannot reliably be used to make inferences about the timing of introgression between diverged species or to distinguish between speciation with gene flow and allopatric speciation followed by one or more episodes of gene flow.


[Lymphangiosis carcinomatosa of the skin in ovarian cancer simulating scleroderma].
Skin metastases, as the first site of manifestation of ovarian carcinoma, are very uncommon. A report on a case of dermal lymphatic carcinomatosis of the lower part of the body and the breast with the clinical appearance of scleroderma is made. Skin biopsies were performed several times and an invasion of cutaneous lymphatic vessels by carcinoma cells and psammoma bodies due to ovarian cancer was observed, which led to the correct diagnosis of ovarian carcinoma.


[Exercise in haemodyalisis patients: a literature systematic review].
Exercise as a therapeutic tool used in End-stage renal disease patients (ESRD) in hemodialysis (HD) is not routinately applied, as it occurs with cardiac or respiratory patients. Lack of awareness of research in this field may contribute to the current situation. Thus, the aims of this review are: 1) to systematically review the literature of exercise training on adult HD patients or patients at a pre-HD stage; 2) to show the evidence on the benefits of exercise for counteracting physiological, functional and psychological impairments found even in older ESRD patients; 3) to recommend requirements of future research in order to include exercise prescription in the HD patients treatment. The Data bases reviewed from 2005 to 2009 were: MEDLINE (Ovid), CINAHL (EBSCOHost), SportDicus (EBSCOHost), Academic Search Complete (EBSCOHost), Fuente Académica (EBSCOHost), MedicLatina (EBSCOHost), PEDro y PubMed. Additionally, references from identified articles, several reviews on ESRD and abstracts to Nephrology Congresses were also reviewed. Randomized Controlled Trials on aerobic, strength and combined programs for HD patients were selected. Data from the studies was compiled and Van Tulder criteria were used for methodological quality assessment. Metanalysis included 6 studies on aerobic exercise, 2 on strength exercise and 5 on combined exercise programs. 640 patients were included in 16 included studies. Effects on physical function, health related quality of life and other secondary measurements were summarized by the Standardized Mean Difference (SMD) Moderate evidence exists on positive effects of aerobic training on peak oxygen consumption at the graded exercise test (SMD 6.55; CI 95%: 4.31-8.78). There is high evidence on positive effects of strength training on health related quality of life (SMD 11.03; CI 95%: 5.63-16.43). Finally, moderate evidence exists on positive effects of combined exercise on peak oxygen consumption at the graded exercise test (SMD 5.57; CI 95%: 2.52-8.61). Summarizing, moderate evidence exists on the improvement on exercise capacity of aerobic training, isolated or combined with strength training. Strength training improves health related quality of life, functional capacity and lower limbs strength. Future studies should clarify which out of the three modalities results in higher benefits for HD patients.


iCap: Instrumented assessment of physical capability.
The aims of this study were to (i) investigate instrumented physical capability (iCap) as a valid method during a large study and (ii) determine whether iCap can provide important additional features of postural control and gait to categorise cohorts not previously possible with manual recordings. Cross-sectional analysis involving instrumented testing on 74 adults who were recruited as part of a pilot intervention study; LiveWell. Participants wore a single accelerometer-based monitor (lower back) during standardised physical capability tests so that outcomes could be compared directly with manual recordings (stopwatch and measurement tape) made concurrently. Time, distance, postural control and gait characteristics. Agreement between manual and iCap ranged from moderate to excellent (0.649-0.983) with mean differences between methods low and deemed acceptable. Additionally, iCap successfully quantified (i) postural control characteristics which showed sensitivity to distinguish between 5 variations of the standing balance test and (ii) 14 gait characteristics known to be sensitive to age/pathology. Our findings show that iCap can provide robust quantitative data about physical capability during standardised tests while also providing sensitive (age/pathology) postural control and gait characteristics not previously quantifiable with manual recordings. The methodology which we propose may have practical utility in a wide range of clinical and public health surveys and studies, including intervention studies, where assessment could be undertaken within diverse settings. This will need to be tested in further validation studies in a wider range of settings.


Distinct mechanisms of CD4+ and CD8+ T-cell activation and bystander apoptosis induced by human immunodeficiency virus type 1 virions.
Apoptosis of uninfected bystander T cells contributes to T-cell depletion during human immunodeficiency virus type 1 (HIV-1) infection. HIV-1 envelope/receptor interactions and immune activation have been implicated as contributors to bystander apoptosis. To better understand the relationship between T-cell activation and bystander apoptosis during HIV-1 pathogenesis, we investigated the effects of the highly cytopathic CXCR4-tropic HIV-1 variant ELI6 on primary CD4(+) and CD8(+) T cells. Infection of primary T-cell cultures with ELI6 induced CD4(+) T-cell depletion by direct cell lysis and bystander apoptosis. Exposure of primary CD4(+) and CD8(+) T cells to nonreplicating ELI6 virions induced bystander apoptosis through a Fas-independent mechanism. Bystander apoptosis of CD4(+) T cells required direct contact with virions and Env/CXCR4 binding. In contrast, the apoptosis of CD8(+) T cells was triggered by a soluble factor(s) secreted by CD4(+) T cells. HIV-1 virions activated CD4(+) and CD8(+) T cells to express CD25 and HLA-DR and preferentially induced apoptosis in CD25(+)HLA-DR(+) T cells in a CXCR4-dependent manner. Maximal levels of binding, activation, and apoptosis were induced by virions that incorporated MHC class II and B7-2 into the viral membrane. These results suggest that nonreplicating HIV-1 virions contribute to chronic immune activation and T-cell depletion during HIV-1 pathogenesis by activating CD4(+) and CD8(+) T cells, which then proceed to die via apoptosis. This mechanism may represent a viral immune evasion strategy to increase viral replication by activating target cells while killing immune effector cells that are not productively infected.


Linking language and categorization: evidence from aphasia.
In addition to its use in communication, language appears to have a variety of extra-communicative functions; disrupting language disrupts performance in seemingly non-linguistic tasks. Previous work has specifically linked linguistic impairments to categorization impairments. Here, we systematically tested this link by comparing categorization performance in a group of 12 participants with aphasia and 12 age- and education-matched control participants. Participants were asked to choose all of the objects that fit a specified criterion from sets of 20 pictured objects. The criterion was either "high-dimensional" (i.e., the objects shared many features, such as "farm animals") or "low-dimensional" (i.e., the objects shared one or a few features, such as "things that are green"). Participants with aphasia were selectively impaired on low-dimensional categorization. This selective impairment was correlated with the severity of their naming impairment and not with the overall severity of their aphasia, semantic impairment, lesion size, or lesion location. These results indicate that linguistic impairment impacts categorization specifically when that categorization requires focusing attention and isolating individual features--a task that requires a larger degree of cognitive control than high-dimensional categorization. The results offer some support for the hypothesis that language supports cognitive functioning, particularly the ability to select task-relevant stimulus features.


Ilizarov external fixation for a periprosthetic tibial fracture in severe osteoporosis: a case report.
The incidence of periprosthetic fractures after total knee arthroplasty (TKA) is rising due to the increasing number of TKAs performed annually and the growing elderly population. A periprosthetic fracture of the proximal tibia following TKA is a rare injury that may be a challenging clinical scenario. The case of an 84-year-old woman who sustained a periprosthetic tibial fracture 10 years after a TKA is presented. This patient had multiple risk factors. The fracture was not deemed amenable to conventional treatment because the bone fragment was too small. This patient underwent fixation of her tibial fracture above the TKA using a five-ring Ilizarov external fixator. This allowed immediate full weight-bearing. The fixator was removed at 12 weeks, at which time the fracture was solidly healed. At the most recent follow-up, 2 years from injury, she was fully weight-bearing without walking aids and had a knee range of motion (ROM) of 0-110°. To the best of our knowledge, this is the first report in which Ilizarov external fixation has been used for a periprosthetic tibial fracture after TKA.


Early systemic sclerosis-opportunities for treatment.
Systemic sclerosis (SSc) is characterized by microvasculopathy (Raynaud's phenomenon and fibrointimal proliferation), presence of autoantibodies and collagen deposition in skin (scleroderma) and internal organs. Microvasculopathy, detected by nailfold capillaroscopy, and disease-specific autoantibodies (anti-topoisomerase I, anti-centromere, anti-RNA polymerase III antibodies) usually appear earlier, even years before scleroderma. At that stage of the disease, immune activation with T cells and B cells promote fibrosis. Diagnosis of SSc has been relied on scleroderma, and by this time, internal organs may have developed fibrosis, a lethal feature with no available treatment. The new EULAR/ACR 2013 criteria for the classification of SSc will help identify SSc patients before fibrosis of internal organs. The early diagnosis of SSc, before the development of fibrosis in internal organs, will allow the introduction of immunosuppressive medications in these patients in a controlled setting (randomized trials). It is anticipated that this approach will change the hitherto grim prognosis of SSc for the better.


Human brain endothelial cells are responsive to adenosine receptor activation.
The blood-brain barrier (BBB) of the central nervous system (CNS) consists of a unique subset of endothelial cells that possess tight junctions which form a relatively impervious physical barrier to a large variety of blood components. Until recently, there have been no good in vitro models for studying the human BBB without the co-culture of feeder cells. The hCMEC/D3 cell line is the first stable, well-differentiated human brain endothelial cell line that grows independently in culture with characteristics that closely resemble those of resident human brain endothelial cells. As our previously published findings demonstrated the importance of adenosine receptor (AR) signaling for lymphocyte entry into the CNS, we wanted to determine if human brain endothelial cells possess the capacity to generate and respond to extracellular adenosine. Utilizing the hCMEC/D3 cell line, we determined that these cells express CD73, the cell surface enzyme that converts extracellular AMP to adenosine. When grown under normal conditions, these cells also express the A(1), A(2A), and A(2B) AR subtypes. Additionally, hCMEC/D3 cells are responsive to extracellular AR signaling, as cAMP levels increase following the addition of the broad spectrum AR agonist 5'-N-ethylcarboxamidoadenosine (NECA). Overall, these results indicate that human brain endothelial cells, and most likely the human BBB, have the capacity to synthesize and respond to extracellular adenosine.


Approach to women who become pregnant while on tenofovir disoproxil fumarate for chronic B hepatitis: A report of two cases.
Mother-to-child transmission of hepatitis B virus can occur during the intrauterine, antenatal and postnatal periods, with an increased risk of perinatal transmission. Appropriate management of patients who are hepatitis B surface antigen positive during pregnancy can substantially reduce the rates of perinatal transmission. Herein, two pregnant women with chronic hepatitis B are presented; one became pregnant while receiving tenofovir disoproxil fumarate and continued the treatment during pregnancy, the other discontinued tenofovir disoproxil fumarate treatment on her own due to conception, but restarted at 26 weeks of pregnancy. At birth the newborns of both women were vaccinated and immunoglobulin was given, with no perinatal transmission. Whether pregnant women should receive antiviral therapy or immunoprophylaxis still remains controversial. In order to keep the mother's liver stable and to prevent perinatal transmission, it is of paramount importance to manage pregnant women in line with the current information and guidelines.


Challenges of connectedness in personal recovery for rural mothers with mental illness.
Social connection is a fundamental human need, but challenging for individuals with characteristics that are socially stigmatized. Parenting with mental illness presents obstacles, as well as opportunities, for connection. In the present study, we examined connectedness within a personal recovery paradigm for rural mothers with a mental illness. In-depth interviews with 17 mothers with a mental illness, utilizing constructivist grounded theory, resulted in six categories of meaning, including 'yearning for connection', 'connecting intensely', 'encountering rejection and exclusion', 'choosing isolation', 'being known', and 'finding peers/helping others'. Women expressed a strong desire for connection, but for many, prior experiences of trauma and rejection created barriers to the development of trust, preventing some women from seeking opportunities for connection. Connectedness to self and significant others, and a broader life meaning and purpose can support and expedite personal recovery from mental illness for rural women. However the factors that contribute to the mental illness might also inhibit the development of trust needed to attain social connection. Increasing connectedness in mothers with mental illness is a complex endeavour requiring concerted focus as distinct from other service-delivery goals. The perinatal period could be a key time for intervention.


Flow cytometric analysis of androgen receptor expression in human prostate tumors and benign tissues.
Androgen receptor (AR) plays an important role in growth and hormonal therapy of human prostate tumors. Immunohistochemical analysis of AR expression, a nonquantitative technique, is currently used for screening of receptor expression in prostate tissues. The present report describes a laser flow cytometric method for monitoring AR expression in human cell lines and in archival formalin-fixed paraffin-embedded prostate tissues and tumors. Multiparametric flow analysis can be used for simultaneous detection of other cellular markers (e.g., DNA aneuploidy), and by gated analysis, AR expression in subpopulations of a tumor can be quantitatively determined.


[Functional state of the hypophyseal-adrenal system in lung cancer].
The results are reported on studies of the secretion of adrenocorticotropic (ACTH), somatotropic (STH) hormones and cortisol, using a standard set for in vitro diagnosis. A total of 66 patients aged 31--70 (64 males and 2 females) have been examined. Among these patients stage II was noted in 17, stage III--in 31, stage IV--in 18. In 19 of them a peripheral cancer and in 47--central cancer was detected. The data obtained indicate an increased basal level of ACTH, STH, cortisol which is directly dependent on the cancer process stage. The maximum increased level of these hormones was noted in low differentiated cancer of the lung.


Nickel-induced down-regulation of ΔNp63 and its role in the proliferation of keratinocytes.
Epidemiological, animal, and cell studies have demonstrated that nickel compounds are human carcinogens. The mechanisms of their carcinogenic actions remain to be investigated. p63, a close homologue of the p53 tumor suppressor protein, has been linked to cell fate determination and/or maintenance of self-renewing populations in several epithelial tissues, including skin, mammary gland, and prostate. ΔNp63, a dominant negative isoform of p63, is amplified in a variety of epithelial tumors including squamous cell carcinomas and carcinomas of the prostate and mammary glands. The present study shows that nickel suppressed ΔNp63 expression in a short-time treatment (up to 48 h). Nickel treatment caused activation of NF-κB. Blockage of NF-κB partially reversed nickel-induced ΔNp63 suppression. Nickel decreased interferon regulatory factor (IRF) 3 and IRF7, IKKε, and Sp100. Over-expression of IRF3 increased ΔNp63 expression suppressed by nickel. Nickel was able to activate p21, and its activation was offset by the over-expression of ΔNp63. In turn, elevated p63 expression counteracted the ability of nickel to restrict cell growth. The present study demonstrated that nickel decreased interferon regulatory proteins IRF3 and IRF7, and activated NF-κB, resulting in ΔNp63 suppression and then p21 up-regulation. ΔNp63 plays an important role in nickel-induced cell proliferation.


Cartilaginous sesamoid or nodule of the interphalangeal joint of the big toe.
Since 1971, a cartilaginous sesamoid or nodule has been identified in the plantar ligament of the interphalangeal joint of the big toe in 29 of the 58 patients (50%) from whom spurs of the plantar medical aspect of the adjacent phalanges were removed because of painful callouses. It is felt that the firm mass of the cartilaginous sesamoid may have contributed to the callous formation in many cases. These cartilaginous sesamoids have all been removed when found.


Glycosaminoglycans and mucopolysaccharidosis type III.
Mucopolysaccharidosis type III (MPS III), or Sanfilippo syndrome, is a lysosomal storage disease in which heparan sulfate is accumulated in lysosomes, as well as outside of cells, as the primary storage material. This disease is a complex of four conditions caused by dysfunctions of one of genes coding for lysosomal enzymes involved in degradation of heparan sulfate: SGSH (coding for heparan N-sulfatase) - causing MPS IIIA, NAGLU (coding for alpha-N-acetylglucosaminidase) - causing MPS IIIB, HGSNAT (coding for acetyl CoA alpha-glucosaminide acetyltransferase) - causing MPS IIIC), and GNS (coding for N-acetylglucosamine-6-sulfatase) - causing MPS IIID. The primary storage is responsible for some disease symptoms, but other arise as a result of secondary storage, including glycosphingolipids, and subsequent processes, like oxidative stress and neuroinflammation. Central nervous system is predominantly affected in all subtypes of MPS III. Heparan sulfate and its derivatives are the most commonly used biomarkers for diagnosis and prediction procedures. Currently, there is no therapy for Sanfilippo syndrome, however, clinical trials are ongoing for enzyme replacement therapy, gene therapy and substrate reduction therapy (particularly gene expression-targeted isoflavone therapy).


Sleep disorders in people with type 2 diabetes and associated health outcomes: a review of the literature.
Sleep disorders are linked to development of type 2 diabetes and increase the risk of developing diabetes complications. Treating sleep disorders might therefore play an important role in the prevention of diabetes progression. However, the detection and treatment of sleep disorders are not part of standardised care for people with type 2 diabetes. To highlight the importance of sleep disorders in people with type 2 diabetes, we provide a review of the literature on the prevalence of sleep disorders in type 2 diabetes and the association between sleep disorders and health outcomes, such as glycaemic control, microvascular and macrovascular complications, depression, mortality and quality of life. Additionally, we examine the extent to which treating sleep disorders in people with type 2 diabetes improves these health outcomes. We performed a literature search in PubMed from inception until January 2021, using search terms for sleep disorders, type 2 diabetes, prevalence, treatment and health outcomes. Both observational and experimental studies were included in the review. We found that insomnia (39% [95% CI 34, 44]), obstructive sleep apnoea (55-86%) and restless legs syndrome (8-45%) were more prevalent in people with type 2 diabetes, compared with the general population. No studies reported prevalence rates for circadian rhythm sleep-wake disorders, central disorders of hypersomnolence or parasomnias. Additionally, several cross-sectional and prospective studies showed that sleep disorders negatively affect health outcomes in at least one diabetes domain, especially glycaemic control. For example, insomnia is associated with increased HbA1c levels (2.51 mmol/mol [95% CI 1.1, 4.4]; 0.23% [95% CI 0.1, 0.4]). Finally, randomised controlled trials that investigate the effect of treating sleep disorders in people with type 2 diabetes are scarce, based on a small number of participants and sometimes inconclusive. Conventional therapies such as weight loss, sleep education and cognitive behavioural therapy seem to be effective in improving sleep and health outcomes in people with type 2 diabetes. We conclude that sleep disorders are highly prevalent in people with type 2 diabetes, negatively affecting health outcomes. Since treatment of the sleep disorder could prevent diabetes progression, efforts should be made to diagnose and treat sleep disorders in type 2 diabetes in order to ultimately improve health and therefore quality of life.


Dynamic Stark control: model studies based on the photodissociation of IBr.
The Stark effect is produced when a static field alters molecular states. When the field applied is time dependent, the process is known as the dynamic Stark effect. Of particular interest for the control of molecular dynamics is the Non-Resonant Dynamic Stark Effect (NRDSE), in which the time dependent field is unable to effect a one-photon excitation. The intermediate strength laser pulse instead shapes the potential energy surfaces (PES) and so guides the evolution of the system. A prototype control scheme uses the NRDSE to change the topography of PES in regions where they intersect, thus providing control over photochemistry. Following earlier experimental work, in this paper we study the NRDSE on a new 3 state model of the IBr molecule to gain insight into the mechanism of control at the avoided crossing that governs the branching ratio of the photodissociation.


Pharmacogenomic knowledge and awareness among diverse patients treated with angiotensin converting enzyme inhibitors.
We developed novel electronic phenotyping algorithms for the BioMe biobank data, which accurately identified angiotensin converting enzyme inhibitor (ACEi)-induced angioedema cases and controls. A survey was mailed to all 1075 patients and 91 were returned. Over a third reported that prescribing physicians had not discussed with them the concepts of interindividual drug response variability or adverse event risk, and 73% of patients were previously unaware of pharmacogenomics; however, most patients were interested in having pharmacogenomic testing. Moreover, 67% of patients indicated that pharmacogenomic testing would positively influence their medication compliance. In addition to identifying an innovative approach to define biobank cohorts for pharmacogenomic studies, these results indicate that patients are interested in pharmacogenomic testing, which could translate to improved adherence.


Two dimensional correlation analysis of Fourier transform ion cyclotron resonance mass spectra of dissolved organic matter: a new graphical analysis of trends.
Two-dimensional (2D) correlation analysis was applied to 20 Fourier transform ion cyclotron resonance mass spectra (FTICR-MS) of ultrafiltered dissolved organic matter samples from a salinity transect of the lower Chesapeake Bay. We were able to investigate the chemical changes in the dissolved organic matter pool at the molecular level and classify the individual peaks based on their biogeochemical reactivity. The power of this technique is its ability to be used on either the presence/absence of the individual peaks or their normalized magnitudes. The presence or absence of the peaks are utilized to identify the reactivity and correlation between peaks that plot in different regions of the van Krevelen diagram, whereas the normalized magnitudes are used to correlate the changes among individual peaks. One of the promising advantages of 2D correlation of FTICR-MS data is the ability to associate the variations of the individual peaks with the changes in the functional groups that are measured by other spectroscopic techniques. This approach takes us one step further from identifying molecular formulas to proposing chemical structures.


"I will not stop visiting!" a qualitative study of community health workers' reluctance to withdraw household support following the end of a community-based intervention in Zimbabwe.
Community Health Worker (CHW) programmes are increasingly important in HIV service delivery. CHWs' familiarity with the local context can improve intervention acceptability and sustainability but concerns have been raised about potential exploitation and "burnout" of CHWs as they become emotionally involved in clients' lives. Little attention has been paid to what happens at the end of time-limited CHW interventions. This study aimed to examine the experience of CHWs' withdrawal from clients and their families. We conducted a qualitative study of CHWs' experiences of "exiting" from households during the ZENITH (Zimbabwe Study for Enhancing Testing and Improving Treatment of HIV in Children) intervention, which provided 12 structured home visits over 72 weeks to families with children recently diagnosed with HIV. We conducted semi-structured interviews at 12 and 18 months with all 19 CHWs delivering the intervention and 36 purposively selected caregivers who received home visits. Analysis focused on perceptions of the end of the trial, when CHWs completed the scheduled home-based visits and there was no guarantee of programme continuation beyond the study. Termination of scheduled home visits caused significant distress to both CHWs and the households they visited. We identify 3 thematic "lessons learned" for CHW programmes. First, CHWs derived pride and self-worth from emotional labour as they became integral to families' improved ability to cope, motivating them to go beyond formal job requirements. Second, clients' growing dependence on CHWs led to "exit" being interpreted as abandonment by both CHWs and households, causing distress on both sides. Finally, in response to anxiety about "abandoning" families, CHWs maintained contact with families long after scheduled withdrawal of services. CHWs can forge genuine bonds with households, creating expectations of long-term engagement. On the positive side, CHW derive pride from their work, attach social responsibility to their roles, and feel personal fulfilment in supporting families. If CHWs do not disengage from interventions as planned, or become demoralised by "exits", interventions will prove less sustainable. CHWs are often lauded for their ability to develop trust with peers, yet this willingness and ability to create enduring emotional bonds could threaten programme delivery.


Multi-resonant absorption in ultra-thin silicon solar cells with metallic nanowires.
We propose a design to confine light absorption in flat and ultra-thin amorphous silicon solar cells with a one-dimensional silver grating embedded in the front window of the cell. We show numerically that multi-resonant light trapping is achieved in both TE and TM polarizations. Each resonance is analyzed in detail and modeled by Fabry-Perot resonances or guided modes via grating coupling. This approach is generalized to a complete amorphous silicon solar cell, with the additional degrees of freedom provided by the buffer layers. These results could guide the design of resonant structures for optimized ultra-thin solar cells.


An investigation into natural resistance to African swine fever in domestic pigs from an endemic area in southern Africa.
A population of domestic pigs in northern Mozambique with increased resistance to the pathogenic effects of African swine fever (ASF) virus was identified by the high prevalence of circulating antibodies to ASF virus. An attempt was made to establish whether the resistance in this population was heritable. Some of these pigs were acquired and transported to a quarantine facility and allowed to breed naturally. Offspring of the resistant pigs were transferred to a high security facility where they were challenged with two ASF viruses, one of which was isolated from one of the Mozambican pigs and the other a genetically closely-related virus from Madagascar. All but one of the 105 offspring challenged developed acute ASF and died. It therefore appears that the resistance demonstrated by these pigs is not inherited by their offspring, or could not be expressed under the conditions of the experiment. The question remains therefore as to the mechanism whereby pigs in the population from which the experimental pigs were derived co-existed with virulent ASF viruses.


Classification of intra-specific variation in plant functional strategies reveals adaptation to climate.
In plants, extensive intra-specific variation exists in the allocation of resources between vegetative growth and reproduction, reflecting different functional strategies. A simple method for the classification of intra-specific variation in these strategies would enable characterization of evolutionary and ecological processes. C-S-R theory can be applied to classify functional strategies (competitive C; stress tolerant, S; ruderal, R) in different plant species. Using a diverse set of arabidopsis ( Arabidopsis thaliana ) accessions grown under common conditions, it was tested whether a simple approach designed for allocating C-S-R strategies at the species level can also be used to analyse intra-specific variation. Substantial intra-specific variation between arabidopsis accessions was found along the S-R axis. There was a positive correlation of temperature at the geographical origin with the dimension of S and a negative correlation with the dimension of R. Flowering time in a natural annual cycle and leaf dry matter content were identified as the main determinants of this adaptation, with plants originating from warmer climates having a higher leaf dry matter content and flowering earlier in a common garden. It was shown that functional strategies reflect adaptation to climate, with consequences for important traits such as fecundity and total plant dry weight. The approach could be used in genome-wide association studies to determine the genetic basis of functional strategies in wild species or crops.


Congenital paraesophageal hernia with intrathoracic gastric volvolus in two sisters.
Congenital paraesophageal hernia is rare in infants and children. This paper describes our experience with seven infants and children with congenital paraesophageal hernia with emphasis on two sisters who presented with unusually large paraesophageal hernias and herniation of most of the stomach resulting in intrathoracic gastric volvolus. The literature on the subject is also reviewed.


Spatio-temporal prediction of land use and land cover change in Bahi (Manyoni) Catchment, Tanzania, using multilayer perceptron neural network and cellular automata-Markov chain model.
Evaluation of land use and land cover (LULC) change is among vital tools used for tracking environmental health and proper resource management. Remote sensing data was used to determine LULC change in Bahi (Manyoni) Catchment (BMC) in central Tanzania. Landsat satellite images from Landsat 5 TM and Landsat 8 OLI/TIRS were used, and support vector machine (SVM) algorithm was applied to classify the features of BMC. The obtained kappa values were 0.74, 0.83 and 0.84 for LULC maps of 1985, 2005 and 2021, respectively, which indicates the degree of accuracy from produced being substantial to almost perfect. Classified maps along with geospatial, socio-economic and climatic drivers with sufficient explanatory power were incorporated into MLP-NN to produce transition potential maps. Transition maps were subsequently used in cellular automata (CA)-Markov chain model to predict future LULC for BMC in immediate-future (2035), mid-future (2055) and far-future (2085). The findings indicate BMC is expected to experience significant expansion of agricultural lands and built land from 31.89 to 50.16% and 1.48 to 9.1% from 2021 to 2085 at the expense of open woodland, shrubland and savanna grassland. Low-yield crop production, water scarcity and population growth were major driving forces for rapid expansion of agricultural lands and overall LULC in BMC. The findings are essential for understanding the impact of LULC on hydrological processes and offer insights for the internal drainage basin (IDB) board to make necessary measures to lessen the expected dramatic changes in LULC in the future while sustaining harmonious balance with livelihood activities.


Activation of latent HIV using drug-loaded nanoparticles.
Antiretroviral therapy is currently only capable of controlling HIV replication rather than completely eradicating virus from patients. This is due in part to the establishment of a latent virus reservoir in resting CD4+ T cells, which persists even in the presence of HAART. It is thought that forced activation of latently infected cells could induce virus production, allowing targeting of the cell by the immune response. A variety of molecules are able to stimulate HIV from latency. However no tested purging strategy has proven capable of eliminating the infection completely or preventing viral rebound if therapy is stopped. Hence novel latency activation approaches are required. Nanoparticles can offer several advantages over more traditional drug delivery methods, including improved drug solubility, stability, and the ability to simultaneously target multiple different molecules to particular cell or tissue types. Here we describe the development of a novel lipid nanoparticle with the protein kinase C activator bryostatin-2 incorporated (LNP-Bry). These particles can target and activate primary human CD4+ T-cells and stimulate latent virus production from human T-cell lines in vitro and from latently infected cells in a humanized mouse model ex vivo. This activation was synergistically enhanced by the HDAC inhibitor sodium butyrate. Furthermore, LNP-Bry can also be loaded with the protease inhibitor nelfinavir (LNP-Bry-Nel), producing a particle capable of both activating latent virus and inhibiting viral spread. Taken together these data demonstrate the ability of nanotechnological approaches to provide improved methods for activating latent HIV and provide key proof-of-principle experiments showing how novel delivery systems may enhance future HIV therapy.


Spatially localized in vivo 1H magnetic resonance spectroscopy of an intracerebral rat glioma.
Surface coil MRI combined with spatially localized spectroscopy was used to noninvasively detect 1H signals from metabolites within an intracerebral malignant glioma in rats. The MRS pulse sequence was based upon two-dimensional ISIS, which restricted 1H signals to a column-shaped volume, combined with one-dimensional spectroscopic imaging, which further resolved the signals into 8 or 16 slices along the major axis of the column. All experiments were executed with adiabatic pulses which induced uniform spin excitation despite the inhomogeneous radiofrequency field distribution produced by the surface coil transmitter. Surface coil MRI and MRS experiments were performed on phantom samples, normal rat brains, and rat brains harboring malignant gliomas. Spatially resolved in vivo 1H spectra of intracerebral gliomas revealed significantly decreased concentrations of N-acetyl-aspartate and creatine and increased lactic acid (or lipids) as compared to the contralateral hemisphere. These results demonstrate that metabolic abnormalities in intracerebral rat gliomas can be spatially resolved in a noninvasive manner using localized in vivo 1H MRS.


Goals of fecal incontinence management identified by community-living incontinent adults.
The purpose of this study was to identify goals of fecal incontinence (FI) management and their importance to community-living adults if complete continence would not be possible. Participants expressed their goals of FI management in a semistructured interview, selected others from 12 investigator-identified goals, and rated their importance. Five thematic categories emerged from the 114 participant-identified goal statements: Fecal Incontinence/Bowel Pattern, Lifestyle, Emotional Responses, Adverse Effects of Fecal Incontinence, and Self-Care Practices. Participants selected a median of seven investigator-identified goals (range = 2 to 12). Goals selected by the most participants were decreased number of leaks of stool and greater confidence in controlling fecal incontinence. These goals also had the highest importance along with decreased leakage of loose or liquid stool. The type and number of management goals identified by participants offer a toolbox of options from which to focus therapy when cure is not possible and promote patient satisfaction.


Effect of different external attention of focus instruction on learning of golf putting skill.
The effect of different sources of external attentional focus on learning a motor skill was assessed in the present study. 30 students (12 men, 18 women) participated voluntarily and were divided, according to type of external focus, into target, club swing, and target-club swing groups. The task was a golf putting skill. The target focus group attended to the target (hole), the club swing focus group attended to the execution of the club's swing, and the target-club swing focus group attended to both. All participants performed 50 trials of the putting skill in the acquisition phase and 10 trials in the 24-hr. delayed retention phase. The dependent variable was the error in the putting skill measured as the distance from the hole to the ball after each strike. Results showed the target-club swing focus group had better scores in the acquisition and retention phases than the other groups. It was concluded that external focus instruction helped the learners to integrate target cue with action cue and is more effective in skill learning than other external-focus instructions. These results support the claims of ecological psychology theorists concerning the effects of external focus of attention.


HeartWare Ventricular Assist Device as a Bridge-to-Transplant in a Small Boy with Complicated Kawasaki Disease.
We report a case of HeartWare ventricular assist device (HVAD) implant as a Bridge-to-Transplant in the smallest and the youngest known patient, a 32-month-old boy (body surface area of 0.66 m2) with known Kawasaki disease and giant coronary artery aneurysms. The disease course was complicated by coronary thromboembolism resulting in acute myocardial infarction, ventricular fibrillation, and cardiac arrest. After short-term support with extracorporeal membrane oxygenation for 7 days and long-term support with an HVAD for 5 months, he underwent heart transplantation and is doing well 2 months after the transplant.


Development of a quantitative-competitive polymerase chain reaction assay for serotype 1 Marek's disease virus.
We have developed a quantitative-competitive (QC) polymerase chain reaction (PCR) for the detection of Marek's disease virus (MDV) DNA. The assay utilizes a competitor DNA that differs from the viral DNA of interest by having a small insertion. The competitor DNA acts as an internal standard for the estimation of viral DNA in an unknown sample. The amount of viral DNA in a sample is quantitated by coamplification in the presence of a known amount of competitor DNA. The same PCR primers that amplify the viral DNA also amplify the competitor DNA. When the amount of competitor is equal to the amount of viral DNA in a sample, there is equal amplification of the competitor and the virus. Thus, we are able to quantitate the viral DNA in an unknown sample. To establish the utility of this assay, in vivo correlations between virulence and virus replication were studied. Our data demonstrated that a more virulent strain of MDV (648A) replicated better in thymus during cytolytic infection than did a less virulent strain (GA). However, no differences in virus titer were observed when these two viruses were propagated in tissue culture. Our data are consistent with the generally held idea that "hot" strains of MDV replicate earlier and better in birds. Thus, QC-PCR is extremely specific and sensitive to measure MDV DNA over a wide range and can be applied to in vivo studies of viral pathogenesis.


Safety and effectiveness of enzalutamide in men with metastatic, castration-resistant prostate cancer.
Enzalutamide (MDV3100) is a second-generation androgen receptor antagonist that improves survival in metastatic, castration-resistant prostate cancer (mCRPC). Alternatives include chemotherapy, radiation, immunotherapy and abiraterone. The Phase I/II study showed early evidence of efficacy and determined that fatigue is the dose-limiting toxicity. Two randomized, placebo-controlled trials have demonstrated superiority of enzalutamide 160 mg by mouth daily over placebo in terms of overall survival, radiographic progression-free survival as well as a broad range of secondary and exploratory end points in men who had received previous chemotherapy (AFFIRM) and in those who were chemotherapy naive (PREVAIL). Common side effects include fatigue, arthralgias and constipation. A post hoc analysis from AFFIRM found that enzalutamide is safe and effective in men aged ≥ 75 years. The Phase I/II studies as well as AFFIRM and PREVAIL are described in this review. Enzalutamide extends overall and progression-free survival and is associated with robust response rates and quality of life benefits in men with mCRPC. Enzalutamide has not been proven to be effective in biochemically relapsed disease or in castration-sensitive prostate cancer. It should not be used in men at high risk for seizure, and patients should be counseled about the increased risk of falls.


Pneumococcal Vaccination in High-Risk Individuals: Are We Doing It Right?
Controversy exists regarding the optimal use of the 23-valent pneumococcal conjugate vaccine for the protection of high-risk individuals, such as children and adults with immunocompromising conditions and the elderly. The effectiveness and immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPV23) are limited in such high-risk populations compared to the healthy, with meta-analyses failing to provide robust evidence on vaccine efficacy against invasive pneumococcal disease (IPD) or pneumonia. Moreover, several studies have demonstrated a PPV23-induced state of immune tolerance or hyporesponsiveness to subsequent vaccination, where the response to revaccination does not reach the levels achieved with primary vaccination. The clinical significance of hyporesponsiveness is not yet clarified, but attenuated humoral and cellular response could lead to reduced levels of protection and increased susceptibility to pneumococcal disease. As disease epidemiology among high-risk groups shows that we are still in need of maximum serotype coverage, the optimal use of PPV23 in the context of combined conjugate/polysaccharide vaccine schedules is an important priority. In this minireview, we discuss PPV23-induced hyporesponsiveness and its implications in designing highly effective vaccination schedules for the optimal protection for high-risk individuals.


Clinical spectrum of non-syndromic microphthalmos, anophthalmos and coloboma in the paediatric population: a multicentric study from North India.
To describe the clinical features, visual acuity and causes of ocular morbidity in children (0-18 years) with microphthalmos, anophthalmos, and coloboma (MAC) from North India. A retrospective study conducted between October 2017 and September 2018 in three tertiary eye institutes, part of the Bodhya Eye Consortium with consensus led common pro formas. Children with complete clinical data and without syndromic/systemic involvement were included. The clinical phenotype was divided into isolated ocular coloboma (CB), coloboma with microcornea (CBMC), colobomatous microphthalmos (CBMO), non-colobomatous microphthalmos (MO) and anophthalmos (AO). A total of 532 children with MAC were examined. Seventeen records were excluded due to incomplete data (0.2%). 515 children (845 eyes) were included: 54.4% males and 45.6% females. MAC was unilateral in 36% and bilateral in 64%. CB, CBMC, CBMO, MO and AO were seen in 26.4%, 31%, 22%, 8% and 12.5% of eyes, respectively. Nystagmus was found in 40%, strabismus in 23%, cataract in 18.7% and retinal detachment in 15%. Best-corrected visual acuity (BCVA) of <3/60 was seen in 62.4% eyes. Blindness (BCVA <3/60 in better eye) was seen in 42.8% of bilateral patients. Those with microcornea or microphthalmos with coloboma had worse BCVA (p<0.001). There were regional differences in the type of MAC phenotype presenting to the three institutes. The MAC group of disorders cause significant ocular morbidity. The presence of microcornea or microphthalmos with coloboma predicts worse BCVA. The variation of the MAC phenotype with the district of origin of the patient raises questions of aetiology and is subject to further studies.


Management of colovesical and colovaginal diverticular fistulas Our experience and literature reviewed.
This study aims evaluate the effectiveness of various surgical techniques in treating diverticular fistulas, and the safety and efficacy of the laparoscopic procedure comparing our results with those of the literature. This was a prospective and uncontrolled study performed at a general surgery units. Between 2005 and 2011, 16 patients (11 men, 5 women) underwent surgery for diverticular fistulas. The mean age was 70.2 (range, 35-87) years. The medical evaluation of these patients was based on symptoms and diagnostic procedures confirming the diagnosis of diverticular fistulas. Our surgical options included one-stage, two-stage, and defunctioning procedures. Out of 16 cases of diverticular fistula 14 were colovesical and 2 colovaginal. One-stage procedure was performed in 12 patients, two-stage procedure in 3 and defunctioning colostomy in 1. The overall complication rate was 31.2%. We recorded 1 colovesical recurrent fistula. The laparoscopic surgery was performed in 4 patients, nobody was converted to open and there were no post-operative complications and recurrence. The data show that one-stage procedure is effective in the majority of cases of diverticular fistulas. However, the surgery of colovesical and colovaginal fistulas is often associated to high complication rates. This is often due to the shoddy clinical conditions and long-term diverticular illness of this group of patients. At present, the laparoscopy in an elective setting is not considered any more a contraindication in the treatment of diverticular fistulas. Diverticular fistulas, Laparoscopic surgery.


RGS proteins: G protein-coupled receptors meet their match.
Many drugs act on receptors coupled to heterotrimeric G proteins. Historically, drug discovery has focused on agents that bind to the receptors and either stimulate or inhibit the receptor-initiated signal. This is an approach that is both direct and logical, and has proven extremely fruitful in the past. However, as our understanding of G-protein signaling has increased, novel opportunities for drug development have emerged. RGS proteins are multifunctional GTPase-accelerating proteins that inactivate G-protein signaling pathways. GTPase-accelerating protein activity is a general feature of RGS proteins, and serves to facilitate the inactivation of the G protein rather than the receptor. Thus, agents that bind and inhibit RGS proteins could modulate endogenous neurotransmitter and hormone signaling, in a manner analogous to neurotransmitter uptake inhibitors. Here we discuss the potential of RGS proteins as drug targets.


Connexin-26 mutations in deafness and skin disease.
Gap junctions allow the exchange of ions and small molecules between adjacent cells through intercellular channels formed by connexin proteins, which can also form functional hemichannels in nonjunctional membranes. Mutations in connexin genes cause a variety of human diseases. For example, mutations in GJB2, the gene encoding connexin-26 (Cx26), are not only a major cause of nonsyndromic deafness, but also cause syndromic deafness associated with skin disorders such as palmoplantar keratoderma, keratitis-ichthyosis deafness syndrome, Vohwinkel syndrome, hystrix-ichthyosis deafness syndrome and Bart-Pumphrey syndrome. The most common mutation in the Cx26 gene linked to nonsyndromic deafness is 35DeltaG, a frameshift mutation leading to an early stop codon. The large number of deaf individuals homozygous for 35DeltaG do not develop skin disease. Similarly, there is abundant experimental evidence to suggest that other Cx26 loss-of-function mutations cause deafness, but not skin disease. By contrast, Cx26 mutations that cause both skin diseases and deafness are all single amino acid changes. Since nonsyndromic deafness is predominantly a loss-of-function disorder, it follows that the syndromic mutants must show an alteration, or gain, of function to cause skin disease. Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause deafness and skin disease.


Insulin analogs for the management of type 2 diabetes.
Evolving practice recommendations on the use of insulin analogs versus other forms of insulin therapy in adults with type 2 diabetes are reviewed, with an emphasis on supporting evidence from practice guidelines and clinical trials published over the last six years. Current consensus guidelines call for aggressive pharmacotherapy to attain specific glycosylated hemoglobin (HbA(1c)) targets as a means of reducing the risk of macrovascular events (e.g., myocardial infarction, stroke, cardiovascular [CV] death) and the tailoring of HbA(1c)-lowering regimens according to patient-specific factors such as the duration of diabetes, life expectancy, and comorbid conditions. Joint guidelines issued in 2009 by two leading organizations of endocrinology specialists recommend the use of insulin analogs (e.g., detemir, glargine) versus neutral protamine Hagedorn insulin, citing a more predictable time course and a lower potential for hypoglycemia; growing evidence indicates that the use of insulin analogs may offer other advantages such as enhanced dosing flexibility (with the possibility of self-titration by some patients) and less weight gain. Some evidence from trials published since 2007 indicates that early or intensive insulin analog therapy and very aggressive glycemic goals (e.g., HbA(1c) of <6%) may be associated with an increased mortality risk, especially in patients with longstanding diabetes and major CV comorbidities. Ongoing research is expected to help elucidate the comparative merits of intensive and standard HbA(1c)-lowering regimens and optimal strategies for individualized treatment of diabetic and prediabetic patients. Published evidence suggests that insulin analogs may ofer advantages over other insulins as part of individualized pharmacotherapy regimens for appropriately selected patients with type 2 diabetes.


Dual perfluorocarbon method to noninvasively monitor dissolved oxygen concentration in tissue engineered constructs in vitro and in vivo.
Noninvasive in vivo monitoring of tissue implants provides important correlations between construct function and the observed physiologic effects. As oxygen is a key parameter affecting cell and tissue function, we established a monitoring method that utilizes (19) F nuclear magnetic resonance (NMR) spectroscopy, with perfluorocarbons (PFCs) as oxygen concentration markers, to noninvasively monitor dissolved oxygen concentration (DO) in tissue engineered implants. Specifically, we developed a dual PFC method capable of simultaneously measuring DO within a tissue construct and its surrounding environment, as the latter varies among animals and with physiologic conditions. In vitro studies using an NMR-compatible bioreactor demonstrated the feasibility of this method to monitor the DO within alginate beads containing metabolically active murine insulinoma βTC-tet cells, relative to the DO in the culture medium, under perfusion and static conditions. The DO profiles obtained under static conditions were supported by mathematical simulations of the system. In vivo, the dual PFC method was successful in tracking the oxygenation state of entrapped βTC-tet cells and the surrounding peritoneal DO over 16 days in normal mice. DO measurements correlated well with the extent of cell growth and host cell attachment examined postexplantation. The peritoneal oxygen environment was found to be variable and hypoxic, and significantly lower in the presence of metabolically active cells. The significance of the dual PFC system in providing critical DO measurements for entrapped cells and other tissue constructs, in vitro and in vivo, is discussed.


Heart rate reactivity is associated with future cognitive ability and cognitive change in a large community sample.
The relationship between cardiovascular reactions to acute mental challenge in the laboratory and cognitive ability has received scant attention. The present study examined the association between reactivity and future cognitive ability. Heart rate and blood pressure reactions to a mental stress task were measured in 1647 participants comprising three distinct age cohorts. Cognitive ability was assessed using the Alice Heim-4 test of general intelligence and choice reaction time 5 and 12 years later. High heart rate reactivity was related to higher general intelligence scores and faster choice reaction times at both follow-ups. High heart rate reactivity was also associated with a smaller decline in cognitive ability between assessments. These associations were still evident following adjustment for a wide range of potentially confounding variables. The present results are consistent with the notion that high reactivity may not always be a maladaptive response and that low or blunted reactivity may also have negative corollaries.


Immunological response of sheep to injections of plasmids encoding Toxoplasma gondii SAG1 and ROP1 genes.
Infection with the intracellular protozoan parasite Toxoplasma gondii (T. gondii) causes health problems to both humans and livestock and has a large economic impact worldwide. The immune response in sheep following infection with T. gondii was evaluated using six different combinations of plasmid DNA, recombinant antigen and adjuvant. Sheep were generally vaccinated twice by intramuscular injection with plasmid DNA containing gene sequences for either the surface antigen (SAG1) or the rhoptry protein (ROP1) of T. gondii. Two of the groups injected with plasmid DNA SAG1 were boosted with recombinant protein (SAG1). We investigated the efficacy of including oligodeoxynucleotides (ODN) that contain CG motifs (CpG) and the gene coding for ovine granulocyte-macrophage colony stimulating factor (GM-CSF) as potential adjuvants. Administration of the plasmid encoding the ROP1 gene significantly enhanced both IFN-gamma production from peripheral blood cells when cultured in vitro with Toxoplasma antigen, and ROP1-specific IgG1 and IgG2 antibody levels present in serum. However, injection with SAG1 did not stimulate IFN-gamma production. These results indicate the potential of ROP1, given as plasmid DNA, as a potential vaccine candidate to protect sheep against T. gondii infection.


Evaluation of exotic soybean accessions and their use in developing improved soybean lines with resistance to Phomopsis seed decay.
Poor seed quality of soybean is often associated with Phomopsis seed decay (PSD), which is one of the most economically important seed diseases. Diaporthe longicolla (syn. Phomopsis longicolla) is the primary cause of PSD. Control of PSD is best accomplished by planting PSD-resistant cultivars. Sixteen exotic soybean accessions from the USDA soybean germplasm collection were screened for reaction to PSD at Stoneville, Mississippi. They consisted of maturity groups (MG) II, III and IV. Seeds from inoculated and non-inoculated plots harvested either promptly at maturity, or after a two-week delay in harvest, were assessed for infection by D. longicolla. Seed infection ranged from 0 to 36.7%. Overall, PI 417050 (MG II), PI 417017 (MG III), and PI 594692 (MG IV) had significantly (P ≤ 0.05) lower percentages of seed infected by D. longicolla and higher seed germinations than other genotypes in the same maturity groups. PI 587982A also performed well. As a result of these findings, these resistant accessions were used over multiple cycles of breeding to develop improved breeding lines with resistance to PSD and low seed damage. Breeding line 11043-225-72, with combined resistance from both PIs 417050 and 587982A, had low scores for PSD (6.7%) and seed damage (3.4%), while DS65-1, deriving resistance from PI 587982A, had the lowest seed damage score (1.1%) and the highest seed germination (85.6%) among all lines tested in 2017. DS65-1 and 11043-225-72, along with five other improved breeding lines, were provided to public soybean breeders for developing improved cultivars and germplasm lines. DS31-243 (PI 700941), derived from PI 587982A, was publicly released by the USDA in 2022. This research will lead to future releases of improved germplasm lines and cultivars with PSD resistance and high seed quality. It will also aid in disease management and be a benefit to soybean producers and the industry at large.


Ultrasonography, MRI and classic radiography of skin and MSK involvement in juvenile scleroderma.
Scleroderma is a rare, autoimmune, chronic condition that affects the connective tissue by excessive collagen production. If diagnosed before the age of 16, it is referred to as juvenile scleroderma. There are two major types of the condition: localized and generalized scleroderma. Localized scleroderma has a much higher incidence than the generalized type which is extremely rare among children and affects mostly adults. In either case, imaging can prove to be useful in both the diagnosis and monitoring of the disease. In this article, we aim to review the imaging findings that can be present in juvenile scleroderma, focusing on ultrasonography, magnetic resonance imaging, and classic radiography. Ultrasound provides high-resolution images in real-time dynamic examination. With high-frequency transducers, it may provide a considerable input into the imaging of skin and musculoskeletal involvement. Several findings might be present when using B-mode or Doppler modalities such as thickening and hypervascularization of the cutis and subcutaneous tissue, synovitis and tenosynovitis, as well as small calcifications. Magnetic resonance imaging is also useful to evaluate inflammatory skin infiltration or skin atrophy, as well as deeply located structures, including fasciae, muscles and joints that might not be seen on ultrasonography. This modality is, however, expensive and time-consuming, and might require sedition in children. Classic radiology can show soft tissue calcifications, acroosteolysis, contractures, and subluxations. Computed tomography, which requires a high dose of radiation, is generally avoided in children, except in very specific cases.


Super-Utilization of the Emergency Department in a Universally Insured Population.
Super-utilizers (patients with 4 or more emergency department [ED] visits a year) account for 10% to 26% of all ED visits and are responsible for a growing proportion of healthcare expenditures. Patients recognize the ED as a reliable provider of acute care, as well as a timely resource for diagnosis and treatment. The value of ED care is indisputable in critical and emergent conditions, but in the case of non-urgent conditions, ED utilization may represent an inefficiency in the healthcare system. We sought to identify patient and clinical characteristics associated with ED super-utilization in a universally insured population. We performed a retrospective cohort study using TRICARE claims data from the Military Health System Data Repository (2011-2015). We reviewed the claims data of all adult patients (aged 18-64 years) who had at least one encounter at the ED for any cause. Multivariable logistic regression was used to determine independent factors associated with ED super-utilization. Factors associated with increased odds of ED super-utilization included Charlson Score ≥2 (adjusted odds ratio [aOR] 1.98, 95% confidence interval [CI]: 1.90-2.06), being eligible for Medicare (aOR 1.95, 95% CI: 1.90-2.01), and female sex (aOR 1.35, 95% CI: 1.33-1.37). Active duty service members (aOR 0.69, 95% CI 0.68-0.72) and beneficiaries with higher sponsor-rank (Officers: aOR 0.50, 95% CI: 0.55-0.57; Senior enlisted: aOR 0.82, 95% CI: 0.81-0.83) had lower odds of ED super-utilization. The most common primary diagnoses for ED visits among super-utilizers were abdominal pain, headache and migraine, chest pain, urinary tract infection, nausea and vomiting, and low back pain. Risk of ED super-utilization appears to increase with age and diminished health status. Patient demographic and clinical characteristics of ED super-utilization identified in this study can be used to formulate healthcare policies addressing gaps in primary care in diagnoses associated with ED super-utilization and develop interventions to address modifiable risk factors of ED utilization.


Patterns of presentations of dizziness in primary care--a cross-sectional cluster analysis study.
Dizziness is a common symptom in adults in primary care. We explored in a sample of people recruited from general practice the existence of patterns of presentations, their characteristics, and clinical and health service predictors. We assessed in a cross-sectional random sample of people registered at London general practices in the United Kingdom the following: subtypes of dizziness, effect on personal activity and physical function, relevant medical and drug history, level of anxiety or depression, treatments received, and information on whether help was sought from their general practitioners. Of 1820 subjects, 442 (24.3%) reported symptoms of dizziness. We identified three clinical presentations. Group 1 was a "nonspecific" presentation experienced by 113 (25.5%) people and characterized by true vertigo, presyncope, disequilibrium, and other types of dizziness with severe impact on all aspects of function. The other two groups were characterized by true vertigo and presyncope. In Group 2 [193 (43.7%)], these symptoms had some impact on personal and daily function, whereas in Group 3 [136 (30.7%)], there was no impact. Eighty-four percent of the people in Group 1 consulted their family practitioner on account of their symptoms, 61% did so in Group 2, and only 38% in Group 3. On multinomial logistic regression analysis, current depression, unemployment, and use of prescribed medication were predictors of the Group 1 compared with Group 2, whereas increasing anxiety and depression scores on the Hospital Anxiety and Depression Scale were predictors of the Group 2 compared with the Group 3. This is the first step in classifying dizziness from a symptomatic and functional point of view. Further research is required on the natural progression of these presentations and their relationship to each other.


Three-dimensional database of subcortical electrophysiology for image-guided stereotactic functional neurosurgery.
We present a method of constructing a database of intraoperatively observed human subcortical electrophysiology. In this approach, patient electrophysiological data are standardized using a multiparameter coding system, annotated to their respective magnetic resonance images (MRIs), and nonlinearly registered to a high-resolution MRI reference brain. Once registered, we are able to demonstrate clustering of like interpatient physiologic responses within the thalamus, globus pallidus, subthalamic nucleus, and adjacent structures. These data may in turn be registered to a three-dimensional patient MRI within our image-guided visualization program enabling prior to surgery the delineation of surgical targets, anatomy with high probability of containing specific cell types, and functional borders. The functional data were obtained from 88 patients (106 procedures) via microelectrode recording and electrical stimulation performed during stereotactic neurosurgery at the London Health Sciences Centre. Advantages of this method include the use of nonlinear registration to accommodate for interpatient anatomical variability and the avoidance of digitized versions of printed atlases of anatomy as a common database coordinate system. The resulting database is expandable, easily searched using a graphical user interface, and provides a visual representation of functional organization within the deep brain.


Proliferation and functionality of human umbilical vein endothelial cells on angiopoietin-1 immobilized 316L stainless steel.
Angiopoietin-1 (Ang-1), a vascular-specific growth factor secreted from periendothelial cells, has drawn increasing attention in clinical applications because it can promote the reconstruction of blood vessels and has an anti-inflammatory effect compared with vascular endothelial growth factor (VEGF). In this study, Ang-1 was firstly covalently conjugated onto polydopamine (PDA) coated 316L stainless steel (SS), aiming at developing an Ang-l modified surface for endothelialization. The results of Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS) and water contact angle (WCA) measurements confirmed the successful immobilization of Ang-1. Quartz crystal microbalance with dissipation (QCM-D) studies demonstrated that ∼154 ng cm-2 of Ang-1 were bonded onto the PDA surface. To confirm its functionality, the effects of the Ang-1-modified coating on the growth behavior of human umbilical vein endothelial cells (HUVECs) were studied. As a result, the Ang-1 functionalized surface significantly enhanced endothelial cell adhesion, proliferation and migration. It was also found the Ang-1 functionalized coating could promote the release of nitric oxide (NO), secretion of prostacyclin-2 (PGI2) and inhibit the apoptosis of HUVECs. These data effectively suggested angiopoietin-1 could potentially be applied not only in neovascularization such as ischemic reperfusion and vascularization of tissue engineering scaffolds, but also in surface modification of cardiovascular implant materials for re-endothelialization.


The promise of plant polyphenols as the golden standard skin anti-inflammatory agents.
Inflammation is a key event in the skin normally occurring in response to the constant exposure to environmental and endogenous stimuli as well as to accidental damage. It also plays a central role in the pathogenesis of major cutaneous pathologies, ultimately resulting in skin carcinogenesis. As the acute mild inflammatory process is mainly adaptive in nature, chronic inflammation is a multi-factorial and complex noxious process, extremely difficult to combat. The wealth of data documenting the involvement of redox-dependent regulatory and damaging processes in the skin inflammation has prompted research on a steadily growing number of plant-derived active substances, mainly polyphenols, and selected principally on the basis of their free radical scavenging and antioxidant properties. In spite of the wide recognition of their anti-inflammatory efficacy in vitro, the clinical use for the prevention and treatment of major skin inflammatory conditions is in most cases yet to be conclusively proven. The complex nature of the cutaneous inflammatory process involves oxygen (ROS), nitrogen (RNS) and lipid reactive species, but is also driven by other mechanisms highlighted in these recent years, related to the regulation of gene expression, and to metabolic and signaling pathways that are ROS/RNS-independent. The screening of the enormous array of plant secondary metabolites, first of all polyphenols, for new effective and safe anti-inflammatory agents should be rather directed towards molecules targeting specific inflammatory pathways recognized to be active in the peculiar skin compartment.


The effects of hormones on milk-fat synthesis in mammary explants from pseudopregnant rabbits.
1. When freshly prepared explants from pseudopregnant-rabbit mammary gland were incubated with sodium [1-(14)C]acetate plus glucose, they synthesized triglyceride and phospholipid containing long-chain fatty acids. Explants cultured with insulin and corticosterone also synthesized these products. The addition of prolactin to this culture medium increased the rate of fatty acid synthesis up to 40-fold and the explants synthesized predominantly triglyceride enriched with C(8:0) and C(10:0) fatty acids characteristic of rabbit milk. 2. The maximum rates of fatty acid synthesis obtained by explants from pseudopregnant-rabbit mammary gland after culture with insulin, corticosterone and prolactin were similar to those observed with freshly prepared explants from lactating-rabbit mammary gland. The time in culture required to attain these maximum rates varied between animals, and did not appear to be connected with the time required (6-7 days) to synthesize the maximum proportions of C(8:0) and C(10:0) acids. 3. As the pattern of short- and medium-chain milk fatty acids is characteristic for many species, the techniques described to determine the time-course for the development of this pattern can be used to investigate hormonal response.


Evaluation of 2 Intervention Models to Integrate Family Planning Into Worker Health and Livelihood Programs in Egypt: A Difference-in-Differences Analysis.
Recent increases in fertility rates in Egypt and an increase in desired fertility among unmarried young people highlight the need for renewed attention to awareness of and demand for family planning (FP) among young people. Between 2017 and 2018, the United States Agency for International Development-funded Evidence Project tested 2 intervention models to increase awareness of and demand for FP and reproductive health (RH) services among people aged 18-35 years in Souhag and Port Said governorates, Egypt. In Souhag, FP/RH information was integrated into a 5-day livelihood training program for job seekers. In Port Said, garment factory workers received FP/RH information through trained peer educators, social and behavior change materials, and social media. Workshop participants and factory workers interested in FP services were referred to private project-trained physicians and pharmacists. We present the results of an evaluation of the impact of each intervention on young people's reported exposure to FP messages and their FP knowledge, attitudes, and behaviors. Phone interviews were conducted with participants in intervention and comparison groups before and after the intervention. In Souhag, 1,519 intervention group participants (778 at baseline; 741 at endline) and 1,082 comparison group participants (699 at baseline; 383 at endline) completed the phone interview. In Port Said 1,958 participants from intervention factories (1,145 at baseline; 813 at endline) and 1,047 participants from comparison factories (621 at baseline; 426 at endline) completed the phone interview. A difference-in-differences analysis compared intervention and comparison groups between baseline and endline. Results showed significant differences in knowledge and attitudes over time between the intervention and comparison groups in Souhag but less so in Port Said. FP use did not change among project participants in either governorate. We discuss lessons learned from integrating FP into worker health and livelihood training programs and methodological considerations for evaluating such interventions.


Effect of film thickness on the phase behaviors of diblock copolymer thin film.
A phase diagram was constructed for a polystyrene-block-polyisoprene (PS-b-PI, M(W) = 32 700, f(PI) = 0.670) in thin films on Si wafer as a function of film thickness over the range of 150-2410 nm (7-107L(0) (L(0): domain spacing)). The PS-b-PI exhibits a variety of ordered phases from hexagonally perforated lamellar (HPL) via double gyroid (DG) to hexagonally packed cylinder (HEX) before going to the disordered (DIS) phase upon heating. The morphology of the PS-b-PI in thin film was investigated by grazing incidence small-angle X-ray scattering, transmission electron microscopy, and transmission electron microtomography. In thin film, the phase transition temperature is difficult to be determined unequivocally with in situ heating processes since the phase transition is slow and two phases coexist over a wide temperature range. Therefore, in an effort to find an "equilibrium" phase, we determined the long-term stable phase formed after cooling the film from the DIS phase to a target temperature and annealing for 24 h at the temperature. The temperature windows of stable ordered phases are strongly influenced by the film thickness. As the film thickness decreases, the temperature window of layer-like structures such as HPL and HEX becomes wider, whereas that of the DG stable region decreases. For the films thinner than 160 nm (8L(0)), only the HPL phase was found. In the films exhibiting DG phase, a perforated layer structure at the free surface was found, which gradually converts to the internal DG structure. The relief of interfacial tension by preferential wetting appears to play an important role in controlling the morphology in very thin films.


Laminin-5 (gamma2 chain) is a marker of invading cancer cells in human gallbladder carcinoma: special emphasis on extension of carcinoma in situ along Rokitansky-Aschoff sinuses.
Gallbladder carcinoma (GC) is a relatively uncommon malignancy and is often caused by diagnostic difficulties in distinguishing the extension of carcinoma in situ (CIS) from invasive carcinoma along Rokitansky-Aschoff sinuses (RAS). The laminin-5, a heterotrimer, is composed of alpha-3, beta-3 and gamma-2 chains. The gamma-2 chain is expressed in various invasive carcinoma cells. There are numerous reports that have described that laminin-5-gamma-2 is associated with tissue invasion in many organs. However, few studies are found in gallbladder carcinoma. To clarify the relationship between laminin-5-gamma-2 chain (LN-5) expression and the development of GCs, we performed an immunohistochemical study of 93 GCs. Cases were classified into three groups: CIS with/without the extension along RAS (Group A; n=17), carcinoma invading mucosa or muscular layer (Group B; n=5) and carcinoma invading beyond perimuscular connective tissue (Group C; n=71). The immunohistochemical intracytoplasmic expression was detected in the invasive fronts of the tumor. In the invasive components of Group B and C, LN-5 was expressed in 100 and 97% of cases, respectively, whereas in the CIS lesions of GCs, expression was not observed in Group A. LN-5 expression in the GCs tended to increase as tumors developed, which may be an indicator of the potential invasiveness of the tumor. Our results indicate that, in GCs, a strong intracytoplasmic expression of LN-5 was identified in the cancer cells whether in situ they extend along RAS or invading stroma.


The Gridlock transcriptional repressor impedes vertebrate heart regeneration by restricting expression of lysine methyltransferase.
Teleost zebrafish and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through dedifferentiation and proliferation of pre-existing cardiomyocytes (CMs). Although many mitogenic signals that stimulate zebrafish heart regeneration have been identified, transcriptional programs that restrain injury-induced CM renewal are incompletely understood. Here, we report that mutations in gridlock (grl; also known as hey2), encoding a Hairy-related basic helix-loop-helix transcriptional repressor, enhance CM proliferation and reduce fibrosis following damage. In contrast, myocardial grl induction blunts CM dedifferentiation and regenerative responses to heart injury. RNA sequencing analyses uncover Smyd2 lysine methyltransferase (KMT) as a key transcriptional target repressed by Grl. Reduction in Grl protein levels triggered by injury induces smyd2 expression at the wound myocardium, enhancing CM proliferation. We show that Smyd2 functions as a methyltransferase and modulates the Stat3 methylation and phosphorylation activity. Inhibition of the KMT activity of Smyd2 reduces phosphorylated Stat3 at cardiac wounds, suppressing the elevated CM proliferation in injured grl mutant hearts. Our findings establish an injury-specific transcriptional repression program in governing CM renewal during heart regeneration, providing a potential strategy whereby silencing Grl repression at local regions might empower regeneration capacity to the injured mammalian heart.


Optimization of water washing for mitigation of 3-monochloropropane 1,2 diol ester in palm oil physical refining process.
The presence of 3-monochloropropane-1,2 diol ester (3-MCPDE) and glycidyl ester (GE) in processed palm oils is of concern, as these oils are widely used for edible purposes. The mitigation method studied here optimizes the removal of chloride through water washing of crude palm oil (CPO), to limit the formation of 3-MCPDE. The contaminant removal obtained via washing CPO supports the quantitative findings. By utilizing 5% water in the washing step, water-soluble chlorides in CPO are removed by up to 76%, resulting in a 71% reduction of 3-MCPDE to within statutory limits. In this study, a linear correlation was developed between the chloride and the corresponding 3-MCPDE with a correlation coefficient (R2) of 0.99. Using the correlations, 1.0 mg/kg of 3-MCPDE in refined, bleached and deodorized palm oil (RBDPO) will be obtained from CPO with 1.2 mg/kg chloride with 7% wash water usage. The study also showed minor GE reduction between 7 and 11% was attained after water washing.


A monovalent anti-human CD28 domain antibody antagonist: preclinical efficacy and safety.
Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4-mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell-dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.


Subfreezing activity of microorganisms and the potential habitability of Mars' polar regions.
The availability of water-ice at the surface in the Mars polar cap and within the top meter of the high-latitude regolith raises the question of whether liquid water can exist there under some circumstances and possibly support the existence of biota. We examine the minimum temperatures at which liquid water can exist at ice grain-dust grain and ice grain-ice grain contacts, the minimum subfreezing temperatures at which terrestrial organisms can grow or multiply, and the maximum temperatures that can occur in martian high-latitude and polar regions, to see if there is overlap. Liquid water can exist at grain contacts above about -20 degrees C. Measurements of growth in organisms isolated from Siberian permafrost indicate growth at -10 degrees C and metabolism at -20 degrees C. Mars polar and high-latitude temperatures rise above -20 degrees C at obliquities greater than ~40 degrees, and under some conditions rise above 0 degrees C. Thus, the environment in the Mars polar regions has overlapped habitable conditions within relatively recent epochs, and Mars appears to be on the edge of being habitable at present. The easy accessibility of the polar surface layer relative to the deep subsurface make these viable locations to search for evidence of life.


Polymorphic control of inhalation microparticles prepared by crystallization.
Milling processes are known to cause polymorphic transition in enantiotropic systems and the micronization process employed to produce microparticles for inhalation formulations has been reported to result in solid-state damage. The aim of the current work was to investigate the polymorphism of salmeterol xinafoate (SX) following antisolvent micronization from poly(ethylene glycol) (PEG) solvents and compare this to the properties of SX conventionally crystallized and micronized. Powder X-ray diffraction revealed that SX crystallized predominantly as the SX form I polymorph following rapid precipitation from PEG solvents and cooling crystallization from propan-2-ol. Thermo-kinetic analysis using a modified Avrami-Erofe'ev equation was applied to differential scanning calorimetric thermographs of crystallized and micronized SX. The kinetic analysis revealed that SX crystallized from PEG solvents underwent significantly less or no re-crystallization of SX form II from the melt. A polymorphic transition was identified upon heating ball-milled SX, although the untreated material was resistant to such transformation. The thermal behaviour of SX crystallized from PEG solvents was consistent with a lower degree of crystal lattice disorder and higher enantiotropic purity than SX crystallized from propan-2-ol; the same was also true when comparing SX before and after micronization.


Brain energy metabolism in patients with spontaneous subarachnoid hemorrhage and global cerebral edema.
Previous studies of spontaneous subarachnoid hemorrhage (SAH) have shown that global cerebral edema on the first computed tomography scan is associated with a more severe initial injury and is an independent predictor of poor outcome. Effects of secondary ischemic events also influence outcome after SAH. This study demonstrates that early global edema is related to markers of an increased cerebral energy metabolism as measured with intracerebral microdialysis, which could increase vulnerability to adverse events. Fifty-two patients with microdialysis monitoring after spontaneous SAH were stratified according to the occurrence of global cerebral edema on the first computed tomography scan taken a median of 2 hours after the initial bleed. Microdialysis levels of glucose, lactate, and pyruvate were compared between the global edema (n = 31) and no global edema (n = 21) groups. Clinical outcome was assessed with the Glasgow Outcome Scale score at >/= 6 months. Patients with global edema showed significantly elevated lactate and pyruvate levels 70 to 79 hours after SAH and marginally significantly higher levels of lactate 60 to 69 hours and 80 to 89 hours after SAH. There was a trend toward worse outcome in the edema group. Patients with global cerebral edema have higher interstitial levels of lactate and pyruvate. The edema group may have developed a cerebral hypermetabolism to meet the increased energy demand in the recovery phase after SAH. This stress would make the brain more vulnerable to secondary insults, increasing the likelihood of energy failure.


Chlorinated iridoid glucosides from Veronica longifolia and their antioxidant activity.
From Veronica longifolia were isolated three chlorinated iridoid glucosides, namely, asystasioside E (6) and its 6-O-esters 6a and 6b, named longifoliosides A and B, respectively. The structures of 6a and 6b were proved by analysis of their spectroscopic data and by conversion to the catalpol ester verproside (5a) or to catalpol (5), respectively. The configuration of the previously known vanilloyl analogue, urphoside B, was shown to be the 6β-epimer (6c) of the structure originally reported. Longifoliosides A (6a) and B (6b) were found to exhibit radical-scavenging activity against nitric oxide, superoxide, and 2,2-diphenyl-1-picrylhydrazyl radicals.


Telos versus Praxis in Bioethics.
The authors of "A Conceptual Model for the Translation of Bioethics Research and Scholarship" argue that bioethics must respond to institutional pressures by demonstrating that it is having an impact in the world. Any impact, the authors observe, must be "informed" by the goals of the discipline of bioethics. The concept of bioethics as a discipline is central to their argument. They begin by citing an essay that Daniel Callahan wrote in the first issue of Hastings Center Studies. Callahan argued in this 1973 piece that bioethics had yet to attain the status of a discipline, and he lauded the freedom of being able to define a new discipline. Callahan's essay shares with Mathews and colleague's a peculiarity: neither ever defines what it means to refer to something as a "discipline." To define a discipline does mean attending to the intended end product of scholarly activity, so I concur with Mathews et al.'s focus on outcomes. But I am concerned that in their argument they confusingly entangle their understanding of an academic discipline's internal goals, its telos, with its potential to have an impact on the external world, its praxis. The confusion that this can bring exposes what I believe is a profound problem within bioethics, the discipline's peculiar and at times intellectually hazardous relationship with its institutional hosts.


Conjunctival nevi: Clinical and histopathologic features in a Saudi population.
Conjunctival nevi are benign lesions with wide variation in clinical and histopathological features. The differentiation between benign nevi and other pigmented lesions is essential. The aim of our study was to identify the distribution of the histopathologic types of conjunctival nevi among the Saudi population and to provide the basic knowledge needed for proper clinical diagnosis. This retrospective study of surgically excised benign conjunctival nevi was conducted at a tertiary care eye hospital from 1995 to 2006. Clinical data was collected from medical records and the histopathologic features reviewed by a single pathologist. A total 105 conjunctival nevi were included from 104 consecutive patients (mean age, 26 years, 54 males and 50 females). The anatomical location was the bulbar conjunctiva in 83%, juxtalimbal in 12%, caruncle in 4% and palpebral in 1%. The lesion was removed for cosmetic reasons in 38% while 8% of the lesions were removed to rule out malignancy. The compound nevus was the commonest (72%) in all age groups, followed by subepithelial nevus (24%) and finally junctional nevus (3%). The distribution of the histopathologic types of this tumor in our population matches the pattern in other areas of the world with the compound nevus being the commonest lesion. However, fewer lesions among our patients are removed to rule out malignancy.


Vitamin D vs broad spectrum phototherapy in the treatment of seasonal affective disorder.
Seasonal Affective Disorder (SAD) is prevalent when vitamin D stores are typically low. Broad-spectrum light therapy includes wavelengths between 280-320 nm which allow the skin to produce vitamin D. This study was designed to test the hypothesis that vitamin D deficiency might play a role in SAD. A prospective, randomized controlled trial was conducted in a group of 15 subjects with SAD. Eight subjects received 100,000 I.U. of vitamin D and seven subjects received phototherapy. At the onset of treatment and after 1 month of therapy subjects were administered the Hamilton Depression scale, the SIGH-SAD, and the SAD-8 depression scale. All subjects also had serum levels of 25-hydroxyvitamin D (25-OH D) measured before and 1 week after intervention therapy. All subjects receiving vitamin D improved in all outcome measures. The phototherapy group showed no significant change in depression scale measures. Vitamin D status improved in both groups (74% vitamin D group, p < 0.005 and 36% phototherapy group, p < 0.01). Improvement in 25-OH D was significantly associated with improvement in depression scale scores (r2=0.26; p=0.05). Vitamin D may be an important treatment for SAD. Further studies will be necessary to confirm these findings.


Rate-limiting biotransformation of triamterene is mediated by CYP1A2.
Triamterene (TA), a potassium-sparing diuretic, is extensively metabolized by hydroxylation in 4'-position and subsequent conjugation by cytosolic sulfotransferases. To identify the cytochrome P450 enzyme(s) catalyzing hydroxylation of triamterene (the rate-limiting step in the formation of the sulfate ester (STA)), in vitro incubation studies were performed with human liver microsomes. Initial rates of TA hydroxylation (0 - 300 microM) were determined during a ten-minute-incubation period with liver microsomes of two donors. The role of individual CYP enzymes was determined by pre-incubation with selective inhibitors/alternative substrates. Vice versa, the effect of TA (0 - 500 microM) on 3-demethylation of caffeine (0 - 1,000 microM) was assessed. Metabolite concentrations were estimated by reversed-phase HPLC methods. TA Km values without inhibitors were 60 and 142 microM, Vmax was 177 and 220 pmol/min/mg protein, respectively. Mean inhibitor induced changes of 4'-hydroxy-TA formation were as follows: Furafylline 25 microM (CYP1A2), complete inhibition (-100%); omeprazole 250 microM (CYP1A2 inhibitor/CYP2C 19 substrate), -30%; coumarin 25 microM (CYP2A6), -11%; quinidine 25 microM (CYP2D6), -9%; ketoconazole 25 microM (CYP3A), -18%; and erythromycin 250 microM (CYP3A), -8%. In the reverse inhibition studies, TA competitively inhibited caffeine 3-demethylation with Ki values of 65 and 111 microM, respectively. 4'-hydroxylation of TA in humans appears to be mediated exclusively by CYP1A2. Inhibition or induction of CYP1A2 will change the time course of both TA and its active phase-II metabolite. The net pharmacodynamic effect of such changes is difficult to predict and needs to be evaluated in clinical studies.


Loss of supernumerary axons during neuronal morphogenesis.
The morphogenesis of individual neurons was investigated in the cardiac ganglion of the frog. Intracellular injection of horseradish peroxidase shows that mature neurons lack dendrites and have a single axon. Early in development, more than half of the neurons are multipolar and have as many as four processes emanating from their cell body. The most likely mechanism for the developmental transformation of larval neurons is that the supernumerary processes are pruned from the cell body. Supernumerary processes in larval neurons have features characteristic of axons. The processes of larval neurons can be highly branched and extend throughout the target with distinctive varicosities along the length of each process. Electron microscopy shows that all processes of individually injected cells contain clusters of vesicles apposed to active zones. Thus, the larval cardiac ganglion neuron is capable of extending more than one axon from its cell body.