Ribosomal DNA deletions modulate genome-wide gene expression: "rDNA-sensitive" genes and natural variation.
The ribosomal rDNA gene array is an epigenetically-regulated repeated gene locus. While rDNA copy number varies widely between and within species, the functional consequences of subtle copy number polymorphisms have been largely unknown. Deletions in the Drosophila Y-linked rDNA modifies heterochromatin-induced position effect variegation (PEV), but it has been unknown if the euchromatic component of the genome is affected by rDNA copy number. Polymorphisms of naturally occurring Y chromosomes affect both euchromatin and heterochromatin, although the elements responsible for these effects are unknown. Here we show that copy number of the Y-linked rDNA array is a source of genome-wide variation in gene expression. Induced deletions in the rDNA affect the expression of hundreds to thousands of euchromatic genes throughout the genome of males and females. Although the affected genes are not physically clustered, we observed functional enrichments for genes whose protein products are located in the mitochondria and are involved in electron transport. The affected genes significantly overlap with genes affected by natural polymorphisms on Y chromosomes, suggesting that polymorphic rDNA copy number is an important determinant of gene expression diversity in natural populations. Altogether, our results indicate that subtle changes to rDNA copy number between individuals may contribute to biologically relevant phenotypic variation.


Mechanisms by which HIV envelope minimizes immunogenicity.
With many viruses, vaccines containing the appropriate envelope antigens have provided strong and long lasting immunity. Not so with HIV-1 envelope, despite two decades of experience with various envelope and core constituent vaccines, protection provided has been weak or absent. Our laboratory has been systematically investigating the characteristics of HIV-1 envelope gp140, the principle HIV-1 envelope protein heterodimer responsible for HIV infectivity. We have identified two properties of HIV-1 envelope gp140 that may be important factors in reducing immunogenicity. HIV envelope protein gp140 rejects complement binding. Such binding can be of vital importance, since an extensive literature suggests that complement binding markedly increases immunogenicity, and, more importantly, complement binding influences the type of immune response. For many antigens, C3 binding is required for normal transport of antigens into follicles to initiate a normal germinal center response, and in the absence of appropriate complement binding, the antibody response is reduced, short lived with short-lived memory cell formation, and for an unknown reason, the antibody response shows increased affinity maturation of antibody. These features are characteristic of the HIV-1 antibody response. Just as important is the finding that envelope gp140 is highly unstable on injection, is rapidly removed from the circulation, and is degraded into peptides. This short-lived antigen may be available on initial exposure to the immune system for too short a period of time, particularly in the absence of complement binding, to be an adequate immunogen.


Response of bipotential human marrow stromal cells to insulin-like growth factors: effect on binding protein production, proliferation, and commitment to osteoblasts and adipocytes.
Insulin-like growth factors (IGFs) are important regulators of the activity of mature osteoblasts, but their effects on osteoprogenitor cells in human bone marrow stroma are unclear. In this study, we assessed the effects of IGFs on a conditionally immortalized human marrow stromal cell line, hMS(3-4), which has the ability to differentiate to either mature osteoblasts or adipocytes. hMS(3-4) cells expressed functional receptors for IGFs as well as specific IGF-binding proteins (IGFBP-3, -4, -5, and -6). IGF treatment of hMS(3-4) cells did not alter IGFBP expression, but resulted in distinct posttranslational modifications of secreted IGFBP-3 and IGFBP-4 proteins. IGF-I, IGF-II, and their receptor-activating analogs significantly increased by 2-fold the proliferation rate of the hMS(3-4) cells, but had a more complex effect on hMS(3-4) cell differentiation. Treatment with IGFs did not affect gene expression of Cbfa1 or peroxisome proliferator-activated receptor gamma2 (transcription factors involved in commitment to osteoblast and adipocyte pathways, respectively), alkaline phosphatase, type I collagen, and osteocalcin (markers of the osteoblast lineage), or lipoprotein lipase and adipsin (markers of the adipocyte lineage) and did not change alkaline phosphatase activity or type I collagen and osteocalcin protein relative to total protein production. In contrast, IGFs significantly increased type I collagen expression in differentiated hMS(3-4) cells as well as mature osteoblasts and promoted lipid accumulation in differentiated adipocytes. In summary, hMS(3-4) cells express essential components of the IGF system and respond to IGF treatment with increased proliferation. There was no evidence for IGFs directly modulating the commitment of hMS(3-4) cells to either osteoblast or adipocyte pathways, and their effects on differentiation within these lineages were dependent on the stage of cell maturation.


Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal.
In embryonic stem (ES) cells, a well-characterized transcriptional network promotes pluripotency and represses gene expression required for differentiation. In comparison, the transcriptional networks that promote differentiation of ES cells and the blastocyst inner cell mass are poorly understood. Here, we show that Sox17 is a transcriptional regulator of differentiation in these pluripotent cells. ES cells deficient in Sox17 fail to differentiate into extraembryonic cell types and maintain expression of pluripotency-associated transcription factors, including Oct4, Nanog, and Sox2. In contrast, forced expression of Sox17 down-regulates ES cell-associated gene expression and directly activates genes functioning in differentiation toward an extraembryonic endoderm cell fate. We show these effects of Sox17 on ES cell gene expression are mediated at least in part through a competition between Sox17 and Nanog for common DNA-binding sites. By elaborating the function of Sox17, our results provide insight into how the transcriptional network promoting ES cell self-renewal is interrupted, allowing cellular differentiation.


Person-Centered Healthcare Practice in a Pandemic Context: An Exploration of People's Experience of Seeking Healthcare Support.
Background: The recent COVID-19 pandemic increased pressure upon healthcare resources resulting in compromised health services. Enforced national lockdown led to people being unable to access essential services in addition to limiting contact with social support networks. The novel coronavirus, and subsequent condition known as long covid were not well-understood and clinicians were not supported by existing guidelines or pathways. Our study explored people's experiences of healthcare during this period with a person-centered "lens." Methods: Ninety-seven people participated in our online survey about their experiences of the pandemic, particularly while socially isolated and their experiences of healthcare. Following completion of the survey, 11 of these participants agreed to further semi-structured interviews to explore this further in their own words. Interview conversations were transcribed, checked; together with the responses to open questions in the survey. The data were then analyzed thematically by members of the research team. We conducted framework analysis from a post-positivist perspective, using the Person-centered Practice Framework to explore participants' experiences. Results: There were few examples of people describing person-centered care. People experienced barriers to accessing support, and negative experiences of care that represented complexities enacting person-centered care at each level of the framework (processes, practice environment, prerequisites, and macro context). These barriers were influenced greatly by the pandemic, for example, with health professionals being harder to access. Some experiences related to the ways in which health professionals responded to the context, for example, positive examples included active listening, recognition of people's experiences, seeking to find out more, and engaging in collaborative problem-solving. Discussion: People want to feel heard, supported to navigate healthcare systems, source trustworthy information, find appropriate services, and collaborate in learning and problem-solving with healthcare professionals. There have been enormous challenges to the provision of healthcare throughout the pandemic. Moving forward is crucial with emphasis on overcoming barriers to person-centered healthcare. This should focus on steps now and also in planning for the possibility of further rapid changes in the demand for and provision of healthcare.


Raccoon roundworm (Baylisascaris procyonis) encephalitis: case report and field investigation.
Baylisascaris procyonis is a common and widespread parasite of raccoons in the United States and Canada. With large raccoon populations occurring in many areas, the potential risk of human infection with B procyonis is high. We report a case of severe raccoon roundworm (B procyonis) encephalitis in a young child to illustrate the unique clinical, diagnostic, and treatment aspects, as well as public health concerns of B procyonis infection. Acute and convalescent serum and cerebrospinal fluid samples from the patient were tested for antibodies against B procyonis to assist in documenting infection. An extensive field survey of the patient's residence and the surrounding community was performed to investigate raccoon abundance and to determine the extent of raccoon fecal contamination and B procyonis eggs in the environment. The patient evidenced serologic conversion, and the field investigation demonstrated a raccoon population far in excess of anything previously reported. There was abundant evidence of B procyonis eggs associated with numerous sites of raccoon defecation around the patient's residence and elsewhere in the community. Because B procyonis can produce such severe central nervous system disease in young children, it is important that pediatricians are familiar with this infection. The public should be made aware of the hazards associated with raccoons and B procyonis to hopefully prevent future cases of B procyonis infection.


[Rate of the morning heart rate rising as an indicator of circadian rhythm disturbances in patients with hypertensive disease].
The aim of the study was to measure a rise in the morning heart rate (HR) and assess the possibility of using this parameter to characterize circadian HR rhythm disturbances in patients with arterial hypertension (AH). A total of 44 subjects were examined by 24 hour ECG monitoring; 30 of them had grade II AH (group 1, mean age 46.0 +/- 9.4 yr) and 14 were healthy (group 2, mean age 39.1 +/- 5.3 yr). Morning HR immediately after awakening in AH patients and healthy subjects increased at a rate of 16.9 +/- 6.39 and 8.91 +/- 3.21 beats/min respectively. Group 1 proved inhomogeneous in terms of this parameter. Patients of subgroup B (27%) were not significantly different from healthy subjects (HR increased by 9.82 +/- 1.34 and 8.91 +/- 3.21 beats/min). Subgroup A (73%) included patients with enhanced HR reactivity after awakening compared with subgroup B and healthy subjects (19.54 +/- 5.42; 9.82 +/- 1.34; 8.91 +/- 3.21 respectively). It suggested disturbed circadian HM rhythm in subgroup A. It is concluded that the character of morning rise in HR may be used for the evaluation of circadian HM rhythm disturbances in AH.


Does Ozone Pollution Share the Same Formation Mechanisms in the Bay Areas of China?
As important regions of transition between land and sea, the three bay areas of Bohai Bay (BHB), Hangzhou Bay (HZB), and Pearl River Estuary (PRE) in China often suffer from severe photochemical pollution despite scarce anthropogenic emissions. To understand the causes of high ozone (O3) concentrations, the high O3 episode days associated with special synoptic systems in the three bays were identified via observations and simulated by the weather research and forecasting coupled with community multiscale air quality (WRF-CMAQ) model. It was revealed that the interaction between synoptic winds and mesoscale breezes resulted in slow wind speeds over the HZB and PRE, where air pollutants transported from upwind cities gained a long residence time and subsequently participated in intensive photochemical reactions. The net O3 production rates within the bay areas were even comparable to those in surrounding cities. This finding was also applicable to BHB but with lower net O3 production rates, while high levels of background O3 and the regional transport from farther upwind BHB partially elevated the O3 concentrations. Hence, these three bay areas served as O3 "pools" which caused the accumulation of air pollutants via atmospheric dynamics and subsequent intense photochemical reactions under certain meteorological conditions. The results may be applicable to other similar ecotones around the world.


Human alpha-galactosidase A: characterization of the N-linked oligosaccharides on the intracellular and secreted glycoforms overexpressed by Chinese hamster ovary cells.
Human alpha-galactosidase A (alpha-Gal A) is the lysosomal glycohydrolase that cleaves the terminal alpha-galactosyl moieties of various glycoconjugates. Overexpression of the enzyme in Chinese hamster ovary (CHO) cells results in high intracellular enzyme accumulation and the selective secretion of active enzyme. Structural analysis of the N -linked oligosaccharides of the intracellular and secreted glycoforms revealed that the secreted enzyme's oligosaccharides were remarkably heterogeneous, having high mannose (63%), complex (30%), and hybrid (5%) structures. The major high mannose oligosaccharides were Man5-7GlcNAc2 species. Approximately 40% of the high mannose and 30% of the hybrid oligosaccharides had phosphate monoester groups. The complex oligosaccharides were mono-, bi-, 2,4-tri-, 2,6-tri- and tetraantennary with or without core-region fucose, many of which had incomplete outer chains. Approximately 30% of the complex oligosaccharides were mono- or disialylated. Sialic acids were mostly N -acetylneuraminic acid and occurred exclusively in alpha2, 3-linkage. In contrast, the intracellular enzyme had only small amounts of complex chains (7.7%) and had predominantly high mannose oligosaccharides (92%), mostly Man5GlcNAc2 and smaller species, of which only 3% were phosphorylated. The complex oligosaccharides were fucosylated and had the same antennary structures as the secreted enzyme. Although most had mature outer chains, none were sialylated. Thus, the overexpression of human alpha-Gal A in CHO cells resulted in different oligosaccharide structures on the secreted and intracellular glycoforms, the highly heterogeneous secreted forms presumably due to the high level expression and impaired glycosylation in the trans- Golgi network, and the predominately Man5-7GlcNAc2 cellular glycoforms resulting from carbohydrate trimming in the lysosome.


Performance and views of examiners in the Applied Knowledge Test for the nMRCGP licensing examination.
A new computer-based Applied Knowledge Test (AKT) has been developed for the licensing examination for general practice administered by the Royal College of General Practitioners. The aim of this evaluation was to assess the acceptability, feasibility, and validity of the test as well as its transfer to a computerised format at local test centres. Computer-based test and postal questionnaire. Panel of examiners, Membership of the Royal College of General Practitioners (MRCGP) examination, UK. Self-administered postal questionnaires were sent to examiners not involved with the development of the test after completing it. Their performance scores were compared with those of candidates. The majority of participants (80.9%) were satisfied with the new computer-based test. Responses relating to content and attitudes to the test were also positive overall, but some problems with content were highlighted. Fewer examiners (61.9%) were positive about the physical comfort of the test centre, including seating, heating, and lighting. Examiners had significantly higher scores (mean 83.3%, range 69 to 93%, 95% confidence interval [CI] = 81.9 to 84.7%) than 'real' candidates (mean 75.0%, range 45 to 94%, 95% CI = 74.6 to 75.5%), who subsequently took an identical test. The new computer-based licensing test (the AKT) was found to be acceptable to the majority of examiners. The pass-fail standard, determined by routine methods including an Angoff procedure, was supported by the higher success rate of examiners compared with candidates. The use of selected groups to assess high-stakes (licensing) examinations can be useful for assessing test validity.


[Important pharmaceutical-chemical characteristics of the central muscle relaxant chlormezanone].
The enantinomers of chlormezanone (1) may be achieved by enantioselective HPLC separation with a yield of 98% using a OD-Daicel column. Both enantiomers bind to human serum albumin (HSA) at pH 7.4 to a range of 11-12%. Binding to the globuline fractions is much less (2-4%, equilibrium dialysis, validation by ultrafiltration). It could be demonstrated by means of 1H-NMR spectroscopy that 1 binds to HSA with the benzene ring as well as with the thiazanone ring. The velocity of racemization could be measured for the first time using a BSA column. The enantiomers undergo racemization at pH 7.4 and 37 degrees C with a halflife of approx. 20.5 h.


Melatonin protects against apoptotic and autophagic cell death in C2C12 murine myoblast cells.
In this study, we investigated whether or not melatonin inhibits apoptotic and autophagic cell death in C2C12 murine myoblast cells. Treatment of cells with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, was shown to induce cell death, and treatment with melatonin (100 μm) significantly attenuated the occurrence of NO-induced cell death. Decreased p-Akt expression in response to NO was also arrested by melatonin. Under these conditions, p-Bad (Ser 136) expression increased with melatonin treatment prior to NO treatment. Treatment with Akt inhibitors (LY 294002, wortmannin) plus melatonin reduced p-Akt expression. Compared with NO treatment, Bcl-2 expression increased with melatonin treatment, while Bax expression was inhibited by melatonin treatment. Expression of catalase and Mn-superoxide dismutase (SOD) was elevated with melatonin treatment, whereas Cu/Zn-SOD expression decreased with melatonin, lower than NO treatment, respectively. Next, we investigated the question of whether or not melatonin may restrain autophagic cell death in C2C12 cells. Nutrient starvation induced a rise in expression of the microtubule-associated protein 1 light chain 3 (LC3)-II; however, melatonin treatment suppressed LC3-II expression by nutrient deprivation. Expression of Bcl-2, Bax, catalase, and Cu/Zn-SODs coincided with results of apoptotic cell death. Together, these results suggest that melatonin protects against apoptotic and autophagic cell death through the common pathway resulted in the increment of Bcl-2 expression and the reduction of Bax expression in C2C12 murine myoblast cells.


Differential regulation of human monocyte programmed cell death (apoptosis) by chemotactic factors and pro-inflammatory cytokines.
In the absence of appropriate stimuli, monocytes undergo programmed cell death (PCD) or apoptosis. IL-1 beta and TNF-alpha prevent monocyte PCD, which suggests that viability may be regulated by biologically active peptides released during inflammation. To explore this possibility, we evaluated several chemotactic factors and pro-inflammatory cytokines for their ability to regulate PCD. The recruitment factors, FMLP, C fragment C5a, monocyte chemotactic protein-1, or transforming growth factor-beta 1, were incapable of rescuing monocytes from PCD nor did they enhance PCD, whereas several inflammatory cytokines in addition to IL-1 beta and TNF-alpha, including granulocyte-monocyte-CSF and IFN-gamma, prevented monocyte PCD provided that sufficient levels of these cytokines were continuously maintained in the cultures. Cytokine-mediated inhibition of PCD could be blocked by specific antisera, ruling out potential effects caused by LPS contamination. When tested at equivalent concentrations, IL-2, IL-4, and IL-6 had no effect on PCD indicating selectivity in cytokine modulation of monocyte PCD. Because monocytes produce IL-1 beta, TNF-alpha, and granulocyte-monocyte CSF when activated, the data suggest autocrine as well as paracrine control of cell survival and accumulation. The results also suggest that monocytes recruited to a site of inflammation will undergo PCD in the absence of specific cytokines and/or other stimuli that block this process.


Platelets and stromal cell-derived factor-1 in progenitor cell recruitment.
Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine that binds to its sole counterreceptor, CXCR4. It is well reported that the SDF-1/CXCR4 signaling pathway is of vital importance to human development and to various pathophysiological phenomena, including hematopoiesis, angiogenesis, atherosclerosis, cancer growth, metastasis, and human immunodeficiency virus infection. SDF-1 promotes mobilization of bone marrow-derived endothelial progenitor cells (EPCs) to the circulation in response to vascular injury. Recently, we found that platelets express and release SDF-1 into the microcirculation upon activation and we observed that platelet-derived SDF-1 is functionally involved in recruitment of EPCs to arterial thrombi in vivo. This review discusses the unique functions of this chemokine and the newly discovered impact of platelet-derived SDF-1 into the recruitment of progenitor cells to vascular injury areas, and its subsequent effects in atherosclerosis, vascular repair, and angiogenesis.


[Retino-pulvinar pathway of the cat brain].
Peculiarities on axonal distribution and termination of the retinal ganglionar cells within the limits of the thalamic pulvinar nuclei have been studied in 10 cats by means of the radioautography method combined with silver nitrate impregnation (Fink--Heimer technique). The ganglionar cells have projections on two pulvinar nuclei -- the lateral and the inferior. The medial pulvinar nucleus has no similar connections. The retinal projections in the pulvinar nuclear complex are bilateral and nearly symmetrical, the contralateral projections of the pathway somewhat predominate.


Integrative proteogenomics for differential expression and splicing variation in a DM1 mouse model.
Dysregulated mRNA splicing is involved in the pathogenesis of many diseases including cancer, neurodegenerative diseases, and muscular dystrophies such as myotonic dystrophy type 1 (DM1). Comprehensive assessment of dysregulated splicing on the transcriptome and proteome level has been methodologically challenging, and thus investigations have often been targeting only few genes. Here, we performed a large-scale coordinated transcriptomic and proteomic analysis to characterize a DM1 mouse model (HSALR) in comparison to wild-type. Our integrative proteogenomics approach comprised gene- and splicing-level assessments for mRNAs and proteins. It recapitulated many known instances of aberrant mRNA splicing in DM1 and identified new ones. It enabled the design and targeting of splicing-specific peptides and confirmed the translation of known instances of aberrantly spliced disease-related genes (e.g. Atp2a1, Bin1, Ryr1), complemented by novel findings (Flnc and Ywhae). Comparative analysis of large-scale mRNA and protein expression data showed quantitative agreement of differentially expressed genes and splicing patterns between disease and wild-type. We hence propose this work as a suitable blueprint for a robust and scalable integrative proteogenomic strategy geared towards advancing our understanding of splicing-based disorders. With such a strategy, splicing-based biomarker candidates emerge as an attractive and accessible option, as they can be efficiently asserted on the mRNA and protein level in coordinated fashion.


Barriers to anti-retroviral therapy adherence among adolescents aged 10 to 19 years living with HIV in sub-Saharan Africa: A mixed-methods systematic review protocol.
Antiretroviral therapy (ART) adherence is fundamental in achieving viral load suppression and consequently attaining positive health outcomes among people living with HIV. However, ART adherence is sub-optimum among adolescents living with HIV (ALHIV) thus the high AIDS-related mortality even after World Health Organization (WHO) revised HIV treatment eligibility guidelines in 2010, 2013 and 2016. Consolidated trends of barriers to ART adherence among ALHIV aged 10 to 19 years in sub-Saharan countries post each eligibility guidelines revision to date are unknown. We will conduct comprehensive search of peer-reviewed and grey literature databases publishing observational studies reporting data adherence and barriers to ART among ALHIV on ART. We will further search the reference lists of included studies and other relevant reviews. We will also do a citation search for included studies in the review. We will search in the following databases PubMed, Cochrane Review, Scopus on Excerpta Medica Database (Embase) and Cumulated Index to Nursing and Allied Health Literature (CINAHL). Furthermore WHO, Joint United Nations Programme on HIV/AIDS (UNAIDS) websites, conference proceedings and country reports will be searched to identify relevant literature. Data will be extracted from eligible studies and synthesis will be through categorizing studies by year of study, barriers, and outcomes. Meta-analysis and meta-synthesis will be conducted for quantitative and qualitative data, respectively. Where meta-synthesis is impossible, narrative synthesis will be conducted. We will only include studies conducted between 2010 and 2022 within sub-Saharan Africa countries. Adherence to ART at a high level is required to achieve adequate viral suppression and improve quality of life in ALHIV. The knowledge of barriers to ART among ALHV may aid in the design of interventions aimed at improving ART adherence. Systematic review protocol registration: PROSPERO CRD42021284891.


Association of Cumulative Viral Load With the Incidence of Hypertension and Diabetes in People With HIV.
HIV induces several metabolic derangements that contribute to cardiovascular disease, but it is unclear if HIV increases diabetes or hypertension risk. Refining longitudinal relationships between HIV-specific factors and cardiovascular disease risk factors across different care settings may help inform cardiovascular disease prevention among people with HIV (PWH). We tested the hypothesis that long-term higher cumulative viral load (viremia-copy-year) is associated with higher risk of diabetes and hypertension by analyzing electronic records of PWH from 2 distinct health systems in Chicago (Northwestern Medicine and Howard Brown Health Care) receiving care in 2004 to 2019. We used joint longitudinal-survival models to assess multivariable-adjusted associations. Subgroup analyses per site were also conducted. We observed 230 (3.0%) incident diabetes cases in 7628 PWH without baseline diabetes and 496 (6.7%) hypertension cases in 7450 PWH without baseline hypertension. Pooled analysis showed a direct association of viremia-copy-year with incident hypertension (hazards ratio, 1.20 [95% CI, 1.14-1.26]) but not with diabetes (hazards ratio, 1.03 [95% CI, 0.96-1.10]). However, site-specific differences existed whereby the Northwestern-only analysis demonstrated a significant association of viremia-copy-year with hypertension (hazards ratio, 1.29 [95% CI, 1.08-1.32]). Additionally, higher social deprivation index (both sites) and diagnosis of mental health disorder (Howard Brown Health only) was associated with higher diabetes and hypertension risk. Cumulative viral load may be associated with incident hypertension among PWH. Associations of HIV control with cardiovascular disease risk factors among PWH may differ by health care system context.


Mitochondrial SIRT3 and heart disease.
Sirtuins are emerging as key regulators of many cellular functions including metabolism, cell growth, apoptosis, and genetic control of ageing. In mammals there are seven sirtuin analogues, SIRT1 to SIRT7. Among them SIRT3 is unique because this is the only analogue whose increased expression has been found to be associated with extended lifespan of humans. SIRT3 levels have been shown to be elevated by exercise and calorie restriction. Although the role of SIRT3 in cell biology is only beginning to be understood, initial studies have shown that SIRT3 plays a major role in free fatty acid oxidation and maintenance of cellular ATP levels. In the heart SIRT3 has been found to block development of cardiac hypertrophy and protect cardiomyocytes from oxidative stress-mediated cell death. Similarly, SIRT3 has been reported to have tumour-suppressive characteristics. In this article, we review the known effects of SIRT3 in different tissues and relate them to the protection of cardiomyocytes under stress.


[Increase in the fraction of non-repaired mutations in Escherichia coli cells, incubated in the absence of glucose after UV-irradiation].
In E. coli WP2 trpE65 cells irradiated with UV-dose of 11 J/m2, the additional small portion of induced Trp+ mutations became resistant to photoreactivation or "dark" (excision) repair after a short-termed (10-30 min) postirradiation incubation of bacteria in a minimal medium deprived of glucose and tryptophan. Since protein synthesis could not proceed in those cells because of the lack of energy and tryptophan, the data indicate that an unknown mechanism exists which imparts some mutations with the resistance to antimutagenic repair in the absence of the inducible mutagenic system. In the light of this result, one could suggest that the normal process of mutation fixation (that is the loss of sensitivity of mutations to photoreactivation or to excision repair in cells incubated in growth medium after irradiation) should not necessarily be a direct consequence of manifestation of the activity of an inducible mutagenic system.


Intercostal leiomyoma in a child: review of the literature.
Leiomyomas of the chest wall are very rare. In a review of the current literature twelve cases were found, of which only one concerns of an intercostal leiomyoma of the chest wall. We report a case of 1 year old male child with intercostal leiomyoma who presented with a painless rigid swelling of the right chest wall. The radiological control revealed a solid mass in the right anterior sixth intercostal space. En-bloc excision of the mass by abrading of the sixth rib through right anterior thoracotomy was performed. Histopatological analysis showed a localized intercostal leiomyoma. The patient has a close follow-up for 6 months without evidence of recurrence. This is the first case of a primary intercostal leiomyoma in a child which was excised totally without reconstruction of the chest wall.


windex: Analyzing Convergent Evolution Using the Wheatsheaf Index in R.
windex is a package developed for the R statistical environment to provide novel tools for the analysis of convergent evolution. The recently described Wheatsheaf index provides quantitative measures of the strength of convergence and opens up new possibilities for exploring this evolutionary phenomenon. The windex package allows implementation of this method with additional functions that can be used to create plots and perform statistical tests. R provides compatibility with other packages, and the R environment is familiar to many researchers. The windex package is freely available from CRAN: http://cran.r-project.org/web/packages/windex/. Consequently, windex can be installed directly from R and is distributed under the GNU General Public License 2.0.


In situ management of late thrombosis of a renal graft vein in a patient with Cockett syndrome
Late thrombosis of the renal graft vein is a rare complication that results in graft loss in the majority of cases. We describe the case of a 57-year-old female patient who had a kidney transplant 32 years ago and developed a late thrombosis of the graft vein, accompanied by extensive thrombosis in the common femoral and iliac veins. Risk factors included severe malnutrition, chronic inflammation due to an anal fistula, and Cockett syndrome. The treatment consisted of mechanical thrombectomy of the iliac vein, placement of a stent in the common iliac vein, partial thromboaspiration of the renal vein thrombus with local thrombolysis, followed by systemic anticoagulation. With this approach, renal function fully recovered without major complications.


Distinctive neuropsychological profiles differentiate patients with functional memory disorder from patients with amnestic-mild cognitive impairment.
Patients with functional memory disorder (FMD) report significant memory failures in everyday life. Differentiating these patients from those with memory difficulties due to early stage neurodegenerative conditions is clinically challenging. The current study explored whether distinctive neuropsychological profiles could be established, suitable to differentiate patients with FMD from healthy individuals and those experiencing amnestic mild cognitive impairment (a-MCI). Patients with a clinical diagnosis of FMD were compared with patients with a-MCI, and healthy matched controls on several tests assessing different cognitive functions. Patients with clinically established mood disorders were excluded. Patients with FMD and a-MCI were broadly comparable on the level of their subjective memory complaints as assessed by clinical interview. The neuropsychological profile of the FMD patients, although they expressed subjective memory and attention concerns during their clinical interview was distinct from patients with a-MCI on tests of memory [semantic fluency, age of acquisition (AoA) analysis of semantic fluency, verbal and non-verbal memory]. FMD patients did not differ significantly from healthy controls, but their scores on the letter fluency and digit cancellation tasks were not significantly different from those of the a-MCI patients indicating a possible sub-threshold deficit on these tasks. Whilst subjective complaints are common within the FMD population, no objective impairment could be detected, even on a sensitive battery of tasks designed to detect subtle deficits caused by an early neurodegenerative brain disease. This study indicates that FMD patients can be successfully differentiated from patients with neurodegenerative memory decline by characterising their neuropsychological profile.


Lifestyle measures in the management of gastro-oesophageal reflux disease: clinical and pathophysiological considerations.
Several lifestyle and dietary factors are commonly cited as risk factors for gastro-oesophageal reflux disease (GORD) and modification of these factors has been advocated as first-line measures for the management of GORD. We performed a systematic review of the literature from 2005 to the present relating to the effect of these factors and their modification on GORD symptoms, physiological parameters of reflux as well as endoscopic appearances. Conflicting results existed for the association between smoking, alcohol and various dietary factors in the development of GORD. These equivocal findings are partly due to methodology problems. There is recent good evidence that weight reduction and smoking cessation are beneficial in reducing GORD symptoms. Clinical and physiological studies also suggest that some physical measures as well as modification of meal size and timing can also be beneficial. However, there is limited evidence for the role of avoiding alcohol and certain dietary ingredients including carbonated drinks, caffeine, fat, spicy foods, chocolate and mint.


[Wording and content of national anthems -- preliminary findings from a transcultural investigation of suicide].
Suicide is still a major health concern, although suicide rates widely differ among different countries and cultures. Thus, besides biological and clinical studies, there is an increasing transcultural research activity on suicidal behaviour. We are presenting here some important transcultural aspects of suicidal behaviour and report some preliminary findings of our transcultural suicide research. Based on the previous data and on our investigations it is likely that the national character and the attitudes toward self-harm are reflecting in some major cultural, historical texts of a nation.


Omega-3 fatty acids modify human cortical visual processing--a double-blind, crossover study.
While cardiovascular and mood benefits of dietary omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are manifest, direct neurophysiological evidence of their effects on cortical activity is still limited. Hence we chose to examine the effects of two proprietary fish oil products with different EPA:DHA ratios (EPA-rich, high EPA:DHA; DHA-rich) on mental processing speed and visual evoked brain activity. We proposed that nonlinear multifocal visual evoked potentials (mfVEP) would be sensitive to any alteration of the neural function induced by omega-3 fatty acid supplementation, because the higher order kernel responses directly measure the degree of recovery of the neural system as a function of time following stimulation. Twenty-two healthy participants aged 18-34, with no known neurological or psychiatric disorder and not currently taking any nutritional supplementation, were recruited. A double-blind, crossover design was utilized, including a 30-day washout period, between two 30-day supplementation periods of the EPA-rich and DHA-rich diets (with order of diet randomized). Psychophysical choice reaction times and multi-focal nonlinear visual evoked potential (VEP) testing were performed at baseline (No Diet), and after each supplementation period. Following the EPA-rich supplementation, for stimulation at high luminance contrast, a significant reduction in the amplitude of the first slice of the second order VEP kernel response, previously related to activation in the magnocellular pathway, was observed. The correlations between the amplitude changes of short latency second and first order components were significantly different for the two supplementations. Significantly faster choice reaction times were observed psychophysically (compared with baseline performance) under the EPA-rich (but not DHA-rich) supplementation, while simple reaction times were not affected. The reduced nonlinearities observed under the EPA-rich diet suggest a mechanism involving more efficient neural recovery of magnocellular-like visual responses following cortical activation.


Assessment of the reproducibility of baseline and hyperemic myocardial blood flow measurements with 15O-labeled water and PET.
PET with 15O-labeled water allows noninvasive quantification of myocardial blood flow (MBF) at baseline and during pharmacologically induced hyperemia to assess the coronary vasodilator reserve (CVR = hyperemic/baseline MBF). Despite widespread use of PET, its reproducibility during one study session has not been tested. Intravenous adenosine (Ado), a powerful coronary vasodilator with a very short decay time, is commonly used for the induction of hyperemia. However, it is not known whether Ado can induce tachyphylaxis after short-term repetitive administration. In this study, we aimed to test the reproducibility of PET assessment of CVR during Ado-induced hyperemia. In 21 healthy volunteer men, baseline and Ado MBF were measured twice using PET with 15O-labeled water to obtain two CVR assessments within 1 h. There was no significant difference between the two baselines (0.89 +/- 0.14 versus 0.99 +/- 0.15 mL/min/g, mean difference 13% +/- 11%) or between the two hyperemic MBFs (3.51 +/- 0.45 versus 3.83 +/- 0.49 mL/min/g, mean difference 10% +/- 14%), resulting in comparable values of CVR (4.05 +/- 0.75 versus 3.93 +/- 0.72, mean difference 2% +/- 15%). The repeatability coefficient for MBF was 0.17 mL/min/g at baseline and 0.94 mL/min/g during hyperemia. The repeatability coefficient of the rate pressure product (RPP) was lower at baseline (1,304 mm Hg x beat/min) than during hyperemia (3,448 mm Hg x beat/min). Repeated measurements of MBF and CVR during the same study session were not significantly different, demonstrating the validity of the technique. The larger variability of hyperemic flow, as indicated by the larger repeatability coefficient, was paralleled by a greater variability of the RPP. This could mean that the greater variability of MBF during stress is more likely due to a variable response to Ado rather than to a measurement error.


The essential dialogue: a Norwegian study of art communication in mental health care.
This study focuses on how semi-structured art dialogues can be used to communicate with older patients with impaired mental health. The study was conducted on a geropsychiatric ward at a university hospital in Norway. To communicate with the patients via works of art, health professionals used semi-structured art dialogues; data were collected by qualitative methods. The findings are based on verbatim quotations regarding the health professionals' experiences of their communication with the patients. Two main categories were identified: the physical domain and the caring domain. Dialogues about figurative as well as nonfigurative art forms were found to stimulate and evoke memories; for some patients, these dialogues were an essential step in creating well-being as well as more-being.


Characterization of the beta amyloid precursor protein-like gene in the central nervous system of the crab Chasmagnathus. Expression during memory consolidation.
Human β-amyloid, the main component in the neuritic plaques found in patients with Alzheimer's disease, is generated by cleavage of the β-amyloid precursor protein. Beyond the role in pathology, members of this protein family are synaptic proteins and have been associated with synaptogenesis, neuronal plasticity and memory, both in vertebrates and in invertebrates. Consolidation is necessary to convert a short-term labile memory to a long-term and stable form. During consolidation, gene expression and de novo protein synthesis are regulated in order to produce key proteins for the maintenance of plastic changes produced during the acquisition of new information. Here we partially cloned and sequenced the beta-amyloid precursor protein like gene homologue in the crab Chasmagnathus (cappl), showing a 37% of identity with the fruit fly Drosophila melanogaster homologue and 23% with Homo sapiens but with much higher degree of sequence similarity in certain regions. We observed a wide distribution of cappl mRNA in the nervous system as well as in muscle and gills. The protein localized in all tissues analyzed with the exception of muscle. Immunofluorescence revealed localization of cAPPL in associative and sensory brain areas. We studied gene and protein expression during long-term memory consolidation using a well characterized memory model: the context-signal associative memory in this crab species. mRNA levels varied at different time points during long-term memory consolidation and correlated with cAPPL protein levels cAPPL mRNA and protein is widely distributed in the central nervous system of the crab and the time course of expression suggests a role of cAPPL during long-term memory formation.


A brief anti-stigma intervention for Chinese immigrant caregivers of individuals with psychosis: adaptation and initial findings.
Mental illness stigma has adverse effects on both the caregivers' psychological well-being and the effectiveness of care that consumers receive. While anti-stigma interventions for family caregivers from Western settings have recently shown efficacy, these interventions may not be equally applicable across culturally diverse groups. Specifically, Chinese immigrant caregivers experience heightened internalized stigma, which predisposes the adoption of harmful coping strategies and reduced quality of social networks. We present an anti-stigma intervention based on a peer-family group format, co-led by a clinician and a trained family caregiver, to counter stigma among Chinese immigrants. Data are presented from a brief intervention administered to a pilot sample of 11 Chinese immigrant caregivers that provides: psychoeducation, strategies to counter experienced discrimination, and techniques to resist internalized stigma. Case vignettes illustrate implementation of this intervention, and how the peer-family format via interactive contact counteracts internalized stereotypes, encourages adaptive coping strategies, and reinvigorates social networks. Quantitative results further suggest preliminary efficacy in reducing internalized stigma for caregivers who evidenced at least some prior internalized stigma. This study constitutes an initial but important step towards reducing mental illness stigma among Asian Americans, for whom stigma has played a powerful role in the delay and underuse of treatment.


Discovery and biochemical characterisation of four novel biomarkers for osteoarthritis.
Knee osteoarthritis (OA) is a heterogeneous, complex joint pathology of unknown aetiology. Biomarkers have been widely used to investigate OA but currently available biomarkers lack specificity and sensitivity. Therefore, novel biomarkers are needed to better understand the pathophysiological processes of OA initiation and progression. Surface enhanced laser desorption/ionisation-time of flight-mass spectrometry proteomic technique was used to analyse protein expression levels in 284 serum samples from patients with knee OA classified according to Kellgren and Lawrence (K&L) score (0-4). OA serum samples were also compared to serum samples provided by healthy individuals (negative control subjects; NC; n=36) and rheumatoid arthritis (RA) patients (n=25). Proteins that gave similar signal in all K&L groups of OA patients were ignored, whereas proteins with increased or decreased levels of expression were selected for further studies. Two proteins were found to be expressed at higher levels in sera of OA patients at all four K&L scores compared to NC and RA, and were identified as V65 vitronectin fragment and C3fpeptide. Of the two remaining proteins, one showed increased expression (unknown protein at m/z of 3762) and the other (identified as connective tissue-activating peptide III protein) was decreased in K&L scores >2 subsets compared to NC, RA and K&L scores 0 or 1 subsets. The authors detected four unexpected biomarkers (V65 vitronectin fragment, C3f peptide, CTAP-III and m/z 3762 protein) that could be relevant in the pathophysiological process of OA as having significant correlation with parameters reflecting local inflammation and bone remodelling, as well as decrease in cartilage turnover.


Gout in females: an analysis of 92 patients.
Ninety-two females with gout are reported. The preliminary ARA criteria for acute gout classified 60% of the patients. Forty patients were diagnosed by finding tophi or urate crystals in the synovial fluid, 16 patients had the ARA clinical criteria for gout, and a further 36 patients were considered to have good clinical grounds for gouty arthritis. Classification of the patients was difficult. A subacute pauci-/polyarthritis was the presenting feature in 64 (70%) patients and in 49 (77%) there was no history of a preceding recurrent monoarthritis. Seventy-two patients (78%) were on diuretics. Tophi were usually indolent and showed little surrounding inflammation. 87% of the patients had an associated disease.


The Henry M. Vars Award. The effect of lipid emulsions on reticuloendothelial system function in the injured animal.
Use of intravenous lipid emulsions in trauma and sepsis still remains controversial. In order to examine the impact lipid emulsions have on host defense against bacterial infection during total parenteral nutrition (TPN), 56 male Sprague-Dawley rats underwent jugular cannulation and were randomly divided into three groups, each receiving one of three TPN regimens. All regimens delivered approximately 250 kcal/kg X body weight/day, of which 12.5 g were as amino acids. Group 1 received 100% of the nonprotein calories as glucose (AA + G). Group 2 was given 50% of the nonprotein calories as a longchain triglyceride emulsion (100% LCT). Group 3 received 50% of nonprotein calories as a mixed lipid system, composed of medium- and long-chain triglycerides (75% MCT/25% LCT). After 24 hr on intravenous nutrition, all animals received bilateral septic femur fractures and were continued on TPN for 3 days. On the last day, the level of bacteremia and the in vivo response to an intravenous challenge of 59Fe-labeled Escherichia coli were examined. Three days following the septic injury, animals given MCT as part of their lipid calories were not bacteremic, whereas the other groups had greater than 10(2) cfu/ml of blood. Animals receiving TPN with MCT sequestered a greater percentage of exogenously administered bacteria in the liver and sequestered less in the lung compared to animals given 100% LCT (p less than 0.05). From these data, we conclude that parenteral nutrition formulas where LCT has been partially replaced with MCT may better support host bactericidal capacity than similar regimens comprised of LCT as the sole lipid source.


Craniofacial anomalies in the Upper Missouri River over a millennium: archeological and clinical evidence.
Congenital facial clefting occurs more often in Native Americans from the Upper Missouri River Basin (UMRB) than it does in the general population. However, no facial clefts were seen in 3,750 ancient UMRB skeletons. Very few reports concerning defective palate crania are in the literature of paleopathology. Findings regarding craniofacial anomalies in today's native Americans in the UMRB are presented briefly and compared to those in skeletons from this region. There is a marked difference between the frequency of anomalies which occurred in the past and those which are present today. Although the people sampled here were from many cultures and lived during different time periods, encompassing over a millenium, the fundamental denominator was a common geographic location. Reasons for the differences between the past and the present are advanced. It may be possible to estimate the frequency of anomalies which have not been found in archeological specimens but which are present today. By comparing data concerning "occult" congenital anomalies of the past with those of the present, the actual prevalence of past cranio-facial anomalies may be estimated through careful extrapolation.


Phenotypic mixing during coinfection of cells with two strains of human rotavirus.
Coinfection of MA-104 cells with serotype 1 (Wa strain) and serotype 3 (P strain) human rotaviruses resulted in progeny viruses that were phenotypically mixed in their major outer-shell structural-protein VP7 and in the genome segment that encodes this protein (segment 9). Segments from the Wa virus predominated in these progeny whether they were of parental or reassortant genotype. Neutralization with monoclonal antibodies specific for VP7 proteins of the coinfecting viruses caused an alteration in genomic distribution favoring the strain heterologous to the neutralizing monoclonal antibody. Because the percentage of change in distribution of segment 9 was similar to that of the other combined segments, there appeared to be no greater association between VP7 and segment 9 than with other segments of the homologous virus during encapsulation. From these results, it was calculated that the progeny of coinfection with P segment 9 were 77.4% mosaic structures and 14.8% pseudotypes; progeny of coinfection with Wa segment 9 were 40.2% mosaic structures and 1.3% pseudotypes. Similar determinations were made for the reassortant progeny alone.


Identification of the mouse low-salt-eluting single-stranded DNA-binding protein as a mammalian lactate dehydrogenase-A isoenzyme.
A 36,000-Mr protein purified from mouse myeloma on the basis of selective binding to a single-stranded DNA (ssDNA)-cellulose column has been identified as the lactate dehydrogenase A (LDH-A) subunit. A homogeneous preparation of this mouse myeloma ssDNA-binding protein, termed the 'low-salt-eluting protein', was found to possess LDH activity, and rabbit antiserum prepared against this protein was shown to cross-react with purified 36,000-Mr LDH-A subunits from mouse and bovine sources. In addition, bovine and human LHD-A4 isoenzymes were shown to be capable of binding ssDNA. These enzymic and immunological identities with LDH-A were not observed with purified helix-destabilizing protein 1 from mouse myeloma. A model for ssDNA-LDH binding is discussed.


Evaluation of aortic valve stenosis using cardiovascular magnetic resonance: comparison of an original semiautomated analysis of phase-contrast cardiovascular magnetic resonance with Doppler echocardiography.
Accurate quantification of aortic valve stenosis (AVS) is needed for relevant management decisions. However, transthoracic Doppler echocardiography (TTE) remains inconclusive in a significant number of patients. Previous studies demonstrated the usefulness of phase-contrast cardiovascular magnetic resonance (PC-CMR) in noninvasive AVS evaluation. We hypothesized that semiautomated analysis of aortic hemodynamics from PC-CMR might provide reproducible and accurate evaluation of aortic valve area (AVA), aortic velocities, and gradients in agreement with TTE. We studied 53 AVS patients (AVA(TTE)=0.87±0.44 cm(2)) and 21 controls (AVA(TTE)=2.96±0.59 cm(2)) who had TTE and PC-CMR of aortic valve and left ventricular outflow tract on the same day. PC-CMR data analysis included left ventricular outflow tract and aortic valve segmentation, and extraction of velocities, gradients, and flow rates. Three AVA measures were performed: AVA(CMR1) based on Hakki formula, AVA(CMR2) based on continuity equation, AVA(CMR3) simplified continuity equation=left ventricular outflow tract peak flow rate/aortic peak velocity. Our analysis was reproducible, as reflected by low interoperator variability (<4.56±4.40%). Comparison of PC-CMR and TTE aortic peak velocities and mean gradients resulted in good agreement (r=0.92 with mean bias=-29±62 cm/s and r=0.86 with mean bias=-12±15 mm Hg, respectively). Although good agreement was found between TTE and continuity equation-based CMR-AVA (r>0.94 and mean bias=-0.01±0.38 cm(2) for AVA(CMR2), -0.09±0.28 cm(2) for AVA(CMR3)), AVA(CMR1) values were lower than AVA(TTE) especially for higher AVA (mean bias=-0.45±0.52 cm(2)). Besides, ability of PC-CMR to detect severe AVS, defined by TTE, provided the best results for continuity equation-based methods (accuracy >94%). Our PC-CMR semiautomated AVS evaluation provided reproducible measurements that accurately detected severe AVS and were in good agreement with TTE.


NeuralPolish: a novel Nanopore polishing method based on alignment matrix construction and orthogonal Bi-GRU Networks.
Oxford Nanopore sequencing producing long reads at low cost has made many breakthroughs in genomics studies. However, the large number of errors in Nanopore genome assembly affect the accuracy of genome analysis. Polishing is a procedure to correct the errors in genome assembly and can improve the reliability of the downstream analysis. However, the performances of the existing polishing methods are still not satisfactory. We developed a novel polishing method, NeuralPolish, to correct the errors in assemblies based on alignment matrix construction and orthogonal Bi-GRU networks. In this method, we designed an alignment feature matrix for representing read-to-assembly alignment. Each row of the matrix represents a read, and each column represents the aligned bases at each position of the contig. In the network architecture, a bi-directional GRU network is used to extract the sequence information inside each read by processing the alignment matrix row by row. After that, the feature matrix is processed by another bi-directional GRU network column by column to calculate the probability distribution. Finally, a CTC decoder generates a polished sequence with a greedy algorithm. We used five real datasets and three assembly tools including Wtdbg2, Flye and Canu for testing, and compared the results of different polishing methods including NeuralPolish, Racon, MarginPolish, HELEN and Medaka. Comprehensive experiments demonstrate that NeuralPolish achieves more accurate assembly with fewer errors than other polishing methods and can improve the accuracy of assembly obtained by different assemblers. https://github.com/huangnengCSU/NeuralPolish.git. Supplementary data are available at Bioinformatics online.


Rotation of the eyes (not the head) potentiates the postauricular muscle response.
The authors investigated how eye and head rotation modulate the human postauricular muscle response (PAMR), to determine the optimal strategy for potentiating the PAMR, or minimizing it to reduce contamination of small neurogenic responses. The authors recorded the PAMR evoked by binaural bipolar clicks (50 dB SL, 360 µsec per phase with 53-msec interval) from behind the right ear of 12 normally hearing adults, and attempted to enhance it with (a) voluntary ear contraction alone, (b) head rotation alone (with the eyes forward-directed and tracking a target attached to the head), or (c) by lateral eye movement alone (toward the right measurement side, with the head facing forward). When the head alone was rotated with eyes fixed relative to the head, the PAMR increased only slightly in some subjects, as did the ongoing electromyography (EMG) (probably due to EMG activity from nearby neck muscles). On returning the head to the forward control position, the PAMR dropped rapidly to control amplitudes. When the eyes alone were rotated, both the EMG and the PAMR increased markedly in most subjects, and returning the eyes to their control position produced a gradual return to control amplitudes. Voluntary PAM contraction (in those subjects who could accomplish it) increased the EMG tone and the PAMR amplitude concomitantly, with vigorous voluntary PAM contraction saturating the PAMR but not the EMG. Head rotation alone was not effective in potentiating the PAMR when lateral eye movement relative to the head was avoided during the head rotation maneuver. When lateral eye movement was controlled appropriately, the PAMR could be potentiated reliably, or reliably avoided when recording smaller neurogenic responses. If head rotation was used to optimize the PAMR without explicit control of eye movement, a false impression of variability was produced.


A comparison of the risk of postoperative recurrence between African-American and Caucasian patients with Crohn's disease.
Many patients with Crohn's disease will develop complications that require surgery. Recurrence after surgery is common. To assess racial differences in postoperative recurrence between African-Americans and Caucasians. Medical records of Crohn's disease patients who underwent surgery (ileal, colonic, or ileocolonic resection) between June 2014 and June 2016 were reviewed. The primary endpoints were clinical and endoscopic remission at 6-12 months after a Crohn's disease surgery. Secondary outcomes included biological and histologic remission. Risks of recurrence were assessed by univariate, multivariate, and propensity score-matched analysis. Thirty-six African-American and 167 Caucasian patients with Crohn's disease were included for analysis. There was no difference in disease location, disease behaviour, type of surgery performed, and pre- or postoperative medication use between the two groups. The rate of endoscopic remission did not differ between African-American and Caucasian patients (50% vs 42%, P = 0.76), and race did not influence the risk of endoscopic recurrence on univariate, multivariate, or propensity score-matched analysis. The rate of clinical remission was significantly lower in African-American patients compared to Caucasian patients (36% vs. 63%, P = 0.008). African-American race was significantly associated with clinical recurrence on univariate (odds ratio (OR) 6.76, 95% CI 1.50-30.40; P = 0.01), multivariate (OR 5.02, 95% CI 1.60-15.80; P = 0.006), and propensity-matched analysis (68% vs. 32% in Caucasians, P = 0.005). Rates of biologic and histologic remission were similar between the two groups on all analyses. We found that African-American patients with Crohn's disease have a similar degree of objective measures of mucosal inflammation after surgery including endoscopic recurrence as compared to Caucasian patients. However, African-American race was significantly associated with clinical recurrence, suggesting the presence of ethnic variation in postoperative presentation in Crohn's disease.


Acute acalculous cholecystitis associated with severe EBV hepatitis in an immunocompetent child.
Acute acalculous cholecystitis (AAC) is an inflammation of the gallbladder in the absence of demonstrated stones, which is rarely seen in paediatric population. The diagnosis is accomplished mainly through abdominal ultrasonography in the appropriate but usually non-specific clinical picture. Complicated cases need surgical intervention; the medical management is mainly constituted by supportive and antibiotic therapy, as most AAC are observed in the setting of systemic bacterial or parasitic infections. However, AAC has been rarely reported in association with Epstein-Barr virus (EBV) infection, where the gastrointestinal involvement is often mild and thus unrecognised. We report a case of EBV-related AAC associated with unusually severe hepatitis in an immunocompetent and otherwise healthy patient. We describe its benign clinical course, despite the serious liver impairment, by a medical management characterised by the prompt discontinuation of broad-spectrum antibiotics, as soon as EBV aetiology is ascertained, and by the appropriate analgesia and fluid resuscitation.


Acceptance of COVID-19 Vaccine Booster Doses Using the Health Belief Model: A Cross-Sectional Study in Low-Middle- and High-Income Countries of the East Mediterranean Region.
Coronavirus disease (COVID-19) booster doses decrease infection transmission and disease severity. This study aimed to assess the acceptance of COVID-19 vaccine booster doses in low, middle, and high-income countries of the East Mediterranean Region (EMR) and its determinants using the health belief model (HBM). In addition, we aimed to identify the causes of booster dose rejection and the main source of information about vaccination. Using the snowball and convince sampling technique, a bilingual, self-administered, anonymous questionnaire was used to collect the data from 14 EMR countries through different social media platforms. Logistic regression analysis was used to estimate the key determinants that predict vaccination acceptance among respondents. Overall, 2327 participants responded to the questionnaire. In total, 1468 received compulsory doses of vaccination. Of them, 739 (50.3%) received booster doses and 387 (26.4%) were willing to get the COVID-19 vaccine booster doses. Vaccine booster dose acceptance rates in low, middle, and high-income countries were 73.4%, 67.9%, and 83.0%, respectively (p < 0.001). Participants who reported reliance on information about the COVID-19 vaccination from the Ministry of Health websites were more willing to accept booster doses (79.3% vs. 66.6%, p < 0.001). The leading causes behind booster dose rejection were the beliefs that booster doses have no benefit (48.35%) and have severe side effects (25.6%). Determinants of booster dose acceptance were age (odds ratio (OR) = 1.02, 95% confidence interval (CI): 1.01-1.03, p = 0.002), information provided by the Ministry of Health (OR = 3.40, 95% CI: 1.79-6.49, p = 0.015), perceived susceptibility to COVID-19 infection (OR = 1.88, 95% CI: 1.21-2.93, p = 0.005), perceived severity of COVID-19 (OR = 2.08, 95% CI: 137-3.16, p = 0.001), and perceived risk of side effects (OR = 0.25, 95% CI: 0.19-0.34, p < 0.001). Booster dose acceptance in EMR is relatively high. Interventions based on HBM may provide useful directions for policymakers to enhance the population's acceptance of booster vaccination.


The role of bone scintigraphy in detecting child abuse.
This review of diagnostic imaging in cases of suspected child abuse characterizes the significant differences between bone scintigraphy and x-ray evaluation, describes the advantages and disadvantages of each modality, postulates on the specific mechanisms of injury that produce the characteristic scintigraphic findings, and emphasizes the influences that scintigraphic studies have on the medical, social, and legal aspects of child abuse. The major advantages of bone scintigraphy are its increased sensitivity (25% to 50%) in detecting evidence of soft tissue as well as bone trauma in child abuse. Furthermore, it is postulated that the specific mechanisms of inflicting the trauma relate to the patient's size and are characterized by bone scintigraphy. During fits of anger or frustration, the perpetrator of child abuse grasps the small infant or child by the thorax during the shaking activity. This produces characteristic rib injuries. The older and heavier child is more likely to be grabbed by the extremities, which produces periosteal injuries manifested as characteristic abnormal localizations in the diaphyses of the extremities. The roentgenograms of these injuries are frequently normal. The importance of bone scintigraphy is its complementary nature in defining and characterizing the extent and severity of trauma from child abuse. Such findings have direct bearing on the medical, social, and legal outcomes for the abused child. The quality of scintigraphic imaging is important, requiring the use of magnification techniques in the infant. The interpretation of the scintigraphic images depends on an understanding of the mechanisms by which the radionuclide localizes in bone. The same traumatic incident can lead to decreased, normal, or increased localization at the trauma site. Radionuclide scintigraphy is a complementary rather than competitive imaging modality to X-ray evaluation in the diagnosis and management of physical child abuse.


Amazonian malaria vector anopheline relationships interpreted from ITS2 rDNA sequences.
Species identification of anopheline mosquitoes (Diptera: Culicidae) can be problematic because many of them belong to complexes of morphologically similar species, often with contrasted ecology, behaviour and vectorial importance. The application of DNA-based diagnostics has proved to be useful for distinguishing between such species. We determined ribosomal DNA sequences of the second internal transcribed spacer (ITS2) from samples of 16 species of Anopheles captured in the Amazon Basin, Brazil. Length of the ITS2 varied from 323 to 410 base pairs, with GC content ranging from 50.7% to 66.5% and sequence identity from 25% to 99% between species. Maximum-likelihood paup analysis separated two distinct groups of species conforming with the recognized subgenera Anopheles (represented by eiseni, mattogrossensis, mediopunctatus and peryassui) and Nyssorhynchus (represented by 12 spp.). For the latter group, the neighbour-joining tree generated from rDNA sequence ITS2 relationships is compatible with the morphological taxonomic key established for these Amazonian species: albitarsis, aquasalis, benarrochi, braziliensis, darlingi, deaneorum, dunhami, evansae, nuneztovari, oswaldoi, rangeli and triannulatus. These ITS2 sequence data proved to be a useful tool for species identification and, potentially, to solve taxonomic problems.


Parenting programs for women with mental illness who have young children: a review.
To provide an overview of the literature relevant to, and describing, parenting programs for women with mental illness who have young children. A literature search was undertaken, including MEDLINE, PsycINFO, CINAHL, Cochrane Database of Systematic Reviews and EMBASE: Psychiatry. Searches were limited to English journals and books and to the last five years in the first instance, with earlier literature considered where appropriate. Maternal mental illness can impact negatively on a child's life, especially where an insecure attachment is formed between mother and baby during the important early developmental years. The potential sequelae of maternal mental illness for children include impaired cognitive development, behavioural difficulties and increased risk of psychiatric disorder. Effective parenting skills are suggested to be a protective factor against these sequelae. However, the effects of parenting programs for women with mental illness have not been empirically tested, so that the potential long-term benefits of such interventions are not known. Parenting skills training for women with mental illness may be a useful selective preventive intervention. It is unlikely generic programs will be suitable. Rather, interventions for women with a mental illness will need to address the commonly experienced parenting problems as well as the more specific needs of women with mental illness.


An interdisciplinary meta-analysis of the potential antecedents, correlates, and consequences of protégé perceptions of mentoring.
This meta-analysis summarized youth, academic, and workplace research on the potential antecedents (demographics, human capital, and relationship attributes), correlates (interaction frequency, relationship length, performance, motivation, and social capital), and consequences (attitudinal, behavioral, career-related, and health-related outcomes) of protégé perceptions of instrumental support, psychosocial support, and relationship quality to the mentor or to the relationship. A total of 173 meta-analytic correlations were computed based on data from 173 samples and a combined N of 40,737. Among antecedents, positive protégé perceptions were most strongly associated with greater similarity in attitudes, values, beliefs, and personality with their mentors (ρ ranged from .38 to .59). Among correlates, protégé perceptions of greater instrumental support (ρ = .35) and relationship quality (ρ = .54) were most strongly associated with social capital while protégé perceptions of greater psychosocial support were most strongly associated with interaction frequency (ρ = .25). Among consequences, protégé perceptions of greater instrumental support (ρ = .36) and relationship quality (ρ = .38) were most strongly associated with situational satisfaction while protégé perceptions of psychosocial support were most highly associated with sense of affiliation (ρ = .41). Comparisons between academic and workplace mentoring generally revealed differences in magnitude, rather than direction, of the obtained effects. The results should be interpreted in light of the methodological limitations (primarily cross-sectional designs and single-source data) and, in some instances, a small number of primary studies.


Influence of late Quaternary climate change on present patterns of genetic variation in valley oak, Quercus lobata Née.
Phylogeography and ecological niche models (ENMs) suggest that late Quaternary glacial cycles have played a prominent role in shaping present population genetic structure and diversity, but have not applied quantitative methods to dissect the relative contribution of past and present climate vs. other forces. We integrate multilocus phylogeography, climate-based ENMs and multivariate statistical approaches to infer the effects of late Quaternary climate change on contemporary genetic variation of valley oak (Quercus lobata Née). ENMs indicated that valley oak maintained a stable distribution with local migration from the last interglacial period (~120 ka) to the Last Glacial Maximum (~21 ka, LGM) to the present compared with large-scale range shifts for an eastern North American white oak (Quercus alba L.). Coast Range and Sierra Nevada foothill populations diverged in the late Pleistocene before the LGM [104 ka (28-1622)] and have occupied somewhat distinct climate niches, according to ENMs and coalescent analyses of divergence time. In accordance with neutral expectations for stable populations, nuclear microsatellite diversity positively correlated with niche stability from the LGM to present. Most strikingly, nuclear and chloroplast microsatellite variation significantly correlated with LGM climate, even after controlling for associations with geographic location and present climate using partial redundancy analyses. Variance partitioning showed that LGM climate uniquely explains a similar proportion of genetic variance as present climate (16% vs. 11-18%), and together, past and present climate explains more than geography (19%). Climate can influence local expansion-contraction dynamics, flowering phenology and thus gene flow, and/or impose selective pressures. These results highlight the lingering effect of past climate on genetic variation in species with stable distributions.


DNA taxonomy in morphologically plastic taxa: algorithmic species delimitation in the Boodlea complex (Chlorophyta: Cladophorales).
DNA-based taxonomy provides a convenient and reliable tool for species delimitation, especially in organisms in which morphological discrimination is difficult or impossible, such as many algal taxa. A group with a long history of confusing species circumscriptions is the morphologically plastic Boodlea complex, comprising the marine green algal genera Boodlea, Cladophoropsis, Phyllodictyon and Struveopsis. In this study, we elucidate species boundaries in the Boodlea complex by analysing nrDNA internal transcribed spacer sequences from 175 specimens collected from a wide geographical range. Algorithmic methods of sequence-based species delineation were applied, including statistical parsimony network analysis, and a maximum likelihood approach that uses a mixed Yule-coalescent model and detects species boundaries based on differences in branching rates at the level of species and populations. Sequence analyses resulted in the recognition of 13 phylogenetic species, although we failed to detect sharp species boundaries, possibly as a result of incomplete reproductive isolation. We found considerable conflict between traditional and phylogenetic species definitions. Identical morphological forms were distributed in different clades (cryptic diversity), and at the same time most of the phylogenetic species contained a mixture of different morphologies (indicating intraspecific morphological variation). Sampling outside the morphological range of the Boodlea complex revealed that the enigmatic, sponge-associated Cladophoropsis (Spongocladia) vaucheriiformis, also falls within the Boodlea complex. Given the observed evolutionary complexity and nomenclatural problems associated with establishing a Linnaean taxonomy for this group, we propose to discard provisionally the misleading morphospecies and genus names, and refer to clade numbers within a single genus, Boodlea.


The choice of targets and ligands for site-specific delivery of nanomedicine to atherosclerosis.
As nanotechnologies advance into clinical medicine, novel methods for applying nanomedicine to cardiovascular diseases are emerging. Extensive research has been undertaken to unlock the complex pathogenesis of atherosclerosis. However, this complexity presents challenges to develop effective imaging and therapeutic modalities for early diagnosis and acute intervention. The choice of ligand-receptor system vastly influences the effectiveness of nanomedicine. This review collates current ligand-receptor systems used in targeting functionalized nanoparticles for diagnosis and treatment of atherosclerosis. Our focus is on the binding affinity and selectivity of ligand-receptor systems, as well as the relative abundance of targets throughout the development and progression of atherosclerosis. Antibody-based targeting systems are currently the most commonly researched due to their high binding affinities when compared with other ligands, such as antibody fragments, peptides, and other small molecules. However, antibodies tend to be immunogenic due to their size. Engineering antibody fragments can address this issue but will compromise their binding affinity. Peptides are promising ligands due to their synthetic flexibility and low production costs. Alongside the aforementioned binding affinity of ligands, the choice of target and its abundance throughout distinct stages of atherosclerosis and thrombosis is relevant to the intended purpose of the nanomedicine. Further studies to investigate the components of atherosclerotic plaques are required as their cellular and molecular profile shifts over time.


Anger and depression management: psychoeducational skill training interventions for women caregivers of a relative with dementia.
This study examines the short-term impact of two theoretically based psychoeducational small group interventions with distressed caregivers, and it also examines the role of specific moderator and mediator variables on caregiver outcomes. Female participants (N = 169) aged 50 and older who were caring for a community-dwelling relative with a dementing illness were randomly assigned to one of three treatment interventions: anger management, depression management, or a wait-list control group. These interventions took place over a 3- to 4-month period. The primary outcomes examined were anger or hostile mood, depressed mood, frequency of use of positive and negative coping strategies, and perceived caregiving self-efficacy. Significant main effects in the expected direction were found for changes in most of these measures. Participants in both anger management and depression management groups had significant reductions in their levels of anger or hostility and depression from Time 1 to Time 2 in comparison to participants in the wait-list control group. Use of positive cognitive coping strategies increased in the anger management group only. Self-efficacy significantly increased for participants in both intervention groups, and it was also demonstrated to function as a mediator of intervention effects. Pretreatment levels of depressive symptoms and anger expression style (Anger Expression-Out) moderated the relative effects of the two interventions on mood and coping. These data are consistent with a growing body of evidence supporting the effectiveness of skills training, in small groups, to improve both the affective states and the type of coping strategies used by caregivers. In addition, this study underscores the need to evaluate key pretreatment variables in order to determine which form of treatment may be more compatible with caregiver characteristics and thus more likely to be beneficial to individuals.


Cation-Deficient Ce-Substituted Perovskite Oxides with Dual-Redox Active Sites for Thermochemical Applications.
Identifying thermodynamically favorable and stable non-stoichiometric metal oxides is of crucial importance for solar thermochemical (STC) fuel production via two-step redox cycles. The performance of a non-stoichiometric metal oxide depends on its thermodynamic properties, oxygen exchange capacity, and its phase stability under high-temperature redox cycling conditions. Perovskite oxides (ABO3-δ) are being considered as attractive alternatives to the state-of-the-art ceria (CeO2-δ) due to their high thermodynamic and structural tunability. However, perovskite oxides often exhibit low entropy change compared to ceria, as they generally have one only redox active site, leading to lower mass-specific fuel yields. Herein, we investigate cation-deficient Ce-substituted perovskite oxides as a new class of potential redox materials combining the advantages of perovskites and ceria. We newly synthesized the (CexSr1-x)0.95Ti0.5Mn0.5O3-δ (x = 0, 0.10, 0.15, and 0.20; CSTM) series, with dual-redox active sites comprising Ce (at the A-site) and Mn (at the B-site). By introducing a cation deficiency (∼5%), CSTM perovskite oxides with both phase purity (x ≤ 0.15) and high-temperature structural stability under STC redox cycling conditions are obtained. Thermodynamic properties are evaluated by measuring oxygen non-stoichiometry in the temperature range T = 700-1400 °C and the oxygen partial pressure range pO2 = 1-10-4 bar. The results demonstrate that CSTM perovskite oxides exhibit a composition-dependent simultaneous increase of enthalpy and entropy change with increasing Ce-substitution. (Ce0.20Sr0.80)0.95Ti0.5Mn0.5O3-δ (CSTM20) showed a combination of large entropy change of ∼141 J (mol-O)-1 K-1 and moderate enthalpy change of ∼238 kJ (mol-O)-1, thereby creating favorable conditions for thermochemical H2O splitting. Furthermore, the oxidation states and local coordination environment around Mn, Ce, and Ti sites in the pristine and reduced CSTM samples were extensively studied using X-ray absorption spectroscopy. The results confirmed that both Ce (at the A-site) and Mn (at the B-site) centers undergo simultaneous reduction during thermochemical redox cycling.


Claudin 4 Is differentially expressed between ovarian cancer subtypes and plays a role in spheroid formation.
Claudin 4 is a cellular adhesion molecule that is frequently overexpressed in ovarian cancer and other epithelial cancers. In this study, we sought to determine whether the expression of claudin 4 is associated with outcome in ovarian cancer patients and may be involved in tumor progression. We examined claudin 4 expression in ovarian cancer tissues and cell lines, as well as by immunohistochemical staining of tissue microarrays (TMAs; n = 500), spheroids present in patients' ascites, and spheroids formed in vitro. Claudin 4 was expressed in nearly 70% of the ovarian cancer tissues examined and was differentially expressed across ovarian cancer subtypes, with the lowest expression in clear cell subtype. No association was found between claudin 4 expression and disease-specific survival in any subtype. Claudin 4 expression was also observed in multicellular spheroids obtained from patients' ascites. Using an in vitro spheroid formation assay, we found that NIH:OVCAR5 cells treated with shRNA against claudin 4 required a longer time to form compact spheroids compared to control NIH:OVCAR5 cells that expressed high levels of claudin 4. The inability of the NIH:OVCAR5 cells treated with claudin 4 shRNA to form compact spheroids was verified by FITC-dextran exclusion. These results demonstrate a role for claudin 4 and tight junctions in spheroid formation and integrity.


Regulatory long non-coding RNAs in root growth and development.
As sessile organisms, plants have evolved sophisticated mechanisms of gene regulation to cope with changing environments. Among them, long non-coding RNAs (lncRNAs) are a class of RNAs regulating gene expression at both transcriptional and post-transcriptional levels. They are highly responsive to environmental cues or developmental processes and are generally involved in fine-tuning plant responses to these signals. Roots, in addition to anchoring the plant to the soil, allow it to absorb the major part of its mineral nutrients and water. Furthermore, roots directly sense environmental constraints such as mineral nutrient availability and abiotic or biotic stresses and dynamically adapt their growth and architecture. Here, we review the role of lncRNAs in the control of root growth and development. In particular, we highlight their action in fine-tuning primary root growth and the development of root lateral organs, such as lateral roots and symbiotic nodules. Lastly, we report their involvement in plant response to stresses and the regulation of nutrient assimilation and homeostasis, two processes leading to the modification of root architecture. LncRNAs could become interesting targets in plant breeding programs to subtly acclimate crops to coming environmental changes.


Blood coagulation profile in Indian patients with pre-eclampsia and eclampsia.
Twelve Indian patients with pre-eclampsia, 15 with eclampsia and 15 with normal pregnancy in the third trimester were investigated. A systemic bleeding diathesis was encountered in two patients with eclampsia and in none with pre-eclampsia; two patients with pre-eclampsia, however, had excessive uterine haemorrhage. Coagulation studies showed statistically significant prolongation of thrombin time, elevation of serum fibrinogen degradation products (FDP) and hypofibrinogenaemia in patients with pre-eclampsia as well as eclampsia. In patients with eclampsia, significant thrombocytopenia also occurred. Euglobulin lysis time showed no significant change in patients with pre-eclampsia and eclampsia. There was no significant difference in the coagulation profile between patients with eclampsia and pre-eclampsia, except for more hypofibrinogenaemia in the former. The laboratory findings suggest the occurrence of intravascular coagulation in patients with pre-eclampsia and eclampsia.


A Gerontologist's Perspective on Cancer Biology and Treatment.
Cancer is largely a disease of older people, and mortality in the United States is increasing. Change in immune surveillance is not the only explanation for these phenomena. Time and specific age-related changes in tissues are other important factors. Some tumors in the elderly are biologically less aggressive in both animal tumor models and in humans. The need for more organized laboratory and clinical evaluation of the causes and effects of cancer in the aged is now being recognized.


Effect of enalapril in subjects with hypertension associated with moderate to severe renal dysfunction.
The purpose of this study was to define the effect of the angiotensin-converting enzyme inhibitor, enalapril maleate, on blood pressure, renal function, protein excretion, and potassium homeostasis in patients with hypertension associated with moderate to severe renal dysfunction. Nine patients, having an initial inulin clearance between 9 and 48 mL/min/1.73 m2, were treated with enalapril monotherapy (n = 6) or enalapril/furosemide (n = 3) combination therapy. Systolic and diastolic blood pressures were well controlled. Supine plasma renin activity was stimulated; the supine plasma aldosterone level was suppressed, with a resultant increase in the serum potassium level. Clinical hyperkalemia was not observed. Glomerular filtration rate, assessed by inulin and creatinine clearances, was not significantly changed. Effective renal plasma flow, assessed by paraaminohippurate clearance was significantly increased, with a resultant decrease in filtration fraction. Importantly, urinary protein excretion was markedly reduced. These results suggest that enalapril therapy produces efferent arteriolar dilitation with preservation of the glomerular filtration rate. Enalapril therapy may also blunt the effects of angiotensin II on transglomerular passage of protein, as demonstrated by reduced proteinuria. These findings suggest that interruption of the renin-angiotensin system in patients with preexisting renal disease may have renal protective effects.


Nephrin forms a complex with adherens junction proteins and CASK in podocytes and in Madin-Darby canine kidney cells expressing nephrin.
Mutations in the NPHS1 gene encoding nephrin lead to congenital nephrotic syndrome of the Finnish type. Nephrin is a key component of the glomerular slit diaphragms between epithelial foot processes, but its role in the pathogenesis of this disease is poorly understood. To further clarify the molecular mechanisms involved we investigated the interactions between nephrin and other components of the foot processes and filtration slits, especially adherens junction proteins, and searched for novel nephrin interacting proteins. Using co-immunoprecipitation and pull-down assays we show here that nephrin forms a multiprotein complex with cadherins and p120 catenin and with three scaffolding proteins, ZO-1, CD2AP, and CASK, in kidney glomeruli and when expressed in Madin-Darby canine kidney cells. CASK was identified as a novel binding partner of nephrin by mass spectrometry and was localized to podocytes in the glomerulus. CASK is a scaffolding protein that participates in maintenance of polarized epithelial cell architecture by linking membrane proteins and signaling molecules to the actin cytoskeleton. Our results support a model whereby the glomerular slit diaphragms are composed of cell adhesion molecules of the immunoglobulin and cadherin superfamilies that are connected to each other and to the actin cytoskeleton and signaling networks via the cytoplasmic scaffolding proteins CASK, CD2AP, and ZO-1.


The actin of muscle and fibroblasts.
The isolation and quantification of an 18-residue peptide from the N-terminal region of chicken actin was used to quantify the amount of actin in acetone-dried powders of chicken breast muscle and chicken-embryo fibroblasts. Either isotope dilution or double labelling can be used for peptide quantification. About 17% of the protein of chicken breast muscle was estimated to be actin. However, only 0.25% of the protein of chicken-embryo fibroblasts was determined to be actin by quantification of this peptide. The actin content of fibroblasts may be low or the amino acid sequences of muscle and fibroblast actin may differ in the N-terminal region. The methodology used can be extended to examine whether other regions of muscle actin sequence are present in fibroblasts or other cell types.


Blood dyscrasias secondary to non-steroidal anti-inflammatory drugs.
Drug reactions may be classified into 2 categories. The first category comprises reactions to the pharmacological properties of the drug which is given either in excessive amounts or to a subject who is highly susceptible to a given pharmacological action (e.g. G6PD-deficient subjects with regard to oxidants and patients with von Willebrand's disease with regard to drugs which inhibit platelet aggregability). The second category concerns reactions caused by a drug-dependent immune mechanism. By far the largest proportion of NSAID-induced side effects belong to the second category. The sensitising potential of a drug is probably connected to its protein-binding capacity. The clinical aspect depends on the type of immune reaction as well as its localisation within the organism. Cellular immunity usually leads to erythematous skin rashes. However, it is possible that some of the haematological side effects may be caused by T-lymphocytes reacting specifically with haematopoietic cells to which a drug adheres. Antibody-mediated immune reactions are more common. Today, we can distinguish 5 different mechanisms: IgE-mediated drug reactions usually lead to eosinophilia, sometimes with eosinophilic infiltrates in the lung. In such cases, patients frequently develop urticarial rashes. In a number of drug-induced cytopenias the underlying mechanism resides in the action of soluble immune complexes on red cells, leucocytes or platelets as in the case of agranulocytosis secondary to medication with pyrazoles. IgG and/or IgM may be implicated in the formation of the immune complexes. In this system, blood cells are affected when incubated with the serum of an allergic subject previously incubated with the offending drug or one of its metabolites. Some drugs or drug metabolites have a strong affinity for certain blood cells to which they become attached. If a patient develops antibodies to these drugs, an antibody interaction with the drug-coated cells can lead to the destruction of the cells. This mechanism may be operative not only in the periphery but also within the bone marrow. In the serological testing, preincubation of the serum with the offending drug will inhibit the reaction of the antibody to drug-coated cells. This mechanism may coexist with the immune complex type of blood cell damage. Today it appears established that patients may develop antibodies the specificity of which depends on a drug as well as on a membrane component of blood cells. The haematological specificity of the immune reaction would then be explained by the autoantigenic constituent of the drug-autoantigen complex.(ABSTRACT TRUNCATED AT 400 WORDS)


Rsu1 contributes to regulation of cell adhesion and spreading by PINCH1-dependent and - independent mechanisms.
Cell adhesion and migration are complex processes that require integrin activation, the formation and dissolution of focal adhesion (FAs), and linkage of actin cytoskeleton to the FAs. The IPP (ILK, PINCH, Parvin) complex regulates FA formation via binding of the adaptor protein ILK to β1 integrin, PINCH and parvin. The signaling protein Rsu1 is linked to the complex via binding PINCH1. The role of Rsu1 and PINCH1 in adhesion and migration was examined in non-transformed mammary epithelial cells. Confocal microscopy revealed that the depletion of either Rsu1 or PINCH1 by siRNA in MCF10A cells decreased the number of focal adhesions and altered the distribution and localization of β1 integrin, vinculin, talin and paxillin without affecting the levels of FA protein expression. This correlated with reduced adhesion, failure to spread or migrate in response to EGF and a loss of actin stress fibers and caveolae. In addition, constitutive phosphorylation of actin regulatory proteins occurred in the absence of PINCH1. The depletion of Rsu1 caused significant reduction in PINCH1 implying that Rsu1 may function by regulating levels of PINCH1. However, while both Rsu1- or PINCH1-depleted cells retained the ability to activate adhesion signaling in response to EGF stimulation, only Rsu1 was required for EGF-induced p38 Map Kinase phosphorylation and ATF2 activation, suggesting an Rsu1 function independent from the IPP complex. Reconstitution of Rsu1-depleted cells with an Rsu1 mutant that does not bind to PINCH1 failed to restore FAs or migration but did promote spreading and constitutive p38 activation. These data show that Rsu1-PINCH1 association with ILK and the IPP complex is required for regulation of adhesion and migration but that Rsu1 has a critical role in linking integrin-induced adhesion to activation of p38 Map kinase signaling and cell spreading. Moreover, it suggests that Rsu1 may regulate p38 signaling from the IPP complex affecting other functions including survival.


Structure and mechanism of monoclonal antibody binding to the junctional epitope of Plasmodium falciparum circumsporozoite protein.
Lasting protection has long been a goal for malaria vaccines. The major surface antigen on Plasmodium falciparum sporozoites, the circumsporozoite protein (PfCSP), has been an attractive target for vaccine development and most protective antibodies studied to date interact with the central NANP repeat region of PfCSP. However, it remains unclear what structural and functional characteristics correlate with better protection by one antibody over another. Binding to the junctional region between the N-terminal domain and central NANP repeats has been proposed to result in superior protection: this region initiates with the only NPDP sequence followed immediately by NANP. Here, we isolated antibodies in Kymab mice immunized with full-length recombinant PfCSP and two protective antibodies were selected for further study with reactivity against the junctional region. X-ray and EM structures of two monoclonal antibodies, mAb667 and mAb668, shed light on their differential affinity and specificity for the junctional region. Importantly, these antibodies also bind to the NANP repeat region with equal or better affinity. A comparison with an NANP-only binding antibody (mAb317) revealed roughly similar but statistically distinct levels of protection against sporozoite challenge in mouse liver burden models, suggesting that junctional antibody protection might relate to the ability to also cross-react with the NANP repeat region. Our findings indicate that additional efforts are necessary to isolate a true junctional antibody with no or much reduced affinity to the NANP region to elucidate the role of the junctional epitope in protection.


Recognition of pseudodementia.
The most common features of cognitive impairment due to pseudodementia are a relatively acute onset, symptoms of six to 12 months duration; past psychiatric history, particularly depressive illness; age over 50; frequent "don't know" as opposed to "near miss" answers; normal electroencephalogram and computed tomographic scan of the brain, and absence of nocturnal worsening. With this profile, or three or four of these clinical features, a carefully monitored, aggressive trial of an antidepressant regimen is justified.