Melanoma Developing from an Intradermal Nevus: Report on Two Patients.
Dear Editor, Approximately 25-33% of cutaneous melanomas arise from nevi (1). Shitara et al. suggested that junctional and compound nevi are more likely give rise to melanoma than intradermal nevi, but this has not been definitively confirmed (2). Based on these results and our own clinical observation on rare malignant transformation in intradermal nevi, we present two patients with melanoma developing from an intradermal nevus. The first patient, a 63-year-old woman, presented with a suspicious lesion in 2017 on the upper back in the form of a dark brown macula juxtapositioned next to the dermal nevus (Figure 1, a). Dermoscopy of a flat part showed a dark-brown reticular, slightly structureless pattern (Figure 1, b). The patient was therefore referred to surgical excision. Histopathology of the elevated part showed aggregates of intradermal nevus cells of normal morphological characteristics. Atypical and irregularly sized melanocytes were observed in the flat part, infiltrating the entire depth of the epidermis and the upper parts of the papillary dermis. The diagnosis of malignant melanoma developing from a dermal nevus was established (Breslow 0.4 mm, pT1A) (Figure 1, c). The second patient, a 71-year-old man, presented in 2018 with a pendular non pigmented intradermal nevus on middle part of the back. The left-hand lateral side of the intradermal nevus showed a brown to dark-brown spot which measured 12 mm (Figure 2, a). A central blue white veil, atypical pigment network, and dots and globules of various sizes and shapes were observed on dermoscopy (Figure 2, b). The base of the nevus showed an asymmetric pigmentation. Because the lesion was highly suspicious of melanoma, an urgent excision was indicated. The histopathology of the elevated part (dermal nevus) showed a regular maturation of the nest of nevus cells in the dermis. The histopathology of the dark-brown macule showed proliferation of atypical melanocytes with well-marked nucleoli throughout the epidermis with the infiltration of the suprabasal epidermal layers and papillary dermis. The lesion was classified as melanoma with a partial regression (Breslow 1.3 mm, pT2A), arising in association with an acquired intradermal nevus (Figure 2, c). Case reports with melanoma developed from a small congenital or acquired dermal nevus are extremely rare in the literature. In all published cases, histopathology revealed a melanoma component situated below or laterally, next to the merging dermal nevus (3) and in one case next to and above the dermal component (4), which is very similar to our cases. In both of our cases, melanoma presented an epidermal component with atypical, large melanocytes next to or above the typical and small intradermal melanocytes of the Unna nevus. Despite the fact that the reported statistical occurrence of malignant transformation of every individual nevus is very low in the elderly population (>60 years of age), 1 in 33,000 (5), we believe our two presented cases show a striking similarity in the melanoma manifesting in the vicinity of a previously existing lesion, indicating nevus-associated melanoma (NAM). This letter presents an interesting finding of two cases, with a form of melanoma (NAM) that is statistically very rare in older patients but occurred twice within the span of a year within the same town and was diagnosed in the same hospital. Intradermal nevi are most commonly considered to be benign skin lesions. However, previous research and our two cases shows that intradermal nevi are not immune to malignant alteration. Based on these results, we suggest a detailed clinical and dermoscopic evaluation of each skin lesion, including intradermal nevi. Flat melanocytic parts in the vicinity of intradermal nevi should always raise suspicion and warrant excision with histopathological evaluation of the lesion so as to allow timely response to any malignant alteration.


Total-Body PET: Maximizing Sensitivity to Create New Opportunities for Clinical Research and Patient Care.
PET is widely considered the most sensitive technique available for noninvasively studying physiology, metabolism, and molecular pathways in the living human being. However, the utility of PET, being a photon-deficient modality, remains constrained by factors including low signal-to-noise ratio, long imaging times, and concerns about radiation dose. Two developments offer the potential to dramatically increase the effective sensitivity of PET. First by increasing the geometric coverage to encompass the entire body, sensitivity can be increased by a factor of about 40 for total-body imaging or a factor of about 4-5 for imaging a single organ such as the brain or heart. The world's first total-body PET/CT scanner is currently under construction to demonstrate how this step change in sensitivity affects the way PET is used both in clinical research and in patient care. Second, there is the future prospect of significant improvements in timing resolution that could lead to further effective sensitivity gains. When combined with total-body PET, this could produce overall sensitivity gains of more than 2 orders of magnitude compared with existing state-of-the-art systems. In this article, we discuss the benefits of increasing body coverage, describe our efforts to develop a first-generation total-body PET/CT scanner, discuss selected application areas for total-body PET, and project the impact of further improvements in time-of-flight PET.


Difference in flowering time can initiate speciation of nocturnally flowering species.
Isolation mechanisms that prevent gene flow between populations prezygotically play important roles in achieving speciation. In flowering plants, the nighttime flowering system provides a mechanism for isolation from diurnally flowering species. Although this system has long been of interest in evolutionary biology, the evolutionary process leading to this system has yet to be elucidated because of the lack of good model species. However, the genetic mechanisms underlying the differences in flowering times and the traits that attract pollinators between a pair of diurnally and nocturnally flowering species have recently been identified in a few cases. This identification enables us to build a realistic model for theoretically studying the evolution of a nocturnally flowering species. In this study, based on previous experimental data, we assumed a model in which two loci control the flowering time and one locus determines a trait that attracts pollinators. Using this model, we evaluated the possibility of the evolution of a nocturnally flowering species from a diurnally flowering ancestor through simulations. We found that a newly emerging nighttime flowering flower exhibited a sufficiently high fitness, and the evolution of a nocturnally flowering species from a diurnally flowering species could be achieved when hybrid viability was intermediate to low, even in a completely sympatric situation. Our results suggest that the difference in flowering time can act as a magic trait that induces both natural selection and assortative mating and would play an important role in speciation between diurnally and nocturnally flowering species pairs.


Neural correlates of metamemory: a comparison of feeling-of-knowing and retrospective confidence judgments.
Metamemory refers to knowledge and monitoring of one's own memory. Metamemory monitoring can be done prospectively with respect to subsequent memory retrieval or retrospectively with respect to previous memory retrieval. In this study, we used fMRI to compare neural activity during prospective feeling-of-knowing and retrospective confidence tasks in order to examine common and distinct mechanisms supporting multiple forms of metamemory monitoring. Both metamemory tasks, compared to non-metamemory tasks, were associated with greater activity in medial prefrontal, medial parietal, and lateral parietal regions, which have previously been implicated in internally directed cognition. Furthermore, compared to non-metamemory tasks, metamemory tasks were associated with less activity in occipital regions, and in lateral inferior frontal and dorsal medial prefrontal regions, which have previously shown involvement in visual processing and stimulus-oriented attention, respectively. Thus, neural activity related to metamemory is characterized by both a shift toward internally directed cognition and away from externally directed cognition. Several regions demonstrated differences in neural activity between feeling-of-knowing and confidence tasks, including fusiform, medial temporal lobe, and medial parietal regions; furthermore, these regions also showed interaction effects between task and the subjective metamemory rating, suggesting that they are sensitive to the information monitored in each particular task. These findings demonstrate both common and distinct neural mechanisms supporting metamemory processes and also serve to elucidate the functional roles of previously characterized brain networks.


Bactericidal properties of human cell-free lymph.
The bactericidal properties of human cell-free lymph have been investigated. Gram-negative and gram-positive bacteria are susceptible to the killing action of lymph fluid. The colony-forming ability of Escherichia coli and Bacillus subtilis was reduced by 3 logs after 20 min of incubation with 10% (vol/vol) lymph. Salmonella and Listeria were less susceptible to killing. The presence of multiple killing factors in lymph showing different specificities for different bacterial cells was demonstrated.


Hymenialdisine: A Marine Natural Product That Acts on Both Osteoblasts and Osteoclasts and Prevents Estrogen-Dependent Bone Loss in Mice.
Excessive osteoclast (OC) activity together with relatively weak osteoblast (OB) function are strongly connected to osteolytic diseases, including osteoporosis, tumor-induced osteolysis, and inflammatory bone erosion. Very few natural products or compounds have been shown to exert therapeutic effects on both OCs and OBs, limiting the potential development of natural compounds for clinical application. Hymenialdisine (HMD) is a marine sponge-derived natural inhibitor of protein kinases with previously reported anti-osteoarthritis and anti-cancer properties. However, the roles of HMD in OCs, OBs, and osteoporosis have not yet been well established. Here, we found that HMD not only suppressed osteoclastogenesis but also promoted OB differentiation. HMD exerted dose-dependent inhibitory effects on RANKL-induced OC formation, bone resorption, and OC-specific gene expression. These strong inhibitory effects were achieved by blocking the NF-κB and MAPK signaling pathways, and NFATc1 expression. In addition, HMD potentially stimulated OB differentiation by activating alkaline phosphatase (ALP) and enhancing OB matrix mineralization. We found that HMD can activate the glycogen synthase kinase 3β (GSK-3β)/β-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway to upregulate Runx-2 expression, the main transcription factor in this pathway. Increased expression of Runx-2 was also correlated with expression of the OB-specific genes Col1a1 and osteocalcin (Ocn). Furthermore, we also evaluated the therapeutic potential of HMD in a female C57BL/6j mouse model of ovariectomy (OVX)-induced systematic bone loss. HMD showed a remarkable ability to prevent decreases in bone volume (BV/TV) and trabecular thickness (Tb.Th). In summary, HMD exerts notable effects in inhibiting OC-related osteolysis and enhancing OB-induced ossification, suggesting the potential application of HMD in osteoporosis treatment. © 2020 American Society for Bone and Mineral Research.


AUDITORY HABITUATION: A TEST OF A CENTRIFUGAL AND A PERIPHERAL THEORY.
Evoked potentials recorded at the cochlear nucleus of unanesthetized cats show that auditory habituation is a process with a rapid onset and a slower rate of dissipation, and that the habituation is a direct function of the rate of stimulation. Neither the middle ear muscles nor the reticular formation appear to participate in this process. It is suggested that auditory habituation might be a function of the interaction of the olivocochlear bundle and some intrinsic property of higher synaptic areas.


The unique contribution of key existential factors to the prediction of psychological well-being of older adults following spousal loss.
This study examined the unique contribution of key existential factors to the prediction of psychological well-being of older adults following spousal loss. A number of measures to assess psychological well-being, sociodemographic standing, social resources, and religious and spiritual resources were administered to a volunteer sample of widows and widowers to test the hypothesis that existential factors such as personal meaning, religiosity, and spirituality are more potent predictors of psychological well-being than are previously hypothesized variables of sociodemographic, social support, and physical factors. A hierarchical regression analysis of the data supported the hypothesis that existential factors are major contributors to psychological well-being of older adults following spousal loss. Findings showed that widowers, compared to widows, scored lower on the measure of psychological well-being. Implications of the findings are discussed for practitioners working with bereaved spouses; suggestions for further research concerning bereavement and psychological well-being are made.


Observing a late folding intermediate of Ubiquitin at atomic resolution by NMR.
The study of intermediates in the protein folding pathway provides a wealth of information about the energy landscape. The intermediates also frequently initiate pathogenic fibril formations. While observing the intermediates is difficult due to their transient nature, extreme conditions can partially unfold the proteins and provide a glimpse of the intermediate states. Here, we observe the high resolution structure of a hydrophobic core mutant of Ubiquitin at an extreme acidic pH by nuclear magnetic resonance (NMR) spectroscopy. In the structure, the native secondary and tertiary structure is conserved for a major part of the protein. However, a long loop between the beta strands β3 and β5 is partially unfolded. The altered structure is supported by fluorescence data and the difference in free energies between the native state and the intermediate is reflected in the denaturant induced melting curves. The unfolded region includes amino acids that are critical for interaction with cofactors as well as for assembly of poly-Ubiquitin chains. The structure at acidic pH resembles a late folding intermediate of Ubiquitin and indicates that upon stabilization of the protein's core, the long loop converges on the core in the final step of the folding process.


[A clinical analysis of 5 patients with infratentorial primary angiitis of central nervous system].
Objective: To explore the clinical characteristics of infratentorial primary angiitis in central nervous system(PACNS). Methods: A total of 5 cases diagnosed as infratentorial PACNS in the neurology department of Navy General Hospital of PLA in 2015 were enrolled in the study. The clinical, imaging and pathological data were collected and analyzed. Results: All the 5 cases were male with the median onset age of thirty-four. Five cases presented with dizziness, two with headache, three with walking unstable, two with facial numbness and one with dysarthria. Rising pressure of cerebrospinal fluid (CSF) (190-245 cmH(2)O, 1 cmH(2)O=0.098 kPa) was found in 4 cases by the lumbar puncture, mildly increased number of leukocyte in 2 cases [(12-28)×10(6)/L], increased CSF protein in 3 cases(540-979 mg/L) and increased IgG index in 3 cases(0.84-1.45). Pons lesions were revealed by magnetic resonance imaging(MRI)in 4 cases, brachium pontis lesions in 2 cases, cerebellum lesions in 2 cases, one with midbrain lesion in 1 case, unilateral lesions in 4 cases and bilateral lesion in 1 case. Different degree of edema and mass effect were shown in all lesions by MRI. Patch like enhancement was found by contrast MRI in 5 cases and meningeal enhancement in 2 cases. Elevation of choline(Cho)peak was found by magnetic resonance spectroscopy(MRS)in 4 cases, reduction of N-acetyl aspartate(NAA) peak in 3 cases, appearance of lactate peak in 1 case and lipid peak in another case. Arterial spin labeling(ASL) was performed in 4 cases and no hyperperfusion was found. Susceptibility weighted imaging(SWI) was performed in 3 cases and microhemorrhage in the lesions was found in 2 cases and normal in 1 case. Magnetic resonance arteriography(MRA) was performed in 1 case and no stenosis was found. Digital subtraction arteriography(DSA) was performed in 1 case and multiple stenosis of the intracranial arteries was showed. Two cases had taken the stereotactic brain biopsy and the histopathologic diagnosis was angiitis. Five cases were treated with methylprednisolone and cyclophosphamide was added on in 1 case. Good prognosis was found in all cases. Conclusions: Infratentorial PACNS mostly attacks middle-aged males. The lesions tend to locate in unilateral pons, brachium pontis, cerebellum and midbrain. Hemorrhage or microhemorrhage in lesions is often found by SWI and no hyperperfusion is shown by ASL, which would be useful to distinguish PACNS from malignant tumors. Given the limitations of brain biopsy in clinical practice, clinical and imaging features would be helpful to diagnose PACNS.


Routine use of PCR-restriction fragment length polymorphism analysis for identification of mycobacteria growing in liquid media.
A PCR-restriction fragment length polymorphism (PCR-RFLP) procedure capable of rapidly identifying 28 species of clinically encountered mycobacteria was evaluated for use in the routine identification of acid-fast isolates growing in BACTEC 12B and 13A liquid media. PCR-RFLP identified 100 of 103 acid-fast isolates recovered from 610 patient specimens submitted for culture during the study. The three isolates unidentifiable by PCR-RFLP produced restriction patterns not included in the PCR-RFLP algorithm and could therefore not be assigned to a species. These isolates were characterized by their morphologic and biochemical characteristics. Two of the isolates were identified as M. terrae complex and M. gordonae. The third isolate could not be definitively identified and could only be characterized as a Mycobacterium sp. most closely resembling M. chelonae. PCR-RFLP identifications agreed with the conventional identifications for 96 of the 100 isolates identified by PCR-RFLP. Subsequent identification of the four discordant isolates by gas chromatography analysis supported the PCR-RFLP identification of each isolate. Amplification products were also obtained from isolates of Streptococcus albus and Rhodococcus equi recovered from patient specimens; however, the restriction patterns of these nonmycobacterial species did not resemble the patterns of any mycobacterial species included in the PCR-RFLP algorithm. PCR-RFLP seems to be a reliable procedure for the routine identification of mycobacteria and has the potential for providing identifications of mycobacterial isolates which are more accurate than conventional identification techniques based on morphologic and biochemical characteristics.


Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis.
Herein, we report on the identification of nonbasic, potent, and highly selective, nitrile-containing cathepsin K (Cat K) inhibitors that are built on our previously identified cyclohexanecarboxamide core structure. Subsequent to our initial investigations, we have found that incorporation of five-membered heterocycles as P2-P3 linkers allowed for the introduction of a methyl sulfone P3-substitutent that was not tolerated in inhibitors containing a six-membered aromatic P2-P3 linker. The combination of a five-membered N-methylpyrazole linker and a methyl sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in our functional bone resorption assay. Issues that arose because of metabolic demethylation of the N-methylpyrazole were addressed through introduction of a 2,2,2-trifluoroethyl substituent. This culminated in the identification of 31 (MK-1256), a potent (Cat K IC 50 = 0.62 nM) and selective (>1100-fold selectivity vs Cat B, L, S, C, H, Z, and V, 110-fold vs Cat F) inhibitor of cathepsin K that is efficacious in a monkey model of osteoporosis.


Secondary infections in dracunculiasis: bacteria and morbidity.
In the course of a study to determine the nature and type of secondary bacterial infection in dracunculiasis. The most common organisms cultured from lesions were Escherichia coli, Enterobacter and Staphylococcus aureus. E. coli and Enterobacter which were found to carry high morbidity were sensitive to Gentamycin, Claforan and Septrin.


[Conservative treatment of hip and knee osteoarthritis: a systematic, step-by-step treatment strategy].
In the Netherlands the current, conservative management of osteoarthritis of the hip and knee is heterogeneous and suboptimal. Existing guidelines only provide indications for certain interventions, but they do not provide recommendations about the sequence of these treatments. A step-by-step treatment strategy has now been developed in addition to the guidelines. Its aim is to optimize and clarify the conservative policy for osteoarthritis. In addition, communication between patients and professionals and between professionals themselves must be encouraged. According to the treatment strategy, relatively advanced interventions are considered only after simpler interventions have had insufficient results. A care booklet has also been developed that contains information for patients about osteoarthritis, treatment options, healthcare professionals and the treatment strategy.


Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation.
Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.


Radial Width of the Lateral Meniscus at the Popliteal Hiatus: Relevance to Saucerization of Discoid Lateral Menisci.
A discoid lateral meniscus (DLM) is a congenital anomaly of the knee in which the lateral meniscus has an "O" shape and contains irregular, abnormal collagenous tissue. A DLM can cause mechanical symptoms and pain. Treatment of a symptomatic DLM is arthroscopic saucerization to reshape the meniscus to a more normal contour. Enough tissue must be removed to eliminate mechanical symptoms but not too much to create instability. The residual width of the meniscus is crucial at the popliteus hiatus because here the peripheral rim is unattached at the capsule. Reports in the literature recommend a residual width of 6 to 8 mm. The purpose of this research was to determine the width of the lateral meniscus at the popliteal hiatus in normal specimens. Our null hypothesis was that a residual width of 6 to 8 mm will be sufficient to approximate normal anatomy. Cross-sectional study; Level of evidence, 3. We made direct measurements of the radial width of the lateral meniscus from the outer rim at the popliteal hiatus to the inner edge in 19 specimens (age, 2-120 months.) We measured one 4-year-old specimen with a bilateral complete DLM. We also measured 39 digital images of specimens (age, 1-132 months) using ImageJ. Finally, we made direct arthroscopic measurements of 8 skeletally mature specimens. The average width of specimens <3 years old was 5.5 mm. The average width of the 10-year-old specimens was 12 mm. The average width of the skeletally mature specimens was 16 mm. A 4-year-old DLM specimen measured 19 mm. We rejected our null hypothesis. Direct measurements suggest that a residual width of 6 to 8 mm is insufficient for children ≥8 years old. A width of at least a full centimeter approximates the normal for 8-year-olds and at least 15 mm for adolescents.


Taurine trials in animal models offer no support for anxiolytic, antidepressant or stimulant effects.
Taurine is a conditionally-essential amino acid that is found in high concentrations in the CNS and is essential for growth and survival of neurons. Taurine had been clinically tested in a number of diseases with variable results. In the context of neuropsychiatry, taurine was found to be altered in some neurological and psychiatric disorders and its levels affected by mood stabilizers and by antidepressants as well as anti-Alzheimer drugs. Taurine is also a common component in energy drinks and it is claimed (without scientific support) to have stimulant properties. The present study was designed to test taurine's effects in animal models of affective and anxiety disorders and to evaluate its properties as a stimulant. Mice were treated with two doses of taurine with sub-chronic or chronic administration (for different experiments) and tested in the open field, the black/white box and the forced swim test. Taurine's possible stimulant effects were also tested in conjunction with amphetamine administration. For the doses and schedules tested, taurine did not have an effect on measures of anxiety- or depression-like behaviors and did not act as a stimulant, neither alone nor in conjunction with amphetamine. In contrast, high dose taurine administration resulted in a transient decrease in activity. We suggest that any effects of taurine on affective-like behavioral measures may be very subtle (if any) and that prudence is recommended in claims regarding taurine activity as a stimulant.


Cyanobacterial anatoxin-a does not induce in vitro developmental neurotoxicity, but changes gene expression patterns in co-exposure with all-trans retinoic acid.
Cyanobacterial blooms are increasing in frequency and intensity globally, and impacting recreational waters as well as waters used for drinking water provisioning. They are sources of bioactive metabolites including retinoids and the neurotoxin anatoxin-a. Here, we investigated the effects of anatoxin-a on a differentiating in vitro human neural stem cell model previously characterised with retinoic acids. Effects on protein and gene expression upon exposure for 9 or 18 days to anatoxin-a alone or in co-exposure with all-trans retinoic acid were evaluated using a panel of neural and glial differentiation biomarkers. Anatoxin-a did not cause distinct developmental neurotoxicity alone, or in co-exposure with retinoic acid. However, in line with its excitotoxicity, in co-exposure with 200 nM all-trans retinoic acid it reduced the differentiation of acetylcholinergic neuron subtypes in the culture at 1000 nM (highest tested concentration). While this could have substantial functional implications for the developing nervous system, there is no indication for developmental neurotoxicity beyond its (excito-)toxicity to acetylcholinergic neurons, which only occurred in co-exposure to all-trans retinoic acid.


Overexpression of Arabidopsis ECERIFERUM1 promotes wax very-long-chain alkane biosynthesis and influences plant response to biotic and abiotic stresses.
Land plant aerial organs are covered by a hydrophobic layer called the cuticle that serves as a waterproof barrier protecting plants against desiccation, ultraviolet radiation, and pathogens. Cuticle consists of a cutin matrix as well as cuticular waxes in which very-long-chain (VLC) alkanes are the major components, representing up to 70% of the total wax content in Arabidopsis (Arabidopsis thaliana) leaves. However, despite its major involvement in cuticle formation, the alkane-forming pathway is still largely unknown. To address this deficiency, we report here the characterization of the Arabidopsis ECERIFERUM1 (CER1) gene predicted to encode an enzyme involved in alkane biosynthesis. Analysis of CER1 expression showed that CER1 is specifically expressed in the epidermis of aerial organs and coexpressed with other genes of the alkane-forming pathway. Modification of CER1 expression in transgenic plants specifically affects VLC alkane biosynthesis: waxes of TDNA insertional mutant alleles are devoid of VLC alkanes and derivatives, whereas CER1 overexpression dramatically increases the production of the odd-carbon-numbered alkanes together with a substantial accumulation of iso-branched alkanes. We also showed that CER1 expression is induced by osmotic stresses and regulated by abscisic acid. Furthermore, CER1-overexpressing plants showed reduced cuticle permeability together with reduced soil water deficit susceptibility. However, CER1 overexpression increased susceptibility to bacterial and fungal pathogens. Taken together, these results demonstrate that CER1 controls alkane biosynthesis and is highly linked to responses to biotic and abiotic stresses.


The Price of Distrust: Trust, Anxious Attachment, Jealousy, and Partner Abuse.
Trust is essential to the development of healthy, secure, and satisfying relationships (Simpson, 2007a). Attachment styles provide a theoretical framework for understanding how individuals respond to partner behaviors that either confirm or violate trust (Hazan & Shaver, 1994). The current research aimed to identify how trust and attachment anxiety might interact to predict different types of jealousy and physical and psychological abuse. We expected that when experiencing lower levels of trust, anxiously attached individuals would report higher levels of both cognitive and behavioral jealousy as well as partner abuse perpetration. Participants in committed romantic relationships (N = 261) completed measures of trust, attachment anxiety and avoidance, jealousy, and physical and psychological partner abuse in a cross-sectional study. Moderation results largely supported the hypotheses: Attachment anxiety moderated the association between trust and jealousy, such that anxious individuals experienced much higher levels of cognitive and behavioral jealousy when reporting lower levels of trust. Moreover, attachment anxiety moderated the association between trust and nonphysical violence. These results suggest that upon experiencing distrust in one's partner, anxiously attached individuals are more likely to become jealous, snoop through a partner's belongings, and become psychologically abusive. The present research illustrates that particularly for anxiously attached individuals, distrust has cascading effects on relationship cognitions and behavior, and this should be a key area of discussion during therapy.


Feasibility of gaining access to women in jail for health interventions.
Female jail populations are comprised of women at high-risk for an array of psychological and physical health problems. Jails offer an opportune site to deliver clinical health interventions to women who often quickly cycle back into the community. In contrast with prison population studies, many investigators have encountered recruitment problems when attempting to engage the jailed population in clinical research. This study addressed the feasibility of recruiting detained women for eligibility for clinical research. Commitments to the Women's Facility at the Rhode Island Department of Corrections were chronicled for 40 months, from February 2004 to June 2007. Research staff, working 8 a.m. to 5 p.m., Monday through Friday, attempted to screen all detained women for a randomized clinical trial. During the 40-month study period, 4,131 individual women had 8,010 commitments to the facility. Staff was able to gain access to nearly 50% of women. Of the inaccessible women, 65% were released in less than 24 hours. In total, 88% of accessed women agreed to be screened for study participation. No significant differences were observed by race/ethnicity or age between women who were screened and those who were not. Clinical research with the female jail population is feasible. The jail setting requires researchers to plan for short-commitment lengths and high rates of recidivism to optimize screening and recruitment in this population.


Molecular Diversity of Neuron Types in the Salamander Amygdala and Implications for Amygdalar Evolution.
The amygdala is a complex brain structure in the vertebrate telencephalon, essential for regulating social behaviors, emotions, and (social) cognition. In contrast to the vast majority of neuron types described in the many nuclei of the mammalian amygdala, little is known about the neuronal diversity in non-mammals, making reconstruction of its evolution particularly difficult. Here, we characterize glutamatergic neuron types in the amygdala of the urodele amphibian Pleurodeles waltl. Our single-cell RNA sequencing data indicate the existence of at least ten distinct types and subtypes of glutamatergic neurons in the salamander amygdala. These neuron types are molecularly distinct from neurons in the ventral pallium (VP), suggesting that the pallial amygdala and the VP are two separate areas in the telencephalon. In situ hybridization for marker genes indicates that amygdalar glutamatergic neuron types are located in three major subdivisions: the lateral amygdala, the medial amygdala, and a newly defined area demarcated by high expression of the transcription factor Sim1. The gene expression profiles of these neuron types suggest similarities with specific neurons in the sauropsid and mammalian amygdala. In particular, we identify Sim1+ and Sim1+ Otp+ expressing neuron types, potentially homologous to the mammalian nucleus of the lateral olfactory tract (NLOT) and to hypothalamic-derived neurons of the medial amygdala, respectively. Taken together, our results reveal a surprising diversity of glutamatergic neuron types in the amygdala of salamanders, despite the anatomical simplicity of their brain. These results offer new insights on the cellular and anatomical complexity of the amygdala in tetrapod ancestors.


A retrospective analysis of sphenoid sinus hypoplasia and agenesis using dental volumetric CT in Turkish individuals.
In adults, sphenoid sinus agenesis is an extremely rare anomaly. The objective of this study was to investigate the prevalence of sphenoid sinus hypoplasia and agenesis using dental volumetric computed tomography (DVCT) in a population of Turkish individuals. DVCT scans in the axial, coronal and sagittal planes of the sphenoid sinus of 384 patients were examined for evidence of sphenoid sinus agenesis and hypoplasia. In the DVCT scans, bilateral agenesis of sphenoid sinus was not seen. Unilateral agenesis of sphenoid sinus was seen in 0.26% of the sample, and sphenoid sinus hypoplasia was seen in 0.52%. Unilateral hypoplasia of the sphenoid sinus was observed in 0.26% of the sample, and bilateral hypoplasia of sphenoid sinus was observed in 0.26%. In this study, we found a low frequency of sphenoid sinus agenesis. Compared with sphenoid sinus agenesis, the frequency of sphenoid sinus hypoplasia was higher. DVCT may be used as a diagnostic tool to investigate the paranasal sinus.


Dysregulated retinoic acid signaling in airway smooth muscle cells in asthma.
Vitamin A deficiency has been shown to exacerbate allergic asthma. Previous studies have postulated that retinoic acid (RA), an active metabolite of vitamin A and high-affinity ligand for RA receptor (RAR), is reduced in airway inflammatory condition and contributes to multiple features of asthma including airway hyperresponsiveness and excessive accumulation of airway smooth muscle (ASM) cells. In this study, we directly quantified RA and examined the molecular basis for reduced RA levels and RA-mediated signaling in lungs and ASM cells obtained from asthmatic donors and in lungs from allergen-challenged mice. Levels of RA and retinol were significantly lower in lung tissues from asthmatic donors and house dust mite (HDM)-challenged mice compared to non-asthmatic human lungs and PBS-challenged mice, respectively. Quantification of mRNA and protein expression revealed dysregulation in the first step of RA biosynthesis consistent with reduced RA including decreased protein expression of retinol dehydrogenase (RDH)-10 and increased protein expression of RDH11 and dehydrogenase/reductase (DHRS)-4 in asthmatic lung. Proteomic profiling of non-asthmatic and asthmatic lungs also showed significant changes in the protein expression of AP-1 targets consistent with increased AP-1 activity. Further, basal RA levels and RA biosynthetic capabilities were decreased in asthmatic human ASM cells. Treatment of human ASM cells with all-trans RA (ATRA) or the RARγ-specific agonist (CD1530) resulted in the inhibition of mitogen-induced cell proliferation and AP-1-dependent transcription. These data suggest that RA metabolism is decreased in asthmatic lung and that enhancing RAR signaling using ATRA or RARγ agonists may mitigate airway remodeling associated with asthma.


The influence of a verbal prompt on school lunch fruit consumption: a pilot study.
This study evaluated an environmental intervention intended to increase consumption of the fruit serving among elementary school children participating in the National School Lunch Program (NSLP). Children's fruit consumption was measured in two schools by observation. In the intervention school, cafeteria workers provided the verbal prompt, "Would you like fruit or juice with your lunch?" as the children stood in line in front of the fruit serving options. The control school had the same fruit and 100% juice options available, but the cafeteria workers did not provide a verbal prompt to take a fruit serving. Two variables were assessed: (1) Did children leave the lunch line with a fruit serving on their trays? and (2) Did they subsequently eat the fruit serving? The average percentage of children who took a fruit serving was 60% in the control school and 90% in the intervention school. In both schools, approximately 80% of children ate the fruit on their tray. As a result, nearly 70% of the children in the intervention school consumed a fruit serving at lunch, while fewer than 40% did so in the control school. A simple verbal prompt appears to have a significant impact on the likelihood that children will take, and subsequently consume, a fruit serving as part of their purchased school lunch. If these findings are replicated, policymakers may consider adding verbal prompts to the serving policy of the NSLP in an effort to increase fruit consumption among school children.


The impact of periconceptional alcohol exposure on fat preference and gene expression in the mesolimbic reward pathway in adult rat offspring.
Alcohol consumption around the time of conception is highly prevalent in Western countries. Exposure to ethanol levels during gestation has been associated with altered development of the mesolimbic reward pathway in rats and increased propensity to addiction, however the effect of exposure only around the time of conception is unknown. The current study investigated the effects of periconceptional alcohol exposure (PC:EtOH) on alcohol and palatable food preferences and gene expression in the ventral tegmental area (VTA) and the nucleus accumbens of the adult offspring. Rats were exposed to a liquid diet containing ethanol (EtOH) (12.5% vol/vol) or a control diet from 4 days before mating until 4 days after mating. PC:EtOH had no effect on alcohol preference in either sex. At 15 months of age, however, male PC:EtOH offspring consumed more high-fat food when compared with male control offspring, but this preference was not observed in females. Expression of the dopamine receptor type 1 (Drd1a) was lower in the VTA of male PC:EtOH offspring compared with their control counterparts. There was no effect of PC:EtOH on mRNA expression of the µ-opioid receptor, tyrosine hydroxylase (Th), dopamine receptor type 2 (Drd2) or dopamine active transporter (Slc6a3). These data support the hypothesis that periconceptional alcohol exposure can alter expression of key components of the mesolimbic reward pathway and heighten the preference of offspring for palatable foods and may therefore increase their propensity towards diet-induced obesity. These results highlight the importance of alcohol avoidance when planning a pregnancy.


Macular thickness after glaucoma filtration surgery.
The aim of present study was to analyze early postoperative changes in the macular area using optical coherence tomography (OCT) after uncomplicated glaucoma filtration surgery. This prospective study included 32 patients (34 eyes) with open-angle glaucoma, which underwent trabeculectomy with or without use of mitomycin C. Exclusion criteria were macular edema, uveitis, age-related macular degeneration, blurred optical media, secondary glaucoma and angle-closure glaucoma. All standard clinical examinations were made before surgery, at the 2nd day, 1 week and 1 month after surgery. Tomography of the macula was performed during every examination using Cirrus HD OCT for the analysis of central subfield thickness. Results show that thickening of the macula was slightly higher 1 week and 1 month after operation in comparison with baseline end 2nd day postoperativelly. There was no significant difference in the change of macular thickness in patients who have used topical prostaglandins compared with those who have used other topical medications. Also, there was no difference in macular changes between patients treated with or without mitomycin C. In conclusion, we found a slight subclinical increase in macular thickness after uncomplicated trabeculectomy, for which we considered that was the result in reduction of intraocular pressure after glaucoma surgery. Macular thickening after glaucoma filtering surgery could be a physiological reaction to the stress of the retina caused by a sudden reduction of intraocular pressure and it is the consequence of altered relationship between capillary pressure and interstitial fluid pressure.


Intracisternal des-acyl ghrelin inhibits food intake and non-nutrient gastric emptying in conscious rats.
Although des-acyl ghrelin is thought of as a non-functional peptide, studies show that it decreases food intake and gastric emptying in mice. However, no studies have examined the effects of centrally administered des-acyl ghrelin on food intake and gastrointestinal transit in rats. We investigated the effects of intracisternal (IC) administration of des-acyl ghrelin on food intake in free-feeding and food-deprived rats, as well as on the gastrointestinal transit in conscious rats. IC injection of des-acyl ghrelin dose-dependently (0.1 and 1.0 nmol/rat) decreased 20-min, 1-h and 2-h cumulative food intake in 16-h food-deprived, but not free-feeding rats, while IC administration of O-n-octanoylated (acylated) ghrelin (1 nmol/rat) increased food intake in both fed and fasted rats. IC-administered des-acyl ghrelin dose-dependently inhibited charcoal semi-liquid gastric emptying (0.01, 0.1, 0.3 and 1.0 nmol/rat) compared to saline-injected controls, but did not affect the geometric center and running percentage of small intestinal transit. However, IC acylated ghrelin enhanced gastric emptying and geometric center of small intestinal transit, but did not change running percentage of small intestinal transit. The studies suggest that IC des-acyl ghrelin decreases food intake in food-deprived rats and inhibits gastric emptying without altering small intestinal transit. These results establish the role of des-acyl ghrelin in regulating food intake as well as gastric emptying.


Changes in real-life practice for hepatocellular carcinoma patients in the Republic of Korea over a 12-year period: A nationwide random sample study.
Comprehensive analyses through nationwide hepatocellular carcinoma (HCC) registries are important to understand health care issues. We assessed changes in real-life practice for HCC over a long time period. The Korean Liver Cancer Association and the Korean Central Cancer Registry jointly established the nationwide cohorts of newly diagnosed HCC patients between 2003 and 2005 and between 2008 and 2014. According to sorafenib reimbursement in the Republic of Korea (January 2011), patients were divided into early (E-Cohort: 2003~2010) and late (L-Cohort: 2011~2014) cohorts. L-Cohort (n = 4776) comprised patients with older age (60.8 vs. 58.3 years), higher proportions of patients with well-preserved liver function (75.6% vs. 68.2%) and non-viral etiologies (28.6% vs. 19.4%), and lower proportion of patients with Barcelona Clinic Liver Cancer [BCLC] 0~A stage (46.2% vs. 53.9%) than E-Cohort (n = 8203) (all p<0.05). Proportions of patients undergoing curative treatments were higher in L-Cohort than in E-Cohort (55.0% vs. 35.1%, 23.2 vs. 11.3%, and 17.3% vs. 9.6% in BCLC 0A, B, and C stages, respectively; all p<0.05). Accordingly, compared with that in E-Cohort, overall survival in L-Cohort significantly improved in patients with BCLC 0~A, B, and C stages (all p<0.05). As first-line treatment, 62.4% underwent locoregional treatments (LRTs), whereas only 9.7% received sorafenib, among BCLC stage C patients in L-Cohort. For the past 12 years, curative treatments became more widely available to BCLC 0~A, B, and C stage patients, generally improving prognosis. Despite sorafenib reimbursement, LRTs remain the mainstay of first-line treatment for BCLC C stage patients.


Psychometric Properties of the Persian Version of Care Dependency Scale in Nursing Homes.
The purpose of the study was to examine the psychometric properties of the Persian version of the Care Dependency Scale (CDS) in nursing homes. Instrument development. The English version of the CDS was translated into Persian. A convenience sample of 140 (100 older people without dementia and 40 patients with dementia) Persian-speaking people were selected from the nursing homes in Ahvaz, Iran. Cronbach's alpha, discriminant validity, and construct validity (exploratory factor analysis) were examined. Exploratory factor analysis indicated that the CDS has two factors, including psychosocial and somatic factors. Discriminant validity showed that the CDS can differentiate patients with dementia from the older adults without dementia. The results of the study showed that the Persian CDS is a reliable and valid scale when used in nursing homes. The Persian version of the CDS can help clinicians and nurses to assess patients' need and the degree of care dependency among older adults in Persian-speaking areas.


Distinct molecular mechanisms involved in carbon catabolite repression of the arabinose regulon in Bacillus subtilis.
The Bacillus subtilis proteins involved in the utilization of L-arabinose are encoded by the araABDLMNPQ-abfA metabolic operon and by the araE/araR divergent unit. Transcription from the ara operon, araE transport gene and araR regulatory gene is induced by L-arabinose and negatively controlled by AraR. Additionally, expression of both the ara operon and the araE gene is regulated at the transcriptional level by glucose repression. Here, by transcriptional fusion analysis in different mutant backgrounds, it is shown that CcpA most probably complexed with HPr-Ser46-P plays the major role in carbon catabolite repression of the ara regulon by glucose and glycerol. Site-directed mutagenesis and deletion analysis indicate that two catabolite responsive elements (cres) present in the ara operon (cre araA and cre araB) and one cre in the araE gene (cre araE) are implicated in this mechanism. Furthermore, cre araA located between the promoter region of the ara operon and the araA gene, and cre araB placed 2 kb downstream within the araB gene are independently functional and both contribute to glucose repression. In Northern blot analysis, in the presence of glucose, a CcpA-dependent transcript consistent with a message stopping at cre araB was detected, suggesting that transcription 'roadblocking' of RNA polymerase elongation is the most likely mechanism operating in this system. Glucose exerts an additional repression of the ara regulon, which requires a functional araR.


Mining influential genes based on deep learning.
Currently, large-scale gene expression profiling has been successfully applied to the discovery of functional connections among diseases, genetic perturbation, and drug action. To address the cost of an ever-expanding gene expression profile, a new, low-cost, high-throughput reduced representation expression profiling method called L1000 was proposed, with which one million profiles were produced. Although a set of ~ 1000 carefully chosen landmark genes that can capture ~ 80% of information from the whole genome has been identified for use in L1000, the robustness of using these landmark genes to infer target genes is not satisfactory. Therefore, more efficient computational methods are still needed to deep mine the influential genes in the genome. Here, we propose a computational framework based on deep learning to mine a subset of genes that can cover more genomic information. Specifically, an AutoEncoder framework is first constructed to learn the non-linear relationship between genes, and then DeepLIFT is applied to calculate gene importance scores. Using this data-driven approach, we have re-obtained a landmark gene set. The result shows that our landmark genes can predict target genes more accurately and robustly than that of L1000 based on two metrics [mean absolute error (MAE) and Pearson correlation coefficient (PCC)]. This reveals that the landmark genes detected by our method contain more genomic information. We believe that our proposed framework is very suitable for the analysis of biological big data to reveal the mysteries of life. Furthermore, the landmark genes inferred from this study can be used for the explosive amplification of gene expression profiles to facilitate research into functional connections.


The use of ECMO in HIV/AIDS with Pneumocystis jirovecii Pneumonia: a case report and review of the literature.
There are few reports of extracorporeal membrane oxygenation (ECMO) therapy for respiratory failure because of Pneumocystis jirovecii pneumonia (PJP) in patients with acquired immunodeficiency syndrome (AIDS). None of the cases reported involvement of immune reconstitution inflammatory syndrome (IRIS), a paradoxical clinical worsening after the initiation of antiretroviral therapy (ART) in ART-naïve patients because of an exaggerated systemic inflammation with cell count recovery. We present a patient with newly diagnosed AIDS and PJP pneumonia that progressed to acute respiratory distress syndrome (ARDS) secondary to probable IRIS for which veno-venous ECMO was initiated. He transitioned to conventional ventilator after 57 days of ECMO therapy. However, he did not survive to hospital discharge. Combined with four previously reported cases of ARDS in human immunodeficiency virus patients secondary to PJP treated with ECMO, three of the five patients survived to ECMO decannulation. Extracorporeal membrane oxygenation is considered an accepted modality for adult patients with respiratory and/or cardiac failure refractory to maximal medical therapy. As ECMO becomes increasingly utilized in clinical practice, there is ongoing controversy regarding the appropriate selection of patients. In the past, contraindications to ECMO included immunocompromised states and conditions with known poor prognosis. The cases herein suggest the indications and contraindications warrant further discussion and research.


Adenosine deaminase activity in peripheral lymphocytes of patients with gynaecologic malignancies.
Peripheral lymphocyte adenosine deaminase (ADA) activity was assessed in a group of 31 patients with gynaecologic malignancies (19 with carcinoma of the portio, 7 with endometrial adenocarcinoma, 3 with ovarian cancer, 1 with adenocarcinoma of the cervix, 1 with liposarcoma myxoide). 30 female subjects, aged 30 to 70 years, were studied as the control group. Lymphocyte ADA activity in the 31 patients ranged from 0 to 7 U/10(7) cells with a mean of 2.3 U/10(7) cells (normal values: range 2-5 U/10(7) cells; mean 2.8 U/10(7) cells). In cases where the enzyme was absent or far below the controls, a faster evolution of the disease was observed. We would point out that lymphocyte ADA activity in the patients under investigations shows a broad range of variability. Our preliminary observations would suggest that lymphocyte ADA assessment in a larger series of cancer patients may add further prognostic informations.


Induced pluripotent stem cells: advances to applications.
Induced pluripotent stem cell (iPS) technology has enriched the armamentarium of regenerative medicine by introducing autologous pluripotent progenitor pools bioengineered from ordinary somatic tissue. Through nuclear reprogramming, patient-specific iPS cells have been derived and validated. Optimizing iPS-based methodology will ensure robust applications across discovery science, offering opportunities for the development of personalized diagnostics and targeted therapeutics. Here, we highlight the process of nuclear reprogramming of somatic tissues that, when forced to ectopically express stemness factors, are converted into bona fide pluripotent stem cells. Bioengineered stem cells acquire the genuine ability to generate replacement tissues for a wide-spectrum of diseased conditions, and have so far demonstrated therapeutic benefit upon transplantation in model systems of sickle cell anemia, Parkinson's disease, hemophilia A, and ischemic heart disease. The field of regenerative medicine is therefore primed to adopt and incorporate iPS cell-based advancements as a next generation stem cell platforms.


Implementation of a Postoperative Outpatient Care Pathway for Delayed Hyponatremia Following Transsphenoidal Surgery.
After transsphenoidal surgery, delayed hyponatremia (DH) is the leading cause of 30-d unplanned hospital readmissions. To determine the impact of a DH care pathway on 30-d readmissions after transsphenoidal surgery. Data from before and after DH care pathway implementation were retrospectively reviewed. Patient demographics and clinical characteristics were compared. Readmission causes, clinical pathway failures, sodium trends, and symptoms were evaluated. Before the DH care pathway implementation, 229 (55%) patients were treated (group 1); afterward, 188 (45%) were treated (group 2). Baseline characteristics were equivalent between groups, except for glucocorticoid supplementation, which was higher in group 2. The incidence of detected DH was significantly lower in group 1 (16/229, 7%) than group 2 (29/188, 15%) (P = .006) likely due to the impact of routine screening in group 2. Ten group 1 patients (4%) were readmitted for hyponatremia and 6 (3%) were managed as outpatients. Eleven group 2 patients (6%) were readmitted and 17 (9%) were managed as outpatients. Readmission rates between groups were similar (P = .49). Patients readmitted with severe hyponatremia experienced symptoms ≥24 h before presentation. The protocol failed to prevent readmission because outpatient management for mild or moderate DH (n = 4) failed, sodium levels precipitously declined after normal screening (n = 3), and severe hyponatremia developed after scheduled screenings were missed (n = 3). Although more DH patients were identified after care pathway implementation, readmission rates were not reduced and clinical outcomes were not changed. Because DH onset timing varies, some patients have highly acute presentation, and most readmitted patients develop symptoms before reaching their sodium nadir, close symptom monitoring may be a reasonable alternative to routine screening.


Acetate is a beneficial nutrient for E. coli at low glycolytic flux.
Acetate, a major by-product of glycolytic metabolism in Escherichia coli and many other microorganisms, has long been considered a toxic waste compound that inhibits microbial growth. This counterproductive auto-inhibition represents a major problem in biotechnology and has puzzled the scientific community for decades. Recent studies have however revealed that acetate is also a co-substrate of glycolytic nutrients and a global regulator of E. coli metabolism and physiology. Here, we used a systems biology strategy to investigate the mutual regulation of glycolytic and acetate metabolism in E. coli. Computational and experimental analyses demonstrate that decreasing the glycolytic flux enhances co-utilization of acetate with glucose. Acetate metabolism thus compensates for the reduction in glycolytic flux and eventually buffers carbon uptake so that acetate, rather than being toxic, actually enhances E. coli growth under these conditions. We validated this mechanism using three orthogonal strategies: chemical inhibition of glucose uptake, glycolytic mutant strains, and alternative substrates with a natively low glycolytic flux. In summary, acetate makes E. coli more robust to glycolytic perturbations and is a valuable nutrient, with a beneficial effect on microbial growth.


Survival benefit of combined curative resection of the stomach (D2 resection) and liver in gastric cancer patients with liver metastases.
The benefit of surgical resection of liver metastases from gastric cancer has not been well established. The aim of this study was to evaluate the rationale for hepatic resection in patients with hepatic metastases from gastric cancer. Among 10 259 patients diagnosed with gastric adenocarcinoma in the Yonsei University Health System from 1995 to 2005, we reviewed the records of 58 patients with liver-only metastases from gastric cancer who underwent gastric resection regardless of hepatic surgery. The overall 1-year, 3-year, and 5-year survival rates of 41 patients who underwent hepatic resection with curative intent were 75.3%, 31.7%, and 20.8%, respectively, and three patients survived >7 years. Of the 41 patients, 22 had complete resection and 19 had palliative resection. Between the curative and palliative resections, survival rates after curative intent were not different. The number of liver metastasis (solitary or multiple) was a marginally significant prognostic factor for survival. Surgery for liver metastases arising from gastric adenocarcinoma is reasonable if complete resection seems feasible after careful preoperative staging, even if complete resection is not actually achieved. Hepatic resection should be considered as an option for gastric cancer patients with hepatic metastases.


The reversible effect of lignocaine on the stimulated metabolic activity of bronchoalveolar lavage cells.
Lignocaine concentrations were measured in the aspirate from a low volume (100 ml) bronchoalveolar lavage (BAL) in twenty patients who had received topical 4% lignocaine as required, and compared to those found in the aspirate from a 180 ml BAL in ten patients who had received 1.5% isotonic lignocaine. The median BAL supernatant lignocaine concentration was significantly lower at 0.14 mM (range 0.07-0.44 mM) in the group who received 1.5% lignocaine, compared to 1.08 mM (range 0.03-7.05 mM) in those given 4% lignocaine (p less than 0.01). The effect of increasing concentrations of lignocaine on BAL neutrophil and pulmonary macrophage metabolic activity, as assessed by latex-stimulated luminol- and lucigenin-amplified chemiluminescence (CL), respectively, in mixed BAL cell populations, were measured following preincubation of "washed" harvested BAL cells with 0.4-8.0 mM lignocaine. There was no demonstrable decline in either cell activity with lignocaine concentrations of up to 2 mM, with dose-dependent inhibition of both above this threshold. Cell viability was unaffected. In a further experiment, the inhibition induced by 8 mM lignocaine on both pulmonary macrophage (lucigenin-amplified CL of harvested BAL cells) and isolated peripheral blood neutrophil metabolic activity was completely reversed by a single "wash", following both 30 and 60 min incubations at 4 degrees C, which was equivalent to resuspending harvested BAL cells in fresh medium after separation from BAL supernatant.(ABSTRACT TRUNCATED AT 250 WORDS)


Importance of distinguishing between asthma and chronic obstructive pulmonary disease in primary care.
To facilitate distinction between asthma and chronic obstructive pulmonary disease (COPD) in day-to-day primary care practice, and provide practical treatment strategies using spirometric cases to outline how to recognize the clinical and spirometric overlap between asthma and COPD. The approaches described here were developed using evidence-based guidelines and the expertise of the authors, including research findings by the authors in the areas of asthma, COPD management, and spirometric testing in primary care. There are patients with clinical or spirometric features of both asthma and COPD. Both asthma and COPD are associated with some degree of inflammation of the respiratory tract, mediated by the increased expression of inflammatory proteins. However, there are clear differences between asthma and COPD in the pattern of inflammation that occurs in the lungs. Diagnostic confusion between COPD and asthma is most likely to arise in older patients with respiratory complaints, particularly against a background that includes cigarette smoke or workplace exposure. Both asthma and COPD are clinical diagnoses based on patient history, symptoms, physical examination findings, and objective measures of lung function. Postbronchodilator spirometry is always needed to confirm a new diagnosis of COPD and should also be performed prebronchodilator for the diagnosis of asthma. However, in many cases, the interpretation of spirometry results is not straightforward. Understanding the nature and extent of the spirometric overlap between asthma and COPD is critical for tailoring a therapeutic strategy that is based on factors that include medical and family history, signs and symptoms, and a clear interpretation of spirometry data. This information will be leveraged differently for individual patients to arrive at the correct clinical diagnosis and to select the most appropriate therapy.


Protein-containing nutrient supplementation following strength training enhances the effect on muscle mass, strength, and bone formation in postmenopausal women.
We evaluated the response of various muscle and bone adaptation parameters with 24 wk of strength training in healthy, early postmenopausal women when a nutrient supplement (protein, carbohydrate, calcium, and vitamin D) or a placebo supplement (a minimum of energy) was ingested immediately following each training session. At inclusion, each woman was randomly and double-blindedly assigned to a nutrient group or a placebo (control) group. Muscle hypertrophy was evaluated from biopsies, MRI, and dual-energy X-ray absorptiometry (DEXA) scans, and muscle strength was determined in a dynamometer. Bone mineral density (BMD) was measured using DEXA scans, and bone turnover was determined from serum osteocalcin and collagen type I cross-linked carboxyl terminal peptide. The nutrient group improved concentric and isokinetic (60 degrees /s) muscle strength from 6 to 24 wk by 9 +/- 3% (P < 0.01), whereas controls showed no change (1 +/- 2%, P > 0.05). Only the nutrient group improved lean body mass (P < 0.05) over the 24 wk. BMD responded similarly at the lumbar spine but changed differently in the two groups at the femoral neck (P < 0.05) [control: 0.943 +/- 0.028 to 0.930 +/- 0.024 g/mm(3) (-1.0 +/- 1.4%); nutrient group: 0.953 +/- 0.051 to 0.978 +/- 0.043 g/mm(3) (3.8 +/- 3.4%)] when adjusted for age, body mass index, and BMD at inclusion. Bone formation displayed an interaction (P < 0.05), mainly caused by increased osteocalcin at 24 wk in the nutrient group. In conclusion, we report that nutrient supplementation results in superior improvements in muscle mass, muscle strength, femoral neck BMD, and bone formation during 24 wk of strength training. The observed differences following such a short intervention emphasize the significance of postexercise nutrient supply on musculoskeletal maintenance.


Long COVID Symptoms in Non-Hospitalised Patients: A Retrospective Study.
The COVID-19 pandemic has presented numerous challenges to healthcare systems. As the number of affected individuals continues to rise, it is crucial to find preventive, diagnostic, and therapeutic approaches. This study aims to describe different COVID-19 sequelae within a Primary Health Care population. A retrospective cohort study was conducted in adults diagnosed with COVID-19 from March 2020 to April 2022, excluding pregnant women, minors, nursing home residents, hospitalizations, and deaths. Data was gathered from surveillance records on the Trace COVID-19® platform, a pre-set original questionnaire (which included the Portuguese version of the World Health Organization's Quality of Life Assessment Instrument), and, if needed, patient electronic health records. Information on sociodemographic and clinical characteristics of acute COVID-19 was collected along with long COVID symptoms. This study included 284 patients, aged 19 to 99 years old. The five most prevalent acute COVID-19 symptoms were fever (50.0%), tiredness (48.2%), myalgias (44.7%), dry cough (37.7%) and odynophagia (36.3%). Symptoms related to the neurological system (23.2%) and tiredness (22.9%) were the most prevalent in long COVID symptoms. Acute tiredness and arthralgia were associated with all long COVID outcomes. The associations between acute COVID-19 symptoms with long COVID outcomes were stronger for anosmia [OR = 5.07, 95% confidence interval (CI) 2.49 - 10.36, p < 0.001] on a neurological chapter, acute tiredness for long lasting tiredness (OR = 4.07, 95% CI 2.07 - 8.02, p = 0.041), fatigue for muscles and/or bones chapter (OR = 7.55, 95% CI 3.06 - 18.66, p < 0.001), tiredness on an endocrine/hormonal chapter (OR = 6.54, 95% CI 2.37 - 18.04, p < 0.001), dyspnea for respiratory symptoms (OR = 5.67, 95% CI 1.92 - 16.74, p = 0.002) and fever for stomach or intestine symptoms (OR = 8.06, 95% CI 2.55 - 25.47, p < 0.001). Almost all quality of life dimensions were negatively associated with the number of long COVID symptoms. A higher number of acute symptoms, as well as the presence of specific COVID-19 symptoms were associated with reported symptoms ≥ 12 weeks after infection. In the studied population, an increased number of symptoms in both acute and long COVID had a significant negative impact on the perception of overall quality of life. The identification of these relationships could provide a new perspective for post-COVID care.


Fbxo41 Promotes Disassembly of Neuronal Primary Cilia.
Neuronal primary cilia are signaling organelles with crucial roles in brain development and disease. Cilia structure is decisive for their signaling capacities but the mechanisms regulating it are poorly understood. We identify Fbxo41 as a novel Skp1/Cullin1/F-box (SCF) E3-ligase complex subunit that targets to neuronal centrioles where its accumulation promotes disassembly of primary cilia, and affects sonic hedgehog signaling, a canonical ciliary pathway. Fbxo41 targeting to centrioles requires its Coiled-coil and F-box domains. Levels of Fbxo41 at the centrioles inversely correlate with neuronal cilia length, and mutations that disrupt Fbxo41 targeting or assembly into SCF-complexes also disturb its function in cilia disassembly and signaling. Fbxo41 dependent cilia disassembly in mitotic and post-mitotic cells requires rearrangements of the actin-cytoskeleton, but requires Aurora A kinase activation only in mitotic cells, highlighting important mechanistical differences controlling cilia size between mitotic and post-mitotic cells. Phorbol esters induce recruitment of overexpressed Fbxo41 to centrioles and cilia disassembly in neurons, but disassembly can also occur in absence of Fbxo41. We propose that Fbxo41 targeting to centrosomes regulates neuronal cilia structure and signaling capacity in addition to Fbxo41-independent pathways controlling cilia size.


New insights into compliance with a mobile phone diary and pedometer use in sedentary women.
The purposes of this study were 1) to determine compliance with a pedometer and mobile phone- based physical activity diary, and 2) to assess concordance between self-reported daily steps recorded and transmitted by a mobile phone and pedometer-measured daily steps in sedentary women. In this 3-week pilot clinical study, 41 sedentary women who met all inclusion criteria were recruited from local communities. We asked the participants to wear a pedometer every day and to report their daily steps using a mobile phone diary each night before retiring. In the first week, women were asked to monitor their daily steps (baseline steps). In the second and third weeks, they were asked to increase their steps by 20% from the previous week. Although the pedometer can automatically store the most recent 41 days' performance, the participants were not informed of this function of the pedometer. Overall compliance was 93.8% with pedometer use and 88.3% with the mobile phone physical activity diary. Bland Altman plots showed that the agreement between self-reported daily steps by mobile phone diary and pedometer-recorded daily steps from week 1 to week 3 was high. The combination of a pedometer and a mobile phone diary may enhance the quality of self-reported data in clinical studies.


Prenatal Exposure to Perfluoroalkyl Substances and Body Fatness in Girls.
Perfluoroalkyl substances (PFASs) are used in surface coatings that resist stains, grease, and water. The association between in utero PFAS exposure and girls' body fatness at age 9 was analyzed in The Avon Longitudinal Study of Parents and Children (UK). Maternal serum [median 15 weeks: interquartile range (IQR) 10 and 28 weeks of gestation] was analyzed for perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoate (PFNA). Body composition was measured by dual X-ray emission absorptiometry, and percent total body fat (%BF) was calculated. Associations between PFASs and body fatness were modeled by multivariable linear regression. Among 359 girls, median (IQR) %BF was 27.5 (IQR 21.7-34.6). Median (IQR) concentrations (all ng/mL) were 3.7 (2.9-4.8) for PFOA, 19.8 (15.0-25.3) for PFOS, 1.6 (1.3-2.2) for PFHxS, and 0.5 (0.4-0.7) for PFNA. Maternal PFAS concentrations were not significantly associated with daughters' total %BF overall. Mothers' educational status modified associations for PFOA and PFOS with %BF (P-interactions: 0.005 and 0.02, respectively). %BF was higher [1.4%; 95% confidence interval (95% CI): 0.3 to 2.5] for each one unit (ng/mL) higher PFOA among girls with mothers in the middle education group, but lower (-0.6%; 95% CI: -1.12 to -0.04) for the corresponding comparison among girls with mothers with the highest education. %BF was lower (-0.2%; 95% CI: -0.3 to -0.1) for each one unit higher PFOS among girls with the most educated mothers. Prenatal exposure to PFOA and PFOS was associated with girls' %BF within some strata of maternal education status. PFHxS and PFNA were not associated with %BF.


Multiple transcripts of a gene for a leucine-rich repeat receptor kinase from morning glory (Ipomoea nil) originate from different TATA boxes in a tissue-specific manner.
TATA boxes are the most common regulatory elements found in the promoters of eukaryotic genes because they are associated with basal transcription initiation by RNA polymerase II. Often only a single TATA element is found in a given promoter, and tissue-, stage- and/or stimulus-specific expression occurs because the TATA box is associated with other cis -acting elements that enhance or repress transcription. We used software tools for gene analysis to assist in locating potential TATA box(es) in an AT-rich region of the promoter of a gene, inrpk1, which codes for a leucine-rich receptor protein kinase in morning glory (Ipomoea nil). Through the use of RT-PCR and various combinations of forward primers bracketing most of the promoter region we were able to define the 5'-ends of transcripts in this region. The region was then targeted for analysis by RNA Ligase-Mediated-5' Rapid Amplification of cDNA Ends (RLM-5' RACE) to identify the transcript initiation site(s). Positioning of initiation sites with respect to TATA boxes identified by gene analysis tools allowed us to identify three operational TATA elements which regulate basal transcription from this gene. Two TATA boxes were responsible for all of the inrpk1 transcripts found in leaves and cotyledons, and about 25-30% of the transcripts in roots. A third TATA box was involved only in expression in roots and accounted for the remaining 50-70% of root transcripts. RNAs expressed from this element lack two potentially functional upstream AUG codons, and may be translated more efficiently than transcripts originating from the other TATA boxes.


The map of dizziness in vestibular schwannoma.
Dizziness is a frequent complaint in patients with vestibular schwannoma (VS). An abnormal vestibulo-ocular reflex (VOR) can explain this dizziness in patients with VS. The video Head impulse test (vHIT) offers a chance to describe specifically the VOR findings in such patients. Retrospective cases series study in a tertiary referral hospital. Fifty consecutive patients with VS were classified in accordance with the morphology of the VOR; gain, covert saccade, and overt saccade were analyzed both in the affected side and in the healthy side. For all patients, caloric tests were performed. All patients were tested before surgery. Caloric response was normal in 31 of 50 patients. The video Head impulse test was abnormal in 45 of 50 patients. For the affected side, low horizontal VOR gain was found in 27 of 50 patients, covert saccade was observed in 37 of 50, and overt saccade was observed in 26 of 50. In the healthy side, vHIT was abnormal in 29 of 50 patients, with a low gain in four of 50, covert saccade in seven of 50, and overt saccade in 23 of 50. In VS, gain for the affected side is not associated with caloric response, but gain for the affected side is associated with gain in the healthy side. Covert and overt saccade for the affected side is associated with gain for the affected side. In the healthy side, overt saccade is associated with low gain for the affected side. Video head impulse test improves the vestibular testing before surgery in patients with VS and should be included in the usual clinical tests for these patients. 4.


Polarization Encoded Color Image Embedded in a Dielectric Metasurface.
Optical metasurfaces have shown unprecedented capabilities in the local manipulation of the light's phase, intensity, and polarization profiles, and represent a new viable technology for applications such as high-density optical storage, holography and display. Here, a novel metasurface platform is demonstrated for simultaneously encoding color and intensity information into the wavelength-dependent polarization profile of a light beam. Unlike typical metasurface devices in which images are encoded by phase or amplitude modulation, the color image here is multiplexed into several sets of polarization profiles, each corresponding to a distinct color, which further allows polarization modulation-induced additive color mixing. This unique approach features the combination of wavelength selectivity and arbitrary polarization control down to a single subwavelength pixel level. The encoding approach for polarization and color may open a new avenue for novel, effective color display elements with fine control over both brightness and contrast, and may have significant impact for high-density data storage, information security, and anticounterfeiting.


Tobacco and cancer awareness program among school children in rural areas of Ratnagiri district of Maharashtra state in India.
Promoting awareness of tobacco and cancer in the community needs multipronged efforts. We performed a study to evaluate whether we could raise awareness about the harmful effects of tobacco, oral and esophageal cancer among school students by providing them health education. Moreover, we also compared the awareness level in students of age group 12 to ≤14 years with the age group >14 to 18 years. We conducted an awareness program in the schools of Ratnagiri district of Maharashtra state. Students aged 12-18 years participated in this study. We provided health education to school students using a standard presentation; the presentation was rich in illustrations depicting the harmful effects of tobacco as well as oral and esophageal cancer's signs, symptoms, diagnosis, treatment, and preventive measures. After the health talk, a questionnaire was circulated. The questions were focused on tobacco, signs, and symptoms of the diseases along with early detection, prevention, and treatment of cancer. A total of 1354 students participated in the program. Totally, 567 (41.9%) students were from 6th to 8th grade (Group A, age group 12 to ≤14) and 787 (58.1%) students were from 9th to 12th standards (Group B, age group >14 to 18). Overall scores were high, ranging from 69% to 98%. Group A scored in the range of 69% to 95%, and Group B scored in the range 72%-98% The difference between the two groups was found to be statistically significant (P-value ≤0.05). A standardized health education program helped to raise awareness about the harmful effects of tobacco and cancer amongst school children. Further studies are needed to evaluate whether educating school children has an impact on community understanding of the disease.


Substrate stiffness modulates cardiac fibroblast activation, senescence, and proinflammatory secretory phenotype.
In vitro cultures of primary cardiac fibroblasts (CFs), the major extracellular matrix (ECM)-producing cells of the heart, are used to determine molecular mechanisms of cardiac fibrosis. However, the supraphysiologic stiffness of tissue culture polystyrene (TCPS) triggers the conversion of CFs into an activated myofibroblast-like state, and serial passage of the cells results in the induction of replicative senescence. These phenotypic switches confound the interpretation of experimental data obtained with cultured CFs. In an attempt to circumvent TCPS-induced activation and senescence of CFs, we used poly(ethylene glycol) (PEG) hydrogels as cell culture platforms with low and high stiffness formulations to mimic healthy and fibrotic hearts, respectively. Low hydrogel stiffness converted activated CFs into a quiescent state with a reduced abundance of α-smooth muscle actin (α-SMA)-containing stress fibers. Unexpectedly, lower substrate stiffness concomitantly augmented CF senescence, marked by elevated senescence-associated β-galactosidase (SA-β-Gal) activity and increased expression of p16 and p21, which are antiproliferative markers of senescence. Using dynamically stiffening hydrogels with phototunable cross-linking capabilities, we demonstrate that premature, substrate-induced CF senescence is partially reversible. RNA-sequencing analysis revealed widespread transcriptional reprogramming of CFs cultured on low-stiffness hydrogels, with a reduction in the expression of profibrotic genes encoding ECM proteins, and an attendant increase in expression of NF-κB-responsive inflammatory genes that typify the senescence-associated secretory phenotype (SASP). Our findings demonstrate that alterations in matrix stiffness profoundly impact CF cell state transitions, and suggest mechanisms by which CFs change phenotype in vivo depending on the stiffness of the myocardial microenvironment in which they reside.NEW & NOTEWORTHY Our findings highlight the advantages and pitfalls associated with culturing cardiac fibroblasts on hydrogels of varying stiffness. The findings also define stiffness-dependent signaling and transcriptional networks in cardiac fibroblasts.


Suppression of distal urinary acidification after recovery from chronic hypocapnia.
This study examined urinary acidification shortly after recovery from chronic hypocapnia induced by hypoxemia. Distal acidification was evaluated by measuring the urinary PCO2 and urine-blood PCO2 difference (U-B PCO2) when blood PCO2 had returned to normal. In posthypocapnic rats, maximal alkalinization of the urine by acute sodium bicarbonate loading failed to increase urine PCO2 and U-B PCO2 to the level of posthypoxemic control rats and normal control rats with comparable blood pH and urine bicarbonate concentration. To test the hypothesis that decreased distal hydrogen ion secretion in posthypocapnic rats resulted from intracellular alkalosis secondary to protracted hypocarbia, posthypocapnic rats were exposed to hypercapnia of brief duration (30 min) and prolonged duration (120 min) in an attempt to restore distal acidification to normal. In posthypocapnic rats, hypercapnia of brief duration was associated with a significant increase in urine PCO2 and a fall in urine pH. Prolonged hypercapnia resulted in a marked increase in urine PCO2 and a further fall in urine pH. At any urinary bicarbonate concentration, however, the urine PCO2 and U-B PCO2 posthypocapnic rats exposed to hypercapnia were still significantly lower than in normal control rats identically subjected to prolonged hypercapnia and with comparable blood PCO2 and blood pH. Our findings indicate that distal acidification after abrupt recovery from chronic hypocapnia is decreased as if the kidneys were still under the influence of sustained hypocapnia. These findings could not be ascribed to extracellular alkalemia but could be explained by postulating that decreased urinary acidification resulted from persistence of cell alkalinity secondary to the accumulation of non-CO2 buffers generated during protracted hypocarbia. Alternatively, factors other than cell pH could mediate the adaptive decrease in distal hydrogen ion secretion of posthypocapnic rats.


A synthetic protein selected for ligand binding affinity mediates ATP hydrolysis.
How primitive enzymes emerged from a primordial pool remains a fundamental unanswered question with important practical implications in synthetic biology. Here we show that a de novo evolved ATP binding protein, selected solely on the basis of its ability to bind ATP, mediates the regiospecific hydrolysis of ATP to ADP when crystallized with 1 equiv of ATP. Structural insights into this reaction were obtained by growing protein crystals under saturating ATP conditions. The resulting crystal structure refined to 1.8 A resolution reveals that this man-made protein binds ATP in an unusual bent conformation that is metal-independent and held in place by a key bridging water molecule. Removal of this interaction using a null mutant results in a variant that binds ATP in a normal linear geometry and is incapable of ATP hydrolysis. Biochemical analysis, including high-resolution mass spectrometry performed on dissolved protein crystals, confirms that the reaction is accelerated in the crystalline environment. This observation suggests that proteins with weak chemical reactivity can emerge from high affinity ligand binding sites and that constrained ligand-binding geometries could have helped to facilitate the emergence of early protein enzymes.


Clinical outcomes of ankle fractures in sub-Saharan Africa: a systematic review.
Ankle fractures may cause disability and socioeconomic challenges, even when managed in a high-resource setting. The outcomes of ankle fractures in sub-Saharan Africa are not widely reported. We present a systematic review of the patient-reported outcomes and complications of patients treated for ankle fractures in sub-Saharan Africa. Medline, Embase, Google Scholar and the Cochrane Central Register of Controlled Trials were searched, utilising MeSH headings and Boolean search strategies. Ten papers were included. Data included patient demographics, surgical and non-surgical management, patient-reported outcome measures and evidence of complications. A total of 555 patients with ankle fractures were included, 471 of whom were followed up (range 6 weeks-73 months). A heterogenous mix of low-quality observational studies and two methodologically poor-quality randomised trials demonstrated mixed outcomes. A preference for surgical management was found within the published studies with 87% of closed fractures being treated operatively. A total of five different outcome scoring systems were used. Most studies included in this review were published by well-resourced organisations and as such are not representative of the actual clinical practice taking place. The literature surrounding the clinical outcomes of ankle fractures in sub-Saharan Africa is sparse. There appears to be a preference for surgical fixation in the published literature and considering the limitations in surgical resources across sub-Saharan Africa this may not be representative of real-life care in the region.


[Validation of the Italian version of the GHAA-9 m questionnaire on patient satisfaction in digestive Endoscopy].
There isn't a validated questionnaire in Italian language to evaluate the quality perceived by the patient in Digestive Endoscopy. validation of the translation of a questionnaire from English to Italian language to measure the level of patient satisfaction. we conducted a prospective study on validation in Italian of a short questionnaire adapted for Endoscopy by the American Society of Gastrointestinal Endoscopy, the GHAA-9m. It's been tested with the technique of the questionnaire/interview on 80 outpatients who underwent in the month of September 2014 to endoscopic examinations of the gastrointestinal tract. The patients were divided into 2 groups of 40 patients: group 1 was administered before the questionnaire and subsequently the interview was conducted, on the contrary on the group 2 was administered before the interview and subsequently the questionnaire. The results of the two groups were compared using the inter-rater agreement. It was also evaluated the internal consistency of the questions. The results show that the instrument is experienced as simple and quick to use for patients. Data analysis allowed us to conclude that the Italian translation is valid and consistent. In the phase of the interview there were some aspects that suggest, in a development of this tool, some changes that could increase the accuracy and informational content. The Italian version of the questionnaire GHAA-9m has good validity, reliability, and shows property valuation comparable to those of the American version and can therefore be used in daily practice Digestive Endoscopy.


Shifting the equilibrium in cancer immunoediting: from tumor tolerance to eradication.
The continual interaction of the immune system with a developing tumor is thought to result in the establishment of a dynamic state of equilibrium. This equilibrium depends on the balance between effector and regulatory T-cell compartments. Whereas regulatory T cells can infiltrate and accumulate within tumors, effector T cells fail to efficiently do so. Furthermore, effector T cells that do infiltrate the tumor become tightly controlled by different regulatory cellular subsets and inhibitory molecules. The outcome of this balance is critical to survival, and whereas in some cases the equilibrium can rapidly result in the elimination of the transformed cells by the immune system, in many other cases the tumor manages to escape immune control. In this review, we discuss relevant work focusing on the establishment of the intratumor balance, the dynamic changes in the populations of effector and regulatory T cells within the tumor, and the role of the tumor vasculature and its activation state in the recruitment of different T-cell subsets. Finally, we also discuss work associated to the manipulation of the immune response to tumors and its impact on the infiltration, accumulation, and function of tumor-reactive lymphocytes within the tumor microenvironment.


Idiopathic bile acid malabsorption--a review of clinical presentation, diagnosis, and response to treatment.
Between 1982 and 1989, the seven day retention of 75SeHCAT was measured in 181 patients with chronic diarrhoea that remained unexplained after full investigation. Altogether 121 of the 181 had a seven day 75SeHCAT retention greater than or equal to 15% and thus had no evidence of abnormal bile acid turnover. Twenty one had a seven day 75SeHCAT retention greater than or equal to 10% but less than 15%. Their clinical features were typical of the irritable bowel syndrome, and none of eight treated with cholestyramine showed symptomatic improvement. Sixteen patients had a seven day retention greater than or equal to 5% and less than 10%, six of whom had improved symptoms after treatment with bile acid chelating agents. The remaining 23 patients had a 75SeHCAT retention of less than 5% at seven days and responded to bile acid chelators. This group had a characteristic illness with intermittent watery diarrhoea, but no constitutional upset. It was not possible to distinguish the patients with bile acid malabsorption exclusively on the basis of the clinical symptoms and investigations, other than 75SeHCAT retention. We conclude that the measurement of 75SeHCAT retention is useful, appropriate, and necessary in patients with unexplained chronic diarrhoea.


Content Analysis and User Characteristics of a Smartphone-Based Online Support Group for People Living with HIV.
Although there is growing interest in mobile applications and online support groups to enhance chronic disease self-management, little is known about their potential impact for people living with HIV (PLWH). We developed an innovative online support group delivered through a community message board (CMB) within a clinic-affiliated smartphone application Positive Links (PL). We analyzed characteristics of posters and nonposters to the CMB and evaluated content posted to the CMB. For this study, 38 HIV-infected patients received cell phones with the PL application that included the opportunity to interact with other users on a CMB. Logistic regressions investigated associations between participant characteristics and posting. CMB messages were downloaded and analyzed qualitatively. 24 participants posted to the CMB; 14 did not. Participants had lower odds of posting if they were white (p = 0.028) and had private insurance (p = 0.003). Participants had higher odds of posting if they had unsuppressed viral loads (p = 0.034). Of the 840 CMB messages over 8 months, 62% had psychosocial content, followed by community chat (29%), and biomedical content (10%). Psychosocial content was most prevalent on this CMB, in contrast to other online forums dominated by informational content. Participants who posted expressed support for each other, appreciation for the community, and a perception that the app played a positive role in their HIV self-management. This CMB on a clinic-affiliated mobile application may reach vulnerable populations, including racial/ethnic minorities and those of lower socioeconomic status, and provide psychosocial support to PLWH.


Interstitial Granulomatous Variant of Scleromyxedema-A Diagnostic Pitfall.
Scleromyxedema is a rare disorder where patients may develop systemic manifestations such as monoclonal gammopathy, inflammatory polyarthritis, and esophageal and neurological dysfunction. Histologically, there may be atypical variants of scleromyxedema showing features resembling interstitial granuloma annulare. We report an unusual case of scleromyxedema with interstitial granulomatous pattern and highlight potential diagnostic pitfalls when encountered with such a variant.


Clinical outcomes after final kissing balloon inflation compared with no final kissing balloon inflation in bifurcation lesions treated with a dedicated coronary bifurcation stent.
We evaluated differences in clinical outcomes between patients who underwent final kissing balloon inflation (FKBI) and patients who did not undergo FKBI in bifurcation treatment using the Tryton Side Branch Stent (Tryton Medical, Durham, North Carolina, USA). Clinical outcomes were defined as target vessel failure (composite of cardiac death, any myocardial infarction and clinically indicated target vessel revascularisation), cardiac death, myocardial infarction (MI), clinically indicated target vessel revascularisation and stent thrombosis. Cumulative event rates were estimated using the Kaplan-Meier method. A multivariable logistic regression analysis was performed to evaluate which factors were potentially associated with FKBI performance. Follow-up data was available in 717 (96%) patients with a median follow-up of 190 days. Cardiac death at 1 year occurred more often in the no-FKBI group (1.7% vs 4.6%, respectively, p=0.017), although this difference was no longer observed after excluding patients presenting with ST segment elevation MI (1.6% vs 3.3%, p=0.133). No significant differences were observed concerning the other clinical outcomes. One-year target vessel failure rates were 10.1% in the no-FKBI group and 9.2% in the FKBI group (p=0.257). Multivariable logistic regression analysis identified renal dysfunction, ST segment elevation MI as percutaneous coronary intervention indication, narrow (<30°) bifurcation angle and certain stent platforms as being independently associated with unsuccessful FKBI. A lower cardiac death rate was observed in patients in whom FKBI was performed compared with a selection of patients in whom FKBI could not be performed, probably explained by an unbalance in the baseline risk profile of the patients. No differences were observed regarding the other clinical outcomes.


Chromosome cohesion decreases in human eggs with advanced maternal age.
Aneuploidy in human eggs increases with maternal age and can result in infertility, miscarriages, and birth defects. The molecular mechanisms leading to aneuploidy, however, are largely unknown especially in the human where eggs are exceedingly rare and precious. We obtained human eggs from subjects ranging from 16.4 to 49.7 years old following in vitro maturation of oocyte-cumulus complexes isolated directly from surgically removed ovarian tissue. A subset of these eggs was used to investigate how age-associated aneuploidy occurs in the human. The inter-kinetochore distance between sister chromatids increased significantly with maternal age, indicating weakened cohesion. Moreover, we observed unpaired sister chromatids from females of advanced age. We conclude that loss of cohesion with increasing maternal age likely contributes to the well-documented increased incidence of aneuploidy.


Insulin biosynthesis in isolated pancreatic islets of fetal and newborn rats.
The effect of glucose and glucose plus glucagon on the incorporation of H-3-L-leucine into proinsulin and insulin was examined in isolated islets of twenty-one-day old fetal and five- and ten-day old newborn rats. Maximal stimulation of (pro-) insulin biosynthesis was achieved with 100 mg. per cent of glucose in isolated islets of twenty-one-day old fetal rats. No additional effect was observed with 300 mg. per cent of glucose. On the other hand, in islets of five- and ten-day old newborn rats the incorporation of H-3-L-leucine into proinsulin and insulin was gradually augmented by glucose up to concentrations of 300 mg. per cent. Addition of glucagon to the various glucose concentrations only enhanced the synthesis of insulin in ten-day old newborn islets, whereas it had no effect on the islets of the younger age groups. The results show a different pattern of insulin biosyntheses in fetal and newborn islets, which may be related to the varied plasma glucose concentrations of the perinatal period.


Processing, secretion, and biological properties of a novel growth factor of the fibroblast growth factor family with oncogenic potential.
We recently reported that the protein encoded in a novel human oncogene isolated from Kaposi sarcoma DNA was a growth factor with significant homology to basic and acidic fibroblast growth factors (FGFs). To study the properties of this growth factor (referred to as K-FGF) and the mechanism by which the K-fgf oncogene transforms cells, we have studied the production and processing of K-FGF in COS-1 cells transfected with a plasmid encoding the K-fgf cDNA. The results show that, unlike basic and acidic FGFs, the K-FGF protein is cleaved after a signal peptide, glycosylated, and efficiently secreted as a mature protein of 176 or 175 amino acids. Inhibition of glycosylation impaired secretion, and the stability of the secreted K-FGF was greatly enhanced by the presence of heparin in the cultured medium. We have used the conditioned medium from transfected COS-1 cells to test K-FGF biological activity. Similar to basic FGF, the K-FGF protein was mitogenic for fibroblasts and endothelial cells and induced the growth of NIH 3T3 mouse cells in serum-free medium. Accordingly, K-fgf-transformed NIH 3T3 cells grew in serum-free medium, consistent with an autocrine mechanism of growth. We have also expressed the protein encoded in the K-fgf protooncogene in COS-1 cells, and it was indistinguishable in its molecular weight, glycosylation, secretion, and biological activity from K-FGF. Taken together, these results suggest that the mechanism of activation of this oncogene is due to overexpression rather than to mutations in the coding sequences.