Metabolic aspects of trans fatty acids.
The consumption of trans isomers of unsaturated fatty acids has been associated withuntoward metabolic effects. Several clinical investigations demonstrated that trans fatty acids increase plasma LDL-cholesterol and lipoprotein (a) and reduce HDL-cholesterol concentrations. These alterations of plasma lipid profiles indicate an atherogenic effect of trans fatty acids. Both in preterm infants and in healthy children aged 1-15 years, we found blood plasma arachidonic acid (C20:4omega-6) levels and the product/substrate ratios of arachidonic acid synthesis (C20:4omega-6/C18:2omega-6) inversely correlated to the level of the principal trans fatty acid, trans octadecaenoic acid (C18:1omega-9/7, trans), which is compatible with a dose-dependent inhibition of arachidonic acid synthesis by trans fatty acids. Moreover, in premature infants trans fatty acids in blood plasma correlated inversely with birth weight in an observational study, indicating that trans fatty acids may impair early human growth. It appears desirable to limit the dietary intake of trans fatty acids. The major dietary sources of trans fatty acids are partially hydrogenated vegetable and fish oils. Refinement of the industrial technology of partial hydrogenation and appropriate food labelling may lead to a considerably decrease of human exposure to trans fatty acids.


HTLV-1: A real pathogen or a runaway guest of a diseased cell?
The human T-cell lymphotropic virus type 1 (HTLV-1) is a deltaretrovirus claimed to be aetiologically linked to the adult T-cell leukaemia/lymphoma (ATLL) and associated myelopathy/tropical spastic paraparesis (HAM/TSP) besides other minor pathologies. HTLV-1 infection is worldwide distributed, despite its heterogeneous prevalence. Environmental factors and host-genetic background are very likely to determine the epidemiological profile of HTLV-1 prevalence and related disease confinement in distinct human ethnic populations and geographical coordinates, which raises the question if the virus is a real pathogen or a runaway well-organized packed genome of a burden host cell near death process. New methodological approaches need to be proposed and applied in order to prove or discard the hypotheses emerged in the present review.


Increased nuclear envelope permeability and Pep4p-dependent degradation of nucleoporins during hydrogen peroxide-induced cell death.
The death of yeast treated with hydrogen peroxide (H(2)O(2)) shares a number of morphological and biochemical features with mammalian apoptosis. In this study, we report that the permeability of yeast nuclear envelopes (NE) increased during H(2)O(2)-induced cell death. Similar phenomena have been observed during apoptosis in mammalian tissue culture cells. Increased NE permeability in yeast was temporally correlated with an increase in the production of reactive-oxygen species (ROS). Later, after ROS levels began to decline and viability was lost, specific nuclear pore complex (NPC) proteins (nucleoporins) were degraded. Although caspases are responsible for the degradation of mammalian nucleoporins during apoptosis, the deletion of the metacaspase gene YCA1 had no effect on the stability of yeast nucleoporins. Instead, Pep4p, a vacuolar cathepsin D homolog, was responsible for the proteolysis of nucleoporins. Coincident with nucleoporin degradation, a Pep4p-EGFP reporter migrated out of the vacuole in H(2)O(2)-treated cells. We conclude that increases in ROS and NPC permeability occur relatively early during H(2)O(2)-induced cell death. Later, Pep4p migrates out of vacuoles and degrades nucleoporins after the cells are effectively dead.


(1)H-MRS metabolic patterns for distinguishing between meningiomas and other brain tumors.
Yet meningiomas have characteristic neuroimaging features, some other lesions are still confusing with meningiomas. The aim of this study was trying to find the typical (1)H-MRS metabolic factors of histologic subtyped meningiomas, schwannomas, metastases, and other brain tumors for differential diagnosis among them. (1)H-MRS using STEAM (TE/30 ms, TR/2 sec) and PRESS (TE/288 ms, TR/2 sec) sequences were performed on 44 untreated brain tumors. Obtained metabolic patterns from the typical spectra of meningioma, schwannoma, metastasis were compared with each other or other brain tumors to evaluate the usefulness for diagnosis between them. Alanine(Ala) was observed in 15 cases of the 19 meningiomas with a little variation to three histologic subtypes, while minimal lipids were observed in every 19 meningiomas. Elevated glutamate/glutamine(Glx) was detected in 12 cases of the meniningiomas. Increased myo-inositol(mI) was detected in 11 cases of the 13 schwannomas. Dominant lipids signals as well as long-T2 lipids were detected in every metastasis in conjunction with elevated choline (Cho). Enhanced Glx was observed in 4 cases of the 8 metastases without correlation of primary tumor site or types. Hemangiopericytoma showed different spectral patterns from typical meningiomas: only dominant Cho, minimal lipids and absence of Ala or Glx signals. These metabolic patterns in typical tumors may provide a basis for differential diagnosis (average value of chi(2) = 23.33, p < 0.01) between meningiomas and schwannomas as well as metastases. However proton spectral distinction among the different histologic subtypes of meningiomas was not definite.


Acyclovir for recurrent erythema multiforme caused by herpes simplex.
Herpes-associated erythema multiforme can be controlled by continuous suppressive treatment with oral acyclovir. Erythema multiforme is not prevented if oral acyclovir is administered after a herpes simplex recurrence is evident and it is of no value after erythema multiforme has occurred. There is some question whether continuous topical treatment with acyclovir to sites of recurrent herpes will sometimes prevent erythema multiforme. Erythema multiforme may be precipitated by orolabial and genital recurrences and by recurrences on skin of the buttocks and other sites. Some herpetic recurrences are associated with erythema multiforme and some are not and episodes of erythema multiforme are not always associated with clinical herpetic recurrences.


DISCOVER: A facile structure-based screening method for vinyl compound producing microbes.
Here we report a novel structure-based microbial screening method for vinyl compound discovery, DISCOVER (direct screening method based on coupling reactions for vinyl compound producers). Through a two-step screening procedure based on selective coupling reactions of terminal alkenes, the thiol-ene reaction (1st step of screening) and Mizoroki-Heck reaction, followed by iodine test (2nd step of screening), microbes producing vinyl compounds like itaconic acid (IA) can be isolated from soil samples. In the 1st step of screening, soil sources are plated on agar medium supplemented with an antimicrobial agent, α-thioglycerol (TG), and a radical initiator, VA-044 (VA). In the 2nd step of screening, vinyl compounds produced in the cultures are labelled with iodobenzene via the Mizoroki-Heck reaction, followed by an iodine test, leading to the detection and characterisation of labelled products. We evaluated the validity of DISCOVER using IA and its producer Aspergillus terreus. Experimental data supported our hypothesis that IA reacts with TG in the medium via the thiol-ene reaction and consequently, A. terreus rapidly forms colonies on the agar medium because of the loss of the antimicrobial activity of TG. Using DISCOVER, high throughput and selective isolation of A. terreus strains producing IA was possible from soils.


Tuning of the electronic and vibrational properties of epitaxial MoS2through He-ion beam modification.
Atomically thin transition metal dichalcogenides (TMDs), like MoS2with high carrier mobilities and tunable electron dispersions, are unique active material candidates for next generation opto-electronic devices. Previous studies on ion irradiation show great potential applications when applied to two-dimensional (2D) materials, yet have been limited to micron size exfoliated flakes or smaller. To demonstrate the scalability of this method for industrial applications, we report the application of relatively low power (50 keV)4He+ion irradiation towards tuning the optoelectronic properties of an epitaxially grown continuous film of MoS2at the wafer scale, and demonstrate that precise manipulation of atomistic defects can be achieved in TMD films using ion implanters. The effect of4He+ion fluence on the PL and Raman signatures of the irradiated film provides new insights into the type and concentration of defects formed in the MoS2lattice, which are quantified through ion beam analysis. PL and Raman spectroscopy indicate that point defects are generated without causing disruption to the underlying lattice structure of the 2D films and hence, this technique can prove to be an effective way to achieve defect-mediated control over the opto-electronic properties of MoS2and other 2D materials.


Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer.
Exosomes are well-known key mediators of intercellular communication and contribute to various physiological and pathological processes. Their biogenesis involves four key steps, including cargo sorting, MVB formation and maturation, transport of MVBs, and MVB fusion with the plasma membrane. Each process is modulated through the competition or coordination of multiple mechanisms, whereby diverse repertoires of molecular cargos are sorted into distinct subpopulations of exosomes, resulting in the high heterogeneity of exosomes. Intriguingly, cancer cells exploit various strategies, such as aberrant gene expression, posttranslational modifications, and altered signaling pathways, to regulate the biogenesis, composition, and eventually functions of exosomes to promote cancer progression. Therefore, exosome biogenesis-targeted therapy is being actively explored. In this review, we systematically summarize recent progress in understanding the machinery of exosome biogenesis and how it is regulated in the context of cancer. In particular, we highlight pharmacological targeting of exosome biogenesis as a promising cancer therapeutic strategy.


Hepatitis B surface antigen and hepatocellular carcinoma in Southern Africa.
Most series in Africa show a high percentage of hepatitis B surface antigen in hepatocellular carcinoma. Two groups of cases were investigated in this study. The one was derived from the autopsy material at Baragwanath hospital from subjects who had lived in Soweto, a large Black urban town. The second group consisted of male Black mineworkers generally originating from rural areas. A combination of the aldehydefuchsin stain and immunoperoxidase technique was used. The two groups showed totally different results. The Baragwanath series consisted of 24 hepatocellular carcinomas of which only 4 (17%) were HBsAg positive. Of the 24 cases, 14 had cirrhosis of which 9 were macronodular and 5 micronodular. Ten of these cases showed heavy iron overload. The series of male Black mineworkers comprised 22 cases of which 16 (72%) were HBsAg positive. Twelve of the 22 cases showed a macronodular cirrhosis and there were no micronodular cirrhoses. Only one case showed severe iron overload. These findings delineate two different populations of hepatocellular carcinoma in Southern Africa.


Activation of the lectin pathway of complement in pig-to-human xenotransplantation models.
Natural IgM containing anti-Gal antibodies initiates classic pathway complement activation in xenotransplantation. However, in ischemia-reperfusion injury, IgM also induces lectin pathway activation. The present study was therefore focused on lectin pathway as well as interaction of IgM and mannose-binding lectin (MBL) in pig-to-human xenotransplantation models. Activation of the different complement pathways was assessed by cell enzyme-linked immunosorbent assay using human serum on wild-type (WT) and α-galactosyl transferase knockout (GalTKO)/hCD46-transgenic porcine aortic endothelial cells (PAEC). Colocalization of MBL/MASP2 with IgM, C3b/c, C4b/c, and C6 was investigated by immunofluorescence in vitro on PAEC and ex vivo in pig leg xenoperfusion with human blood. Influence of IgM on MBL binding to PAEC was tested using IgM depleted/repleted and anti-Gal immunoabsorbed serum. Activation of all the three complement pathways was observed in vitro as indicated by IgM, C1q, MBL, and factor Bb deposition on WT PAEC. MBL deposition colocalized with MASP2 (Manders' coefficient [3D] r=0.93), C3b/c (r=0.84), C4b/c (r=0.86), and C6 (r=0.80). IgM colocalized with MBL (r=0.87) and MASP2 (r=0.83). Human IgM led to dose-dependently increased deposition of MBL, C3b/c, and C6 on WT PAEC. Colocalization of MBL with IgM (Pearson's coefficient [2D] rp=0.88), C3b/c (rp=0.82), C4b/c (rp=0.63), and C6 (rp=0.81) was also seen in ex vivo xenoperfusion. Significantly reduced MBL deposition and complement activation was observed on GalTKO/hCD46-PAEC. Colocalization of MBL/MASP2 with IgM and complement suggests that the lectin pathway is activated by human anti-Gal IgM and may play a pathophysiologic role in pig-to-human xenotransplantation.


"Masculine" Describes Gender Expressions, Not Neurobiologies: Response to Dutton and Madison (2020).
This letter is a response to "Gender Dysphoria and Transgender Identity Is Associated with Physiological and Psychological Masculinization: a Theoretical Integration of Findings, Supported by Systematic Reviews" by Dutton and Madison (2020), which relies on theorisations for which substantial counter-evidence exists, fails to engage with these or other criticisms of the theories upon which it seeks to build, and reaches conclusions that contradict existing evidence. Furthermore, the original theorisations contained in Dutton and Madison (2020), and the conclusions drawn from those theorisations, risk causing serious harm to already-marginalised groups.


Beyond the fearful ape hypothesis: Humans are also supplicating and appeasing apes.
We review research suggesting that several of the functions attributed to fear, in the target article's fearful ape hypothesis, also apply to supplication and appeasement emotions. These emotions facilitate support provisioning from others and the formation and maintenance of cooperative relationships. We therefore propose that the fearful ape hypothesis be expanded to include several other distinctively human emotional tendencies.


Congenital diverticulum of the bladder mimicking tumour.
The incidence of bladder diverticula is low and identification is usually straightforward with contrast studies. We present a case of a child who had a clearly identified bladder diverticulum as well as a soft-tissue lesion in the posterior wall of the bladder that was suspected to be a rhabdomyosarcoma. Despite ultrasound scanning, micturating cystourethrogram, computed tomography and cystoscopy, open surgery was required to rule out tumour.


Comparison of three molecular detection methods for detection of Trichinella in infected pigs.
Different molecular detection methods require diverse molecular platforms, but there is no uniform standard for people to reference in the detection of Trichinella. In this study, real-time PCR, loop-mediated isothermal amplification (LAMP), and conventional PCR were developed for the detection of Trichinella by targeting mitochondrial large subunit ribosomal DNA (mt-lsrDNA). We compared the performance of the three newly developed assays. The results revealed that the detection limits of the real-time PCR, LAMP, and conventional PCR assays were 10 and 100 fg/μL and 1 pg/μL of Trichinella spiralis genomic DNA, respectively. The assays were used in the detection of Trichinella in the field. A total of 192 samples were obtained from pigs: 75 samples from free range farming and 117 from intensive feeding factory. The infection rate was 8/192 (4.2 %), 7/192 (3.6 %), and 1/192 (1.0 %) through the real-time PCR, LAMP, and conventional PCR assays, respectively. These data indicate that Taqman real-time PCR was a rapid, specific, and sensitive tool as a preferred option for investigation of valuable samples, but that LAMP assay was closed tube, highly sensitive, cost-effective, rapid, easy-to-perform, and was the optimal choice for detection of Trichinella in the field. The results of a model of experimental infection in mice indicated that spleen can be used as sampling site for the detection of early T. spiralis infection. However, the diaphragm and myocardium were the most suitable sampling sites for the detection of T. spiralis.


Lucifer yellow stains displaced amacrine cells of the chicken retina during embryonic development.
We have used Lucifer Yellow for histological tracing of displaced amacrine cells within the ganglion cell layer (GCL) during the embryonic development of the chicken retina. Incubating whole eyes in the dye leads to bright staining of all displaced amacrine cells, whereas ganglion cells and glial cells are not stained. A subpopulation of cells of the inner part of the inner nuclear layer (INL) are also stained (for further details see ref. 13). Kainic acid, which is known to interfere with and kill amacrine cell systems, blocks the staining of these cells fully. This in addition to histological evidence confirms that the LY-stained cells in the GCL are displaced amacrine cells. Of the cells in the GCL, 23% (+/- 3%) are of the displaced amacrine type. Further, we find that the cytoarchitectural arrangement of these cells changes significantly during development.


In vivo delivery of CRISPR-Cas9 genome editing components for therapeutic applications.
Since its mechanism discovery in 2012 and the first application for mammalian genome editing in 2013, CRISPR-Cas9 has revolutionized the genome engineering field and created countless opportunities in both basic science and translational medicine. The first clinical trial of CRISPR therapeutics was initiated in 2016, which employed ex vivo CRISPR-Cas9 edited PD-1 knockout T cells for the treatment of non-small cell lung cancer. So far there have been dozens of clinical trials registered on ClinicalTrials.gov in regard to using the CRISPR-Cas9 genome editing as the main intervention for therapeutic applications; however, most of these studies use ex vivo genome editing approach, and only a few apply the in vivo editing strategy. Compared to ex vivo editing, in vivo genome editing bypasses tedious procedures related to cell isolation, maintenance, selection, and transplantation. It is also applicable to a wide range of diseases and disorders. The main obstacles to the successful translation of in vivo therapeutic genome editing include the lack of safe and efficient delivery system and safety concerns resulting from the off-target effects. In this review, we highlight the therapeutic applications of in vivo genome editing mediated by the CRISPR-Cas9 system. Following a brief introduction of the history, biology, and functionality of CRISPR-Cas9, we showcase a series of exemplary studies in regard to the design and implementation of in vivo genome editing systems that target the brain, inner ear, eye, heart, liver, lung, muscle, skin, immune system, and tumor. Current challenges and opportunities in the field of CRISPR-enabled therapeutic in vivo genome editing are also discussed.


Arrest and non-fatal suicide attempts among men: analysis of survey data from the National Survey on Drug Use and Health.
Studies have found an association between recent arrest and suicide attempts, but the population-level significance of this link has not been reported. We estimated the population attributable risk percent (PAR%) of self-reported non-fatal suicide attempts based on recent arrest in a national sample of adult men. This study included men aged ≥18 who completed the 2008-2019 National Surveys on Drug Use and Health. The outcome measure was any non-fatal suicide attempts in the past year. The primary independent variable was any arrest in the past year. Major depression and substance use disorders were also included as independent variables for comparison. Descriptive statistics and multivariate logistic regression with postestimation marginal effects ascertained the PAR% of non-fatal suicide attempts for arrest, major depression, and substance use disorders, while controlling for sociodemographic covariates. All analyses applied survey weights. We disaggregated analyses by race/ethnicity. In the sample of 220,261 men, arrest accounted for 8.9% (99% CI 5.1 to 12.6%, p < 0.001) of non-fatal suicide attempts, while major depression accounted for 40.3% (99% CI 35.0 to 45.1%. p < 0.001) and substance use disorders for 24.1% (99% CI 17.6 to 30.2%, p < 0.001). After disaggregating by race/ethnicity, arrest accounted for 9.5% (99% CI 4.5 to 14.3%, p < 0.001) of suicide attempts among Non-Hispanic White men and fell short of statistical significance for Non-Hispanic Black men (10.2, 99% CI - 3.0 to 21.6%, p = 0.043) and Hispanic men (8.1, 99% CI - 0.5 to 15.9%, p = 0.016). Arrest accounted for nearly one in eleven non-fatal suicide attempts in a national sample of American men, which is by extension about 50,000 suicide attempts per year. Results were similar for Non-Hispanic White, Non-Hispanic Black, and Hispanic men, although there were differences in prevalence of arrest and suicide attempts. Unlike major depression, arrest is an easily identifiable event, and the period after arrest might provide an opportunity to support mental health and coping.


Melatonin induces a stimulatory action on the scrotal skin components of Soay ram in the non-breeding season.
Fifteen adult Soay rams were employed in this study to investigate the effect of melatonin on the scrotal skin using histological, histochemical, and morphometrical analysis. The results revealed that the melatonin treated group showed a significant increase in the thickness of the epidermis, the cross-sectional area of blood capillaries and nerve fibers compared with the control one. In addition, obvious hypertrophy and hyperplasia were detected in the sebaceous glands in association with a significant increase in the number and diameter of apocrine sweat glands with well-developed secretory activity. S100 protein and cytokeratin-19 strongly stained the basal cells of sebaceous glands in the melatonin treated group incomparable to the control group. Moreover, the nerve fibers were intensively immunoreacted for S100 and cytokeratin proteins in the melatonin treated group in contrast to the control one. A high number of telocytes (TCs) could be identified in the treated group around the nerve fibers and blood vessels in the dermis. The number of Langerhans cells showed a significant increase in the melatonin groups that were identified by MHC II and PGP 9.5 within the epidermal layer. Furthermore, a significant increase in the number of dendritic cells was identified in the melatonin group, which were distributed within the dermis, around hair follicles, sebaceous glands, and sweat glands and were strongly expressed PGP-9.5, MHC-II, VAMP, SNAP, keratin-5, and cytokeratin-19 immunoreactivity. Notably, Merkel cells showed a significant increase in the number in the melatonin group that could be stained against nestin, SNAP, and VAMP. On the other hand, the secretory granules in sweat glands were exhibited a strong positive reactivity for synaptophysin in melatonin group. The current study showed that the administration of melatonin induced a stimulatory effect on keratinocytes, non-keratinocytes, sebaceous and sweat glands, hair follicles, as well as the vascular, neuronal, and cellular constituents of the dermis.


Ribosomal DNA variation, recombination and inheritance in the basidiomycete Trichaptum abietinum: implications for reticulate evolution.
Two divergent nuclear ribosomal DNA (nrDNA) types, designated alpha and beta, were found distributed in 11 North European populations of the basidiomycete Trichaptum abietinum. These types differed by a 220 bp indel in the internal transcribed spacer 1 (ITS1) sequence and a number of linked substitutions and small indel motives in the internal transcribed and intergenic spacers (ITS1, ITS2, IGS1 and IGS2). The alpha and beta haplotypes co-occurred in heterozygous somatic individuals (dikaryons) and segregated in a Mendelian fashion in monokaryotic single spore progenies. This result suggests that the haplotypes are encoded in different nuclei of field-collected dikaryons and inherited as a single locus. No meiotic recombinants were observed among the sequenced monokaryons. Population genetic analyses by PCR-RFLP revealed that a low frequency of evolutionary intermediate nrDNA types also existed in natural populations, presumably as a result of meiotic recombination of alpha and beta nrDNA. The existence of divergent nrDNA types in T. abietinum could be a result of a former independent evolution followed by a hybridization event. Phylogenetic analyses of ITS sequences suggest that the sister taxon T. fusco-violaceum has been involved in the evolutionary history of T. abietinum. Sequence polymorphisms observed in the translation elongation factor 1alpha (efa) and glyceraldehyde-3-phosphate dehydrogenase (gpd) genes, did not reveal two well-defined types of these genes. The results are discussed in the light of other evolutionary mechanisms as well.


Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway.
To examine the effects of combination therapy with metformin and paclitaxel in endometrial cancer cell lines. ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed after exposure to paclitaxel and metformin. Cell cycle progression was assessed by flow cytometry. hTERT expression was determined by real-time RT-PCR. Western immunoblotting was performed to determine the effect of metformin/paclitaxel on the mTOR pathway. Paclitaxel inhibited proliferation in a dose-dependent manner in both cell lines with IC(50) values of 1-5nM and 5-10nM for Ishikawa and ECC-1 cells, respectively. Simultaneous exposure of cells to various doses of paclitaxel in combination with metformin (0.5mM) resulted in a significant synergistic anti-proliferative effect in both cell lines (Combination Index<1). Metformin induced G1 arrest in both cell lines. Paclitaxel alone or in combination with metformin resulted in predominantly G2 arrest. Metformin decreased hTERT mRNA expression while paclitaxel alone had no effect on telomerase activity. Metformin stimulated AMPK phosphorylation and decreased phosphorylation of the S6 protein. In contrast, paclitaxel inhibited AMPK phosphorylation in the ECC-1 cell line and induced phosphorylation of S6 in both cell lines. Treatment with metformin and paclitaxel resulted in decreased phosphorylation of S6 in both cell lines but only had an additive effect on AMPK phosphorylation in the ECC-1 cell line. Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway. This combination may be a promising targeted therapy for endometrial cancer.


HLAMatchmaker: a molecularly based algorithm for histocompatibility determination. I. Description of the algorithm.
This report describes an algorithm for identifying acceptable HLA antigens for highly alloimmunized patients without the need for extensive serum screening. This algorithm is based on the concept that immunogenic epitopes are represented by amino acid triplets on exposed parts of protein sequences of human leukocyte antigen chains (HLA-A, HLA-B, and HLA-C) accessible to alloantibodies. A computer program (HLAMatchmaker) has been developed to determine class I HLA compatibility at the molecular level. It makes intralocus and interlocus comparisons of polymorphic triplets in sequence positions to determine the spectrum of non-shared triplets on donor HLA antigens. In most cases is it possible to identify certain mismatched HLA antigens that share all their polymorphic triplets with the patient's HLA antigens and could therefore, be considered fully compatible. HLAMatchmaker permits also the identification of additional mismatches that are acceptable as determined from the triplet information on HLA-typed panel cells that do not react with patient's serum.HLAMatchmaker provides an assessment of donor-recipient HLA compatibility at the structural level and this algorithm is different from conventional methods based on the mere counting of numbers of mismatched HLA antigens or CREGs. This donor selection strategy is suitable especially for allosensitized patients in need of a compatible transplant or platelet transfusion.


Localization of cathepsin D in rat liver. Immunocytochemical study using post-embedding immunoenzyme and protein A-gold techniques.
Light and electron microscopic localization of cathepsin D in rat liver was investigated by post-embedding immunoenzyme and protein A-gold techniques. By light microscopy, cytoplasmic granules of parenchymal cells and Kupffer cells were stained for cathepsin D. Weak staining was also noted in sinusoidal endothelial cells. In the parenchymal cells many of positive granules located around bile canaliculi. In the Kupffer cells and the endothelial cells, diffuse staining was noted in the cytoplasm in addition to granular staining. By electron microscopy, gold particles representing the antigenic sites for cathepsin D were seen in typical secondary lysosomes and some multivesicular bodies of the parenchymal cells and Kupffer cells. The lysosomes of the endothelial cells and fat-storing cells were weakly labeled. Quantitative analysis of the labeling density in the lysosomes of these three types of cells demonstrated that the lysosomes of parenchymal cells and Kupffer cells are main containers of cathepsin D in rat liver. The results suggest that cathepsin D functions in the intracellular digestive system of parenchymal cells and Kupffer cells but not so much in that of the endothelial cells.


[Pneumopathy caused by nitrofurantoin].
Two cases of nitrofurantoin induced acute pneumopathy are reported. The characteristics of the pulmonary reactions to this drug are described, and currently accepted pathogenic mechanisms, and diagnostic and therapeutic means discussed.


Low-dose estrogen and drospirenone combination: effects on metabolism and endothelial function in postmenopausal women with metabolic syndrome.
Metabolic syndrome and endothelial dysfunction play a relevant role in the cardiovascular risk in post-menopause. The aim of the study was to assess the effects of a low-dose hemihydrate estradiol and drospirenone combination on cardiovascular risk parameters in postmenopausal women with metabolic syndrome. Twenty-eight healthy women (group A) and 28 women with metabolic syndrome (group B) were treated with hemihydrate estradiol one mg + drospirenone two mg. At recruitment and after six months, clinical and laboratory parameters of metabolic syndrome were evaluated. Endothelial function was assessed measuring the flow-mediated dilatation of the brachial artery and the intima-media thickness of the common carotid artery. After six months an overall improvement of metabolism was observed in both groups reaching statistical significance for triglycerides, total cholesterolemia, and systolic pressure in group B. A trend to lower baseline flow-mediated dilatation was also found in group B. Drospirenone improves cardiovascular risk factors and does not impair endothelial function in menopausal women with metabolic syndrome.


Human phase response curve to a 1 h pulse of bright white light.
The phase resetting response of the human circadian pacemaker to light depends on the timing of exposure and is described by a phase response curve (PRC). The current study aimed to construct a PRC for a 1 h exposure to bright white light (∼8000 lux) and to compare this PRC to a <3 lux dim background light PRC. These data were also compared to a previously completed 6.7 h bright white light PRC and a <15 lux dim background light PRC constructed under similar conditions. Participants were randomized for exposure to 1 h of either bright white light (n=18) or <3 lux dim background light (n=18) scheduled at 1 of 18 circadian phases. Participants completed constant routine (CR) procedures in dim light (<3 lux) before and after the light exposure to assess circadian phase. Phase shifts were calculated as the difference in timing of dim light melatonin onset (DLMO) during pre- and post-stimulus CRs. Exposure to 1 h of bright white light induced a Type 1 PRC with a fitted peak-to-trough amplitude of 2.20 h. No discernible PRC was observed in the <3 lux dim background light PRC. The fitted peak-to-trough amplitude of the 1 h bright light PRC was ∼40% of that for the 6.7 h PRC despite representing only 15% of the light exposure duration, consistent with previous studies showing a non-linear duration–response function for the effects of light on circadian resetting.


The behavioral risk factor surveys: I. State-specific prevalence estimates of behavioral risk factors.
The prevalence of most behavioral risk factors varies substantially among states. The prevalence of current cigarette smoking ranges from 22 percent to 38 percent. Estimates of alcohol use show geographic clustering, with lower rates in the southeastern states. The prevalence of sedentary lifestyle, uncontrolled hypertension, overweight, and seatbelt use differs markedly among states. These findings represent an initial step toward the analysis of state-specific baseline risk-factor data for use in developing state programs aimed at reducing the leading causes of death in the United States.


Testicular microlithiasis is associated with testicular pathology.
To evaluate the impact of testicular microlithiasis (TM) on male health by describing our experience. TM is an uncommon condition characterized by calcium deposits in the lumina of seminiferous tubules. These intratesticular calcifications appear as bright, 2- to 3-mm echogenic foci on testicular ultrasound (US). Patients diagnosed with TM by high-frequency testicular US over a 4-year period from two separate institutions were included in this study. Approximately 1100 testicular USs were performed (both hospitals combined) over the 4-year period. Patients were clinically identified by the characteristic appearance of TM on testicular US. Pathologic specimens were obtained in 14 (64%) of 22 patients. Thirty-eight testicles (16 bilateral cases) in 22 patients were found to have TM. The incidence of TM was approximately 2%. Mean age at presentation was 29 years (range 8 to 63). Eight (36%) of 22 patients had testicular malignancies. Five (23%) of 22 patients were infertile. Three (14%) of 22 patients presented with unilateral necrosis of the testes due to spermatic cord torsion. Two patients had varicoceles, 1 patient had epididymitis, and another patient had torsion of an appendix testis. Previously unreported associations of TM and neurofibromatosis (1 patient) and acquired immunodeficiency syndrome (AIDS) (1 patient) were noted. No patient with TM later developed a testicular malignancy, yet the mean follow-up was only 31 months (range 1 to 108). One patient with unilateral TM developed bilateral TM, and 1 patient with bilateral TM subsequently developed unilateral TM. One patient developed spermatic cord torsion and testicular infarction 4 years after previously documented TM. TM is usually diagnosed by testicular US performed for various indications. TM is an uncommon condition that is found in testes with both malignant and nonmalignant conditions. The association of TM and testicular malignancy suggests regular follow-up with testicular US examinations.


A comparison of the response to arm and leg work in patients with ischemic heart disease.
An exercise test based on arm work was evaluated in a series of 33 male patients, mean age 52 years, with ischemic heart disease. The responses to arm exercise on a modified table-mounted bicycle ergometer and to standard bicycle exercise were compared. Twenty six of 33 patients (79 per cent) had identical end-points with both tests. Three patients had an ischemic response, i.e., significant ST abnormality and/or angina pectoris during leg work only, and four patients during arm work only. 41 per cent of the peakload during leg exercise. Mean values were 181 and 439 kpm./min. (p less than 0.001). Comparison of individual data on peak load demonstrated only a weak correlation between arm and leg work capacity (r = 0.37, p less than 0.05). Peak heart rate was slightly higher during leg work, 129 compared to 122 beats/min. (p less than 0.05) but the mean heart rate-systolic blood pressure products were not significantly different. A subgroup of seven patients had a history of angina pectoris preferentially precipitated by arm work but their physiological responses did not differ significantly from those of patients without a history of arm work sensitivity. The data indicate that arm work is a satisfactory alternate diagnostic test method with respect to myocardial ischemia, but measurements of physical work capacity defined as aerobic capacity, cannot be based on arm work.


Grand multiparity and incidence of endometrial cancer: a population-based study in Finland.
The hormonal background of endometrial cancer is insufficiently characterised. We investigated the significance of parity, age at first birth, intensity between births, length of time from the first to the last birth and length of delivery-free premenopausal period in a cohort of grand multiparous (GM) women, i.e., women with at least 5 births. Data of the Population Register of Finland (86,978 GM-women) and the population-based Finnish Cancer Registry were combined. Standardised incidence ratios (SIRs) were calculated by dividing the number of observed cancer cases by the expected number based on the national incidence rates. Multivariate relative risks (RRs) were estimated by Poisson regression analysis. The SIR for endometrial cancer among GM-women was low [419 cases; SIR=0.57, 95% confidence interval (CI) 0.52-0.63]. The RR of endometrial cancer was 0.58 (95% CI 0.34-0.97) among women giving their first birth at an age of more than 30 years compared to women with first birth before the age of 20. In ages 50+ (94% of endometrial cancer cases), the RR for women with at least 8 births was 0.63 (95% CI 0.44-0.92) compared to those with 5 births, and those with a birth period of 20+ years had RR=0.57 (95% CI 0.34-0.96) compared to those with a period of <10 years, while prolonged average intensity between births showed only a small protective effect. The RR of endometrial cancer also correlated with the length of premenopausal delivery-free period (RR = 0.61, 95% CI 0.44-0.86) for women with a short (<10 years) period compared to women with a long (>15 years) period. Our findings, that a large number of births, old age at first birth, a long birth period and a short premenopausal delivery-free period reduced the risk of postmenopausal endometrial cancer of GM-women, emphasise the protective role of progesterone and the stimulatory role of estradiol in the hormonal background of this disease.


Treatment-related premature ovarian failure as a long-term complication after Hodgkin's lymphoma.
One of the medical sequelae that chemo- and radiotherapy may cause is premature ovarian failure (POF). The scope of this study was to investigate the risk of developing POF as a long-term complication in young women treated for Hodgkin's lymphoma. The 99 women included in the study were treated between 1975 and 1992 at the Norwegian Radium Hospital. All patients received radiotherapy and 67 of the women also received chemotherapy. POF was found in 37.4% of the patients. The risk of developing POF was significantly higher if the patient received chemotherapy in addition to radiotherapy. Furthermore, the risk increased if chemotherapy included alkylating agents. Long-term follow-up revealed that women who at the time of treatment were under 30 years of age developed POF later, but with the same cumulative risk as women above 30 years of age. The risk of developing POF after radio- and chemotherapy is higher than earlier estimates suggest. After an observation time of 15 years the cumulative risk is 38% independent of age at the time of treatment. Age below 30 years at the time of treatment delays the development of POF, but does not decrease the life-time risk.


Recurrence after inguinal hernioplasty. A retrospective analysis of 122 cases.
The records of 122 patients treated for inguinal hernia in 1974 or 1975 were retrospectively analyzed. In 1981 all surviving and traceable patients were examined for recurrence of hernia. The overall recurrence rate was 9.6%. For indirect hernia the rate was 7.4% and for direct hernia 9.7%. Altogether 125 operations were performed, ten of them as emergencies for irreducible hernia. One patient died in association with surgery.


Evaluating the penetration of Cladosporium spores into the human respiratory system on the basis of aerobiological sampling results.
The penetration of Cladosporium spores and spore aggregates into human airways was studied using three different spore sampling methods: 1) a Burkard spore trap for determining the aggregation degree of Cladosporium; two samplers, simulating the human respiratory system, 2) a 6-stage Andersen 2000 sampler, and 3) a new size-selective bioaerosol sampler (SSBAS), designed specifically for immunochemical and chemical analyses. The aggregation degree of Cladosporium spores varied between 1.0 and 1.3 spores per dispersal unit. Grouping seems to be of little if any importance to the penetration ability of Cladosporium spores into the respiratory tract. The distribution of spores in the Andersen and SSBAS differed significantly in the largest size class (spores greater than 7 microns in diameter); with the Andersen sampler only 10.8% of the spores were detected in stage 1, compared with 43% with the SSBAS. On the Andersen culture plates 95% of all colonies were detected in stages 1-4, where particles greater than 2.1 microns in diameter are trapped. In the SSBAS altogether 99.4% of spores were found in the first two filter stages (cutoff point approx. 2.5 microns in diameter). Conclusions regarding the penetration of spores to the lungs on the basis of aerobiological results should always be based on the use of properly calibrated spore traps.


The alpha7 nicotinic acetylcholine receptor in schizophrenia: decreased mRNA levels in peripheral blood lymphocytes.
Recent studies have suggested that the alpha7 nicotinic acetylcholine receptor (alpha7 AChR) may play a role in the pathogenesis of schizophrenia. In search for peripheral biological markers for schizophrenia we have investigated alpha7 mRNA levels in peripheral blood lymphocytes (PBLs) of schizophrenic patients and healthy controls. Peripheral blood samples were collected from medicated and non-medicated (drug naive) schizophrenic patients as well as from healthy (non-mentally ill) smokers and non-smokers. RNA was prepared from isolated lymphocytes. Polymerase chain reaction products specific for human alpha7 AChR were quantified by densitometry using Scion image-analysis (shared NIH software). We observed a significant decrease of alpha7 mRNA levels on PBLs of schizophrenic patients compared with controls. The decrease in alpha7 mRNA levels was not a result of medication management, because non-medicated schizophrenic patients displayed the same level of reduction in alpha7 mRNA as did patients receiving medication. In addition, we exclude the possibility that the observed decrease in alpha7 mRNA levels resulted from nicotine consumption in smoking, because healthy smokers exhibited the same levels of alpha7 mRNA as non-smokers. We propose that alpha7 AChR may be involved in the pathophysiology of the disease and may serve as a reliable peripheral biological marker in schizophrenia.


Multidimensional biomarker predicts disease control in response to immunotherapy in recurrent or metastatic head and neck squamous-cell carcinoma.
Anti-PD-1 therapy provides clinical benefit in 40-50% of patients with relapsed and/or metastatic head and neck squamous cell carcinoma (RM-HNSCC). Selection of anti- PD-1 therapy is typically based on patient PD-L1 immunohistochemistry (IHC) which has low specificity for predicting disease control. Therefore, there is a critical need for a clinical biomarker that will predict clinical benefit to anti-PD-1 treatment with high specificity. Clinical treatment and outcomes data for 103 RM-HNSCC patients were paired with RNA-sequencing data from formalin-fixed patient samples. Using logistic regression methods, we developed a novel biomarker classifier based on expression patterns in the tumor immune microenvironment to predict disease control with monotherapy PD-1 inhibitors (pembrolizumab and nivolumab). The performance of the biomarker was internally validated using out-of-bag methods. The biomarker significantly predicted disease control (65% in predicted non-progressors vs. 17% in predicted progressors, p < 0.001) and was significantly correlated with overall survival (OS; p = 0.004). In addition, the biomarker outperformed PD-L1 IHC across numerous metrics including sensitivity (0.79 vs 0.64, respectively; p = 0.005) and specificity (0.70 vs 0.61, respectively; p = 0.009). This novel assay uses tumor immune microenvironment expression data to predict disease control and OS with high sensitivity and specificity in patients with RM-HNSCC treated with anti-PD-1 monotherapy.


Role of spatiotemporal expression of iodothyronine deiodinase proteins in cerebellar cell organization.
Thyroid hormones (TH) play a crucial role in various developmental processes in all vertebrates. The expression of a number of thyroid hormone responsive genes is of critical importance in processes like cell maturation and migration. Since these genes are mostly regulated by binding of the receptor-active TH (T(3)) to the thyroid hormone receptor, the availability of this T(3) is indispensable for correct brain lamination. One important way to regulate local TH availability is via the ontogenetic changes in activating and inactivating iodothyronine deiodinases. The current study was set up to investigate the distribution of type I, type II and type III (D1, D2 and D3) iodothyronine deiodinase protein in the chicken cerebellum at two important developmental ages, namely embryonic day 18 when cerebellar cell migration is fully in progress, and 1 day posthatch, when cerebellar maturation is mostly finished. The results show that the deiodinase proteins are divergently expressed in the cerebellar cell population. D1 and D3 are expressed in the granule cells at E18, whereas D2 is found mostly in the molecular layer and the Purkinje cells at that time. One day posthatch, the expression of D1 is limited to the mature granule cells and that of D3 to the Purkinje cells exclusively, whereas D2 remains clearly present in the molecular layer. Comparison of the deiodinase protein distribution with the expression of TH-responsive proteins involved in cell migration (reelin, disabled protein 1 and tenascin-C) allows speculating about the effect of this spatiotemporal distribution pattern on cerebellar cell communicative pathways.


Discordance in the histopathologic diagnosis of difficult melanocytic neoplasms in the clinical setting.
The gold standard for diagnosing melanocytic neoplasms is by histopathologic examination. However, lack of agreement among expert dermatopathologists in evaluating these tumors has been well established in experimental settings. This study examines the discordance among dermatopathologists in evaluating difficult melanocytic neoplasms in a clinical setting where the diagnosis impacts patient management. Retrospective review of consultation reports over a 6-year period. There was complete agreement among the consultants in 54.5% of the cases. However, a high level of disagreement was found in 25% of the cases. The analysis was limited to two consultant dermatopathologists. There are limitations to the practical applications of histologic criteria for diagnosing difficult melanocytic tumors. It is not malpractice for a pathologist to have rendered a diagnosis that did not predict clinical outcome as long as 'standard of care' has been followed in his/her evaluation of the specimen.


Allergy to local anaesthetic agents used in dentistry--what are the signs, symptoms, alternative diagnoses and management options?
This paper addresses the signs and symptoms of local anaesthetic hypersensitivity, differential diagnoses and the management of a patient with suspected allergy to local anaesthetics. While allergy to anaesthetic is rare, knowledge of other causes of similar symptoms is important.


A simplified cardiac cannulation technique.
A technique for venous cannulation, left heart venting, and aortic root cannulation is described. It is simple and tidy and permits full mobility of the cannula with minimal manipulation and no blood loss.


[Effect of x-irradiation on the properties of cyclic AMP-dependent protein kinases from rat spleen lymphocytes].
It was shown, that in conditions of acute radiation affection in doze 0.5 and 1 Gy, there was a decrease of 32 and 55% in activity of cyclic AMP-dependent protein kinases, isolated from cytosol of lymphocytes. The analysis of cAMP-dependent protein kinases properties has shown, that disturbance in the interaction of the enzyme with protein substrate of phosphotransferase reaction and main modulater enzymes activity--cAMP proceeds of the ionising radiation effect.


Hip Arthroscopy for Femoroacetabular Impingement Syndrome Results in 2 Recovery Patterns Based on Preoperative Pain and on Arthritis: Improvers and Non-improvers.
To analyze whether subgroups of patients could be distinguished with different functional recovery trajectories after hip arthroscopy for femoroacetabular impingement (FAI) syndrome and to identify differences between those subgroups using data from our prospective cohort registration. We retrospectively reviewed the prospectively registered data of patients who had undergone hip arthroscopy for FAI syndrome in our clinic from 2015 through 2018. Latent class growth modeling and growth mixture modeling were used to identify and classify groups of patients according to the trajectory of functional recovery using the Hip Outcome Score-Activities of Daily Life (HOS-ADL). We used univariable analysis and descriptive statistics to explore whether differences in group membership could be identified. A total of 100 patients were analyzed. Growth mixture modeling identified 2 main types of recovery pattern after surgery: patients in whom the HOS-ADL improved significantly after surgery to 90, whom we called the "improvers" (with fast initial improvement within 3 months that is maintained during follow-up), and patients who did not significantly benefit from surgery (with only mild improvement in the HOS-ADL at 3 months and no further change during follow-up), whom we called the "non-improvers." Univariable analysis and comparison of differences between subgroups showed higher preoperative visual analog scale scores for pain and more intraoperative arthrosis of the femoral head for the non-improvers. We identified 2 main types of recovery pattern after arthroscopic treatment of FAI syndrome: improvers and non-improvers. Both groups recover in a different manner postoperatively. Preoperative pain and intraoperative arthrosis of the femoral head differed in the non-improvers compared with the improvers. Level III, retrospective cohort study.


Success and complication rates of conduction system pacing: a meta-analytical observational comparison of left bundle branch area pacing and His bundle pacing.
Left bundle branch area pacing (LBBAP) and His bundle pacing (HBP) are the main strategies to achieve conduction system pacing (CSP), but only observational studies with few patients have compared the two pacing strategies, sometimes with unclear results given the different definitions of the feasibility and safety outcomes. Therefore, we conducted a meta-analysis aiming to compare the success and complications of LBBAP versus HBP. We systematically searched the electronic databases for studies published from inception to March 22, 2023, and focusing on LBBAP versus HBP. The study endpoints were CSP success rate, device-related complications, CSP lead-related complications and non-CSP lead-related complications. Fifteen observational studies enrolling 2491 patients met the inclusion criteria. LBBAP led to a significant increase in procedural success [91.1% vs 80.9%; RR: 1.15 (95% CI: 1.08-1.22); p < 0.00001] with a significantly lower complication rate [1.8% vs 5.2%; RR: 0.48 (95% CI: 0.29-0.78); p = 0.003], lead-related complications [1.1% vs 4.3%; RR: 0.38 (95% CI: 0.21-0.72); p = 0.003] and lead failure/deactivation [0.2% vs 3.9%; RR: 0.16 (95% CI: 0.07-0.35); p < 0.00001] than HBP. No significant differences were found between CSP lead dislodgement and non-CSP lead-related complications. This meta-analysis of observational studies showed a higher success rate of LBBAP compared to HBP with a lower incidence of complications.


Sirtuin 1 (SIRT1): a potential immunohistochemical marker and therapeutic target in soft tissue neoplasms with myoid differentiation.
Sirtuin, silent mating-type information regulation 2 homolog Saccharomyces cerevisiae 1 (SIRT1), is a protein that has been implicated in multiple mammalian functions including cell aging, stress resistance, and differentiation. SIRT1 has also been shown to be involved in multiple tumors. In addition, new pharmacotherapies have recently been approved that target SIRT1. The purpose of this study was to use immunohistochemistry to characterize SIRT1 protein expression in human soft tissue neoplasms with the hopes of finding new diagnostic and therapeutic modalities. SIRT1 immunoreactivity was reviewed in a series of 164 soft tissue tumors including alveolar soft part sarcoma, angiomyolipoma, clear cell sarcoma, desmoid/fibromatosis, desmoplastic small round cell tumor, Ewing sarcoma, gastrointestinal stromal tumor, glomus tumor, leiomyoma, leiomyosarcoma, lipoma, liposarcoma, malignant peripheral nerve sheath tumor, nodular fasciitis, osteosarcoma, rhabdomyosarcoma, schwannoma, solitary fibrous tumor, synovial sarcoma, undifferentiated pleomorphic sarcoma, and Wilms tumor. In addition, numerous benign tissues were tested for SIRT1 reactivity. In nonneoplastic tissue, strong cytoplasmic SIRT1 reactivity was observed in all prostate stroma, smooth muscle, and striated muscle. A similar pattern of cytoplasmic SIRT1 expression was observed in soft tissue neoplasms with myoid differentiation, namely, angiomyolipoma (100%), glomus tumor (100%), leiomyoma (90%), leiomyosarcoma (76.5%), and rhabdomyosarcoma (87%). The other lesions examined were negative. Although the physiologic role of SIRT1 remains to be clarified in myoid tissues and neoplasms differentiating along these lines, this observation points to a potential role for this marker in diagnostic immunohistochemistry. Furthermore, the recent emergence of drugs capable of selectively inhibiting SIRT1 raises the possibility of a potential application for targeted therapy. Additional studies are necessary to further characterise the role of SIRT1 in myoid tissues and neoplasms.


Nothing matters: the significance of the unidentifiable, the superficial and nonsense.
Purpose: The aim of this study is to explore the ways in which "small things" may be of importance for people with mental health difficulties.Method: Empirical material from three different studies was reanalysed through a phenomenological, dialogical, approach.Results: We discovered some paradoxical aspects of small things: i.e., they could be about "something" that was difficult or even impossible to identify. The unidentifiable could be about bodily, sensual experiences that are superficial (i.e., belonging to the surface). The interaction with others highlighted as significant could be about doing something fun, talking nonsense or kidding around, and hence not at all about making sense of something-a kind of important nonsense. We summarize these aspects in three themes: the importance of the unidentifiable, the superficial and nonsense. These aspects can be regarded as small things-even "nothings"-that make it possible "to stay in the world".Conclusion: We elaborate on the findings in relation to the following: Gumbrecht's critique of the prevailing hermeneutic world-view with its idea that "interpretation is humankind's exclusive way of relating to the world", Ingold's idea that social life is lived in relations of "interfacility" and hence a turn to surfaces is needed for a "restoration of social life", and Biesta's idea of existence as "coming into the world in the presence of others".


A critical review on approaches to regulate the release rate of bioactive compounds from biopolymeric matrices.
Recently, there has been a growing interest in novel food formulations and packaging materials using controlled release systems in order to enhance the functional performance of food bioactive ingredients and to prolong the shelf-life of food products. Correspondingly, numerous types of matrices (polymers, biopolymers, synthetic materials) could be implemented as carriers based on their compatibility with the bioactive ingredients and the type of releasing medium. A plethora of applications of controlled release can be identified in the pharmaceutical, agriculture, cosmetics, and particularly the food industries. Moreover, several physical and chemical stimuli are applied to regulate the release behavior of a bioactive molecule in the desired medium, which is under development. This review highlights the strategies applied to regulate the release rate of biopolymeric networks mainly including mixing of biopolymers, physical and chemical crosslinkers along with encapsulation systems, furthermore, the future prospects of release concept are discussed.


Highly sensitive and rapid profiling method for carotenoids and their epoxidized products using supercritical fluid chromatography coupled with electrospray ionization-triple quadrupole mass spectrometry.
Epoxy carotenoids, which are products of carotenoid oxidation, are potential oxidative stress markers. However, it is difficult to profile epoxy carotenoids owing to their small amount and difficulty in their separation from hydroxy carotenoids. In this study, a high-performance analytical system based on supercritical fluid chromatography (SFC) coupled with tandem mass spectrometry (MS/MS) was developed for the simultaneous analysis of carotenoids and epoxy carotenoids. SFC is an effective separation technique for hydrophobic compounds, by which major carotenoids in human serum and their epoxidation products can be analyzed within 20 min. The use of MS/MS increased the sensitivity; the detection limit for each carotenoid was of the sub-fmol order. When the constructed method was applied to biological samples such as human serum and low-density lipoprotein (LDL), the precise detection of the target carotenoids was disturbed by several isomers. However, highly selective detection of epoxy carotenoids was performed by targeting product ions that were generated with a structure-specific neutral loss of 80Da. Furthermore, the sample volume needed for the analysis was only 0.1ml for the serum, indicating the efficiency of this system in performing small-scale analyses. Using the analytical system developed in this study, highly sensitive and selective analysis of epoxy carotenoids could be performed in a short time. These features show the usefulness of this system in application to screening analysis of carotenoid profiles that are easily modified by oxidative stress.


Ethnic populations: community mental health services ten years later.
In a replication of a series of studies conducted by Sue and colleagues in the mid-1970s, demographic and service data were retrieved for the Seattle-King County area from the Washington Mental Health Information System. Caucasian clients were compared against Asian, black, Hispanic, and Native American client groups, and, where possible, against the findings reported earlier by Sue. These clients were compared in terms of basic demographic characteristics, characteristics of staff providing the services, dropout rates, and average number of services received. The most notable findings are (a) that failure-to-return rates are dramatically lower for the current sample than for Sue's and not greatly different for minorities than for Caucasians, (b) that variability in failure-to-return rates is most strongly related to level of functioning and not related to minority status, and (c) that although Asian Americans still average fewer services than Caucasians (other minorities do not differ significantly), the mean number of services had increased substantially for all groups but more for minorities than for Caucasians.


Cyclic GMP, calcium and photoreceptor sensitivity in mice heterozygous for the rod dysplasia gene designated "rd".
The rise in photoreceptor cGMP, induced by less than 1.0 nM extracellular calcium, is delayed in retinas of mice heterozygous for the rod dysplasia gene (+/rd). The calcium ionophore A23187 reduces the delay, suggesting that +/rd outer segments contain more calcium than normal. In turn, this might explain the increased photosensitivity of the +/rd retina. During the response to low calcium there is no correlation in +/rd retinas between the total concentration of cGMP and the photoresponse amplitude and its time to peak. The observations imply that either free cGMP is abnormally independent of the bound pool in the +/rd photoreceptor outer segment or that factors other than cGMP and its phosphodiesterase are modulating the rising phase of the response. The time-to-peak of PIII in a +/rd retina, incubated in a standard medium and stimulated with dim light, is abnormally delayed. Reduction of extracellular calcium induces an abnormal delay as well in responses to higher light levels. In addition to this, a second delay manifests slowly in both the normal and the +/rd retina. More studies are needed to explain these observations.


Mechanisms of SHP-1 P2 promoter regulation in hematopoietic cells and its silencing in HTLV-1-transformed T cells.
The Src homology-2-containing protein-tyrosine phosphatase 1 (SHP-1), is a negative regulator of cell signaling. It is also considered a tumor suppressor gene because of its ability to antagonize the action of tyrosine kinases. Although SHP-1 is expressed strongly in hematopoietic cells, decreased expression has been observed in various hematological malignancies, which suggests a central involvement of SHP-1 in leukemogenesis. We have shown previously that human T cell lymphotropic virus type-1 (HTLV-1) Tax-induced promoter silencing (TIPS) is an early event causing down-regulation of SHP-1 expression, which is dependent on NF-kappaB. In this study, DNase I footprinting and EMSA also revealed binding of transcription factors, specificity protein 1 (Sp1) and octamer-binding transcription factor 1 (Oct-1) to the P2 promoter, and site-directed mutagenesis confirmed that these factors contribute to the basal P2 promoter activity. Chromatin immunoprecipitation (CHIP) assays showed that Sp1, Oct-1, NF-kappaB, CREB-1, and RNA polymerase II interacted with the core SHP-1 P2 promoter in CD4+ T cells and Jurkat cells but not in HTLV-1-transformed MT-2 and HUT102 cells when HTLV-1 Tax is present. Furthermore, bisulfite sequencing of the SHP-1 P2 core region revealed heavy CpG methylation in HTLV-1-transformed cells compared with freshly isolated CD4+ T cells and HTLV-1-noninfected T cell lines. A significant inverse correlation between degree of CpG methylation and expression of SHP-1 mRNA or protein was observed. Taken together, our data support the notion that in HTLV-1-transformed CD4+ T cells, TIPS causes dissociation of transcription factors from the core SHP-1 P2 promoter, which in turn leads to subsequent DNA methylation, an important early step for leukemogenesis.


Outcome of children with IgA vasculitis with nephritis treated with steroids: a matched controlled study.
IgA vasculitis (IgAV) is the most common vasculitis in children. IgAV long-term prognosis depends on kidney involvement or IgA vasculitis with nephritis (IgAVN). To date, steroid treatment (oral steroids or methylprednisolone pulses) has not proven to be formally efficient. This study aimed to assess the role of steroids on IgAVN outcome. All children with IgAVN diagnosed 2000-2019 in 14 French pediatric nephrology units with minimal follow-up of 6 months were retrospectively included. Outcomes of patients treated with steroids were compared with those of a control group of untreated patients matched for age, sex, proteinuria, eGFR, and histological features. The primary endpoint was IgAVN remission defined as urine protein-to-creatinine ratio < 20 mg/mmol without impaired eGFR one year after disease onset. A total of 359 patients with IgAVN were included with a median follow-up time of 249 days (range 43-809). One hundred eight (30%) patients received oral steroids alone, 207 (51%) patients received three methylprednisolone pulses followed by oral steroids, and 44 patients (12.5%) did not receive steroids. Thirty-two children treated with oral steroids alone were compared with 32 matched control patients who did not receive steroids. One year after disease onset, IgAVN remission proportion was not different between these two groups: 62% versus 68%, respectively. Ninety-three children treated with oral steroids alone were compared with 93 matched patients treated with three methylprednisolone pulses followed by oral corticosteroids. IgAVN remission proportion was not different between these two groups: 77% versus 73%, respectively. The benefit of oral steroids alone and methylprednisolone pulses could not be established based on this observational study. Randomized controlled trials are thus required to determine the efficacy of steroids in IgAVN. A higher resolution version of the Graphical abstract is available as Supplementary information.


Using reference data on quality of life--the importance of adjusting for age and gender, exemplified by the EORTC QLQ-C30 (+3).
Interpretation of health related quality of life (HRQOL) results in cancer patients is facilitated by knowledge of the levels of HRQOL in the general population. However, direct comparisons can be misleading unless age and gender are considered. We demonstrate the derivation of age- and gender-specific 'expected' values from population reference values by means of simple calculations. This survey included 3000 randomly selected Norwegians above 18 years of age who received the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30 (+3) by mail. 1965 responses from 2,892 eligible persons (68%) were received. The population was divided into six disease groups based on self-reported health problems. The observed mean scale scores of the different groups deviated greatly from those obtained in the general population. The score for physical function, for example, was 72 for cancer patients and ranged from 73.3 to 82.5 in other disease groups, as opposed to 89.9 in the general population and 98.9 in those with no health problems. The range for one of the quality of life (QOL) scales was 57.7 to 84.7 compared with 73.7 in the general population. Expected mean scores for the patient groups were computed from the reference values, based on the concept of equivalence of age and gender. The differences between the observed mean scores and the reference values were strongly mediated by this method. The expected scores for physical function then ranged from 83.3 to 93.1 and from 70.3 to 75 for the QOL scale. The impact of age and gender on the reference data from the EORTC QLQ-C30 (+3) obtained in a general population shows that these variables must be considered when interpreting data on HRQOL for cancer patients. The demonstration of how to generate mean values which are adjusted according to the age and gender distribution of a population should increase the usefulness of this questionnaire among clinicians.


Up-regulation of B-cell lymphoma factor-2 expression, inhibition of oxidative stress and down-regulation of pro-inflammatory cytokines are involved in the protective effect of cabbage (Brassica oleracea) juice in lead-induced endothelial dysfunction in rats.
Oxido-inflammatory stress and dysregulation of nitric oxide (NO) system has been implicated in lead toxicity. Cabbage is an antioxidant-rich household vegetable with plethora of therapeutic potentials. The present study investigated the anti-oxido-inflammatory activity of cabbage in lead-induced endothelial dysfunction. Twenty (20) male Wistar rats were selected into four groups (n = 5) and treated with distilled water (1 mL/100 g b.wt), lead acetate (25 mg/kg b.wt), cabbage juice (1 mL/100 g b.wt) and lead acetate (25 mg/kg b.wt) plus cabbage juice (1 mL/100 g b.wt) respectively. Treatment was done orally for 28 days, thereafter, oxidative stress (SOD, CAT, GSH, and MDA), inflammatory (TNF-α and IL-6) and apoptotic (Bcl-2) markers were assayed using standard biochemical assays as well as histoarchitectural study of the endothelium. The results showed that they were significant increase in MDA, ET-1, TNF-α and IL-6 while SOD, GSH, CAT, NO and Bcl-2 protein expression were decreased in Lead exposed animals. Endothelial histoarchitecture was also altered. Following Cabbage juice treatment, MDA, ET-I, TNF-α and IL-6 were down-regulated while SOD, GSH, CAT, NO and Bcl-2 protein expression were up-regulated. Histoarchitecture was significantly recovered. The study suggests that cabbage juice could mitigates Lead-induced endothelial dysfunction by modulating oxido-inflammatory and anti-apoptotic mediators. All data are available upon request.


Rhesus monkey embryos produced by nuclear transfer from embryonic blastomeres or somatic cells.
Production of genetically identical nonhuman primates would reduce the number of animals required for biomedical research and dramatically impact studies pertaining to immune system function, such as development of the human-immunodeficiency-virus vaccine. Our long-term goal is to develop robust somatic cell cloning and/or twinning protocols in the rhesus macaque. The objective of this study was to determine the developmental competence of nuclear transfer (NT) embryos derived from embryonic blastomeres (embryonic cell NT) or fetal fibroblasts (somatic cell NT) as a first step in the production of rhesus monkeys by somatic cell cloning. Development of cleaved embryos up to the 8-cell stage was similar among embryonic and somatic cell NT embryos and comparable to controls created by intracytoplasmic sperm injection (ICSI; mean +/- SEM, 81 +/- 5%, 88 +/- 7%, and 87 +/- 4%, respectively). However, significantly lower rates of development to the blastocyst stage were observed with somatic cell NT embryos (1%) in contrast to embryonic cell NT (34 +/- 15%) or ICSI control embryos (46 +/- 6%). Development of somatic cell NT embryos was not markedly affected by donor cell treatment, timing of activation, or chemical activation protocol. Transfer of embryonic, but not of somatic cell NT embryos, into recipients resulted in term pregnancy. Future efforts will focus on optimizing the production of somatic cell NT embryos that develop in high efficiency to the blastocyst stage in vitro.


Cost-Effectiveness of an Online Intervention for Caregivers of People Living With Dementia.
Little evidence exists on costs or cost-effectiveness of online interventions for caregivers of people living with dementia. We aimed to assess cost-effectiveness of online cognitive behavioral therapy (CBT) for dementia caregivers with mild-to-moderate depression/anxiety, with or without telephone support, relative to a psychoeducational control treatment. Cost-effectiveness study of data from 3-armed randomized controlled trial comparing computerized CBT (cCBT) or telephone-supported cCBT (cCBT+Telephone) to modular online educational program on dementia (Psychoeducation). UK-resident adult dementia caregivers with mild-to-moderate anxiety/depression. We calculated health and social care costs, from participant-reported data collected at baseline, 12, 26 weeks, costs of intervention delivery. We examined 3 outcomes: cost of one-point reduction in General Health Questionnaire-12 (GHQ-12) rating at 26-weeks, cost of prevented "caseness" on GHQ-12 at 26 weeks, and cost per quality-adjusted life year (QALY) based on Short Form-6 Dimensions (SF-6D) over 26 weeks. Data from 176 participants (44 cCBT, 91 cCBT+Telephone, 41 Psychoeducation) were analyzed. Costs did not differ between cCBT and Psychoeducation; costs were £125 higher in cCBT+Telephone. Control and intervention groups did not differ on GHQ-12. Caseness was lower in cCBT+Telephone than Psychoeducation; cost of preventing a case was £610, and probability of cost-effectiveness on this outcome reached 98.5% at willingness to pay (WTP) of £12,900. Mean QALY did not differ between cCBT+Telephone and Psychoeducation. QALY gain in cCBT was 0.01 (95% CI 0.001, 0.021). Cost per QALY was £8130. Although base case probability of cost-effectiveness of cCBT was 93% at WTP-per-QALY of £27,600, sensitivity analyses suggested cCBT+Telephone was the more cost-effective. We report preliminary evidence for adopting telephone-supported online CBT. This may be cost-effective in preventing a case of mental health disorder if, absent a societally accepted WTP threshold for this outcome, payers are willing to pay £12,900. Future research should investigate whether supported/unsupported online CBT improves health-related quality of life.


[Rehabilitation of patients suffering from closed spinal trauma with damage to the spinal cord].
Results of complex rehabilitative treatment of 652 patients with above kind of pathology are examined. Outcomes of motor mobility depending on the level and severity of the injury are shown. In spine-spinal cord injury 77.3% of patients could walk using supplementing devices. The percent of I group invalidity depending on the level of spinal cord injury varies from 74.6-92.7%, II group invalidity--0.8-7.5%, III group invalidity--0.8-3.5%.


Kahweol inhibits proliferation and induces apoptosis by suppressing fatty acid synthase in HER2-overexpressing cancer cells.
Kahweol is a coffee-specific diterpene found in the beans of Coffea arabica and has been reported to demonstrate various biological activities, including anti-inflammatory, antioxidant, and apoptotic properties. In the present study, we examined the molecular mechanism of kahweol in human epidermal growth factor receptor-2 (HER2)-overexpressing breast cancer cells. Kahweol preferentially inhibited cell proliferation and induced cell death through the induction of a caspase 3-dependent pathway in HER2-overexpression breast cancer cell lines. Kahweol treatment substantially reduced the levels of HER2 protein, mRNA, and transcriptional activity in SKBR3 cells. Kahweol exerts its potent anticancer efficacy by the upregulation of polyomavirus enhancer activator 3 (PEA3) and downregulation of activator protein 2 (AP-2) to inhibit aberrantly activated HER2 signaling. Fatty acid synthase (FASN) expression and sterol regulatory element-binding protein-1c (SREBP-1c) activity were downregulated by kahweol. In addition, kahweol lowered the levels of phosphorylated Akt and its downstream targets mammalian target of rapamycin (mTOR) and cyclin D1. Furthermore, we found that blocking Akt signaling through kahweol treatment significantly reduced FASN expression and subsequently suppressed cell proliferation in HER2-overexpressing cancer cells. Overall, this study suggests that kahweol could be a useful adjuvant therapeutic agent in the treatment of HER2-overexpressing breast cancer.


Enhancing the implementation and sustainability of fundamental movement skill interventions in the UK and Ireland: lessons from collective intelligence engagement with stakeholders.
To have population-level impact, physical activity (PA) interventions must be effectively implemented and sustained under real-world conditions. Adequate Fundamental Movement Skills (FMS) is integral to children being able to actively participate in play, games, and sports. Yet, few FMS interventions have been implemented at scale, nor sustained in routine practice, and thus it is important to understand the influences on sustained implementation. The study's aim was to use Collective Intelligence (CI)-an applied systems science approach-with stakeholder groups to understand barriers to the implementation of FMS interventions, interdependencies between these barriers, and options to overcome the system of barriers identified. Three CI sessions were conducted with three separate groups of experienced FMS intervention researchers/practitioners (N = 22) in the United Kingdom and Ireland. Participants generated and ranked barriers they perceive most critical in implementing FMS interventions. Each group developed a structural model describing how highly ranked barriers are interrelated in a system. Participants then conducted action mapping to solve the problem based on the logical relations between barriers reflected in the model. The top ranked barriers (of 76) are those related to policy, physical education curriculum, and stakeholders' knowledge and appreciation. As reflected in the structural model, these barriers have influences over stakeholders' efficacy in delivering and evaluating interventions. According to this logical structure, 38 solutions were created as a roadmap to inform policy, practice, and research. Collectively, solutions suggest that efforts in implementation and sustainability need to be coordinated (i.e., building interrelationship with multiple stakeholders), and a policy or local infrastructure that supports these efforts is needed. The current study is the first to describe the complexity of barriers to implementing and sustaining FMS interventions and provide a roadmap of actions that help navigate through the complexity. By directing attention to the ecological context of FMS intervention research and participation, the study provides researchers, policy makers, and practitioners with a framework of critical components and players that need to be considered when designing and operationalising future projects in more systemic and relational terms.


Protective effect of prostaglandin E1 against ischemia/reperfusion-induced liver injury: results of a prospective, randomized study in cirrhotic patients undergoing subsegmentectomy.
The cytoprotective effects of prostaglandin E1 on livers suffering from ischemia/reperfusion injury in the clinical setting are unproved. These effects were examined, focusing on inflammatory cytokine and nitric oxide metabolism. Twenty-four cirrhotic patients with hepatocellular carcinoma undergoing subsegmentectomy under ischemia induced only by Pringle's maneuver were divided into two groups (patients given prostaglandin E1 by injection and untreated controls) and postoperative results were compared. Peripheral blood was taken perioperatively and the plasma aminotransferase, cytokines and nitrate/nitrite levels of the two groups were compared. Two liver specimens were taken from each patient, one before ischemia and the other after hepatectomy, and the levels of inducible nitric oxide synthase and cytokine mRNAs and proteins were analyzed. Although no apparent differences were recognized in postoperative complications or duration of postoperative hospital stay between the groups, the perioperative plasma aminotransferase level was significantly lower in the prostaglandin E1 group. Significant differences were also seen in interleukin-6 and nitrate plasma levels during the observation period and the interleukin-6 protein levels in the liver supernatants after hepatectomy in the two groups. In contrast, no significant differences were apparent between the interleukin-1 beta and tumor necrosis factor-alpha plasma levels of the two groups. The corrected fluorescence activities of interleukin-6 and inducible nitric oxide synthase mRNAs in the liver after hepatectomy correlated significantly. No interleukin-1 beta or tumor necrosis factor-alpha mRNAs or proteins were detected. Prostaglandin E1 exerted hepatoprotective effects on livers suffering from ischemia/reperfusion injury, and interleukin-6 might play an important role in these effects.


Varicella-zoster virus acute myelitis in a patient with MS treated with natalizumab.
We report a case of varicella-zoster virus (VZV) myelitis in a woman with relapsing-remitting multiple sclerosis (RRMS) receiving natalizumab, a humanized monoclonal antibody that induces an immunosuppression localized to the CNS.


Lack of mutant huntingtin in cortical efferents improves behavioral inflexibility and corticostriatal dynamics in Huntington's disease mice.
Abnormal communication between cerebral cortex and striatum plays a major role in the motor symptoms of Huntington's disease (HD), a neurodegenerative disorder caused by a mutation of the huntingtin gene (mHTT). Because cortex is the main driver of striatal processing, we recorded local field potential (LFP) activity simultaneously in primary motor cortex (M1) and dorsal striatum (DS) in BACHD mice, a full-length HD gene model, and in a conditional BACHD/Emx-1 Cre (BE) model in which mHTT is suppressed in cortical efferents, while mice freely explored a plus-shaped maze beginning at 20 wk of age. Relative to wild-type (WT) controls, BACHD mice were just as active across >40 wk of testing but became progressively less likely to turn into a perpendicular arm as they approached the choice point of the maze, a sign of HD motor inflexibility. BE mice, in contrast, turned as freely as WT throughout testing. Although BE mice did not exactly match WT in LFP activity, the reduction in alpha (8-13 Hz), beta (13-30 Hz), and low-gamma (30-50 Hz) power that occurred in M1 of turning-impaired BACHD mice was reversed. No reversal occurred in DS. In fact, BE mice showed further reductions in DS theta (4-8 Hz), beta, and low-gamma power relative to the BACHD model. Coherence analysis indicated a dysregulation of corticostriatal information flow in both BACHD and BE mice. Collectively, our results suggest that mHTT in cortical outputs drives the dysregulation of select cortical frequencies that accompany the loss of behavioral flexibility in HD.NEW & NOTEWORTHY BACHD mice, a full-length genetic model of Huntington's disease (HD), express aberrant local field potential (LFP) activity in primary motor cortex (M1) along with decreased probability of turning into a perpendicular arm of a plus-shaped maze, a motor inflexibility phenotype. Suppression of the mutant huntingtin gene in cortical output neurons prevents decline in turning and improves alpha, beta, and low-gamma activity in M1. Our results implicate cortical networks in the search for therapeutic strategies to alleviate HD motor signs.


Randomized, prospective, multicenter trial assessing the numen coil embolization system in the endovascular treatment of small intracranial aneurysms: outcomes from the CATCH Trial.
The CATCH (Coil Application Trial in China) trial was designed to assess the safety and efficacy of the Numen Coil Embolization System in the treatment of intracranial aneurysms in comparison with the Axium coil (ev3/Medtronic). Although the endovascular treatment of small (< 5 mm) intracranial aneurysms has been reported with favorable long-term clinical and angiographic outcomes, randomized trials are still lacking. Data for aneurysms smaller than 5 mm were extracted from the CATCH trial. A randomized, prospective, multicenter trial was conducted at ten centers throughout China. Enrolled subjects with small intracranial aneurysms were randomly assigned to receive treatment with the Numen Coil or the Axium coil. The primary outcome was successful aneurysm occlusion at the 6-month follow-up. In contrast, the secondary outcomes included complete aneurysm occlusion, recurrence rate, clinical deterioration, and safety data at the 6-month and 12-month follow-ups. A total of 124 patients were enrolled in the study. Overall, 58 patients were assigned to the Numen group, and 66 were assigned to the Axium group. At the 6-month follow-up, the successful aneurysm occlusion rate was 93.1% (54/58) in the MicroPort NeuroTech group and 97.0% (64/66) in the Axium group, with a common odds ratio of 0.208 (95% confidence interval, 0.023-1.914; P = 0.184). Complications were comparable between the groups. Compared with the Aixum coil, the Numen coil is safe and effective in treating small intracranial aneurysms. (13/12/2016, NCT02990156).


Association between anthropometry-based nutritional status and malaria: a systematic review of observational studies.
Multiple studies in various parts of the world have analysed the association of nutritional status on malaria using anthropometric measures, but results differ due to the heterogeneity of the study population, species of the parasite, and other factors involved in the host and parasite relationship. The aim of this study was to perform a systematic review on the inter-relationship of nutritional status based on anthropometry and malarial infection. Two independent reviewers accessed the MEDLINE and LILACS databases using the same search terms related to malaria and anthropometry. Prospective studies associating anthropometry and malaria (incidence or severity) were selected. References from the included studies and reviews were used to increase the review sensitivity. Data were extracted using a standardized form and the quality of the prospective studies was assessed. Selected articles were grouped based on exposures and outcomes. The search identified a total of 1688 studies: 1629 from MEDLINE and 59 from LILACS. A total of 23 met the inclusion criteria. Five additional studies were detected by reading the references of the 23 included studies and reviews, totaling 28 studies included. The mean sample size was 662.1 people, ranging from 57 to 5620. The mean follow-up was 365.8 days, ranging from 14 days to 1 year and 9 months, and nine studies did not report the follow-up period. Prospective studies assessing the relationship between malaria and malnutrition were mostly carried out in Africa. Of the 20 studies with malarial outcomes, fifteen had high and five had average quality, with an average score of 80.5 %. Most anthropometric parameters had no association with malaria incidence (47/52; 90.4 %) or parasite density (20/25; 80 %). However, the impact of malnutrition was noted in malaria mortality and severity (7/17; 41.2 %). Regarding the effects of malaria on malnutrition, malaria was associated with very few anthropometric parameters (8/39; 20.6 %). This systematic review found that most of the evidence associating malaria and malnutrition comes from P. falciparum endemic areas, with a significant heterogeneity in studies' design. Apparently malnutrition has not a great impact on malaria morbidity, but could have a negative impact on malaria mortality and severity. Most studies show no association between malaria and subsequent malnutrition in P. falciparum areas. In Plasmodium vivax endemic areas, malaria was associated with malnutrition in children. A discussion among experts in the field is needed to standardize future studies to increase external validity and accuracy.


Anatomical evidence for the efferent pathway from the hypothalamus to autonomic innervation in the anterior chamber structures of eyes.
The autonomic innervation in the anterior chamber (AC) structures might play an efferent role in neural intraocular pressure (IOP) regulation, the center of which is thought to be located in the hypothalamus. In this study, we identified the efferent pathway from the hypothalamus to the autonomic innervation in the AC structures. Retrograde trans-multisynaptic pseudorabies virus (PRV) expressing green or red fluorescent protein, PRV531 and PRV724, was injected into the right and left AC of five rats, respectively; PRV531 was injected into the right AC of another five rats, and a non-trans-synaptic tracer, FAST Dil, was injected into the right AC of five rats as a control. Fluorescence signals in autonomic ganglia,the spinal cord and the central nervous system (CNS) were observed. Seven days after FAST Dil right AC injection, FAST Dil-labeled neurons were observed in the ipsilateral autonomic ganglia, including the superior cervical ganglion, pterygopalatine ganglion, and ciliary ganglion, but not in the CNS. Four and a half days after PRV531 injection into the right AC, PRV531-labeled neurons could be observed in the ipsilateral autonomic ganglia and bilateral hypothalamus nuclei, especially in the suprachiasmatic nucleus, paraventricular nucleus, dorsomedial hypothalamus, perifornical hypothalamus and ventral mammillary nucleus. Fluorescence signals of PRV531 mainly located in the ipsilateral autonomic preganglionic nuclei (Edinger-Westphal nucleus, superior salivatory nucleus and intermediolateral nucleus), but not in sensory trigeminal nuclei. Four and a half days after PRV531 right AC injection and PRV724 left AC injection, PRV531-labeled, PRV724-labeled, and double-labeled neurons could be observed in the above mentioned bilateral hypothalamus nuclei; but few contralateral infection-involving neurons (including double-labeled neurons) could be detected in the autonomic preganglionic nuclei. Our results indicate that there exist a both crossed and uncrossed hypothalamo-pre-parasympathetic and -pre-sympathetic tracts in the efferent pathways between the bilateral hypothalamic nuclei and the autonomic innervation of the bilateral AC.


Amino acid sequence of S-adenosyl-L-homocysteine hydrolase from Dictyostelium discoideum as deduced from the cDNA sequence.
S-Adenosyl-L-homocysteine hydrolase has been cloned from a lambda gt11 cDNA library prepared from Dictyostelium discoideum that had been starved for 3 hours. The sequence of the cloned cDNA was determined and the deduced amino acid sequence was compared to the amino acid sequence of rat AdoHcy hydrolase. When the sequences from the two species were aligned, 74% of the amino acids were in identical positions. If conservative changes were taken into account the homology was 84%. Because differences have been reported in the binding characteristics of NAD+ to the D. discoideum and rat AdoHcy hydrolases, changes in the amino acids of the putative NAD+-binding site were of particular interest. Six changes were observed in this region but the changes appeared to be in regions that are not critical to the three dimensional folding of the NAD+-binding site.


Blood pressure and albuminuria in a female mouse model of systemic lupus erythematosus: impact of long-term high salt consumption.
Hypertension and kidney involvement are common in patients with autoimmune disease. Sodium intake is linked to hypertension in both human and animal studies. Evidence suggests that dietary salt may be an important environmental factor that promotes autoimmune activity. Therefore, we hypothesized that a long-term high-salt diet would accelerate the progression of autoimmunity, hypertension, and albuminuria during systemic lupus erythematosus (SLE), an autoimmune disease that predominantly affects young women and has a high prevalence of hypertension and renal disease. To test this hypothesis, an established experimental model of SLE (female NZBWF1 mice) that develops hypertension and renal disease was used. SLE mice were fed a high-salt (4% NaCl) or normal (0.4% NaCl) diet for 24 wk beginning at 10 wk of age and ending at 34 wk of age, a time by which female NZBWF1 mice typically have hypertension and exhibit signs of renal disease. Plasma anti-dsDNA autoantibodies were measured as an indicator of active SLE disease, and urinary albumin was monitored longitudinally as a marker of renal disease. Arterial pressure was measured in conscious, freely moving mice at 34 wk of age. Urinary endothelin-1 (ET-1) excretion, renal endothelin A and B receptor protein expression, and renal mRNA expression of NOS1, NOS2, NOX2, MCP-1, TNF-α, serum- and glucocorticoid-regulated kinase 1, and interleukin-2 (IL-2) were assessed to determine the impact on gene products commonly altered by a high-salt diet. SLE mice fed a high-salt diet had increased circulating autoantibodies, but the high-salt diet did not significantly affect albuminuria or arterial pressure. Urinary ET-1 excretion was increased, whereas renal endothelin A receptor and IL-2 expression were decreased in response to a high-salt diet. These data suggest that a chronic high-salt diet may not accelerate cardiovascular and renal consequences commonly associated with SLE.


Long-term stability of conservative orthodontic treatment in a patient with rheumatoid arthritis and severe condylar resorption.
Rheumatoid arthritis is a chronic inflammatory condition that can result in progressive destruction of the articular surfaces of the joints, including the temporomandibular joint. The purpose of this article is to report the conservative correction of a Class II malocclusion in a woman with rheumatoid arthritis. The patient was 32 years 6 months old at the start of treatment. She had a convex profile and a skeletal Class II jaw-base relationship caused by severe condylar resorption. An anterior open bite of -2.0 mm and an excessive overjet of 10.0 mm were observed. Severe crowding was shown in the mandibular incisors. After 8 months of splint therapy, all first premolars were extracted, and 0.018-in preadjusted edgewise appliances were placed in both arches. Class II elastics were used during space closure. After 41 months of active orthodontic treatment, an acceptable occlusion was achieved, and the facial profile was considerably improved. From the cephalometric evaluations, the mandible was rotated counterclockwise, and the mandibular plane angle was significantly decreased. However, the anteroposterior position of the chin was not changed. The condylar resorption was not changed during and after orthodontic treatment. Conclusively, the proper facial profile was maintained, and the occlusion was stable after a 5-year retention period. Our results suggest the possibility of compromised treatment in a Class II malocclusion with an anterior open bite because of rheumatoid arthritis.


Use of ultrasound and targeted physiotherapy to manage nerve sutures placed under joint flexion: a case series.
Joint flexion to diminish the gap and avoid nerve grafts fell into disuse for decades, but recently attention for using this technique was regained. We report a case series of nerve suture under joint flexion, ultrasound monitoring, and physiotherapy. Our main objective was to determine how effective this multimodality treatment is. A retrospective review of 8 patients treated with direct repair with joint flexion was done. Depending on the affected nerve, either the knee or the elbow was flexed intraoperatively to determine if direct suturing was possible. After surgery, the limb was held immobilized. Through serial ultrasounds and a physiotherapy program, the limb was fully extended. If a nerve repair rupture was observed, the patient was re-operated and grafts were used. Of the eight nerve sutures analyzed, four sustained a nerve rupture revealed by US at an early stage, while four did not show any sign of dehiscence. In the patients in whom the nerve suture was preserved, an early and very good response was observed. Ultrasound was 100% accurate at identifying nerve suture preservation. Early detection of nerve failure permitted early re-do surgery using grafts without flexion, ultimately determining good final results. We observed a high rate of dehiscence in our group of patients treated with direct repair and joint flexion. We believe this was due to an incorrect use of the immobilization device, excessive movement, or a broken device. In opposition to this, we observed that applying direct nerve sutures and joint flexion offers unusually good and fast results. If this technique is employed, it is mandatory to closely monitor suture status with US, together with physiotherapy providing progressive, US-guided extension of the flexed joint. If nerve rupture occurs, the close monitoring dictated by this protocol should ensure the timely application of a successful graft repair.


Impact of lung function impairment after allogeneic hematopoietic stem cell transplantation.
Late-onset noninfectious pulmonary complications (LONIPC) are a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). However, the clinical impact of lung function deterioration itself in long-term adult survivors of HSCT remains to be fully investigated. This retrospective, longitudinal study aimed to investigate pulmonary function following HSCT in terms of its change and the clinical significance of its decline. We examined 167 patients who survived for at least 2 years without relapse. The median follow-up period was 10.3 years. A linear mixed-effects model showed that the slope of pulmonary function tests values, including percent vital capacity (%VC), percent forced expiratory volume in one second (%FEV1), and FEV1/forced VC ratio (FEV1%), decreased over time. The cumulative incidence of newly obstructive and restrictive lung function impairment (LFI) at 10 years was 15.7% and 19.5%, respectively. Restrictive LFI was a significant, independent risk factor for overall survival (hazard ratio 7.11, P = 0.007) and non-relapse mortality (hazard ratio 12.19, P = 0.003). Our data demonstrated that lung function declined over time after HSCT and that the decline itself had a significant impact on survival regardless of LONIPC.