Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress.
Physical exercise exacerbates the cytotoxic effects of statins in skeletal muscle. Mitochondrial impairments may play an important role in the development of muscular symptoms following statin treatment. Our objective was to characterize mitochondrial function and reactive oxygen species (ROS) production in skeletal muscle after exhaustive exercise in atorvastatin-treated rats. The animals were divided into four groups: resting control (CONT; n = 8) and exercise rats (CONT+EXE; n = 8) as well as resting (ATO; n = 10) and exercise (ATO+EXE; n = 8) rats that were treated with atorvastatin (10 mg·kg(-1)·day(-1) for 2 wk). Exhaustive exercise showed that the distance that was covered by treated animals was reduced (P < 0.05). Using dihydroethidium staining, we showed that the ROS level was increased by 60% in the plantaris muscle of ATO compared with CONT rats and was highly increased in ATO+EXE (226%) compared with that in CONT+EXE rats. The maximal mitochondrial respiration (V(max)) was decreased in ATO rats compared with that in CONT rats (P < 0.01). In CONT+EXE rats, V(max) significantly increased compared with those in CONT rats (P < 0.05). V(max) was significantly lower in ATO+EXE rats (-39%) compared with that in CONT+EXE rats (P < 0.001). The distance that was covered by rats significantly correlated with V(max) (r = 0.62, P < 0.01). The glycogen content was decreased in ATO, CONT+EXE, and ATO+EXE rats compared with that in CONT rats (P < 0.05). GLUT-4 mRNA expression was higher after exhaustive exercise in CONT+EXE rats compared with the other groups (P < 0.05). Our results show that exhaustive exercise exacerbated metabolic perturbations and ROS production in skeletal muscle, which may reduce the exercise capacity and promote the muscular symptoms in sedentary atorvastatin-treated animals.


Acute sleep deprivation during pregnancy in rats: Rapid elevation of placental and fetal inflammation and kynurenic acid.
The kynurenine pathway (KP) is the dominant pathway for tryptophan degradation in the mammalian body and emerging evidence suggests that acute episodes of sleep deprivation (SD) disrupt tryptophan metabolism via the KP. Increases in the neuroactive KP metabolite kynurenic acid (KYNA) during pregnancy may lead to a higher risk for disrupted neurodevelopment in the offspring. As pregnancy is a critical period during which several factors, including sleep disruptions, could disrupt the fetal environment, we presently explored the relationship between maternal SD and KP metabolism and immune pathways in maternal, placenta, and fetal tissues. Pregnant Wistar rat dams were sleep deprived by gentle handling for 5 h from zeitgeber time (ZT) 0 to ZT 5. Experimental cohorts included: i) controls, ii) one session of SD on embryonic day (ED) 18 or iii) three sessions of SD occurring daily on ED 16, ED 17 and ED 18. Maternal (plasma, brain), placental and fetal (plasma, brain) tissues were collected immediately after the last session of SD or after 24 h of recovery from SD. Respective controls were euthanized at ZT 5 on ED 18 or ED 19. Maternal plasma corticosterone and fetal brain KYNA were significantly elevated only after one session of SD on ED 18. Importantly, maternal plasma corticosterone levels correlated significantly with fetal brain KYNA levels. In addition, placental levels of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) were increased following maternal SD, suggesting a relationship between placental immune response to SD and fetal brain KYNA accumulation. Collectively, our results demonstrate that sleep loss during the last week of gestation can adversely impact maternal stress, placental immune function, and fetal brain KYNA levels. We introduce KYNA as a novel molecular target influenced by sleep loss during pregnancy.


Repositioning of displaced guglielmi detachable coils after endosaccular embolisation using a modification of the neck plastic technique. A technical note.
After undergoing prior partial surgical clipping of an acutely ruptured internal carotid aneurysm, a 29-year-old woman was referred for endovascular treatment of the gradually enlarging aneurysm remnant. The aneurysm had a somewhat peculiar ellipsoid configuration due to placement of the clip, with the largest dimension measuring less than 4 mm, and the neck measuring approximately 2 mm. Using the conventional endosaccular coil embolisation technique, two small electrolytically detachable coils were carefully folded into the aneurysm sac to produce excellent tight packing. However, immediately after detachment,a loop of the second coil inadvertently herniated out of the aneurysm into the center of the parent artery, exhibiting substantial pulse synchronous displacement. This created a potentially unstable situation for the remaining coils within the embolised aneurysm. To correct this problem we attempted to reposition the loop into the aneurysm using a modification of the previously described neck plastic technique. This technique succeeded without untoward complication. Although there are theoretical risks and limitations, the modified neck plastic technique may be useful in selective cases of inadvertent coil misplacement during endosaccular coil embolisation of aneurysms with the GDC system.


Lidoflazine and propranolol combination treatment in chronic stable angina.
The short-term (1 month) and long-term (6 months) safety of combination lidoflazine-propranolol therapy was investigated in an open trial of 15 patients with stable angina of effort. The possible advantages of adding lidoflazine (titrated to 360 mg daily) to patients having a therapeutic response to propranolol (80-400 mg daily) was also evaluated. Effects on non-invasive indexes of left ventricular function (echocardiography, systolic time intervals, radionuclide ventriculography) and exercise tolerance (treadmill exercise testing) were determined. There was no change in mean resting heart rate with the combination therapy, although one patient developed sinus bradycardia at a rate of 44 and had to have his propranolol dose reduced. Electrocardiographic analysis showed significant prolongation of the QTc intervals on lidoflazine-propranolol therapy compared to propranolol alone, with 3 patients having QTc interval prolongation to above .53 seconds, but there was no evidence of increased arrhythmogenesis with the combination therapy compared to propranolol alone. Left ventricular end-diastolic volume index tended to rise with combination therapy. However, lidoflazine-propranolol therapy did not produce any significant effects on resting ejection fraction determined by M-mode echocardiography or by radionuclide ventriculography. Radionuclide ventriculography determined peak exercise ejection fractions were also not significantly changed with combination therapy compared to propranolol alone. There were only small, insignificant improvements in exercise tolerance with the lidoflazine-propranolol combination treatment compared to propranolol alone. It is concluded that lidoflazine-propranolol combination therapy is generally safe but has the potential of causing serious adverse effects in certain patients, i.e. those with sick sinus disease, prolonged QTc intervals, and severe baseline left ventricular dysfunction, and that caution must be exercised in its use. Furthermore, it would appear that combination therapy provides only slight, if any, improvements in exercise tolerance in patients with chronic stable angina having a therapeutic response to oral propranolol.


Somatotopic mapping of the human breast using 7 T functional MRI.
How are tactile sensations in the breast represented in the female and male brain? Using ultra high-field 7 T MRI in ten females and ten males, we demonstrate that the representation of tactile breast information shows a somatotopic organization, with cortical magnification of the nipple. Furthermore, we show that the core representation of the breast is organized according to the specific nerve architecture that underlies breast sensation, where the medial and lateral sides of one breast are asymmetrically represented in bilateral primary somatosensory cortex. Finally, gradual selectivity signatures allude to a somatotopic organization of the breast area with overlapping, but distinctive, cortical representations of breast segments. Our univariate and multivariate analyses consistently showed similar somatosensory breast representations in males and females. The findings can guide future research on neuroplastic reorganization of the breast area, across reproductive life stages, and after breast surgery.


Empowering patients with high myopia: The significance of education.
To investigate the status of patient education among highly myopic individuals focusing on the presence, sources, content, timing of the education and impact on patients. Self-reported data were collected through an online 13-item questionnaire consisting of open and multiple-choice questions. The questionnaire was sent to 250 highly myopic members of a patient organization in the Netherlands, of whom 128 (51%) responded. At least one acute event had occurred in 66% (84/128) of participants at the time of the questionnaire. Among all participants, 25% (32/128) had not received patient education regarding alarm symptoms for any of these events. Among those who had been informed, the ophthalmologist was the most frequent (57%, 73/128) source of information. Participants who visited the ophthalmologist annually were more frequently informed than participants without annual visits (53%, 26/49 versus 26%, 9/35, p = 0.002). Those not informed were more likely to have a more than 3 days patient delay (92%, 12/13). Doctors delay was also present; 26% (22/84) of the participants with alarm symptoms had to wait 2 or more days before the first appointment. Long-term consequences of myopia had been discussed with 102 participants (80%, 102/128), again with the ophthalmologist as the most frequent source (59%, 76/128). Many myopic individuals have not been educated about their increased risk of acute events, which can result in patient delay and serious consequences with respect to visual prognosis. These findings underscore the critical importance of integrating patient education across the entire ophthalmic care chain for myopia.


A Violaxanthin Deepoxidase Interacts with a Viral Suppressor of RNA Silencing to Inhibit Virus Amplification.
RNA silencing plays a critical role against viral infection. To counteract this antiviral silencing, viruses have evolved various RNA silencing suppressors. Meanwhile, plants have evolved counter-counter defense strategies against RNA silencing suppression (RSS). In this study, the violaxanthin deepoxidase protein of maize (Zea mays), ZmVDE, was shown to interact specifically with the helper component-proteinase (HC-Pro; a viral RNA silencing suppressor) of Sugarcane mosaic virus (SCMV) via its mature protein region by yeast two-hybrid assay, which was confirmed by coimmunoprecipitation in Nicotiana benthamiana cells. It was demonstrated that amino acids 101 to 460 in HC-Pro and the amino acid glutamine-292 in ZmVDE mature protein were essential for this interaction. The mRNA levels of ZmVDE were down-regulated 75% to 65% at an early stage of SCMV infection. Interestingly, ZmVDE, which normally localized in the chloroplasts and cytoplasm, could relocalize to HC-Pro-containing aggregate bodies in the presence of HC-Pro alone or SCMV infection. In addition, ZmVDE could attenuate the RSS activity of HC-Pro in a specific protein interaction-dependent manner. Subsequently, transient silencing of the ZmVDE gene facilitated SCMV RNA and coat protein accumulation. Taken together, our results suggest that ZmVDE interacts with SCMV HC-Pro and attenuates its RSS activity, contributing to decreased SCMV accumulation. This study demonstrates that a host factor can be involved in secondary defense responses against viral infection in monocot plants.


Dermatological Findings in Turkish Paediatric Haematology-Oncology Patients.
Diagnoses of skin, mucosae, hair and nail manifestations in malignant diseases are often challenging because of life-threatening drug reactions, opportunistic infections or skin involvement of primary processes. Description of morphology, configuration and distribution of lesions is important in order to differentiate the self-healing eruptions from serious side effects of chemotherapy. There are case reports from Turkey including dermatological manifestations of malignancies and case series in adult patients but there are no published large group studies assessing all manifestations in children. The aim of this study was to evaluate the morphological features of dermatological findings in children with haemato-oncological diseases. The study was performed at the Erciyes University, Faculty of Medicine Pediatric Hematology-Oncology Clinic, Turkey. Three dermatologists daily consulted all patients admitted to the clinic during a one-year period. The study group comprised of 157 children (79 female/78 male) aged 1-16 years (mean 7.19±4.63). Detailed dermatological examinations were performed, including oral-genital mucosae, hair and nails. Thorough skin examination revealed that 70% of the patients exhibited at least one dermatological finding. Generalized xerosis and hyperpigmentation were the most common findings among patients undergoing chemotherapy (24.19%). Multiple nevi on at least 10 covered areas were very frequent among patients undergoing long-term chemotherapy (18.47%). Three were identified as dysplastic nevus, but malignant transformation was not observed during the one-year study period. Regular dermatological consultation may help resolve the diagnostic and therapeutic problems in paediatric haemato-oncology clinics.


Outcome of Full-Thickness Macular Hole Surgery in Choroideremia.
The development of a macular hole is relatively common in retinal dystrophies eligible for gene therapy such as choroideremia. However, the subretinal delivery of gene therapy requires an uninterrupted retina to allow dispersion of the viral vector. A macular hole may thus hinder effective gene therapy. Little is known about the outcome of macular hole surgery and its possible beneficial and/or adverse effects on retinal function in patients with choroideremia. We describe a case of a unilateral full-thickness macular hole (FTMH) in a 45year-old choroideremia patient (c.1349_1349+2dup mutation in CHM gene) and its management. Pars plana vitrectomy with internal limiting membrane (ILM) peeling and 20% SF₆ gas tamponade was performed, and subsequent FTMH closure was confirmed at 4 weeks, 3 months and 5 months postoperatively. No postoperative adverse events occurred, and fixation stability improved on microperimetry from respectively 11% and 44% of fixation points located within a 1° and 2° radius, preoperatively, to 94% and 100% postoperatively. This case underlines that pars plana vitrectomy with ILM peeling and gas tamponade can successfully close a FTMH in choroideremia patients, with subsequent structural and functional improvement. Macular hole closure may be important for patients to be eligible for future submacular gene therapy.


Endoplasmic reticulum retention of xylosyltransferase 1 (XYLT1) mutants underlying Desbuquois dysplasia type II.
Desbuquois syndrome is a heterogeneous rare type of skeletal dysplasia with a prevalence of less than 1 in 1,000,000 individuals. It is characterized by short-limbed dwarfism, dysmorphic facial features, and severe joint laxity. Two types have been recognized depending on the presence of distinctive carpal and phalangeal features. Mutations in the calcium activated nucleotidase 1 (CANT1) have been found to be responsible for type I and lately, for the Kim type of Desbuquois dysplasia. In addition, a number of Desbuquois dysplasia type II patients have been attributed to mutations in xylosyltransferase 1, encoded by the XYLT1 gene, an enzyme that catalyzes the transfer of UDP-xylose (a marker of cartilage destruction) to serine residues of an acceptor protein, essential for the biosynthesis of proteoglycans. We report here a patient with features consistent with Desbuquois dysplasia II including short long bones, flat face, mild monkey wrench appearance of the femoral heads. Whole exome sequencing revealed a novel homozygous duplication of a single nucleotide in XYLT1 gene (c.2169dupA). This variant is predicted to result in a frame-shift and stop codon p.(Val724Serfs*10) within the xylosyltransferase catalytic domain. Immunoflourescence staining of HeLa cells transfected with mutated XYLT1 plasmids constructs of the current as well as the previously reported missense mutations (c.1441C>T, p.(Arg481Trp) and c.1792C>T, p.(Arg598Cys)), revealed aberrant subcellular localization of the enzyme compared to wild-type, suggesting endoplasmic reticulum retention of these mutants as the likely mechanism of disease.


Macrophage colony-stimulating factor gene expression in vascular cells and in experimental and human atherosclerosis.
The infiltration of monocytes into the vascular wall and their transformation into lipid-laden foam cells characterizes early atherogenesis. Macrophages are also present in more advanced human atherosclerotic plaques and can produce many mediators that may contribute to lesion formation and progression. Macrophage colony-stimulating factor (MCSF) enhances the proliferation and differentiation of monocyte progenitors and is required for the survival and activation of mature monocytes and macrophages. The authors therefore examined the expression of the MCSF gene in cultured human vascular endothelial (EC) and smooth muscle cells (SMC) as well as in atheromatous lesions from rabbits and humans. Growth arrested EC and SMC contain a low level of MCSF mRNA. Bacterial lipopolysaccharide (LPS), recombinant human interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor alpha (TNF alpha) induced MCSF mRNA accumulation in a concentration-dependent manner in both EC and SMC. These stimuli induced large increases in MCSF mRNA with peak induction between 4-8 hours after treatment. LPS, IL-1 alpha, and TNF alpha stimulated EC and SMC also showed increased fluorescent antibody staining for MCSF protein and released immunoreactive MCSF in a time-dependent manner. In contrast, phorbol 12-myristate 13-acetate (PMA) was a less potent inducer of MCSF gene expression and iron-oxidized low-density lipoproteins (ox-LDL) did not increase consistently MCSF mRNA or the synthesis and secretion of immunoreactive protein. Northern analysis of mRNA isolated from the atheromatous aorta of rabbits fed a 1% cholesterol diet for 10 weeks showed elevated MCSF mRNA compared with controls. Immunostaining of atheromatous arterial lesions of rabbits demonstrated MCSF protein in association with intimal SMC as well as macrophages. Furthermore, polymerase chain reaction (PCR) analysis of MCSF mRNA in human atheromata showed higher levels than found in nonatherosclerotic arteries and veins. Since the authors found no mRNA for the MCSF receptor, c-fms, in cultured EC or SMC macrophages are likely the primary target for MCSF within atheromatous vessels. The authors therefore investigated the effects of MCSF on monocyte functions related to foam cell development. Treatment of cultured human monocytes with recombinant human MCSF (10(3) U/ml, 72 hr) led to the accumulation of mRNA for the acetyl-LDL (scavenger) receptor and apolipoprotein E (apo E). These studies establish that vascular EC and SMC produce substantial MCSF in response to a variety of stimuli. The local production of MCSF during atherogenesis may contribute to macrophage survival and proliferation or activate specific macrophage functions such as expression of the scavenger receptor and secretion of apo E.


What the "Nonteaching" Service Can Teach Us.
"Teaching" services usually incorporate a cadre of learners such as resident physicians and medical students as part of the care team, led by a faculty physician. "Nonteaching" services, in contrast, are usually defined by the absence of resident physicians on the care team. The care for patients on a nonteaching service is frequently managed directly by a faculty or nonfaculty physician. Nonteaching services have grown in number and size at academic medical centers (AMCs) in response to regulatory requirements, operational demands, and efforts to improve clinical education. The allocation of patients to teaching and nonteaching services is frequently based on perceived teaching value of hospitalized patients, which can potentially lead to a number of unintended consequences for medical education, professional satisfaction, and patient care. Through a series of four lessons, the authors describe how the structure of nonteaching services can result in curricular gaps, devalue attending physicians, and undermine the educational and clinical missions of AMCs. Anticipating the continued expansion and evolution of nonteaching services, the authors propose seven design principles for nonteaching services to ensure robust education for students and resident physicians, advance quality of care, and enhance attending physician and patient experience.


Advances in higher-order chromatin architecture: the move towards 4D genome.
In eukaryotes, the genome is hierarchically packed inside the nucleus, which facilitates physical contact between cis-regulatory elements (CREs), such as enhancers and promoters. Accumulating evidence highlights the critical role of higherorder chromatin structure in precise regulation of spatiotemporal gene expression under diverse biological contexts including lineage commitment and cell activation by external stimulus. Genomics and imaging-based technologies, such as Hi-C and DNA fluorescence in situ hybridization (FISH), have revealed the key principles of genome folding, while newly developed tools focus on improvement in resolution, throughput and modality at single-cell and population levels, and challenge the knowledge obtained through conventional approaches. In this review, we discuss recent advances in our understanding of principles of higher-order chromosome conformation and technologies to investigate 4D chromatin interactions. [BMB Reports 2021; 54(5): 233-245].


Tuning dCas9's ability to block transcription enables robust, noiseless knockdown of bacterial genes.
Over the past few years, tools that make use of the Cas9 nuclease have led to many breakthroughs, including in the control of gene expression. The catalytically dead variant of Cas9 known as dCas9 can be guided by small RNAs to block transcription of target genes, in a strategy also known as CRISPRi. Here, we reveal that the level of complementarity between the guide RNA and the target controls the rate at which RNA polymerase "kicks out" dCas9 from the target and completes transcription. We use this mechanism to precisely and robustly reduce gene expression by defined relative amounts. Alternatively, tuning repression by changing dCas9 concentration is noisy and promoter-strength dependent. We demonstrate broad applicability of this method to the study of genetic regulation and cellular physiology. First, we characterize feedback strength of a model auto-repressor. Second, we study the impact of amount variations of cell-wall synthesizing enzymes on cell morphology. Finally, we multiplex the system to obtain any combination of fractional repression of two genes.


Targeting Murine Mesenchymal Stem Cells to Kidney Injury Molecule-1 Improves Their Therapeutic Efficacy in Chronic Ischemic Kidney Injury.
Mesenchymal stem cells (MSC) have been experimentally used for kidney repair, but modest retention limits their efficacy. Cell-surface coating allows modulating MSC homing and interaction with target cells. We coated mouse adipose tissue-derived MSC with antibodies directed against kidney injury molecule-1 (ab-KIM1), which is upregulated in injured kidneys, and tested the hypothesis that this would enhance their therapeutic effects in ischemic kidney injury. Untreated MSC, ab-KIM1-coated MSC (KIM-MSC), or vehicle, were injected systemically into the carotid artery of 2-kidneys, 1-clip mice 2 weeks after surgery. MSC retention in different organs was explored 24 hours, 48 hours, or 2 weeks after injection. Renal volume, perfusion, and oxygenation were studied 2 weeks after injection using magnetic resonance imaging in vivo, and renal inflammation, apoptosis, capillary density, and fibrosis ex vivo. The ab-KIM1 coating had little effect on MSC viability or proliferation. The stenotic kidney showed upregulated KIM1 expression, selective homing, and greater retention of KIM-MSC compared to untreated MSC and compared to other organs. KIM-MSC-injected mice improved renal perfusion and capillary density, and attenuated oxidative damage, apoptosis, and fibrosis compared to mice treated with vehicle or with native MSC. In conclusion, MSC coating with ab-KIM1 increased their retention in the ischemic kidney and enhanced their therapeutic efficacy. This novel method may be useful to selectively target injured kidneys, and supports further development of strategies to enhance cell-based treatment of ischemic kidney injury. Stem Cells Translational Medicine 2018;7:394-403.


Anastomotic Revision in Head and Neck Free Flaps.
Predictors of free tissue transfer (FTT) failure and the need for postoperative revision (POR) have been extensively studied; however, there are little data evaluating outcomes when intraoperative revision (IOR) at initial surgery is required. This study seeks to better understand the impact IOR of the pedicle has on FTT outcomes. Retrospective review of 2482 consecutive patients across three tertiary institutions. Adult patients (>18) who received a FTT and underwent anastomotic revision from 2006 to 2019 were included. Logistic regression was performed to predict revision, and recursive partitioning was performed to classify risk of failure based on type of revision and vessels revised. Failure rates for IOR (19%) and POR (27%) were higher compared to a nonrevised failure rate of 2% (P < .01 and P < .01, respectively). Intraoperative venous revision (IORv, n = 13), arterial (IORa, n = 114), and both (IORb, n = 11) were associated with failure rates of 8% (odds ratio [OR] 3.5, P = .23), 18% (OR = 9.0, P < .01), 45% (OR = 35.3, P = <.01), respectively. Arterial revision was most common among IOR (83%, P < .01). Postoperative venous revision (PORv, n = 35), arterial (PORa, n = 36), and both (PORb, n = 11) were associated with failure rates of 20% (OR = 15.7, P < .01), 27% (OR = 10.6, P < .01), and 39% (OR = 27.0, P < .01), respectively. Failure rate for flaps that had POR after IOR (PORi, n = 11) was 45% (OR = 18.2, P < .01). Diabetes predicted IOR (P = .006); tobacco use, heavy alcohol use, and prior radiation predicted POR (P = .01, P = .05, and P = .01, respectively). Both IOR and POR were associated with increased failure compared to nonrevised flaps. The risk of failure increases sequentially with intraoperative or POR of the vein, artery, or both vessels. Revision of both vessels and POR after IOR are strongly predictive of failure. 3 Laryngoscope, 131:1035-1041, 2021.


Transplacental transmission of Human Papillomavirus.
This paper aimed at studying the transplacental transmission of HPV and looking at the epidemiological factors involved in maternal viral infection. The following sampling methods were used: (1) in the pregnant woman, (a) genital; (b) peripheral blood; (2) in the newborn, (a) oral cavity, axillary and inguinal regions; (b) nasopharyngeal aspirate, and (c) cord blood; (3) in the placenta. The HPV DNA was identified using two methods: multiplex PCR of human beta-globin and of HPV using the PGMY09 and PGMY11 primers; and nested-PCR, which combines degenerated primers of the E6/E7 regions of the HPV virus, that allowed the identification of genotypes 6/11, 16, 18, 31, 33, 42, 52 and 58. Transplacental transmission was considered when type-specific HPV concordance was found between the mother, the placenta and the newborn or the mother and cord blood. The study included 49 HPV DNA-positive pregnant women at delivery. Twelve placentas (24.5%, n = 12/49) had a positive result for HPV DNA. Eleven newborn were HPV DNA positive in samples from the nasopharyngeal or buccal and body or cord blood. In 5 cases (10.2%, n = 5/49) there was HPV type-specific agreement between genital/placenta/newborn samples. In one case (2%, n = 1/49) there was type specific HPV concordance between genital/cord blood and also suggested transplacental transmission. A positive and significant correlation was observed between transplacental transmission of HPV infection and the maternal variables of immunodepression history (HIV, p = 0.011). In conclusion the study suggests placental infection in 23.3% of the cases studied and transplacental transmission in 12.2%. It is suggested that in future HPV DNA be researched in the normal endometrium of women of reproductive age. The possible consequence of fetal exposure to HPV should be observed.


Four methods of estimating the minimal important difference score were compared to establish a clinically significant change in Headache Impact Test.
To estimate the smallest decrease in Headache Impact Test (HIT) scores that reflects meaningful clinical change among patients with chronic daily headache (CDH). We applied four methods of estimating the minimum important difference (MID) to data from 71 patients with CDH who participated in a clinical trial. The HIT was administered at baseline and at the 6-week follow-up assessment. Patients were considered to have experienced meaningful improvement if they reported that their headache condition was "somewhat better" or "much better" at the 6-week follow-up. Mean HIT scores at baseline and 6 weeks for all patients were 64.5 (standard deviation SD = 6.0) and 62.6 (SD = 5.7), respectively. HIT scores decreased 3.7 (SD = 4.4) and 1.4 (SD = 3.6) units, respectively, among patients who reported "somewhat better" change and those who reported no change at 6 weeks. Estimates of the MID of the HIT ranged from -2.7 to -2.3. The method that we judge to be most valid estimated the MID of the HIT at -2.3 units (95% confidence interval = -4.3, -0.3). This suggests that a between-group difference in HIT change scores of 2.3 units over time among patients with CDH reflects improvement in patients' headache condition that may be considered clinically significant.


Polymorphic expression of decay-accelerating factor in human colorectal cancer.
We have previously shown that expression of decay-accelerating factor (DAF), a complement regulatory protein, is enhanced immunohistochemically on the luminal surface of cancer glands in human colorectal cancer and is detected in stool specimens of patients with colorectal cancer. The amount of DAF present in the stools might be influenced by the stability of DAF on the cell surface which is regulated by biochemical properties such as glycosylation of the protein. In the present study, to help elucidate the mechanism for the release of DAF from human colorectal cancers, we biochemically analyzed DAF expression by western and northern blotting by using surgically resected specimens of colorectal cancers. Surgically resected colorectal cancer tissues were obtained from 10 patients. Expression of DAF was determined by western and northern blotting, and glycosylation of DAF protein was analyzed with glycosidase digestion. Northern blot analysis demonstrated that the expression of DAF mRNA in colorectal cancer was enhanced two- to threefold compared with normal tissues. In western blotting, expression of DAF protein in the cancer tissue was increased, and heterogeneity in the apparent molecular weight of DAF was observed among patients. When o-linked sugars were removed, this heterogeneity of DAF size diminished. The polymorphic expression of DAF in colorectal cancer is likely to reflect variability in the o-glycosylation of the protein. We speculate that this variability could affect the stability of DAF on the surfaces of cancer cells and, in turn, the amount of DAF shed into the stools of colorectal cancer patients.


Prevalence of lymphoreticular prion protein accumulation in UK tissue samples.
This study aims to provide an estimate of the number of individuals in the UK who may be incubating variant Creutzfeldt-Jakob disease and at risk of causing iatrogenic spread of the disease. Lymphoreticular accumulation of prion protein is a consistent feature of variant Creutzfeldt-Jakob at autopsy and has also been demonstrated in the pre-clinical phase. Immunohistochemical accumulation of prion protein in the lymphoreticular system remains the only technique that has been shown to predict neurological disease reliably in animal prion disorders. In this study, immunohistochemistry was used to demonstrate the presence of prion protein, with monoclonal antibodies KG9 and 3F4, in surgically removed tonsillectomy and appendicectomy specimens. The samples were collected from histopathology departments across the UK and anonymised prior to testing. Samples were tested from 16 703 patients (14 964 appendectomies, 1739 tonsillectomies), approximately 60% of whom were from the age group 20-29 years at operation. Twenty-five per cent of the samples were excluded from the final analyses because they contained inadequate amounts of lymphoid tissue. Three appendicectomy samples showed lymphoreticular accumulation of prion protein, giving an estimated prevalence of 3/12 674 or 237 per million (95% CI 49-692 per million). The pattern of lymphoreticular accumulation in two of these samples was dissimilar from that seen in known cases of variant Creutzfeldt-Jakob disease. Although it is uncertain whether immunohistochemical accumulation of prion protein in the lymphoreticular system is specific for variant Creutzfeldt-Jakob disease, it has not been described in any other disease, including other forms of human prion disease or a range of inflammatory and infective conditions. These findings reinforce the importance of measures taken by the UK Department of Health to reduce the risk of spread of variant Creutzfeldt-Jakob via blood products and surgical instruments, and of the urgency to proceed with large-scale screening of fresh tonsil specimens for the presence of prion protein.


Pectin modifications promote haustoria development in the parasitic plant Phtheirospermum japonicum.
Parasitic plants are globally prevalent pathogens with important ecological functions but also potentially devastating agricultural consequences. Common to all parasites is the formation of the haustorium which requires parasite organ development and tissue invasion into the host. Both processes involve cell wall modifications. Here, we investigated a role for pectins during haustorium development in the facultative parasitic plant Phtheirospermum japonicum. Using transcriptomics data from infected Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), we identified genes for multiple P. japonicum pectin methylesterases (PMEs) and their inhibitors (PMEIs) whose expression was upregulated by haustoria formation. Changes in PME and PMEI expression were associated with tissue-specific modifications in pectin methylesterification. While de-methylesterified pectins were present in outer haustorial cells, highly methylated pectins were present in inner vascular tissues, including the xylem bridge that connects parasite to host. Specifically blocking xylem bridge formation in the haustoria inhibited several PME and PMEI genes from activating. Similarly, inhibiting PME activity using chemicals or by overexpressing PMEI genes delayed haustoria development. Our results suggest a dynamic and tissue-specific regulation of pectin contributes to haustoria initiation and to the establishment of xylem connections between parasite and host.


Prognostic Value of Type D Personality for In-stent Restenosis in Coronary Artery Disease Patients Treated With Drug-Eluting Stent.
To evaluate the predictive value of Type D personality on in-stent restenosis (ISR) rates at 1 and 2 years post-percutaneous coronary intervention (PCI) in patients with coronary artery disease. Consecutive patients with coronary artery disease who underwent PCI for drug-eluting stents (n = 173) completed the Type D Scale-14 (DS14) at baseline. Follow-up coronary angiographic evaluation was routinely planned at 1 and 2 years after the procedure. Follow-up coronary angiography was performed in 159 and 112 patients at 1 and 2 years post-PCI, respectively. On multivariate analysis, Type D personality was found to be an independent predictor of ISR at 1 year (odds ratio [OR] = 2.67, 95% confidence interval [CI] = 1.16-6.14, p = .021) and 2 years (OR = 4.92, 95% CI = 1.82-9.60, p = .017) after adjusting for cardiovascular risk factors. However, Type D did not predict ISR when the analysis was performed using the interaction between negative affectivity and social inhibition. The main effect of negative affectivity emerged as a significant risk factor for 1-years (OR = 4.22, 95% CI = 1.18-7.86, p = .034) and 2-year ISR (OR = 6.93, 95% CI = 2.25-11.50, p = .016). In this study, Type D personality was an independent predictor of ISR at 1 and 2 years post-PCI; the association strengthened with time. The negative affectivity component seems to drive the relationship between Type D and ISR over time. Our findings provide new insights into the mechanisms involved in the association between Type D and adverse clinical outcomes of PCI.


Incubation periods and survival times for mice injected stereotaxically with three scrapie strains in different brain regions.
Incubation period and survival time were determined in C57BL mice which had been injected stereotaxically with either the 139A, ME7 or 22L strain of scrapie in one of five different brain regions (cerebral cortex, caudate nucleus, thalamus, substantia nigra, cerebellum). The injection of 139A in the caudate nucleus, thalamus, substantia nigra or cerebellum resulted in significantly shorter incubation periods than following cerebral cortex injection. For ME7, mice injected in the thalamus and cerebellum had incubation periods approximately 2 weeks shorter than the cerebral cortex group. For 22L, the incubation periods after substantia nigra or cerebellum injection were significantly shorter than after cortex injection. The cerebellum injection group had a significantly shorter incubation period than the substantia nigra injection group. The survival times for mice injected with a particular scrapie strain were directly related to the incubation periods. The groups with the shortest incubation also had the shortest survival time (e.g. 22L in the cerebellum). On histological examination, 139A and ME7 produced brain lesions in all brain areas regardless of injection site. For the 22L strain, after cerebellum injection vacuolation was limited to the cerebellum, while injection into the cerebral cortex and other forebrain regions resulted in vacuolation in all brain regions examined. Despite the difference in the distribution of vacuolation seen in cerebellum- compared to cortex-injected (22L) mice, infectivity titres were similar in the cortex, cerebellum, cerebellar cortex and medulla plus pons.


Medicare program; hospital inpatient value-based purchasing program. Final rule.
This final rule implements a Hospital Inpatient Value-Based Purchasing program (Hospital VBP program or the program) under section 1886(o) of the Social Security Act (the Act), under which value-based incentive payments will be made in a fiscal year to hospitals that meet performance standards with respect to a performance period for the fiscal year involved. The program will apply to payments for discharges occurring on or after October 1, 2012, in accordance with section 1886(o) (as added by section 3001(a) of the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively known as the Affordable Care Act)). Scoring in the Hospital VBP program will be based on whether a hospital meets or exceeds the performance standards established with respect to the measures. By adopting this program, we will reward hospitals based on actual quality performance on measures, rather than simply reporting data for those measures.


No Evidence of SARS-CoV-2 Infection in Wild Mink (Mustela lutreola and Neogale vison) from Northern Spain during the First Two Years of Pandemic.
The impact of the SARS-CoV-2 pandemic on wildlife is largely unevaluated, and extended surveillance of animal species is needed to reach a consensus on the role of animals in the emergence and maintenance of SARS-CoV-2. This infection has been detected in farmed and domestic animals and wild animals, mainly in captivity. The interactions or shared resources with wildlife could represent a potential transmission pathway for the SARS-CoV-2 spill over to other wild species and could lead to health consequences or the establishment of new reservoirs in susceptible hosts. This study evaluated the presence of SARS-CoV-2 in European mink (Mustela lutreola) and American mink (Neogale vison) in Spain by enzyme-linked immunosorbent assay (ELISA) using the receptor binding domain (RBD) of Spike antigen in serum samples and/or by RT-qPCR assays in oropharyngeal and rectal swabs. From January 2020 to February 2022, a total of 162 animals (127 European mink and 35 American mink) with no evidence of SARS-CoV-2 infection were included in the study. Antibodies against the SARS-CoV-2 were not found in the serum samples analysed (n = 126), nor was the virus amplified by RT-qPCR (n = 160 swabs). Our results suggest that the potential role of wild mink and the European mink bred in captivity and released to the wild as dispersers of SARS-CoV-2 is so far low. However, wildlife surveillance for early detection of human and animal risks should be continued. In this sense, epidemiological monitoring measures, including serology and molecular analysis, are necessary.


Lichenoid folliculitis: A unifying concept.
Skin diseases presenting with keratotic papules, atrophy, cicatricial alopecia and/or "lichenoid" histopathologic changes have been described under at least 30 names. This family of diseases contains 2 subgroups, largely based on clinical features: keratosis pilaris atrophicans (KPA; including keratosis pilaris atrophicans faciei/ulerythema ophryogenes, atrophoderma vermiculatum, and keratosis follicularis spinulosa decalvans); and the lichen planopilaris (LPP) subgroup (including LPP, frontal fibrosing alopecia, Graham-Little-Piccardi-Lassueur Syndrome and fibrosing alopecia in a pattern distribution). An interface dermatitis with lichenoid inflammation is characteristic of the LPP group of disorders, but the literature provides scant information about the histopathology of the KPA group. Our experience has been that the 2 subgroups show a unifying histologic similarity as well as considerable clinical overlap. Because these conditions overlap clinically and histologically, we propose that the term lichenoid folliculitis (LF) be used to refer to this group of diseases, thus simplifying cumbersome nomenclature and highlighting the possibility of shared pathogenesis and treatment options.


Vaginal fetal fibronectin as a predictor of spontaneous preterm delivery in the patient with cervical cerclage.
The purpose of this study was to assess the validity of vaginal fetal fibronectin as a screening test for spontaneous preterm birth in patients with cervical cerclage. A historic cohort of 117 patients who underwent cervical cerclage placement between 1996 and 2002 were identified. All patients were followed up in a maternal-fetal medicine faculty practice in a university setting. Serial fetal fibronectin samples of vaginal secretions were collected every 2 to 3 weeks, starting at 22 weeks of gestation and continuing until 32 weeks or delivery, whichever came first. There were 81 singleton, 23 twin, 12 triplet, and 1 quadruplet pregnancies. There were 61 ultrasound-indicated, 47 prophylactic, and 9 emergency cerclages that were placed. Most cerclages were of the modified Shirodkar type (95%) with a median gestational age at cerclage placement of 16.6 weeks. Overall, 33.3% of gestations were delivered spontaneously before 37 weeks of gestation; 17.1% of gestations were delivered spontaneously before 34 weeks. For deliveries within 2 weeks and 3 weeks of a single fetal fibronectin assessment, the test had a sensitivity of 50% and 48.3%, a specificity of 90% and 91.1%, a positive predictive value of 16.3% and 28.6%, and a negative predictive value of 97.9% and 96%, respectively. Subgroup analysis by number of fetuses (singleton, twin, and higher order multiple gestations) revealed similar values. For delivery before 34 weeks of gestation, fetal fibronectin had a sensitivity of 50%, a specificity of 78.4%, a positive predictive value of 33.3%, and a negative predictive value of 88%. This study is the first to evaluate the use of vaginal fetal fibronectin assessments to screen for preterm birth in patients who had undergone cervical cerclage procedures. We conclude that this test has similar validity to predict spontaneous preterm delivery in these high-risk pregnancies, as in previously published cohorts.


Giant cell granuloma of the temporal bone: a case report with immunohistochemical, enzyme histochemical, and in vitro studies.
A case of giant cell granuloma (GCG) that occurred in the right temporal bone is reported. The lesion showed histologic features identical to GCG. The multinuclear giant cells (MGCs) in the lesion showed strong reactivity with CD68, but patchy staining for myeloid/histiocyte antigen, alpha-1-antitrypsin, alpha-1-antichymotrypsine, and lysozyme. Activity of tartrate-resistant acid phosphatase was also consistently detected in the MGCs. Some of the mononuclear cells of the lesion exhibited similar immunocytochemical and histochemical reactivity as the MGCs. Ki-67 staining, however, was only detected in the mononuclear cells. The MGCs isolated from the lesion presented characteristic morphology of osteoclasts and possessed the ability to excavate bone in vitro. Thus, the MGCs in GCG appeared to express both macrophage- and osteoclast-associated phenotypes. The mononuclear cells were the major proliferative elements in the lesion and a subpopulation of these cells may represent precursors of the MGCs.


Auditory sense in certain sphingid moths.
Moths of the genus Celerio, hovering and feeding from blossoms, have been observed to react vigorously to high-pitched sounds. The acoustic receptor appears to involve the labial palps. Its characteristics have been determined from responses made, when the moth is exposed to artificial sound pulses, by an interneuron originating in its head. These responses have been found only in 4 out of 19 sphingid species tested.


Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007.
Highlights of the National Asthma Education and Prevention Program's Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Full Report 2007 are presented in this EPR-3 summary report. The updated guidelines emphasize the importance of asthma control. Asthma control is the degree to which the manifestations of asthma are minimized by therapeutic intervention and the goals of therapy are met. Because asthma is highly variable, the level of control must be monitored on a periodic basis to determine whether therapy should be maintained or adjusted (stepped up if necessary, stepped down if possible). On the other hand, asthma severity is the intrinsic intensity of the disease process, most easily and directly measured in a patient not receiving long-term control therapy. For managing asthma, the recommendation is to assess severity to initiate therapy and assess control to adjust therapy. Recommendations for managing asthma include an expanded section on childhood asthma with addition of an age group 5 to 11 years old (earlier guidelines combined this group with adults). The guidelines provide new recommendations on patient education in settings beyond the physician's office, and new advice for controlling environmental factors that can cause asthma symptoms. The concepts of current impairment (frequency and intensity of symptoms, low lung function, and limitations of daily activities) and future risk (likelihood of exacerbations, progressive loss of lung function, or adverse side effects from medications) support a new approach to assessing and monitoring the patient's level of asthma control through use of multiple measures. The guidelines stress that some patients can still be at high risk for frequent exacerbations even if they have few day-to-day effects of asthma.Moreover, EPR-3 confirms the importance of teaching patients skills to self-monitor and manage asthma and to use a written asthma action plan, which should include instructions for daily treatment and ways to recognize and handle worsening asthma. New recommendations encourage expanding educational opportunities to reach patients in a variety of settings, such as pharmacies, schools, community centers, and patients' homes. A new section addresses the need for clinician education programs to improve communication with patients and to use system-wide approaches to integrate the guidelines into health care practice. The guidelines describe new evidence for using multiple approaches to limit exposure to allergens and other substances that can worsen asthma; research shows that single steps are rarely sufficient. EPR-3 also expands the section on common conditions that can affect asthma and notes that management of these conditions may help to improve asthma control. Expert Panel Report 3 continues the use of a stepwise approach to control asthma. When assessing the level of asthma control to determine the need for adjusting therapy, EPR-3 reconfirms the importance of assessing patient adherence to medication, inhaler technique, and environmental control measures before making a step up in therapy. The stepwise approach expands from 4 steps to 6 steps of care. Medications have been repositioned within these 6 steps. Recommendations on medications are updated to reflect the latest evidence on effectiveness and safety. EPR-3 reaffirms that patients with persistent asthma need both long-term control medications to control asthma and prevent exacerbations and quick-relief medication for symptoms, as needed. EPR-3 also reaffirms that inhaled corticosteroids are the most effective long-term control medication across all age groups. New recommendations on treatment options such as leukotriene receptor antagonists and cromolyn for long-term control; long-acting beta-agonists as adjunct therapy with inhaled corticosteroids; omalizumab for severe asthma; and albuterol, levalbuterol, and corticosteroids for acute exacerbations are included.


Chemotherapy vs tamoxifen in platinum-resistant ovarian cancer: a phase III, randomised, multicentre trial (Ovaresist).
Chemotherapy in platinum-resistant ovarian cancer (PROC) aims for palliation and prolonging of progression-free survival (PFS). This study compares Health-related Quality of Life (HRQoL) and efficacy between single-agent chemotherapy and tamoxifen in PROC. Patients with PROC were randomised (2 : 1) to chemotherapy (weekly paclitaxel 80 mg m-2 or four weekly pegylated liposomal doxorubicin 40 mg m-2) or tamoxifen 40 mg daily. The primary end point was HRQoL. Secondary end points were PFS by RECIST and overall survival (OS). Between March 2002 and December 2007, 156 and 82 patients were randomised to chemotherapy and tamoxifen, respectively. In the chemotherapy arm, a significantly larger proportion of patients experienced a worsening in their social functioning. There was no difference in the proportion of patients experiencing improvement of gastrointestinal symptoms. Median PFS on tamoxifen was 8.3 weeks (95% CI, 8.0-10.4) compared with 12.7 weeks (95% CI, 9.0-16.3) on chemotherapy (HR, 1.54; 95% CI, 1.16-2.05; log-rank P=0.003). There was no difference in OS between the treatment arms. Patients on chemotherapy had longer PFS but experienced more toxicity and poorer HRQoL compared with tamoxifen. Control over gastrointestinal symptoms was not better on chemotherapy. These data are important for patient counselling and highlight the need to incorporate HRQoL end points in studies of PROC.


[Surgical treatment of nonspecific ulcerative colitis in children].
The experience of treatment of 285 children with nonspecific ulcerative colitis enabled the authors to conclude that the surgical treatment should be more widely recommended in children with severe and even mild nonspecific ulcerative colitis when the conservative treatment proved to be ineffective. They believe that such operations should be fulfilled in two steps: the first step consists in a complete removal of the colon and anastomosing of the separated part of the ileum to the rectum stump. The second step should liquidate the ileostoma and repair the continuity of the intestine.


The effects of psychological intervention on anxiety symptoms of COVID19-positive patients isolated in hospital wards.
The study aimed to explore the effects of psychological intervention on alleviating anxiety in patients in novel coronavirus (2019-nCoV) isolation wards. Between January 24th, 2020 and March 5th, 2020, 103 patients were studied. Among these, 32 were patients in the isolation ward of the Infectious Disease Department in Baoding Second Hospital with suspected 2019-nCoV, and 71 patients diagnosed with 2019-nCoV were in the Tangshan Infectious Disease Hospital. Of the 103 patients included, 97 cases were observed in isolation. Using a self-control study design, each patient's anxiety was scored on a self-rating anxiety scale before receiving the psychological intervention (on the 7th day of isolation) and after receiving the intervention (on the 14th day of isolation). The severity of anxiety was evaluated based on the anxiety score before receiving the intervention. The anxiety scores before and after receiving the intervention were then compared using the paired t-test, and p<0.05 was considered statistically significant. After receiving the psychological intervention once or twice a week, the anxiety of the patients improved significantly after one week. The anxiety of patients with 2019-nCoV in isolation wards can be alleviated through psychological intervention. By alleviating patient anxiety, this intervention also helps patients maintain their psychological wellbeing, which promotes rehabilitation and helps with the control of 2019-nCoV.


Occupational Health Risks and Hazards Among the Fisherfolk in Kampi Samaki, Lake Baringo, Kenya.
Globally, almost 2.78 million deaths that occur annually are attributed to work-related health risks. Worldwide and, especially, in developing countries, about 20% to 50% of the workers are exposed to health risks. Fishing is an ancient occupation, and like many others, it is characterized by numerous health risks and hazards. This study sought to understand the exposure of fisherfolk to human health risks, through fish handling and processing in Lake Baringo, Kenya. The study adopted a cross-sectional social survey design. A systematic random sampling technique was used to select respondents for this study. A semi-structured questionnaire was administered to the respondents to collect data on risks involved during the handling and processing of fish. Key informant interviews and observation checklists were also used to collect more information. Both descriptive and inferential statistics were used to analyze data. Inferential statistics included Pearson χ2 test, which was used to test the association of various factors on the encounter with occupational health risks. The level of significance was tested at α = 0.05. The study findings reveal the fisherfolk-encountered risks such as cuts, eye irritability, sunburns, skin burn, cold, falls, and musculoskeletal injuries during their work. The results showed that only 12% of the fisherfolk use personal protective equipments (PPEs) at work. Pearson χ2 test analysis showed there was an association between gender and gender roles (χ2 = 39.517, P < .05). In addition, an association was revealed between occupational health risks and gender (χ2 = 16.283, P < .05). There was also an association between occupational hazards and gender (χ2 = 21.352, P < .05). However, there was no association revealed between occupational health risk and marital status (χ2 = 1.305, P > .05) and PPEs (χ2 = 1.089, P > .05). Furthermore, results indicate that 61% of the fisherfolk who suffered from occupational health risks missed work. The study concludes that all the fisherfolk at Kampi Samaki are exposed to various health risks while working, which is thus likely to affect their health. We recommend public health campaigns to sensitize fisherfolk on the associated risks in fish handling and processing. There is also a need for health campaigns for the fisherfolk to appreciate the need for First Aid Kits during the fishing operations.


[Treatment of status epilepticus with rectally administered diazepam].
Rectal administration of diazepam is a good alternative to intravenous acute treatment in severe epileptic crises, but there is scarce information about its usefulness in status epilepticus. Treatment with rectal diazepam, 0.6 to 0.8 mg x kg of body weight as a single drug, in 10 children with 13 episodes of status epilepticus, defined as epileptic crises lasting 30 or more minutes (ten of these were generalized tonic and clonic, two were unilateral tonic and clonic, and one was of the partial complex type) is described. Nine status epilepticus episodes subsided at an average 4.4 minutes after the drug was given; in 3 cases there were no favourable effects, and one case recurred after initial response. There were no significant complications, with the exception of slight respiratory depression in a patient with encephalitis. In spite of the small size of the sample, these results suggest that rectal diazepam is an effective alternative to intravenous drug administration in the management of status epilepticus whenever venous access is difficult.


The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility.
Cone photoreceptor cyclic nucleotide-gated (CNG) channels play a pivotal role in cone phototransduction, which is a process essential for daylight vision, color vision, and visual acuity. Mutations in the cone channel subunits CNGA3 and CNGB3 are associated with human cone diseases, including achromatopsia, cone dystrophies, and early onset macular degeneration. Mutations in CNGB3 alone account for 50% of reported cases of achromatopsia. This work investigated the role of CNGB3 in cone light response and cone channel structural stability. As cones comprise only 2-3% of the total photoreceptor population in the wild-type mouse retina, we used Cngb3(-/-)/Nrl(-/-) mice with CNGB3 deficiency on a cone-dominant background in our study. We found that, in the absence of CNGB3, CNGA3 was able to travel to the outer segments, co-localize with cone opsin, and form tetrameric complexes. Electroretinogram analyses revealed reduced cone light response amplitude/sensitivity and slower response recovery in Cngb3(-/-)/Nrl(-/-) mice compared with Nrl(-/-) mice. Absence of CNGB3 expression altered the adaptation capacity of cones and severely compromised function in bright light. Biochemical analysis demonstrated that CNGA3 channels lacking CNGB3 were more resilient to proteolysis than CNGA3/CNGB3 channels, suggesting a hindered structural flexibility. Thus, CNGB3 regulates cone light response kinetics and the channel structural flexibility. This work advances our understanding of the biochemical and functional role of CNGB3 in cone photoreceptors.


Warming by resistive heating maintains perioperative normothermia as well as forced air heating.
Even mild perioperative hypothermia is associated with several severe adverse effects. Resistive heating has possible advantages compared with other active warming systems because it can heat several fields independently. To assess this new warming system, we measured core temperature in patients during surgery who were warmed with circulating water mattresses, forced air covers or resistive heating covers. Twenty-four patients undergoing laparoscopic cholecystectomy were randomly assigned to (i) circulating water mattress (38 degrees C), (ii) forced air warming (set to 'medium') or (iii) carbon-fibre resistive warming (38 degrees C). Warming was applied throughout anaesthesia and surgery. The groups were compared using one-way ANOVA and Student-Newman-Keuls tests. Confounding factors were similar among the groups. Core temperatures in each group decreased for 20 min, but subsequently increased in the forced air and resistive heating groups. There was no significant difference between the forced air and resistive heating groups at any time. In contrast, core temperature in the circulating water group continued to decrease. Consequently, core temperature in the circulating water group was significantly lower than in the other groups 30 min after anaesthetic induction and at later times. Resistive heating maintains core body temperature as well as forced air heating and both are better than circulating water. Resistive heating offers the advantage of adjustable heating pods.


Scalp micropigmentation: a concealer for hair and scalp deformities.
Cosmetic deformities, resulting from some dermatologic diseases or deformities caused by hair restoration surgeries, have had few, if any, good, permanent solutions. Most of these patients have learned to live with their problems. A cosmetic tattoo technique has been developed to address unsightly scalp and hair conditions. The technique called scalp micropigmentation uses specialized techniques and conventional cosmetic tattoo instruments and pigments in a stippling pattern on the scalp. A variety of alopecias, refractory to treatment and hair transplant deformities, impact millions of men and women. Many of these deformities can be concealed with scalp micropigmentation, making the deformities minimally detectable. Included are the results of treatment. Patient satisfaction is very high. Scalp micropigmentation offers a good nonsurgical alternative treatment for hair and scalp deformities. This paper demonstrates scalp micropigmentation results and discusses the histology, physiology, and pathology of tattoo pigments in the skin. The regulation of the tattoo process by the United States Food and Drug Administration and state governments is summarized. Unlike medical devices, scalp micropigmentation offers a tattoo-based, non-medical "cover-up" that effectively hides unsightly conditions on the scalp and creates the illusion of thicker hair. The authors believe that scalp micropigmentation is destined to become a standardized offering for physicians specializing in cosmetic office procedures.


Pylorus preserving pancreatoduodenectomy for gastrinoma. A case report.
A case of a young female patient affected by Zollinger-Ellison syndrome with occult gastrinoma during exploratory laparotomy, is reported. On the basis of transhepatic portal catheterization the patient underwent pylorus preserving pancreatoduodenectomy according to Longmire-Traverso. A malignant gastrinoma of the duodenal wall, 2 mm in diameter, was observed on the operative specimen in the suspected gastrinogenic area. The procedure led to complete clinical recovery of the patient who did not respond to the medical treatment of the ulcer. The prognosis was good with oncologic radicality of surgery confirmed at follow-up and excellent digestive function.


Klippel-Trenaunay syndrome: the risks and benefits of vascular interventions.
Our experience with Klippel-Trenaunay syndrome (KTS), a rare congenital malformation, has increased considerably in recent years and now includes 144 patients (65 male and 79 female patients). Hemangioma was present in 137 patients (95.1%), varicosity in 110 (76.4%), and hypertrophy of the soft tissues or bones in 134 (93.1%). In most patients (71.5%) the disease involved one lower extremity. Diagnostic workup included roentgenogram to document limb length discrepancy, noninvasive arterial and venous evaluation, contrast venography, and nuclear magnetic resonance imaging. Most patients did well without treatment or with elastic compression only. Surgical treatment for the vascular malformation in KTS is rarely needed and it continues to be controversial. To evaluate the risks and benefits of vascular interventions, we examined in detail the clinical histories of nine patients who in the last decade underwent operation for a vascular malformation of the lower extremity. In seven patients we removed varicose veins or resected hemangioma of the lower extremity. Although none was cured, all five who underwent resection of varicose veins and one of the two patients who underwent resection of a hemangioma improved. Two additional patients, however, who underwent resection of varicose veins in another institution had worsening of the symptoms. In one patient we performed deep venous reconstruction for atresia of the superficial femoral vein, using the contralateral saphenous vein. Such operation in KTS has not been reported previously. The patient has a patent graft with a competent valve and clinical improvement 6 months after the operation. Although patients with severe chronic venous insufficiency, disturbing cosmetic appearance, or complications of hemangioma may benefit from surgical treatment, detailed preoperative imaging of the extremity and pelvis with magnetic resonance imaging and contrast venography is needed to decrease complications. Rarely, reconstruction for atresia or hypoplasia of the deep veins may be needed.


DC-HIL-expressing myelomonocytic cells are critical promoters of melanoma growth.
A major barrier to successful cancer immunotherapy is the tumor's ability to induce T-cell tolerance by exploiting host regulatory mechanisms. Having discovered the DC-HIL receptor, which inhibits T-cell responses by binding to syndecan-4 on effector T cells, we posited the DC-HIL/syndecan-4 pathway to have an important role in cancer promotion. Among DC-HIL(+) myelomonocytic cells, during growth of implanted mouse melanoma, CD11b(+)Gr1(+) cells were the most expanded population and the most potent at suppressing T-cell activation. Deletion of the DC-HIL gene or infusion of anti-DC-HIL mAb abrogated these cells' suppressor function and expansion, and markedly diminished melanoma growth and metastasis. IL-1β and IFN-γ were elevated in mice bearing melanoma, and concurrent exposure to both cytokines optimally induced DC-HIL expression by tumor-infiltrating CD11b(+)Gr1(+) cells. Ligation of DC-HIL transduced phosphorylation of its intracellular immunoreceptor tyrosine-based activation motif, which in turn induced intracellular expression of IFN-γ and inducible nitric oxide synthase (iNOS), known to mediate T-cell suppression by CD11b(+)Gr1(+) cells. Thus, DC-HIL is the critical mediator of these cells' suppressor function in melanoma-bearing mice and a potential target for improving melanoma immunotherapy.


Clinical spectrum and radiographic features of the syndrome of the trephined.
Craniectomy is a common neurosurgical procedure. Syndrome of the trephined (ST) occurring after craniectomy results in neurologic symptoms that are reversible with cranioplasty. While well-documented, previous literature consisted of case reports, symptom spectrum and risk factors have not been well characterized. A retrospective review of 29 consecutive cases who underwent decompressive craniectomy within a 30-month period was performed. Patients were considered affected by ST if a previously stable neurological deficit improved within 3 weeks after cranioplasty. Prevalence of ST was measured and association with demographic information, clinical symptoms patterns, indication for and size of craniectomy, as well as radiological signs were tested. Seven patients (24%) developed ST. Chronic rehabilitation arrest was more common than acute neurologic decline. Factors such as craniectomy size and patient age did not reach statistical significance in development of ST. Radiographic factors were predictive, with a sunken skin flap contour being most sensitive, while ventricular effacement was most specific. ST may have a higher incidence than previously thought, with a chronic rehabilitation arrest being a more common presentation than an acute decline. Medical providers involved in the post surgical care and rehabilitation of these patients should maintain a high index of suspicion for ST.


Geometry of the vascular pedicle in free tissue transfers to the head and neck.
Traditionally, the most important parameters for success in free tissue transfer have been expertise in performing small vessel anastomoses, meticulous donor site dissection, and careful recipient vessel preparation. It has been our experience, in free flap transfers for head and neck reconstruction, that a very crucial, often unrecognized, parameter is the geometry of the vascular pedicle. This term encompasses the three-dimensional positioning of the nutrient vascular pedicle as well as vessel tension and redundancy. The ideal axis for the lie of the vascular pedicle in the neck is in the longitudinal direction. This configuration helps to eliminate the kinking of the pedicle that is observed with side-to-side movements of the head. The primary objectives in recipient vessel selection are to use a healthy artery and vein and to perform the anastomoses in a location that provides easy access for the surgeon and assistant. Recipient vessel selection is also a major determining factor in the achievement of the desired pedicle geometry. We believe that the transverse cervical artery and the external jugular vein are the best recipient vessels for free tissue transfer. The reasons for this selection, as well as technical details to improve pedicle geometry, are discussed in depth. Representative cases that demonstrate pitfalls in vascular pedicle geometry are presented.


Transcription factor MdNAC33 is involved in ALA-induced anthocyanin accumulation in apples.
5-Aminolevulinic acid (ALA), as a new natural plant growth regulator, has a significant function in promoting anthocyanin accumulation in many species of fruits. However, the mechanisms underlying remain obscure. In a transcriptome study of our group, it was found that many transcription factors (TFs) including NACs responsive to ALA treatment during anthocyanin accumulation. In the present study, we found a NAC of apple, MdNAC33 was coordinatively expressed with anthocyanin accumulation after ALA treatment in the apple fruits and leaves, suggesting that this TF may be involved in anthocyanin accumulation induced by ALA. We found that the MdNAC33 protein was localized in the nucleus and exhibited strong transcriptional activity in both yeast cells and plants, where its C-terminal contributed to the transcriptional activity. Functional analysis showed that overexpression of MdNAC33 promoted the accumulation of anthocyanin, while the silencing vector of MdNAC33 (RNAi) significantly impaired the anthocyanin accumulation induced by ALA. Yeast one-hybrid (Y1H), luciferase assay and electrophoretic mobility shift assay (EMSA) indicated that MdNAC33 could bind to promoters of MdbHLH3, MdDFR and MdANS to activate the gene expressions. In addition, MdNAC33 specifically interacts with MdMYB1, a positive regulator of anthocyanin biosynthesis, which was then in turn binding to its target genes MdUFGT and MdGSTF12, to promote anthocyanin accumulation in apples. Taken together, our data indicate that MdNAC33 plays multiple roles in ALA-induced anthocyanin biosynthesis. It provides new insights into the mechanisms of anthocyanin accumulation induced by ALA.


Elucidating solvent contributions to solution reactions with ab initio QM/MM methods.
Computer simulations of reaction processes in solution in general rely on the definition of a reaction coordinate and the determination of the thermodynamic changes of the system along the reaction coordinate. The reaction coordinate often is constituted of characteristic geometrical properties of the reactive solute species, while the contributions of solvent molecules are implicitly included in the thermodynamics of the solute degrees of freedoms. However, solvent dynamics can provide the driving force for the reaction process, and in such cases explicit description of the solvent contribution in the free energy of the reaction process becomes necessary. We report here a method that can be used to analyze the solvent contributions to the reaction activation free energies from the combined QM/MM minimum free-energy path simulations. The method was applied to the self-exchange S(N)2 reaction of CH(3)Cl + Cl(-), showing that the importance of solvent-solute interactions to the reaction process. The results were further discussed in the context of coupling between solvent and solute molecules in reaction processes.


Developing and Validating a Pediatric Potentially Avoidable Transfer Quality Metric.
This study aimed to evaluate a quality metric that identifies pediatric potentially avoidable transfers from diagnosis and procedure codes. Using physician medical record review as the gold standard, the following steps were used: (1) develop the initial metric definition, (2) estimate initial metric definition operating characteristics, (3) refine this definition to optimize the c-statistic, and (4) validate this optimized metric definition using a separate sample. The initial metric using Sample A patient transfers had a c-statistic of 0.63 (95% confidence interval = 0.53-0.73). Following 22 revisions, the optimized metric definition was a transfer discharged within 24 hours that did not receive any of a select list of 60 268 specialized diagnoses or procedures. The optimized metric on Sample B demonstrated a sensitivity of 80.6%, specificity of 85.7%, and c-statistic of 0.83 (95% confidence interval = 0.75-0.91). The quality metric developed and validated in this study demonstrated satisfactory operating characteristics, providing a feasible means to measure this important outcome.


Liver cystic echinococcosis and human host immune and autoimmune follow-up: A review.
Cystic echinococcosis (CE) is an infectious disease caused by the larvae of parasite Echinococcus granulosus (E. granulosus). To successfully establish an infection, parasite release some substances and molecules that can modulate host immune functions, stimulating a strong anti-inflammatory reaction to carry favor to host and to reserve self-survival in the host. The literature was reviewed using MEDLINE, and an open access search for immunology of hydatidosis was performed. Accumulating data from animal experiments and human studies provided us with exciting insights into the mechanisms involved that affect all parts of immunity. In this review we used the existing scientific data and discuss how these findings assisted with a better understanding of the immunology of E. granulosus infection in man. The aim of this study is to point the several facts that challenge immune and autoimmune responses to protect E. granulosus from elimination and to minimize host severe pathology. Understanding the immune mechanisms of E. granulosus infection in an intermediate human host will provide, we believe, a more useful treatment with immunomodulating molecules and possibly better protection from parasitic infections. Besides that, the diagnosis of CE has improved due to the application of a new molecular tool for parasite identification by using of new recombinant antigens and immunogenic peptides. More studies for the better understanding of the mechanisms of parasite immune evasion is necessary. It will enable a novel approach in protection, detection and improving of the host inflammatory responses. In contrast, according to the "hygiene hypothesis", clinical applications that decrease the incidence of infection in developed countries and recently in developing countries are at the origin of the increasing incidence of both allergic and autoimmune diseases. Thus, an understanding of the immune mechanisms of E. granulosus infection is extremely important.


Position of the American Dietetic Association: food insecurity in the United States.
It is the position of the American Dietetic Association that systematic and sustained action is needed to achieve food and nutrition security for all in the United States. To eliminate food insecurity, interventions are needed, including adequate funding for and increased utilization of food and nutrition assistance programs, inclusion of food and nutrition education in such programs, and innovative programs to promote and support individual and household economic self-sufficiency. More than 49 million individuals living in the United States experienced food insecurity in 2008. Negative nutrition and non-nutrition-related outcomes have been associated with food insecurity in children, adolescents, and adults, including substandard academic achievement, inadequate intake of key nutrients, poor health, increased risk for and development of chronic disease, poor disease management, and poor psychological and cognitive functioning. Registered dietitians and dietetic technicians, registered, can play key roles in ending food insecurity and are uniquely positioned to make valuable contributions through provision of comprehensive food and nutrition education; competent and collaborative practice; innovative research related to accessing a safe, secure, and sustainable food supply; and advocacy efforts at the local, state, regional, and national levels.


Classical conditioned learning using transcranial magnetic stimulation.
This study examined whether brain responses to transcranial magnetic stimulation (TMS) would be amenable to classical conditioning. Motor cortex in human participants was stimulated with TMS pulses, which elicited a peripheral motor response in the form of a motor evoked potential (MEP). The TMS pulses were paired with audio-visual cues that served as conditioned stimuli. Over the course of training, MEPs following the conditioned stimuli decreased in amplitude. Two experiments demonstrated that the attenuated response only occurred when the TMS was preceded by the conditioned stimulus. Unsignaled TMS and TMS preceded by a cue that was not previously paired did not attenuate the response. The experiments demonstrate that the modulation of the motor response depended on the prior pairings of the conditioned stimuli and TMS and that the effects were stimulus specific. Thus we demonstrate here, for the first time, that TMS can serve as the unconditioned stimulus in Pavlovian conditioning.


CLSCs in Quebec: thirty years of community action.
Local community service centres (CLSCs) emerged in Quebec in the early 1970s, in the context of the reform of Quebec's healthcare system and the North American movement for popular clinics or Neighbourhood Health Centers. The first CLSCs-primary healthcare institutions before the World Health Organization (WHO) popularized the concept-were mandated to offer a range of basic health and social services, while developing community action. The latter, defined as the art and method of getting the population to take part in identifying and solving health and social problems through information, education and group discussions, gradually asserted itself, thanks to the activism of a new category of professionals: community practitioners. Covering the entire province, throughout their existence, the 160 CLSCs were veritable laboratories for community organizations and a remarkable creative force behind the development of a policy of home support services and mental health in the community. Although their structure changed many times, particularly in the current context of reform to implement 95 local integrated service networks in the province, it continues to be a source of inspiration and of major actors.


Glycolysis and mitochondrial respiration in mouse LDHC-null sperm.
We demonstrated previously that a knockout (KO) of the lactate dehydrogenase type C (Ldhc) gene disrupted male fertility and caused a considerable reduction in sperm glucose consumption, ATP production, and motility. While that study used mice with a mixed genetic background, the present study used C57BL/6 (B6) and 129S6 (129) Ldhc KO mice. We found that B6 KO males were subfertile and 129 KO males were infertile. Sperm from 129 wild-type (WT) mice have a lower glycolytic rate than sperm from B6 WT mice, resulting in a greater reduction in ATP production in 129 KO sperm than in B6 KO sperm. The lower glycolytic rate in 129 sperm offered a novel opportunity to examine the role of mitochondrial respiration in sperm ATP production and motility. We observed that in media containing a mitochondrial substrate (pyruvate or lactate) as the sole energy source, ATP levels and progressive motility in 129 KO sperm were similar to those in 129 WT sperm. However, when glucose was added, lactate was unable to maintain ATP levels or progressive motility in 129 KO sperm. The rate of respiration (ZO2) was high when 129 KO or WT sperm were incubated with lactate alone, but addition of glucose caused a reduction in ZO2. These results indicate that in the absence of glucose, 129 sperm can produce ATP via oxidative phosphorylation, but in the presence of glucose, oxidative phosphorylation is suppressed and the sperm utilize aerobic glycolysis, a phenomenon known as the Crabtree effect.


Maternal B-vitamin and vitamin D status before, during, and after pregnancy and the influence of supplementation preconception and during pregnancy: Prespecified secondary analysis of the NiPPeR double-blind randomized controlled trial.
Maternal vitamin status preconception and during pregnancy has important consequences for pregnancy outcome and offspring development. Changes in vitamin status from preconception through early and late pregnancy and postpartum have been inferred from cross-sectional data, but longitudinal data on vitamin status from preconception throughout pregnancy and postdelivery are sparse. As such, the influence of vitamin supplementation on vitamin status during pregnancy remains uncertain. This study presents one prespecified outcome from the randomized controlled NiPPeR trial, aiming to identify longitudinal patterns of maternal vitamin status from preconception, through early and late pregnancy, to 6 months postdelivery, and determine the influence of vitamin supplementation. In the NiPPeR trial, 1,729 women (from the United Kingdom, Singapore, and New Zealand) aged 18 to 38 years and planning conception were randomized to receive a standard vitamin supplement (control; n = 859) or an enhanced vitamin supplement (intervention; n = 870) starting in preconception and continued throughout pregnancy, with blinding of participants and research staff. Supplement components common to both treatment groups included folic acid, β-carotene, iron, calcium, and iodine; components additionally included in the intervention group were riboflavin, vitamins B6, B12, and D (in amounts available in over-the-counter supplements), myo-inositol, probiotics, and zinc. The primary outcome of the study was glucose tolerance at 28 weeks' gestation, measured by oral glucose tolerance test. The secondary outcome reported in this study was the reduction in maternal micronutrient insufficiency in riboflavin, vitamin B6, vitamin B12, and vitamin D, before and during pregnancy. We measured maternal plasma concentrations of B-vitamins, vitamin D, and markers of insufficiency/deficiency (homocysteine, hydroxykynurenine-ratio, methylmalonic acid) at recruitment, 1 month after commencing intervention preconception, in early pregnancy (7 to 11 weeks' gestation) and late pregnancy (around 28 weeks' gestation), and postdelivery (6 months after supplement discontinuation). We derived standard deviation scores (SDS) to characterize longitudinal changes among participants in the control group and measured differences between the 2 groups. At recruitment, the proportion of patients with marginal or low plasma status was 29.2% for folate (<13.6 nmol/L), 7.5% and 82.0% for riboflavin (<5 nmol/L and ≤26.5 nmol/L, respectively), 9.1% for vitamin B12 (<221 pmol/L), and 48.7% for vitamin D (<50 nmol/L); these proportions were balanced between the groups. Over 90% of all participants had low or marginal status for one or more of these vitamins at recruitment. Among participants in the control group, plasma concentrations of riboflavin declined through early and late pregnancy, whereas concentrations of 25-hydroxyvitamin D were unchanged in early pregnancy, and concentrations of vitamin B6 and B12 declined throughout pregnancy, becoming >1 SDS lower than baseline by 28 weeks gestation. In the control group, 54.2% of participants developed low late-pregnancy vitamin B6 concentrations (pyridoxal 5-phosphate <20 nmol/L). After 1 month of supplementation, plasma concentrations of supplement components were substantially higher among participants in the intervention group than those in the control group: riboflavin by 0.77 SDS (95% CI 0.68 to 0.87, p < 0.0001), vitamin B6 by 1.07 SDS (0.99 to 1.14, p < 0.0001), vitamin B12 by 0.55 SDS (0.46 to 0.64, p < 0.0001), and vitamin D by 0.51 SDS (0.43 to 0.60, p < 0.0001), with higher levels in the intervention group maintained during pregnancy. Markers of vitamin insufficiency/deficiency were reduced in the intervention group, and the proportion of participants with vitamin D insufficiency (<50 nmol/L) during late pregnancy was lower in the intervention group (35.1% versus 8.5%; p < 0.0001). Plasma vitamin B12 remained higher in the intervention group than in the control group 6 months postdelivery (by 0.30 SDS (0.14, 0.46), p = 0.0003). The main limitation is that generalizability to the global population is limited by the high-resource settings and the lack of African and Amerindian women in particular. Over 90% of the trial participants had marginal or low concentrations of one or more of folate, riboflavin, vitamin B12, or vitamin D during preconception, and many developed markers of vitamin B6 deficiency in late pregnancy. Preconception/pregnancy supplementation in amounts available in over-the-counter supplements substantially reduces the prevalence of vitamin deficiency and depletion markers before and during pregnancy, with higher maternal plasma vitamin B12 maintained during the recommended lactational period. ClinicalTrials.gov NCT02509988; U1111-1171-8056.


Systematic structural coordination chemistry of p-tert-butyltetrathiacalix[4]arene: 1. Group 1 elements and congeners.
Determinations of the crystal structures of complexes of the alkali metal ions with, in the case of Li, the dianion and, in the cases Na-Cs, the monoanion of p-tert-butyltetrathiacalix[4]arene have shown that both the sulfur atoms which form part of the macrocyclic ring, as well as the pendent phenolic/phenoxide oxygen donor atoms, are involved in coordination to these metals. Although the Li and Na complex structures are similar to those of the corresponding complexes of p-tert-butylcalix[4]arene, there is no similarity in the structures of the Cs complexes, with the present structure showing no evidence of polyhapto Cs(+)-pi interactions. Instead, the complex crystallizes as a ligand-bridged (S-, O-donor) aggregate of three Cs ions, solvent molecules, and four calixarenes, somewhat like the Rb complex, though here four Rb ions are present, and higher in aggregation than the K+ complex, where two K+ ions are sandwiched between two calixarene moieties. The triethylammonium complex of the thiacalixarene monoanion, though formally analogous in that it involves a monocation, has a simpler structure than any of the alkali metal derivatives, based formally on proton coordination (H-bonding). However, interestingly, it can be isolated in both solvated (dmf, dmso) and unsolvated forms, as indeed can the "free", p-tert-butyltetrathiacalix[4]arene ligand itself.


Adipose conversion of 3T3-L1 cells in a serum-free culture system depends on epidermal growth factor, insulin-like growth factor I, corticosterone, and cyclic AMP.
A culture system for 3T3-L1 preadipocytes based on a serum-free chemically defined medium containing fetuin, transferrin, and pantothenate is described. In this system, adipose conversion depends on the following conditions. 1) In the presence of high insulin concentrations (1 microM), addition of corticosterone together with 1-methyl-3-isobutylxanthine (MIX) for not more than the first 4 days after confluence to the culture medium induces maximal adipose conversion within 12-14 days. MIX may be replaced by forskolin or permeable analogues of cAMP, indicating that its effect is due to elevated cellular cAMP levels. 2) At low insulin concentrations (1 nM), adipose conversion is reduced. Growth hormone or insulin-like growth factor I together with epidermal growth factor have to be present as a medium supplement together with corticosterone and MIX to get maximal adipose conversion. 3) The induction of adipose conversion by corticosterone and MIX in the presence of either high insulin concentrations or insulin-like growth factor I together with epidermal growth factor is accompanied by post-confluent mitoses. Inhibitors of DNA replication markedly reduce adipose conversion. Fibroblast growth factor and platelet-derived growth factor, although acting as potent mitogens on 3T3-L1 cells, do not support adipose conversion induced by corticosterone and MIX.


Applying plastic surgery principles to ovarian tissue transplantation.
Ovarian tissue cryopreservation (OTC) and transplantation is an innovative procedure increasingly utilized to help preserve fertility after gonadotoxic treatments especially in cancer patients. Approximately 30% of autotransplanted patients are able to achieve live birth, typically with the help of in-vitro fertilization. Numerous techniques and grafting sites have been described to continue to increase this figure. In the field of plastic surgery, tissue grafting has been successful performed for thousands of years and knowledge in this area has been significantly refined. A qualitative review of the literature using PubMed, Cochrane, SCOPUS and Medline databases was performed to look for articles relating to ovarian tissue transplantation (OTT) and comparisons made to plastic surgery tissue grafting. Many parallels were found between the principles of grafting in plastic surgery and the principles of OTT, including pre-operative patient optimization, suitable donor site selection, tissue harvest and preparation, graft site choice, immobilization of the graft and post-operative care. Consideration of the benefits and risks of using orthotopic versus heterotopic recipient sites is also highly important with regards to graft take, morbidity and ease of access of oocyte collection. We believe that ongoing discussion between disciplines can have the potential to improve knowledge, surgical techniques and patient outcomes.


Wechsler Intelligence Scale profiles, the cholinergic system, and Alzheimer's disease.
Forty-one patients with putative Alzheimer's Disease (AD) were evaluated to determine the diagnostic utility of a profile of Wechsler Adult Intelligence Scale (WAIS) subtests which has been proposed by Fuld (1984) to identify cholinergic dysfunction. Only nine (21.9%) of these patients had positive Wechsler profiles. Half (n = 21) of the AD patients had been given the WAIS, and the other half (n = 20) the Wechsler Adult Intelligence Scale-Revised (WAIS-R). Positive profiles occurred more often in the AD subgroup given the WAIS-R, but this difference was not statistically significant. Specificity of the formula was evaluated using Wechsler results of 42 older normals and 30 patients who were being evaluated for dementia but who did not have AD. One of the 42 normals (2.4%) and five of the patient controls (16.7%) showed a positive Wechsler profile. Because of the Fuld formula's low sensitivity, a negative Wechsler profile cannot be used to help rule out AD. Although specificity of the formula is high, the diagnostic value of a positive Wechsler profile is modest even under the most favorable AD baserate conditions.


Development of subcortical speech representation in human infants.
Previous studies have evaluated representation of the fundamental frequency (F0) in the frequency following response (FFR) of infants, but the development of other aspects of the FFR, such as timing and harmonics, has not yet been examined. Here, FFRs were recorded to a speech syllable in 28 infants, ages three to ten months. The F0 amplitude of the response was variable among individuals but was strongly represented in some infants as young as three months of age. The harmonics, however, showed a systematic increase in amplitude with age. In the time domain, onset, offset, and inter-peak latencies decreased with age. These results are consistent with neurophysiological studies indicating that (1) phase locking to lower frequency sounds emerges earlier in life than phase locking to higher frequency sounds and (2) myelination continues to increase in the first year of life. Early representation of low frequencies may reflect greater exposure to low frequency stimulation in utero. The improvement in temporal precision likely parallels an increase in the efficiency of neural transmission accompanied by exposure to speech during the first year of life.


Sensory Interactions between Sweetness and Fat in a Chocolate Milk Beverage.
Fat and sugar-reduced foods and beverages have become increasingly popular for a variety of reasons, mainly relating to health and wellbeing. Depending on the food or beverage, it may be difficult to reduce the fat and/or sugar content and still maintain optimal sensory properties for the specific product. One way of approaching the problem is to gain a better understanding of how a product is affected by a reduction in fat and/or sugar. This paper aims to investigate the sensory interactions between fat and sweetness perception in a chocolate-flavored milk beverage by using a descriptive analysis with a trained sensory panel. The reduction of fat significantly reduced the sweetness intensity of the chocolate milk, while the reduction of sucrose significantly decreased the cream flavor and the fruity and lactic flavor. The perception of acesulfame-K was affected by fat concentration, similarly to sucrose. These results highlight the importance of considering the effects of reducing either sugar and fat on product attributes that are not directly related to the sugar or fat.


Assessment of brown adipose tissue function.
In this review we discuss practical considerations for the assessment of brown adipose tissue in rodent models, focusing on mice. The central aim of the review is to provide a critical appraisal of the utility of specialized techniques for assessing brown adipose tissue function in vivo. We cover several of the most common specialized methods for analysing brown adipose tissue function in vivo, including assessment of maximal thermogenic capacity by indirect calorimetry and the measurement of sympathetic tone to brown adipose tissue. While these techniques are powerful, they are not readily available to all laboratories; therefore we also cover several simple measurements that, particularly in combination, can be used to determine if a mouse model is likely to have alterations in brown adipose tissue function. Such techniques include: pair feeding, analysis of brown adipose tissue lipid content and mRNA and protein markers of brown adipose tissue activation.


Behavioral and Neural Dissociation of Social Anxiety and Loneliness.
Loneliness is a public health concern with detrimental effects on physical and mental well-being. Given phenotypical overlaps between loneliness and social anxiety (SA), cognitive-behavioral interventions targeting SA might be adopted to reduce loneliness. However, whether SA and loneliness share the same underlying neurocognitive mechanisms is still an elusive question. The current study aimed at investigating to what extent known behavioral and neural correlates of social avoidance in SA are evident in loneliness. We used a prestratified approach involving 42 (21 females) participants with high loneliness (HL) and 40 (20 females) participants with low loneliness (LL) scores. During fMRI, participants completed a social gambling task to measure the subjective value of engaging in social situations and responses to social feedback. Univariate and multivariate analyses of behavioral and neural data replicated known task effects. However, although HL participants showed increased SA, loneliness was associated with a response pattern clearly distinct from SA. Specifically, contrary to expectations based on SA differences, Bayesian analyses revealed moderate evidence for equal subjective values of engaging in social situations and comparable amygdala responses to social decision-making and striatal responses to positive social feedback in both groups. Moreover, while explorative analyses revealed reduced pleasantness ratings, increased striatal activity, and decreased striatal-hippocampal connectivity in response to negative computer feedback in HL participants, these effects were diminished for negative social feedback. Our findings suggest that, unlike SA, loneliness is not associated with withdrawal from social interactions. Thus, established interventions for SA should be adjusted when targeting loneliness.SIGNIFICANCE STATEMENT Loneliness can cause serious health problems. Adapting well-established cognitive-behavioral therapies targeting social anxiety might be promising to reduce chronic loneliness given a close link between both constructs. However, a better understanding of behavioral and neurobiological factors associated with loneliness is needed to identify which specific mechanisms of social anxiety are shared by lonely individuals. We found that lonely individuals show a consistently distinct pattern of behavioral and neural responsiveness to social decision-making and social feedback compared with previous findings for social anxiety. Our results indicate that loneliness is associated with a biased emotional reactivity to negative events rather than social avoidance. Our findings thus emphasize the distinctiveness of loneliness from social anxiety and the need for adjusted psychotherapeutic protocols.