Animal experiments scrutinised: systematic reviews demonstrate poor human clinical and toxicological utility.
The assumption that animal models are reasonably predictive of human outcomes provides the basis for their widespread use in toxicity testing and in biomedical research aimed at developing cures for human diseases. To investigate the validity of this assumption, the comprehensive "Scopus" biomedical bibliographic databases were searched for published systematic reviews of the human clinical or toxicological utility of animal experiments. Of 20 reviews examining clinical utility, authors concluded that the animal models were substantially consistent with or useful in advancing clinical outcomes in only two cases, and the conclusion in one case was contentious. Included were reviews of the clinical utility of experiments expected by ethics committees to lead to medical advances, of highly-cited experiments published in major journals, and of chimpanzee experiments - the species most likely to be predictive of human outcomes. Seven additional reviews failed to clearly demonstrate utility in predicting human toxicological outcomes such as carcinogenicity and teratogenicity. Consequently, animal data may not generally be assumed to be substantially useful for these purposes. Possible causes include interspecies differences, the distortion of experimental outcomes arising from experimental environments and protocols, and the poor methodological quality of many animal experiments evident in at least 11 reviews. No reviews existed in which a majority of animal experiments were of good quality. While the latter problems might be minimised with concerted effort, given their widespread nature, the interspecies limitations are likely to be technically and theoretically impossible to overcome. Yet, unlike non-animal models, animal models are not normally subjected to formal scientific validation. Instead of simply assuming they are predictive of human outcomes, the consistent application of formal validation studies to all test models is clearly warranted, regardless of their animal, non-animal, historical, contemporary or possible future status. Expected benefits would include greater selection of models truly predictive of human outcomes, increased safety of people exposed to chemicals that have passed toxicity tests, increased efficiency during the development of human pharmaceuticals, and decreased wastage of animal, personnel and financial resources. The poor human clinical and toxicological utility of most animal models for which data exists, in conjunction with their generally substantial animal welfare and economic costs, justify a ban on animal models lacking scientific data clearly establishing their human predictivity or utility.


Preclinical evaluation of 86Y-labeled inhibitors of prostate-specific membrane antigen for dosimetry estimates.
(86)Y (half-life = 14.74 h, 33% β(+)) is within an emerging class of positron-emitting isotopes with relatively long physical half-lives that enables extended imaging of biologic processes. We report the synthesis and evaluation of 3 low-molecular-weight compounds labeled with (86)Y for imaging the prostate-specific membrane antigen (PSMA) using PET. Impetus for the study derives from the need to perform dosimetry estimates for the corresponding (90)Y-labeled radiotherapeutics. Multistep syntheses were used in preparing (86)Y- 4: - 6: PSMA inhibition constants were evaluated by competitive binding assay. In vivo characterization using tumor-bearing male mice was performed by PET/CT for (86)Y- 4: - 6: and by biodistribution studies of (86)Y- 4: and (86)Y- 6: out to 24 h after injection. Quantitative whole-body PET scans were recorded to measure the kinetics for 14 organs in a male baboon using (86)Y- 6 RESULTS: Compounds (86)Y- 4: - 6: were obtained in high radiochemical yield and purity, with specific radioactivities of more than 83.92 GBq/μmol. PET imaging and biodistribution studies using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor-bearing mice revealed that (86)Y- 4-6: had high site-specific uptake in PSMA-positive PC-3 PIP tumor starting at 20 min after injection and remained high at 24 h. Compound (86)Y- 6: demonstrated the highest tumor uptake and retention, with 32.17 ± 7.99 and 15.79 ± 6.44 percentage injected dose per gram (%ID/g) at 5 and 24 h, respectively. Low activity concentrations were associated with blood and normal organs, except for the kidneys, a PSMA-expressing tissue. PET imaging in baboons reveals that all organs have a 2-phase (rapid and slow) clearance, with the highest uptake (8 %ID/g) in the kidneys at 25 min. The individual absolute uptake kinetics were used to calculate radiation doses using the OLINDA/EXM software. The highest mean absorbed dose was received by the renal cortex, with 1.9 mGy per MBq of (86)Y- 6: Compound (86)Y- 6: is a promising candidate for quantitative PET imaging of PSMA-expressing tumors. Dosimetry calculations indicate promise for future (90)Y or other radiometals that could use a similar chelator/scaffold combination for radiopharmaceutical therapy based on the structure of 6.


Cultivation of microalgal biomass using swine manure for biohydrogen production: Impact of dilution ratio and pretreatment.
This study assessed the impact of swine manure (SM) dilution ratio on the microalgal biomass cultivation and further tested for biohydrogen production efficiency from the mixed microalgal biomass. At first, various solid/liquid (S/L) ratio of the SM ranged from 2.5 to 10 g/L was prepared as a nutrient medium for the algal biomass cultivation without addition of the external nutrient sources over a period of 18 d. The peak biomass concentration of 2.57 ± 0.03 g/L was obtained under the initial S/L loading rates of 5 g/L. Further, the cultivated biomass was subjected to two-step (ultrasonication + enzymatic) pretreatment and evaluated for biohydrogen production potential. Results showed that the variable amount of hydrogen production was observed with different S/L ratio of the SM. The peak hydrogen yield of 116 ± 6 mL/g TSadded was observed at the 5 g/L grown SM mixed algal biomass.


Inadvertent epidural injection of potassium chloride. Report of two cases.
Two patients underwent thoracotomy for resection of pulmonary or esophageal carcinoma. Postoperatively, epidural catheters were inserted for pain management. Complaints of severe injection pain over the abdomen or lower extremities were made during one administration of pain medication. Progressive weakness and numbness developed over the lower trunk and lower extremities, with subsequent respiratory difficulties. Potassium chloride (KCl) was suspected to have been mistaken for normal saline as the diluent for morphine. In addition to endotracheal intubation and ventilatory support, steroids were administered both intravenously and epidurally to suppress spinal cord irritation. The two patients regain motor and sensory functions 14 and 18 hours later, respectively, without sequelae.


Neurally-mediated and neurally-independent beneficial actions of melatonin in the gastrointestinal tract.
Melatonin (N-acetyl-5-methoxytryptamine), originally discovered in the pineal gland, is now known also to be present in the gastrointestinal tract from the stomach to the colon. It is localized and likely synthesized in the enterochromaffin cells of the mucosal lining. Its functions in the gut generally seem to be protective of the mucosa from erosion and ulcer formation and to possibly influence movement of the gastrointestinal contents through the digestive system. In this brief review, we summarize the work documenting the function of melatonin in influencing bicarbonate secretion in the stomach and its role in preventing and repairing ulcers in the stomach and duodenum. Melatonin's actions in the control of bicarbonate secretion involve the central and peripheral sympathetic nervous systems and the actions are receptor mediated. Conversely, melatonin's actions in reducing ulcer formation also seemingly involve the ability of the indole to directly scavenge toxic oxygen-based reactants, e.g., the hydroxyl radical, and possibly to promote antioxidative enzyme activities. These same processes may be involved in the mechanisms by which melatonin promotes ulcer healing. Additionally, however, melatonin's effects on the healing of ulcers includes actions of blood flow in the margins of the ulcer and also on the sensory nerves. All indications are that melatonin has a variety of beneficial effects in the gastrointestinal tract. It is likely, however, that additional actions of melatonin on the digestive system will be uncovered.


Anti-beta 2-glycoprotein I antibodies and anti-endothelial cell antibodies induce tissue factor in endothelial cells.
Anti-beta 2-glycoprotein I antibodies bind to endothelial cells through beta 2-GPI. The antibodies are present in patients with systemic lupus erythematosus and antiphospholipid syndrome and are associated with the pathogenesis of the disease. Anti-endothelial cell antibodies that react with constitutive antigens on ECs are present in patients with vasculiditis and other diseases. Both types of antibodies can activate ECs. Frequent findings in APLS and vasculitis are fibrin deposits and thromboembolic phenomena. These indicate that the coagulation system is activated. However, the mechanism of activation is not clear. ECs generate tissue factor upon stimulation with various substances. In the present study we report that monoclonal anti-beta 2-GPI antibodies and AECAs, derived from a patient with primary APLS and a patient with Takayasu's arteritis, respectively, induce a potent tissue factor in ECs. The production of TF activity, TF antigen and TF mRNA is dose and time dependent. The TF activity was induced also by F(ab)2 but not by Fc fragments and was abolished completely by pre-incubation with ant-TF antibodies. The TF that is induced in ECs by AECAs with and without beta 2-GPI specificity may activate the coagulation and thereby play a major role in the pathogenesis of fibrin deposition and thrombus formation in diseases that are associated with the presence of these antibodies.


Trends over time in the risk of stroke after an incident transient ischemic attack.
Long-term population trends in the early risk of stroke after transient ischemic attack (TIA) are unknown. We hypothesized that there has been an appreciable decline in the risk of stroke after TIA for the last decade. Population-level cohort study from Victoria, Australia (population 5.6 million), using linked data from hospitals, emergency departments, and death records (2001-2011), with a 2-year clearance period to define incident TIAs. Age-specific rates/1000, yearly incident rate ratios, and age-sex-adjusted risk of stroke after TIA were computed. The mean age of 46 971 patients with TIA was 71 (SD=15), 52% women. In patients ≥65 years, annual TIA rates declined between 2001 and 2011 from 5.8 to 4.8/1000 (men) and from 5.3 to 4.2/1000 (women). Yearly incident rate ratios were 0.97 (95% confidence interval, 0.96-0.98) in men and 0.97 (95% confidence interval, 0.97-0.98) in women. Overall, the 90-day stroke risk was 3.1%. Age-sex-adjusted risk of stroke at 90 days after a TIA decreased by 3% per year (odds ratio for the effect of year, 0.97; 95% confidence interval, 0.95-0.99). Male sex, direct discharge from emergency departments, public hospital care, stroke unit care, and absence of vascular risk factors were associated with a downward yearly trend of stroke within 90 days of TIA. Over the last 10 years, there has been a measurable decline in the 90-day risk of stroke after an incident TIA and overall decline in rates of TIA in Victoria, Australia. These trends may reflect improved primary and secondary prevention efforts for the last decade.


Exposure to perchlorate, nitrate and thiocyanate, and prevalence of diabetes mellitus.
It is known that perchlorate, nitrate and thiocyanate have the property of inhibiting sodium iodide symporter. Animal studies have suggested that these compounds, especially perchlorate, might also interfere with insulin secretion. However, the association between their exposure and diabetes risk is largely unknown in humans. Among 11 443 participants (mean age 42.3 years) from the National Health and Nutritional Examination Survey 2001-14, urinary perchlorate, nitrate and thiocyanate were measured by using ion chromatography coupled with electrospray tandem mass spectrometry. Diabetes was defined as self-reported doctor diagnosis, use of oral hypoglycaemic medication or insulin, fasting plasma glucose ≥ 126 mg/dl or glycated haemoglobin A1c (HbA1c) ≥ 6.5%. The median (interquartile range) levels of urinary perchlorate, nitrate and thiocyanate were 3.32 (1.84, 5.70) μg/l, 46.4 (27.9, 72.0) mg/l and 1.23 (0.59, 2.78) mg/l, respectively. Higher levels of urinary perchlorate were associated with elevated levels of fasting glucose, HbA1c, insulin and homeostatic model assessment of insulin resistance (all Ptrend < 0.001). After multivariate adjustment including urinary creatinine, smoking status and body mass index (BMI), higher urinary perchlorate, but not nitrate or thiocyanate, was associated with an increased prevalence of diabetes mellitus. Comparing extreme quintiles, the odds ratio (95% confidence interval) of diabetes was 1.53 (1.21, 1.93; Ptrend < 0.001) for perchlorate, 1.01 (0.77, 1.32; Ptrend = 0.44) for nitrate and 0.98 (0.73, 1.31; Ptrend = 0.64) for thiocyanate. When urinary perchlorate, nitrate and thiocyanate were further mutually adjusted, the results did not materially change. Similar results were observed when analyses were stratified by smoking status, as well as by age, gender, kidney function and BMI. Higher urinary perchlorate levels are associated with an increased prevalence of diabetes mellitus, independent of traditional risk factors. Future prospective studies are needed to confirm these findings.


Improved Dissolution and Oral Bioavailability of Celecoxib by a Dry Elixir System.
The purpose of this study was to develop and evaluate a dry elixir (DE) system for enhancing the dissolution rate and oral bioavailability of celecoxib. DE system has been used for improving solubility, oral bioavailability of poorly water-soluble drugs. The encapsulated drugs or solubilized drugs in the matrix are rapidly dissolved due to the co-solvent effect, resting in both an enhanced dissolution and bioavailability. DEs containing celecoxib were prepared by spray-drying method and characterized by morphology, drug/ethanol content, drug crystallinity, dissolution rate and oral bioavailability. The ethanol content and drug content in DE system could be easily altered by controlling the spraydrying conditions. The dissolution profile of celecoxib from DE proved to be much higher than that of celecoxib powder due to the nano-structured matrix, amorphous state and encapsulated ethanol. The bioavailability of celecoxib from DEs was compared with celecoxib powder alone and commercial product (Celebrex®) in rats. In particular, blood concentrations of celecoxib form DE formulation were much greater than those of native celecoxib and market product. The data demonstrate that the DE system could provide an useful solid dosage form to enhance the solubility, dissolution rate and oral bioavailability of celecoxib.


Forms of aggression, social-psychological adjustment, and peer victimization in a Japanese sample: the moderating role of positive and negative friendship quality.
The purpose of these studies was to examine the frequency and stability of relational and physical aggression and their associations with social-psychological adjustment or peer victimization, and how friendships are involved in the relations between forms of aggression and peer victimization in Japanese children. The sample consisted of 452 (Study 1) and 138 (Study 2) children who were in the fourth and fifth grades. Results of Study 1 demonstrated that relational aggression was uniquely and more strongly associated with internalizing adjustment problems than physical aggression. Moreover, Study 2 revealed that relational aggression and physical aggression were stable over a 6-month period and the stability of relational aggression was reinforced by negative friendships (i.e., high levels of exclusivity and friend victimization). Further, the association between relational aggression and relative increases in relational victimization was attenuated by positive friendships (i.e., high levels of intimacy, companionship, and friendship satisfaction). Interestingly, friendships were unrelated to physical aggression and its relation to physical victimization. The age and gender of the children in the two studies were also examined. Cultural and developmental processes involving forms of aggression, friendships, social-psychological adjustment, and peer victimization were discussed.


Post-cardiac arrest Sedation Promotes Electroencephalographic Slow-wave Activity and Improves Survival in a Mouse Model of Cardiac Arrest.
Patients resuscitated from cardiac arrest are routinely sedated during targeted temperature management, while the effects of sedation on cerebral physiology and outcomes after cardiac arrest remain to be determined. The authors hypothesized that sedation would improve survival and neurologic outcomes in mice after cardiac arrest. Adult C57BL/6J mice of both sexes were subjected to potassium chloride-induced cardiac arrest and cardiopulmonary resuscitation. Starting at the return of spontaneous circulation or at 60 min after return of spontaneous circulation, mice received intravenous infusion of propofol at 40 mg · kg-1 · h-1, dexmedetomidine at 1 µg · kg-1 · h-1, or normal saline for 2 h. Body temperature was lowered and maintained at 33°C during sedation. Cerebral blood flow was measured for 4 h postresuscitation. Telemetric electroencephalogram (EEG) was recorded in freely moving mice from 3 days before up to 7 days after cardiac arrest. Sedation with propofol or dexmedetomidine starting at return of spontaneous circulation improved survival in hypothermia-treated mice (propofol [13 of 16, 81%] vs. no sedation [4 of 16, 25%], P = 0.008; dexmedetomidine [14 of 16, 88%] vs. no sedation [4 of 16, 25%], P = 0.002). Mice receiving no sedation exhibited cerebral hyperemia immediately after resuscitation and EEG power remained less than 30% of the baseline in the first 6 h postresuscitation. Administration of propofol or dexmedetomidine starting at return of spontaneous circulation attenuated cerebral hyperemia and increased EEG slow oscillation power during and early after sedation (40 to 80% of the baseline). In contrast, delayed sedation failed to improve outcomes, without attenuating cerebral hyperemia and inducing slow-wave activity. Early administration of sedation with propofol or dexmedetomidine improved survival and neurologic outcomes in mice resuscitated from cardiac arrest and treated with hypothermia. The beneficial effects of sedation were accompanied by attenuation of the cerebral hyperemic response and enhancement of electroencephalographic slow-wave activity.


The structural correlates of functional deficits in early huntington's disease.
Neuropathological studies in Huntington disease (HD) have demonstrated neuronal loss in the striatum, as well as in other brain regions including the cortex. With diffusion tensor MRI we evaluated the hypothesis that the clinical dysfunction in HD is related to regionally specific lesions of circuit-specific cortico-basal ganglia networks rather than to the striatum only. We included 27 HD and 24 controls from the TRACK-HD Paris cohort. The following assessments were used: self-paced tapping tasks, trail B making test (TMT), University of Pennsylvania smell identification test (UPSIT), and apathy scores from the problem behaviors assessment. Group comparisons of fractional anisotropy and mean diffusivity and correlations were performed using voxel-based analysis. In the cortex, HD patients showed significant correlations between: (i) self paced tapping and mean diffusivity in the parietal lobe at 1.8 Hz and prefrontal areas at 3 Hz, (ii) UPSIT and mean diffusivity in the parietal, and median temporal lobes, the cingulum and the insula, and fractional anisotropy in the insula and the external capsule, (iii) TMT B and mean diffusivity in the white matter of the superior frontal, orbital, temporal, superior parietal and post central areas, and (iv) apathy and fractional anisotropy in the white matter of the rectus gyrus. In the basal ganglia, we found correlations between the self paced tapping, UPSIT, TMT tests, and mean diffusivity in the anterior part of the putamen and the caudate nucleus. In conclusion, disruption of motor, associative and limbic cortico-striatal circuits differentially contribute to the clinical signs of the disease.


Steatocystoma multiplex. A facial papular variant.
A 32-year-old man had multiple asymptomatic, yellowish to normal skin-colored, moderately firm papules that were disseminated on the forehead, temple, and periauricular region. The histologic, enzyme histochemical, and ultrastructural findings were those of steatocystoma multiplex.


A putative white adipose tissue specific nuclear orphan receptor that interacts with the cAMP-response element of the human beta3-adrenergic receptor gene.
The authors previously reported that one of the cAMP-response elements (CREs) of the human beta3-AR gene, beta3CRE2, interacts with a nuclear factor which is distinct from CREB/ATF family. We named this factor WATSF-1 (white adipose tissue specific factor-1) since it is preferentially expressed in WAT. In this work, we have shown the absence of DNA binding or transcriptional activity of this factor in several non-adipose cells tested. By computer analysis, beta3CRE2 was found to constitute an octameric element that is highly homologous to the binding site for some members of the nuclear hormone receptor superfamily. Using the response elements of other adipocyte-specific nuclear receptors as competitors, a 'cross-talk' between WATSF-1 and these response elements has been demonstrated. However, the affinity of WATSF-1 for these response elements differs from that for beta3CRE2 (self), implying that WATSF-1 is distinct from these adipocyte-specific nuclear receptors. Furthermore the DNA-binding activity of WATSF-1 was shown to be enhanced by phosphatase treatment, suggesting that phosphorylation may play an important role in the functional modulation of this factor. In an effort to prove that it is indeed an adipocyte-specific factor, we used 3T3-L1 cells, a cellular model of WAT, that can undergo differentiation into adipocytes. The DNA binding and transcriptional activity of this factor appeared during differentiation of the cells. Taken together, these results demonstrate that WATSF-1 is a putative white adipocyte-specific nuclear orphan receptor induced during adipogenesis and is a transcriptional activator through one of the CREs of the human beta3-AR gene. Targeting this factor may be a novel therapeutic approach to stimulation of the beta3-AR signal transduction pathway in adipose tissues.


Emotional expressions as appeals to recipients.
Emotion expressions convey information. One important kind of information, from a communicative perspective, is information about what is demanded of the recipients of the expression. Compared to the vast body of research that focuses on whether, and to what degree, emotion expressions convey information about inner states, there is surprisingly little systematic research on the information emotion expressions convey about what the expresser wants the recipient to do. The present research documents for the first time the set of appeals associated with the expressions of anger, fear, happiness, sadness, and disgust. In two studies, we found that (a) generally, for each emotional expression, a core appeal is perceived as being made on recipients, but also a range of complementary demands, and that (b) context matters, as is the case for social perception of emotions in general. In this case, who caused the emotion expression affects the mapping between emotional expressions and appeals. Finally, (c) recipients report intentions to comply with these appeals, as can be expected from a functional point of view. Overall, these findings put the focus squarely on the imperative dimension of emotional expressions and lend support to the view that emotional communication entails an attempt to influence recipients rather than simply to inform them about how expressers feel or what they may do next. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children.
Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression. We investigated the relationship between urine biomarkers of kidney tubular health (EGF and α-1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m2. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period. Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and α-1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression. After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and α-1 microglobulin concentrations were each associated with CKD progression in children.


Total vertex craniopagus with crossed venous drainage: case report of successful surgical separation.
Twin boys joined at the head in a total vertex configuration were born in Egypt in June 2001. At 12 months, they were transported to Dallas for evaluation and eventual surgical separation. In Dallas, a large multidisciplinary team of health care providers from two pediatric hospitals was assembled to care for the boys. Extensive radiographic evaluation revealed that the twins had essentially separate, well-formed brains, each with regions of schizencephaly. Each child's left cerebral hemisphere drained most of the venous blood to the right jugular system of the other. A detailed assessment of the foreseeable risks of surgical separation was then estimated and presented to the parents, as well as to the ethics committee of the two institutions. The decision was then made to proceed with separation. Surgical planning included the construction of multiple polymer models, and the design and construction of customized head holders and an operating table. Prior to separation a series of preparatory operations were performed to expand the scalp, as well as the fascia lata for dural grafting. At the age of 28 months, the twins were successfully separated during a 33-h operation. No attempt was made to reconstruct the dural venous sinuses. Scalp closure was adequate, requiring a split-thickness skin graft on one boy. Postoperatively each child demonstrated an incomplete right hemiparesis. One twin required cerebral spinal fluid shunting. Neither child had a CSF leak or a CSF infection. At 6 months follow-up, both boys are rapidly acquiring speech in both English and Arabic, motor function is improving, and both are progressing toward independent ambulation.


Enantiomers of 3-methylspermidine selectively modulate deoxyhypusine synthesis and reveal important determinants for spermidine transport.
Eukaryotic translation initiation factor 5A (eIF5A) is essential for cell proliferation, becoming functionally active only after post-translational conversion of a specific Lys to hypusine [N(ε)-(4-amino-2-hydroxybutyl)lysine]. Deoxyhypusine synthase (DHS) is the rate-limiting enzyme of this two-step process, and the polyamine spermidine is the only natural donor of the butylamine group for this reaction, which is very conserved-hypusine biosynthesis suffers last when the intracellular spermidine pool is depleted. DHS has a very strict substrate specificity, and only a few spermidine analogs are substrates of the enzyme and can support long-term growth of spermidine-depleted cells. Herein, we compared the biological properties of earlier unknown enantiomers of 3-methylspermidine (3-MeSpd) in deoxyhypusine synthesis, in supporting cell growth and in polyamine transport. Long-term treatment of DU145 cells with α-difluoromethylornithine (inhibitor of polyamine biosynthesis) and (R)-3-MeSpd did not cause depletion of hypusinated eIF5A, and the cells were still able to grow, whereas the combination of α-difluoromethylornithine with a racemate or (S)-3-MeSpd caused cessation of cell growth. Noticeably, DHS preferred the (R)- over the (S)-enantiomer as a substrate. (R)-3-MeSpd competed with [(14)C]-labeled spermidine for cellular uptake less efficiently than the (S)-3-MeSpd (Ki = 141 μM vs 19 μM, respectively). The cells treated with racemic 3-MeSpd accumulated intracellularly mainly (S)-3-MeSpd, but not DHS substrate (R)-3-MeSpd, explaining the inability of the racemate to support long-term growth. The distinct properties of 3-MeSpd enantiomers can be exploited in designing polyamine uptake inhibitors, facilitating drug delivery and modulating deoxyhypusine synthesis.


The theoretical optimal center of rotation for a temporomandibular joint prosthesis: a three-dimensional kinematic study.
A unilateral temporomandibular joint (TMJ) prosthesis may cause dysfunction of the contralateral, natural TMJ because of lack of translatorial movements of the prosthetic side. The natural translatorial capacity of the mandible can be restored in part by a TMJ prosthesis with a fixed center of rotation (CR), positioned inferiorly to the center of the natural mandibular condyle. The aim of this study was to determine the optimal position for the fixed CR of a unilateral TMJ prosthesis. A mathematical model was used to analyze different positions of the CR. These positions were evaluated based on the calculated rotation of the mandible in the frontal (theta f) and horizontal (theta h) plane, and the mediolateral movement (MLM) of the contralateral natural condyle. For current TMJ prostheses, with the CR positioned in the center of the natural condyle, theta h exceeded the natural limits. When the CR was shifted inferiorly, all parameters improved, particularly theta h. The addition of an anterior shift to an inferior shift slightly worsened theta f, while the addition of a posterior shift to an inferior shift slightly improved theta f and worsened MLM. We concluded that the functioning of the contralateral TMJ improves by shifting the CR inferiorly. An anterior shift may be added to remain within the contour of the mandibular ramus. The proposed position of the CR is 15 mm inferior to the center of the natural condyle, combined, if necessary, with an additional anterior shift of 5 mm.


Fluorescence interferometry: principles and applications in biology.
The use of fluorescence radiation is of fundamental importance for tackling measurement problems in the life sciences, with recent demonstrations of probing biological systems at the nanoscale. Usually, fluorescent light-based tools and techniques use the intensity of light waves, which is easily measured by detectors. However, the phase of a fluorescence wave contains subtle, but no less important, information about the wave; yet, it has been largely unexplored. Here, we introduce the concept of fluorescence interferometry to allow the measurement of phase information of fluorescent light waves. In principle, fluorescence interferometry can be considered a unique form of optical low-coherence interferometry that uses fluorophores as a light source of low temporal coherence. Fluorescence interferometry opens up new avenues for developing new fluorescent light-based imaging, sensing, ranging, and profiling methods that to some extent resemble interferometric techniques based on white light sources. We propose two experimental realizations of fluorescence interferometry that detect the interference pattern cast by the fluorescence fields. This article discusses their measurement capabilities and limitations and compares them with those offered by optical low-coherence interferometric schemes. We also describe applications of fluorescence interferometry to imaging, ranging, and profiling tasks and present experimental evidences of wide-field cross-sectional imaging with high resolution and large range of depth, as well as quantitative profiling with nanometer-level precision. Finally, we point out future research directions in fluorescence interferometry, such as fluorescence tomography of whole organisms and the extension to molecular interferometry by means of quantum dots and bioluminescence.


Prognostic value of N-terminal probrain natriuretic peptide level on admission in patients with acute myocardial infarction and preserved left ventricular ejection fraction.
Little is known about the prognosis of patients with acute myocardial infarction (MI) and preserved left ventricular ejection fraction (LVEF), a condition that is becoming increasingly common. This study sought to identify independent predictors of adverse outcomes in patients with acute MI and preserved LVEF. We studied the prognosis of 555 patients with acute MI (mean age 62 years, 287 men) and preserved LVEF (>40%). Primary endpoint was a composite of cardiovascular (CV) death and rehospitalization for heart failure (HF). During follow-up of a median 24 months (range 0-50 months), there were 34 cardiac events (cardiac death in 28 and rehospitalization for HF in six patients). Significant univariate predictors of CV death and rehospitalization for HF were age, Killip class greater than I, revascularization, estimated glomerular filtration rate, log N-terminal probrain natriuretic peptide (NT-proBNP), LVEF, left atrial volume index, and the ratio of early diastolic mitral inflow velocity to early diastolic mitral annular velocity (E/E') greater than 15. In multivariate Cox analysis, age (hazard ratio 1.05, 95% confidence interval: 1.01-1.09, P=0.02) and log NT-proBNP (hazard ratio 2.08, 95% confidence interval: 1.61-2.70, P<0.001) independently predicted CV death and rehospitalization for HF. Receiver operating curve analysis indicated that NT-proBNP showed significantly higher areas under the receiver operating characteristic curve value than other significant predictors including left atrial volume index and estimated glomerular filtration rate for prediction of adverse outcomes. NT-proBNP showed a strong predictive power for adverse outcomes beyond traditional risk factors and echocardiographic indices of LV systolic and diastolic function in patients with acute MI and preserved LVEF.


Genetics of human brain development.
Brain development in humans is achieved through precise spatiotemporal genetic control, the mechanisms of which remain largely elusive. Recently, integration of technological advances in human stem cell-based modelling with genome editing has emerged as a powerful platform to establish causative links between genotypes and phenotypes directly in the human system. Here, we review our current knowledge of complex genetic regulation of each key step of human brain development through the lens of evolutionary specialization and neurodevelopmental disorders and highlight the use of human stem cell-derived 2D cultures and 3D brain organoids to investigate human-enriched features and disease mechanisms. We also discuss opportunities and challenges of integrating new technologies to reveal the genetic architecture of human brain development and disorders.


Red Blood Cell Transfusions at 21 Days of Age or Older in Previously Transfusion-Naive Very Preterm Infants: Association with Neonatal Outcomes.
This study aims to assess the association of red blood cell (RBC) transfusion in a cohort of preterm infants with mortality, retinopathy of prematurity (ROP), and chronic lung disease (CLD) transfused at ≥21 days of life. This retrospective cohort study included infants born at <30 weeks' gestation who survived ≥21 days, had not received any RBC transfusions before reaching 21 days of age, and were admitted to participating units in the Canadian neonatal network (2003-2009). Out of the 3,799 eligible infants, 3,309 infants did not receive RBC transfusion at ≥21 days of age, whereas 490 received transfusion at ≥21 days of age. Infants who did not receive RBC transfusion/s at ≥21 days of age had higher birth weight (p<0.01) and higher gestational age at the time of birth (p<0.01) as compared with those who received transfusion/s at ≥21 days of age. Receipt of RBC transfusion/s at ≥21 days of age was not associated with mortality (adjusted odds ratio [AOR] 1.20; 95% confidence interval [CI] 0.33-4.34) or severe ROP (AOR 1.02; 95% CI 0.59-1.77) but was associated with increased odds of CLD (AOR 1.78; 95% CI 1.43-2.22). RBC transfusion/s at ≥21 days of age in previously transfusion-naive preterm infants was associated with increased odds of CLD but not with ROP or mortality.


Effects of glucocorticoid treatment on cardiac protein synthesis and degradation.
We treated rats with dexamethasone (DEX, 1 mg . kg-1 . day-1) and examined the effects of this glucocorticoid on heart protein metabolism using atrial explant and Langendorff perfusion preparations. Fasted rats treated with DEX for 2 days had significantly lower body weights (92% of control, P less than 0.001) and larger hearts (106% of control, P less than 0.005) than fasted control animals. Protein and RNA concentrations remained constant. In atrial explants, DEX treatment produced a 19% increase in protein synthesis (P less than 0.001) and a 13% increase in protein degradation (P less than 0.002). In Langendorff-perfused hearts, DEX treatment caused a 36% increase in protein synthesis (P less than 0.02), while protein degradation was 8% above control (P greater than 0.05). Thus, in contrast to their catabolic effects on skeletal muscle, glucocorticoids are anabolic on the heart. The increased accumulation of total cardiac protein during early glucocorticoid administration is mediated entirely via increased rates of synthesis.


Co-mutagenicity of coumarin (1,2-benzopyrone) with aflatoxin B1 and human liver S9 in mammalian cells.
Coumarin (1,2-benzopyrone), a natural dietary constituent and drug currently under evaluation for treatment of certain cancers and lymphedema, reduces polycyclic aromatic hydrocarbon-induced neoplasms in rodents. Because most rodents metabolize coumarin through 3,4-epoxidation, whereas 7-hydroxylation predominates in humans, their suitability as a model for coumarin effects in humans has been questioned. We examined coumarin chemoprotection against the promutagen and dietary contaminant aflatoxin B1 with human liver S9 bioactivation in the Chinese hamster ovary cell/hypoxanthine-guanine phosphoribosyltransferase mutation assay. Coumarin in the absence of aflatoxin B1 was not mutagenic or cytotoxic up to 500 microM. When included with either 1 or 10 microM aflatoxin B1, coumarin produced a dose-dependent increase in mutant frequency and cytotoxicity. At concentrations greater than 50 microM, coumarin stimulated human liver S9 bioactivation of aflatoxin B1 to the mutagenic 8,9-epoxide. This increase was 12- and fivefold at 500 microM coumarin with 1 and 10 microM aflatoxin B1, respectively, compared with incubations with aflatoxin B1 alone. These findings differ from previous results with liver S9 from other species, and indicate that coumarin co-mutagenicity with aflatoxin B1 and human liver S9 is through increased aflatoxin B1 bioactivation.


Common variable immunodeficiency-associated endotoxemia promotes early commitment to the T follicular lineage.
Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional TH cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear. We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements. Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression. Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production. Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs.


What factors are critical to attracting NHS foundation doctors into specialty or core training? A discrete choice experiment.
Multiple personal and work-related factors influence medical trainees' career decision-making. The relative value of these diverse factors is under-researched, yet this intelligence is crucially important for informing medical workforce planning and retention and recruitment policies. Our aim was to investigate the relative value of UK doctors' preferences for different training post characteristics during the time period when they either apply for specialty or core training or take time out. We developed a discrete choice experiment (DCE) specifically for this population. The DCE was distributed to all Foundation Programme Year 2 (F2) doctors across Scotland as part of the National Career Destination Survey in June 2016. The main outcome measure was the monetary value of training post characteristics, based on willingness to forgo additional potential income and willingness to accept extra income for a change in each job characteristic calculated from regression coefficients. 677/798 F2 doctors provided usable DCE responses. Location was the most influential characteristic of a training position, followed closely by supportive culture and then working conditions. F2 doctors would need to be compensated by an additional 45.75% above potential earnings to move from a post in a desirable location to one in an undesirable location. Doctors who applied for a training post placed less value on supportive culture and excellent working conditions than those who did not apply. Male F2s valued location and a supportive culture less than female F2s. This is the first study focusing on the career decision-making of UK doctors at a critical careers decision-making point. Both location and specific job-related attributes are highly valued by F2 doctors when deciding their future. This intelligence can inform workforce policy to focus their efforts in terms of making training posts attractive to this group of doctors to enhance recruitment and retention.


Involvement of CD26 in Differentiation and Functions of Th1 and Th17 Subpopulations of T Lymphocytes.
CD26, acting as a costimulator of T cell activation, plays an important role in the immune system. However, the role of CD26 in the differentiation of T cell subsets, especially of new paradigms of T cells, such as Th17 and Tregs, is not fully clarified. In the present study, the role of CD26 in T cell differentiation was investigated in vitro. CD26 expression was analyzed in the different subsets of human peripheral blood T lymphocytes after solid-phase immobilized specific anti-CD3 mAb stimulation. Here, the percentage of CD4+ cells significantly increased and most of these cells were coexpressed with CD26, suggesting a close correlation of CD26 expression with the proliferation of CD4+ cells. Subsequently, after immobilized anti-CD3 mAb stimulation, CD26 high-expressing cells (CD26high) were separated from CD26 low-expressing cells (CD26low) by magnetic cell sorting. We found that the percentages of cells secreting Th1 typical cytokines (IL-2, IFN-γ) and Th17 typical cytokines (IL-6, IL-17, and IL-22) or expressing Th17 typical biomarkers (IL-23R, CD161, and CD196) in the CD26high group were markedly higher than in those in the CD26low group. In addition, a coexpression of CD26 with IL-2, IFN-γ, IL-17, IL-22, and IL-23R in lymphocytes was demonstrated by fluorescence microscopy. These results provide direct evidence that the high expression of CD26 is accompanied by the differentiation of T lymphocytes into Th1 and Th17, indicating that CD26 plays a crucial role in regulating the immune response.


Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study.
Acquired hemophilia A (AHA) is a severe auto-immune bleeding disorder. Treatment of AHA is burdensome and optimal management is still unresolved. Therefore a retrospective nationwide multi-center cohort study (1992-2018) was performed to evaluate clinical presentation and treatment efficacy and safety of AHA in the Netherlands. Multivariate logistic and Cox regression analysis was used to study independent associations between patient characteristics and clinical outcomes. A total of 143 patients (median age 73 years; 52.4% male) were included with a median follow-up of 16.8 months (IQR 3.6-41.5 months). First-line immunosuppressive treatment was mostly steroid monotherapy (67.6%), steroids/cyclophosphamide (11.9%) and steroids/rituximab (11.9%), with success rates of 35.2%, 80.0% and 66.7% respectively, P < .05. Eventually 75% of patients achieved complete remission (CR). A high anti-FVIII antibody titer, severe bleeding and steroid monotherapy were associated with lower CR rates. Infections, the most important adverse event, occurred significantly more often with steroid combination therapy compared to steroids alone (38.7% vs 10.6%; P = .001). Overall mortality was 38.2%, mostly due to infections (19.2%) compared to 7.7% fatal bleeds. Advanced age, underlying malignancy and ICU admission were predictors for mortality. This study showed that AHA is characterized by significant disease-related and treatment-related morbidity and mortality. A high anti-FVIII titer, severe bleeding and steroid monotherapy were associated with a lower CR rate. The efficacy of steroid combination therapies however, was overshadowed by higher infection rates and infections represented the most important cause of death. The challenging and delicate balance between treatment effectivity and safety requires ongoing monitoring of AHA and further identification of prognostic markers.


Assessing the Effectiveness of On-Farm and Abattoir Interventions in Reducing Pig Meat-Borne Salmonellosis within E.U. Member States.
As part of the evidence base for the development of national control plans for Salmonella spp. in pigs for E.U. Member States, a quantitative microbiological risk assessment was funded to support the scientific opinion required by the EC from the European Food Safety Authority. The main aim of the risk assessment was to assess the effectiveness of interventions implemented on-farm and at the abattoir in reducing human cases of pig meat-borne salmonellosis, and how the effects of these interventions may vary across E.U. Member States. Two case study Member States have been chosen to assess the effect of the interventions investigated. Reducing both breeding herd and slaughter pig prevalence were effective in achieving reductions in the number of expected human illnesses in both case study Member States. However, there is scarce evidence to suggest which specific on-farm interventions could achieve consistent reductions in either breeding herd or slaughter pig prevalence. Hypothetical reductions in feed contamination rates were important in reducing slaughter pig prevalence for the case study Member State where prevalence of infection was already low, but not for the high-prevalence case study. The most significant reductions were achieved by a 1- or 2-log decrease of Salmonella contamination of the carcass post-evisceration; a 1-log decrease in average contamination produced a 90% reduction in human illness. The intervention analyses suggest that abattoir intervention may be the most effective way to reduce human exposure to Salmonella spp. However, a combined farm/abattoir approach would likely have cumulative benefits. On-farm intervention is probably most effective at the breeding-herd level for high-prevalence Member States; once infection in the breeding herd has been reduced to a low enough level, then feed and biosecurity measures would become increasingly more effective.


[Laparoscopic cholecystectomy in choledocholithiasis and stricture of the terminal part of the common bile duct].
The authors offer the treatment and diagnostic algorithm in choledocholithiasis, stricture of a terminal portion of the common hepatic duct and papilla stenosis revealed in laparoscopic cholecystectomy (LCE). With the purpose of intraoperative assessment of bile ducts states during LCE, the diagnostic system including laparoscopic and ultrasonic examinations, cholangiography and choledochoscopy was developed and applied. In intraoperative revealing of choledocholithiasis without bile outflow disorders and wide cystic duct the authors prefer to remove the concrements during choledochoscopy through cystic duct without intervention on Vater's papilla (VP). In combination of choledocholithiasis with bile outflow disorders and also in isolated papilla stenosis and stricture of a terminal portion of the common hepatic duct, one-stage laparoscopic cholecystectomy, intraoperative antegrade papillosphincterotomy and retrograde calculus extraction is optimal. In cases when complete endoscopic calculus extraction is impossible, the drainage of the common hepatic duct by Cholsted's with subsequent delayed endoscopic papillosphincterotomy (EPST) is acceptable. During intraoperative examination in 49 patients (57.6%) the concrements in choledochus, not diagnosed earlier, were revealed, in 21--stricture of terminal choledochus portion and in 19 patients--papilla stenosis. In 12 cases the concrements were removed during choledochoscopy through the cystic duct stump, 4 patients with big concrements required laparoscopic choledocholithotomy. In 16 cases LCE with various variants of choledochus drainage was performed as the first stage, as the second stage--EPST and lithoextraction. Antegrade papillosphincterotomy was performed in 15 patients during LCE. In 12 cases intraoperatively revealed choledocholithiasis combined with papilla stenosis (7) and choledochus stricture (5) was the indications to intraoperative papillosphincterotomy. Papilla stenosis was the indication to antegrade papillosphincterotomy in 3 patients.


Similarities between static and rotational intensity-modulated plans.
The aim of this study was to explore similarities between intensity-modulated radiotherapy (IMRT) and intensity-modulated arc therapy (IMAT) techniques in the context of the number of multi-leaf collimator (MLC) segments required to achieve plan objectives, the major factor influencing plan quality. Three clinical cases with increasing complexity were studied: (a) prostate only, (b) prostate and seminal vesicles and (c) prostate and pelvic lymph nodes. Initial 'gold-standard' plans with the maximum possible organ-at-risk sparing were generated for all three cases. For each case, multiple IMRT and IMAT plans were generated with varying intensity levels (IMRT) and arc control points (IMAT), which translate into varying MLC segments in both modalities. The IMAT/IMRT plans were forced to mimic the organ-at-risk sparing and target coverage in the gold-standard plans, thereby only allowing the target dose inhomogeneity to be variable. A higher target dose inhomogeneity (quantified as D5--dose to the highest 5% of target volume) implies that the plan is less capable of modulation. For each case, given a similar number of MLC segments, both IMRT and IMAT plans exhibit similar target dose inhomogeneity, indicating that there is no difference in their ability to provide dose painting. Target dose inhomogeneity remained approximately constant with decreasing segments, but sharply increased below a specific critical number of segments (70, 100, 110 for cases a, b, c, respectively). For the cases studied, IMAT and IMRT plans are similar in their dependence on the number of MLC segments. A minimum critical number of segments are required to ensure adequate plan quality. Future studies are needed to establish the range of minimum critical number of segments for different treatment sites and target-organ geometries.


Uncertainty in bulk-liquid hydrodynamics and biofilm dynamics creates uncertainties in biofilm reactor design.
While biofilm reactors may be classified as one of seven different types, the design of each is unified by fundamental biofilm principles. It follows that state-of-the art design of each biofilm reactor type is subject to the same uncertainties (although the degree of uncertainty may vary). This paper describes unifying biofilm principles and uncertainties of importance in biofilm reactor design. This approach to biofilm reactor design represents a shift from the historical approach which was based on empirical criteria and design formulations. The use of such design criteria was largely due to inherent uncertainty over reactor-scale hydrodynamics and biofilm dynamics, which correlate with biofilm thickness, structure and function. An understanding of two fundamental concepts is required to rationally design biofilm reactors: bioreactor hydrodynamics and biofilm dynamics (with particular emphasis on mass transfer resistances). Bulk-liquid hydrodynamics influences biofilm thickness control, surface area, and development. Biofilm dynamics influences biofilm thickness, structure and function. While the complex hydrodynamics of some biofilm reactors such as trickling filters and biological filters have prevented the widespread use of fundamental biofilm principles and mechanistic models in practice, reactors utilizing integrated fixed-film activated sludge or moving bed technology provide a bulk-liquid hydrodynamic environment allowing for their application. From a substrate transformation perspective, mass transfer in biofilm reactors defines the primary difference between suspended growth and biofilm systems: suspended growth systems are kinetically (i.e., biomass) limited and biofilm reactors are primarily diffusion (i.e., biofilm growth surface area) limited.


Quantitative Translation of Microfluidic Transporter in Vitro Data to in Vivo Reveals Impaired Albumin-Facilitated Indoxyl Sulfate Secretion in Chronic Kidney Disease.
Indoxyl sulfate (IxS), a highly albumin-bound uremic solute, accumulates in chronic kidney disease (CKD) due to reduced renal clearance. This study was designed to specifically investigate the role of human serum albumin (HSA) in IxS renal secretion via organic anion transporter 1 (OAT1) in a microfluidic system and subsequently apply quantitative translation of in vitro data to predict extent of change in IxS renal clearance in CKD stage IV relative to healthy. Conditionally immortalized human proximal tubule epithelial cells overexpressing OAT1 were incubated with IxS (5-200 μM) in the HSA-free medium or in the presence of either HSA or CKD-modified HSA. IxS uptake in the presence of HSA resulted in more than 20-fold decrease in OAT1 affinity (Km,u) and 37-fold greater in vitro unbound intrinsic clearance (CLint,u) versus albumin-free condition. In the presence of CKD-modified albumin, Km,u increased four-fold and IxS CLint,u decreased almost seven-fold relative to HSA. Fold-change in parameters exceeded differences in IxS binding between albumin conditions, indicating additional mechanism and facilitating role of albumin in IxS OAT1-mediated uptake. Quantitative translation of IxS in vitro OAT1-mediated CLint,u predicted a 60% decrease in IxS renal elimination as a result of CKD, in agreement with the observed data (80%). The findings of the current study emphasize the role of albumin in IxS transport via OAT1 and explored the impact of modifications in albumin on renal excretion via active secretion in CKD. For the first time, this study performed quantitative translation of transporter kinetic data generated in a novel microfluidic in vitro system to a clinically relevant setting. Knowledge gaps and future directions in quantitative translation of renal drug disposition from microphysiological systems are discussed.


Aryl Hydrocarbon Receptor Deficiency Alters Circadian and Metabolic Rhythmicity.
PAS domain-containing proteins can act as environmental sensors that capture external stimuli to allow coordination of organismal physiology with the outside world. These proteins permit diverse ligand binding and heterodimeric partnership, allowing for varied combinations of PAS-dependent protein-protein interactions and promoting crosstalk among signaling pathways. Previous studies report crosstalk between circadian clock proteins and the aryl hydrocarbon receptor (AhR). Activated AhR forms a heterodimer with the circadian clock protein Bmal1 and thereby functionally inhibits CLOCK/Bmal1 activity. If physiological activation of AhR through naturally occurring, endogenous ligands inhibits clock function, it seems plausible to hypothesize that decreased AhR expression releases AhR-induced inhibition of circadian rhythms. Because both AhR and the clock are important regulators of glucose metabolism, it follows that decreased AhR will also alter metabolic function. To test this hypothesis, rhythms of behavior, metabolic outputs, and circadian and metabolic gene expression were measured in AhR-deficient mice. Genetic depletion of AhR enhanced behavioral responses to changes in the light-dark cycle, increased rhythmic amplitude of circadian clock genes in the liver, and altered rhythms of glucose and insulin. This study provides evidence of AhR-induced inhibition that influences circadian rhythm amplitude.


Catalytic enantioselective one-pot approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines.
The first enantioselective catalytic approach to cis- and trans-2,3-diaryl substituted 1,5-benzothiazepines has been conveniently developed in a one-pot fashion, starting from α,β-unsaturated acyl pyrazoles and 2-aminothiophenol. The organocatalytic two-step sulfa-Michael/lactamization sequence is promoted by a readily available bifunctional thiourea and p-toluenesulfonic acid, respectively. The protocol enables access to both N-unprotected cis- and trans-diastereoisomers in moderate to satisfactory overall yields (up to 84%) and good to excellent ee values (up to 99%). Mechanistic investigations helped to shed light on the regio- and stereoselective outcome of the process.


A spatio-temporal model to reveal oscillator phenotypes in molecular clocks: Parameter estimation elucidates circadian gene transcription dynamics in single-cells.
We propose a stochastic distributed delay model together with a Markov random field prior and a measurement model for bioluminescence-reporting to analyse spatio-temporal gene expression in intact networks of cells. The model describes the oscillating time evolution of molecular mRNA counts through a negative transcriptional-translational feedback loop encoded in a chemical Langevin equation with a probabilistic delay distribution. The model is extended spatially by means of a multiplicative random effects model with a first order Markov random field prior distribution. Our methodology effectively separates intrinsic molecular noise, measurement noise, and extrinsic noise and phenotypic variation driving cell heterogeneity, while being amenable to parameter identification and inference. Based on the single-cell model we propose a novel computational stability analysis that allows us to infer two key characteristics, namely the robustness of the oscillations, i.e. whether the reaction network exhibits sustained or damped oscillations, and the profile of the regulation, i.e. whether the inhibition occurs over time in a more distributed versus a more direct manner, which affects the cells' ability to phase-shift to new schedules. We show how insight into the spatio-temporal characteristics of the circadian feedback loop in the suprachiasmatic nucleus (SCN) can be gained by applying the methodology to bioluminescence-reported expression of the circadian core clock gene Cry1 across mouse SCN tissue. We find that while (almost) all SCN neurons exhibit robust cell-autonomous oscillations, the parameters that are associated with the regulatory transcription profile give rise to a spatial division of the tissue between the central region whose oscillations are resilient to perturbation in the sense that they maintain a high degree of synchronicity, and the dorsal region which appears to phase shift in a more diversified way as a response to large perturbations and thus could be more amenable to entrainment.


Regulation of the NK cell alloreactivity to bone marrow cells by the combination of the host NK gene complex and MHC haplotypes.
Host NK cells can reject MHC-incompatible (allogeneic) bone marrow cells (BMCs), suggesting their effective role for graft-vs leukemia effects in the clinical setting of bone marrow transplantation. NK cell-mediated rejection of allogeneic BMCs is dependent on donor and recipient MHC alleles and other factors that are not yet fully characterized. Whereas the molecular mechanisms of allogeneic MHC recognition by NK receptors have been well studied in vitro, guidelines to understand NK cell allogeneic reactivity under the control of multiple genetic components in vivo remain less well understood. In this study, we use congenic mice to show that BMC rejection is regulated by haplotypes of the NK gene complex (NKC) that encodes multiple NK cell receptors. Most importantly, host MHC differences modulated the NKC effect. Moreover, the NKC allelic differences also affected the outcome of hybrid resistance whereby F1 hybrid mice reject parental BMCs. Therefore, these data indicate that NK cell alloreactivity in vivo is dependent on the combination of the host NKC and MHC haplotypes. These data suggest that the NK cell self-tolerance process dynamically modulates the NK cell alloreactivity in vivo.


[The influence of age on vestibular function].
Regular changes in vestibular responsitivity as a function of age are demonstrated with the maximum speed of the slow phase of caloric nystagmus. The clinical implication of this is that, when doing caloric tests, one should not switch for no reason from a once accepted temperature sequence, otherwise comparison with other tests becomes impossible. It rotation tests the best reactions are found in young people. The amplitude is a good parameter to detect age-factors in rotatory nystagmus.


Screening for Osteoporosis to Prevent Fractures: US Preventive Services Task Force Recommendation Statement.
By 2020, approximately 12.3 million individuals in the United States older than 50 years are expected to have osteoporosis. Osteoporotic fractures, particularly hip fractures, are associated with limitations in ambulation, chronic pain and disability, loss of independence, and decreased quality of life, and 21% to 30% of patients who experience a hip fracture die within 1 year. The prevalence of primary osteoporosis (ie, osteoporosis without underlying disease) increases with age and differs by race/ethnicity. With the aging of the US population, the potential preventable burden is likely to increase in future years. To update the 2011 US Preventive Services Task Force (USPSTF) recommendation on screening for osteoporosis. The USPSTF reviewed the evidence on screening for and treatment of osteoporotic fractures in men and women, as well as risk assessment tools, screening intervals, and efficacy of screening and treatment in subgroups. The screening population was postmenopausal women and older men with no known previous osteoporotic fractures and no known comorbid conditions or medication use associated with secondary osteoporosis. The USPSTF found convincing evidence that bone measurement tests are accurate for detecting osteoporosis and predicting osteoporotic fractures in women and men. The USPSTF found adequate evidence that clinical risk assessment tools are moderately accurate in identifying risk of osteoporosis and osteoporotic fractures. The USPSTF found convincing evidence that drug therapies reduce subsequent fracture rates in postmenopausal women. The USPSTF found that the evidence is inadequate to assess the effectiveness of drug therapies in reducing subsequent fracture rates in men without previous fractures. The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. (B recommendation) The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement).


Hyposensitisation with house dust mite vaccine in bronchial asthma.
In a double-blind placebo-controlled trial of tyrosine-absorbed Dermatophagoides pteronyssinus vaccine no improvement was seen in 45 patients with asthma sensitive to house dust mite. In particular there was no significant improvement in symptom scores, spirometry, and skin and nasal challenge test results. Some patients in other studies have benefited from doses of vaccine much stronger than those now commercially available, but the incidence of side effects has also been high.


Prevalence of lifestyle cardiovascular risk factors and estimated framingham 10-year risk scores of adults with psychotic disorders compared to controls at a referral hospital in Eldoret, Kenya.
Lifestyle factors such as smoking, alcohol use, suboptimal diet, and inadequate physical activity have been associated with increased risk of cardiovascular diseases. There are limited data on these risk factors among patients with psychosis in low- and middle-income countries. This study aimed to establish the prevalence of lifestyle cardiovascular risk factors, and the 10-year cardiovascular risk scores and associated factors in patients with psychosis compared to controls at Moi Teaching and Referral Hospital in Eldoret, Kenya. A sample of 297 patients with schizophrenia, schizoaffective disorder, or bipolar mood disorder; and 300 controls matched for age and sex were included in this analysis. A study specific researcher-administered questionnaire was used to collect data on demographics, antipsychotic medication use, smoking, alcohol intake, diet, and physical activity. Weight, height, abdominal circumference, and blood pressure were also collected to calculate the Framingham 10-year Cardiovascular Risk Score (FRS), while blood was drawn for measurement of glucose level and lipid profile. Pearson's chi-squared tests and t-tests were employed to assess differences in cardiovascular risk profiles between patients and controls, and a linear regression model was used to determine predictors of 10-year cardiovascular risk in patients. Compared to controls, patients with psychosis were more likely to have smoked in their lifetimes (9.9% vs. 3.3%, p = 0.006) or to be current smokers (13.8% vs. 7%, p = 0.001). Over 97% of patients with psychosis consumed fewer than five servings of fruits and vegetables per week; 78% engaged in fewer than three days of vigorous exercise per week; and 48% sat for more than three hours daily. The estimated 10-year risk of CVD was relatively low in this study: the FRS in patients was 3.16, compared to 2.93 in controls. The estimated 10-year cardiovascular risk in patients was significantly associated with female sex (p = 0.007), older patients (p < 0.001), current tobacco smoking (p < 0.001), and metabolic syndrome (p < 0.001). In the setting of Eldoret, there is suboptimal physical exercise and intake of healthy diet among patients with psychosis and controls. While the estimated risk score among patients is relatively low in our study, these data may be useful for informing future studies geared towards informing interventions to promote healthy lifestyles in this population.


Lung angiotensin converting enzyme activity in rats with differing susceptibilities to chronic hypoxia.
The decrease in lung angiotensin converting enzyme (ACE) activity occurring in rats during chronic hypoxia might be related to the pulmonary haemodynamic response or to the hypoxia. A study in rats was carried out to investigate this question. Rats from the Hilltop (H) strain are known to develop more severe pulmonary hypertension as a result of chronic hypoxia than rats from the Madison (M) strain despite having virtually identical arterial and mixed venous oxygen tensions. Rats from H and M strains were exposed to hypoxia (0.5 atm) for 3-21 days and lung and serum ACE activities were determined. After three days' hypobaria lung ACE activity was significantly lower and serum ACE significantly higher in H than in M rats. Linear regressions for lung ACE activity and right ventricular:body weight ratios showed significant inverse correlations and were similar in the two strains. The results suggest that pulmonary hypertension and not hypoxia determines the reduction in lung ACE activity, possibly by releasing ACE into the blood stream.


Long-term follow-up after recovery from acute myocardial infarction. Observations on survival, ventricular arrhythmias, and sudden death.
A long-term 12-year follow-up of 248 patients surviving acute myocardial infarction indicated a cumulative survival of 89%, 68%, 53%, and 45% for 1, 5, 10, and 12 years, respectively. When patients were assessed with five routinely obtained clinical factors, significant prognostic stratification of high- and low-risk survival groups extended throughout the follow-up period. Sudden cardiac death was found to be twice as frequent as nonsudden cardiac death, but a significant relationship between sudden death and complex ventricular ectopic beats could not be defined. The extent of complex features of ventricular ectopic beats such as pairs, multiform, repetitive, and R-on-T was inversely related to survival. During the first year after acute myocardial infarction, frequency of ventricular ectopic beats was also inversely related to survival. A long-term effect of frequency on survival, however, could not be demonstrated.


Social behavior drives the dynamics of respiratory disease in threatened tortoises.
Since the early 1990s, morbidity and mortality in tortoise populations have been associated with a transmissible, mycoplasmal upper respiratory tract disease (URTD). Although the etiology, transmission, and diagnosis of URTD have been extensively studied, little is known about the dynamics of disease transmission in free-ranging tortoise populations. To understand the transmission dynamics of Mycoplasma agassizii, the primary etiological agent of URTD in wild tortoise populations, we studied 11 populations of free-ranging gopher tortoises (Gopherus polyphemus; n = 1667 individuals) over five years and determined their exposure to the pathogen by serology, by clinical signs, and by detection of the pathogen in nasal lavages. Adults tortoises (n = 759) were 11 times more likely to be seropositive than immature animals (n = 242) (odds ratio = 10.6, 95% CI = 5.7-20, P < 0.0001). Nasal discharge was observed in only 1.4% (4/296) of immature tortoises as compared with 8.6% (120/1399) of adult tortoises. Nasal lavages from all juvenile tortoises (n = 283) were negative by PCR for mycoplasmal pathogens associated with URTD. We tested for spatial segregation among tortoise burrows by size class and found no consistent evidence of clustering of either juveniles or adults. We suggest that the social behavior of tortoises plays a critical role in the spread of URTD in wild populations, with immature tortoises having minimal interactions with adult tortoises, thereby limiting their exposure to the pathogen. These findings may have broader implications for modeling horizontally transmitted diseases in other species with limited parental care and emphasize the importance of incorporating animal behavior parameters into disease transmission studies to better characterize the host-pathogen dynamics.


Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant.
There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT. To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP. This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more). The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT. Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia). CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.


Effectiveness of selective use of intravenous pyelography in patients presenting to the emergency department with ureteral colic.
To determine whether i.v. pyelography (IVP) is required routinely for all patients presenting to the ED with ureteral colic. A randomized prospective study was conducted with 2 patient group-a routine IVP group, in which all patients underwent IVP, and a selective IVP group, in which patients were treated, observed, and released without undergoing IVP unless they experienced continued symptoms. The study was performed in a large university-affiliated, community hospital ED. Participants were patients aged 18-65 years with signs and symptoms consistent with ureteral colic. Among the 40 patients enrolled in the routine IVP group, 26 had positive studies, 8 of which necessitated hospitalization. Among the 41 patients randomized to the selective IVP group, there were only 19 IVPs performed, of which 6 were positive and 4 necessitated hospitalization. Compared with the routine IVP group, there were 54% fewer IVPs performed and a 51% lower admission rate in the selective IVP group. Despite the fact that fewer IVPs were performed in the selective IVP group, clinical outcomes in the 2 groups were similar, without significant complication in either group. IVPs do not need to be routinely performed for all patients presenting to the ED with ureteral colic. The decision to perform an IVP may be dictated by symptoms that persist after initial evaluation and treatment.


[Secondary prevention with clopidogrel after TIA or stroke].
In patients with TIA or stroke of arterial origin various antiplatelet agents, or combinations of these, have been found to be effective to reduce the risk of new vascular complications. International guidelines currently recommend three treatment strategies with antiplatelet agents after TIA or stroke: acetylsalicylic acid in combination with dipyridamole, clopidogrel monotherapy, or alternatively acetylsalicylic acid monotherapy. In the Netherlands, current standard antiplatelet therapy after a TIA or stroke is a combination of acetylsalicylic acid and dipyridamole. Clopidogrel monotherapy is probably equally as effective as the combination of acetylsalicylic acid and dipyridamole. Clopidogrel monotherapy is easier to use, has fewer side effects and has recently become cheaper than the combination of acetylsalicylic acid and dipyridamole. For secondary prevention in the Netherlands we advise following the international guidelines on thromboprophylaxis after TIA or stroke. Clopidogrel could be considered as an alternative treatment to the combination of acetylsalicylic acid and dipyridamole.


Infection and smoking are associated with decreased plasma concentration of the anti-aging protein, α-klotho.
The objective of this study was to determine whether maternal plasma concentrations of soluble α-klotho are different between women with microbial invasion of the intra-amniotic cavity (MIAC) and those without MIAC among preterm labor and intact membranes (PTL) or preterm prelabor rupture of membranes (pPROM). A cross-sectional study was conducted to include women in the following groups: i) PTL with MIAC (n=14); ii) PTL without MIAC (n=79); iii) pPROM with MIAC (n=30); and iv) pPROM without MIAC (n=33). MIAC was defined as a positive amniotic fluid culture for microorganisms (aerobic/anaerobic bacteria or genital mycoplasmas). Amniotic fluid samples were obtained within 48 h of maternal blood collection. Plasma concentration of soluble α-klotho was determined by ELISA. i) The median plasma concentration (pg/mL) of soluble α-klotho was significantly lower in patients with MIAC than in those without MIAC (787.0 vs. 1117.8; P<0.001). ii) Among patients with PTL, those with MIAC had a lower median plasma concentration (pg/mL) of soluble α-klotho than those without MIAC (787.0 vs. 1138.9; P=0.007). iii) Among patients with pPROM, those with MIAC had a lower median plasma concentration (pg/mL) of soluble α-klotho than those without MIAC (766.4 vs. 1001.6; P=0.045). iv) There was no significant difference in the median plasma concentration of soluble α-klotho between PPROM without MIAC and PTL without MIAC (1001.6 pg/mL vs. 1138.9 pg/mL, respectively; P=0.5). v) After adjustment for potential confounders (maternal age, tobacco use, gestational age at venipuncture), soluble α-klotho remained significantly associated with MIAC (P=0.02); and vi) Among patients without MIAC, smoking was significantly associated with a lower median plasma concentration soluble α-klotho than in non-smokers (794.2 pg/mL vs. 1382.0 pg/mL, respectively; P<0.001); however, this difference was not observed in patients with MIAC. Intra-amniotic infection occurring at preterm gestations (regardless of membrane status) was associated with a decrease in maternal plasma concentrations of soluble α-klotho. Moreover, among patients without infection, the plasma concentration of α-klotho was lower in smokers.


Vesicular systems for dermal and transdermal drug delivery.
Dermal/transdermal drug delivery continues to grow in importance as a means of enhancing treatment activity while reducing toxicity by avoiding the systemic absorption of the drug. At the same time, this has led to the adjustment of a wide diversity of drug carriers. This paper begins with a review of the skin, including its structure and the parameters that influence drug diffusion, followed by strategies to improve dermal drug delivery. Of the multitude of existing carriers, we will focus on the most advanced vectors in dermal/transdermal delivery, and in particular, on vesicular systems. This review will present the state of the art as well as the new trends in this domain. Through the description of these systems, we will try to obtain information on the ideal properties that the carrier must have in order to improve the cutaneous and transcutaneous penetration of the drug.


Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99).
Lysosomal failure underlies pathogenesis of numerous congenital neurodegenerative disorders and is an early and progressive feature of Alzheimer's disease (AD) pathogenesis. Here, we report that lysosomal dysfunction in Down ayndrome (trisomy 21), a neurodevelopmental disorder and form of early onset AD, requires the extra gene copy of amyloid precursor protein (APP) and is specifically mediated by the β cleaved carboxy terminal fragment of APP (APP-βCTF, C99). In primary fibroblasts from individuals with DS, lysosomal degradation of autophagic and endocytic substrates is selectively impaired, causing them to accumulate in enlarged autolysosomes/lysosomes. Direct measurements of lysosomal pH uncovered a significant elevation (0.6 units) as a basis for slowed LC3 turnover and the inactivation of cathepsin D and other lysosomal hydrolases known to be unstable or less active when lysosomal pH is persistently elevated. Normalizing lysosome pH by delivering acidic nanoparticles to lysosomes ameliorated lysosomal deficits, whereas RNA sequencing analysis excluded a transcriptional contribution to hydrolase declines. Cortical neurons cultured from the Ts2 mouse model of DS exhibited lysosomal deficits similar to those in DS cells. Lowering APP expression with siRNA or BACE1 inhibition reversed cathepsin deficits in both fibroblasts and neurons. Deleting one Bace1 allele from adult Ts2 mice had similar rescue effects in vivo The modest elevation of endogenous APP-βCTF needed to disrupt lysosomal function in DS is relevant to sporadic AD where APP-βCTF, but not APP, is also elevated. Our results extend evidence that impaired lysosomal acidification drives progressive lysosomal failure in multiple forms of AD.SIGNIFICANCE STATEMENT Down syndrome (trisomy 21) (DS) is a neurodevelopmental disorder invariably leading to early-onset Alzheimer's disease (AD). We showed in cells from DS individuals and neurons of DS models that one extra copy of a normal amyloid precursor protein (APP) gene impairs lysosomal acidification, thereby depressing lysosomal hydrolytic activities and turnover of autophagic and endocytic substrates, processes vital to neuronal survival. These deficits, which were reversible by correcting lysosomal pH, are mediated by elevated levels of endogenous β-cleaved carboxy-terminal fragment of APP (APP-βCTF). Notably, similar endosomal-lysosomal pathobiology emerges early in sporadic AD, where neuronal APP-βCTF is also elevated, underscoring its importance as a therapeutic target and underscoring the functional and pathogenic interrelationships between the endosomal-lysosomal pathway and genes causing AD.


Brain imaging of analgesic and antihyperalgesic effects of cyclooxygenase inhibition in an experimental human pain model: a functional MRI study.
One of the most distressing symptoms of many neuropathic pain syndromes is the enhanced pain sensation to tactile or thermal stimulation (hyperalgesia). In the present study we used functional magnetic resonance imaging (fMRI) and explored brain activation patterns during acute impact pain and mechanical hyperalgesia in the human ultraviolet (UV)-B model. To investigate pharmacological modulation, we examined potential differential fMRI correlates of analgesic and antihyperalgesic effects of two intravenous cyclooxygenase inhibitors, i.e. parecoxib and acetylsalicylic acid (ASA). Fourteen healthy volunteers participated in this double-blinded, randomized and placebo-controlled crossover study. Tactile stimuli and mechanical impact hyperalgesia were tested at the site of a UV-B irradiation and acute mechanical pain was tested at a site distant from the irradiated skin. These measurements were conducted before and 30 min after a 5-min intravenous infusion of either saline (placebo), parecoxib 40 mg or ASA 1000 mg. Acute mechanical pain and mechanical hyperalgesia led to widespread activations of brain areas known to comprise the human pain matrix. Analgesic effects were found in primary (S1) and secondary (S2) somatosensory cortices, parietal association cortex (PA), insula, anterior parts of the cingulate cortex and prefrontal cortices. These brain areas were also modulated under antihyperalgesic conditions. However, we observed a greater drug-induced modulation of mainly PA and inferior frontal cortex during mechanical hyperalgesia; during acute mechanical pain there was a greater modulation of mainly bilateral S2. Therefore, the results of the present study suggest that there is a difference in the brain areas modulated by analgesia and antihyperalgesia.


Interleukin-1β Alters Hebbian Synaptic Plasticity in Multiple Sclerosis.
In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1β on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1β were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1β levels were negatively correlated with the LTP-like response in the APB muscle. Moreover, IL-1β levels were associated with synaptic hyperexcitability tested with paired-pulse TMS. Synaptic hyperexcitability caused by IL-1β may critically contribute to alter Hebbian plasticity in MS, inducing a loss of topographic specificity.


Coexisting Diogenes and Capgras syndromes.
The co-occurrence of Diogenes and Capgras syndromes, both unusual in themselves, would be expected to be rare. A MEDLINE search using the terms Diogenes, Capgras, self-neglect and domestic squalor revealed no previous reports of this combination of disorders. Both conditions are somewhat dubiously named as &#164 syndromes' when in fact they are probably no more than symptoms with different causes. Of particular interest in this case is the exacerbation of the self-neglect, characteristic of the Diogenes syndrome, by the delusional misidentification which marks the Capgras syndrome; as well as the reinforcement of the previously recognised association with frontal lobe pathology. The role of medication, though limited, is described. ( Int J Psych Clin Pract 2001; 5:75-76).


Image Guidance in Cranial Neurosurgery: How a Six-Ton Magnet and Fluorescent Colors Make Brain Tumor Surgery Better.
Maximal safe resection can improve patient outcomes for a variety of brain tumor types including low- and high-grade gliomas, pituitary adenomas, and other pathologies. Numerous intraoperative adjuncts exist to guide surgeons with maximizing extent of resection. Three distinct strategies exist including: 1) surgical navigation; 2) intraoperative imaging; and 3) tumor fluorescence. Surgical navigation involves registration of high-resolution three-dimensional imaging to the patient's cranial surface anatomy, allowing real-time localization of tumor and brain structures. Intraoperative imaging devices like intraoperative magnetic resonance imaging (iMRI), intraoperative computed tomography (iCT), 3-D fluoroscopy, and intraoperative ultrasonography (iUS) allow near real time visualization to assess the extent of resection. Intraoperative fluorescence via intravenous fluorescein or oral 5-aminolevulinic acid (5-ALA) causes brain tumors to "light up", which can be viewed through surgical optics using selective filters and specific wavelength light sources. A general overview, as well as implementation and utilization of some of these image guidance strategies at Washington University and by Siteman Cancer Center neurosurgeons at Barnes Jewish Hospital, is discussed in this review.


Prior Choices of Between-Study Heterogeneity in Contemporary Bayesian Network Meta-analyses: an Empirical Study.
Network meta-analysis (NMA) is a popular tool to compare multiple treatments in medical research. It is frequently implemented via Bayesian methods. The prior choice of between-study heterogeneity is critical in Bayesian NMAs. This study evaluates the impact of different priors for heterogeneity on NMA results. We identified all NMAs with binary outcomes published in The BMJ, JAMA, and The Lancet during 2010-2018, and extracted information about their prior choices for heterogeneity. Our primary analyses focused on those with publicly available full data. We re-analyzed the NMAs using 3 commonly-used non-informative priors and empirical informative log-normal priors. We obtained the posterior median odds ratios and 95% credible intervals of all comparisons, assessed the correlation among different priors, and used Bland-Altman plots to evaluate their agreement. The kappa statistic was also used to evaluate the agreement among these priors regarding statistical significance. Among the selected Bayesian NMAs, 52.3% did not specify the prior choice for heterogeneity, and 84.1% did not provide rationales. We re-analyzed 19 NMAs with full data available, involving 894 studies, 173 treatments, and 395,429 patients. The correlation among posterior median (log) odds ratios using different priors were generally very strong for NMAs with over 20 studies. The informative priors produced substantially narrower credible intervals than non-informative priors, especially for NMAs with few studies. Bland-Altman plots and kappa statistics indicated strong overall agreement, but this was not always the case for a specific NMA. Priors should be routinely reported in Bayesian NMAs. Sensitivity analyses are recommended to examine the impact of priors, especially for NMAs with relatively small sample sizes. Informative priors may produce substantially narrower credible intervals for such NMAs.


[Epileptic seizures in children].
There exist various types of epilepsy in children, which can be classified on the basis of nature and severity of the impairment of consciousness and the motor phenomena. The anamnesis is the main aid in distinguishing a seizure from a non-epileptic convulsion. Convulsions may have a number of causes, which may or may not be acute, while several factors may provoke attacks. The extent and necessity of supplementary investigation depend mostly on the child's clinical condition at presentation and on the nature of the seizure(s). The electro-encephalogram is important for the classification of the type of seizure. Anti-epileptic medication should not be started after a single epileptic seizure; whether it will be started after several attacks depends on the frequency and severity of the seizures, and on the syndrome diagnosis made. The long-term prognosis depends mostly on the syndrome diagnosis.


[Effect of xenobiotics on alveolar macrophages].
Under the action of hexachlorcyclogexan in concentration not exceeding the pesticides residues in food staffs the prominent adaptive mechanisms stress of gematoalveolar barier is seen. However, the adaptation has the extensive character and is caused by increase of alveolar monocytes in broncho-alveolar lavage. The phagocytosis functional reservers exceed the control values, but phagocytes activity and phagocytory index remain decreased and reach norms just after the xenobiotic abolition.


Long-term intake of soyabean phytosterols lowers serum TAG and NEFA concentrations, increases bile acid synthesis and protects against fatty liver development in dyslipidaemic hamsters.
Various human trials and pre-clinical studies have suggested that dietary plant sterols possess hypotriacylglycerolaemic properties apart from their cholesterol-lowering properties. We hypothesised that phytosterols (PS) might attenuate triacylglycerolaemia by interfering with the deleterious effects of cholesterol overload in the liver. In the present study, twenty hamsters (Mesocricetus auratus) with diet-induced combined hyperlipidaemia were fed a high-fat diet (HFD, n 10) or a HFD supplemented with soyabean PS (n 10) for 40 d. In parallel, a healthy group was fed a standard diet (n 10). PS normalised fasting plasma cholesterol concentrations completely after 20 d and were also able to normalise serum TAG and NEFA concentrations after 40 d. HFD feeding caused microvesicular steatosis and impaired the expression of key genes related to fatty acid oxidation such as PPARA, carnitine palmitoyltransferase-Iα (CPT1A) and phosphoenolpyruvate carboxykinase 1 (PCK1) in the liver. PS treatment completely protected against HFD-induced steatosis and resulted in a normalised hepatic gene expression profile. The protection of the hepatic function by PS was paralleled by increased faecal cholesterol excretion along with a 2-fold increase in the biliary bile acid (BA):cholesterol ratio. The present study supports the conclusion that long-term consumption of PS can reduce serum TAG and NEFA concentrations and can protect against the development of fatty liver via different mechanisms, including the enhancement of BA synthesis. The results of the present study place these compounds as promising hepatoprotective agents against fatty liver and its derived pathologies.


Conditional antagonism in co-cultures of Pseudomonas aeruginosa and Candida albicans: An intersection of ethanol and phosphate signaling distilled from dual-seq transcriptomics.
Pseudomonas aeruginosa and Candida albicans are opportunistic pathogens whose interactions involve the secreted products ethanol and phenazines. Here, we describe the role of ethanol in mixed-species co-cultures by dual-seq analyses. P. aeruginosa and C. albicans transcriptomes were assessed after growth in mono-culture or co-culture with either ethanol-producing C. albicans or a C. albicans mutant lacking the primary ethanol dehydrogenase, Adh1. Analysis of the RNA-Seq data using KEGG pathway enrichment and eADAGE methods revealed several P. aeruginosa responses to C. albicans-produced ethanol including the induction of a non-canonical low-phosphate response regulated by PhoB. C. albicans wild type, but not C. albicans adh1Δ/Δ, induces P. aeruginosa production of 5-methyl-phenazine-1-carboxylic acid (5-MPCA), which forms a red derivative within fungal cells and exhibits antifungal activity. Here, we show that C. albicans adh1Δ/Δ no longer activates P. aeruginosa PhoB and PhoB-regulated phosphatase activity, that exogenous ethanol complements this defect, and that ethanol is sufficient to activate PhoB in single-species P. aeruginosa cultures at permissive phosphate levels. The intersection of ethanol and phosphate in co-culture is inversely reflected in C. albicans; C. albicans adh1Δ/Δ had increased expression of genes regulated by Pho4, the C. albicans transcription factor that responds to low phosphate, and Pho4-dependent phosphatase activity. Together, these results show that C. albicans-produced ethanol stimulates P. aeruginosa PhoB activity and 5-MPCA-mediated antagonism, and that both responses are dependent on local phosphate concentrations. Further, our data suggest that phosphate scavenging by one species improves phosphate access for the other, thus highlighting the complex dynamics at play in microbial communities.