Vision-based hand-eye calibration for robot-assisted minimally invasive surgery.
The knowledge of laparoscope vision can greatly improve the surgical operation room (OR) efficiency. For the vision-based computer-assisted surgery, the hand-eye calibration establishes the coordinate relationship between laparoscope and robot slave arm. While significant advances have been made for hand-eye calibration in recent years, efficient algorithm for minimally invasive surgical robot is still a major challenge. Removing the external calibration object in abdominal environment to estimate the hand-eye transformation is still a critical problem. We propose a novel hand-eye calibration algorithm to tackle the problem which relies purely on surgical instrument already in the operating scenario for robot-assisted minimally invasive surgery (RMIS). Our model is formed by the geometry information of the surgical instrument and the remote center-of-motion (RCM) constraint. We also enhance the algorithm with stereo laparoscope model. Promising validation of synthetic simulation and experimental surgical robot system have been conducted to evaluate the proposed method. We report results that the proposed method can exhibit the hand-eye calibration without calibration object. Vision-based hand-eye calibration is developed. We demonstrate the feasibility to perform hand-eye calibration by taking advantage of the components of surgical robot system, leading to the efficiency of surgical OR.


Jaccoud's arthritis.
A 16 year old girl with multivalvular heart disease and recurrent episodes of polyarthritis with correctable deformities of hands and feet fitting into that of Jaccoud's arthritis is reported. The condition is rare and often difficult to differentiate from rheumatoid arthritis.


The role of histopathologic subtype in the setting of hippocampal sclerosis-associated mesial temporal lobe epilepsy.
Hippocampal sclerosis (HS) and focal cortical dysplasia (FCD) are among the most common neuropathological findings in those undergoing surgery for refractory mesial temporal lobe epilepsy. Existing data regarding differences among the most recent International League Against Epilepsy (ILAE) HS subtypes remain limited. This study sought to characterize the roles of HS subtype and coexistent FCD. Epilepsy surgery pathologic specimens in 307 cases of temporal lobe epilepsy with HS were reviewed (mean age±SD, 37±15years; 56% women). HS and coexistent FCD were classified according to ILAE guidelines. Medical records were reviewed for data on seizure recurrence and seizure burden (clinical follow-up mean duration ± SD, 5±4years). Cases of typical HS (ILAE type I) predominated (ILAE type Ia: 41%, Ib: 47%, II: 11%, and III: 0.7%]. The HS subtypes shared similar demographic and etiologic characteristics, as well as associated pathology and postoperative seizure outcomes. Individuals with type Ib HS were more likely to remain seizure free at long-term follow-up when compared with other subtypes, and they had a later age of seizure onset. Two hundred forty-three cases (79%) demonstrated FCD within the adjacent temporal lobe. Its presence was associated with a significantly decreased risk of seizure recurrence (P=.02). When present, FCD was predominantly type I (98%). HS subtype does not appear to affect epilepsy surgery outcomes despite some clinical differences between the subgroups. FCD is often observed in association with HS in mesial temporal lobe epilepsy; the finding of FCD was associated with better postoperative outcomes.


FOXG1 is involved in mouse ovarian functions and embryogenesis.
TGF-β superfamily has long been demonstrated to be essential for folliculogenesis and luteinization. Forkhead box G1 (FOXG1, also known as BF1), a member of the FOX family and an inhibitor of TGF-β signaling pathway, is a nucleocytoplasmic transcription factor that is essential for forebrain development. FOXG1 is involved in neurodevelopment and cancer pathology, however, little is known about the role of FOXG1 in reproduction. In this study, the spatiotemporal expression pattern of FOXG1 was examined during early mouse oocyte and embryonic development and its role during corpora luteum (CL) formation was further elucidated. The results showed that FOXG1 is localized in oocytes, theca cells (TCs) and CLs. After fertilization, FOXG1 is expressed at all stages during early embryogenesis, from zygotes to blastocysts. Following gonadotropin administration in immature mice, the expression of Foxg1 significantly increased along with steroidogenic genes, including Star, Hsd3β, Cyp11a1, as well as Cyp17a1 and Cyp19a1. The latter two first increased after pregnant mare serum gonadotropin stimulation, then decreased in response to hCG treatment. In addition, silencing of Foxg1 significantly reduced the concentration of testosterone and estrogen in cultured primary granulosa cells (GCs) and TCs (P < 0.05). Mechanistic studies demonstrated that the expression level of genes that are critical in estrogen synthesis were significantly reduced after Foxg1 silencing, including Cyp17a1 and Cyp19a1. In conclusion, FOXG1 is expressed in a stage-specific manner during folliculogenesis and embryogenesis and exerts a regulatory influence on testosterone and estrogen synthesis.


Priming B cell-mediated anti-HIV envelope responses by vaccination allows for the long-term control of infection in macaques exposed to a R5-tropic SHIV.
The potential of vaccine-elicited anti-HIV envelope antibodies to control HIV-infection was evaluated by immunizing macaques with the HIV envelope protein and transiently depleting them of their CD8+ cells before intravenous challenge with the pathogenic CCR5-tropic SIV/HIV chimeric virus, SHIV(SF162P4). Although sterilizing immunity was not achieved, all vaccinated animals effectively controlled infection and remained free of disease for the duration of observation (over 3 years). In contrast, during the same period, the control animals progressed to disease. Both the vaccinees and the controls developed robust cell-mediated antiviral and neutralizing antibody responses following infection. A comparative analysis of these responses suggests that the more effective long-term control of infection by the vaccinated animals is due to the more rapid development of anti-HIV envelope antibodies. These studies suggest that priming by vaccination of B cell anti-HIV envelope responses maybe crucial for the long-term control of HIV infection.


The reliability of the maternal memory in a retrospective assessment of nutritional status.
This study raises the question of the validity of conclusions based on recalled data by testing the maternal ability to report vital events on her newborn infant after 8 years. First, the retrospective information given by the mother was compared to the prospective data collected immediately after birth. Second, the validity of statistical analyses based on retrospective data was discussed. A dispersion model was used and discrepancies were found between the two sets of data collected in two different ways on the same subjects. It was concluded that the use of retrospective information can lead to false results in regression analyses and could invalidate comparisons in case-control studies because of the difference in variability between cases and controls.


Expression of viral hemagglutinin on the surface of E. coli.
Expression of a foreign protein molecule on the E. coli bacterial surface has been achieved through hybrid plasmid construction of fusion proteins using outer membrane protein ompA as a carrier system. Influenza virus hemagglutinin fusion proteins of this character have been shown to become integrated into the bacterial outer membrane and to expose their hemagglutinin moiety at the exterior surface in a conformation which is at least similar to the authentic viral antigen structure.


Renal infection in autosomal dominant polycystic kidney disease.
Upper urinary tract (renal) infections have been reported to be frequent and difficult to treat in patients with autosomal dominant polycystic kidney disease. This study examined renal infections and responses to therapy in this patient population. Fifteen cyst infections and 11 parenchymal infections occurred during the study. Eighty-seven percent of the cyst and 91 percent of the parenchymal infections occurred in women. Gram-negative enterics were the causative organisms in 92 percent of the cyst and 100 percent of the parenchymal infections. All of the parenchymal but only one of the cyst infections responded to therapy with ampicillin and an aminoglycoside despite favorable sensitivities. Eighty-three percent of the cyst infections were eradicated with use of lipid-soluble antibiotics. It is concluded that Cyst infections are refractory to therapy with the antibiotics commonly used to treat urinary infections; Female preference and enteric organism predominance suggest that these renal infections are acquired retrograde from the urinary bladder.


Factors that determine the severity of Betula spp. pollen seasons in Poland (Poznań and Krakow) and the United Kingdom (Worcester and London).
The aim of this paper is to analyse variations in the severity of Betula pollen seasons, particularly in relation to meteorological parameters at four sites, Poznań and Krakow in Poland, and Worcester and London in the United Kingdom. Results show that there is a significant relationship between Betula pollen season severity and weather conditions both in the year before pollination and in the same year that pollen is released from the plant. Furthermore, it is likely that the magnitude of birch pollen seasons in Poznań, Worcester and London is linked in some way to different phases of the North Atlantic Oscillation (NAO). Significant positive relationships exist between birch pollen counts at Poznań and temperatures, rainfall and averages of the NAO in the year before pollination. An opposite relationship is evident at the two sites studied in the United Kingdom. There were significant positive correlations between the severity of birch pollen seasons recorded at Worcester and temperatures and averages of the NAO during the winter and spring in the year of pollination, and negative correlations at both Worcester and London with similar variables from the previous year. In addition, Betula pollen seasons in Krakow do not appear to be influenced by the NAO, which is probably the result of Krakow having a more continental climate.


Ferulates, amurenlactone A and amurenamide A from traditional Chinese medicine cortex Phellodendri Amurensis.
Two new ferulate compounds, amurenlactone A (1) and amurenamide A (2), along with 11 known compounds have been isolated from the cortex of Phellodendron amurense. The structures of the new compounds were established based on 1D, 2D NMR and mass spectral analyzes. The known compounds were identified by comparison with authentic samples.


The First-in-Class Potassium-Competitive Acid Blocker, Vonoprazan Fumarate: Pharmacokinetic and Pharmacodynamic Considerations.
Vonoprazan fumarate (Takecab) is a first-in-class potassium-competitive acid blocker that has been available in the market in Japan since February 2015. Vonoprazan is administered orally at 20 mg once daily for the treatment of gastroduodenal ulcer, at 20 and 10 mg once daily for the treatment and secondary prevention of reflux esophagitis, respectively, at 10 mg once daily for the secondary prevention of low-dose aspirin- or non-steroidal anti-inflammatory drug-induced peptic ulcer, and at 20 mg twice daily in combination with clarithromycin and amoxicillin for the eradication of Helicobacter pylori. It inhibits H(+),K(+)-ATPase activities in a reversible and potassium-competitive manner with a potency of inhibition approximately 350 times higher than the proton pump inhibitor, lansoprazole. Vonoprazan is absorbed rapidly and reaches maximum plasma concentration at 1.5-2.0 h after oral administration. Food has minimal effect on its intestinal absorption. Oral bioavailability in humans remains unknown. The plasma protein binding of vonoprazan is 80% in healthy subjects. It distributes extensively into tissues with a mean apparent volume of distribution of 1050 L. Being a base with pKa of 9.6 and with acid-resistant properties, vonoprazan is highly concentrated in the acidic canaliculi of the gastric parietal cells and elicited an acid suppression effect for longer than 24 h after the administration of 20 mg. The mean apparent terminal half-life of the drug is approximately 7.7 h in healthy adults. Vonoprazan is metabolized to inactive metabolites mainly by cytochrome P450 (CYP)3A4 and to some extent by CYP2B6, CYP2C19, CYP2D6, and SULT2A1. A mass balance study showed that 59 and 8% of the orally administered radioactivity was recovered in urine as metabolites and in an unchanged form, respectively, indicating extensive metabolism. Genetic polymorphism of CYP2C19 may influence drug exposure but only to a clinically insignificant extent (15-29%), according to the population pharmacokinetic study performed in Japanese patients. When vonoprazan was co-administered with clarithromycin, the mean AUC from time 0 to time of the next dose (dosing interval) of vonoprazan and clarithromycin were increased by 1.8 and 1.5 times, respectively, compared with the corresponding control values, indicating mutual metabolic inhibition. The mean area under the curve from time zero to infinity obtained from patients with severe liver and renal dysfunction were elevated by 2.6 and 2.4 times, respectively, compared with healthy subjects, with no significant changes in plasma protein binding. Vonoprazan increases intragastric pH above 4.0 as early as 4 h after an oral dose of 20 mg, and the extensive anti-secretory effect is maintained up to 24 h post-dose. During repeated dosing of 20 mg once daily, the 24-h intragastric pH >4 holding time ratios were 63 and 83 % on days 1 and 7, respectively. Because vonoprazan elicited a more extensive gastric acid suppression than the proton pump inhibitor, lansoprazole, it also gave rise to two to three times greater serum gastrin concentrations as compared with lansoprazole. In pre-approval clinical studies for the treatment of acid-related disorders, mild to moderate adverse drug reactions (mostly constipation or diarrhea) occurred at frequencies of 8-17%. Neither severe liver toxicity nor neuroendocrine tumor has been reported in patients receiving vonoprazan.


Systemic vasculitis with renal involvement--a review.
Twenty five patients with renal vasculitis presenting over an eight year period were reviewed. Ten had microscopic polyarteritis, 6 classic polyarteritis, 5 overlap syndrome, 2 Churg-Strauss syndrome and 2 Wegener's granulomatosis. Clinical features included hypertension, pulmonary involvement, neurological involvement and arthralgia. Serum creatinine was over 500 umol/l in 13 patients, 10 of whom required dialysis. Visceral angiography was positive in 80% of those studied, Focal and segmental necrotising glomerulonephritis was the commonest renal lesion. Treatment consisted of corticosteroids and cytotoxic agents in most cases. Plasmapheresis was used for rapidly progressive renal failure, severe pulmonary haemorrhage or cerebral vasculitis. Improvement or stabilisation of renal function was seen in 68% of patients treated. There were 4 early deaths and one late death. The diagnosis, histology, treatment and outcome of renal vasculitis is discussed. The importance of early diagnosis and treatment is emphasised in this potentially reversible cause of acute renal failure.


Association between vitamin D deficiency and lipid profiles in overweight and obese adults: a systematic review and meta-analysis.
The association between vitamin D deficiency and lipid profiles in adults with overweight or obesity remains unclear and inconsistent. The aim of our study was to determine the relationship between lipid profiles and vitamin D deficiency in the overweight and obese adults. Four databases, including PubMed, the Web of Science, EMBASE and the Cochrane Library, were used to identify all studies on vitamin D status and lipid levels, including the serum levels of triglycerides (TGs), total cholesterol (TC), low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL). The Weighted mean difference (WMD) with 95% confidence intervals (CIs) using random-effects models was used to assess the association between the lipid profile and vitamin D deficiency. Twenty-one articles that included a total of 7952 adults with overweight or obesity (BMI ≥ 25 kg/m2) were included. The overall results revealed that compared with the controls, individuals with vitamin D deficiency showed higher levels of TG (WMD = 15.01; 95%CI, 2.51-27.52) and TC (WMD = 8.61; 95%CI, 1.31-15.92). Moreover, vitamin D deficiency was related to an increased level of LDL (WMD = 6.12; 95%CI, 0.02-12.23). HDL level was inversely associated with the vitamin D deficiency status (WMD = -2.57; 95%CI, -4.26, -0.88). Among the adults with overweight or obesity, the vitamin D deficient group displayed impaired lipid profiles, including increased TG, TC and LDL levels and reduced HDL level.


Modulation of the cytoplasmic functions of mammalian post-transcriptional regulatory proteins by methylation and acetylation: a key layer of regulation waiting to be uncovered?
Post-transcriptional control of gene expression is critical for normal cellular function and viability and many of the proteins that mediate post-transcriptional control are themselves subject to regulation by post-translational modification (PTM), e.g. phosphorylation. However, proteome-wide studies are revealing new complexities in the PTM status of mammalian proteins, in particular large numbers of novel methylated and acetylated residues are being identified. Here we review studied examples of methylation/acetylation-dependent regulation of post-transcriptional regulatory protein (PTRP) function and present collated PTM data that points to the huge potential for regulation of mRNA fate by these PTMs.


The effects of air gap reflections during air-coupled leaky Lamb wave inspection of thin plates.
Air-coupled ultrasonic inspection using leaky Lamb waves offers attractive possibilities for non-contact testing of plate materials and structures. A common method uses an air-coupled pitch-catch configuration, which comprises a transmitter and a receiver positioned at oblique angles to a thin plate. It is well known that the angle of incidence of the ultrasonic bulk wave in the air can be used to preferentially generate specific Lamb wave modes in the plate in a non-contact manner, depending on the plate dimensions and material properties. Multiple reflections of the ultrasonic waves in the air gap between the transmitter and the plate can produce additional delayed waves entering the plate at angles of incidence that are different to those of the original bulk wave source. Similarly, multiple reflections of the leaky Lamb waves in the air gap between the plate and an inclined receiver may then have different angles of incidence and propagation delays when arriving at the receiver and hence the signal analysis may become complex, potentially leading to confusion in the identification of the wave modes. To obtain a better understanding of the generation, propagation and detection of leaky Lamb waves and the effects of reflected waves within the air gaps, a multiphysics model using finite element methods was established. This model facilitated the visualisation of the propagation of the reflected waves between the transducers and the plate, the subsequent generation of additional Lamb wave signals within the plate itself, their leakage into the adjacent air, and the reflections of the leaky waves in the air gap between the plate and receiver. Multiple simulations were performed to evaluate the propagation and reflection of signals produced at different transducer incidence angles. Experimental measurements in air were in good agreement with simulation, which verified that the multiphysics model can provide a convenient and accurate way to interpret the signals in air-coupled ultrasonic inspection using leaky Lamb waves.


Dermal glands in freshwater mites Limnesia undulata (O.F. Müller, 1776) and Limnesia fulgida (C.L. Koch, 1836) (Acariformes, Limnesiidae).
Dermal glands in the water mites Limnesia undulata (O.F. Müller, 1776) and Limnesia fulgida (C.L. Koch, 1836) and their secretion were studied by means of light microscopical, transmission electron microscopical (TEM) and scanning electron microscopical (SEM) methods. These mites possess two types of dermal glands - the 'common' dermal glands in a number of 14 pairs and one pair of the so-called 'idiosomal' dermal glands. The common dermal glands are bi-lobed organs and consist of high prismatic secretory cells directed to the gland mouth and mostly replacing the intra-alveolar lumen. The cells contain numerous cisterns of rough endoplasmic reticulum (RER) and specifically organized Golgi bodies (GB) producing electron-dense elongated secretory granules. These granules are released from the cells via apocrine secretion and come to the gland mouth, where they are sometimes accompanied by secretory cell cytoplasm. The final secretion may show a fibrous character. The idiosomal glands are sac-like organs stretched along the ventral body wall in posterior direction from the gland orifice corresponding to the epimeroglandularia 4. The secretory epithelium leaves a large intra-alveolar lumen filled with an electron-dense secretory material. Golgi bodies are organized identically with those in the common glands, which indicates the general homology of these two types of dermal glands. The glands' orifices are organized similarly in all glands and possess an internal funnel-shaped sclerite with muscle armament, an internal valve, medial epicuticular flaps and an external circular cuticular ring. All glandularia, except for E4 and V1, are accompanied with a long and thin sensitive seta. During fixation, secretion of the common dermal glands is extruded to the exterior in the form of large amounts of convoluted tube-like structures. In the living organisms, being secreted in mass from the glands, this secretion acquires the form of long rigid mostly hollow un-branched threads comparable with the similar silken threads of other water arthropods. The function of the idiosomal glands secretion still remains unknown.


A novel form of aberrant innervation in congenital cranial dysinnervation disorder.
Certain forms of congenital incomitant strabismus are associated with abnormal cranial nerve development and resultant abnormal orbital innervation (eg, Duane retraction syndrome, congenital fibrosis of the extraocular muscles [CFEOM]); such conditions can be considered congenital cranial dysinnervation disorders (CCDDs). In addition to duction limitation and/or ptosis, orbital CCDD phenotypes include inappropriate extraocular muscle and/or levator innervation by nerves intended for innervation of other structures (eg, some of the innervation intended for the medial rectus muscle inappropriately innervating the ipsilateral lateral rectus muscle in Duane retraction syndrome). This report documents a unique orbital dysinnervational pattern-supraduction during attempted adduction and infraduction during attempted abduction in the left affected eye of a girl with exotropia and enophthalmos.


Multivariate analysis of risk factors in patients with metastatic testicular germ cell tumors treated with vinblastine and bleomycin.
39 patients with testicular germ cell tumor metastases were treated with vinblastine intravenous bolus injection day 1 and day 36 and bleomycin intramuscularly twice weekly for 10 weeks. 8 patients had complete remission. 4 of these are alive with no evidence of disease for 91 + to 109 + months. Studied with Wilk's method for stepwise discriminant analysis tumor volume and performance status significantly predicted the patients who had complete remission. Studied with Cox's proportional hazard model for multivariate analysis hCG in the primary tumor, serum lactate dehydrogenase, performance status, and complete remission had a significant impact on survival. The information from the risk factors may be useful in a differentiated treatment of patients with testicular germ cell tumor metastases.


Multiple density dependence in two sub-populations of the amphipod Monoporeia affinis: a potential for alternative equilibria.
Possible mechanisms for differences in population densities and dynamics were investigated in the amphipod Monoporeia affinis at two deep sites in the northern Bothnian Sea. The two sites were sampled yearly for 10 years. Average sizes, growth and mortality of the different age-classes were estimated from the cohort structure of the two populations. Laboratory experiments also investigated the ability of the common predatory isopod Saduria entomon to cause densitydependent (DD) mortality of the prey M. affinis. At site A, 43 m depth, the average density of M. affinis was twice as high as at site B, 81 m depth. The fluctuations in density were asynchronous between the two sites. Recruitment and subadult sizes of Monoporeia affinis were density dependent at both sites. The main functional difference between the two populations seemed to be the DD mortality of the 1 + cohort that occurred only at the low-density site B. A corresponding DD mortality was found in the predation experiments at densities of 1 + m. affinis corresponding to those found at site B. The potential importance of the predator was also indicated by a significant negative correlation between the biomass of S. entomon and the rate of change in M. affinis density in the field. The similarities in the abiotic factors between the two sites suggested that differences in carrying capacity should be small. The results could be explained by the predation regulation hypothesis for the low-density population at site B, while at site A M. affinis seemed to be regulated by intra-specific competition and limited by predation. It is suggested that in this simple predator-prey system there is potential for the existence of alternative equilibria.


[The production of clones of "man x Chinese hamster" hybrid cells containing different parts of the human genome].
Some approach has been described to create hybrid cell lines (human x Chinese hamster) which contain different parts of human genome, and then efficiently to reveal and isolate the human DNA from these. This method involves the introduction of a selective marker in different sites of the human cell genome, by transfecting them with plasmid SV2neo, and the use of flow cytometry and DNA polymerase chain reaction with primers specific only for human DNA.


Glutathione levels and immune responses in tuberculosis patients.
Glutathione levels are significantly reduced in peripheral blood mononuclear cells and red blood cells isolated from tuberculosis patients. Treatment of blood cultures from tuberculosis patients with N-acetyl cysteine, a glutathione precursor, was associated with improved control of intracellular M. tuberculosis infection. N-acetyl-cysteine treatment decreased the levels of IL-10, IL-6, TNF-alpha and IL-1, in blood cultures derived from tuberculosis patients, favoring the host immune cells to successfully control M. tuberculosis replication.


Attenuation of methylglyoxal-induced peritoneal fibrosis: immunomodulation by interleukin-10.
Peritoneal fibrosis (PF), a serious pathophysiology of peritoneal dialysis (PD), is implicated in various types of chronic inflammation. In the present study, we examined the benefits of interleukin (IL)-10, which exerts anti-inflammatory effects, in an experimental rat model of methylglyoxal (MGO)-induced PF. We injected an adeno-associated virus (AAV) vector encoding rat IL-10 or enhanced green fluorescent protein (GFP) into male Sprague-Dawley rats at 6 weeks of age. Four weeks later, the rats received continuous peritoneal injections of conventional PD fluid (PDF) with MGO for 3 weeks. Then, the peritoneal histology and the expression levels of fibrogenic mediators and proinflammatory cytokines were analyzed. The rats demonstrating persistent IL-10 expression showed significantly reduced fibrous peritoneal thickening compared with those with GFP expression. The infiltration of macrophages, the expression of tumor necrosis factor-α, IL-1β, IL-6, transforming growth factor-β1, Snail, and matrix metalloproteinase 2 genes as well as the proliferation of mesenchymal-like mesothelial cells augmented by MGO were all significantly suppressed by IL-10 expression. IL-10 also abrogated the extent of MGO-induced bowel adhesions mimicking a cocoon-like mass. Our findings provide valuable insight into the potential benefit of immunomodulation with IL-10 as one potentially effective therapeutic strategy for preventing the onset of peritoneal injury resulting in PF.


Complex Enterally Tube-Fed Community Patients Display Stable Tolerance, Improved Compliance and Better Achieve Energy and Protein Targets with a High-Energy, High-Protein Peptide-Based Enteral Tube Feed: Results from a Multi-Centre Pilot Study.
This pilot study evaluated a high-energy, high-protein, peptide-based, (medium-chain triglycerides) MCT-containing enteral tube feed (Nutrison Peptisorb Plus HEHP®, Nutricia Ltd., Trowbridge, BA14 0XQ, UK.) containing 1.5 kcal/mL and 7.5 g protein/100 mL. Fifteen community-based, enterally tube-fed adults (42 (SD 16.3) years) received the intervention feed daily for 28 days, with gastrointestinal tolerance, compliance and nutrient intake assessed at baseline and after the intervention period. Incidence and intensity of constipation (p = 0.496), nausea (p = 1.000), abdominal pain (p = 0.366) and bloating (p = 0.250) remained statistically unchanged, yet the incidence and intensity of diarrhoea improved significantly after receiving the intervention feed (Z = -2.271, p = 0.023). Compliance with the intervention feed was significantly greater compared to the patient's baseline regimens (99% vs. 87%, p = 0.038). Compared to baseline, use of the intervention feed enabled patients to significantly increase total energy (1676 kcal/day (SD 449) to 1884 kcal/day (SD 537), p = 0.039) and protein intake (73 g/day (SD 17) to 89 g/day (SD 23), p = 0.001), allowing patients to better achieve energy (from 88% to 99%, p = 0.038) and protein (from 101% to 121%, p < 0.001) requirements. This pilot study demonstrates that a high-energy, high-protein, peptide-based, MCT-containing enteral tube feed maintains gastrointestinal tolerance and improves compliance, energy and protein intake in complex, enterally tube-fed, community-based adult patients, though more work is recommended to confirm this.


Determination of mefloquine by electron-capture gas chromatography after phosgene derivatization in biological samples and in capillary blood collected on filter paper.
Mefloquine is determined in 100-microliter samples of whole blood, plasma and capillary blood collected on filter paper by gas chromatography with electron-capture detection after derivatization with phosgene. Sample preparation for whole blood and plasma involves a protein precipitation step that uses a combination of zinc and acetonitrile, followed by simultaneous extraction with methylene chloride and derivatization with phosgene at pH 9.50. Filter paper spots are immersed for 12-24 h in 0.1 M hydrochloric acid, followed by simultaneous extraction with methyl tert.-butyl ether and derivatization. After evaporation of the organic phase and reconstitution with ethyl acetate, 1 microliter of the extract is injected into a megabore capillary column. Because of the high sensitivity of the method, mefloquine concentrations down to 25 nmol/l (9.5 micrograms/l) are determined in 100-microliters samples with a relative standard deviation of 12% at the 25 nmol/l level. Excellent precision was obtained over the range of concentrations tested, 0.10-3 mumol/l (45-1100 micrograms/l), in both plasma and whole blood and from filter-paper-collected capillary blood. The day-to-day relative standard deviation in plasma at the therapeutic level (1-3 mumol/l) was 4.5% (n = 8).


Pediatric Acute Respiratory Distress Syndrome and Tracheal Injury in a Patient Requiring Extracorporeal Membrane Oxygenation Following Cement Aspiration: A Case Report.
Ingestion and aspiration of caustic substances is a common problem in pediatrics and carries the risk of associated aspiration pneumonitis, laryngeal injury, and esophageal injury. Extracorporeal membrane oxygenation (ECMO) has been used to support adults with acute respiratory distress syndrome (ARDS) from aspiration of cement dust, however, literature outlining pediatric management in cases of alkali lung and airway injuries is lacking. A 6-year-old boy presented with ARDS from cement aspiration requiring high-pressure ventilation. He had further complications of tracheal injury with subsequent pneumomediastinum secondary to the alkali burn. He required ECMO to facilitate repeat bronchoscopy for cement particle washout and to enable recovery from ARDS and tracheal injury. This case highlights the need to perform early bronchoscopy and gastrointestinal endoscopy for injury assessment and foreign body removal in alkali burns. It also emphasizes the value of ECMO support for respiratory failure and facilitating bronchoalveolar lavage when it is not otherwise tolerated.


Effect of dexamethasone on the fatty acid composition of total liver microsomal lipids and phosphatidylcholine molecular species.
Dexamethasone depresses delta6 and delta5 and increases delta9 desaturase and synthase activities. Therefore, we investigated the effect on the fatty acid composition of microsomal liver lipids and phosphatidylcholine (PtdCho) molecular species. After 15 d of treatment we found a notable decrease in arachidonic acid, a small decrease in stearic acid, and increases of linoleic, oleic, palmitoleic, and palmitic acids in liver microsomal total lipids and PtdCho. The study of the distribution of the PtdCho molecular species indicated that 18:0/20:4n-6, 16:0/20:4n-6, and 16:0/18:2n-6 predominated in the control animals. Dexamethasone, as expected because of its depressing effect on arachidonic acid synthesis and activation of oleic and palmitic acid synthesis, evoked a very significant decrease in 18:0/20:4n-6 PtdCho (P<0.001) and an important increase in 16:0/18:2n-6. The invariability of 16:0/20:4n-6 PtdCho could be related to the antagonistic effect of arachidonic and palmitic acid synthesis. PtdCho species containing oleic acid were not significant. The bulk fluidity and dynamic properties of the microsomal lipid bilayer measured by fluorometry using the probes 1,6-diphenyl-1,3,5-hexatriene and 4-trimethylammonium-phenyl-6-phenyl-1,3,5-hexatriene showed no significant modification, probably owing to a compensatory effect of the different molecular species, but changes of particular domains not detected by this technique are possible. However, the extremely sensitive Laurdan detected increased lipid packing in the less-fluid domains of the polar-nonpolar interphase of the bilayer, possibly evoked by the change of molecular species and cholesterol/phospholipid ratio. The most important effect found is the decrease of arachidonic acid pools in liver phospholipids as one of the corresponding causes of dexamethasone-dependent pharmacological effects.


Impaired facial emotion recognition in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS): Side and age at onset matters.
To define the determinants of impaired facial emotion recognition (FER) in patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS), we examined 76 patients with unilateral MTLE-HS, 36 prior to antero-mesial temporal lobectomy (AMTL) and 40 after AMTL, and 28 healthy control subjects with a FER test consisting of 60 items (20 each for anger, fear, and happiness). Mean percentages of the accurate responses were calculated for different subgroups: right vs. left MTLE-HS, early (age at onset <6 years) vs. late-onset, and before vs. after AMTL. After controlling for years of education, duration of epilepsy and number of antiepileptic drugs (AEDs) taken, on multivariate analysis, fear recognition was profoundly impaired in early-onset right MTLE-HS patients compared to other MTLE patients and control subjects. Happiness recognition was significantly better in post-AMTL MTLE-HS patients compared to pre-AMTL patients while anger and fear recognition did not differ. We conclude that patients with right MTLE-HS with age at seizure onset <6 years are maximally predisposed to impaired fear recognition. In them, right AMTL does not further worsen FER abilities. Longitudinal studies comparing FER in the same patients before and after AMTL will be required to refine and confirm our cross-sectional observations.


Reduced glomerular filtration and elevated urinary protein excretion in diabetic ketoacidosis.
Glomerular filtration rate (GFR) was measured by two methods in 9 children with diabetic ketoacidosis (DKA), directly by true creatinine clearance and indirectly by means of serum beta-2-microglobulin levels. We found significantly reduced GFR in the first hours of DKA. The rapid improvement in GFR after fluid and electrolyte replacement indicates that volume depletion is the major cause of low filtration rate. In spite of the reduced GFR we observed pronounced albuminuria and low molecular weight (LMW) proteinuria. We conclude that the pathological albuminuria and microalbuminuria in DKA are caused not by glomerular hyperfiltration but by tubular dysfunction.


Development and validation of an ultrasound-based nomogram to improve the diagnostic accuracy for malignant thyroid nodules.
The aim of this study was to develop an ultrasound-based nomogram to improve the diagnostic accuracy of the identification of malignant thyroid nodules. A total of 1675 histologically proven thyroid nodules (1169 benign, 506 malignant) were included in this study. The nodules were grouped into the training dataset (n = 700), internal validation dataset (n = 479), or external validation dataset (n = 496). The grayscale ultrasound features included the nodule size, shape, aspect ratio, echogenicity, margins, and calcification pattern. We applied least absolute shrinkage and selection operator (lasso) regression to select the strongest features for the nomogram. Nomogram discrimination (area under the receiver operating characteristic curve, AUC) and calibration were assessed. The nomogram was subjected to bootstrapping validation (1000 bootstrap resamples) to calculate a mean AUC and 95% confidence interval (CI). The nomogram showed good discrimination in the training dataset, with an AUC of 0.936 (95% CI: 0.918-0.953) and good calibration. Application of the nomogram to the internal validation dataset also resulted in good discrimination (AUC: 0.935; 95% CI, 0.915-0.954) and good calibration. The model tested in an external validation dataset demonstrated a lower AUC of 0.782 (95% CI: 0.776-0.789). This ultrasound-based nomogram can be used to quantify the probability of malignant thyroid nodules. • Ultrasound examination is helpful in the differential diagnosis of malignant and benign thyroid nodules. • However, ultrasound accuracy relies heavily on examiner experience. • A less subjective diagnostic model is desired, and the developed nomogram for thyroid nodules showed good discrimination and good calibration.


Lipids, Apolipoproteins, Statins, and Intracerebral Hemorrhage: A Mendelian Randomization Study.
To investigate the causal role of lipid or apolipoprotein traits in intracerebral hemorrhage (ICH) and determine the effect of lipid-lowering interventions on the disease. Two-sample Mendelian randomization (MR) analyses were conducted to evaluate the associations of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein (Apo)B and ApoA1 levels with risks for ICH, and those of LDL-C- (HMGCR, PCSK9, and NPC1L1) and TG-lowering targets (LPL and APOC3) with ICH. Increased levels of ApoB was associated with a decreased risk of overall ICH (OR 0.623, 95% CI 0.413-0.940; p = 0.024) and lobar ICH (OR 0.579, 95% CI 0.342-0.979; p = 0.042). The inverse relationship remained stable in multivariable MR. In addition, elevated TGs showed a causal effect on lobar ICH in multivariable MR (OR 1.600, 95% CI 1.009-2.537; p = 0.046). The LDL-C-reducing genetic variation alleles at or near the HMGCR gene (mimicking the effect of statins) were predicted to increase the overall and deep ICH risk. Additionally, genetic variation at or near the APOC3 gene suggested that genetically reducing the activity of APOC3 (mimicking antisense anti-apoC3 agents) was predicted to decrease lobar ICH. Genetically predicted elevated ApoB may have a protective effect on overall ICH and lobar ICH, whereas elevated TG was associated with a higher risk of lobar ICH conditional on LDL-C and ApoB. MR analysis supports the conclusion that statins may increase the risk of overall and deep ICH independent of their lipid-lowering effect. More specific lipid-lowering targets may end up being the future. ANN NEUROL 2022;92:390-399.


Ontogeny and distribution of cells expressing HLA-B locus-specific determinants in the placenta and extraplacental membranes.
Both the trophectoderm and the inner cell mass of the blastocyst contribute to the cell populations found in the placenta and extraplacental membranes. Previous studies have shown differences between those two embryologically distinct populations of cells in their expression of class I HLA, and further differences among trophectoderm-derived trophoblast cell subpopulations. Binding patterns for antibodies to both monomorphic and allotypic determinants on class I heavy chains have been reported. In the present study, extraembryonic cells were evaluated by immunohistology for binding of the monoclonal antibody 4E, which identifies locus-specific determinants on HLA-B. Some inner cell mass-derived cells (mesenchymal cells) acquired high levels of HLA-B as gestation progressed and other continued to express low levels at late stages of gestation (amnion cells). In contrast, throughout gestation both villous and extravillous trophoblast cells failed to express detectable HLA-B. The binding patterns for 4E followed the patterns established by a monoclonal antibody to class I HLA heavy chains (61D2), and those reported for antisera to allotypic determinants. The findings support the suggestion that trophoblast cells forming the fetal component of the maternal-fetal interface exert highly effective regulation over the expression of class I HLA.


Normalization of urinary oxalate by taurine in glycolate-fed rats.
Oral feeding of sodium glycolate (50 mg/d/rat for ten days) caused a significant (P less than 0.001) increase in oxalate and taurine excretion and a decrease in liver protein content (P less than 0.05), glycolic acid oxidase levels (P less than 0.01), and glycolic acid dehydrogenase levels (P less than 0.01) as compared to normal untreated rats. Taurine (100 mg/d/rat), when administered along with glycolate, prevented these effects of glycolate as evident from normal urinary excretion of oxalate, liver protein content, glycolic acid oxidase, and glycolic acid dehydrogenase levels in glycolate- plus taurine-fed animals.


The impact of oral rehabilitation on oral health-related quality of life in patients receiving radiotherapy for the treatment of head and neck cancer.
To analyze the influence of dental treatment on oral health-related quality of life (OHRQoL) in head and neck cancer patients. This study included the data of 116 patients who underwent radiotherapy (RT) because of head and neck cancer. For each patient, the variables age, sex, tumor site, irradiation technique, dose on the spared parotid gland, concomitant chemotherapy, and denture status were documented. OHRQoL was determined using the OHIP-G14 questionnaire. Patients were divided into subgroups according to denture status: none or fixed partial dentures (none/FPD), removable partial dentures (RPD), and full dentures (CD). OHIP summary scores were determined and tested for clinical relevant differences with respect to the different variables. The association between OHRQol and the variables was assessed using linear regression. No clinically relevant influence on OHRQoL was found for gender, irradiation technique, and chemotherapy. Patients with tumors located in the oral cavity had a significantly higher OHIP score than patients with other tumor sites (p < 0.001). None/FPD and RPD patients had higher values than those found in a normal population, but did not differ significantly from each other (p = 0.387). In contrast to tumor site, teeth and type of denture seem to have a limited effect on OHRQoL in head and neck cancer patients. Prosthetic treatment in head and neck cancer patients do not lead to the same improvement in OHRQoL as found in the normal population. This might be taken into account especially if extensive dental treatment is intended.


The Aldosterone Receptor Antagonist Eplerenone Inhibits Isoproterenol-Induced Collagen-I and 11β-HSD1 Expression in Rat Cardiac Fibroblasts and the Left Ventricle.
β-Adrenergic receptor (β-AR)-induction of collagen-I synthesis is partially mediated by the cardiac mineralocorticoid receptor (MR) system. However, it remains unclear whether the selective MR antagonist, eplerenone, inhibits collagen-I synthesis induced by β-AR stimulation. We investigated the effects of eplerenone on the responses to a non-selective β-AR agonist, isoproterenol, which induced collagen-I synthesis in primary cardiac fibroblasts (CFs) and the left ventricle. mRNAs encoding the MR and 11β-hydroxysteroid dehydrogenase type I (11β-HSD1) were evident in the left ventricle and primary CFs. mRNAs encoding the CYP family 11 subfamily B member 2 (CYP11-B2) were not detected, even after isoproterenol treatment. In vivo, isoproterenol induced collagenous fiber accumulation in the left ventricle. The phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), 11β-HSD1 levels, and mRNA/protein levels of collagen-I increased upon exposure to isoproterenol, but these increases were inhibited by eplerenone co-treatment. In primary CFs, isoproterenol increased the phosphorylation of ERK1/2 and the expression levels of both 11β-HSD1 and collagen-I; these isoproterenol-attributable effects were inhibited by co-treatment with eplerenone and PD98059, a specific inhibitor of mitogen-activated protein kinase/ERK kinase activity. The results suggest that 11β-HSD1 but not CYP11-B2 is expressed in primary CFs. Eplerenone inhibited isoproterenol-induced ERK1/2 phosphorylation and expression of 11β-HSD1 and collagen-I in primary CFs, as well as the progression of cardiac fibrosis in the left ventricle. Therefore, eplerenone inhibited the isoproterenol-induced increases in 11β-HSD1 and collagen-I expression in primary CFs, and progression of cardiac fibrosis in the left ventricle.


Crystal structure, in vitro cytotoxicity, DNA binding and DFT calculations of new copper (II) complexes with coumarin-amide ligand.
This work describes the synthesis, anticancer activity and electron structure study of two Cu (II) complexes with coumarin-3-formyl-(3-(aminomethyl) pyridine) ligand (L) - C1 (Cu2L2(OAc)4) and C2 (CuL2(NO3)2). The structure of C1 and C2 was confirmed by elemental analysis, FTIR, and single-crystal X-ray analysis. Complex C1 crystallizes as binuclear where two Cu (II) ions are bridged by four acetate ligands while C2 is a mononuclear complex with twisted octahedral geometry. Density functional theory (DFT) calculations revealed that electronic transitions originate from metal-ligand charge transfer and d-d transitions of metal ions. According to the results of UV-Vis and fluorescence titrations, C1 and C2 intercalate with DNA with the binding constants of 6.9 × 105 M-1 and 5.9 × 105 M-1, respectively. The in vitro cytotoxicity assays on four cancer cell lines (HeLa, HepG2, MCF-7 and A549) and a normal HUVEC cell line indicated higher anti-MCF-7 activity of C2 compared with cisplatin (IC50 = 2.86 ± 0.08 μM vs. 9.07 ± 0.10 μM). Moreover, C2 had superior selectivity since IC50 toward HUVEC cells was over 150 μM compared with 0.58 ± 0.05 μM for cisplatin. We concluded that the anti-MCF activity of mononuclear C2 complex is better than that of binuclear C1 and cisplatin. Therefore, C2 has been selected as a hit compound to develop novel non‑platinum anticancer agents through modification of coumarin-amide structure and variation of copper (II) salts.


Activation of the electrogenic Na-pump of cardiac muscle fibres by ACh in K-free solutions.
The ionic mechanism of the membrane outward current (ACh-current) of bullfrog atrium muscle, induced by acetylcholine in K-free solution, was analyzed by a voltage-clamp experiment. The results suggested that the ACh-current was induced not only by an increase in K-conductance but also by an activation of the electrogenic Na-pump.


LC-ESI-QTOF-MS identification of novel antioxidant peptides obtained by enzymatic and microbial hydrolysis of vegetable proteins.
Bioactive antioxidant peptides are more and more attracting the attention of food manufacturers for their potential to transform food in functional food, able to prevent a variety of chronic diseases associated with oxidative stress. In the present study proteins extracted from different vegetable sources (KAMUT® khorasan wheat, emmer, lupine and pea) were hydrolyzed with commercial enzymes and Lactobacillus spp. strains. Hydrolysates were separated by size exclusion chromatography and purified fractions were analyzed for their antioxidant activity. Peptides from the fractions with the highest activity were identified by nanoLC-ESI-QTOF-MS and thirteen peptides were selected for synthesis on the basis of their sequence. Four peptides (VLPPQQQY, TVTSLDLPVLRW, VTSLDLPVLRW, FVPY) were found able to scavenge superoxide anion and hydroxyl radicals, organic nitro-radicals (ABTS, DPPH) and to inhibit lipid peroxidation. The impact of this work is targeted to add hydrolysed vegetable proteins to reformulated functional food or to produce health-promoting ingredients and nutraceuticals.


Multi-exposure human health risks assessment of trihalomethanes in drinking water of Egypt.
The present study aims to assess the probable lifetime cancer and non-cancer risks of exposure to the trihalomethanes in Egypt's drinking water through ingestion, dermal contact, and inhalation. A total of 1667 drinking water samples were collected from twenty-three Egyptian governorates over a three-years period. The concentrations of total trihalomethanes ranged between 29.07 and 86.01 μg/L and were always below the maximum contamination level recommended by the Egyptian standards (100 μg/L). Chloroform was the most prominent trihalomethanes species, while bromoform was rarely detected. The cancer risk study revealed that, among the investigated paths, inhalation poses the greatest risk. And bromodichloromethane had the highest impact to cancer (69%), followed by chlorodibromomethane (28%). Geographically, the highest cancer risk value was found in Matruh governorate (42.2 × 10-6) and the lowest was in Minya governorate (1.0 × 10-6). The cancer risk for the studied governorates, except Minya governorate, was higher than the level recommended by the USEPA (1.0 × 10-6). Hazard index (HI) study revealed that the ingestion pathway caused higher HI values than the dermal pathway and that chloroform had the highest contribution to HI value. However, the values of HI were below unity in all studied governorates demonstrating that there would be negligible non-cancer risk.


Regulation of oligodendrocyte precursor maintenance by chondroitin sulphate glycosaminoglycans.
Chondroitin sulfate proteoglycans (CSPGs) have been proven to inhibit morphological maturation of oligodendrocytes as well as their myelination capabilities. Yet, it remained unclear, whether CSPGs and/or their respective chondroitin sulfate glycosaminoglycan (CS-GAG) side chains also regulate the oligodendrocyte lineage progression. Here, we initially show that CS-GAGs detected by the monoclonal antibody 473HD are expressed by primary rat NG2-positive oligodendrocyte precursor cells (OPCs) and O4-positive immature oligodendrocytes. CS-GAGs become down-regulated with ongoing oligodendrocyte differentiation. Enzymatic removal of the CS-GAG chains by the bacterial enzyme Chondroitinase ABC (ChABC) promoted spontaneous differentiation of proliferating rat OPCs toward O4-positive immature oligodendrocytes. Upon forced differentiation, the enzymatic removal of the CS-GAGs accelerated oligodendrocyte differentiation toward both MBP-positive and membrane forming oligodendrocytes. These processes were attenuated on enriched CSPG fractions, mainly consisting of Phosphacan/RPTPβ/ζ and to less extent of Brevican and NG2. To qualify CS-GAGs as universal regulators of oligodendrocyte biology, we finally tested the effect of CS-GAG removal on OPCs from different sources such as mouse cortical oligospheres, mouse spinal cord neurospheres, and most importantly human-induced pluripotent stem cell-derived radial glia-like neural precursor cells. For all culture systems used, we observed a similar inhibitory effect of CS-GAGs on oligodendrocyte differentiation. In conclusion, this study clearly suggests an important fundamental principle for complex CS-GAGs to regulate the oligodendrocyte lineage progression. Moreover, the use of ChABC in order to promote oligodendrocyte differentiation toward myelin gene expressing cells might be an applicable therapeutic option to enhance white matter repair.


The immunoregulatory role of cholesterol and other lipids: a hypothesis.
Membrane lipids play an important role in cellular responses to exogenous signals. In immunocompetent lymphocytes, marked changes in the concentrations of membrane lipids occur following cell-antigen interaction. These changes lead to an increase in membrane fluidity, thus facilitating the microaggregation of receptor-antigen complexes. This event constitutes the inductive signal for lymphocytes. Lipid profile alterations leading to increased concentration of membrane cholesterol, of polyunsaturated lipids, or of both, bring about a decrease in membrane fluidity. The latter interferes with receptor displacement preventing delivery of an inductive signal to the responding cell. Interference with microaggregation is readily brought about in interactions involving low affinity antigens, such as tumoral antigens. We postulate that in hyperlipidemic and hypercholesterolemic states there is decreased immune responsiveness to weak antigens due to the aformentioned lipid profile alterations in the membranes of immunocompetent cells. The manner in which an increase in the concentration of the lipids mentioned can lead to decreased immune responsiveness and hence to an increased incidence of malignancies in hyperlipidemic and hypercholesterolemic states is the hypothesis presented in this paper.


β-cell mitochondria in diabetes mellitus: a missing puzzle piece in the generation of hPSC-derived pancreatic β-cells?
Diabetes mellitus (DM), currently affecting 463 million people worldwide is a chronic disease characterized by impaired glucose metabolism resulting from the loss or dysfunction of pancreatic β-cells with the former preponderating in type 1 diabetes (T1DM) and the latter in type 2 diabetes (T2DM). Because impaired insulin secretion due to dysfunction or loss of pancreatic β-cells underlies different types of diabetes, research has focused its effort towards the generation of pancreatic β-cells from human pluripotent stem cell (hPSC) as a potential source of cells to compensate for insulin deficiency. However, many protocols developed to differentiate hPSCs into insulin-expressing β-cells in vitro have generated hPSC-derived β-cells with either immature phenotype such as impaired glucose-stimulated insulin secretion (GSIS) or a weaker response to GSIS than cadaveric islets. In pancreatic β-cells, mitochondria play a central role in coupling glucose metabolism to insulin exocytosis, thereby ensuring refined control of GSIS. Defects in β-cell mitochondrial metabolism and function impair this metabolic coupling. In the present review, we highlight the role of mitochondria in metabolism secretion coupling in the β-cells and summarize the evidence accumulated for the implication of mitochondria in β-cell dysfunction in DM and consequently, how targeting mitochondria function might be a new and interesting strategy to further perfect the differentiation protocol for generation of mature and functional hPSC-derived β-cells with GSIS profile similar to human cadaveric islets for drug screening or potentially for cell therapy.


Coronal and apical lesions, environmental factors: study in a modern and an archeological population.
Apical periodontitis (AP) are frequent findings in contemporary dental practice in association with dental pathology or dental care. They have also been studied from an anthropological background. The purpose of this study was to compare the prevalence of apical and dental lesions in an archeological Middle Ages sample and a modern population, and to evaluate the influence of environmental factors. Both the archaeological sample group and dental practice subjects were from southern France. The study included full mouth surveys of 252 individuals (2,780 teeth) from a historic necropolis and 223 subjects (5,678 teeth) randomly selected from the Gard area. Tooth wear, caries, and AP were accounted for clinically and radiographically according to specific indexes. Significant differences were found between period and age in the archeological sample as regards the main risk factors for AP. Antemortem teeth loss and dental wear had been reduced, whereas caries rates and AP had increased between archaeological and modern population. The AP ratio was associated with the level of dental care in the modern population. Although significant variations could be observed between archaeological periods, the rupture in E3 (sixteenth and seventeenth centuries) leads to consider the associated population as a premodern. However, it was found that although cultural and alimentary factors seemed to be the main risk factors in an archeological population, dental care seemed to have a strong influence on AP ratio in modern ones.


Efficacy and safety of abatacept in patients with rheumatoid arthritis with previous malignancy.
Abatacept (ABT) is known to lower infection risk than other biologics and is effective and safe in elderly patients with rheumatoid arthritis (RA). However, there were inconsistent reports on the impact of ABT on malignancies which are more common in the elderly and strongly related to prognosis. This study aimed to evaluate the efficacy and safety of ABT in patients with RA with previous malignancy in clinical practice. A multicenter, retrospective study. Patients who received ABT for RA in two hospitals in Yokohama until May 2022 were included in this study. The patients were divided into two groups according to the presence or absence of a history of malignancy (no previous malignancy: NP group, previous malignancy: PM group). The collected parameters were compared between the groups using propensity score matching. In this study, 312 patients were included, of whom 73 had previous malignancies when starting ABT. The age at ABT initiation was significantly higher in the PM group, the rate of methotrexate use was significantly lower in the PM group, and the Steinbrocker stage was significantly higher in the PM group. After matching these 3 factors, 68 patients were selected from each group. No significant differences in the ABT continuation rate, and malignancy incidence were observed between the two groups after ABT initiation. In addition to these factors, when matched for smoking history, interstitial lung disease, disease duration, sex, and inflammatory status, which are known risk factors for malignancy in RA, 40 patients were selected from each group. No significant differences in the ABT continuation rate, and malignancy incidence were observed between the two groups after ABT initiation. In our clinical practice, ABT was as effective and safe in patients with a history of malignancy as in those without.


Impact of donor left ventricular hypertrophy on survival after heart transplant.
Left ventricular hypertrophy (LVH) of the donor heart is believed to increase the risk of allograft failure after transplant. However this effect is not well quantified, with variable findings from single-center studies. The United Network for Organ Sharing database was used to analyze the effect of donor LVH on recipient survival. Three cohorts, selected in accordance with the American Society of Echocardiography guidelines, were examined: recipients of allografts without LVH (<1.1 cm), with mild LVH (1.1-1.3 cm) and with moderate-severe LVH (≥ 1.4 cm). The study group included 2626 patients with follow-up of up to 3.3 years. Mild LVH was present in 38% and moderate-severe LVH in 5.6% of allografts. Predictors of mortality included a number of donor and recipient characteristics, but not LVH. However, a subgroup analysis showed an increased risk of death in recipients of allografts with LVH and donor age >55 years, and in recipients of allografts with LVH and ischemic time ≥ 4 h. In the contemporary era, close to half of all transplanted allografts demonstrate LVH, and survival of these recipients is similar to those without LVH. However, the use of allografts with LVH in association with other high-risk characteristics may result in increased mortality.


Zoledronic acid and skeletal-related events in patients with bone metastatic cancer or multiple myeloma.
Investigations of ZA effectiveness using large, real-world databases are rare. We examined whether zoledronic acid (ZA) decreased the risk of skeletal-related events (SREs) among patients with bone metastases (BMs) from breast cancer (BC) or prostate cancer (PC), or multiple myeloma (MM) in routine clinical practice. We conducted a propensity score-matched cohort study using the Korean National Health Insurance database. Our cohort included patients diagnosed with BM after BC or PC, or MM between 2004 and 2015. SRE was defined as having a record of pathologic fracture, spinal cord compression, radiation, or surgery to bone. The incidence of multiple SREs was calculated according to SRE history. We calculated the incidence rate ratio (IRR) to examine the relative difference in the risk of SREs of ZA users compared to those of ZA non-user. Among 111,679 patients, diagnosed with BM and one of the three cancer types, 5608 were included in the analysis after propensity score matching. A decreased risk of SREs was observed for the ZA use in patients with history of SRE in BC [IRR = 0.74, 95% confidence interval (CI) = 0.66-0.83], PC (IRR = 0.86, 95% CI = 0.73-1.02), and MM (IRR = 0.74, 95% CI = 0.59-0.93). For patients without SRE history, ZA use was not associated with decreased risks of SREs, but rather increased the risks (BC: IRR = 1.96, 95% CI 1.87-2.05; PC: IRR = 1.66, 95% CI 1.54-1.80; MM: IRR = 1.92, 95% CI 1.57-2.34). Our study suggests that the ZA use was associated with a decreased risk of SRE for patients with SRE history. However, no preventive effects of ZA were observed for patients without history.


The role of ATP/ADP ratio in the control of hepatic gluconeogenesis during the early neonatal period.
The hepatic ATP/ADP ratio showed significant changes during the first day of postnatal life in starved newborn rats. The occurrence of a positive linear correlation between the ATP/ADP ratio and the gluconeogenic capacity in vivo is reported in the newborn rat during the first day of life.


Dual-utility NLS drives RNF169-dependent DNA damage responses.
Loading of p53-binding protein 1 (53BP1) and receptor-associated protein 80 (RAP80) at DNA double-strand breaks (DSBs) drives cell cycle checkpoint activation but is counterproductive to high-fidelity DNA repair. ring finger protein 169 (RNF169) maintains the balance by limiting the deposition of DNA damage mediator proteins at the damaged chromatin. We report here that this attribute is accomplished, in part, by a predicted nuclear localization signal (NLS) that not only shuttles RNF169 into the nucleus but also promotes its stability by mediating a direct interaction with the ubiquitin-specific protease USP7. Guided by the crystal structure of USP7 in complex with the RNF169 NLS, we uncoupled USP7 binding from its nuclear import function and showed that perturbing the USP7-RNF169 complex destabilized RNF169, compromised high-fidelity DSB repair, and hypersensitized cells to poly (ADP-ribose) polymerase inhibition. Finally, expression of USP7 and RNF169 positively correlated in breast cancer specimens. Collectively, our findings uncover an NLS-mediated bipartite mechanism that supports the nuclear function of a DSB response protein.


Allogeneic Dermal Fibroblasts Improve Tendon-to-Bone Healing in a Rabbit Model of Chronic Rotator Cuff Tear Compared With Platelet-Rich Plasma.
To compare the effects of allogeneic dermal fibroblasts (ADFs) and platelet-rich plasma (PRP) on tendon-to-bone healing in a rabbit model of chronic rotator cuff tear. Thirty-two rabbits were divided into 4 groups (8 per group). In 2 groups, the supraspinatus tendon was detached and was left as such for 6 weeks. At 6 weeks after creating the tear model, we performed transosseous repair with 5 × 106 ADFs plus fibrin injection in the left shoulder and PRP plus fibrin in the right shoulder. The relative expression of the COL1, COL3, BMP2, SCX, SOX9, and ACAN genes was assessed at 4 weeks (group A) and 12 weeks (group B) after repair. Histologic and biomechanical evaluations of tendon-to-bone healing at 12 weeks were performed with ADF injection in both shoulders in group C and PRP injection in group D. At 4 weeks, COL1 and BMP2 messenger RNA expression was higher in ADF-injected shoulders (1.6 ± 0.8 and 1.0 ± 0.3, respectively) than in PRP-injected shoulders (1.0 ± 0.3 and 0.6 ± 0.3, respectively) (P = .019 and P = .013, respectively); there were no differences in all genes in ADF- and PRP-injected shoulders at 12 weeks (P > .05). Collagen continuity, orientation, and maturation of the tendon-to-bone interface were better in group C than in group D (P = .024, P = .012, and P = .013, respectively) at 12 weeks, and mean load to failure was 37.4 ± 6.2 N/kg and 24.4 ± 5.2 N/kg in group C and group D, respectively (P = .015). ADFs caused higher COL1 and BMP2 expression than PRP at 4 weeks and showed better histologic and biomechanical findings at 12 weeks after rotator cuff repair of the rabbit model. ADFs enhanced healing better than PRP in the rabbit model. This study could serve as a transitional study to show the effectiveness of ADFs in achieving tendon-to-bone healing after repair of chronic rotator cuff tears in humans.


Effect of amino acids on purified rat intestinal brush-border membrane aminooligopeptidase.
When a hexapeptide, Leu-Trp-Met-Arg-Phe-Ala, or a pentoapeptide, Leu-Trp-Met-Arg-Phe, was incubated in vitro with a purified aminooligopeptidase from rat small intestinal mucosa, the respective C-terminal dipeptides, Phe-Ala and Arg-Phe, were observed to be resistant to hydrolysis. The resistance of these C-terminal dipeptides to hydrolysis was found to be due mainly to the accumulation of inhibitory hydrophobic amino acids liberated in the incubation mixture. The hydrolysis of various peptides by the brush-border membrane peptidase is inhibited to a varying extent by the hydrophobic amino acids L-tryptophan, L-methionine, L-isoleucine, L-leucine, L-tyrosine, and L-phenylalanine, but not the D-form of these amino acids. The inhibition of the hydrolysis of three dipeptides by hydrophobic amino acids showed these amino acids to be competitive inhibitors (same Vmax, the maximal velocity of the enzyme reaction; different Km, the substrate concentration at which the enzyme reaction is half maximal) of one of the dipeptides while exhibiting a mode of inhibition that was not competitive (different Vmax, different Km) with either of the other two dipeptides. These data indicate that the effect of amino acids on the hydrolytic rate of the brush-border membrane aminooligopeptidases must be considered in studies of intestinal hydrolysis and absorption of peptides.


Group B streptococcal sepsis impairs cerebral vascular reactivity to acute hypercarbia in piglets.
We investigated whether group B streptococcal (STREP) infusion impairs the cerebral blood flow (CBF) response to acute hypercarbia in piglets, and whether STREP-induced prostanoids or hemodynamic alterations could account for this impairment. Piglets, 2-3 wk old, were anesthetized, paralyzed, and mechanically ventilated (50% O2; partial pressure of arterial CO2 (PaCO2) approximately 40 torr). CBF was assessed by internal carotid artery blood flow (ICBF). Group 1 (n = 5) received a continuous infusion of STREP for 4 h (2.0-8.0 x 10(7) org/kg-min). Group 2 (n = 5) was pretreated with indomethacin (5 mg/kg), then received the identical STREP infusion. Group 3 (n = 6) did not receive STREP, but cardiac output (CO) and systemic blood pressure (BP) were reduced to levels equal to that of group 1 by incremental inflation of a left atrial balloon (LAB) catheter. Cerebral vascular reactivity to acute hypercarbia (PaCO2 approximately 70 torr for 7.5 min) was assessed at baseline and after each hour of STREP infusion or LAB inflation. We found that 4 h of STREP infusion caused CO to fall significantly (634 +/- 121 to 324 +/- 172 mL/min, group 1; 600 +/- 68 to 291 +/- 80 mL/min, group 2) and BP to fall significantly (104 +/- 20 to 57 +/- 4 mm Hg, group 1; 91 +/- 11 to 53 +/- 16 mm Hg, group 2) By design, in group 3 LAB inflation caused CO (573 +/- 181 to 375 +/- 159 mL/min) and BP (104 +/- 14 to 60 +/- 9 mm Hg) to fall to values not significantly different from septic groups 1 and 2. At 4 h, unilateral ICBF decreased significantly during STREP infusion in group 1 (32.0 +/- 10.8 to 21.0 +/- 7.3 mL/min) and group 2 (22.9 +/- 9.9 to 13.1 +/- 4.3 mL/min), but not in nonseptic group 3 (23.1 +/- 7.4 to 19.6 +/- 6.3 mL/min). At baseline, hypercarbia induced an increase in ICBF (% delta ICBF = 68.7 +/- 13.0% in group 1, 62.2 +/- 15.6% in group 2, and 87.7 +/- 34.0% in group 3). After 4 h of STREP, this response was completely ablated as ICBF fell during hypercarbia by -7.8 +/- 23.2% (group 1). Indomethacin did not protect cerebral vascular reactivity after 4 h of STREP infusion, as % delta ICBF fell during hypercarbia by -10.9 +/- 17.7% (group 2). In contrast, despite equivalent reductions in CO and BP after 4 h of LAB inflation in nonseptic group 3, ICBF rose during hypercarbia by 61.8 +/- 23.2%, not significantly different from baseline, but significantly different from the decrease in % delta ICBF in groups 1 and 2. We conclude that STREP infusion reduces ICBF and cerebral vascular reactivity to acute hypercarbia in piglets. This phenomenon is not accounted for by STREP-induced reduction in CO or BP, and is not mediated by prostanoids.


Selection of affinity-improved neutralizing human scFv against HBV PreS1 from CDR3 VH/VL mutant library.
A CDR3 mutant library was constructed from a previously isolated anti-HBV neutralizing Homo sapiens scFv-31 template by random mutant primers PCR. Then the library was displayed on the inner membrane surface in Escherichia coli periplasmic space. Seven scFv clones were isolated from the mutant library through three rounds of screening by flow cytometry. Competition ELISA assay indicates that isolated scFv fragments show more efficient binding ability to HBV PreS1 compared with parental scFv-31. HBV neutralization assay indicated that two clones (scFv-3 and 59) show higher neutralizing activity by blocking the HBV infection to Chang liver cells. Our method provides a new strategy for rapid screening of mutant antibody library for affinity-enhanced scFv clones and the neutralizing scFvs obtained from this study provide a potential alternative of Hepatitis B immune globulin.


In-fibre particle manipulation and device assembly via laser induced thermocapillary convection.
The ability to manipulate in-fibre particles is of technological and scientific significance, yet particle manipulation inside solid environment remains fundamentally challenging. Here we show an accurately controlled, non-contact, size- and material-independent method for manipulating in-fibre particles based on laser-induced thermocapillary convection. The laser liquefaction process transforms the fibre from a solid media into an ideal fluid environment and triggers the in-fibre thermocapillary convection. In-fibre particles, with diameter from submicron to hundreds of microns, can be migrated toward the designated position. The number of particles being migrated, the particle migration velocity and direction can be precisely controlled. As a proof-of-concept, the laser-induced flow currents lead to the migration-to-contact of dislocated in-fibre p- and n-type semiconductor particles and the forming of dual-particle p-n homo- and heterojunction directly in a fibre. This approach not only enables in-fibre device assembly to achieve multi-component fibre devices, but also provide fundamental insight for in-solid particle manipulation.


Development of a combined pretreatment and hydrolysis strategy of rice straw for the production of bioethanol and biopolymer.
The present study highlights the development of a combined pretreatment and hydrolysis strategy of rice straw for the production of bioethanol and biopolymer (poly-3-hydroxybutyrate). Maximum reducing sugar yield was 0.374g/g. The hydrolyzate is devoid of major fermentation inhibitors like furfural and organic acids and can be used for fermentation without any detoxification. Fermentation of the non-detoxified hydrolyzate with Saccharomyces cerevisiae yielded 1.48% of ethanol with a fermentation efficiency of 61.25% and with Comamonas sp. yielded 35.86% of poly-3-hydroxybutyrate without any nutrient supplementation. Characterization of native, control as well as the residue left out after combined pretreatment and hydrolysis of RS by scanning electron microscopy and X-ray diffraction showed difference. Compositional analysis revealed that the residue contains lignin and hemicellulose as the major component indicating that major portion of cellulose were hydrolyzed in this strategy.


A glucogalactomanan polysaccharide isolated from Agaricus bisporus causes an inflammatory response via the ERK/MAPK and IκB/NFκB pathways in macrophages.
In the present study, a glucogalactomanan polysaccharide isolated from Agaricus bisporus named as TJ3 was investigated its immunomodulatory effects and molecular mechanisms in RAW 264.7 cells. Functional analysis showed TJ3 could inhibit the proliferation of RAW 264.7 cells in a certain concentration range. Moreover, TJ3 treatment increased the expression of inducible nitric oxide synthase (iNOS), which was responsible for increasing nitric oxide (NO) production. TJ3 also increased the expression of cyclooxygenase-2 (COX-2) and the mRNA levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and COX-2 in RAW 264.7 cells. In addition, further elucidation of molecular mechanisms showed that ERK/MAPK and IκB/NFκB pathways were activated by TJ3 treatment via increased phosphorylation levels of ERK1/2 and IκB-α, respectively. These findings indicated that TJ3 had a huge promising immunostimulatory activity and its induced immune responses probably through stimulating the ERK/MAPK and IκB/NFκB pathways. Our results demonstrate that TJ3 may be used as a potent immune modulator.


Cardiotrophin-1 requires LIFRbeta to promote survival of mouse motoneurons purified by a novel technique.
The cytokines ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) signal through a receptor complex formed between two transmembrane proteins, gp130 and LIFRbeta. In addition, CNTF also uses a ligand-binding component which is anchored to the cell membrane. In the case of cardiotrophin-1 (CT-1), LIFRbeta is also required in cardiomyocytes, but this has not been proven in neurons, and published data suggest that motoneurons may use a different receptor complex. We used Lifrbeta knockout mice to assess the requirement for this receptor component in the signal transduction of CT-1 in motoneurons. To study purified motoneurons from such mutants, we have developed a method allowing for isolation of highly purified mouse motoneurons. This protocol is based on the immunoaffinity purification of motoneurons using antibodies against the extracellular domain of the neurotrophin receptor, p75, followed by cell sorting using magnetic microbeads. We show that CNTF, LIF, and CT-1 are unable to promote the survival of motoneurons derived from homozygous Lifrbeta-/- mutant embryos. Thus, LIFRbeta is absolutely required to transduce the CT-1 survival signal in motoneurons.


Dysbiosis and reduced small intestinal function are required to induce intestinal insufficiency in mice.
Extensive bowel resection can lead to short bowel syndrome and intestinal failure. Resection-induced dysbiosis may be related to the specific anatomic site of resection and influences the disease progression. Although patients with end-jejunostomy are at high risk for intestinal failure, preservation of the ileocecal valve and colon counteracts this risk. The present study investigated the role of the cecum in maintaining microbial homeostasis after different types of small bowel resection. Male C57BL6/J mice were anesthetized by intraperitoneal injection of ketamine-xylazine and received extended ileocecal resection (extended ICR), limited ileocecal resection (limited ICR), or mid-small bowel resection (SBR). Stool samples were collected before surgery and between postoperative days 2-7, for 16S rRNA gene sequencing. Only extended ICR, but neither limited ICR nor SBR, induced intestinal insufficiency. α-Diversity was reduced in both ICR variants but not after SBR. All resections resulted in an increase in Proteobacteria. Pathobionts, such as Clostridia, Shigella, and Enterococcus, increased after SBR while Muribaculaceae, Lactobacillus, and Lachnospiraceae decreased. Limited ICR resulted in an increase of members of the Clostridium sensu stricto group, Terrisporobacter and Enterococcus and a decrease of Muribaculaceae. The increase of Enterococcus was even more pronounced after extended ICR while Muribaculaceae and Akkermansia were dramatically reduced. Both ICR variants caused a decrease in steroid biosynthesis and glycosaminoglycan degradation-associated pathways, suggesting altered bile acid transformation and mucus utilization.NEW & NOTEWORTHY Resection-induced dysbiosis affects disease progression in patients with short bowel syndrome. Severe dysbiosis occurs after removal of the ileocecal valve, even in the absence of short bowel conditions, and is associated with the loss of Muribaculaceae and Akkermansia and an increase of Clostridium and Enterococcus. The preservation of the cecum should be considered in surgical therapy, and dysbiosis should be targeted based on its specific anatomical signature to improve postoperative bacterial colonization.


Amplified DNA with limited homology to myc cellular oncogene is shared by human neuroblastoma cell lines and a neuroblastoma tumour.
Amplified cellular genes in mammalian cells frequently manifest themselves as double minute chromosomes (DMs) and homogeneously staining regions of chromosomes (HSRs). With few exceptions both karyotypic abnormalities appear to be confined to tumour cells. All vertebrates possess a set of cellular genes homologous to the transforming genes of RNA tumour viruses, and there is circumstantial evidence that these cellular oncogenes are involved in tumorigenesis. We have recently shown that DMs and HSRs in cells of the mouse adrenocortical tumour Y1 and an HSR in the human colon carcinoma COLO320 contain amplified copies of the cellular oncogenes c-Ki-ras and c-myc, respectively. Both DMs and HSRs are found with remarkable frequency in cells of human neuroblastomas. We show here that a DNA domain detectable by partial homology to the myc oncogene is amplified up to 140-fold in cell lines derived from different human neuroblastomas and in a neuroblastoma tumour, but not in other tumour cells showing cytological evidence for gene amplification. By in situ hybridization we found that HSRs are the chromosomal sites of the amplified DNA. The frequency with which this amplification appears in cells from neuroblastomas and its apparent specificity raise the possibility that one or more of the genes contained within the amplified domain contribute to tumorigenesis.


Airway pressures during crying in healthy infants.
Maximal inspiratory and expiratory airway pressures (PI max and PE max) were measured in 100 healthy infants (51 males, 49 females; age range, 0.06-3.76 years) by occluding the airway with a suitable face mask during a crying effort. Mean values +/- SD for PI max and PE max were 118 +/- 21 cm H2O and 125 +/- 35 cm H2O, respectively. Maximal inspiratory pressure was independent of age, sex, and anthropometrics, while maximal expiratory pressure showed a low but statistically significant positive correlation with body weight (P less than 0.001).


Competing against COVID-19: what about the mental health problems of athletes with disabilities?
Although there is growing interest in athletes' mental health (MH), there is a paucity of research exploring MH in athletes with disabilities (AWD). The purpose of this study was to evaluate the impact of the COVID-19 pandemic on the psychological state of AWD. An online survey including demographic questions, SARS-CoV-2-related questions, and standardized scales assessing depression, anxiety, stress, coronavirus anxiety (CAS), and nonspecific psychological distress was distributed to AWD. A total of 362 athletes (183 AWD) participated in the study (response rate 31.2%). AWD infected with SARS-CoV-2 reported higher depression, anxiety, and CAS scores than AWD not infected with SARS-CoV-2 (Z = -2.10, ES = 0.15 Z = -3.45, ES = 0.25; Z = -2.43, ES = 0.18; respectively). Female AWD reported higher anxiety scores compared to males (Z = -2.25, ES = 0.16). Depression (Z = -2.80, ES = 0.20), stress (Z = -2.12, ES = 0.15) and K-10 (Z = -2.02, ES = 0.14 scores of individual sport AWD were higher than team sports AWD. MH problems in AWD were associated with a wide range of variables such as being infected with SARS-CoV-2, female gender, competing in an individual sport, and having performance concerns. In light of these results, MH assessment should be undertaken for AWD to ensure appropriate and timely intervention.


Quantifying the association and dissociation rates of unlabelled antagonists at the muscarinic M3 receptor.
Slow receptor dissociation kinetics has been implicated in the long clinical duration of action of the muscarinic receptor antagonist tiotropium. However, despite the potential benefits of new drugs with slow dissociation kinetics, the rate parameters of new compounds are seldom measured due to technical difficulties and financial implications associated with radiolabeling multiple ligands. Here we describe the development and optimisation of a medium throughput assay which is capable of measuring the kinetic parameters of novel, unlabelled compounds. Radioligand binding studies were performed with membranes derived from CHO cells recombinantly expressing the human M(3) muscarinic receptor.Initial characterisation of the radioligand [(3)H]-NMS yielded on and off rates of 4.1+/-0.2 x 10(8) M(-1) min(-1) and 0.015+/-0.0005 min(-1), respectively. The specific binding of [(3)H]-NMS was measured over time in the presence and absence of several concentrations of unlabelled competitor compounds. These data were analysed using a competition kinetic model to provide on and off rates for the unlabelled competitor. Comparison of the kinetically derived Kd (k(off)/k(on)) with K(i) values generated at equilibrium showed an excellent correlation (r(2)=0.99), providing good validation of the method. The on and off rates were also used in theoretical computer simulations to successfully predict the effect of incubation time on apparent IC(50) values. This study demonstrates that a medium-throughput competition kinetic binding assay can be used to determine accurate on and off rates of unlabelled compounds, providing the opportunity to optimise for kinetic parameters early in the drug discovery process.


3-Carboxy-pyrazolinalanine as a new scaffold for developing potent and selective NMDA receptor antagonists.
A synthetic method for the preparation of suitably protected 3-carboxy-Δ2-pyrazolin-5-yl-alanine was developed. This scaffold is amenable to further decoration at the N1 position and was used to generate novel NMDA receptor ligands. Although weaker than the previously reported N1-Ph derivatives, the new ligands retain the ability to selectively bind to NMDA receptor with micromolar to submicromolar affinity. Considering the relevance of the N-functionalization for the biological activity, the results presented in this communication are preliminary to a full SAR study of this novel class of NMDA receptor antagonists.


Heavy metals accumulation in soil after 4 years of continuous land application of swine manure: A field-scale monitoring and modeling estimation.
Land application of animal manure has been encouraged widely in China. This presents a risk of heavy metals (HMs) accumulation in the soil due to their high contents in the feeds and additives. A 4-year field-scale study was conducted to monitor and estimate HMs accumulation in the soil with land application of swine manure. The results show a clear tendency for As, Hg, Cr, Cu, Zn and Mn to increase gradually with the application duration, yielding an average annual increase of 0.57, 0.011, 6.20, 5.64, 22.58, and 23.45 mg kg-1, respectively, at the annual application rate of about 250 t ha-1 of swine manure. The estimation from the mass balance modeling indicates the environmental risk of Cd, Cu and Zn will exceed the threshold levels for agricultural soils in China in the next 10-50 years. Determination of a suitable application rate of animal manure would be the first consideration for mitigating the environmental risk of HMs currently.


Transcriptomic responses of the endangered freshwater mussel Margaritifera margaritifera to trace metal contamination in the Dronne River, France.
The freshwater pearl mussel Margaritifera margaritifera is one of the most threatened freshwater bivalves worldwide. In this study, we aimed (i) to study the processes by which water quality might affect freshwater mussels in situ and (ii) to provide insights into the ecotoxicological significance of water pollution to natural populations in order to provide necessary information to enhance conservation strategies. M. margaritifera specimens were sampled in two close sites located upstream or downstream from an illegal dumping site. The renal transcriptome of these animals was assembled and gene transcription determined by RNA-seq. Correlations between transcription levels of each single transcript and the bioaccumulation of nine trace metals, age (estimated by sclerochronology), and condition index were determined in order to identify genes likely to respond to a specific factor. Amongst the studied metals, Cr, Zn, Cd, and Ni were the main factors correlated with transcription levels, with effects on translation, apoptosis, immune response, response to stimulus, and transport pathways. However, the main factor explaining changes in gene transcription appeared to be the age of individuals with a negative correlation with the transcription of retrotransposon-related genes. To investigate this effect further, mussels were classified into three age classes. In young, middle-aged and old animals, transcription levels were mainly explained by Cu, Zn and age, respectively. This suggests differences in the molecular responses of this species to metals during its lifetime that must be better assessed in future ecotoxicology studies.


Receptors for substance P. I. The pharmacological preparations.
The undecapeptide substance P (SP) is both a potent stimulant of intestinal (guinea pig ileum), vascular venous (rabbit mesenteric vein) and tracheal (guinea pig trachea) smooth muscles, and a relaxant of large arteries (dog common carotid artery, rabbit aorta). SP also decreases the peripheral vascular resistance in the coronary vessels of rabbit isolated hearts. The contractions of the guinea pig ileum in response to SP are partially antagonised by atropine and significantly depressed by indomethacin, while the contractions of the guinea pig trachea are strongly potentiated by indomethacin. Large arteries, but not the veins, are insensitive to SP when the endothelium is removed, and slightly less responsive to the peptide when this is applied in the presence of mepacrine, eicosatetraynoid acid or BW 755C. These results indicate that all myotropic actions of SP, except that on venous smooth muscle, are partially or completely indirect and most of them are due to the release of endogenous agents: these are acetylcholine, prostaglandins and possibly histamine in the guinea pig ileum, prostaglandins and possibly a leukotriene in the guinea pig trachea and a still unidentified factor of endothelial origin in dog and rabbit large arteries. The effect of substance P on the rabbit isolated anterior mesenteric vein appears to be a direct one.


Kidney biopsy findings in two patients with TAFRO syndrome: case presentations and review of the literature.
TAFRO syndrome is a clinical subtype of idiopathic multicentric Castleman disease (iMCD) that is characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis (or renal dysfunction), and organomegaly. TAFRO syndrome has only recently been described, and many clinicians are unaware of this disease, leading to delays in diagnosis and treatment. We present two patients with TAFRO syndrome in whom renal biopsies were performed. Both patients had subacute onset and exhibited renal insufficiency, edema, anemia, thrombocytopenia, polyserositis and lymphadenopathy over the disease course. However, there were many differences in their clinical manifestations. Case 1 was a 30-year-old woman admitted due to intermittent vaginal bleeding for 3 weeks. Laboratory tests on admission showed severe renal insufficiency (creatinine: 624 μmol/L), severe anemia (Hb: 41 g/L), and moderate thrombocytopenia (61 × 109/L). Case 2 was a 42-year-old man. Acute epigastric pain was his initial complaint, and computed tomography (CT) revealed retroperitoneal exudation around the pancreas. He was diagnosed with acute pancreatitis, and after treatment with a proton pump inhibitor (PPI) and somatostatin, his abdominal pain still recurred. During treatment, renal failure gradually increased, with oliguria, fever, anemia, thrombocytopenia, edema and massive ascites. Lymph node histologies were consistent with the hyaline-vascular (HV) type and mixed type, respectively, and renal histopathologies were consistent with thrombotic microangiopathy (TMA)-like renal lesions and membranoproliferative glomerulonephritis (MPGN), respectively. Their general conditions improved after glucocorticoid therapy, but their renal functions did not recover completely. On the basis of glucocorticoids, second-line treatments with tocilizumab and rituximab, respectively, were applied. The diagnosis of TAFRO syndrome is based mainly on clinical manifestations and lymph node biopsies. A reliable early diagnosis and appropriate rapid treatment are essential to improve patient outcomes. Clinicians should deepen their understanding of this disease and similar conditions. Once the disease is suspected, lymph node biopsies should be performed as soon as possible. In addition, renal biopsies should be actively performed in patients with renal involvement.


[Moderate or severe aquired valvular heart disease in pregnancy--what does determine the management? Experence, intuition or guidelines?].
Epidemiology of acquired valvular heart diseases has changed significantly over last decades. Degenerative aortic valve stenosis is the most common acquired valvular disease with high prevalence in elderly population. Another common disorder is ischemic mitral regurgitation secondary to myocardial infarction. Both above-mentioned heart disorders are not typical for women in reproductive age. Rheumatic heart valve disease has become infrequent in Polish population. Mitral stenosis, the most prevalent of rheumatic valvular disorders, affects 5% of pregnant women with heart disease and rheumatic aortic stenosis is responsible for 0.5-3% of heart diseases in this population. Despite the fact that acquired valvular disorders are becoming less common among pregnant women, they still remain an important issue and their management should be well known. Discussion about pregnancy should be a part of management of young women with valvular heart disease. Severe valve disorders should be corrected when planning pregnancy. The final management should always be based on collaborative decision made by the patient and health professionals.


[Solitary fibrous tumor of the abdomen. A rare neoplasm of vascular origin].
Solitary fibrous tumor (formerly known as hemangiopericytoma) is a rare soft tissue neoplasm, most frequently arising from the retroperitoneum and lower extremities. We present two cases of retroperitoneal solitary fibrous tumors diagnosed after surgical removal. We provide a literature review showing the basic clinical, pathologic and therapeutic features of these tumors.


Pyridinyl imidazoles inhibit IL-1 and TNF production at the protein level.
The mechanism by which SK&F 86002 and other pyridinyl imidazoles inhibit the production of IL-1 and TNF from LPS-stimulated human monocytes was examined. Inhibition of IL-1 and TNF production was found to depend on the time of addition of SK&F 86002, with diminishing effect when added more than 2 h after LPS stimulation. Analysis of Western blots confirmed that both intracellular IL-1 beta and extracellular TNF were significantly reduced in response to SK&F 86002, but these reductions were not paralleled by changes in IL-1 and TNF mRNA. 35S methionine pulse and pulse-chase studies on IL-1 biosynthesis suggest that significant inhibition by SK&F 86002 and related compounds occurs at the translational level.


Deadly encounter: ubiquitin meets apoptosis.
The ubiquitin/proteasome pathway is the main non-lysosomal route for intracellular protein degradation in eukaryotes. It is instrumental to various cellular processes, such as cell-cycle progression, transcription and antigen processing. Recent findings also substantiate a pivotal role of the ubiquitin/proteasome pathway in the regulation of apoptosis. Regulatory molecules that are involved in programmed cell death have been identified as substrates of the proteasome. Moreover, key regulators of apoptosis themselves seem to have an active part in the proteolytic inactivation of death executors.


The exosome-circ_0001359 derived from cigarette smoke exposed-prostate stromal cells promotes epithelial cells collagen deposition and primary ciliogenesis.
Cigarettes consumption is continued to be popular. We found that cigarette smoke (CS) exposure promoted prostatic fibrosis. In this study, human prostate epithelial RWPE-1 cells were co-cultured with exosomes derived from CS exposed-WPMY-1 cells (CS-WPMY-1-exo). The collagen deposition, primary ciliogenesis, epithelial-mesenchymal transition (EMT) and transforming growth factor (TGF)-β1 level of RWPE-1 were evaluated. The circRNAs profiles of WPMY-1-exo were explored by high-throughput RNA sequencing. It was found that CS-WPMY-1-exo significantly promoted RWPE-1 collagen deposition, EMT and primary ciliogenesis. There were 17 differentially expressed (DE) circRNAs (including circ_0001359) between CS-WPMY-1-exo and the negative control. Functional enrichment analyses showed that the DE circRNAs played important roles in ciliary basal body, spindle microtubule and TGF-β signaling pathway. Circ_0001359 siRNA attenuated CS-WPMY-1 induced RWPE-1 cells collagen deposition, EMT and primary ciliogenesis, as well as inhibited the level of TGF-β1. The whole results showed that circ_0001359 derived from CS-WPMY-1-exo contributed to prostatic fibrosis via stimulating epithelial cells phenotypes changes and collagen deposition.


E2F and histone deacetylase mediate transforming growth factor beta repression of cdc25A during keratinocyte cell cycle arrest.
cdc25A is a tyrosine phosphatase that activates G1 cyclin-dependent kinases (Cdk's). In human keratinocytes, cdc25A expression is down-regulated after the initial drop in Cdk activity caused by cell exposure to the antimitogenic cytokine transforming growth factor beta (TGF-beta) or removal of serum factors. Here we show that the TGF-beta-inhibitory-response element in the cdc25A promoter maps to an E2F site at nucleotides -62 to -55 from the transcription start site. This site is not required for basal transcription in keratinocytes. We provide evidence that the cell cycle arrest program activated by TGF-beta in human keratinocytes includes the generation of E2F4-p130 complexes that in association with histone deacetylase HDAC1 inhibit the activity of the cdc25A promoter from this repressor E2F site. This mechanism is part of a program that places keratinocytes in the quiescent state following the initial drop in Cdk activity caused by cell exposure to TGF-beta.