Role of the IgG4-related cholangitis autoantigen annexin A11 in cholangiocyte protection.
Annexin A11 was identified as autoantigen in IgG4-related cholangitis (IRC), a B-cell driven disease. Annexin A11 modulates calcium-dependent exocytosis, a crucial mechanism for insertion of proteins into their target membranes. Human cholangiocytes form an apical 'biliary bicarbonate umbrella' regarded as defense against harmful hydrophobic bile acid influx. The bicarbonate secretory machinery comprises the chloride/bicarbonate exchanger AE2 and the chloride channel ANO1. We aimed to investigate the expression and function of annexin A11 in human cholangiocytes and a potential role of IgG1/IgG4-mediated autoreactivity against annexin A11 in the pathogenesis of IRC. Expression of annexin A11 in human liver was studied by immunohistochemistry and immunofluorescence. In human control and ANXA11 knockdown H69 cholangiocytes, intracellular pH, AE2 and ANO1 surface expression, and bile acid influx were examined using ratio microspectrofluorometry, cell surface biotinylation, and 22,23-3H-glycochenodeoxycholic acid permeation, respectively. The localization of annexin A11-mEmerald and ANO1-mCherry was investigated by live-cell microscopy in H69 cholangiocytes after incubation with IRC patient serum containing anti-annexin A11 IgG1/IgG4-autoantibodies or disease control serum. Annexin A11 was strongly expressed in human cholangiocytes, but not hepatocytes. Knockdown of ANXA11 led to reduced plasma membrane expression of ANO1, but not AE2, alkalization of intracellular pH and uncontrolled bile acid influx. High intracellular calcium conditions led to annexin A11 membrane shift and colocalization with ANO1. Incubation with IRC patient serum inhibited annexin A11 membrane shift and reduced ANO1 surface expression. Cholangiocellular annexin A11 mediates apical membrane abundance of the chloride channel ANO1, thereby supporting biliary bicarbonate secretion. Insertion is inhibited by IRC patient serum containing anti-annexin A11 IgG1/IgG4-autoantibodies. Anti-annexin A11 autoantibodies may contribute to the pathogenesis of IRC by weakening the 'biliary bicarbonate umbrella'. We previously identified annexin A11 as a specific autoantigen in immunoglobulin G4-related cholangitis (IRC), a B-cell driven disease affecting the bile ducts. Human cholangiocytes are protected against harmful hydrophobic bile acid influx by a defense mechanism referred to as the 'biliary bicarbonate umbrella'. We found that annexin A11 is required for the formation of a robust bicarbonate umbrella. Binding of patient-derived annexin A11 autoantibodies inhibits annexin A11 function, possibly contributing to bile duct damage by weakening the biliary bicarbonate umbrella in patients with IRC.


A review of methods for modeling microplastic transport in the marine environments.
Microplastic (MP) pollution is ubiquitous in the oceans and poses serious threats to the marine ecosystems. Nowadays numerical modeling has become one of the widely used tools for monitoring and predicting the transport and fate of MP in marine environments. Despite the growing body of research on numerical modeling of marine MP, the advantages and disadvantages of various modeling methods have not received systematic evaluation in published works. Important aspects such as parameterization schemes for MP behaviors, factors influencing MP transport, and proper configuration in beaching are essential for guiding researchers to choose proper methods in their work. For this purpose, we comprehensively reviewed the current knowledge on factors influencing MP transport, classified modeling approaches according to the governing equations, and summarized up-to-date parameterization schemes for MP behaviors. Critical factors such as vertical velocity, biofouling, degradation, fragmentation, beaching, and washing-off were reviewed in the frame of MP transport processes.


Control of pain through epidural block and incidence of cardiac dysrhythmias in postoperative period of thoracic and major abdominal surgical procedures: a comparative study.
Upper abdomen and thorax surgeries cause intense pain. Some of postoperative pain main complications are cardiocirculatory complications. The objective of this study was to test the hypothesis that postoperative analgesia with employment of local anesthetics plus spinal opioids may reduce the incidence of cardiovascular complications in postoperative period of patients in these conditions, comparing with classical methods of postoperative analgesia, opioids and NSAIDs, administered upon patient's demand. Eighty adult patients, ASA I and II, without ECG alterations, were allocated into two groups of 40: Group A, patients under general anesthesia with propofol, cisatracurium and isoflurane, associated with epidural anesthesia with catheter and control of postoperative analgesia with bupivacaine and epidural morphine; and Group B, patients under general anesthesia with the same drugs and doses of A, plus postoperative analgesia carried out with NSAIDs and intravenous morphine at the end of surgery and in regular intervals. In both groups Holter was applied for 24 hours. Pain evaluation was carried out through visual analog scale. In pain evaluation, an evident predominance of 0 score (p<0.001) was observed in Group A and there was also reduction of blood pressure levels in postoperative period in a more accentuated way. Ventricular and supraventricular dysrhythmias were five times more frequent in Group B (p=0.00001), in which a tendency to a higher frequency of ventricular extrasystoles in age>50 years (22.2% versus 0.0%. p=0.26) was also detected. No significative difference of heart rate among groups (p>0.05) was observed. The best quality of analgesia in postoperative period, carried out in Group A, reduced the incidence of cardiovascular complications.


Close association between basal cell layer antibodies and hepatitis B virus-associated chronic delta infection.
Antibodies reacting in immunofluorescence with the basal cell layer of rat forestomach (BCLA) have been detected in 36 of 121 (30%) hepatitis B virus (HBV)-mediated chronic liver disease (CLD), in 1 of 30 (3%) HBV-negative CLD, in 3 of 36 (8%) alcoholic liver disease (with no correlation with serum HBV markers), in 1 of 25 (4%) primary biliary cirrhosis, in none of 19 HBV-related HBsAg-negative CLD and 60 healthy blood donors. Of 352 hospitalized patients with miscellaneous diseases (including immunological conditions), the antibodies were found in four (1%). In the 36 BCLA positive cases from HBV-mediated CLD, evidence of chronic delta infection was found in 34. The overall prevalence of BCLA in 68 delta cases was 50% (58% in chronic active hepatitis, 46% in cirrhosis), and in 28 delta negative cases was 4% (p less than 0.00002). BCLA of delta cases were mainly of the IgG class (38 of 41 sera), and high titers (up to 40,960) were found in the majority (66% greater than or equal to 1:640). The high titer BCLA has to be considered a marker of chronic delta infection in HBV cases.


The effects of gallic/ferulic/caffeic acids on colour intensification and anthocyanin stability.
The mechanism by which copigments stabilize colour, by protecting anthocyanin chromophores from nucleophilic attack, seems well accepted. This study was to determine effects of gallic/ferulic/caffeic acids on colour intensification and anthocyanin stability. Molecular dynamics simulations were applied to explore molecular interactions. Phenolic acids intensified the colour by 19%∼27%. Colour fading during heating followed first-order reactions with half-lives of 3.66, 9.64, 3.50, and 3.39h, whereas anthocyanin degradation, determined by the pH differential method (or HPLC-PDA), followed second-order reactions with half-lives of 3.29 (3.40), 3.43 (3.39), 2.29 (0.39), and 2.72 (0.32)h alone or with gallic/ferulic/caffeic acids, respectively, suggesting that anthocyanin degradation was faster than the colour fading. The strongest protection of gallic acids might be attributed to the shortest distance (4.37Å) of its aromatic ring to the anthocyanin (AC) panel. Hyperchromic effects induced by phenolic acids were pronounced and they obscured the accelerated anthocyanin degradation due to self-association interruption.


Dramatic verrucae confined to the lower lip.
A 16-year-old boy presented with a 3-year history of development of small papules on his lower lip.


Hispanic Subgroups, Acculturation, and Substance Abuse Treatment Outcomes.
This study explored Hispanic subgroup differences in substance use treatment outcomes, and the relationship of acculturation characteristics to these outcomes. Data were from a multisite randomized clinical trial of motivational enhancement therapy versus treatment as usual in a sample of Spanish-speaking substance abusers. Participants were Cuban American (n=34), Mexican American (n=209), Puerto Rican (n=78), and other Hispanic American (n=54). Results suggested that Cuban Americans and individuals with more connection to Hispanic culture had lower treatment retention. Hispanics born in the U.S and those who spoke English at home had a lower percentage of days abstinent during weeks 5-16, although Puerto Ricans born in the U.S. and Cuban Americans living more years in the U.S. had a higher percentage of days abstinent in weeks 1-4 and 5-16, respectively. Results may inform future hypothesis-driven studies in larger Hispanic treatment seeking samples of the relationship between acculturation and treatment outcome.


Bolbostemma paniculatum (Maxim.) Franquet extract suppresses the development of colorectal cancer through downregulation of PI3K/Akt pathway.
Bolbostemma paniculatum (Maxim.) Franquet (BPF), a kind of Chinese medicine, has been traditionally used in treating mastitis, dysentery, phlegm nuclear, and sore swelling poison. In current study, we tried to investigate the possible anti-colorectal cancer (CRC) effects of BPF. The effects of BPF extract on human colon cancer cells HCT-116 and SW-620, and a colitis associated colorectal cancer (CACC) mouse model were evaluated using the method of experimental pharmacology combined with network pharmacology. The ethyl acetate extract 3 (EA3) of BPF showed the most potent growth inhibitory effect in CRC cells. It could inhibit the clone formation, induce the apoptosis and cell cycle arrest in G1 phase as well as suppress the invasion and migration of CRC cells. And EA3 prevented ICR mice against CACC effectively. Both KEGG and GO analysis indicated that EA3 may inhibit CRC through influencing PI3K/Akt pathway. Results of Western blot analysis and ELISA confirmed that the molecules in the pathway were affected by EA3. These results demonstrate that EA3 from BPF could suppress the development of CRC through inhibiting the activity of PI3K/Akt pathway.


1-Methyl-2-nitrosoimidazole: cytotoxic and glutathione depleting capabilities.
We tested 1-methyl-2-nitrosoimidazole (INO), the two electron reduction product of 1-methyl-2-nitroimidazole (INO2) for its in vitro cytotoxicity and glutathione (GSH) depleting capabilities. The half life of INO was shown to be dependent on cell concentration above 10(5) cells/ml, decreasing with increasing cell concentration up to 2 X 10(6) cells/ml. For a 10-fold decrease in cell concentration, from 10(6) to 10(5) cells/ml, the toxicity curve shifted 10-fold towards lower concentrations. At 10(6) cells/ml, INO depleted GSH, in the range of concentrations where toxicity was observed, down to a plateau of 15% of the control level at a concentration of 100 microM INO. Oxidized glutathione (GSSG) levels were not elevated significantly above control cultures at this concentration. INO2, 1000 microM, did not deplete GSH under similar exposure conditions while 2-hydroxylamino-1-methylimidazole (INHOH) depleted GSH minimally at this same concentration. The nitroso intermediate may play a central role in the toxicity and GSH depleting capabilities of 2-nitroimidazoles in mammalian cells.


In vivo arteriolar dilation in response to parathyroid hormone fragments.
The in vivo responsiveness of small arterioles to the topical administration of two parathyroid hormone fragments was investigated using television microscopy. Male Sprague-Dawley rats were anesthetized with sodium pentobarbital (50 mg/kg) and second- and third-order arterioles in the cremaster muscle were exposed to increasing concentrations (2 X 10(-5) to 6 X 10(-4) mg/ml) of either hPTH (1-34) or bPTH-(3-34). Second- and third-order arterioles within the cremaster dilated (183% and 281% of control, respectively) following exposure to PTH-(1-34) in bath concentration of 10(-4) mg/ml and above. The dilation associated with PTH administration was abolished in second-order and greatly attenuated for third-order arterioles when the first two amino acid residues of the PTH molecule were removed (PTH (3-34) fragment). Inhibition of endogenous prostaglandins synthesis with mefenamic acid did not attenuate the vasodilator response to PTH. However, exposure to the muscarinic blocking agent atropine (10(-7) g/ml) totally inhibited the dilator response to PTH-(1-34). These data suggest that PTH induces arteriolar dilation by stimulation of muscarinic receptors in the vasculature possibly by causing the release of endogenous acetylcholine.


Special Issue: From Host-Pathogen Interaction to Host-Directed Therapies.
Despite the enormous progress made in the last few decades, infectious diseases still represent a huge challenge to human society and health systems, as evidenced by the recent SARS-CoV-2 pandemic [...].


Aminoflavone-loaded EGFR-targeted unimolecular micelle nanoparticles exhibit anti-cancer effects in triple negative breast cancer.
Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer for which there is no available targeted therapy. TNBC cases contribute disproportionately to breast cancer-related mortality, thus the need for novel and effective therapeutic methods is urgent. We have previously shown that a National Cancer Institute (NCI) investigational drug aminoflavone (AF) exhibits strong growth inhibitory effects in TNBC cells. However, in vivo pulmonary toxicity resulted in withdrawal or termination of several human clinical trials for AF. Herein we report the in vivo efficacy of a nanoformulation of AF that enhances the therapeutic index of AF in TNBC. We engineered a unique unimolecular micelle nanoparticle (NP) loaded with AF and conjugated with GE11, a 12 amino acid peptide targeting epidermal growth factor receptor (EGFR), since EGFR amplification is frequently observed in TNBC tumors. These unimolecular micelles possessed excellent stability and preferentially released drug payload at endosomal pH levels rather than blood pH levels. Use of the GE11 targeting peptide resulted in enhanced cellular uptake and strong growth inhibitory effects in TNBC cells. Further, AF-loaded, GE11-conjugated (targeted) unimolecular micelle NPs significantly inhibit orthotopic TNBC tumor growth in a xenograft model, compared to treatment with AF-loaded, GE11-lacking (non-targeted) unimolecular micelle NPs or free AF. Interestingly, the animals treated with AF-loaded, targeted NPs had the highest plasma and tumor level of AF among different treatment groups yet exhibited no increase in plasma aspartate aminotransferase (AST) activity level or observable tissue damage at the time of sacrifice. Together, these results highlight AF-loaded, EGFR-targeted unimolecular micelle NPs as an effective therapeutic option for EGFR-overexpressing TNBC.


Strain-retardant coherent perovskite phase stabilized Ni-rich cathode.
The use of state-of-the-art Ni-rich layered oxides (LiNixCoyMn1-x-yO2, x > 0.5) as the cathode material for lithium-ion batteries can push the energy and power density to a higher level than is currently available1,2. However, volume variation associated with anisotropic lattice strain and stress that is being developed during lithium (de)intercalation induces severe structural instability and electrochemical decay of the cathode materials, which is amplified further when the battery is operating at a high voltage (above 4.5 V), which is essential for unlocking its high energy3-6. Even after much effort by the research community, an intrinsic strain-retardant method for directly alleviating the continuous accumulation of lattice strain remains elusive. Here, by introducing a coherent perovskite phase into the layered structure functioning as a 'rivet', we significantly mitigate the pernicious structural evolutions by a pinning effect. The lattice strain evolution in every single cycle is markedly reduced by nearly 70% when compared with conventional materials, which significantly enhances morphological integrity leading to a notable improvement in battery cyclability. This strain-retardant approach broadens the perspective for lattice engineering to release the strain raised from lithium (de)intercalation and paves the way for the development of high-energy-density cathodes with long durability.


Prevention of Bone Cement Displacement in Kümmell Disease without Neurological Deficits through Treatment with a Novel Hollow Pedicle Screw Combined with Kyphoplasty.
Displacement of bone cement following percutaneous vertebral augmentation for Kümmell disease (KD) presents a significant concern, resulting in increasing back pain and compromising daily activities. Unfortunately, current literature does not yet establish a validated and minimally invasive surgical intervention for this issue. This study aims to investigate the effects of a novel hollow pedicle screw combined with kyphoplasty (HPS-KP) in preventing bone cement displacement following simply percutaneous kyphoplasty for the management of KD. A total of 22 patients (six males, 16 females, averagely aged 77.18 ± 7.63 years) with KD without neurological deficits treated by HPS-KP at the hospital between March 2021 and June 2022 were hereby selected, among which, there were three stage I KD cases, 12 stage II KD cases, and seven stage III KD cases according to Li's classification. Bone mineral density (BMD), spinal X-ray, computed tomography (CT), and magnetic resonance imaging (MRI) were examined before the operation. The operation time, intraoperative blood loss, and postoperative complications were all recorded. The follow-up focused on visual analog scale (VAS) score, Oswestry dysfunction index (ODI), anterior vertebral height (AVH), middle vertebral height (MVH), posterior vertebral height (PVH), wedge-shape affected vertebral Cobb angle (WCA), and bisegmental Cobb angle (BCA). One-way analysis of variance (ANOVA) followed by Bonferroni post-hoc test was employed for performing multiple comparisons in the present study. All patients having received the operation successfully were followed up for more than 8 months (ranging from 8 to 18 months). The operation time, intraoperative blood loss, and BMD (T-score) were 39.09 ± 5.64 min, 14.09 ± 3.98 ml, and - 3.30 ± 0.90 g/cm3 , respectively. Statistically significant differences were observed in the VAS score, ODI, AVH, MVH, and WCA (All p < 0.05), but there was no statistically significant difference in PVH and BCA at different time points (All p > 0.05). During follow-up, five patients suffered from bone cement leakage, and one presented an adjacent vertebral fracture and no bone cement displacement. HPS-KP could be safe and effective in the treatment of KD without neurological deficits, effectively relieving the symptoms of patients, restoring partial vertebral height, and preventing the occurrence of bone cement displacement.


Incorporation of impacted morselized bone allografts in rabbits.
Morselized bone allografts have been used for the treatment of bone stock loss in orthopedic revision surgery with encouraging results. However, several parameters can influence the graft incorporation including the processing treatments. This experimental work used a cavitary bone defect in 90 rabbits to evaluate the sequence of incorporation of three different kinds of morselized bone allografts: uncryopreserved cancellous bone, freeze-dried cancellous bone, and totally demineralized cortical bone each of which were prepared in accordance with our rigid protocol. Revascularization and remodeling of the transplanted bone grafts were evident upon histological evaluation. Bone apposition and bone resorption resulted in a mixture of graft and new bone. Mineralized cancellous grafts showed great osteoconductive capacity, whereas demineralized cortical grafts showed an intense osteoinductive capacity and a weak osteoconductive capacity. In a general evaluation, cryopreserved cancellous bone grafts showed superior biological efficacy for reconstruction of experimental bone defects, closely followed by freeze-dried cancellous bone grafts, and, finally, by demineralized cortical bone grafts. These results validate our protocol for the processing and preservation of these three kinds of bone grafts.


A personal 35 year perspective on Gilles de la Tourette syndrome: assessment, investigations, and management.
After having examined the definition, clinical phenomenology, comorbidity, psychopathology, and phenotypes in the first paper of this Series, here I discuss the assessment, including neuropsychology, and the effects of Gilles de la Tourette syndrome with studies showing that the quality of life of patients with Tourette's syndrome is reduced and that there is a substantial burden on the family. In this paper, I review my local and collaborative studies investigating causal factors (including genetic vulnerability, prenatal and perinatal difficulties, and neuro-immunological factors). I also present my studies on neuro-imaging, electro-encephalograms, and other special investigations, which are helpful in their own right or to exclude other conditions. Finally, I also review our studies on treatment including medications, transcranial magnetic stimulation, biofeedback, target-specific botulinum toxin injections, biofeedback and, in severe refractory adults, psychosurgery and deep brain stimulation. This Review summarises and highlights selected main findings from my clinic (initially The National Hospital for Neurology and Neurosurgery Queen Square and University College London, UK, and, subsequently, at St George's Hospital, London, UK), and several collaborations since 1980. As in Part 1 of this Series, I address the main controversies in the fields and the research of other groups, and I make suggestions for future research.


Recycling of flap pedicle in complex lower extremity reconstruction: A proof of free muscle flap neovascularization.
This article portrays the authors' clinical experience of a complex case of lower extremity reconstruction using a recycled pedicle from 10 years old free latissimus dorsi musculocutaneous flap to supply a new free anterolateral thigh flap for proximal tibia wound defect reconstruction. It provides clinical evidence that muscle neovascularization occurs and supports the dogma peripheral tissue neovascularization. This case stipulates that recycling of pedicle is feasible, when used with appropriate strategy and safety and also provides evidence for the long-term survival of greater saphenous vein grafts in lower extremity reconstruction.


Multislice CT for assessing in-stent dimensions after left main coronary artery stenting: a comparison with three dimensional intravascular ultrasound.
To evaluate the agreement between multislice CT (MSCT) and intravascular ultrasound (IVUS) to assess the in-stent lumen diameters and lumen areas of left main coronary artery (LMCA) stents. Prospective, observational single centre study. A single tertiary referral centre. Consecutive patients with LMCA stenting excluding patients with atrial fibrillation and chronic renal failure. MSCT and IVUS imaging at 9-12 months follow-up were performed for all patients. Agreement between MSCT and IVUS minimum luminal area (MLA) and minimum luminal diameter (MLD). A receiver operating characteristic (ROC) curve was plotted to find the MSCT cut-off point to diagnose binary restenosis equivalent to 6 mm(2) by IVUS. 52 patients were analysed. Passing-Bablok regression analysis obtained a β coefficient of 0.786 (0.586 to 1.071) for MLA and 1.250 (0.936 to 1.667) for MLD, ruling out proportional bias. The α coefficient was -3.588 (-8.686 to -0.178) for MLA and -1.713 (-3.583 to -0.257) for MLD, indicating an underestimation trend of MSCT. The ROC curve identified an MLA ≤ 4.7 mm(2) as the best threshold to assess in-stent restenosis by MSCT. Agreement between MSCT and IVUS to assess in-stent MLA and MLD for LMCA stenting is good. An MLA of 4.7 mm(2) by MSCT is the best threshold to assess binary restenosis. MSCT imaging can be considered in selected patients to assess LMCA in-stent restenosis.


Dietary Cadmium Chloride Supplementation Impairs Renal Function and Bone Metabolism of Laying Hens.
This study was conducted to evaluate the toxic effects of cadmium (Cd) on the kidney function and bone development in laying hens. A total of 480 Hy-line laying hens aged 38 weeks were randomly allocated into five treatments, each of which included six replicates of 16 birds. The concentrations of Cd in the diets of the five groups were 0.47, 7.58, 15.56, 30.55, and 60.67 mg/kg. Results showed that serum calcium (Ca) levels decreased significantly in the 60.67 mg Cd/kg diet group (p < 0.05). The activities of serum alkaline phosphatase (ALP) and bone ALP (BALP) decreased significantly in the 15.56, 30.55 and 60.67 mg Cd/kg diet groups (p < 0.05). The levels of parathyroid hormone (PTH) increased significantly in the 30.55 and 60.67 mg Cd/kg diet groups, and the estradiol (E2), 1,25-(OH)2-D3 and calcitonin (CT) decreased significantly with the increase of dietary Cd supplementation (p < 0.05). Histological results presented enlargements of renal tubules and tubular fibrosis in the kidney and decreased trabecular bone in the tibia. Tartrate-resistant acidic phosphatase (TRAP) staining results of tibia showed that osteoclast was significantly increased at the relatively high dose of dietary Cd (p < 0.05). In addition, the renal function indicators of blood urea nitrogen (BUN), urea acid (UA), and creatinine were significantly increased in Cd supplemented groups compared with the control group (p < 0.05). Low dose Cd exposure induced antioxidant defenses accompanying the increase in activities of catalase (CAT), glutathione peroxidase (GSH-Px), and the levels of glutathione (GSH) in renal tissue. At the same time, with the increased Cd levels, the activities of CAT, GSH-Px decreased significantly, and the level of malondialdehyde (MDA) increased significantly (p < 0.05). The activities of Na+/K+-ATPase and Ca2+/Mg2+-ATPase decreased significantly in the relatively high levels of dietary Cd (p < 0.05). These results suggest that Cd can damage renal function and induce disorders in bone metabolism of laying hens.


A histomorphometric study of alveolar bone modeling and remodeling under experimental anaemia and polycythaemia in rats.
Alveolar bone is the least stable of the periodontal tissues, because it is subjected to continuous modeling and remodeling. To perform a histological and histomorphometric evaluation of bone modeling and remodeling of periodontal alveolar bone under experimental anaemia and polycythaemia. Thirty Wistar rats were divided into three groups: control (C), animals were i.p. injected with 0.5 mL of saline solution; anaemia (A), animals were injected with 6 mg/100 b.w. of phenylhydrazine every 48 h; polycythaemia (P), animals were transfused with 2.5 mL/100 b.w. of 80% suspension of homologous erythrocytes. All the animals were sacrificed 14 days after the onset of the experiment. The mandibles were resected, fixed in formalin, radiographed, processed and embedded in paraffin. Bucco-lingually oriented sections were obtained at the level of the mesial root of the first lower molar, and stained with hematoxylin-eosin. Histological and histomorphometric studies were performed on the buccal and lingual plates of periodontal alveolar bone. Histological and histomorphometric studies showed a statistically significant decrease in bone formation both in buccal and lingual plates in group A (anaemia) as compared to group C (control). An increase in active bone formation was found in the lingual plate in group P (polycythaemia) as compared to group C (control). The results obtained using this experimental model evidenced alterations in bone modeling and remodeling under conditions of anaemia and polycythaemia and/or associated factors.


Changes in the Receptor-Binding Properties of H3N2 Viruses during Long-Term Circulation in Humans.
It was previously shown that hemagglutinin residues Thr155, Glu158, and Ser228 are crucial for the recognition of Neu5Gc. In this study, we demonstrated that the ability to bind the Neu5Gc-terminated receptor is related to the amino acid 145: viruses of years 1972-1999 with Lys145 bind to the receptor, whereas viruses with Asn145 do not. Sporadic appearance and disappearance of the ability to bind Neu5Gc oligosaccharides and the absence of Neu5Gc in the composition of human glycoconjugates indicate the non-adaptive nature of this ability. It was previously shown that unlike H1N1 viruses, H3N2 viruses of years 1968-1989 did not distinguish between Neu5Acα2-6Galβ1-4Glc (6'SL) and Neu5Acα2-6Galβ1-4GlcNAc (6'SLN). H3N2 viruses isolated after 1993 have acquired the ability to distinguish between 6'SL and 6'SLN, similarly to H1N1 viruses. We found that the affinity for 6'SLN has gradually increased from 1992 to 2003. After 2003, the viruses lost the ability to bind a number of sialosides, including 6'SL, that were good receptors for earlier H3N2 viruses, and retained high affinity for 6'SLN only, which correlated with the acquisition of new glycosylation sites at positions 122, 133, and 144, as well as Glu190Asp and Gly225Asp substitutions, in hemagglutinin. These substitutions are also responsible for the receptor-binding phenotype of human H1N1 viruses. We conclude that the convergent evolution of the receptor specificity of the H1N1 and H3N2 viruses indicates that 6'SLN is the optimal natural human receptor for influenza viruses.


Role of mucosal IgA in the resistance to Acanthamoeba keratitis.
To determine whether oral immunization with Acanthamoeba castellanii antigens elicits mucosal antibodies of the IgA isotype and whether mucosal antibodies affect parasite adhesion to the corneal epithelium. Chinese hamsters were immunized with 100 microg aqueous Acanthamoeba antigen mixed with cholera toxin (Ac-CT) and subsequently challenged with parasite-laden contact lenses that were applied to abraded corneal surfaces. Tears and stool samples were examined for the presence of Acanthamoeba-specific IgA antibodies by enzyme-linked immunosorbent assay (ELISA). The effect of mucosal antibody on trophozoite binding to corneal epithelium and viability of trophozoites was examined in vitro. Hamsters immunized orally with Ac-CT showed significantly lower infection rates than did control groups (21.4% versus 72.6%). ELISA analysis of mucosal specimens showed the presence of parasite-specific IgA in stool samples and tears from hamsters orally immunized with Ac-CT, but not in control animals. In vitro assays showed that anti-Acanthamoeba IgA did not affect parasite viability. However, mucosal anti-Acanthamoeba IgA profoundly inhibited (>75%) the binding of parasites to corneal epithelial cells in vitro. Oral immunization with Ac-CT induces the production of parasite-specific IgA in mucosal secretions and prevents corneal infection. Mucosal antibody does not affect the viability of Acanthamoeba trophozoites but seems to prevent infection by inhibiting parasite binding to the corneal epithelium.


Task-induced deactivations during successful paired associates learning: an effect of age but not Alzheimer's disease.
Task-induced fMRI deactivations during successful encoding and retrieval of visuospatial paired associates were examined at different levels of task difficulty in younger and older adults (Experiment 1), and older adults with and without mild probable Alzheimer's disease (AD) (Experiment 2). Irrespective of the level of task difficulty, common deactivations (determined through the use of conjunction analyses) were observed in the lateral and medial prefrontal, anterior and posterior cingulate, and temporal brain regions and in the claustrum during both encoding and retrieval in younger and older adults (Experiment 1). In AD patients and healthy older adults, common deactivations were found in posterior cingulate, temporal, and lateral parietal regions and in the insula and claustrum during encoding and retrieval of paired associates (Experiment 2). As task difficulty increased, irrespective of the type of task, the magnitude of task-induced deactivations increased in the medial prefrontal/superior frontal gyrus and middle/posterior cingulate cortex in younger and older adults (Experiment 1), and in the middle cingulate cortex in older adults with and without AD (Experiment 2). In Experiment 1, greater deactivation was observed in the anterior cingulate gyrus in older compared to younger adults during retrieval of paired associates which was attributed to greater suppression of task-unrelated thoughts in the older group. No significant differences in task-induced deactivation, or in the type of relationship exhibited between deactivation and task difficulty, were observed between older adults with and without AD (Experiment 2). It was suggested that this was related to the matching of successful task performance and task difficulty across patient and control groups. Following previous proposals, task-induced deactivations were suggested to underlie a shifting of attentional focus from monitoring of the self and the environment (through attenuation of these activities) to external, goal-directed behaviour.


Efficient repair of DNA double strand breaks in individuals from high level natural radiation areas of Kerala coast, south-west India.
High level natural radiation areas (HLNRA) of Kerala coastal strip (55km long and 0.5km wide) in southwest India exhibit wide variations in the level of background dose (< 1.0-45.0mGy/year) due to thorium deposits in the beach sand. The areas with ≤1.5mGy/year are considered as normal level natural radiation area (NLNRA), whereas areas with >1.5mGy/year are HLNRA. Individuals belonging to HLNRA were stratified into two groups, Low dose group (LDG: 1.51-5.0mGy/year) and high dose group (HDG: >5.0mGy/year). The mean annual dose received by the individuals from NLNRA, LDG and HDG was 1.3±0.1, 2.7±0.9 and 9.4±2.3mGy/year, respectively. Induction and repair of DNA double strand breaks (DSBs) in terms of gamma-H2AX positive cells were analysed in peripheral blood mononuclear cells (PBMCs) using flow cytometry. Induction of DSBs was studied at low (0.25Gy) and high challenge doses (1.0 and 2.0Gy) of gamma radiation in 78 individuals {NLNRA, N=23; HLNRA (LDG, N=21 and HDG, N=34)}. Repair kinetics of DSBs were evaluated in PBMCs of 30 individuals belonging to NLNRA (N=8), LDG (N=7) and HDG (N=15) at low (0.25Gy) and high doses (2.0Gy) of gamma radiation. Transcription profile of DNA damage response (DDR) and DSB repair genes involved in non-homologous end joining (NHEJ) and homologous recombination repair (HRR) pathways was analysed after a challenge dose of 2.0Gy in PBMCs of NLNRA (N=10) and HDG, HLNRA (N=10) group. Our results revealed significantly lower induction and efficient repair of DSBs in HLNRA groups as compared to NLNRA. Transcription profile of DCLRE1C, XRCC4, NBS1 and CDK2 showed significant up-regulation (p≤0.05) in HDG at a challenge dose of 2.0Gy indicating active involvement of DDR and DSB repair pathways. In conclusion, lower induction and efficient repair of DNA DSBs in HLNRA groups is suggestive of an in vivo radio-adaptive response due to priming effect of chronic low dose radiation prevailing in this area.


The digestion of kiwifruit (Actinidia deliciosa) fibre and the effect of kiwifruit on the digestibility of other dietary nutrients.
The effect of dietary kiwifruit inclusion level on the digestibility of kiwifruit fibre and dietary nutrients was studied. Ileal cannulated pigs (50±1.9 kg) were fed a fibre-free diet for seven days (n=14) followed by kiwifruit-containing diets (133 or 266 g kiwifruit/kg dry matter) (n=7) for 44 days followed by the fibre-free diet (n=14) for seven days. Faecal and ileal samples were collected on days 5, 11, 21, 35, 49 and 56. The soluble kiwifruit fibre was highly digested in the foregut (80%), and the insoluble fibre in the hindgut (95%). Increasing the kiwifruit inclusion level decreased the apparent ileal and faecal digestibilities of several nutrients (P<0.05), including the faecal digestibility of insoluble kiwifruit fibre and led to higher ileal and faecal concentrations of short-chain fatty acids (P<0.05). The decreased digestibility was explained by the lower digestibility of kiwifruit itself. The duration of kiwifruit consumption per se did not affect dietary nutrient digestibility (P>0.05).


Recurrent abrupt occlusion after transluminal angioplasty for basilar artery stenosis: case report.
Angioplasty for basilar artery stenosis is often complicated by recurrent abrupt vessel closure. The clinical results can be catastrophic. In this case report, we assess the effects of intra-arterial papaverine (American Regent Laboratories Inc., Shirley, NJ) on rebound occlusion. The patient presented with crescendo transient ischemic attacks from atherosclerotic narrowing of the midbasilar artery despite maximal medical treatment. Angioplasty of the midbasilar artery was performed with serial balloon inflations. The patient was treated successfully with intra-arterial papaverine and achieved a nearly full recovery, with only mild dysarthria, by the time of the 7-month follow-up examination. Using intra-arterial papaverine, we were able to reverse the effects of this potentially life-threatening complication of basilar artery angioplasty.


Common Blood Test Indices for Predicting Transient Abnormal Myelopoiesis-Related Mortality in Infants with Down Syndrome.
Transient abnormal myelopoiesis (TAM) can cause early death in children with Down syndrome, and liver failure is the most common cause of death. The aim of this single-center retrospective study was to identify a quantitative index for predicting TAM-related mortality at the time of diagnosis. Of the 462 children with Down syndrome admitted to our hospital from 1992 to 2021, we studied 12 infants with TAM-related death and 31 survivors who were diagnosed with TAM. In the death and survival groups, the median gestational ages were 34.9 and 37.1 weeks, respectively (p = 0.12). At diagnosis, the white blood cell (WBC) counts were 99.2 and 36.2 × 109/L (p = 0.011), the hemoglobin concentrations were 131 and 159 g/L (p = 0.009), and the serum albumin concentrations were 23 and 31 g/L (p < 0.001), respectively. The areas under the receiver operating characteristic curve for the abilities of the WBC count, hemoglobin, and serum albumin at diagnosis to predict survival were 0.75, 0.76, and 0.85, respectively. The serum albumin concentration threshold of 28 g/L at diagnosis had sensitivity of 0.79 and specificity of 0.82. Gestational age and serum albumin concentration were entered into a logistic regression model. The serum albumin concentration was an independent indicator of TAM-related death (adjusted odds ratio, 0.78; 95% confidence interval, 0.65-0.93; p = 0.005). In conclusion, a low serum albumin concentration at diagnosis may be a good predictor of TAM-related death.


Synthesis and structure elucidation of some new thioether derivatives of 1,2,4-triazoline-3-thiones and their antimicrobial activities.
5-(4-Pyridinyl)-4-substituted-2.4-dihydro-3H-1,2,4-triazole-3-thiones and 5-(4-pyridinyl)-4-substituted-3-(benzoylmethyl)thio-4H-1,2,4-triazoles were synthesized. The structures of original nine compounds were confirmed by IR, 'H NMR, mass spectral methods and elemental analysis. The antibacterial, antifungal and antimycobacterial activities, together with those of known intermediate 1,4-disubstituted thiosemicarbazides, were reported.


Comparative study of the toxicity between three non-steroidal anti-inflammatory drugs and their UV/Na2S2O8 degradation products on Cyprinus carpio.
The efficiency of advanced oxidation processes (AOPs) for disposing of non-steroidal anti-inflammatory drugs (NSAIDs) has been widely studied, but the environmental fates and effects of the NSAIDs and their degradation products (DPs) are poorly understood. In this study, the efficiency of ultraviolet light/Na2S2O8 (UV/PS) in degrading three NSAIDs-diclofenac, naproxen, and ibuprofen-and the toxicity of their DPs on Cyprinus carpio (C. carpio) was investigated. Results showed that the three NSAIDs can be completely removed (removal rate > 99.9%) by UV/PS, while the mineralization rate of the NSAIDs was only 28%. When C. carpio were exposed to 0.1 μM NSAIDs, 10 μM persulfate (PS), and 0.1 μM DPs of the NSAIDs for 96 h, respectively, the toxicity effects are as the NSAID DPs > PS > NSAIDs. Research results into the time-dependent effect of NSAID DPs on C. carpio demonstrated that obvious toxicity effects were observed in the first 48 hours, and the toxicity effects strengthened over time. NSAID DPs may have more severe toxicity effects than NSAIDs on C. carpio; therefore, the operating conditions of UV/PS must be optimized to eliminate the ecotoxicity of DPs.


Targeting MerTK decreases efferocytosis and increases anti-tumor immune infiltrate in prostate cancer.
The prostate cancer tumor microenvironment (TME) is comprised of many cell types that can contribute to and influence tumor progression. Some of the most abundant prostate cancer TME cells are macrophages, which can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages). A function of M2-like macrophages is efferocytosis, the phagocytosis of apoptotic cells. Based on literature from other models and contexts, efferocytosis further supports the M2-like macrophage phenotype. MerTK is a receptor tyrosine kinase that mediates efferocytosis by binding phosphatidylserine on apoptotic cells. We hypothesize efferocytosis in the prostate cancer TME is a tumor-promoting function of macrophages and that targeting MerTK-mediated efferocytosis will slow prostate cancer growth and promote an anti-tumor immune infiltrate. The aims of this study are to measure efferocytosis of prostate cancer cells by in vitro human M1/M2 macrophage models and assess changes in the M2-like, pro-tumor macrophage phenotype following prostate cancer efferocytosis. Additionally, this study aims to demonstrate that targeting MerTK decreases prostate cancer efferocytosis and promotes an anti-tumor immune infiltrate. We have developed methodology using flow cytometry to quantify efferocytosis of human prostate cancer cells using the LNCaP cell line. We observed that M2 macrophages efferocytose the LNCaP cell line more than M1 macrophages. Following efferocytosis of LNCaP cells by M2 human monocyte-derived macrophages (HMDMs), we observed an increase in the M2-like, pro-tumor phenotype by flow cytometry cell surface marker analysis. By qRT-PCR, flow cytometry, and Western blot, we detected greater MerTK expression in M2 than M1 macrophages. Targeting MerTK with antibody Mer590 decreased LNCaP efferocytosis by M2 HMDMs, establishing the role of MerTK in prostate cancer efferocytosis. In the prostate cancer mouse model hi-myc, Mertk KO increased anti-tumor immune infiltrate including CD8 T cells. These findings support targeting MerTK-mediated efferocytosis as a novel therapy for prostate cancer.


Association of multiple air pollutants with oxygen saturation during sleep in COPD patients: Effect modification by smoking status and airway inflammatory phenotypes.
Air pollution contributes substantially to the development of chronic obstructive pulmonary disease (COPD). To date, the effect of air pollution on oxygen saturation (SpO2) during sleep and potential susceptibility factors remain unknown. In this longitudinal panel study, real-time SpO2 was monitored in 132 COPD patients, with 270 nights (1615 h) of sleep SpO2 recorded. Exhaled nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) were measured to assess airway inflammatory characteristics. Exposure levels of air pollutants were estimated by infiltration factor method. Generalized estimating equation was used to investigate the effect of air pollutants on sleep SpO2. Ozone, even at low levels (<60 μg/m3), was significantly associated with decreased SpO2 and extended time of oxygen desaturation (SpO2 < 90%), especially in the warm season. The associations of other pollutants with SpO2 were weak, but significant adverse effects of PM10 and SO2 were observed in the cold season. Notably, stronger effects of ozone were observed in current smokers. Consistently, smoking-related airway inflammation, characterized by higher levels of exhaled CO and H2S but lower NO, significantly augmented the effect of ozone on SpO2 during sleep. This study highlights the importance of ozone control in protecting sleep health in COPD patients.


Draft Genome Sequence of the Beer Spoilage Bacterium Megasphaera cerevisiae Strain PAT 1T.
The genus Megasphaera harbors important spoilage organisms that cause beer spoilage by producing off flavors, undesirable aroma, and turbidity. Megasphaera cerevisiae is mainly found in nonpasteurized low-alcohol beer. In this study, we report the draft genome of the type strain of the genus, M. cerevisiae strain PAT 1(T).


Inhibition of platelet aggregation by unsaturated fatty acids through interference with a thromboxane-mediated process.
cis- and trans-unsaturated fatty acids with 18 carbon atoms (oleic, linoleic, elaidic and linolelaidic acid) inhibited aggregation of washed rabbit platelets stimulated with collagen, arachidonic acid and U46619 when in the same concentration ranges. Thrombin-induced aggregation was not affected by any of them. Saturated fatty acid (stearic acid) had no effect on this response. The inhibition is independent of the induced change in membrane fluidity, since trans-isomers could not induce the change in fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene. Unsaturated fatty acids, except linoleic acid, did not interfere with the formation of thromboxane B2 from exogenously added arachidonic acid. All the unsaturated fatty acids only slightly inhibited the arachidonic acid liberation by phospholipase A2 in platelet lysate. This indicates that the unsaturated fatty acids may block a process after formation of thromboxane A2 in response to collagen and arachidonic acid. The increase in phosphatidic acid formation stimulated with U46619 was inhibited dose dependently by each of the unsaturated fatty acids but that stimulated with thrombin was not affected by any of them. Phospholipase C activity measured by diacylglycerol formation in unstimulated platelet lysate was not inhibited by the fatty acids. The elevation of cytosolic free Ca2+ induced by arachidonic acid or U46619 and Ca2+ influx by collagen were inhibited almost completely at the same concentration as that which inhibited their aggregation. These data suggest that the unsaturated fatty acids were intercalated into the membrane and inhibited collagen- and arachidonic acid-induced platelet aggregation by causing a significant suppression of the thromboxane A2-mediated increase in cytosolic free Ca2+, probably due to interference with the receptor-operated Ca2+ channel.


Clinical neurochemistry of autism and associated disorders.
Advances in information concerning brain function in animals and advances in analytical neurochemical methods for determining extremely low levels of compounds in physiological fluids have opened great opportunities for clinical neurochemical studies of autism. Nevertheless, the behavioral deficits in autistic individuals are major obstacles to clarification of the relations between symptoms and biochemical dysfunction in the brain. The fundamental preclinical and clinical studies of serotonin, dopamine, and norepinephrine metabolism related to infantile autism are reviewed, and new studies are suggested as examples of the productive strategies that will illuminate features of the autistic syndrome in the next decade.


Prevalence, characterization, and antimicrobial resistance of Listeria monocytogenes isolates from bovine hides and carcasses.
Listeria monocytogenes isolates from bovine hides and carcasses (n = 812) were mainly of serogroup 1/2a. All strains were positive for internalin genes. Several isolates were resistant to oxacillin (72.2%) or clindamycin (37.0%). These findings indicate that L. monocytogenes of beef origin can be considered a public health concern.


Neurological and endocrinological manifestations of 49 children with intracranial pure germinoma at initial diagnosis in Taiwan.
Intracranial pure germinoma is a rare extragonadal neoplasm. Affected patients may have motor impairment, visual disturbance, neurological signs, and endocrine disorder, depending on the size and location of the tumor. This study investigated and analyzed patients' demographic data and neuroimaging, clinical, laboratory, and endocrinological findings. We performed a retrospective chart review of 49 children diagnosed with pure germinoma in Taiwan from 1990 to 2018. The initial clinical presentation, tumor markers (beta-hCG, alpha fetoprotein, and carcinoembryonic antigen), pituitary function, and brain images were reviewed and analyzed. This study included 49 patients (37 boys and 12 girls). Their ages ranged from 7.5 to 17.9 years, and the mean age at diagnosis was 13.6 years. Initial symptoms included visual disturbance (n = 23, 47.9%), motor impairment (n = 20, 40.8%), polyuria (n = 20, 40.8%), headache (n = 17, 34.7%), dizziness or vertigo (n = 14, 28.6%), nausea/vomiting (n = 13, 26.5%), and short stature (n = 8, 18.2%). Laboratory data indicated growth hormone deficiency or low IGF-1 levels (n = 18, 85.7%), adrenal insufficiency (n = 21, 77.8%), central diabetes insipidus (n = 27, 55.1%), central hypothyroidism (n = 15, 48.4%), and hypogonadotropic hypogonadism (n = 4, 44.4%). Intracranial pure germinomas may initially manifest as neurological symptoms or endocrinological findings at diagnosis. As endocrinologic presentation is related to delayed diagnosis, clinicians should be aware of patients with such complaints. Laboratory data should be surveyed carefully, and neuroimaging must be considered if the result is abnormal.


Relationship of age and education to performance on a standardized version of Luria's neuropsychological tests in different patient populations.
A.R. Luria, a Russian neuropsychologist, developed many qualitative bedside tests that have been effective in the diagnosis and localization of neurological disorders. Recently, a standardized and objectively-scored version of Luria's tests has been developed. Knowledge of the effects of patient age and education on neuro-psychological test performance has been found crucial in the neurodiagnostic decision-making process. The present study examined the effects of patient age(younger subjects between 20 and 40 years and older subjects between 50 and 70 years of age), education (grade school, high school, and post-high school), and diagnosis (normal, schizophrenic, brain damaged) on 14 standardized Luria measures. A weighted means analysis of variance found 11 significant age effects, 14 significant educational effects, and 14 significant effects diagnosis. One significant interaction was found between education and diagnosis, the results support the contention that with appropriate age and educational corrections, the standardized Luria battery would satisfy the need for a short, objectively scored, and diagnostically effective neuropsychological battery.


The expressive rationality of inaccurate perceptions.
This commentary uses the dynamic of identity-protective cognition to pose a friendly challenge to Jussim (2012). Like other forms of information processing, this one is too readily characterized as a bias. It is no mistake, however, to view identity-protective cognition as generating inaccurate perceptions. The "bounded rationality" paradigm incorrectly equates rationality with forming accurate beliefs. But so does Jussim's critique.


Solvent-Free Esterification of Carboxylic Acids Using Supported Iron Oxide Nanoparticles as an Efficient and Recoverable Catalyst.
Supported iron oxide nanoparticles on mesoporous materials (FeNP@SBA-15) have been successfully utilized in the esterification of a variety carboxylic acids including aromatic, aliphatic, and long-chain carboxylic acids under convenient reaction conditions. The supported catalyst could be easily recovered after reaction completion and reused several times without any loss in activity after up to 10 runs.


Risk factors for reluxation after toggle rod stabilization for treatment of coxofemoral luxation in 128 dogs.
Evaluate the risk factors for reluxation and outcomes for dogs with a toggle rod construct. Retrospective case series. One hundred twenty-eight client-owned dogs. Medical records from 2007 to 2018 were reviewed for signalment, history, surgery, and outcome for dogs with a coxofemoral luxation repaired with a commercial toggle rod and nylon monofilament suture construct. Univariate and multiple logistics regression analysis were performed to assess risk factors associated with postoperative luxation. Primary veterinarians and owners were contacted for follow-up via telephone or electronic communication. The overall complication rate was 24.2%, and the reluxation rate was 14.8%. There was a decreased risk of reluxation when the cause was traumatic in origin (odds ratio [OR] 0.10) or when the lameness was severe at presentation (OR 0.42). Fifteen of 58 (25.9%) owners contacted completed a follow-up survey. Dogs with nontraumatic, low impact luxations were at a higher risk for reluxation. Dogs of any body condition with a traumatic coxofemoral luxation are at lowest risk for reluxation.


Mapping of proton relaxation near superparamagnetic iron oxide particle-loaded polymer threads for magnetic susceptibility difference quantification.
Conventional radiological methods, including magnetic resonance imaging (MRI), fail to visualize polymeric surgical mesh implants because of small thread dimensions and material characteristics. For MRI delineation of such meshes, superparamagnetic iron oxide particles (SPIOs) are integrated in the mesh polymer. Usually, if SPIOs are used as an intravenous contrast agent, they increase the R1 and R2 of adjacent protons. It can be assumed that embedding SPIOs in polymers alters their molecular dynamics. The aim of this study was to investigate the influence of SPIO integration in polymer on the relaxation of adjacent protons. Polymer threads were placed in an agarose phantom. At 1.5 T, R1, R2, and R2* maps were calculated from multi inversion-recovery spin echo, multi-spin echo, and multi-gradient echo images, respectively. The threads were aligned parallel or orthogonal to B(0). No impact of SPIO on proton R1 and R2 was observed. R2* was increased by the SPIO-loaded threads. R1 and R2 amplitude maps showed a magnetic susceptibility difference of 0.97 ppm/(mg SPIO/g polymer) around SPIO-loaded threads. In contrast to SPIO in aqueous solutions, polymer-embedded SPIO do not affect proton R1 and R2. However, embedded SPIO generate strong local static magnetic field gradients. Thus, SPIO integration is suitable to control the magnetic susceptibility of polymer threads. This can be exploited to visualize implanted polymer-based meshes in MRI using R2* susceptible sequences. Because no impact on R1 and R2 of adjacent protons by SPIO embedded in mesh threads was observed, structures adjacent to implanted meshes will be observable in R1 and R2 maps.


Anti-cancer drug diffusion within living rat brain tissue: an experimental study using [3H](6)-5-fluorouracil-loaded PLGA microspheres.
This study was performed (i) to monitor the diffusion of the anti-cancer drug 5-fluorouracil (5-FU) and (ii) to elucidate the fate of poly(lactide-co-glycolide) (PLGA) based microspheres within living rat brain tissue upon intracranial implantation. Drug-loaded microparticles were prepared using a solvent emulsion/extraction process and administered into healthy and C6 glioma-bearing Sprague-Dawley rats. The same surgical procedure was carried out with magnetite-loaded microspheres. To monitor 5-FU diffusion from the implantation site, tissue combustion was performed on animals implanted with tritiated drug microspheres. T2-weighted nuclear magnetic resonance imaging was undertaken on animals implanted with magnetite-loaded microspheres to determine microsphere localization after deposit. Results show that an important microparticle backflow occurs in healthy rats, whereas the microspheres remain at the site of administration in C6 glioma-bearing rats. Drug diffusion is limited to the vicinity of the implantation site.


Human dirofilariosis in Hungary: an emerging zoonosis in central Europe.
In the temperate regions of Europe, mainly Italy, France, Greece, and in recent years Hungary, a specific filarioid worm, Dirofilaria (Nochtiella) repens, a parasite of dogs, cats and some other carnivores, transmitted by mosquitoes, has occasionally been contracted, causing dirofilariosis in humans. We report a case of dirofilariosis and review all previously observed cases in Hungary. The authors present a case of human subconjunctival dirofilariosis in a 56-year-old man with mild itching and a burning sensation in his right eye. A slow-moving, whitish, thread-like worm was detected by slit-lamp examination. The worm was surgically removed and parasitological examination identified it as an immature male Dirofilaria repens. A review of Hungarian cases from 1880 to 2000 is presented, with updates of earlier reports. In addition, 16 new cases (8 men; 8 women) diagnosed between 2001 and 2006 are reviewed. The mean age of these 16 patients was 60 years; eight cases had ocular localization, seven were subcutaneous and one was diagnosed in a histopathological section of removed axillary lymph node in a patient with lymphoid leukemia. Twelve of the 16 identified Dirofilariae were females, four were males. According to their recorded histories the patients had not traveled internationally. Most of the above cases of dirofilariosis are certainly autochthonous infections. The increasing number of diagnosed cases suggests that this zoonosis is becoming more important in central Europe and that the incidence may increase with the improvement of clinical diagnosis.


Neurodevelopmental assessment of very low birth weight neonates: effect of germinal matrix and intraventricular hemorrhage.
During a recent 36-month interval, all neonates of less than or equal to 1250 gram birth weight who were admitted to our Newborn Special Care Unit and survived the first 36 postnatal hours underwent either computed tomography or echoencephalography or both for the assessment of neonatal germinal matrix hemorrhage and intraventricular hemorrhage. Seventy of the 164 long-term surviving infants experienced neonatal germinal matrix and/or intraventricular hemorrhage (GMH/IVH Group), whereas 94 infants had studies that were negative (Non-hemorrhage Group). Serial neurodevelopmental assessments were performed on 142 (87%) of the 164 long-term surviving infants; these assessments included the Bayley Scales of Infant Development at 3, 6, 12, and 18 months (corrected age) and the Stanford-Binet and Peabody Picture Vocabulary examinations at 30 months (corrected age). At 30 months (corrected age), the incidence of major neurologic abnormalities was extremely low in both the GMH/IVH and the Non-hemorrhage groups. In addition, although there were few survivors of the more severe grades of intraventricular hemorrhage, we could detect no difference between the developmental scores of the GMH/IVH and the Non-hemorrhage Group infants.


Improving outcomes for amputees: The health-related quality of life and cost utility analysis of osseointegration prosthetics in transfemoral amputees.
Some amputees are unable to adequately ambulate using conventional socket prosthetics, osseointegrated prosthetics have been described as an alternative strategy in this patient group. This paper aims to assess the effect of osseointegrated prosthetics, commonly simply referred to as osseointegration, in transfemoral amputees on health-related quality of life and cost analysis. Two centre analysis of patients receiving transcutaneous femoral osseointegration using The Osseointegration Group of Australia Osseointegration Prosthetic Limb (OGAP-OPL) implant. Retrospective health utility and cost analysis of prospectively collected patient reported health outcome data. Osseointegration cost was compared with the yearly cost of a poorly fitting conventional prosthetic determining cost/Quality Adjusted Life Year. Eighty amputees received osseointegration. Mean age was 39 years (range 20-57) and 66% were male (n = 53). The majority of subjects underwent unilateral (n = 62, 77.5%) rather than bilateral surgery (n = 18, 22.5%). Trauma was the most common indication (n = 59, 74%). Maximum follow up was 10.5-years. Mean preoperative EQ5D HUV in pooled data was 0.64 (SEM 0.025) increasing to 0.73 (0.036) at 5-years and 0.78 (0.051) at 6 years with continued improvement up to 10.5-years. In subgroup analysis those with a starting EQ5D HUV <0.60 reached a cost/QALY of <£30,000 at 5-years postoperatively and show statistically significant improvement in EQ5D HUV. The UK military experience was wholly positive with a mean starting EQ5D HUV of 0.48 (0.017) with significant (p < 0.05) improvement in EQ5D HUV at each time point and a resultant reducing cost/QALY at each time point being £28,616.89 at 5 years. There is both a quality of life and financial argument in favour of osseointegration in select patients with above transfemoral amputations. In those unable to mobilise satisfactorily with traditional prostheses and a pre-intervention score of <0.60, a consistent cost effectiveness and quality of life benefit can be seen. Such patients should be considered for osseointegration as these patients reap the maximum benefit and cost effectiveness of the device. This evidence lends strongly to the debate advocating the use of osseointegration through centrally funded resources, including the NHS.


Enteric neural crest-derived cells promote their migration by modifying their microenvironment through tenascin-C production.
The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells that migrate, proliferate, and differentiate into enteric neurons and glia within the gut wall. The mechanisms regulating enteric neural crest-derived cell (ENCC) migration are poorly characterized despite the importance of this process in gut formation and function. Characterization of genes involved in ENCC migration is essential to understand ENS development and could provide targets for treatment of human ENS disorders. We identified the extracellular matrix glycoprotein tenascin-C (TNC) as an important regulator of ENCC development. We find TNC dynamically expressed during avian gut development. It is absent from the cecal region just prior to ENCC arrival, but becomes strongly expressed around ENCCs as they enter the ceca and hindgut. In aganglionic hindguts, TNC expression is strong throughout the outer mesenchyme, but is absent from the submucosal region, supporting the presence of both ENCC-dependent and independent expression within the gut wall. Using rat-chick coelomic grafts, neural tube cultures, and gut explants, we show that ENCCs produce TNC and that this ECM protein promotes their migration. Interestingly, only vagal neural crest-derived ENCCs express TNC, whereas sacral neural crest-derived cells do not. These results demonstrate that vagal crest-derived ENCCs actively modify their microenvironment through TNC expression and thereby help to regulate their own migration.


Elevated albuminuria associated with increased risk of recurrent venous thromboembolism: results of a population-based cohort study.
This study examined the risk of recurrent venous thromboembolism (VTE) in patients with elevated albuminuria. In 1997-1998, inhabitants of Groningen, the Netherlands, aged 28-75 years (n=85,421), were invited to participate in the PREVEND (Prevention of REnal and Vascular ENd stage Disease) Study, an observational, population-based cohort study. Albuminuria was measured and VTE occurrence was monitored in responding subjects (n=40,856). Patients with first VTE between study entry and January 2009, identified through databases of the national registry of hospital discharge diagnoses, death certificates, regional anticoagulation clinic and medical records, were used for analysis. Of 351 subjects with first VTE, 37 subjects developed a recurrence during a median follow-up period of 3.3 (interquartile range, 1.1-6.4) years. The annual incidence of recurrence in subjects with elevated albuminuria (≥ 20 mg/l) was 5.00% [95% confidence interval (CI); 2.16-9.85], compared to 2.38% (95%CI; 1.59-3.41) in subjects with normal albuminuria (<20 mg/l). Hazard ratio for recurrence was 1.95 (95%CI; 0.89-4.30) after adjustment for age and sex. This hazard ratio was 3.35 (95%CI; 1.18-9.47) in patients with first unprovoked, and 1.12 (95%CI; 0.25-5.01) in those with a first provoked event. This study showed that subjects with elevated albuminuria who experience an unprovoked VTE are at an increased risk of recurrence, independent of age and sex.


Mutation screening for the prothrombin variant G20210A by melting point analysis with the Light Cycler system: atypical results, detection of the variant C20209T and possible clinical implications.
In the differential diagnosis of thrombophilic disorders genotyping of prothrombin and factor V are nowadays performed as a routine analysis. In the following we describe the unusual results of the mutation screening using melting point analysis for two patients and the consecutive detection of the mutation C20209T by sequencing the corresponding gene fragments. The molecular result is discussed with special respect to the medical history, ethnic background and clinical findings of both patients.


BNT162b2 vaccine effectiveness was marginally affected by the SARS-CoV-2 beta variant in fully vaccinated individuals.
To evaluate the effectiveness of the Pfizer BNT162b2 vaccine against the SARS-Cov-2 Beta variant. Israel's mass vaccination program, using two doses of the Pfizer BNT162b2 vaccine, successfully curtailed the Alpha variant outbreak during winter 2020-2021, However, the virus may mutate and partially evade the immune system. To monitor this, sequencing of selected positive swab samples of interest was initiated. Comparing vaccinated with unvaccinated PCR positive persons, we estimated the odds ratio for a vaccinated case to have the Beta vs. the Alpha variant, using logistic regression, controlling for important confounders. There were 19 cases of Beta variant (3.2%) among those vaccinated more than 14 days before the positive sample and 79 (3.4%) among the unvaccinated. The estimated odds ratio was 1.26 (95% CI: 0.65-2.46). Assuming the effectiveness against the Alpha variant to be 95%, the estimated effectiveness against the Beta variant was 94% (95% CI: 88%-98%). Despite concerns over the Beta variant, the BNT162b2 vaccine seemed to provide substantial immunity against both the Beta and the Alpha variants. From 14 days following the second vaccine dose, the effectiveness of BNT162b2 vaccine was at most marginally affected by the Beta variant.


Long-duration head down bed rest as an analog of microgravity: Effects on the static perception of upright.
Humans demonstrate many physiological changes in microgravity for which long-duration head down bed rest (HDBR) is a reliable analog. However, information on how HDBR affects sensory processing is lacking. We previously showed [25] that microgravity alters the weighting applied to visual cues in determining the perceptual upright (PU), an effect that lasts long after return. Does long-duration HDBR have comparable effects? We assessed static spatial orientation using the luminous line test (subjective visual vertical, SVV) and the oriented character recognition test (PU) before, during and after 21 days of 6° HDBR in 10 participants. Methods were essentially identical as previously used in orbit [25]. Overall, HDBR had no effect on the reliance on visual relative to body cues in determining the PU. However, when considering the three critical time points (pre-bed rest, end of bed rest, and 14 days post-bed rest) there was a significant decrease in reliance on visual relative to body cues, as found in microgravity. The ratio had an average time constant of 7.28 days and returned to pre-bed-rest levels within 14 days. The SVV was unaffected. We conclude that bed rest can be a useful analog for the study of the perception of static self-orientation during long-term exposure to microgravity. More detailed work on the precise time course of our effects is needed in both bed rest and microgravity conditions.


Plants alter their aboveground and belowground biomass allocation and affect community-level resistance in response to snow cover change in Central Asia, Northwest China.
It is important to elucidate the changing distribution pattern of net primary productivity (NPP) to mechanistically understand the changes in aboveground and belowground ecosystem functions. In water-scarce desert environments, snow provides a crucial supply of water for plant development and the spread of herbaceous species. Yet uncertainty persists regarding how herbaceous plants' NPP allocation responds to variation in snow cover. The goal of this study was to investigate how variation in snow cover in a temperate desert influenced the NPP allocation dynamics of herbaceous species and their resistance to environmental change in terms aboveground and belowground productivity. In the Gurbantunggut Desert, wintertime snow cover depth was adjusted in plots by applying four treatments: snow removal (-S), ambient snow, double snow (+S), and triple snow (+2S). We examined their species richness, aboveground NPP (ANPP), belowground NPP (BNPP), and the resistance of ANPP and BNPP. We found that species diversity of the aboveground community increased significantly with increasing snow cover and decreased significantly Pielou evenness in plots. This resulted in greater ANPP with increasing snow cover; meanwhile, BNPP first increased and then decreased with increasing snow cover. However, this productivity in different soil layers responded differently to changed snow cover. In the 0-10 cm soil layer, productivity first rose and then declined, while it declined linearly in both the 10-20 cm and 20-30 cm soil layers, whereas in the 30-40 cm soil layer it showed an increasing trend. Belowground resistance would increase given that greater snow cover improved the BNPP in deeper soil and maintained the resource provisioning for plant growth, thus improving overall belowground stability. These results can serve as a promising research foundation for future work on how the functioning of desert ecosystems becomes altered due to changes in plant community expansion and, in particular, changes in snow cover driven by global climate change.


Indian Child Welfare Act: ideas for implementation.
The Indian Child Welfare Act of 1978 was passed to curb the excessive rate of placement of Indian children in non-Indian foster and adoptive homes. Congress concluded that these placements were abusive because of their contribution to the identity confusion of the Indian children who had been placed as well as the disruption of tribal culture. This article includes recommendations about implementation of the Indian Child Welfare Act which are based on a survey of individuals involved in Indian child welfare as well as experiences of the author since completion of the survey in November of 1980. In general, the recommendations are: (1) Tribal and state agencies should make special efforts to coordinate services so that the unique difficulties faced by Indian families will be addressed; (2) Urban social service agencies should assign all Indian child welfare cases to one worker or a group of workers and cooperate with urban Indian associations in the transfer of Indian child welfare cases; (3) Social workers handling cases should be involved in all aspects of transfer and not leave the management strictly to attorneys; (4) Where the act is unclear, particularly in off-reservation emergency placements, the state agency must make the policy clear so that all workers understand how Indian children will be protected in emergencies; (5) In individual cases, as well as when negotiating agreements both tribal and state agencies should avoid compromising the rights of the parties involved or the principles of the act.


Assessment of the novel tubulin-binding agent EHT 6706 in combination with ionizing radiation or chemotherapy.
The potential of EHT 6706, a novel tubulin-binding agent, was investigated in combination with ionizing radiation (IR) and with conventional cytotoxic chemotherapy agents. Cell proliferation, cell cycle, apoptosis and clonogenic assays were performed in five human cancer cell lines: H460 (non small cell lung carcinoma, NSCLC), HCT116 and HCT116 p53-/- (colorectal cancer), MDA-MB-231 (breast cancer), and MiaPaca2 cells (pancreatic cancer). The drug inhibited cell proliferation in all cell lines. This effect was associated with G2/M arrest and activation of apoptosis in a dose-dependent manner. The drug was then tested in combination with chemotherapy and IR in vitro. Effects on proliferation and clonogenic survival were analyzed. EHT 6706 treatment inhibited clonogenic survival synergistically with IR in H460 and MiaPaca2 cell lines. In the remaining cell lines, the effects of EHT 6706 and IR were additive. For H460 and MiaPaca2 cell lines, the highest effect was seen when cells were exposed for 20 h to EHT 6706 before being irradiated. EHT 6706 also exerted additive inhibition of proliferation when given in combination with conventional chemotherapy agents, such as oxaliplatin, cisplatin and gemcitabine in H460 and MiaPaca2 tumor cell lines. These data show that EHT 6706 could act synergistically with IR and additively with chemotherapy in tumor cell lines in vitro. This provides a good rationale to further assess EHT 6706 in combination protocols and confirm these effects in vivo.


Assessment of 99mTc-MIBI SPECT(/CT) to monitor multidrug resistance-related proteins and apoptosis-related proteins in patients with ovarian cancer: a preliminary study.
Multidrug resistance (MDR) has been suggested to be a major cause of failure of chemotherapy treatment for cancer. It is associated with the expression of MDR-related and apoptosis-related proteins. Recently, technetium-99m hexakis 2-methoxyisobutylisonitrile ((99m)Tc-MIBI) has been suggested as a tumor-seeking agent for the detection of MDR. The aim of this study was to evaluate (99m)Tc-MIBI single-photon emission computed tomography (SPECT)(/CT) for functional imaging of MDR-related and apoptosis-related proteins in patients with ovarian cancer. Eleven women (mean age 63 years, range 53-76) with a clinical suspicion of ovarian cancer were prospectively studied. All patients were examined with (99m)Tc-MIBI imaging before surgery. After intravenous injection of 740 MBq (99m)Tc-MIBI, SPECT(/CT) imaging at 10 min and 2 h was performed. Based on the semiquantitative analysis of (99m)Tc-MIBI SPECT(/CT), both early and delayed tumor uptake ratios and washout rate % were calculated. The expression of MDR-related and apoptosis-related proteins was assessed in surgically excised tumors. Immunohistochemical staining was performed to quantify the expression levels of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein1 (MRP1), MRP3, lung resistance protein (LRP), breast cancer resistance protein (BCRP), Y-box-binding protein-1 (YB-1), Bcl-2, Bax and glutathione-S-transferase. (99m)Tc-MIBI imaging results and immunohistochemical results were compared. Laparotomy was performed in all patients. Six ovarian cancers were proven by histopathological examination. Five of the six ovarian cancers were positive for (99m)Tc-MIBI uptake on both early and delayed images with (99m)Tc-MIBI SPECT(/CT). MDR-related and apoptosis-related proteins were found to be expressed in all tumors. For the five positive (99m)Tc-MIBI uptake cases, the washout rate % of (99m)Tc-MIBI uptake showed a significant positive correlation with the expression of YB-1 (r = 0.988, P = 0.0015), and the early tumor uptake ratio showed a significant positive correlation with the expression of Bax (r = 0.882, P = 0.047). Our results suggested that (99m)Tc-MIBI SPECT(/CT) might be a valuable diagnostic imaging technique to evaluate MDR-associated YB-1 and Bax-mediated apoptosis in patients with ovarian cancer.


The Effect of Follitropin Alfa in Controlled Ovarian Stimulation Protocol for In Vitro Fertilization Cycles.
Follitropin alfa (FA) is one of the most widely used exogenous gonadotropins in both agonist and antagonist protocols for controlled ovarian stimulation (COS) and in vitro fertilization (IVF). However, reports of its effectiveness are limited, particularly in terms of its impact on overall IVF outcomes and ovarian hyperstimulation syndrome (OHSS). Therefore, in this study, FA competency was investigated by evaluating its effect on IVF outcomes and OHSS, administering agonist and antagonist COS protocols. A retrospective study with 120 subjects was conducted. Outcomes comprising the number of retrieved and fertilized oocytes, quality of embryos, and clinical pregnancies were assessed. Statistical correlation between FA dose, IVF outcomes, and the incidence of OHSS was also analyzed. All statistical analyses were performed at 95% confidence level. There was no significant difference in both protocols regarding retrieved oocytes (p=0.604), fertilized oocytes (p=0.761), embryo quality including good, average, poor embryo (p=0.875, p=0.565, p=0.785), and clinical pregnancy (p= 0.844). However, FA doses in the agonist protocol were shown notably higher (p= 0.001). Negative correlations were also observed between FA dose and the number of retrieved oocytes (r=-0.255, p<0.01), fertilized oocytes (r=-0.296, p<0.01), and good quality embryos (r=-0.231, p<0.05). Our study suggested that FA yields similar outcomes in both COS protocols, but agonist protocols require higher doses of FA and evaluation of its effect on OHSS is an important area of research for further investigation.


[Bacteriological diagnosis of anaerobic infections (author's transl)].
A review on anaerobic bacteria with special reference to their role in human disease and an outline for clinical laboratory practice (collection of the specimens, culture media, isolation, identification, antibiotic sensitivity tests) is presented.


18-Fluorodeoxyglucose positron emission tomography in the diagnosis of prosthetic aortic graft infection: the difference between open and endovascular repair.
18-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) has been reported as useful for diagnosing aortic graft infection. However, 18F-FDG uptake may depend upon various factors including open versus endovascular repair and time from surgery. We aimed to elucidate the factors influencing its uptake and the diagnostic value of 18F-FDG PET/CT after open and endovascular repair. Hospital database of PET/CT (N = 14 490) and our departmental database were cross-checked to identify those who underwent 18F-FDG PET/CT after aortic repair. Patient's data were retrieved from the chart. Images were reviewed by 2 nuclear medicine specialists in consensus, and the presence of increased 18F-FDG uptake was recorded. The maximum standardized uptake value (SUV max) was measured. Among the 1112 patients who underwent aortic repair between 2011 and 2022, 71 patients were identified. Eighteen patients underwent 18F-FDG PET/CT for suspected graft infection and the remaining 53 patients for other purposes (malignancy, etc.). Fourteen patients were treated as aortic graft infection. They had significantly higher SUV max than those without graft infection [mean 8.64 (standard deviation 2.78) vs 3.40 (standard deviation 0.84); P < 0.01]. In the non-infected grafts, SUV max was higher early after open surgical repair, while it remained low after endovascular repair. After endovascular aortic repair, a constant cut-off value of 'SUV max = 4.5' seems appropriate for diagnosing graft infection, since it remains low and stable from the early postoperative period. After open surgical repair, it seems acceptable to have 'stepwise cut-off value' depending on the time from surgery.


RAGE and CYBA polymorphisms are associated with microalbuminuria and end-stage renal disease onset in a cohort of type 1 diabetes mellitus patients over a 20-year follow-up.
We investigated the association of polymorphisms of three genes implicated in oxidative stress: CYBA C242T, RAGE -374T/A and -429T/C, and ALOX12 Arg261Gln, with the delay of microalbuminuria onset in patients with type 1 diabetes mellitus (DT1). A total of 162 T1D patients presenting with diabetes for 32.9 ± 9 years were included in the study; 53 had persistent microalbuminuria (>30 mg/l) and 109 did not. Onset of diabetes, microalbuminuria and end-stage renal disease (ESRD) were recorded as bio-clinical data. We determined polymorphism association of microalbuminuria with a Cox regression model. All polymorphisms respected the Hardy-Weinberg equilibrium. The Cox regression model validated four significant variables associated with microalbuminuria: RAGE 374AA (HR 4.19 [1.84-9.58] (p = 0.001)), CYBA TT+TC (HR 2.1 [1.16-3.80], p = 0.015), male sex (HR 1.92 [1.07-3.43], p = 0.028) and diabetes diagnosis at the pediatric stage (HR 1.85 [1.03-3.32], p = 0.039). The same association was found with ESRD (p = 0.028 and p = 0.033 for CYBA TC+TT and RAGE 374AA, respectively). CYBA C242T and RAGE 374T/A were not significantly associated with diabetic retinopathy. CYBA C242T and RAGE -374T/A correlate with microalbuminuria onset in the French DT1 cohort. The same correlation with ESRD onset supports the argument for the involvement of a genetic predisposition involving kidney-specific oxidative stress for diabetic nephropathy.


3D Scaffolded Nickel-Tin Li-Ion Anodes with Enhanced Cyclability.
A 3D mechanically stable scaffold is shown to accommodate the volume change of a high-specific-capacity nickel-tin nanocomposite during operation as a Li-ion battery anode. The nickel-tin anode is supported by an electrochemically inactive conductive scaffold with an engineered free volume and controlled characteristic dimensions, which engender the electrode with significantly improved cyclability.


[Non-fortuitous dynamin II mutation-related association: neutropenia and Charcot-Marie-Tooth disease].
Charcot-Marie-Tooth (CMT) disease or hereditary motor and sensory neuropathy is a genetically and clinically heterogeneous group of disorders of the peripheral nervous system. Mutations in multiple genes are currently known. We report an original case of CMT associated with chronic neutropenia in a patient with a K562del mutation in the dynamin 2 (DNM2) gene in a patient presenting with alterated cognitive function. Associated manifestations may guide molecular study.


The carcinogen cadmium elevates CpG-demethylation and enrichment of NFYA and E2F1 in the promoter of oncogenic PRMT5 and EZH2 methyltransferases resulting in their elevated expression in vitro.
Cadmium (Cd) is considered as a carcinogenic chemical with potential to endanger normal cellular functioning. The present study was aimed to investigate the impact of Cd on the expression of two oncogenic epigenetic regulators, viz., protein arginine methyltransferase 5 (PRMT5) and the polycomb repressive complex 2 (PRC2) member enhancer of Zeste homolog 2 (EZH2). Our results indicate that Cd at 1 μM concentration increases the viability of HepG2 and MCF7 cells and significantly upregulates the expression of PRMT5 and EZH2, leading to an increased global level of symmetric dimethylarginine (SDMA), H4R3me2s, and H3K27me3. The luciferase reporter assay showed that the promoter activity of PRMT5 and EZH2 is significantly enhanced in both cell lines. Furthermore, Cd exposure induces global DNA hypomethylation due to a decrease in DNA methyltransferases (DNMTs) expression. Methylation-specific and bisulfite sequencing PCR reveal that the proximal promoters of PRMT5 and EZH2, which harbour CpG islands, are almost demethylated when exposed to Cd. The Cd exposure also increases the protein level of transcription factors NFYA and E2F1; consistently, the two transcription factors are found to be enriched at the PRMT5 and EZH2 promoter in chromatin immunoprecipitation experiments. The alterations induced by Cd in the two cancer cell lines were also observed in a non-cancerous cell line (HEK-293). In conclusion, we propose that Cd increases the expression of two oncogenic methyltransferases, possibly with a DNA methylation-dependent mechanism. Further studies focused on the epigenetic alterations induced by Cd would provide mechanistic insights on the carcinogenicity of this metal toxicant at the molecular level.


Development and evaluation of a new methodology for the fast generation of patient-specific Finite Element models of the buttock for sitting-acquired deep tissue injury prevention.
The occurrence and management of Pressure Ulcers remain a major issue for patients with reduced mobility and neurosensory loss despite significant improvement in the prevention methods. These injuries are caused by biological cascades leading from a given mechanical loading state in tissues to irreversible tissue damage. Estimating the internal mechanical conditions within loaded soft tissues has the potential of improving the management and prevention of PU. Several Finite Element models of the buttock have therefore been proposed based on either MRI or CT-Scan data. However, because of the limited availability of MRI or CT-Scan systems and of the long segmentation time, all studies in the literature include the data of only one individual. Yet the inter-individual variability can't be overlooked when dealing with patient specific estimation of internal tissue loading. As an alternative, this contribution focuses on the combined use of low-dose biplanar X-ray images, B-mode ultrasound images and optical scanner acquisitions in a non-weight-bearing sitting posture for the fast generation of patient-specific FE models of the buttock. Model calibration was performed based on Ischial Tuberosity sagging. Model evaluation was performed by comparing the simulated contact pressure with experimental observations on a population of 6 healthy subjects. Analysis of the models confirmed the high inter-individual variability of soft tissue response (maximum Green Lagrange shear strains of 213 ± 101% in the muscle). This methodology opens the way for investigating inter-individual factors influencing the soft tissue response during sitting and for providing tools to assess PU risk.


Suction Rectal Biopsy is Accurate in Late Preterm Infants with Suspected Hirschsprung Disease.
Few data are available to substantiate the dogma commonly held by pediatric surgeons and pediatric pathologists that rectal biopsies may be inaccurate or risky in preterm neonates. We aimed to address these concerns. We performed a single-institution retrospective review of patients who underwent suction rectal biopsies at <37 weeks corrected age from 2009 to 2018. The primary outcomes were accuracy of biopsy results and procedural complications. Forty-nine patients underwent suction rectal biopsy at <37 weeks corrected age. Mean gestational age at biopsy was 35.2 weeks (range 32.1-36.9) and mean weight was 2126 g (range 1590-3100). Five (10%) infants had biopsies positive for Hirschsprung Disease. All 5 later underwent pull-through operations and had pathologic confirmation of an aganglionic segment. The remaining 44 (90%) had biopsies showing ganglion cells. None were later found to have HD during the follow up period. Those who underwent biopsy at <2000 g (16/44) had 100% sensitivity [95% CI 48, 100] and specificity [95% CI 92, 100] (2 true positives, 14 true negatives). There were no complications identified. Suction rectal biopsy can be performed safely in preterm infants as small as 1590-2000 g with high accuracy. Clinicians should not hesitate to perform a biopsy for a premature infant when clinically appropriate. Study of a diagnostic test. Level IV.


CD38-mediated Inhibition of Bruton's Tyrosine Kinase in Macrophages Prevents Endotoxemic Lung Injury.
TLR4 signaling via endotoxemia in macrophages promotes macrophage transition to the inflammatory phenotype through NLRP3 inflammasome activation. This transition event has the potential to trigger acute lung injury (ALI). However, relatively little is known about the regulation of NLRP3 and its role in the pathogenesis of ALI. Here we interrogated the signaling pathway activated by CD38, an ectoenzyme expressed in macrophages, in preventing ALI through suppressing NLRP3 activation. Wild-type and Cd38-knockout (Cd38-/-) mice were used to assess inflammatory lung injury, and isolated macrophages were used to delineate underlying TLR4 signaling pathway. We showed that CD38 suppressed TLR4 signaling in macrophages by inhibiting Bruton's tyrosine kinase (Btk) through the recruitment of Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2) and resulting in the dephosphorylation of activated Btk. Cd38-/- mice show enhanced lung polymorphonuclear leukocyte extravasation and severe lung injury. LPS- or polymicrobial sepsis-induced mortality in Cd38-/- mice were markedly augmented compared with wild types. CD38 in macrophages functioned by inhibiting Btk activation through activation of SHP2 and resulting dephosphorylation of Btk, and thereby preventing activation of downstream targets NF-κB and NLRP3. Cd38-/- macrophages displayed markedly increased activation of Btk, NF-κB, and NLRP3, whereas in vivo administration of the Btk inhibitor ibrutinib (a Food and Drug Administration-approved drug) prevented augmented TLR4-induced inflammatory lung injury seen in Cd38-/- mice. Our findings together show upregulation of CD38 activity and inhibition of Btk activation downstream of TLR4 activation as potential strategies to prevent endotoxemic ALI.


Cell lineages generating axial muscle in the zebrafish embryo.
Cell lineage may contribute to determining the numbers, positions and types of cells formed during embryogenesis. In vitro clonal analyses show that vertebrate cells can autonomously maintain lineage commitments to single fates and that terminal development may include an invariant sequence of cell divisions. In addition, in vivo studies with Xenopus led to the proposal that clonal restrictions to spatial 'compartmental' domains arise during early development, analogous to what is observed in insects. In the zebrafish, individual gastrula cells generate clones of progeny that are confined within single tissues, but spatial restrictions have not been described. We now have examined the in vivo terminal cell lineages of zebrafish axial muscles. We obtained no evidence either for strict developmental regulation of division pattern or for spatial compartmentation within muscle lineages.


Persistence of lipoatrophy after a four-year long interruption of antiretroviral therapy for HIV1 infection: case report.
HIV-infected patients on long-term highly active antiretroviral therapy often present peculiar patterns of fat redistribution, referred to as lipodystrophy. In spite of recent investigations, it is not known whether and to what extent the main features of lipodystrophy--that is lipoatrophy of peripheral fat at face, limbs and buttocks, as well as fat accumulation at breasts, abdomen and the dorso-cervical region--can be reversible once clinically manifest. A 35 year old Caucasian HIV infected female developed severe diffuse lipodystrophy while on highly active antiretroviral therapy. A remarkable increase of breast size, fat accumulation at waist, and a fat pad on her lumbar spine were paralleled by progressive and disfiguring lipoatrophy of face, limbs and buttocks. The patient decided to interrupt her therapy after 20 months, with a stably suppressed viremia and a CD4 lymphocyte count > 500/microL. She could carry on a safe treatment interruption for longer than 4 years. Most sites of fat accumulation switched to nearly normal appearance, whereas lipoatrophy was substantially unchanged at all affected sites. our observation provides pictorial evidence that lipoatrophy may not be reversible even under ideal circumstances. Therefore, strategies to prevent lipoatrophy should be considered when defining therapeutic regimens for HIV infected patients, especially those at high risk.


Expression of matrix metalloproteinases MMP-2, MMP-9 and their tissue inhibitors TIMP-1, -2, and -3 in benign and malignant tumours of the salivary gland.
The balance between matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is involved in the morphogenesis of the normal salivary gland as well as in mechanisms of tumour invasion and metastasis. Our aim was to analyse protein and mRNA expression of MMPs and TIMPs in normal salivary gland tissue and in various salivary gland neoplasms. Immunohistochemistry for MMP-2, MMP-9, TIMP-1, -2 and -3 was performed in 20 malignant and six benign salivary gland tumours. The immunoscores of MMP-2 were significantly higher in carcinomas compared with adenomas (P = 0.0028). The MMP/TIMP ratio was significantly higher in carcinomas than in adenomas (P = 0.0097). In mucoepidermoid carcinomas MMP-2 expression was preferentially observed in the intermediate cell type. Neoplastic acinar cells of acinic cell carcinoma demonstrated de novo expression of MMP-2, MMP-9, TIMP-1, and TIMP-2. Immunoscores of TIMP-3 were not decreased in malignant tumours compared with adenomas. In accordance with the immunostaining of MMP-2 and -9, gelatinolytic activity could be demonstrated by in-situ zymography. The mRNA expression of MMPs and TIMPs analysed by real-time reverse transcriptase-polymerase chain reaction in three malignant and two benign tumours and their corresponding normal tissue did not generally correlate with their protein expression. Our findings suggest a disturbed balance between MMP and TIMP in malignant salivary gland tumours. MMP-2 expression in particular seems to be related to the invasive properties and the malignant potential of these tumours.


Catalytic and Aerobic Oxidative Biaryl Coupling of Anilines Using a Recyclable Heterogeneous Catalyst for Synthesis of Benzidines and Bicarbazoles.
In this study, a heterogeneous rhodium-catalyzed oxidative homocoupling reaction of anilines utilizing molecular oxygen as the sole oxidant is reported. Employing a commercially available and recyclable Rh/C catalyst enabled the oxidative dimerization of various anilines, including N,N-disubstituted and N-monosubstituted anilines, as well as diarylamines, triarylamines, and carbazoles. Additionally, the catalytic protocol was extended to the ortho-ortho coupling of anilines, affording 2,2'-diaminobiphenyls with high regioselectivity. Notably, the developed approach provides rapid access to diversely functionalized benzidines and diaminobiphenyls in an operationally simple, practical, and environmentally friendly manner.


Allergies to Titanium Dental Implants: What Do We Really Know about Them? A Scoping Review.
The purpose of this scoping review was to describe the current state of knowledge and understanding of allergies to titanium dental implants. A scoping review was conducted following the Prisma Extension for Scoping Reviews checklist. An electronic search was performed in five databases complemented by manual and grey literature searches. Fifty-two relevant papers were included for final review. Titanium particles can be released from the surfaces of dental implants in a process called tribocorrosion, which may contribute to bone loss due to inflammatory reaction. Diverse mechanisms have been described that may trigger allergy to titanium, as well as the clinical signs that manifest as the allergy develops. Allergies to titanium are uncommon but represent a real possibility that should not be overlooked in patients requiring prosthodontic rehabilitation with dental implants. Allergy can trigger a range of symptoms. Patients who have already been diagnosed with allergies to other metals will be more predisposed to suffering an allergy to titanium. Further investigation is needed in order to measure the true scope of these allergies.


Self-mutilation and self-blame in incest victims.
A case is made for self-blame as the psychic link between children's experiences of incestuous sexual abuse and their self-mutilating behavior later in life. Representative case histories and the results of a small pilot study are presented to illustrate the author's theoretical formulation.