Holo and apo-transferrins interfere with adherence to abiotic surfaces and with adhesion/invasion to HeLa cells in Staphylococcus spp.
Staphylococcus aureus and Staphylococcus epidermidis are the major cause of infections associated with implanted medical devices. Colonization on abiotic and biotic surfaces is often sustained by biofilm forming strains. Human natural defenses can interfere with this virulence factor. We investigated the effect of human apo-transferrin (apo-Tf, the iron-free form of transferrin, Tf) and holo-transferrin (holo-Tf, the iron-saturated form) on biofilm formation by CA-MRSA S. aureus USA300 type (ST8-IV) and S. epidermidis (a clinical isolate and ATCC 35984 strain). Furthermore S. aureus adhesion and invasion assays were performed in a eukaryotic cell line. A strong reduction in biofilm formation with both Tfs was obtained albeit at very different concentrations. In particular, the reduction in biofilm formation was higher with apo-Tf rather than obtained with holo-Tf. Furthermore, while S. aureus adhesion to eukaryotic cells was not appreciably affected, their invasion was highly inhibited in the presence of holo-Tf, and partially inhibited by the apo form. Our results suggest that Tfs could be used as antibacterial adjuvant therapy in infection sustained by staphylococci to strongly reduce their virulence related to adhesion and cellular invasion.


Expansion of FGFR3-positive nucleus pulposus cells plays important roles in postnatal nucleus pulposus growth and regeneration.
Intervertebral disc degeneration (IVDD) can cause low back pain, a major public health concern. IVDD is characterized with loss of cells especially those in nucleus pulposus (NP), due to the limited proliferative potential and regenerative ability. Few studies, however, have been carried out to investigate the in vivo proliferation events of NP cells and the cellular contribution of a specific subpopulation of NP during postnatal growth or regeneration. We generated FGFR3-3*Flag-IRES-GFP mice and crossed FGFR3-CreERT2 mice with Rosa26-mTmG, Rosa26-DTA and Rosa26-Confetti mice, respectively, to perform inducible genetic tracing studies. Expression of FGFR3 was found in the outer region of NP with co-localized expressions of proliferating markers. By fate mapping studies, FGFR3-positive (FGFR3+) NP cells were found proliferate from outer region to inner region of NP during postnatal growth. Clonal lineage tracing by Confetti mice and ablation of FGFR3·+ NP cells by DTA mice further revealed that the expansion of the FGFR3+ cells was required for the morphogenesis and homeostasis of postnatal NP. Moreover, in degeneration and regeneration model of mouse intervertebral disc, FGFR3+ NP cells underwent extensive expansion during the recovery stage. Our present work demonstrates that FGFR3+ NP cells are novel subpopulation of postnatal NP with long-existing proliferative capacity shaping the adult NP structure and participating in the homeostasis maintenance and intrinsic repair of NP. These findings may facilitate the development of new therapeutic approaches for IVD regeneration.


Beneficial effect of Lactococcus lactis NCC 2287 in a murine model of eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is a severe inflammatory disease of the esophagus which is characterized histologically by an eosinophilic infiltration into the esophageal tissue. The efficacy of probiotics in the context of atopic diseases has been well investigated but, to date, there has been no study which has evaluated probiotic effects on EoE inflammation. This study sought to identify a probiotic which improves esophageal inflammation in experimental EoE. Two candidate probiotics, Lactococcus lactis NCC 2287 and Bifidobacterium lactis NCC 2818, were tested in a murine model of EoE elicited by epicutaneous sensitization with Aspergillus fumigatus protein extract. Administration of bacterial strains in drinking water was used, respectively, as a preventive or treatment measure, or continuously throughout the study. Inflammatory parameters were assessed in the esophagus, skin, and lungs after allergen challenge. In this EoE model, supplementation with L. lactis NCC 2287 significantly decreased esophageal and bronchoalveolar eosinophilia but only when given as a therapeutic treatment. No significant effect on eosinophilia was observed when NCC 2287 was given as a preventive or a continuous intervention. NCC 2287 supplementation had no significant effect on immunoglobulin levels, skin symptom scores, or on transepidermal water loss. Supplementation with another probiotic, B. lactis NCC 2818, had no significant effect on esophageal eosinophilia. We identified a L. lactis strain, able to attenuate esophageal eosinophilic inflammation in a preclinical model of EoE. This effect is strain specific and depends on the timing and duration of bacterial supplementation. Confirmation of these observations in human clinical trials is warranted.


Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic potential?
Skeletal muscle wasting is considered the central feature of cachexia, but the potential for skeletal muscle anabolism in patients with advanced cancer is unproven. We investigated the clinical course of skeletal muscle wasting in advanced cancer and the window of possible muscle anabolism. We conducted a quantitative analysis of computed tomography (CT) images for the loss and gain of muscle in population-based cohorts of advanced cancer patients (lung, colorectal, and pancreas cancer and cholangiocarcinoma) in a longitudinal observational study. Advanced-cancer patients (n = 368; median survival: 196 d) had a total of 1279 CT images over the course of their disease. With consideration of all time points, muscle loss occurred in 39% of intervals between any 2 scans. However, the overall frequency of muscle gain was 15.4%, and muscle was stable in 45.6% of intervals between any 2 scans, which made the maintenance or gain of muscle the predominant behavior. Multinomial logistic regression revealed that being within 90 d (compared with >90 d) from death was the principal risk factor for muscle loss (OR: 2.67; 95% CI: 1.45, 4.94; P = 0.002), and muscle gain was correspondingly less likely (OR: 0.37; 95% CI: 0.20, 0.69; P = 0.002) at this time. Sex, age, BMI, and tumor group were not significant predictors of muscle loss or gain. A window of anabolic potential exists at defined early phases of the disease trajectory (>90 d survival), creating an opportunity for nutritional intervention to stop or reverse cachexia. Cancer patients within 90 d of death have a low likelihood of anabolic potential.


[T-cell lymphoma under immunosuppressive treatment in minimal change glomerulopathy with nephrotic syndrome].
A 43-year-old woman was admitted for treatment of a nephrotic syndrome with increasing oedema, ascites, dyspnoea and nausea during the preceding 2 weeks. There was a proteinuria of 25 g daily. Renal biopsy (seven glomeruli) showed a minimal-change glomerulopathy. Prednisone administration (1 mg/kg daily) achieved complete remission. In the course of this treatment the patient contracted listeriosis with encephalitis, which quickly responded to ampicillin and netilmicin. When the glucocorticoid dosage was reduced or the drug discontinued, the nephrotic syndrome recurred. Cyclosporin treatment was begun (5 mg/kg daily) and quickly led to another remission. 4 weeks after start of the treatment a reddish-blue nodule, about 2 cm in diameter, was noted on the right upper arm. Histologically it showed cutaneous infiltration of a medium-sized T-cell lymphoma. Other efflorescences were found on the trunk and the limbs. Cyclosporin treatment was at once discontinued and the cutaneous changes gradually regressed. There were no other manifestations of a lymphoma. A further recurrence of the nephrotic syndrome responded well to a short course of chlorambucil (cumulative dose 420 mg) and of prednisone with slow dose reduction. There has been no recurrence in the last year.


Contraction and increase in tissue calcium content induced by maitotoxin, the most potent known marine toxin, in intestinal smooth muscle.
Maitotoxin (MTX), the most potent known marine toxin, isolated from toxic dinoflagellates and poisonous fish, caused a dose-dependent contraction of the guinea-pig isolated ileum and taenia caeci at concentrations of 100 pg to 30 ng/ml. These contractile responses to MTX (3 ng/ml) in both tissues were abolished by incubation in Ca2+-free solution and were markedly inhibited by treatment with methoxyverapamil (D600), but were not affected by tetrodotoxin and atropine. Furthermore, MTX markedly elevated tissue Ca2+ content of the taenia caeci. These results suggest that MTX activates Ca2+ channels in the smooth muscle membrane of both tissues to increase Ca2+ influx and thus induces contractions.


Pathophysiology of SARS-CoV2 Mediated Depression, Therapeutics, and Consequences: A Comprehensive Narrative.
The Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), belongs to emerging and reemerging diseases, which was first identified and reported in Wuhan, China, in December 2019. The genetic sequence of SARS-CoV-2 was similar to the SARS virus, a β-coronavirus. The epidemiological studies suggest that the transmission of SARS-CoV-2 mainly occurs from an infected person to others through close contact with the respiratory droplets or by having contact with SARS-CoV-2 adhering to objects and surfaces. The incubation period ranges from 5 to14 days. The symptoms include fever, dry cough, tiredness, aches, chest pain, conjunctivitis, diarrhea, headache, difficulty in breathing or short breath, loss of taste, smell, rashes on the skin, and sore throat. Some reports indicated that males exhibited lower scores than females, the younger populations displayed increased symptoms, Chinese/Taiwanese people registered only scarce symptoms, and Canadians experienced more symptoms. The results of several studies suggested that while COVID-19 had a significant effect on depression, job instability affected anxiety and depression. The diagnostics to detect the presence of coronavirus involve ELISA and RT-PCR. There is no specific treatment available to eradicate COVID-19. The therapeutics used to treat COVID 19 exhibited severe side effects. Recently, some Indian traditional medicinal plants have shown promise in reducing the risk of viral infection and also boosting the immunity of an individual. This paper presents an overview of the current status of depression in the SARS CoV2 infected people and the measures required to overcome COVID-19 induced depression in patients even after recovery.


Protein synthesis in rat cardiac myocytes is stimulated at the level of translation by phorbol esters.
12-O-Tetradecanoylphorbol 13-acetate acutely stimulated the rate of protein synthesis maximally by about 43% in terminally differentiated myocytes freshly isolated from adult rat hearts. Stimulation was rapidly expressed (within 20 min). The relative effects of four phorbol esters on protein synthesis was consistent with a specific effect on protein kinase C. Inhibition of transcription with actinomycin D had no effect on the absolute stimulation of the protein synthesis rate by 12-O-tetradecanoylphorbol 13-acetate. We conclude that protein kinase C may be involved in the regulation of the translational process.


Phosphorylation of membrane proteins by cytosolic casein kinases in human erythrocytes. Effect of monovalent ions, 2,3-bisphosphoglycerate and spermine.
Membrane proteins of human erythrocytes can be phosphorylated not only by membrane casein kinase (MS) but also by cytosolic casein kinases CS and CTS, resembling casein kinase I and II, respectively. Casein kinase CS, like membrane casein kinase MS, preferentially phosphorylates membrane proteins such as band 2 (spectrin, beta-subunit) and band 3, which are the major phosphate-acceptor proteins in the endogenous phosphorylation of isolated ghosts in the presence of [gamma-32P]ATP. By contrast, cytosolic casein kinase CTS phosphorylates, in addition to band 2, some membrane proteins, whose endogenous phosphorylation in isolated ghosts under the same conditions is negligible, if any. The CS- and CTS-catalyzed phosphorylations exhibit different response to increasing NaCl (or KCl) concentrations up to physiological levels (140 mM KCl, 20 mM NaCl); i.e. CS- and MS-catalyzed phosphorylations are strongly inhibited by 75-150 mM KCl (or NaCl), while CTS-catalyzed phosphorylation is practically unaffected. In the absence of added NaCl, CS- and MS-catalyzed phosphorylations are markedly inhibited by 1.5-3 mM 2,3-bisphosphoglycerate, whereas CTS-catalyzed phosphorylation appears to be practically unaffected. Finally, CS- and MS-catalyzed phosphorylations are slightly inhibited also by 1 mM spermine, while CTS-catalyzed phosphorylation is enhanced by this polycation concentration.


Allograft involvement by lymphoproliferative disorders after lung transplantation: report from the PTLD. Int survey.
Few cases of graft posttransplant lymphoproliferative disease (PTLD) in pulmonary transplant recipients have been reported. Published data on PTLD are pooled to analyze and compare characteristics, predictors, and prognosis of pulmonary PTLDs arising in lung allograft recipients. PubMed and Google Scholar were searched for reports of lymphoproliferative disorders occurring within the graft in lung transplant recipients. Data from 23 studies were pooled and analyzed. Data from 137 patients (61 graft locations) with PTLD after lung transplantation were analyzed. Lung recipients with pulmonary graft PTLD were significantly more likely to have early-onset PTLD (70% vs 31%, respectively; P<.001). Lung graft PTLD also was associated with having tested negative for infection with Epstein-Barr virus before transplantation (P=.05). Log-rank test showed significantly higher survival rates for pulmonary transplant recipients with allograft complication than for recipients with PTLD elsewhere (P=.02). Pulmonary transplant recipients who show early symptoms of impaired graft function should be evaluated for a potential lung graft PTLD in addition to being assessed for risk of rejection. Further prospective studies with large populations of patients are needed to confirm these results.


Probable reason why small strongyle EPG counts are returning "early" after ivermectin treatment of horses on a farm in Central Kentucky.
Critical tests were carried out in 2008 in four yearling horses (H-2, H-4, H-10, and H-11) born and raised together on a farm (MC) in Central Kentucky. These horses were treated intraorally with ivermectin paste at the dose rate of 200 microg/kg. The main interest was to try and determine more precisely, from posttreatment (PT) worm count data, the current activity of ivermectin against small strongyles in a horse herd. These horses had been treated repeatedly with this compound and counts of small strongyle eggs per gram of feces (EPGs) of these parasites have been returning sooner than previously in field tests (Lyons et al. Parasitol Res 103:209-215, 2008a). Data from the four horses revealed that a total of 3237 (nonfactored number) specimens of small strongyles was recovered from aliquot samples of feces passed PT and in the large intestinal contents at necropsy; all specimens were examined and identified. Thirteen species of adult small strongyles were recorded. Cylicocyclus (Cyc.) insigne was the predominant species. Three of the yearlings (H-2, H-4, and H-11) were necropsied at 6 days PT with ivermectin, and removals of small strongyles were: 50%, 80%, and 36% of fourth stages (L4), respectively, and 100%, 99%, and 100% of adults, respectively. As indicated, the only incomplete removal of adults from the three horses was for H-4. They consisted of two species: (1) young Cyc. insigne (those passed in the feces were fully developed); removal of this species was 89% and (2) fully developed Cylicostephanus longibursatus; 99% were removed. The fourth yearling (H-10), necropsied at 25 days PT, harbored 19,150 adult small strongyles in the large intestinal contents. Most of the species were Cyc. insigne; all were fifth stage but not sexually mature. Comparing the percentage of adult small strongyles found at necropsy relative to the total number present (those passed in the feces and at necropsy), only 0% to 1% were in the contents of the large intestines of the three horses at 6 days PT but in 26% for horse H-10 at 25 days PT. As mentioned earlier, only a few adults were found in one horse and several L(4) in the three horses at necropsy at 6 days PT. Therefore, in horse H-10, most adults found at 25 days PT presumably developed from "young" specimens not removed by ivermectin. Thus, data from the present critical tests indicate the probable cause of the "early" return of small strongyle EPG values after ivermectin treatment in the horses in field tests on Farm MC. It seems this was the result of incomplete removal of luminal specimens (L(4) and possibly young adults), some of which matured and began laying eggs by about 4 weeks PT (Lyons et al. Parasitol Res 103:209-215, 2008a). The research also showed that ivermectin was highly effective on adult small strongyles. At necropsy, the following other species of parasites (adult) were found, but none was recovered from the feces. These were (n = number of horses infected): (1) ascarids (Parascaris equorum-n = 1), (2) tapeworms (Anoplocephala perfoliata-n = 4), and (3) pinworms (Oxyuris equi-n = 3). Immature (L4) O. equi were present in two horses and removals were 0% in one horse and 39% in the other. Eyeworms (Thelazia lacrymalis) were found in one horse at necropsy. Even though a small number of horses were used in the present research, the commonality of their background made them ideal candidates as a group for this study. This aspect helps strengthen the validity of the interpretation of the findings.


Utility of cardiac CT in infants with congenital heart disease: Diagnostic performance and impact on management.
Advances in cardiac CT (CCT) scanner technology allow imaging without anesthesia, and with low radiation dose, making it an attractive technique in infants with congenital heart disease. However, the utility of CCT using a dual-source scanner with respect to diagnostic performance and impact on management has not been systematically studied in this population. Retrospective review of infants who underwent CCT to determine the utility of CCT with respect to the following: answering the primary diagnostic question, providing new diagnostic information, prompting a change in management, and concordance with catheterization or surgical inspection. A total of 156 infants underwent 172 scans at a median age of 64 days, (IQR 4-188) from Jan 2016-Dec 2019. The most frequent diagnostic question was related to the pulmonary arteries (43%), followed by the aortic arch (30%), pulmonary veins (26%), coronary arteries (17%), patent ductus arteriosus (10%) and others (9%). A high-pitch spiral scan was frequently used (90%). The median effective radiation dose was low (0.66 mSv) and general anesthesia was used infrequently (23%). CCT answered the primary diagnostic question in 168/172 (98%) and added to the diagnostic information already available by echocardiography in 161/172 (96%) scans. CCT led to a change in management following 78/172 (53%) scans and had an impact on management following 167/172 (97%) scans. On follow-up, after 107/172 (62%) scans, subjects underwent cardiac surgery, and after 55/172 (32%) scans, they had cardiac catheterization. CCT findings were concordant with catheterization and/or surgical inspection in 156/159 (98%) scans. In infants with complex congenital heart disease, CCT was accurate, answered the diagnostic questions in nearly all cases, and frequently added diagnostic information that impacted management. Radiation exposure was low, and anesthesia was needed infrequently.


Photoswitchable Sol-Gel Transitions and Catalysis Mediated by Polymer Networks with Coumarin-Decorated Cu24 L24 Metal-Organic Cages as Junctions.
Photoresponsive materials that change in response to light have been studied for a range of applications. These materials are often metastable during irradiation, returning to their pre-irradiated state after removal of the light source. Herein, we report a polymer gel comprising poly(ethylene glycol) star polymers linked by Cu24 L24 metal-organic cages/polyhedra (MOCs) with coumarin ligands. In the presence of UV light, a photosensitizer, and a hydrogen donor, this "polyMOC" material can be reversibly switched between CuII , CuI , and Cu0 . The instability of the MOC junctions in the CuI and Cu0 states leads to network disassembly, forming CuI /Cu0 solutions, respectively, that are stable until re-oxidation to CuII and supramolecular gelation. This reversible disassembly of the polyMOC network can occur in the presence of a fixed covalent second network generated in situ by copper-catalyzed azide-alkyne cycloaddition (CuAAC), providing interpenetrating supramolecular and covalent networks.


The substrate specificity of a recombinant cysteine protease from Leishmania mexicana: application of a combinatorial peptide library approach.
The substrate specificity of CPB2.8DeltaCTE, a recombinant cysteine protease from Leishmania mexicana, was mapped by screening a fluorescence-quenched combinatorial peptide library. Results from library screening indicated a preference for Arg or Lys in the S(3) subsite and for hydrophobic residues, both aliphatic and aromatic, in S(2). The S(1) subsite exhibited a specificity for the basic residues Arg and Lys. Generally, the specificity of the primed subsites was less strict compared with the non-primed side which showed preference for Arg, Lys and Ala in S'(1), Arg, Pro and Gly in S'(2) and Lys, Arg and Ser in S'(4). By contrast, a strict preference for the basic residues Arg and Lys was found for S'(3). Overall, there was a trend for basic residues in alternating subsites and smaller residues in the primed sites compared with the non-primed sites. In addition, there were strict requirements for the amino acids in subsites S(3)--S(1). Fluorescence-quenched peptides from the library with the highest on-resin cleavage were resynthesised and their kinetics of hydrolysis by CPB2.8DeltaCTE assessed in solution phase assays. Several good substrates containing the quintessential dipeptide particular to cathepsin-L-like enzymes, -F-R/K-, in P(2) and P(1) were identified (e.g. Y(NO(2))-EKFR down arrow RGK-K(Abz)G, Abz=2-aminobenzoyl; k(cat)K(m)(-1)=4298 mM(-1)s(-1)). However, novel substrates containing the dipeptide -L/I-Q- in P(2) and P(1) were also well hydrolysed (e.g. Y(NO(2))-YLQ down arrow GIQK-K(Abz)G; k(cat)K(m)(-1)=2583 mM(-1)s(-1)). The effect of utilising different fluorescent donor--quencher pairs on the value of k(cat)K(m)(-1) was examined. Generally, the use of the Abz/Q-EDDnp donor--quencher pair (EDDnp=N-(2,4-dinitrophenyl)ethylenediamine) instead of K(Abz)/Y(NO(2)) resulted in higher k(cat)K(m)(-1) values for analogous substrates.


Expression of p53 and p21 proteins in oral squamous cell carcinoma: correlation with lymph node metastasis and response to chemoradiotherapy.
p53 protein, a product of the p53 cancer suppressor gene, and p21 protein, a cyclin-dependent kinase inhibitor, were immunohistochemically investigated in 150 oral squamous cell carcinomas (SCCs) and the relationship between their expression and clinicopathological findings were evaluated. The positivity for p53 and p21 proteins was not correlated with the T-stage, mode of tumor cell invasion or tumor cell differentiation. However, the expression of p53 and p21 proteins was correlated with lymph node metastasis. Of 62 SCCs with regional lymph node metastasis, 45 SCCs (72.6%) were positive for p53 while 45 (52.9%) of 88 SCCs without metastasis expressed p53 protein (p < 0.02). In addition, p21 protein was observed in 25 (38.5%) and 18 (21.2%) SCCs with and without metastasis, respectively (p < 0.05). Furthermore, p53 protein was inversely correlated with the histopathological effect of inductive chemoradiotherapy; the rate of chemoradiotherapy-induced lethal degeneration (56.7%) in p53-negative SCCs was significantly higher than that (28.9%) in p53-positive SCCs (p < 0.005). However, no clear difference in the effect was observed between p21-positive and p21-negative SCCs. Finally, the 5-year-survival rate was highest in p53(-)-p21(+) (80.0%) followed by 76.3% in p53(-)-p21(-), 65.9% in p53(+)-p21(+) and 65.4% in p53(+)-21p(-) SCCs. These results indicate that although the expression of p21 protein is only weakly correlated with the clinico-histopathological findings, p53 protein is a useful prognostic marker and that inductive chemoradiotherapy can be successfully planned by immunohistochemical examination of p53 protein.


Early stimulation of phospholipid methylation in Xenopus oocytes by progesterone.
Progesterone induced a transient increase in the incorporation of [3H]methyl groups into phospholipids of Xenopus oocytes followed by a rise in 45Ca2+ uptake. Phospholipid methylation reached a maximum as early as 15 s after progesterone treatment and returned to basal level within 2 min. Steroids inactive in promoting oocyte maturation were less effective in affecting phospholipid methylation. Methyltransferase inhibitors, 3-deaza-SIBA, SIBA, and Sinefungin, inhibited progesterone-activated stimulation of phospholipid methylation, calcium uptake and meiotic maturation. Phospholipid methylation is the earliest detectable biochemical event occurring in oocytes after exposure to progesterone followed by calcium influx and leading to germinal vesicle dissolution.


Blood protein reactions to ablation of capsaicin-sensitive neurons.
The effects of ablation of afferent neurons with neurotoxic doses of capsaicin (150 mg/kg) on protein levels in plasma fractions were studied by polyacrylamide gel electrophoresis in Wistar rats at different times points after administration of capsaicin and in inflammatory reactions induced by zymosan (10 mg/100 g). Administration of neurotoxic doses of capsaicin induced biphasic changes in protein levels in plasma fractions. During the initial period (up to seven days), "acute-type" changes in protein content were seen; at 11-30 days, there were chronic increases in the albumin level with decreases in alpha(1), alpha(2), and gamma globulins. Defunctionalization of capsaicin-sensitive nerves 14-30 days before induction of inflammation prevented the "acute-phase" changes in protein contents in the albumin, alpha(1), alpha(2), and beta globulin fractions in response to induction of inflammation with zymosan.


A novel sono-assisted acid pretreatment of chili post harvest residue for bioethanol production.
The objective of the present study was to develop a sono-assisted acid pretreatment strategy for the effective removal of lignin and hemicelluloses and to improve the sugar yield from chili post harvest residue. Operational parameters that affect the pretreatment efficiency were studied and optimized. Inhibitor analysis of the hydrolyzate revealed that major fermentation inhibitors like furfural, hydroxymethyl furfural and organic acids like citric acid, succinic acid and propionic acid were absent. Changes in structural properties of the biomass were studied in relation to the pretreatment process using scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier Transform Infrared (FTIR) analysis, and the changes in chemical composition was also monitored. The biomass pretreated with the optimized novel method yielded 0.465g/g of reducing sugars on enzymatic hydrolysis. Fermentation of the non-detoxified hydrolysate yielded 2.14% of bioethanol with a fermentation efficiency of 71.03%.


The effect of obesity on the ratio of type 3 17beta-hydroxysteroid dehydrogenase mRNA to cytochrome P450 aromatase mRNA in subcutaneous abdominal and intra-abdominal adipose tissue of women.
To investigate (1) whether type 3 17beta-hydroxysteroid dehydrogenase (17beta-HSD), the enzyme which catalyzes the conversion of androstenedione to testosterone in the testis, is co-expressed with P450aromatase in the preadipocytes of women, and (2) whether the relative expression of type 3 17beta-HSD and aromatase varies in subcutaneous abdominal vs intra-abdominal adipose tissue of women. Subcutaneous abdominal and intra-abdominal adipose tissue was obtained from women undergoing elective abdominal surgery (age 22-78 y, body mass index (BMI) 22.4-52.9 kg/m(2)). Expression of type 3 17beta-HSD in adipose cell fractions was determined using RT-PCR. Preadipocyte steroidogenesis was investigated in primary cultures using androstenedione as substrate. Messenger RNA levels for type 3 17beta-HSD and aromatase were measured in adipose tissue from the subcutaneous abdominal and intra-abdominal depots using a quantitative multiplex competitive RT-PCR assay. Type 3 17beta-HSD is co-expressed with aromatase in the abdominal preadipocytes of women. Cultured preadipocytes from both subcutaneous abdominal (n=5) and intra-abdominal (n=5) sites converted androstenedione to testosterone, and there was minimal conversion of androstenedione to estrone. Consistent with this, the levels of type 3 17beta-HSD mRNA were significantly higher than aromatase mRNA at both sites (P<0.05; n=8 subcutaneous abdominal, n=12 intra-abdominal adipose tissue). The ratio of levels of 17beta-HSD mRNA to aromatase mRNA in intra-abdominal adipose tissue was positively correlated with BMI (n=11, r=0.61, P<0.05) and waist circumference (n=10, r=0.65, P<0.05). The converse was found in subcutaneous abdominal adipose tissue. The intra-abdominal adipose tissue of women may be substantially androgenic, increasingly so with increasing obesity, particularly central obesity. While androgen production by this adipose tissue deposit may not contribute to circulating testosterone levels due to hepatic clearance, it may have hitherto unrecognised local effects in the intra-abdominal adipose tissue and also on the liver via the hepatic portal system. These studies suggest a mechanism linking central obesity with insulin resistance and dyslipidaemia.


The neuronal pathway subserving the pupillary light reflex.
The pupillary light reflex was investigated using electrical stimulation along the pathway and recording in the short ciliary nerves. The discharge of single units in the ciliary ganglion was compared during diffuse light stimuli and electrical stimuli. It was concluded that the early reflex discharge in the short ciliary nerves following electrical stimulation on the optic tract is due to excitation of fibres active during the pupillary light reflex. The light reflex is conveyed by slow (less than 10 m/sec) optic tract fibres which synapase in the medial part of the pretectal area. In turn, pretectal neurones with conduction velocities of about 6 m/sec pass to the Edinger-Westphal complex from which the preganglionic 'pupilloconstrictor' neurones originate. Latency measurements show that there are synapses in the pretectal region and the Edinger-Westphal nucleus. The amplitude of the 'pupilloconstrictor' responses in the short ciliary nerves can be used as a measure of the excitability in the pathway of the pupillary light reflex under various conditions, e.g. following conditioning stimuli of other interacting pathways. In addition to the 'pupilloconstrictor' response there is also another short-latency discharge in the short ciliary nerves following stimulation of the posterior commissure and the Edinger-Westphal nucleus. That discharge is presumably due to activation of fibres which cause accommodation of the lens.


Sensorineural hearing loss in patients with typical retinitis pigmentosa.
We performed detailed audiologic testing in 45 patients with retinitis pigmentosa and 45 age- and sex-matched controls. Ten (22%) of the retinitis pigmentosa patients had a sensorineural hearing loss that varied from mild to severe. None of the control subjects had a hearing loss. Audiograms measured over a ten- to 30-year period were available for four patients with retinitis pigmentosa and each showed progressive hearing loss. The results indicate the important role of audiologic evaluation in treating patients with retinitis pigmentosa.


Assessment of mouthguards worn by Irish children playing contact sports: an observational cross-sectional cohort study.
Traumatic dental injuries occur during participation in sports. Prevention of these injuries by wearing a mouthguard (MG) is desirable, especially in a paediatric population. There are several types of MG available, and their effectiveness depends on device design. The aim of this study was to examine the features of MG worn by children playing a contact sport (Gaelic football), and to determine whether these MG fulfilled recommendations for adequate dentoalveolar protection. A cross-sectional observational cohort study design was developed. Dentists were trained and calibrated in assessing MGs, both qualitatively (retention, extension, integrity) and quantitatively (thickness). A convenience sample of male and female subjects aged 9-16 years was selected for MG assessment via their sports clubs. Data were collected anonymously and analysed using descriptive and comparative statistics. One hundred and six children presented with their MG for assessment. Two-thirds were wearing mouth-formed MG (N = 71, 66.96%). Only four were wearing custom MG (3.77%). Most MG had inadequate retention (N = 86, 81.13%) and labial extension (N = 89, 83.96%), with a significant relationship between MG type and retention. Mouthguard thickness varied widely at each site. Mouth-formed MG were significantly thicker than both stock and custom MG. Mouth-formed MG were the most common type followed by stock MG. Most MG did not have appropriate retention or labial extension. Parents and coaches need to be aware of MG features that maximise protection. If mouth-formed MG are provided in this age group, education on how to adapt them is essential. Paediatric dentists should check MG routinely for appropriate fit.


Stromal expression of CD10 in invasive breast carcinoma and its association with tumour stage, grade, ER, PR and HER2 status.
Tumour microenvironment (TME) has been postulated to be involved in cancer development and disease progression. Studies have shown CD10 expressed in cancer-associated fibroblasts (CAF) within TME is associated with aggressive biological behaviour and poor prognosis. The aim of this study was to evaluate stromal CD10 expression in invasive breast cancer and its correlation with tumour stage, grade, Estrogen receptor (ER), Progesterone receptor (PR) and HER2 status. A total of 226 invasive breast carcinoma cases were selected and assembled into tissue microarrays (TMAs). The stromal expression of CD10 was immunohistochemically analysed. Stromal CD10 was positive in 67 (29.6%) cases of invasive breast carcinoma. The frequency of positive stromal staining was significantly higher in the cases with ER-negative (P=0.000). CD10 stromal negativity was significantly higher in luminaltype cases (P=0.001). However, there was no correlation between stromal CD10 expression with tumour grade, stage, PR and HER2 status. Positive CD10 stromal expression correlates with ER-negative invasive breast carcinomas, while negative CD10 stromal expression correlates with luminal type invasive breast carcinomas. This demonstrates that stromal CD10 expression within the TME constitutes a potential prognostic marker and therapeutic target. Future studies are necessary to evaluate other stromal markers within the TME immunohistochemically as well as its molecular basis in order to confirm the definite role of stromal CD10.


A transcriptional signaling pathway in the IFN system mediated by 2'-5'-oligoadenylate activation of RNase L.
Virus replication in higher vertebrates is restrained by IFNs that cause cells to transcribe genes encoding antiviral proteins, such as 2'-5' oligoadenylate synthetases. 2'-5' oligoadenylate synthetase is stimulated by dsRNA to produce 5'-phosphorylated, 2'-5'-linked oligoadenylates (2-5A), whose function is to activate RNase L. Although RNase L is required for a complete IFN antiviral response and mutations in the RNase L gene (RNASEL or HPC1) increase prostate cancer rates, it is unknown how 2-5A affects these biological endpoints through its receptor, RNase L. Presently, we show that 2-5A activation of RNase L produces a remarkable stimulation of transcription (>/=20-fold) for genes that suppress virus replication and prostate cancer. Unexpectedly, exposure of DU145 prostate cancer cells to physiologic levels of 2-5A (0.1 muM) induced approximately twice as many RNA species as it down-regulated. Among the 2-5A-induced genes are several IFN-stimulated genes, including IFN-inducible transcript 1/P56, IFN-inducible transcript 2/P54, IL-8, and IFN-stimulated gene 15. 2-5A also potently elevated RNA for macrophage inhibitory cytokine-1/nonsteroidal antiinflammatory drug-activated gene-1, a TGF-beta superfamily member implicated as an apoptotic suppressor of prostate cancer. Transcriptional signaling to the macrophage inhibitory cytokine-1/nonsteroidal antiinflammatory drug-activated gene-1 promoter by 2-5A was deficient in HeLa cells expressing a nuclease-dead mutant of RNase L and was dependent on the mitogen-activated protein kinases c-Jun N-terminal kinase and extracellular signal-regulated kinase, both of which were activated in response to 2-5A treatments. Because 2-5A and RNase L participate in defenses against viral infections and prostate cancer, our findings have implications for basic cellular mechanisms that control major pathogenic processes.


Hyperdense pelvic and inguinal lymph nodes.
This small series reports on the computed tomography appearance of hyperdense iliac, inguinal, and femoral lymph nodes in four cases of lymphoma and one case each of ovarian and breast carcinoma. The mean attenuation value of the lymph nodes was 93.8 Hounsfield units (HU), compared to 61 HU for adjacent muscle and 110.7 HU for blood vessels. A relatively homogeneous enhancement pattern was noted, which could not be directly related to hypervascularity, inflammation, or previous treatment with drugs or radiation.


The development of a decision analytic model of changes in mean deviation in people with glaucoma: the COA model.
To create and validate a statistical model predicting progression of primary open-angle glaucoma (POAG) assessed by loss of visual field as measured in mean deviation (MD) using 3 landmark studies of glaucoma progression and treatment. A Markov decision analytic model using patient level data described longitudinal MD changes over 7 years. Patient-level data from the Collaborative Initial Glaucoma Treatment Study (n = 607), the Ocular Hypertension Treatment Study (OHTS; n = 148; only those who developed POAG in the first 5 years of OHTS) and Advanced Glaucoma Intervention Study (n = 591), the COA model. We developed a Markov model with transition matrices stratified by current MD, age, race, and intraocular pressure categories and used a microsimulation approach to estimate change in MD over 7 years. Internal validation compared model prediction for 7 years to actual MD for COA participants. External validation used a cohort of glaucoma patients drawn from university clinical practices. Change in visual field as measured in MD in decibels (dB). Regressing the actual MD against the predicted produced an R(2) of 0.68 for the right eye and 0.63 for the left. The model predicted ending MD for right eyes of 65% of participants and for 63% of left eyes within 3 dB of actual results at 7 years. In external validation the model had an R(2) of 0.79 in the right eye and 0.77 in the left at 5 years. The COA model is a validated tool for clinicians, patients, and health policy makers seeking to understand longitudinal changes in MD in people with glaucoma.


Multiple feeding techniques in the sessile hermit crab, Discorsopagurus schmitti, inhabiting polychaete tubes.
In the sessile hermit crab Discorsopagurus schmitti, four different feeding techniques are described: antennary beating, body-trap feeding, feeding on wafting particles, and scraping. This species' potential for being a generalist in its diet and opportunistic in its foraging behavior certainly opened the way for a sedentary life, allowing occupation of the unusual microhabitat provided by attached polychaete tubes. Nonetheless, deposit-feeding and/or browsing are the most conspicuous foraging strategies, when both the percentage of behavioral acts performed and the quantity of potential food collected are estimated. The question still remains of whether species' reliance on benthos as the main food source should be regarded as an efficient strategy for a sedentary life, or simply as the heritage of its not-so-remote past as a mobile, and shell-dwelling hermit crab.


Mesenchymal Stem Cell-Derived Exosomes are Effective for Radiation Enteritis and Essential for the Proliferation and Differentiation of Lgr5+ Intestinal Epithelial Stem Cells by Regulating Mir-195/Akt/β-Catenin Pathway.
Radiation enteritis (RE) is a common complication of abdominal or pelvic radiotherapy, which when severe, could be life-threatening. Currently, there are no effective treatments. Studies have shown that mesenchymal stem cells (MSCs)-derived exosomes (MSC-exos) exhibit promising therapeutic effects in inflammatory diseases. However, the specific role of MSC-exos in RE and the regulatory mechanisms remain elusive. In vivo assay was carried out by injecting MSC-exos into the total abdominal irradiation (TAI)-induced RE mouse model. For in vitro assay, Lgr5-positive intestinal epithelial stem cells (Lgr5+ IESC) were extracted from mice, followed by irradiation along with MSC-exos treatment. HE staining was performed to measure histopathological changes. mRNA expression of inflammatory factors TNF-α and IL-6 and stem cell markers LGR5, and OCT4 were quantified by RT-qPCR. EdU and TUNEL staining was performed to estimate cell proliferation and apoptosis. MiR-195 expression in TAI mice and radiation-induced Lgr5+ IESC was tested. We found that the injection of MSC-exos inhibited inflammatory reaction, increased stem cell marker expression, and maintained intestinal epithelial integrity in TAI mice. Furthermore, MSC-exos treatment increased the proliferation and simultaneously suppressed apoptosis in radiation-stimulated Lgr5+ IESC. MiR-195 expression increased by radiation exposure was decreased by MSC-exos therapy. MiR-195 overexpression facilitated the progress of RE by counteracting the effect of MSC-exos. Mechanistically, the Akt and Wnt/β-catenin pathways inhibited by MSC-exos were activated by miR-195 upregulation. MSC-Exos are effective in treating RE and are essential for the proliferation and differentiation of Lgr5+ IESCs. Moreover, MSC-exos mediates its function by regulating miR-195 Akt β-catenin pathways.


Chromosomal instability triggers cell death via local signalling through the innate immune receptor Toll.
Chromosomal instability (CIN) is a hallmark of cancer and has been implicated in cancer initiation, progression and the development of resistance to traditional cancer therapy. Here we identify a new property of CIN cells, showing that inducing CIN in proliferating Drosophila larval tissue leads to the activation of innate immune signalling in CIN cells. Manipulation of this immune pathway strongly affects the survival of CIN cells, primarily via JNK, which responds to both Toll and TNFα/Eiger. This pathway also activates Mmp1, which recruits hemocytes to the CIN tissue to provide local amplification of the immune response that is needed for effective elimination of CIN cells.


Significance of different inoculum sources for the Fusarium infection of wheat ears.
From 1997 to 1999 the occurrence ofFusarium spp. on wheat grain and its contamination with the mycotoxins deoxynivalenol and invalenol were investigated under organic farming conditions in the Rhineland, Germany. For comparison, some trials were also run under integrated farming conditions. The importance of the seed contamination withFusarium spp. as well as the impact of farming system, previous crop and soil preparation on the inoculum sources ofFusarium spp. in the soil were investigated. The data on the inoculum sources was compared to the Fusarium infection of grains and their content of DON and NIV. The crop residues in the soil were the most important inoculum source for the Fusarium species infecting wheat ears and grains. The amount of potential inoculum in the soil largely depended on the previous crop and the system of soil preparation.


Sesterterpene ophiobolin biosynthesis involving multiple gene clusters in Aspergillus ustus.
Terpenoids are the most diverse and abundant natural products among which sesterterpenes account for less than 2%, with very few reports on their biosynthesis. Ophiobolins are tricyclic 5-8-5 ring sesterterpenes with potential pharmaceutical application. Aspergillus ustus 094102 from mangrove rizhosphere produces ophiobolin and other terpenes. We obtained five gene cluster knockout mutants, with altered ophiobolin yield using genome sequencing and in silico analysis, combined with in vivo genetic manipulation. Involvement of the five gene clusters in ophiobolin synthesis was confirmed by investigation of the five key terpene synthesis relevant enzymes in each gene cluster, either by gene deletion and complementation or in vitro verification of protein function. The results demonstrate that ophiobolin skeleton biosynthesis involves five gene clusters, which are responsible for C15, C20, C25, and C30 terpenoid biosynthesis.


Relationships among intragastric meal distribution during gastric emptying scintigraphy, water consumption during water load satiety testing, and symptoms of gastroparesis.
Gastric emptying scintigraphy (GES) measures total gastric retention after a solid meal and can assess intragastric meal distribution (IMD). Water load satiety test (WLST) measures gastric capacity. Both IMD immediately after meal ingestion [ratio of proximal gastric counts after meal ingestion to total gastric counts at time 0 (IMD0)] and WLST (volume of water ingested over 5 min) are indirect measures of gastric accommodation. In this study, IMD0 and WLST were compared with each other and to symptoms of gastroparesis to gauge their clinical utility for assessing patients with symptoms of gastroparesis. Patients with symptoms of gastroparesis underwent GES to obtain gastric retention and IMD0, WLST, and filled out patient assessment of upper GI symptoms. A total of 234 patients with symptoms of gastroparesis were assessed (86 patients with diabetes, 130 idiopathic, 18 postfundoplication) and 175 (75%) delayed gastric emptying. Low IMD0 <0.568 suggesting initial rapid transit to the distal stomach was present in 8% and correlated with lower gastric retention, less heartburn, and lower volumes consumed during WLST. Low WLST volume (<238 mL) was present in 20% and associated with increased severity of early satiety, postprandial fullness, loss of appetite, and nausea. Low IMD0 is associated with less gastric retention and less heartburn. Volume of water consumed during WLST, while associated with IMD0, has associations with early satiety, postprandial fullness, loss of appetite, and nausea. Thus, IMD0 and WLST appear to overlap somewhat in their assessment of gastric physiology in adults with symptoms of gastroparesis but relate to different dyspeptic symptoms.NEW & NOTEWORTHY IMD0 and WLST were assessed for their clinical utility in assessing patients with symptoms of gastroparesis. Low IMD0 is associated with less gastric retention and less heartburn. Volume of water consumed during WLST, while associated with IMD0, has associations with early satiety, postprandial fullness, loss of appetite, and nausea. IMD0 and WLST appear to overlap somewhat in their assessment of gastric physiology in adults with symptoms of gastroparesis but relate to different dyspeptic symptoms.


Separation and quantitation of fatty acids, sterols and bile acids in feces by gas chromatography as the butyl ester-acetate derivatives.
A system allowing the separation and quantitation of individual species of fecal fatty acids, sterols and bile acids in a single chromatographic step is described. The system is based on the butylation of carboxyl groups and acetylation of free hydroxyls of the compounds in fecal lipid extracts, followed by their resolution by temperature-programmed gas chromatography. As the butyl ester-acetate derivatives, fatty acids, sterols and bile acids elute separately and with no overlap on a variety of chromatographic columns, obviating the need for prior separation of each class by thin-layer or column chromatography. All common bile acids, a wide variety of sterols and keto-steroids, as well as saturated and unsaturated fatty acids may be routinely resolved. Quantitation is facilitated by the addition of the internal standards, heptadecanoic acid and nor-deoxycholic acid to each sample. With an automatic sample injector, the rapid assessment of a wide range of potential risk factors for colorectal cancer may be carried out in large numbers of samples.


I heard it through the grapevine: On herd immunity and why it is important.
A. David Napier has been studying immunology and immunologists for more than three decades. In this article, he argues that the medicalization of viral epidemics has distracted us from the importance of their true social drivers: that is, the behaviour of people when they are together - what epidemiologists call human herds. On their own, viruses cannot 'invade' us. Our cells bring them to life and make them infectious through our social actions. Confusing viruses with invasive microbes not only leads us to misuse antibiotics, but fosters xenophobic responses towards outside carriers - as even our neighbours become categorical 'others' in the face of a foreign threat. Indeed, new work in viral epidemiology indicates that many viruses have infectious potential long before an epidemic develops. It is not only changes within viruses that cause epidemics, but also the condition of human herds - how we behave socially - that ignites the rapid circulation of viral information.


Early controlled mobilization using dart-throwing motion with a twist for the conservative management of an intra-articular distal radius fracture and scapholunate ligament injury: A case report.
This case describes an early controlled mobilization (ECM) approach that uses dart-throwing motion (DTM) with a twist orthoses as an alternative to immobilization for conservative management of a minimally displaced and intra-articular distal radius styloid fracture with an associated scapholunate ligament injury in a 47-year-old female health care administrator (JP). Pain-free active DTM began at day 10 (5 times/d) with a dynamic DTM with a twist orthosis worn during the day from weeks 3 to 6. At 6 weeks, JP had pain-free functional mobility and strength with minimal limitation in household and occupational activities, returning to her normal sporting activities by 3 months. ECM led to rapid return of normal functioning in the short term with no apparent impact on intermediate outcomes at 8 months. This case allows hand therapists to consider a similar ECM approach for the management of similar injuries in their patients. Level 5 and case report.


A randomised controlled trial of care of the perineum during second stage of normal labour.
To compare the effect of two methods of perineal management used during spontaneous vaginal delivery on the prevalence of perineal pain reported at 10 days after birth. Randomised controlled trial. Two English maternity care units. 5471 women who gave birth between December 1994 and December 1996. At the end of the second stage of labour women were allocated to either the 'hands on' method, in which the midwife's hands put pressure on the baby's head and support ('guard') the perineum; lateral flexion is then used to facilitate delivery of the shoulders, or the 'hands poised' method, in which the midwife keeps her hands poised, not touching the head or perineum, allowing spontaneous delivery of the shoulders. Perineal pain in the previous 24 hours reported by women in self-administered questionnaire 10 days after birth. Questionnaires were completed by 97% of women at 10 days after birth. 910 (34.1%) women in the 'hands poised' group reported pain in the previous 24 hours compared with 823 (31.1%) in the 'hands on' group (RR 1.10, 95% CI 1.01 to 1.18: absolute difference 3%, 0.5% to 5%, P = 0.02). The rate of episiotomy was significantly lower in the 'hands poised' group (RR 0.79, 99% CI 0.65 to 0.96, P = 0.008) but the rate of manual removal of placenta was significantly higher (RR 1.69, 99% CI 1.02 to 2.78; P = 0.008). There were no other statistically significant differences detected between the two methods. The reduction in pain observed in the 'hands on' group was statistically significant and the difference detected potentially affects a substantial number of women. These results provide evidence to enable individual women and health professionals to decide which perineal management is preferable.


Hepatic effects of xylidine isomers in rats.
The effect of repeated (4 weeks) oral administration of 2,4-, 2,5- or 2,6-xylidine (at dose levels of 400--500 mg/kg/day) on the morphology and microsomal drug metabolising enzyme activity of the liver was studied in rats. All 3 isomers caused hepatomegaly which was considered to be due to proliferation of the smooth endoplasmic reticulum. Decreases in glycogen content and glucose-6-phosphatase activity were demonstrated histochemically. Biochemical investigations showed increases in microsomal protein and cytochrome P-450 content in rats dosed with 2,4- or 2,5-xylidine and in glucuronyltransferase activity in rats given 2,4-, 2,5- or 2,6-xylidine. Aniline hydroxylase activity was increased in all treated rats except males dosed with 2,6-xylidine. The results of the study indicate that all isomes of xylidine can be inducers of microsomal drug-metabolising enzyme activity, that they may be metabolised by oxidation and that the xylidine molecule may be eliminated as a conjugate with glucuronic acid.


Genetic influences on spatial ability: transmission in an extended kindred.
Transmission of six spatial tests, Card Rotations, Cube Comparisons, Group Embedded Figures, Hidden Patterns, Mental Rotations, and portable Rod and Frame, is examined among 73 members in four generations of an extended kindred. Nonadditive genetic variance is substantial for one of the six tests, Card Rotations. Whether this nonadditive genetic variance is due to a major autosomal gene is equivocal based on results from segregation and linkage analysis. There is no evidence for genetic variance for Mental Rotations or Hidden Patterns, in contrast to previous findings suggesting major gene involvement (Ashton et al., 1979). If spatial ability is due, in part, to an autosomal major gene, the gene has variable expression (reflected in different tests) or genetic heterogeneity is pronounced.


Suprachiasmatic nucleus neurones: excitation and inhibition mediated by the direct retino-hypothalamic projection in female rats.
The suprachiasmatic nucleus (SCN) of female rats was surveyed with microelectrodes under urethane anaesthesia. In rats with bilateral transection of the optic tracts, repetitive three pulses of 100 Hz applied to the contralateral optic nerve excited 8 and inhibited 11 other of the 86 SCN units examined. Transection of the optic tract did not significantly influence frequency of occurrence of the SCN units that were excited or inhibited by stimulation of the optic nerve. Certain SCN units responded to both of contralateral and ipsilateral stimulations of the optic nerve, indicating that bilateral visual inputs converge on the same single SCN neurones. Oscillatory responses with a period of 100--200 msec were occasionally produced by stimulation of the optic nerve. Flash stimuli with relatively weak intensity, even insufficient for producing wavelets in electroretinograms, produced an excitation and inhibition in SCN units. The mean firing rates were significantly altered by either electrical or flash stimuli repeated 500 times at 0.97 Hz in those units which showed no transitory response. Some of the SCN neurones receiving visual inputs were identified to be the tuberoinfundibular neurone and some other SCN neurones were found to receive converging inputs both from the optic nerve and from the axon collaterals of tuberoinfundibular neurones.


Successful penile reimplantation after 8 h post penile self-mutilation: A case report.
Penile self-mutilation may result from a suicidal attempt during a major depression crisis. The management of this urological emergency should be multidisciplinary. A macroscopic penile reimplantation performed meticulously by a urological surgeon may yield an excellent cosmetic and functional outcome. Penile self-mutilation is an infrequent form of self-harming behavior seen primarily in patients with schizophrenia spectrum disorders and rarely reported in those with major depressive disorders.We herewith present a major depression related case of penile self-mutilation successfully managed by macroscopic penile reimplantation performed 8 h after the incident.


[Preliminary pharmacokinetics of metoclopramide in humans. Plasma levels following a single oral and intravenous dose (author's transl)].
A quantitative thin-layer chromatographic method is discribed for the determination of metoclopramide in human plasma for the 40--320 ng/ml range. Similar plasma levels were observed after single oral dosing with capsules (5 X 11.62 mg metoclopramide X 2 HC'L X H2O) and i.v. injection (2 X 11.62 mg metoclopramide X 2 HCl X H2O). The shape of the plasma level curve after i.v. administration indicates the presence of an open two-compartment model for metoclopramide in humans. Following a very short distributive phase an elimination phase is observed with a half-life of 3--6 h over the period studied. The present data suggest that under the conditions employed in this study metoclopramide is bioavailable by only about 50%; a "first-pass" metabolism is indicated.


Distribution, metabolism and excretion of butylidenephthalide of Ligustici chuanxiong rhizoma in hairless mouse after dermal application.
The absorption, distribution and excretion of butylidenephthalide after dermal application to hairless mouse have been examined with [8-14C]butylidenephthalide. By the investigation of the whole body autoradiogram and liquid scintillation analysis, it was indicated that the transdermally applied butylidenephthalide quickly permeate into peripheral circulation system without accumulation in the skin and then distribute into lung, liver, bile and kidney. The total radioactivity, however, was decreased due to excretion into urine, and in the case of i.v.-administration, 80% of the administered butylidenephthalide was excreted into urine within 24 h, while only 5% was excreted into feces within 24 h. Then, the metabolite in urine was determined to be a cysteine conjugate by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method. Thus, it has been concluded that after dermal application butylidenephthalide quickly permeates through skin into peripheral circulation system; distributes to lung, liver, bile and kidney; and then excreted into urine as a cysteine adduct.


[Blunt abdominal trauma in children and adolescents: treatment concepts in the acute phase].
Fatal accidents due to blunt force trauma are the leading cause of death in children and adolescents [1]. Abdominal trauma is the third most common cause of death after traumatic brain injury and thoracic injuries [2]. Abdominal injury is seen in approximately 2-5% of children involved in accidents [3]. Blunt abdominal injuries are common sequelae of traffic accidents (for example as seat belt injury), falls, and sports accidents. Penetrating abdominal injuries are rare in central Europe. Spleen, liver, and kidney lacerations are the most common injuries after blunt abdominal trauma [4]. In most situations, nonoperative management (NOM) has become the gold standard with the surgeon leading the multidisciplinary treatment [5].


Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial.
Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma. This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, 11, 22, 25, 29, and 32), and dexamethasone (20 mg orally on days 1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, and 32-33). Isatuximab was given as 10 mg/kg intravenously on days 1, 8, 15, 22, and 29 of cycle 1 and on days 1, 15, and 29 of cycles 2 and 3. The primary endpoint was minimal residual disease (MRD) negativity assessed by flow cytometry, in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT03617731. Between Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma. Sanofi and Bristol Myers Squibb (Celgene).


Regulation of chromatin structure by long noncoding RNAs: focus on natural antisense transcripts.
In the decade following the publication of the Human Genome, noncoding RNAs (ncRNAs) have reshaped our understanding of the broad landscape of genome regulation. During this period, natural antisense transcripts (NATs), which are transcribed from the opposite strand of either protein or non-protein coding genes, have vaulted to prominence. Recent findings have shown that NATs can exert their regulatory functions by acting as epigenetic regulators of gene expression and chromatin remodeling. Here, we review recent work on the mechanisms of epigenetic modifications by NATs and their emerging role as master regulators of chromatin states. Unlike other long ncRNAs, antisense RNAs usually regulate their counterpart sense mRNA in cis by bridging epigenetic effectors and regulatory complexes at specific genomic loci. Understanding the broad range of effects of NATs will shed light on the complex mechanisms that regulate chromatin remodeling and gene expression in development and disease.


Erratum to Cytotoxic Effects and Production of Cytokines Induced by the Endophytic Paenibacillus polymyxa RNC-D In Vitro.
CORRIGENDUM Corrigendum to Manuscript entitled Cytotoxic Effects and Production of Cytokines Induced by the Endophytic Paenibacillus polymyxa RNC-D In Vitro by Débora M. Neris1,3,*, Genoveva L.F. Luna2,3, Joice M. de Almeida Rodolpho1,3, Ana C. Urbaczek4, Ricardo de Oliveira Correia3, Karina A. Feitosa1,3, Nadja F.G. Serrano2,3, Cristina P. de Sousa2,3 and Fernanda de Freitas Anibal1,2,3. Curr. Pharm. Biotechnol., 2017; 18(9), 758-768. I hereby informed that all the authors agree with the inclusion of the name of the funding agency (FAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo) and the process number (2018/12846-5) to the acknowledgements section of the manuscript.


The place of the pain clinic.
Chronic pain is a debilitating and degrading condition. Its aetiology is largely multifactorial, and only proper appreciation of the various factors which can combine to produce the patient's misery will allow appropriate therapies. If the mechanisms of chronic pain were better taught and the therapies available were better used by medical practitioners, then the standard of alleviation of pain would increase greatly. There is an urgent need for greatly improved facilities for treating chronic pain by multidisciplinary groups in specialized clinics, a fact which has been realized for over 30 years. However, in spite of this there is a great delay in the setting up of such units. There is also an urgent need for proper training of doctors in pain relief, and a need for a much larger amount of money to be spent on research into the causes and treatment of human pain. It is disturbing to me that so much money goes on research into possible cures of malignant disease in the future, which is all very well, but which does not help the sufferer from severe pain at the present time; whereas these poor unfortunates, dying with their misery unassuaged, must suffer unnecessarily because of lack of information amongst physicians, and lack of proper facilities for treatment. Likewise, our own unit and many others have extremely long waiting lists, making even more difficult the treatment of an already complex problem. In spite of this, more than 50% of patients who attend multidisciplinary pain clinics obtain long-term benefit from their therapy. The fact that facilities do not exist for many sufferers is not only disgraceful, but also very expensive both from social security payments and from inappropriate use of health care facilities as these patients wander from clinic to clinic in search of a cure which is not available. Chronic pain should be recognized for what it is--a severe and debilitating condition--and proper steps should be taken to provide the treatment within the health service for its alleviation.


Evolution of randomized controlled trials and surrogacy of progression-free survival in advanced/metastatic urothelial cancer.
Clinical trials in advanced/metastatic urothelial cancer have been difficult to perform. We review the current characteristics of randomized controlled trials (RCTs) and evaluate whether PFS could be a potential surrogate endpoint for overall survival (OS) in advanced/metastatic urothelial cancer. We identified trials by a systematic review of Medline, Embase, and the Cochrane Central Register of Controlled Trials from inception to April 2017. We included RCTs of patients with locally advanced/metastatic urothelial cancer that involved systemic therapy as an intervention, and those with reported hazards ratios (HRs) and corresponding 95% confidence intervals (CIs) for both OS and PFS, or provided Kaplan-Meier curves from which HRs and 95% CI could be calculated. The correlation coefficient between log of HRs for OS and PFS was calculated using linear regression weighted by sample size. Forty eight trials that enrolled 7019 patients were included in the review and 24 RCTs were included in the surrogacy analysis. 27(56.3%) of identified 48 RCTs were phase II trials, and the median sample size was 107(range, 30-626) for all RCTs. The correlation coefficient between log HR for PFS and log HR for OS was 0.79 (95% CI, 0.58-0.91). The correlation coefficient increased to 0.87 (95% CI, 0.72-0.94) after excluding the only trial with immune checkpoint inhibitor. Multiple sensitivity analyses did not change the results..aph."/> CONCLUSIONS: PFS is strongly correlated with OS in trials of advanced/metastatic urothelial cancer assessing the treatment benefit of new drugs And PFS warrants further exploration as a surrogate endpoint in clinical trial datasets.


Whiplash injuries.
Whiplash injuries are very common and usually are associated with rear-end collisions. However, a whiplash injury can be caused by any event that results in hyperextension and flexion of the cervical spine. These injuries are of serious concern to all consumers due to escalating cost of diagnosis, treatment, insurance, and litigation. Most acute whiplash injury cases respond well to conservative treatments, which result in resolution of symptoms usually within weeks to a few months after the injury occurred. Chronic whiplash injuries often are harder to diagnose and treat and often result in poor outcomes. Current research shows that various structures in the cervical spine receive nociceptive innervation and potentially may be the cause of chronic pain symptoms. One potential pain generator showing promise is the facet or zygapophyseal joints. Various researchers have proven that these joints are injured during whiplash injuries and that diagnosis and temporary pain relief can be obtained with facet joint injections. The initial evaluation of any patient should follow an organized and stepwise approach, and more serious causes of neck pain must first be ruled out through the history, physical examination, and diagnostic testing. Treatment regimens should be evidence-based, focusing on treatments that have proven to be effective in treating acute and chronic whiplash injuries.


Enzyme-substrate interactions in the hydrolysis of peptides by cathepsins B and H from rat liver.
The number of possible subsites of the rat liver cysteine proteinases cathepsin B and cathepsin H was determined in the N-terminal direction from the scissile bond. An elongation of the substrate peptide chain of up to four amino acid residues enhances the hydrolysis rate of both cathepsins. The greatest increase in activity was observed by elongation to the dipeptide substrate for cathepsin B and to the tetrapeptide substrate for cathepsin H. Both proteinases discriminate proline from their subsites S1 and S2, but accept it well in S3. A quantitative distinction between the endopeptidase and the peptidyl dipeptidase activity of cathepsin B was feasible by using two model peptides: (Formula: see text) (Z = benzyloxycarbonyl; X = NH2 or OH; the arrow shows the cleavage site). Whereas the peptide acid, representing the peptidyl dipeptidase substrate, was hydrolysed by cathepsin B twice as fast as the peptide amide as an endopeptidase substrate, cathepsin H clearly had a preference for the amide substrate.


Application of minimally invasive treatment for early gastric cancer.
Although various types of minimally invasive treatment have emerged as the best front-line therapies for early gastric cancer (EGC), there have been no established indications that these attempts are applicable. The purpose of this study was to propose indications for the application of minimally invasive therapy for EGC. A total of 566 patients with EGC who had undergone gastrectomy with D2 or more extended lymphadenectomy, from July 1993 to December 1997 were retrospectively analyzed. The risk factors that determine lymph node metastasis were investigated by univariate and multivariate analysis. The rate of lymph node metastasis was 11.8% for all EGC, 3.4% for mucosal cancer, and 21.0% for submucosal cancer. Lymph node metastasis was associated with submucosal invasion, larger tumor size, undifferentiated histology, and the presence of lymphatic or blood vessel invasion (LBVI) by univariate and multivariate analyses. When LBVI was absent, there was no lymph node metastasis if the tumor was smaller than 2.5 cm with differentiated histology, and smaller than 1.5 cm with undifferentiated histology, regardless of depth of invasion. Extra-perigastric lymph node metastases were noted in patients with submucosal tumors that have LBVI while none of mucosal cancer showed extra-perigastric lymph node metastases. Minimally invasive treatment can be possibly applied for patients with EGC using these four independent risk factors for lymph node metastasis in EGC. For mucosal cancers, EMR is indicated for EGCs without lymph node involvement based on tumor size and histology. When we found LBVI by pathologic examination after EMR, gastrectomy with D1 lymph node dissection is mandatory. For submucosal cancers, patients with small tumors could be treated with laparoscopic wedge resection without lymph node dissection. However, patients with larger sized tumors or tumors with LBVI should be treated with extended (D2) lymph node dissection.


Differential effects of caffeine on DNA damage and replication cell cycle checkpoints in the fission yeast Schizosaccharomyces pombe.
Caffeine potentiates the lethal effects of ultraviolet and ionising radiation on wild-type Schizosaccharomyces pombe cells. In previous studies this was attributed to the inhibition by caffeine of a novel DNA repair pathway in S. pombe that was absent in the budding yeast Saccharomyces cerevisiae. Studies with radiation-sensitive S. pombe mutants suggested that this caffeine-sensitive pathway could repair ultraviolet radiation damage in the absence of nucleotide excision repair. The alternative pathway was thought to be recombinational and to operate in the G2 phase of the cell cycle. However, in this study we show that cells held in G1 of the cell cycle can remove ultraviolet-induced lesions in the absence of nucleotide excision repair. We also show that recombination-defective mutants, and those now known to define the alternative repair pathway, still exhibit the caffeine effect. Our observations suggest that the basis of the caffeine effect is not due to direct inhibition of recombinational repair. The mutants originally thought to be involved in a caffeine-sensitive recombinational repair process are now known to be defective in arresting the cell cycle in S and/or G2 following DNA damage or incomplete replication. The gene products may also have an additional role in a DNA repair or damage tolerance pathway. The effect of caffeine could, therefore, be due to interference with DNA damage checkpoints, or inhibition of the DNA damage repair/tolerance pathway. Using a combination of flow cytometric analysis, mitotic index analysis and fluorescence microscopy we show that caffeine interferes with intra-S phase and G2 DNA damage checkpoints, overcoming cell cycle delays associated with damaged DNA. In contrast, caffeine has no effect on the DNA replication S phase checkpoint in response to inhibition of DNA synthesis by hydroxyurea.


A high-content platform to characterise human induced pluripotent stem cell lines.
Induced pluripotent stem cells (iPSCs) provide invaluable opportunities for future cell therapies as well as for studying human development, modelling diseases and discovering therapeutics. In order to realise the potential of iPSCs, it is crucial to comprehensively characterise cells generated from large cohorts of healthy and diseased individuals. The human iPSC initiative (HipSci) is assessing a large panel of cell lines to define cell phenotypes, dissect inter- and intra-line and donor variability and identify its key determinant components. Here we report the establishment of a high-content platform for phenotypic analysis of human iPSC lines. In the described assay, cells are dissociated and seeded as single cells onto 96-well plates coated with fibronectin at three different concentrations. This method allows assessment of cell number, proliferation, morphology and intercellular adhesion. Altogether, our strategy delivers robust quantification of phenotypic diversity within complex cell populations facilitating future identification of the genetic, biological and technical determinants of variance. Approaches such as the one described can be used to benchmark iPSCs from multiple donors and create novel platforms that can readily be tailored for disease modelling and drug discovery.


Regulation of oxidative stress by Nrf2 in the pathophysiology of infectious diseases.
The innate immune system, including phagocytic cells, is the first line of defense against pathogens. During infection by microorganisms such as viruses, bacteria, or parasites, phagocytic cells produce an excess of oxidants, a crucial process for the clearance of pathogens. This increase in oxidants creates an imbalance between oxidants and endogenous antioxidants. Left unchecked, this acute or chronic oxidative stress can lead to apoptotic cell-death and oxidative stress-induced diseases including neurodegenerative and cardiovascular disorders, premature aging, secondary infections, and cancer. The activation of nuclear factor E2-related factor 2 (Nrf2) is an efficient antioxidant defensive mechanism used by host cells to counteract oxidative stress. The transcription factor Nrf2 has been identified as the master regulator of several hundred of genes involved in the antioxidant defense response. The review objectives were to collect recent findings on the contribution of oxidative stress to complications of infection, and to highlight the beneficial impact of antioxidants in reducing inflammation and oxidant-related tissue damage. Furthermore, a direct relationship between infection and decline in Nrf2 activity has been demonstrated. Thus, an interesting therapeutic approach in disease prevention and treatment of stress-related diseases may consist in optimizing antibiotic or antiviral therapy with a combination of Nrf2 inducer treatment.


Morphological and biochemical modifications during neuroblastoma cell differentiation.
In order to define some distinctive criteria of differentiation, we studied the effects of retinoic acid (RA), γ-interferon (γ-IFN), cytosine arabinoside (ARA-C), nerve growth factor (NGF), tumor necrosis factor (TNF), and 12-0-tetradecanoylphorbol-13 acetate (TPA) on the human neuroblastoma cell line, LAN-5. Intracellular levels of acetylcholinesterase, neuron specific enolase, catecholamines, and related neurotransmitters were evaluated after 8 days of treatment with various inducers. Our data indicate that the most striking biochemical changes accompanying LAN-5 cell differentiation are a shift from a catecholaminergic to a cholinergic phenotype, and/or a drastic increase in the catecholamines levels. Moreover, small changes may be independent of thein vitro maturation. Thus, biochemical phenotyping, more than morphological evaluation, is a fruitful approach to monitor neuronal cell differentiation.


BARTONELLA QUINTANA-ASSOCIATED NEURORETINITIS: LONGITUDINAL SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHIC FINDINGS.
To report an unusual case of neuroretinitis caused by Bartonella quintana and its spectral-domain optical coherence tomographic (SD-OCT) features. A 12-year-old girl presented with unilateral neuroretinitis with stellate maculopathy. Bartonellosis was confirmed after serologic testing for antibodies to B. quintana. Color photograph of the right eye revealed papillitis and stellate macular exudation. spectral-domain optical coherence tomography of the right eye revealed hyperreflective dots in the outer nuclear and outer plexiform layers, as well as disruption and loss of the external limiting membrane, ellipsoid zone, and interdigitation zone in the foveal area. The authors report an unusual case of neuroretinitis by B. quintana and its spectral-domain optical coherence tomographic findings.


Verifying monitor unit calculations for tangential whole breast fields in 3-dimensional planning.
An essential component of quality assurance in radiation therapy is verifying the accuracy of monitor unit calculations. For tangential breast fields, monitor unit differences between primary calculations and second checks are usually larger than considered acceptable at other anatomical sites. A simple model to reconcile the differences between sophisticated and simple algorithms is presented, based on estimating the the volume irradiated by the field, replacing the breast contour with a rectangular block having an equal volume but a new field width which provides almost equivalent scatter to the prescription point. This analysis can also assist the treatment planning physicist in selecting a tolerance window for verifying monitor unit calculations for tangential breast fields.


A new absolute method for the standardization of radionuclides emitting low-energy radiation.
Microcalorimeters (or bolometers) operated at temperatures below 100 mK allow individual counting of photons and electrons with a very low energy detection threshold. The physics is based on the pulse temperature increase of the target (or absorber) of the detector due to the complete absorption of both electrons and photons. Since this target can be constructed with a perfect 4-pi geometry, a bolometer offers potentially a new method for absolute activity measurements of radionuclides emitting low-energy radiation. In this paper we present our first results of a feasibility study of activity standardization of a 55Fe solution with a prototype 4-pi bolometer.


Shock Wave Intravascular Lithotripsy (IVL)-Assisted Staged Percutaneous Coronary Intervention (PCI) for a Calcified Right Coronary Artery in a Patient With Unstable Angina: Shock the Rock.
Coronary artery calcification represents one of the challenging and demanding subsets of percutaneous coronary intervention (PCI). Accumulated evidence has aptly outlined that shockwave intravascular lithotripsy (IVL) is a reliable tool to overcome calcified stenosis in coronary arteries. However, there is a lack of published case reports in the Indian context. Herein, we describe a case of right coronary artery (RCA) calcifications successfully managed with shock wave IVL-assisted staged PCI. Initially, a 74-year-old male patient presented with ST-segment elevation myocardial infarction (STEMI). At that time, coronary angiography demonstrated calcific thrombotic occlusion in the left anterior descending artery (LAD) and stenosis in proximal and mid tubular RCA. It was decided to proceed with immediate PCI of LAD followed by staged PCI of RCA. The patient presented with unstable angina at the time of the second repeat PCI of RCA and was managed with shock wave IVL-assisted staged PCI. Ultimately, the patient's condition was improved with good thrombolysis in myocardial infarction (TIMI) flow.


In vitro fatigue behavior and in vivo osseointegration of the auxetic porous bone screw.
The incidence of screw loosening, migration, and pullout caused by the insufficient screw-bone fixation stability is relatively high in clinical practice. To solve this issue, the auxetic unit-based porous bone screw (AS) has been put forward in our previous work. Its favorable auxetic effect can improve the primary screw-bone fixation stability after implantation. However, porous structure affected the fatigue behavior and in vivo longevity of bone screw. In this study, in vitro fatigue behaviors and in vivo osseointegration performance of the re-entrant unit-based titanium auxetic bone screw were studied. The tensile-tensile fatigue behaviors of AS and nonauxetic bone screw (NS) with the same porosity (51%) were compared via fatigue experiments, fracture analysis, and numerical simulation. The in vivo osseointegration of AS and NS were compared via animal experiment and biomechanical analysis. Additionally, the effects of in vivo dynamic tensile loading on the osseointegration of AS and NS were investigated and analyzed. The fatigue strength of AS was approximately 43% lower while its osseointegration performance was better than NS. Under in vivo dynamic tensile loading, the osseointegration of AS and NS both improved significantly, with the maximum increase of approximately 15%. Preferrable osseointegration of AS might compensate for the shortage of fatigue resistance, ensuring its long-term stability in vivo. Adequate auxetic effect and long-term stability of the AS was supposed to provide enough screw-bone fixation stability to overcome the shortages of the solid bone screw, developing the success of surgery and showing significant clinical application prospects in orthopedic surgery. STATEMENT OF SIGNIFICANCE: This research investigated the high-cycle fatigue behavior of re-entrant unit-based auxetic bone screw under tensile-tensile cyclic loading and its osseointegration performance, which has not been focused on in existing studies. The fatigue strength of auxetic bone screw was lower while the osseointegration was better than non-auxetic bone screw, especially under in vivo tensile loading. Favorable osseointegration of auxetic bone screw might compensate for the shortage of fatigue resistance, ensuring its long-term stability and longevity in vivo. This suggested that with adequate auxetic effect and long-term stability, the auxetic bone screw had significant application prospects in orthopedic surgery. Findings of this study will provide a theoretical guidance for design optimization and clinical application of the auxetic bone screw.


First Report of the Clinical Use of a Commercial Automated System for Daily Patient QA Using EPID Exit Images.
To characterize the clinical utility of a new commercially available system for daily patient treatment quality assurance using electronic portal imaging detector (EPID) exit dose images. The PerFRACTION automated quality assurance system was used to acquire integrated EPID images for every field every day for 60 treatment courses for 57 patients. Four thousand seventy-nine field values from 855 fractions were analyzed. Gamma passing rates were computed by the system for each field daily. Passing rates and pass-fail status were recorded by treatment modality (intensity modulated radiation therapy or 3-dimensional conformal radiotherapy) and location. When failures occurred, an attempt was made to determine the reason. Overall, 23% and 8% of fields failed at 2%/2 mm and 3%/3 mm, respectively. Forty-eight percent and 24% of fields failed at least once during the course of therapy for the 2 tolerance settings. Eighteen percent and 8% of all fractions failed and 60% and 28% of courses failed for the 2 tolerance settings, respectively. Eighteen percent of daily field passing rates were below 75% for 3%/3 mm tolerances. Intensity modulated radiation therapy had higher passing rates than 3-dimensional conformal radiation therapy. For 3%/3 mm tolerances, the fraction fail rate for the brain, extremity, and spine treatment sites failed the least, whereas the abdomen, chest, and head and neck failed more often. The most commonly identified reason for failure was body position change, but the reason for about half the daily field value failures could not be identified. This is the first report of the clinical utility of a commercial daily patient treatment quality assurance system using EPID exit images. Variations were found in a clinically relevant percentage of images, and these potentially indicate important treatment variations. Reasons for failures are not always discernable. The system was practical to use because of automation and continues to be used for monitoring of nearly every patient in every field every day.


Influence of chemical composition, porosity and fractal dimension on the electrical conductivity of carbon blacks.
Carbonaceous materials analyzed in this investigation were six nanometric particle size carbon blacks. Carbons were texturally characterized by gas adsorption (N2, 77 K), helium and mercury density and mercury porosimetry measurements. Electrical conductivity was determinated by impedance spectroscopy, at room temperature. Several works related to the electrical conductivity and to textural parameters of carbon blacks, such as: porosity, specific surface area, etc., have been carried out. However, there are a type of parameters, such as the fractal dimension, the percentage of macropores, the particle size, or the packing density, that are also related to the electrical conductivity, but they have not been previously investigated. In this work, it has been researched how the increase in interparticle/intraparticle porosity decreases the electrical conductivity of the samples studied. Therefore, it is possible to conclude that in this study a complete research work on electrical conductivity has been carried out.


SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells.
The cystine transporter solute carrier family 7 member 11 (SLC7A11; also called xCT) protects cancer cells from oxidative stress and is overexpressed in many cancers. Here we report a surprising finding that, whereas moderate overexpression of SLC7A11 is beneficial for cancer cells treated with H2O2, a common oxidative stress inducer, its high overexpression dramatically increases H2O2-induced cell death. Mechanistically, high cystine uptake in cancer cells with high overexpression of SLC7A11 in combination with H2O2 treatment results in toxic buildup of intracellular cystine and other disulfide molecules, NADPH depletion, redox system collapse, and rapid cell death (likely disulfidptosis). We further show that high overexpression of SLC7A11 promotes tumor growth but suppresses tumor metastasis, likely because metastasizing cancer cells with high expression of SLC7A11 are particularly susceptible to oxidative stress. Our findings reveal that SLC7A11 expression level dictates cancer cells' sensitivity to oxidative stress and suggests a context-dependent role for SLC7A11 in tumor biology.


No place to shelter: ethnography of the homeless population in the COVID-19 pandemic.
to analyze how homeless people live, in times of COVID-19 pandemic, in the city of Rio de Janeiro. an ethnographic research that used interviews and observations and articles published in newspapers and magazines of great circulation, using domain analysis. the results tell how the COVID-19 pandemic emerged for the homeless population. Isolation led to emptying the streets and reducing passers-by, damaging their ways of living and their survival tactics. Hunger, thirst, absence of places for bathing and for fulfilling physiological needs became part of their daily lives. given the impossibility of having a place to shelter, acquiring food and water and the limitations in carrying out preventive measures, care actions offered by managers to limit the virus to spread, even in this population, are ineffective.


β-hairpin peptide that targets vascular endothelial growth factor (VEGF) receptors: design, NMR characterization, and biological activity.
VEGF receptors have been the target of intense research aimed to develop molecules able to inhibit or stimulate angiogenesis. Based on the x-ray structure of the complex placental growth factor-VEGF receptor 1(D2), we designed a VEGF receptor-binding peptide reproducing the placental growth factor β-hairpin region Gln(87)-Val(100) that is involved in receptor recognition. A conformational analysis showed that the designed peptide adopts the expected fold in pure water. Moreover, a combination of NMR interaction analysis and cell binding studies were used to demonstrate that the peptide targets VEGF receptors. The VEGF receptor 1(D2)-interacting residues were characterized at the molecular level, and they correspond to the residues recognizing the placental growth factor sequence Gln(87)-Val(100). Finally, the peptide biological activity was characterized in vitro and in vivo, and it showed a VEGF-like behavior. Indeed, the peptide activated VEGF-dependent intracellular pathways, induced endothelial cell proliferation and rescue from apoptosis, and promoted angiogenesis in vivo. This compound is one of the few peptides known with proangiogenic activity, which makes it a candidate for the development of a novel peptide-based drug for medical applications in therapeutic angiogenesis.


Analysis of postrevascularization syndrome after orthotopic liver transplantation: the experience of an Australian liver transplantation center.
We investigated the causes and examined patient outcomes following the postrevascularization syndrome (PRS) during orthotopic liver transplantation (OLTx). PRS was defined as a fall in the mean arterial pressure at 5 min after revascularization to less than 70% of the baseline and lasting for 5 min. Data from 100 adult patients who underwent OLTx between January 1998 and September 2000 were analyzed. Analyzed data included donor and recipient demographic data, recipient operative and postoperative courses, and recipient outcome. Twenty-nine patients (29%) exhibited PRS during OLTx (PRS group). There was a higher incidence of older donors (>50 years) in the PRS group (48% vs 23%; P < 0.05). Postrevascularization hyperkalemia and metabolic acidosis were observed in both the PRS and non-PRS groups. Transaminase and lactate levels after revascularization were significantly higher in the PRS group ( P < 0.05). Alkaline phosphatase and gamma-glutamyl transpeptidase levels on day 7 tended to be higher in the PRS group; although the difference was not significant (p > or = 0.05). Serum creatinine was significantly elevated on day 7 in the PRS group ( P < 0.01). Our results indicate that PRS following OLTx tended to be more common in liver allografts from older donors and was associated with posttransplantation liver and renal dysfunction.


Distortion of the terminal portion of the QRS is associated with poor collateral flow before and poor myocardial perfusion after percutaneous revascularization for myocardial infarction.
The distortion of the terminal portion of the QRS has been related to adverse outcome in patients with ST-segment elevation myocardial infarction. We studied the relationship of this electrocardiographic pattern with the angiographic findings in patients treated with percutaneous revascularization for ST-segment elevation myocardial infarction. We included 349 patients, 318 treated with primary angioplasty and 31 with rescue angioplasty after failed thrombolysis. Eighty-five patients were found with distortion of the terminal portion of the QRS complex (group 1) and 264 without it (group 2). Collateral flow was absent in 30 patients (35%) from group 1, versus 52 patients (20%) from group 2 [odds ratio (OR) 1.806, 1.097-2.974, P 0.019]. No-reflow occurred in 12 (14%) patients in group 1 versus 17 (6.4%) in group 2 (OR 2.388, 1.091-5.230, P 0.016). Myocardial perfusion was graded 2-3 in 28 patients (58%) of group 1 versus 98 (76%) in group 2 (OR 0.443, 0.220-0.893, P 0.021). Patients with ST-segment elevation myocardial infraction showing distortion of the terminal portion of the QRS have worse collateral flow, and present more often no-reflow or poor myocardial perfusion after percutaneous revascularization. These data contribute to explain the worse clinical outcome of these patients.


[Odontogenic focus as the etiology of cerebral ischemia].
Recent studies have shown that acute infections, especially of the respiratory tract, are an important risk factor for cerebral ischemia. Additionally we know that chronic dental infections may be a risk for myocardial infarction and artherosclerosis. However, the connection between stroke and dental infections has hardly been examined so far. Therefore we performed a case-control study using a standardized questionaire and examination. We investigated 66 patients consecutive to a acute cerebral ischemia/stroke and 60 age- and sex-matched nonstroke neurological patients as a control group. Dental status was determined by a so called total dental index (TDI) which reflects primarily caries, periodontitis, periapical lesions, devital and missing teeth as well as by a panoramic index (PI). Specifically, older patients with cerebrovascular ischemia tended to have a significantly worse dental status and had more severe periodontitis and periapical lesions than control subjects. A predefined poor dental status was associated with cerebrovascular ischemia independent from other vascular risk factors and social status. In conclusion, poor dental health, mainly resulting from chronic dental infections, may be associated with an increased risk for cerebrovascular ischemia. The results must now be verified in larger studies. As chronic dental infections are a common and also easily treatable factor, their identification as a risk factor for stroke would be quite important in the field of preventive medicine.


Anesthetic considerations for emergency equine abdominal surgery.
The physiologic changes that take place in horses presented for emergency abdominal surgery and the effects of these changes on the horse's anesthetic management are discussed.