Effect of various aminoglycoside antibiotics on glucose formation in isolated rabbit kidney-cortex tubules.
The effect of six aminoglycoside antibiotics on the rate of gluconeogenesis was studied in isolated rabbit kidney-cortex tubules incubated with various substrates. All antibiotics studied did not affect glucose formation from both malate and 2-oxoglutarate. The rank order of the drug-induced inhibition of glucose formation from lactate, pyruvate and propionate was the following: neomycin = gentamicin greater than tobramycin greater than kanamycin = amikacin greater than streptomycin. This in principle corresponds to their ability to diminish pyruvate carboxylation in isolated kidney-cortex mitochondria, as well as to their known nephrotoxic potential observed in vivo. Aminoglycoside antibiotics decreased the respiration of tubule suspension incubated with various substrates. However, the rank order of the inhibition by antibiotics of oxygen uptake was different from that observed for gluconeogenesis, suggesting that the rate of energy generation does not limit glucose formation under conditions studied.


Trazodone regulates neurotrophic/growth factors, mitogen-activated protein kinases and lactate release in human primary astrocytes.
In the central nervous system, glial cells provide metabolic and trophic support to neurons and respond to protracted stress and insults by up-regulating inflammatory processes. Reactive astrocytes and microglia are associated with the pathophysiology of neuronal injury, neurodegenerative diseases and major depression, in both animal models and human brains. Several studies have reported clear anti-inflammatory effects of anti-depressant treatment on astrocytes, especially in models of neurological disorders. Trazodone (TDZ) is a triazolopyridine derivative that is structurally unrelated to other major classes of antidepressants. Although the molecular mechanisms of TDZ in neurons have been investigated, it is unclear whether astrocytes are also a TDZ target. The effects of TDZ on human astrocytes were investigated in physiological conditions and following inflammatory insult with lipopolysaccharide (LPS) and tumour necrosis factor-α (TNF-α). Astrocytes were assessed for their responses to pro-inflammatory mediators and cytokines, and the receptors and signalling pathways involved in TDZ-mediated effects were evaluated. TDZ had no effect on cell proliferation, but it decreased pro-inflammatory mediator release and modulated trophic and transcription factor mRNA expression. Following TDZ treatment, the AKT pathway was activated, whereas extracellular signal-regulated kinase and c-Jun NH2-terminal kinase were inhibited. Most importantly, a 72-h TDZ pre-treatment before inflammatory insult completely reversed the anti-proliferative effects induced by LPS-TNF-α. The expression or the activity of inflammatory mediators, including interleukin-6, c-Jun NH2-terminal kinase and nuclear factor κB, were also reduced. Furthermore, TDZ affected astrocyte metabolic support to neurons by counteracting the inflammation-mediated lactate decrease. Finally, TDZ protected neuronal-like cells against neurotoxicity mediated by activated astrocytes. These effects mainly involved an activation of 5-HT1A and an antagonism at 5-HT2A/C serotonin receptors. Fluoxetine, used in parallel, showed similar final effects nevertheless it activates different receptors/intracellular pathways. Altogether, our results demonstrated that TDZ directly acts on astrocytes by regulating intracellular signalling pathways and increasing specific astrocyte-derived neurotrophic factor expression and lactate release. TDZ may contribute to neuronal support by normalizing trophic and metabolic support during neuroinflammation, which is associated with neurological diseases, including major depression.


Conformational fluctuation in palladium(II)-methyl aldopentopyranoside complexes.
Four methyl d-pentopyranosides (β-Ara, α-Lyx, β-Rib, β-Xyl), as well as Me-β-l-Ara, some of them residing in a well-defined conformation in the solution state (Ara, Xyl) and some showing pronounced chair inversion in solution (Lyx, Rib), form bidentate chelates of the general formula [Pd(chxn)(LH₋₂)-κO,O'] and [Pd(tmen)(LH₋₂)-κO,O'], chxn=(R,R)-cyclohexane-1,2-diamine, tmen=N,N,N',N'-ethane-1,2-diamine and L=glycoside, with Pd(II)N₂-type metal probes. The dynamic behaviour of the free glycosides is maintained in their chelates, the only case where the metal is bonded by a cis-vicinal diol function. Thus, one fluctuating chelate was detected with the lyxopyranoside in the κO(2,3) binding mode, and two fluctuating chelates were found for the ribopyranoside (κO(2,3) and κO(3,4)). No fluctuating chelate was found for the arabinopyranoside (the free arabinopyranoside being non-fluctuating as well), or for the xylopyranoside (no cis-vicinal diol function). In addition, syn-diaxial chelation (κO(2,4)) was observed for the ribopyranoside and the xylopyranoside. The spectroscopic results were supplemented by X-ray analyses.


Inflammatory and metabolic markers and short-time outcome in patients with acute ischemic stroke in relation to TOAST subtypes.
The aim of this study was to evaluate the association between inflammatory and metabolic markers and short-time outcome with acute ischemic stroke subtypes. A total of 121 patients was classified according to TOAST criteria, such as large artery atherosclerosis (LAAS), lacunar infarct (LAC), cardioembolic infarct (CEI), other determined etiology (ODE), and undetermined etiology (UDE). The functional impairment was evaluated within the first eight hours of stroke and the outcome after three-month follow-up using the modified Rankin Scale. Blood samples were obtained up to 24 h of stroke. Compared with 96 controls, patients with LAAS, CEI, and LAC subtypes showed higher levels of white blood cells, high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), metalloproteinase 9 (MMP-9), glucose, and iron (p < 0.05); and lower high-density lipoprotein cholesterol (HDL-C) (p < 0.0001); platelets, insulin, insulin resistance, and homocysteine were higher in LAC (p < 0.0001); ferritin was higher in LAAS (p < 0.0001); and total cholesterol (TC) was lower in LAAS and CEI (p < 0.01). When stroke subtypes were compared, insulin was higher in LAAS vs. LAC and in LAC vs. CEI (p < 0.05); and TC was lower in LAAS vs. LAC (p < 0.05). Outcome and rate of mortality after three-month were higher in LAAS vs. LAC (p < 0.001 and p = 0.0391 respectively). The results underscored the important role of the inflammatory response and metabolic changes in the pathogenesis of ischemic stroke subtypes that might be considered on the initial evaluation of stroke patients to identify those that could benefit with individualized therapeutic strategies that taken into account these markers after acute ischemic event.


Oligodendroglioma with Neuronal Differentiation in Two Boxer Dogs.
Two cases of high-grade glioma comprising sheets of oligodendroglial cells multifocally disrupted by regions of remarkable neuronal differentiation are described. These tumours morphologically resemble 'oligodendroglioma with ganglioglioma-like maturation', a rare tumour of man, but appear to be phenotypically more aggressive. Neuronal markers (synaptophysin, neuron-specific enolase and βIII-tubulin) effectively highlight neuronal elements within these tumours and could potentially help to further investigate the prevalence and biological significance of neuronal differentiation in canine oligodendroglioma.


Conservation of the ID sequence and its expression as small RNA in rodent brains: analysis with cDNA for mouse brain-specific small RNA.
Two cDNA clones for mouse brain-specific small RNA were isolated, whose sequences turn out to be highly homologous to that of a genomic mouse ID-like clone isolated previously. By use of one of these cDNA clones as a probe, the copy numbers of ID-related sequences in several mammalian species were determined. The ID sequence was found to be conserved in mice, rats, hamsters and guinea pigs, but not in non-rodent species. There were about 3 orders of magnitude of difference in the copy numbers of the gene, i.e. rat 4.0 X 10(4), mouse 4.5 X 10(2), hamster 1.5 X 10(2), and guinea pig less than 50. The gene was transcribed as small RNA in the brain of rodent species. The relative concentration of small RNA in the brain was roughly proportional to the copy number of the ID sequence in mice, hamsters, and probably in guinea pigs also. On the other hand, the amount of the RNA in rat brain was much less than that expected from the large copy number of the gene. On the basis of these observations, the possibility is discussed that most of the ID sequences in the rat are pseudogenes.


The role of CXCR3 and its ligands expression in Brucellar spondylitis.
Brucellar spondylitis (BS) is one of the most serious complications of brucellosis. CXCR3 is closely related to the severity of disease infection. This research aimed to study the degree of BS inflammatory damage through analyzing the expression levels of CXCR3 and its ligands (CXCL9 and CXCL10) in patients with BS. A total of 29 BS patients and 15 healthy controls were enrolled. Real-Time PCR was used to detect the mRNA expression levels of IFN-γ, CXCR3, CXCL9 and CXCL10 in peripheral blood mononuclear cells (PBMCs) of BS patients and healthy controls. Hematoxylin-Eosin staining was used to show the pathological changes in BS lesion tissues. Immunohistochemistry staining was used to show the protein expression levels of Brucella-Ab, IFN-γ, CXCR3, CXCL9 and CXCL10 in BS lesion tissues. At the same time, ELISA was used to detect the serum levels of IFN-γ, CXCL9 CXCL10 and autoantibodies against CXCR3 in patients with BS. In lesion tissue of BS patients, it showed necrosis of cartilage, acute or chronic inflammatory infiltration. Brucella-Ab protein was abundantly expressed in close lesion tissue. And the protein expression levels of IFN-γ, CXCR3 and CXCL10 were highly expressed in close lesion tissue and serum of BS patients. At the same time, the mRNA expression levels of IFN-γ, CXCR3 and CXCL10 in PBMCs of BS patients were significantly higher than those in controls. In our research, the expression levels of IFN-γ, CXCR3 and its ligands were significantly higher than those in controls. It suggested that high expression levels of IFN-γ, CXCR3 and its ligands indicated a serious inflammatory damage in patients with BS.


Successful treatment of CMV, EBV, and adenovirus tissue infection following HLA-mismatched allogeneic stem cell transplant using infusion of third-party T cells from multiple donors in addition to antivirals, rituximab, and surgery.
Viral infections, principally cytomegalovirus, Epstein Barr virus (EBV) and adenovirus, are a leading cause of morbidity and mortality after allogeneic stem cell transplantation. The use of systemic antivirals is limited by limited efficacy and organ toxicities. Inability to clear infection is exacerbated by transplant-related immunosuppression and prophylaxis or treatment of acute graft versus host disease. We report the first patient to clear three serious viral infections after stem cell transplant using third-party donor partially human leukocyte antigen (HLA) matched virus-specific cytotoxic T cells. The patient, a 53 year old female with transplanted for relapsed leukemia, with severe graft versus host disease received five T cell infusions from three separate donors that ultimately cleared serious systemic infections with cytomegalovirus and adenovirus, and an EBV-driven lymphoma. Systemic antivirals had resulted in failed clinical responses. Use of repeated infusions of partially HLA matched virus-specific T cells from banks containing cryopreserved cells should be strongly considered in transplant recipients with single or multiple refractory viral infections.


Propagule type influences competition between two submersed aquatic macrophytes.
Glasshouse competition experiments with Hydrilla verticillata (L.f.) Royle indicate that plants grown from turions are weaker competitors than those grown from tubers, when compared to the widely distributed macrophyte, Potamogeton pectinatus L. These results support an earlier hypothesis about the importance of propagule size for predicting the outcome of plant competition (Grace 1985; Schaffer and Gadgil 1980). Results of outdoor growth experiments indicate that even though Hydrilla plants from turions are relatively weaker competitors, they are able to grow succesfully in an existing macrophyte bed composed of either, P. pectinatus or P. gramineus. During the early stages of Hydrilla invasion into an area of existing macrophytes, native plants may coexist with Hydrilla. However, once the abundance of Hydrilla tubers in the sediment increases, Hydrilla may displace existing plants.


Tracing our roots: the rocky road toward recognition of clinical laboratory science's professional status (1962-1977).
To discuss the progress clinical laboratory science made between 1962 and 1977 toward developing and acquiring characteristics associated with the traditional professions of medicine and law. A survey of literature on the history of clinical laboratory science was conducted. References consulted included various books and professional journals. Between 1962 and 1977, the field of clinical laboratory science experienced many changes. Medical technologists in supervisory positions became more involved in higher management functions, such as organizing and directing laboratory operations. Clinical laboratory science educators developed graduate programs that would prepare faculty for positions in two- and four-year colleges and in hospital-based programs.


Macular hole in cat scratch disease.
To report the development of a macular hole as a complication of cat scratch disease. Case report. A 10-year-old girl was seen with unilateral neuroretinitis from serologically confirmed cat scratch disease. Twelve days later, she developed a macular hole in the involved eye. Fundus photography and optical coherence tomography (OCT) were obtained at presentation and after the development of a macular hole. Fundus photography and OCT on presentation revealed a nasal neurosensory detachment and multiple inflammatory foci throughout the macula, including a subfoveal lesion. Fundus photography and OCT 12 days later revealed the development of a partial posterior vitreous detachment and a full thickness macular hole. Macular hole should be included among posterior segment complications of cat scratch disease. In this case, the macular hole was associated with partial vitreous detachment and a preexisting subfoveal lesion, likely representing an inflammatory focus.


Endothelium-derived relaxing factors and the human pulmonary circulation.
The vasodilator effect of acetylcholine on the pulmonary circulation was first described over 30 years ago, however, the mechanism remained unknown until Furchgott described the endothelium-dependent relaxation of certain vasodilators. It was not until 1987 that endothelium-derived relaxant factor (EDRF) was demonstrated to dilate human pulmonary arteries in vitro. Despite this work, the physiologic role of EDRF in the pulmonary circulation is not known. It has been suggested that hypoxia-induced inhibition of EDRF action or release from pulmonary artery endothelial cells may have a role in hypoxic pulmonary vasoconstriction (HPV) but present evidence suggests that loss of EDRF activity is not directly involved in the phenomenon of HPV. It is more likely that EDRF is released from pulmonary artery endothelial cells during hypoxia and this released EDRF then modulates HPV. If EDRF does modulate HPV in vivo then the role of EDRF in the altered HPV found in disease merits attention. It is known that in disease states such as acute lung injury and pneumonia there is loss or attenuation of HPV which inevitably leads to increased V/Q mismatch and hypoxemia. Whether this attenuation of HPV is due to release of an endogenous vasodilator such as EDRF is presently being investigated. Additionally, there is in vitro evidence that loss of EDRF activity may be important in the genesis of pulmonary hypertension such as found in severe cystic fibrosis. During the next decade the role of EDRF in the human pulmonary circulation in both health and disease will undoubtedly be elucidated.


Randomized controlled trial of late in-hospital angiography and angioplasty versus conservative management after treatment with recombinant tissue-type plasminogen activator in acute myocardial infarction.
Although both the European Cooperative Study Group and the Thrombolysis in Myocardial Infarction IIB trial indicated that angiography and angioplasty as routine measures after thrombolytic treatment do not improve clinical outcome in patients with acute myocardial infarction, the potential benefit of angioplasty may have been negated by the fact that the procedure was performed too soon (less than 32 hours) after admission. A similar study was designed in which delayed invasive treatment was compared with conservative treatment in 201 patients with acute myocardial infarction given recombinant tissue-type plasminogen activator. The 97 patients randomized to the invasive group underwent routine coronary angiography and angioplasty 5 +/- 2 days after thrombolytic therapy, whereas the 104 patients randomized to the conservative group underwent angiography only for recurrent postinfarction angina or exercise-induced ischemia. Baseline characteristics of both groups were similar. In the invasive group, 92 patients underwent angiography, 49 angioplasty and 11 coronary artery bypass surgery. In the conservative group, 40 patients experienced early ischemia, 39 underwent angiography, 20 angioplasty and 4 coronary artery bypass surgery. Reinfarction rate and preservation of left ventricular function at discharge or 8 weeks after discharge did not differ in the 2 groups. Total mortality after a mean follow-up of 10 months was 8 of 97 in the invasive and 4 of 104 in the conservative groups (p = 0.15). However, if only patients who died after the timing of the scheduled protocol catheterization in the invasive arm were included, mortality was 5 of 94 and 0 of 100 in the invasive and conservative treatment groups, respectively (p = 0.02). (ABSTRACT TRUNCATED AT 250 WORDS)


Targeting LSCs through membrane antigens selectively or preferentially expressed on these cells.
Studies of xenotransplantation of bone marrow and blood cells of AML patients have supported the existence of rare leukemic stem cells, able to initiate and maintain the leukemic process and bearing the typical leukemic abnormalities. LSCs possess self-renewal capacity and are responsible for the growth of the more differentiated leukemic progeny in the bone marrow and in the blood. These cells are more resistant than bulk leukemic cells to anti-leukemic drugs, thus survive to treatment and are, at a large extent, responsible for leukemia relapse. During the last two decades, considerable progresses have been made in the understanding of the peculiar cellular and molecular properties of LSCs. In this context, particularly relevant was the discovery of several membrane markers, selectively or preferentially expressed on LSCs. These membrane markers offer now unique opportunities to identify LSCs and to distinguish them from normal HSCs, to monitor the response of the various anti-leukemic treatments at the level of the LSC compartment, to identify relevant therapeutic targets. Concerning this last point, the most promising therapeutic targets are CD33 and CD123.


Evaluation of error sources in a gravimetric technique for preparation of a reference gas mixture (carbon dioxide in synthetic air).
One method of preparing a primary reference gas mixture is the gravimetric blending method. Uncertainty of a few mg in mass measurements is unavoidable when preparing reference gas mixtures under current laboratory conditions with our facilities, equipment, and materials. There are many sources of errors when using this method. In this study, several sources of errors were re-evaluated for our process for preparation of carbon dioxide in synthetic air. As a consequence of the re-evaluation, it was found that some sources of errors had significant effects on gravimetric concentrations of the gas mixtures. These sources are: (1) different masses of the reference cylinder and sample cylinder (an error in the readings of the electronic mass comparator), (2) leakage of the inner gas from valves of the cylinders, and (3) cooling of the gas cylinder caused by filling with high-pressure liquefied carbon dioxide gas. When the mass measurements were performed under uncontrolled conditions, the errors due to sources (1), (2), and (3) were as high as 20 mg, 24 mg, and 13 mg, respectively. In this paper, the detailed results from re-evaluation of these sources of errors are discussed.


Multiple-Dose Pharmacokinetics of Ceftibuten in Healthy Adults and Geriatric Volunteers.
The steady-state pharmacokinetics of ceftibuten, an orally active cephalosporin were investigated in 12 healthy male volunteers (19--38 years) and in 12 geriatric volunteers (65--76 years). Each received one 200-mg ceftibuten capsule every 12 h on days 1--3 and one capsule in the morning on day 4. Plasma and urine samples were collected at various times on days 1--4 and assayed by high-pressure liquid chromatographic method for ceftibuten and ceftibuten-trans, a conversion product. The T(max) for ceftibuten and ceftibuten-trans occurred at about 2 and 3 h, respectively, in both populations. The C(max) and AUC((0--12 h)) ranged from 10.8 to 12.4 &mgr;g ml(minus sign1) and from 47.5 to 55.1 &mgr;g h ml(minus sign1), respectively, for normal volunteers compared to 12.9--17.5 &mgr;g ml(minus sign1) and 62.3--87.1 &mgr;g h ml(minus sign1), respectively, for geriatric volunteers. The respective values for ceftibuten-trans in normal and geriatric volunteers were 1.3 and 1.3 &mgr;g ml(minus sign1), respectively, and 6.9--8.2 and 5.9--9.8 &mgr;g h ml(minus sign1). At steady state, the C(max) and AUC((0--12 h)) of ceftibuten-trans were about 10--11% and 13--16% those of ceftibuten in normal volunteers and about 8--9% and 9--11% those of ceftibuten, respectively, in geriatric volunteers. The accumulation factor of ceftibuten in normal volunteers was 1.1 as compared to 1.3 in geriatric volunteers. The terminal phase half-life was 2.5 h in healthy volunteers and 3.2 h in geriatric volunteers. Urinary excretion appeared to be the major route of elimination in both populations accounting for more than 90% of the dose recovered in the urine during the dosing interval. The results of this study demonstrate that ceftibuten, 200 mg given twice a day, is safe and well tolerated, is well absorbed, and that steady-state is achieved on days 3 and 4. There is some accumulation in the elderly, but dosage regimen based on age is not warranted.


Cellulose Acetate Membrane Electrophoresis Based Urinary Proteomics for the Identification of Characteristic Proteins.
Analysis of urinary proteins using cellulose acetate membrane electrophoresis (CAME) is a useful and challenging method for the recognition of damaged sites in the kidney. However, protein content of each CAME fraction is still not completely understood. In this study, an effective method of protein extraction from each band fractionated by CAME was established, which enabled us to examine the extracted proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and mass spectrometry. Proteins were extracted from the gel and analyzed by mass spectrometry. In all, 31 proteins were identified, including 20 urinary proteins that were newly identified in the CAME-based analysis. This methodology was useful for identifying the proteins responsible for creating unique bands on CAME in a urine sample of a patient with drug-induced interstitial nephritis. These findings provide in-depth characterization of urinary protein contents in each CAME fraction.


Illustration of anti-rheumatic mechanism of rheumavedic capsule.
The present study was taken up to illustrate the mechanism of anti-rheumatic activity of 'Rheumavedic capsule', a polyherbal formulation of Vedic-bio Labs, Bangalore, in adjuvant induced arthritic rats. Anti-inflammatory mechanism is illustrated using phlogistic agents induced paw edema in rats. Analgesic mechanism is illustrated using Eddy's hot plate and acetic acid (0.6%v/v) induced writhing in mice. Histopathology of knee joint was studied. Rheumavedic showed inhibition of inflammation mediated through Histamine, 5-Hydroxy tryptamine, and Bradykinin. Rheumavedic showed protection in both acetic acid and Eddy's hot plate induced pain. Histopathology of knee joint of rat pre-treated with rheumavedic showed significant reduction in the mononuclear infiltration, pannus formation and adhesion molecules. The anti-rheumatic mechanism of rheumavedic is due to; inhibition of inflammatory mediators i.e., Histamine, 5-Hydroxy tryptamine and Bradykinin., protection against prostaglandins mediated pain, by inhibiting cyclo-oxygenase synthesis and reduction in pannus formation, by inhibiting mononuclear infiltration.


Koilonychia, dome-shaped epiphyses, and vertebral platyspondylia.
A 2.5-year-old girl presented with koilonychia since birth and was subsequently found to have dome-shaped femoral epiphyses and platyspondylia with anterior central tongues on a skeletal survey.


Identification of fibronectin as a major factor in human serum to recruit subchondral mesenchymal progenitor cells.
Human serum has the potential for mesenchymal progenitor cell recruitment in repair of articular cartilage lesions. It is unclear which factor(s) in serum mediate this migratory effect. Our goal was to identify cell recruiting factors in human serum fractions obtained by ion exchange chromatography. The recruiting activity of serum fractions on human subchondral mesenchymal progenitor cells was analyzed using 96-well chemotaxis assays. Protein composition of recruiting serum fractions were analyzed by mass spectrometry and showed 58 potential candidates. Fibronectin, gelsolin, lumican, thrombospondin-1 and WNT-9a were identified as key candidates for progenitor cell recruitment. Only human plasma derived and recombinant fibronectin showed significant recruiting activity on progenitors reaching 50-90% of the recruiting activity of normal human serum. Presence of fibronectin in all human serum fractions with recruiting activity was verified by Western blot analysis. This study shows that fibronectin is a key factor in human serum to recruit mesenchymal progenitor cells and might be involved in subchondral mesenchymal progenitor cell migration into cartilage defects after microfracture.


Stability of medicines after repackaging into multicompartment compliance aids: eight criteria for detection of visual alteration.
Multicompartment compliance aids (MCA) are widely used by patients. They support the management of medication and reduce unintentional nonadherence. MCA are filled with medicines unpacked from their original packaging. Swiss pharmacists currently provide MCA for 1-2 weeks, although little and controversial information exists on the stability of repackaged medicines. We aimed to validate the usefulness of a simple screening method capable of detecting visual stability problems with repackaged medicines. We selected eight criteria for solid formulations from The International Pharmacopoeia: (1) rough surface, (2) chipping, (3) cracking, (4) capping, (5) mottling, (6) discoloration, (7) swelling, and (8) crushing. A selection of 24 critical medicines was repackaged in three different MCA (Pharmis®, SureMed™, and self-produced blister) and stored at room temperature for 4 weeks. Pharmis® was additionally stored at accelerated conditions. Appearance was scored weekly. Six alterations (rough surface, cracking, mottling, discoloration, swelling, and crushing) were observed at accelerated conditions. No alteration was observed at room temperature, except for the chipping of tablets that had been stuck to cold seal glue. The eight criteria can detect alterations of the appearance of oral solid medicines repackaged in MCA. In the absence of specific guidelines, they can serve as a simple screening method in community pharmacies for identifying medicines unsuitable for repackaging.


Association between conjunctival goblet cells and corneal resident dendritic cell density changes in new contact lens wearers.
To explore the interlink between conjunctival goblet and corneal dendritic cell density after six months of lens wear and to predict dendritic cell migration to the central cornea based on goblet cell loss in the conjunctiva as a response to contact lens wear. Sixty-nine subjects who had never previously worn contact lenses were observed for six months; 46 were fitted with contact lenses and 21 served as a control group. Corneal confocal microscopy was used to quantify goblet and dendritic cell density before and after six months of daily lens wear. Symptomatic and asymptomatic groups were identified in the lens-wearing group using a combination of signs and symptoms present. Pearson's correlation was used to determine associations between the total change of cell densities after six months of lens wear. At baseline, there was no association between conjunctival goblet and corneal dendritic cell density (p > 0.05). After six months, there was an inverse association between the absolute change of conjunctival goblet and corneal dendritic cell density (ρ = -0.34, p = 0.03) in all participants (n = 69). Dendritic cell density in the central cornea was increased by 1.5 cells/mm2 for every decrease of 1 goblet cell/mm2 in the conjunctiva. After six months of wear, contact lens-induced goblet cell loss can partially predict resident corneal dendritic cell migration to the central cornea (observed as an increase in dendritic cell density). The associations between total cell density change after six months was established in wearers regardless of lens symptomatology, suggesting that cell density changes as a physiological adaptation to regulate the effect of contact lens wear on the ocular surface.


[Clinical study and gastroscopy of biliary gastritis following gastric resection and Roux-en-Y anastomosis].
Between 1981 and 1985, seven patients (mean age 44 years) underwent surgery for benign gastroduodenal ulcer in the Department of Surgery. Cantonal Hospital, Fribourg, Switzerland. Surgical indications were a double subcardial and prepyloric ulcer recurring after medical treatment, a duodenal and jejunal anastomotic ulcer after gastroenterostomy, two duodenal ulcers which recurred after vagotomy, and three perforated ulcers (subcardial, prepyloric, duodenal). All patients underwent two-thirds gastrectomy with a Roux-en-Y loop. Clinical investigations and gastroscopy were performed 1-5 years postoperatively. Clinical results were excellent in 5 cases (Visick 1), good in one (Visick 2), and moderate in one (Visick 3). Symptoms and signs associated with biliary gastritis were found as follows: vomiting 1 patient; epigastric pain 1 patient; weight loss 1 patient; anemia 1 patient. No bile staining was seen in any patient. Gastric biopsy demonstrated a normal mucosa in 2 patients and gastritis in 5 patients. Roux-en-Y gastrectomy gives satisfactory results in certain benign gastroduodenal ulcer situations. Perianastomotic and gastric stump gastritis may exist without biliary reflux.


Involvement of α-klotho, fibroblast growth factor-, vitamin-D- and calcium-sensing receptor in 53 patients with primary hyperparathyroidism.
The presentation of patients with primary hyperparathyroidism is often atypical and ranges from normocalcemic, primary hyperparathyroidism to severe, symptomatic hypercalcemia. G-protein-coupled, calcium-sensing receptor (CaSR), vitamin D receptor (VDR), and fibroblast growth factor receptor (FGFR)/klotho complexes seem to be involved in the development of pHPT. Parathyroid glands from 53 patients with pHPT and normal parathyroid tissue from 7 patients were obtained during parathyroidectomy. Conventional detailed morphological and immunohistochemical analyses of parathyroid glands were performed after dividing each slide in a 3 × 3 array. From morphology, the number of lipocytes was significantly lower in parathyroid tissue glands in the pHPT group (p < 0.001). Protein expressions of klotho, CaSR, and VDR were significantly reduced in the pHPT compared with the control group (p = 0.004, p = 0.007, p < 0.001). No differences were seen between the two groups (p = 0.35) regarding expression of FGFR. Correlations between expression showed significant positively correlations between klotho and CaSR and FGFR and VDR. No correlations between klotho expression and serum calcium levels could be detected (R = -0.13, p = 0.66), but there were positive correlations between expressions of CaSR/serum phosphate and klotho/serum phosphate. Impaired protein expression of CaSR and VDR seem to be involved in the development of pHPT. The role of the FGFR/klotho-axis remains still unclear. Correlations between protein expression of CaSR and serum phosphate and klotho and serum phosphate levels could be detected. Whether these findings give new insights into the pathogenesis of the disease is yet unknown and has to be elucidated.


Adult versus paediatric undifferentiated embryonal sarcoma of the liver: a SEER database analysis.
Undifferentiated embryonal sarcoma of the liver (UESL) is a rare liver tumour that occurs mainly in children. Herein, we aimed to identify any differences in clinical characteristics and survival between adult and paediatric patients with UESL. From 1975 to 2015 in the Surveillance, Epidemiology and End Results (SEER) database, patients diagnosed with UESL were identified and divided into paediatric (<18 years) and adult (≥18 years) groups. We then compared the clinical characteristics, management, and overall survival (OS) of adults and children diagnosed with UESL. We analysed 113 patients with UESL (81 children and 32 adults). UESL was significantly more common in adult male than paediatric male patients (71.9% vs. 48.2%; P = 0.022). When compared to adult patients, paediatric patients were more likely to receive chemotherapy (93.8% vs. 65.6%; P < 0.001). Adults had a significantly worse OS than paediatric patients (5-year OS, 30.0% vs. 81.2%; P < 0.001). Univariate analysis found that adult age, surgical therapy and chemotherapy were associated with OS. Multivariate analysis revealed that adult age, SEER summary stage and surgical therapy were independent prognostic factors for OS. UESL had a male predominance among adult patients. Moreover, the prognosis of adult patients with UESL was significantly worse than that of paediatric patients. Surgery and chemotherapy should be considered in the treatment of patients with UESL.


Biosynthesis of glycoproteins in Candida albicans: biochemical characterization of dolichol phosphate glucose synthase.
A mixed membrane fraction isolated from C. albicans yeast cells catalyzed the transfer of glucose from UDP-Glc into three classes of endogenous acceptors: glucolipid, glycoprotein and lipid-linked oligosaccharides. About 80% of the total radioactivity transferred into these products corresponded to the glucolipid which was identified as dolichol phosphate glucose by several criteria. The remainder was detected in about equal proportions in the other two fractions. Conditions that stimulated or inhibited glucolipid synthesis did not affect the extent of glycoprotein labeling. The synthesis of dolichol phosphate glucose exhibited a K(m) of 104 microM UDP-Glc and was stimulated by Mg2+ but not by Mn2+ or Ca2+. The latter cations were, however, better stimulators of glycoprotein labeling than Mg2+. Most nucleotides strongly inhibited the synthesis of dolichol phosphate glucose, UMP being a competitive inhibitor with a Ki of 100 microM. The dolichol phosphate glucose synthase reaction was reversed about 57% by 0.62 mM UDP but not by UMP.


Description of new genus Baikalozercon (Acari: Mesostigmata: Zerconidae) with two new species from South Siberia Mountains (Russia).
This paper describes a new genus and two new species of mites in the family Zerconidae collected from litter and soil in the South Siberia Mountains. Baikalozercon gen. nov. is described to accommodate two new species B. dracunculus sp. nov. and B. irbis sp. nov. on the basis of adults specimens and immature stages. The new genus is characterised by unique characters such as very large size of idiosoma (9001000 m length); long peritremes in adults reaching to coxae I; sexual dimorphism of male gnathosomal structures; modified fixed digit of chelicerae with extended apical edge and large apical outgrowth; a pair of massive subcapitular denticles located between h3 and pc setae in B. dracunculus sp. nov.; and modified setae on legs II.


Particulates, unregulated and regulated emissions and catalytic converter efficiency evaluation of methanol (M15) fuelled BS-VI compliant light-duty spark-ignition engine.
Methanol adaptation in the transport sector is being encouraged worldwide. Methanol, a high-octane fuel, is emerging as a strong fuel candidate for powering spark-ignition (SI) engines and it can be indigenously produced from low-value agricultural biomass waste and high-ash coal. This study investigated particulates and unregulated and regulated emissions from M15 (15 % v/v methanol, 82 % v/v gasoline, 3 % v/v propanol) fueled Bharat Stage-VI (BS-VI) 2020 compliant light-duty SI engine equipped with a multipoint port fuel injection system and compared it with baseline gasoline fueled engine. The catalytic conversion efficiency for controlling regulated and unregulated emission species are also discussed for both test fuels. The experimental results showed a reduction in carbonaceous emissions from M15 fueled engine. Hydrocarbons (HC), carbon monoxide (CO) and particulate emissions reduced, while oxides of nitrogen (NOx) emissions were comparable to baseline gasoline-fueled engine. The catalytic conversion of CO emission was higher for M15 but lower for HC and NOx emissions. Various unregulated trace emission components such as formaldehyde, acetaldehyde, methane, ethene and propene reduced with methanol addition to gasoline. Considerable reductions in benzene and toluene trace emissions were observed for M15, but methanol and ethane trace emissions were higher. The catalytic conversion of all unregulated trace emission components was comparable for both test fuels except alcohols, where M15 exhibited increased trace emission values. The study reflected that M15 could easily replace gasoline in BS-VI-compliant light-duty SI transportation engines. However, verification of all regulatory emission compliances, diagnostics and durability compliances need be ascertained before large-scale implemetation.


Opicapone enhances the reversal of MPTP-induced Parkinson-like syndrome by levodopa in cynomolgus monkeys.
Opicapone is a third generation nitrocatechol catechol-O-methyltransferase inhibitor that has received regional market approval for use as adjunctive therapy to levodopa in Parkinson's disease patients with motor fluctuations. This study evaluated the effects of opicapone as adjunct to levodopa in reversing a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinson's-like syndrome in cynomolgus monkeys in during opicapone preclinical development program. A Parkinson's-like syndrome was induced in cynomolgus monkeys by daily administrations of MPTP. Evaluation of the animals included scoring with the Primate Parkinsonism Motor Rating Scale (PPMRS) and assessment of locomotor activity. MPTP produced a stable Parkinson's-like behavioural syndrome as evidenced by tremor, postural changes, rigidity, impaired movements and balance, (PPMRS scores of 10-15) and decreased locomotor activity (13% of pre-MPTP values). Opicapone treatment alone, for 14 days, did not change Parkinson's-like symptoms nor decreased subject's locomotor behaviour. Ascending combinations of levodopa/benserazide dose-dependently decreased PPMRS and improved locomotor behaviour reaching statistical significance for levodopa/benserazide doses of 18/4.5 mg/kg and those effects were enhanced in opicapone treated subjects. Opicapone treated subjects as compared vehicle-treated, had markedly reduced erythrocyte catechol-O-methyltransferase activity, significantly increased plasma levodopa levels (1.8-fold higher AUC) with no statistically significant changes in Cmax and significantly reduced 3-OMD AUC and Cmax values (7.8- and 6.8-fold respectively). Opicapone potentiated the improvements in Parkinson's-like symptoms produced by levodopa/benserazide combinations with concomitant increase in plasma levodopa exposure, reduction of plasma 3-O-methyldopa levels and erythrocyte catechol-O-methyltransferase activity, results that were later demonstrated in 2 large Phase 3 studies in Parkinson's disease patients.


[Observations on the growth rate of polypoid type gastric cancers with doubling times based on a retrospective roentgenological study].
For the purpose of estimating the growth rate, 11 cases of polypoid type gastric cancer have been studied. The mean doubling time was found to be 16.6 months in early cases, and 7.6 months in advanced cases. There were two groups with different growth rates in polypoid type gastric cancer. However, from a study of a case growing faster according to the extension of tumor, it is suggested that the difference of the growth rate between the two groups may have resulted from a discrepancy of when the observation began.


Cluster analysis of insomniacs' MMPI profiles: relation of subtypes to sleep history and treatment outcome.
The Minnesota Multiphasic Personality Inventory (MMPI) profiles of 100 insomniacs who presented for treatment at a university medical center were analyzed by a hierarchical clustering procedure. This analysis revealed two major personality types that accounted for 88% of the sample. The two types referred to as "Type 1" and "Type 2" insomniacs differed significantly in regard to sleep history questionnaire responses and responsivity to treatment. MMPI scales and sleep history questionnaire items suggested that Type 1 insomniacs were less defended, more aroused/activated, and had sleep histories characterized by more childhood sleep problems and greater difficulties with sleep-disruptive cognitions than did Type 2 patients. Further, Type 1 patients had a poorer response to behavioral treatment as measured by change in sleep-onset latency than did Type 2 patients. These results suggest that the MMPI may be useful in identifying distinctive personality subgroups among insomniacs. Treatment implications are discussed, and mechanisms underlying the group differences are considered.


Surgical treatment of chronic visceral ischemia.
Our experience with the operative repair for chronic visceral ischemia in eight patients, including two patients without visceral ischemic symptoms, is described. We prefer revascularization of as many vessels as possible and have used a small diameter Dacron bifurcation graft directed cephalad from the infrarenal aorta to the superior mesenteric artery and hepatic or splenic artery in four patients. One patient died postoperatively of an arrhythmia. Three patients died of unrelated causes 7 to 36 months after surgery. Four patients are alive 8 to 48 months after surgery. All patients were relieved of the intestinal ischemic symptoms by surgery.


Internal fixation of single mandibular fracture under mandibular nerve block.
The aim of this study was to assess the results of open reduction and internal fixation (OR/IF) of isolated mandibular fracture under regional anesthesia using mandibular nerve block. This prospective study was carried out on 44 patients who had isolated traumatic parasymphyseal mandibular fractures. All patients were managed by OR/IF by two titanium miniplates using manual maxillomandibular fixation (MMF). All patients were sedated by (0.05 mg/kg) midazolam and (2 μg/kg) fentanyl. The patients were randomly classified into two groups: the control group (22 patients) treated under general anesthesia (GA) and the study group (22 patients) repaired under regional anesthesia. The results were assessed as regards dental occlusion, average intrinsic vertical mouth opening, actual operative time, complication, tolerance and patient's satisfaction, and postoperative hospital stay time. Both groups were matched for age and sex. There were no statistically significant differences of the postoperative complication, dental occlusion, and mouth opening between both groups. Duration for anesthesia induction, intubation, and anesthesia recovery was not needed in regional anesthesia. Regional anesthesia was tolerable and highly satisfactory in all patients with no intraoperative or postoperative anesthesia-related problems and no reported complications. Regional anesthesia can effectively replace GA in selected cases of mandibular fracture obviating the risks of GA.


A multicenter, phase I, pharmacokinetic study of osimertinib in cancer patients with normal renal function or severe renal impairment.
Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL <30 mL/min), received a single 80-mg oral dose of osimertinib and standard PK measures were assessed. Part B: patients with SRI were treated for 3 months to obtain safety data, if deemed clinically appropriate. The geometric mean osimertinib plasma concentrations were higher in patients with SRI (n = 7) vs NRF (n = 8) and were highly variable. Osimertinib exposure based on Cmax and area under the plasma concentration-time curve, was 1.19-fold (90% CI: 0.6, 2.0) and 1.85-fold (90% CI: 0.9, 3.6), respectively, higher for patients with SRI vs patients with NRF, with no clear correlation between CrCL and exposure. No new safety signals were identified after 12 weeks of osimertinib 80 mg continuous dosing. PK parameters pooled across this study and other phase I, II, and III osimertinib clinical studies (exploratory population PK analysis), showed minimal correlation between CrCL and total clearance. In conclusion, no dose adjustment is required for osimertinib for patients with SRI.


The kinetics of a novel cyclic reaction system and its use in the assay of polynucleotide phosphorylase or adenosine diphosphate plus adenosine triphosphate.
1. A sensitive new method is described for the rapid optical assay of polynucleotide phosphorylase in crude bacterial extracts of low specific activity. 2. The assay is non-linear with time and a quick method for determining the approximate activity by using a nomograph is given. 3. The dependence of the assay on Mg(2+) concentration was investigated and the conditions that gave first-order kinetics were determined. 4. The theoretical behaviour of the system was examined mathematically and shown to tend to a simple dynamic steady state, under certain conditions. 5. The potential uses of such cyclic systems are discussed.


The thermal decomposition process of Composition B by ReaxFF/lg force field.
Composition B is a melt-cast explosive consisting of mixtures of TNT and RDX. It has many excellent properties, but there are still multiple safety problems when it is used. Therefore, it is of importance to understand the thermal decomposition mechanism of Composition B. In this paper, during the establishment of the supercell model, the mass ratio of TNT to RDX is about 2:3, which accords with the actual proportion of formula of Composition B. Afterward, the thermal decomposition reaction of Composition B is conducted at various temperatures (2000 K, 2500 K, 3000 K, 3500 K, and 4000 K) by using molecular dynamics simulation of ReaxFF/lg. In terms of potential energy (PE) evolution, primary reaction, intermediate product, final product, and clusters, the thermal decomposition mechanism of Composition B is made an analysis. The activation energy of Composition B is 141.8 kJ/mol by fitting the kinetic parameters of the reaction. During the decomposition process of Composition B, the decay rate of RDX is faster than that of TNT, and the decay rates of TNT and RDX is accelerated significantly with the increasing temperature. The higher the temperature, the shorter the time difference between the two to fully decompose. It can be revealed from the result that the initial reaction path of Composition B decomposition is N-NO2 of RDX cleavage to form NO2, followed by the reaction of TNT with NO2 and other molecules. The initial decomposition reaction path of Composition B is the similar at different temperatures. The main products are small molecules (NO2, NO, N2O, H2O, CO2, N2, H2, HNO2, and HNO). Temperature can make a great difference for the structure of clusters. Large clusters in the system will break down into smaller molecules at high temperature.


Locomotor activity, ultrasonic vocalization and oxytocin levels in infant CD38 knockout mice.
Oxytocin (OT), a neurohormone involved in reproduction, plays a critical role in social behavior in a wide range of mammalian species from rodents to humans. The role of CD38 in regulating OT secretion for social behavior has been demonstrated in adult mice, but has not been examined in pups or during development. Separation from the dam induces stress in 7-day-old mouse pups. During such isolation, locomotor activity was higher in CD38 knockout (CD38(-/-)) pups than in wild-type (CD38(+/+)) or heterozygous (CD38(+/-)) controls. The number of ultrasonic vocalizations was lower in CD38(-/-) pups than in CD38(+/+) pups. However, the difference between the two genotypes was less severe than that in OT knockout or OT receptor knockout mice. To explain this, we measured plasma OT levels. The level was not lower in CD38(-/-) pups during the period 1-3 weeks after birth, but was significantly reduced after weaning (>3 weeks). ADP-ribosyl cyclase activities in the hypothalamus and pituitary were markedly lower from 1 week after birth in CD38(-/-) mice and were consistently lower thereafter to the adult stage (2 months old). These results showed that the reduced severity of behavioral abnormalities in CD38(-/-) pups was due to partial compensation by the high level of plasma OT.


Inhibitory theta burst stimulation of affected hemisphere in chronic stroke: a proof of principle, sham-controlled study.
Non-invasive brain stimulation is presently being tested as a potential therapeutic intervention for stroke rehabilitation. Following a model of competitive interactions between the hemispheres, these interventions aim to increase the plasticity of stroke hemisphere by applying either excitatory protocols to the damaged hemisphere or inhibitory protocols to the non-stroke hemisphere. Here we test the safety and feasibility of using an inhibitory protocol on the stroke hemisphere to improve the response to conventional therapy via a homeostatic increase in learning capacity. Twelve chronic stroke patients received TBS to stroke hemisphere (6 patients inhibitory TBS and 6 sham TBS) followed by physical therapy daily for 10 working days. Patients and therapists were blinded to the type of TBS. Action Research Arm Test (ARAT), Nine-Hole Pegboard Test (NHPT) and Jebsen-Taylor Test (JTT) were the primary outcome measures, grip and pinch-grip dynamometry were the secondary outcome measures. All patients improved ARAT and JTT scores for up to 3 months post-treatment. ARAT scores improved significantly in both real and sham groups, but only patients receiving real TBS significantly improved on the JTT: 3 months post-treatment mean execution time was reduced compared to baseline by 141 s for real group and by 65s for the sham group. This small exploratory study suggests that ipsilesional inhibitory TBS is safe and that it has the potential to be used in a larger trial to enhance the gain from a late rehabilitation program in chronic stroke patients.


In vitro estimation of the proliferative state of murine bone marrow "colony forming units in culture" (CFUc) with hydroxyurea (HU).
Exposure of CFUc to 1.0 mM of HU for two hours was at the plateau of both the dose--and time--respose curves, killing 38% of the CFUc. This is compatible with the result of the 3HTdR "suicide" method, a standard procedure for the estimation of the proportion of CFUc being in the S phase.


Purification of adenovirus hexon protein by high-performance liquid chromatography.
Adenovirus (Type 2)-infected HeLa cells were sonicated and treated with 1,1,2-trichlorotrifluoroethane. The water-soluble extract was ultracentrifuged and the supernatant, containing the dissociated proteins, was subjected to anion-exchange high-performance liquid chromatography on a Mono Q column in 50 mM bis-Tris-HCl (pH 6.5). Elution with a linear salt gradient resulted in a major peak, containing the hexon protein.


Synthesis, characterization, and antimicrobial evaluation of carbostyril derivatives of 1H-pyrazole.
A new series of 12 derivatives of 4-pyrazolyl-N-arylquinoline-2,5-dione (4a-l) were synthesized by one pot base catalyzed cyclocondensation reaction of 1-aryl-5-chloro-3-methyl-1H-pyrazole-4-carbaldehyde (1a-c), Meldrum's acid (2) and 3-arylamino-5,5-disubstitutedcyclohex-2-enone (3a-d). All the compounds were characterized by elemental analysis, FT-IR, (1)H NMR and (13)C NMR spectral data and were screened, against six bacterial pathogens, namely Bacillus subtilis, Clostridium tetani, Streptococcus pneumoniae, Salmonella typhi, Vibrio cholerae, Escherichia coli and antifungal activity, against two fungal pathogens Aspergillus fumigatus and Candida albicans, using broth microdilution MIC (minimum inhibitory concentration) method. Some of the compounds were found to be equipotent or more potent than commercial drugs, against most of the employed strains, as evident from the screening data.


Constraint of the mother with pups restores some aspects of the maternal behavior of mutant staggerer mice.
Under normal breeding conditions, the female staggerer is unable to rear her pups. She does not care for them, does not suckle, never retrieves them, and she may even reject them. Most of the staggerer mother's offspring die within the first day. By forcing the mother to remain with foster pups for 24 hours immediately after deliver, and thereafter replacing them with older pups, maternal behavior can partly be restored. Although badly cleaned and not retrieved, 67 percent of the staggerer offspring survived under these conditions. The results obtained demonstrate considerable environmentally induced plasticity in the behavior of the staggerer mouse.


Identification of the cuproptosis-related molecular subtypes and an immunotherapy prognostic model in hepatocellular carcinoma.
Cuproptosis, a newly discovered mode of cell death, has been less studied in hepatocellular carcinoma (HCC). Exploring the molecular characteristics of different subtypes of HCC based on cuproptosis-related genes (CRGs) is meaningful to HCC. In addition, immunotherapy plays a pivotal role in treating HCC. Exploring the sensitivity of immunotherapy and building predictive models are critical for HCC. The 357 HCC samples from the TCGA database were classified into three subtypes, Cluster 1, Cluster 2, and Cluster 3, based on the expression levels of ten CRGs genes using consensus clustering. Six machine learning algorithms were used to build models that identified the three subtypes. The molecular features of the three subtypes were analyzed and compared from some perspectives. Moreover, based on the differentially expressed genes (DEGs) between Cluster 1 and Cluster 3, a prognostic scoring model was constructed using LASSO regression and Cox regression, and the scoring model was used to predict the efficacy of immunotherapy in the IMvigor210 cohort. Cluster 3 had the worst overall survival compared to Cluster 1 and Cluster 2 (P = 0.0048). The AUC of the Catboost model used to identify Cluster 3 was 0.959. Cluster 3 was significantly different from the other two subtypes in gene mutation, tumor mutation burden, tumor microenvironment, the expression of immune checkpoint inhibitor genes and N6-methyladenosine regulatory genes, and the sensitivity to sorafenib. We believe Cluster 3 is more sensitive to immunotherapy from the above analysis results. Therefore, based on the DEGs between Cluster 1 and Cluster 3, we obtained a 7-gene scoring prognostic model, which achieved meaningful results in predicting immunotherapy efficacy in the IMvigor210 cohort (P = 0.013). Our study provides new ideas for molecular characterization and immunotherapy of HCC from machine learning and bioinformatics. Moreover, we successfully constructed a prognostic model of immunotherapy.


Endoscopic Removal of Premalignant Lesions Reduces Long-Term Colorectal Cancer Risk: Results From the Japan Polyp Study.
To date, no regional evidence of long-term colorectal cancer (CRC) risk reduction after endoscopic premalignant lesion removal has been established. We aimed to analyze this over a long-term follow-up evaluation. This was a prospective cohort study of participants from the Japan Polyp Study conducted at 11 Japanese institutions. Participants underwent scheduled follow-up colonoscopies after a 2-round baseline colonoscopy process. The primary outcome was CRC incidence after randomization. The observed/expected ratio of CRC was calculated using data from the population-based Osaka Cancer Registry. Secondary outcomes were the incidence and characteristics of advanced neoplasia (AN). A total of 1895 participants were analyzed. The mean number of follow-up colonoscopies and the median follow-up period were 2.8 years (range, 1-15 y) and 6.1 years (range, 0.8-11.9 y; 11,559.5 person-years), respectively. Overall, 4 patients (all males) developed CRCs during the study period. The observed/expected ratios for CRC in all participants, males, and females, were as follows: 0.14 (86% reduction), 0.18, and 0, respectively, and 77 ANs were detected in 71 patients (6.1 per 1000 person-years). Of the 77 ANs detected, 31 lesions (40.3%) were laterally spreading tumors, nongranular type. Nonpolypoid colorectal neoplasms (NP-CRNs), including flat (<10 mm), depressed, and laterally spreading, accounted for 59.7% of all detected ANs. Furthermore, 2 of the 4 CRCs corresponded to T1 NP-CRNs. Endoscopic removal of premalignant lesions, including NP-CRNs, effectively reduced CRC risk. More than half of metachronous ANs removed by surveillance colonoscopy were NP-CRNs. The Japan Polyp Study: University Hospital Medical Information Network Clinical Trial Registry: University Hospital Medical Information Network Clinical Trial Registry, C000000058; cohort study: UMIN000040731.


Sini San ameliorates duodenal mucosal barrier injury and low‑grade inflammation via the CRF pathway in a rat model of functional dyspepsia.
The gut‑brain interaction is associated with impaired duodenal mucosal integrity and low‑grade inflammation, which have been proven to be important pathological mechanisms of functional dyspepsia (FD). Sini San (SNS) is a classical Chinese medicine used to treat FD, but its underlying mechanisms are poorly understood. The aim of the present study was to evaluate the effects of SNS on duodenal mucosal barrier injury and low‑grade inflammation with FD, and to assess its potential molecular mechanisms on the brain‑gut axis. FD rats were established using the iodoacetamide and tail‑squeezed methods. The expression of corticotropin‑releasing factor (CRF), CRF receptor 1 (CRF‑R1) and CRF‑R2, were determined by western blot analysis and/or immunohistochemistry (IHC). In addition, mast cell (MC) migration was assessed by IHC with an anti‑tryptase antibody, and histamine concentration was quantified using ELISA. The mRNA expression levels of tryptase and protease‑activated receptor 2 (PAR‑2) were quantified using reverse transcription‑quantitative PCR, and the protein expression levels of zona occludens protein 1 (ZO‑1), junctional adhesion molecule 1 (JAM‑1), β‑catenin and E‑cadherin were determined via western blot analysis. It was demonstrated that the expression level of CRF was downregulated in the central nervous system and duodenum following SNS treatment, and that SNS modulated the expression of both CRF‑R1 and CRF‑R2. In addition, SNS suppressed MC infiltration and the activity of the tryptase/PAR‑2 pathway in the duodenum. Furthermore, treatment with SNS restored the normal expression levels of ZO‑1, JAM‑1 and β‑catenin in FD rats. These findings suggested that the therapeutic effects of SNS on FD were achieved by restoring mucosal barrier integrity and suppressing low‑grade inflammation in the duodenum, which was at least partially mediated via the CRF signaling pathway.


Percutaneous radiofrequency ablation for patients with malignant lung tumors: a phase II prospective multicenter study (JIVROSG-0702).
This prospective multicenter study aimed to evaluate the efficacy and safety of percutaneous radiofrequency (RF) ablation for lung cancer. From May 2008 to April 2012, 33 patients (26 men, 7 women; mean age 70.5 years) were enrolled. RF ablation was performed using an internally cooled or expandable multitined electrode. The primary endpoint was complete response (CR) determined using (18)F fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) performed 6 months after RF ablation. The secondary endpoint was the incidence and grade of adverse events (AEs) evaluated using the Common Toxicity Criteria for Adverse Events, version 3.0. All patients underwent RF ablation and had efficacy analyses evaluated; however, FDG-PET/CT images before RF ablation were not available for two patients. The CR rate was 68 % (21 of 31 patients). One patient had a grade 5 AE unrelated to RF ablation. Grade ≥3 AEs occurred in 12 % of patients. During the follow-up period (median 37 months; range 1-55 months), five patients developed local tumor progression and nine (29 %) died. Overall survival at 1, 2, and 3 years was 97, 82, and 74 %, respectively. Percutaneous RF ablation is a safe, feasible, and effective treatment for small malignant lung tumors.


Neuroanatomical distribution of testosterone-metabolizing enzymes in the Japanese quail.
We describe a very sensitive and precise assay which allows one to study the metabolism of testosterone (T) in small brain nuclei dissected out according to the method of Palkovits and Brownstein. With this method, the neuroanatomical distributions of aromatase, and 5 alpha- and 5 beta-reductase activities were studied in adult male quail (Coturnix coturnix japonica). The different enzymes show different neuroanatomical distributions. Production of estradiol-17 beta (E2) was highest in the sexually dimorphic nucleus preopticus medialis (POM). We showed previously that the preoptic aromatase activity is higher in male than in female quail. As the POM is a central and very large structure within the preoptic area, the present results suggest a relationship between the neuroanatomical and the biochemical sex differences. By contrast, the production of 5 alpha-DHT was highest in the lateral hypothalamic area (LHY), the bed nucleus of the pallial commissure (BPC) and the lateral septum (SL). The 5 beta-reductase activity was highest in the lateral septum and in the ventral part of the archistriatum (AV). Moreover, there was a rostral to caudal decrease in 5 beta-reductase activity in the hypothalamus.


Study of tracheal dyskinesia impact on the cardiac hemodynamics.
Tracheal dyskinesia (TD) was recently recognized as a possible mechanism for acute pulmonary edema (Elamin and Firdose, J Bronchol 2004;11:118-21; Khan and Elamin Eur Respir J 2005;26:319). This study was designed to evaluate possible impact of TD on cardiac hemodynamics. Patients were prospectively assigned to either study "A" or control "B" groups (TD >50% or <50%, respectively) diagnosed by bronchoscopy or dynamic chest computed tomography. The cardiac hemodynamics was assisted by impedance cardiography (BioZ; CardioDynamics, San Diego, CA) at rest and during coughing. The latter was repeated after 5 minutes of rest. Thirteen patients were assigned to group A and 14 to group B. There was higher incidence of hypertension, diabetes mellitus, and history of congestive heart failure in group A compared with group B. The percentage of TD was 85% +/- 10.0% versus 25% +/- 2.5%, in the A and B groups, respectively (P < 0.05). Stroke volume index (normal = 35-65 mL/beat/body surface area) was significantly reduced in group A 29.68 [95% confidence interval (CI), 25.557-33.818] compared with group B 38.321 (95% CI, 35.199-41.444; P < 0.05). In addition, the velocity index (representative of aortic blood velocity) was 32.188 (95% CI, 20.841-43.534, P < 0.049) in group A compared with 46.786 (95% CI, 38.209-55.363) in group B, and the left ventricular ejection time measured in milliseconds was 265.813 (95% CI, 246.065-285.560 in group A, P < 0.004) compared with 303.821(95% CI, 288.894-318.749) in group B. This prospective study demonstrated the importance of recognizing TD as a pathologic entity and the need to consider TD in the workup of acute pulmonary edema especially if other tests were unrevealing.


Leaf carbon isotope tracks the facilitation pattern of legume shrubs shaped by water availability and species replacement along a large elevation gradient in Trans-Himalayas.
Understanding patterns and mechanisms of nurse plant facilitation is important to predict the resilience of arid/semi-arid ecosystems to climate change. We investigate whether water availability and nurse species turnover interact to shape the facilitation pattern of widespread legume shrubs along a large elevation gradient. We also investigate whether leaf δ13C of nurse plants can track the facilitation pattern. We measured the relative interaction index (RII) of the number of species within and outside the canopy of two widespread legume shrub species (Caragana gerardiana and Caragana versicolor) alternatively distributed along a large elevation gradient in the Trans-Himalayas. We also assessed the proportional increase of species richness (ISR) at the community level using the paired plot data. To determine site-specific water availability, we measured the leaf δ13C of nurse shrubs and calculated the Thornthwaite moisture index (MI) for each elevation site. Elevational variations in RII, ISR and δ13C were mainly explained by the MI when the effects of soil nitrogen and plant traits (leaf nitrogen and shrub size) were controlled. Variations in RII and ISR across the two nurse species were explained better by δ13C than by smoothly changing climatic factors along elevation. At the transition zone between the upper limit of C. gerardiana (4100 m) and the lower limit of C. versicolor (4200 m), RII and ISR were much higher in C. versicolor than in C. gerardiana under a similar MI. Such an abrupt increase in facilitation induced by nurse species replacement was well tracked by the variation of δ13C. Water availability and nurse species replacement are crucial to shaping facilitation patterns by legume shrubs along a large elevation gradient in dry mountainous regions, such as the Trans-Himalayas. Turnover in nurse species under global change might significantly alter the pattern of nurse plant facilitation associated with water availability, which can be well tracked by leaf δ13C.


Multi-wavelength in-band OSNR monitor based on Lyot-Sagnac interferometer.
A novel in-band OSNR monitor is proposed and experimentally demonstrated for WDM signal. By using a Lyot-Sagnac interferometer, the monitor realized OSNR measurement from 7.5~25 dB (within an accuracy of ± 0.5 dB) for 4-channel 40 Gbaud NRZ-QPSK signals, without requirement for prior knowledge of the noise-free coherence properties of signal. Further investigation proved that this OSNR monitor had high tolerance to chromatic dispersion (0~1152 ps/nm), first-order polarization mode dispersion (0~100 ps), and polarized noise. Moreover, the monitor worked very well even with input optical power as low as -8.24 dBm, and also worked in in C-band. Theoretical analysis and experimental results prove that it is capable of measuring OSNR for polarization-division-multiplexing signals.


Microfluorometric investigations on the cell cycle progression of experimental ascites tumors treated with alkaloidic drugs.
The effects of the antitumor agents vincristine (VCR) and vincaleucoblastine (VLB) on the cell cycle progression of three different ascites tumor cell lines in vivo (Ehrlich, Crocker S 180, and leukemia L 1210) were studied in detail by flow microfluorometric techniques over a 5-day period of drug treatment and during the post-treatment course. These investigations give evidence that the tumor lines employed show completely different sensitivity against VCR and VLB. During the treatment massive polyploidization was demonstrated to be, in general, the second response of treated cells overcoming an initial proliferative block in the G 2 phase of their life cycle.


Enhancement of biophysical activity of lung surfactant extracts and phospholipid-apoprotein mixtures by surfactant protein A.
The effects of surfactant protein (SP)-A on the dynamic surface tension lowering and resistance to inhibition of dispersions of calf lung surfactant extract (CLSE) and mixtures of synthetic phospholipids combined with SP-B,C hydrophobic apoproteins were studied at 37 degrees C and rapid cycling rate (20 cycles/min). Addition of SP-A to CLSE, which already contains SP-B and -C, gave a slight improvement in the time course of surface tension lowering on an oscillating bubble apparatus in the absence of inhibitory protein molecules such as albumin or hemoglobin. However, when these proteins were present at concentrations of 10-50 mg/ml, SP-A substantially improved the resistance of CLSE to their inhibitory effects. The beneficial effect of SP-A required the presence of Ca2+ ions, and disappeared when EDTA was substituted for this divalent cation in the subphase. The effect was also retained when SP-A was heated to 50 degrees C prior to addition to CLSE, but was abolished by heating SP-A to 99 degrees C. Additional studies showed that similar improvements in resistance to inhibition were found when SP-A was added to synthetic mixtures of dipalmitoyl phosphatidylcholine (DPPC):egg phosphatidylglycerol (PG) (80:20 by weight) reconstituted with 1% SP-B or SP-B and -C, but not to phospholipid mixtures containing only SP-C. The requirements for SP-B and calcium for the beneficial effects of SP-A on surface activity suggest that the formation of ordered, larger phospholipid-apoprotein aggregates may be involved in the process. The finding that SP-A enhances the ability of CLSE and other surfactant mixtures containing SP-B to resist inhibition is an advantage that will need to be weighed against other factors such as increased antigenicity and heat sensitivity in therapeutic applications in surfactant replacement therapy.


Waiting time for transfer of patients with prostaglandin dependant congenital heart defects to tertiary cardiac centers.
Worldwide congenital heart defects (CHD) are the leading cause of infant deaths owing to congenital anomalies. Delay in diagnosing and operating in neonates with prostaglandin dependant CHD may lead to significant morbidity and mortality. To assess the time interval needed for acceptance and transfer of patients with critical CHD to a tertiary cardiac center and the impact on the patient's survival. Retrospective database reviews of all cases diagnosed to have prostaglandin dependant (PG) CHD at Prince Sultan Cardiac Center-Qassim during a 43 months period (from May 2007 to December 2010). During the study period 104 patients were diagnosed to have PG dependant CHD. Patients with PG dependant systemic circulation constitute 60% of patients. Patients with ventricular septal defect (VSD) associated with coarctation of the aorta constituted 16% of patients. The mean waiting time for transfer to a tertiary cardiac center was 10 ± 10 days. Twenty-two (21%) patients died while waiting for acceptance and transfer. Eleven patients were diagnosed with hypoplastic left heart syndrome (HLHS). There was no significant difference in the waiting time for those with or without HLHS, with a mean of 9 days for both. Six of our patients had infections with positive blood cultures. The mean waiting period for those with proved infection was 25 days compared with 8 days for those with no proved infection (p value < 0.005). There are a significant number of patients with severe CHD who die while waiting for acceptance and transfer to a tertiary cardiac center. The causes for delay could be the presence of infection, prematurity and low birth weight. The limited numbers of tertiary cardiac centers in Saudi Arabia as well as cardiac ICU beds are among the factors delaying the acceptance of patients requiring cardiac surgery.


Effect of trypsin, S-adenosylmethionine and ethionine on L-serine sulfhydrase activity.
Trypsin causes an activation of serine sulfhydrase in the liver extracts from intact animals, but inhibits enzyme activity in the liver of ethionine treated rats. Trypsin also decreases an elevation of serine sulfhydrase activity caused by S-adenosylmethionine.


Differential colocalization of neuropeptide Y- and methionine-enkephalin-Arg6-Gly7-Leu8-like immunoreactivity in catecholaminergic neurons in the rat brain stem.
The present study, using a combination of catecholamine (CA) histofluorescence and peptide immunocytochemistry in the same tissue sections, investigated the coexistence of neuropeptide Y (NPY) and methionine-enkephalin-Arg6-Gly7-Leu8 (MEAGL)-like immunoreactivity (LI) in catecholaminergic neurons of colchicine-treated rat brain stems. Of the total number of catecholaminergic neurons in the A1/C1, A2/C2, A3, A4, and A6 regions approximately 83, 28, 98, 76, and 36%, respectively, contained both NPY-LI and CA. Of the total number of catecholaminergic neurons in A1/C1, A2/C2, A3, and A5 regions, approximately 47, 4, 8, and 17%, respectively, contained both MEAGL-LI and CA. Moreover, about 24% of the catecholaminergic neurons in the A1/C1 region contained both NPY- and MEAGL-LI. Neither the noradrenergic neurons (A7) in the pons nor any of the dopaminergic neurons in the midbrain (A8, A9, A10) contained NPY- or MEAGL-LI. Neurons containing both NPY- and MEAGL-like immunoreactive peptides without CA were not found in the rat brain stem. These findings indicate that catecholaminergic neurons in the brain stem of the rat can be subdivided into distinct subgroups on the basis of the coexistence of specific peptides.


Persistence of challenging behaviours in adults with intellectual disability over a period of 11 years.
Challenging behaviours in people with an intellectual disability (ID) often develop early and tend to persist throughout life. This study presents data on the chronicity of challenging behaviours in adults with ID over a period of 11 years, and explores the characteristics of people with persistent serious behaviour problems. Support staff provided data on 58 adults living in a long-term residential facility using an interview survey schedule assessing challenging behaviours in 1992 and 2003. Participants presenting with serious physical attacks, self-injury and frequent stereotypy were the most likely to persist in these behaviours over time. These behaviours were characterised by high persistence percentages and associations over time. However, the earlier presence of serious challenging behaviours did not significantly affect the likelihood of serious challenging behaviours in 2003. Individuals with persisting behaviour problems differed from those who did not present serious behaviour problems on the basis of their younger age, increased mobility, and decreased sociability and daily living skills in 1992. Estimates of persistence for challenging behaviours are affected by the statistics chosen to represent stability. The apparent persistence of serious challenging behaviours highlights the need to identify the factors related to maintenance of these behaviours over time. The participant characteristics and adaptive behaviours identified in the present study were not consistently related to the persistence of challenging behaviours. Therefore, other factors, including environmental characteristics, are likely to be related to challenging behaviour persistence.


Co-existence of leptin- and orexin-receptors in feeding-regulating neurons in the hypothalamic arcuate nucleus-a triple labeling study.
The arcuate nucleus (ARC) of the hypothalamus has been identified as a prime feeding regulating center in the brain. Several feeding regulating peptides, such as neuropeptide Y (NPY) and proopiomelanocortin (POMC), are present in neurons of the ARC, which also serves as a primary targeting site for leptin, a feeding inhibiting hormone secreted predominantly by adipose tissues, and for orexin (OX)-containing neurons. OX is expressed exclusively around the lateral hypothalamus, an area also established as a feeding regulating center. Some recent physiological analyses have shown that NPY- and POMC-containing neurons are activated or inactivated by leptin and OX. Moreover, we have already shown, using double immunohistochemical staining techniques, that NPY- and POMC-containing neurons express leptin receptors (LR) and orexin type 1 receptors (OX-1R). However, no morphological study has yet described the possibility of whether or not these arcuate neurons are influenced by both leptin and OX simultaneously. In order to address this issue, we performed histochemistry on ARC neurons using a triple immunofluorescence method. We found that 77 out of 213 NPY- and 99 out of 165 POMC-immunoreactive neurons co-localized with both LR- and OX-1R-immunoreactivities. These findings strongly suggest that both NPY- and POMC-containing neurons are regulated simultaneously by both leptin and OX.


Nanoparticle for delivery of antisense γPNA oligomers targeting CCR5.
The development of a new class of peptide nucleic acids (PNAs), i.e., gamma PNAs (γPNAs), creates the need for a general and effective method for its delivery into cells for regulating gene expression in mammalian cells. Here we report the antisense activity of a recently developed hydrophilic and biocompatible diethylene glycol (miniPEG)-based gamma peptide nucleic acid called MPγPNAs via its delivery by poly(lactide-co-glycolide) (PLGA)-based nanoparticle system. We show that MPγPNA oligomers designed to bind to the selective region of chemokine receptor 5 (CC R5) transcript, induce potent and sequence-specific antisense effects as compared with regular PNA oligomers. In addition, PLGA nanoparticle delivery of MPγPNAs is not toxic to the cells. The findings reported in this study provide a combination of γPNA technology and PLGA-based nanoparticle delivery method for regulating gene expression in live cells via the antisense mechanism.


Spinal seeding of a pilocytic astrocytoma following multiple subtotal resections.
We report the case of a 4-year-old girl presenting with spinal and leptomeningeal dissemination following several subtotal resections of cerebellar pilocytic astrocytomas.


Reactions of silica chloride (SiO(2)Cl)/DMSO, a heterogeneous system for the facile regeneration of carbonyl compounds from thioacetals and ring-expansion annelation of cyclic thioacetals.
Silica chloride (SiO(2)Cl)/DMSO, as a heterogeneous system, has been efficiently used for deprotection of thioacetals into aldehydes in dry CH(2)Cl(2) at room temperature. Thioketals without enolizable hydrogens adjacent to a sulfur atom are converted easily to the corresponding ketones in high yields under similar reaction conditions. However, thioketals with enolizable methyl and methylene groups undergo ring-expansion reactions to afford 1,4-dithiepins and 1,4-dithiins in dry CH(2)Cl(2) at room temperature in good yields.


National Institutes of Health Stroke Scale-Time Score Predicts Outcome after Endovascular Therapy in Acute Ischemic Stroke: A Retrospective Single-Center Study.
Outcomes after successful endovascular therapy in acute ischemic stroke are associated with onset-to-reperfusion time (ORT) and the National Institutes of Health Stroke Scale (NIHSS) score. In intravenous recombinant tissue plasminogen activator therapy, the NIHSS-time score, calculated by multiplying onset-to-treatment time with the NIHSS score, has been shown to predict clinical outcomes. In this study, we assessed whether a similar combination of the ORT and the NIHSS score can be applied to predict the outcomes after endovascular therapy. We retrospectively reviewed the charts of 128 consecutive ischemic stroke patients with successful reperfusion after endovascular therapy. We analyzed the association of the ORT, the NIHSS score, and the NIHSS-time score with good outcome (modified Rankin Scale score ≤ 2 at 3 months). Good outcome rates for patients with NIHSS-time scores of 84.7 or lower, scores higher than 84.7 up to 127.5 or lower, and scores higher than 127.5 were 72.1%, 44.2%, and 14.3%, respectively (P < .01). Multivariate logistic regression analysis revealed that the NIHSS-time score was an independent predictor of good outcomes (odds ratio, .372; 95% confidence interval, .175-.789) after adjusting for age, sex, internal carotid artery occlusion, plasma glucose level, ORT, and NIHSS score. The NIHSS-time score can predict good clinical outcomes after endovascular treatment.


Sex- and Age-Specific Centile Curves and Downloadable Calculator for Clinical Muscle Strength Tests to Identify Probable Sarcopenia.
Identifying muscle weakness and probable sarcopenia using strength tests requires reference data. This study aimed to provide age- and sex-specific normative data for grip strength and common variations of the Sit-to-Stand (STS) test: time to complete 5 stands (5x-STS) and number of stands completed in 30 seconds (30s-STS). Predictors of test performance were also explored. Dominant hand grip strength was assessed in adults (age = 18-80 years) using a digital dynamometer, and 5x-STS and 30s-STS performance were assessed synchronously during a single 30-second test. Sex-specific centile curves were generated using the lambda-mu-sigma method. Data from 2301 participants (female = 1682, male = 619) were included. Peak median grip strength occurred in female participants at 33.9 years of age (27.9 kg) and in male participants at 37.6 years of age (47.2 kg). 5x-STS and 30s-STS performance peaked at the youngest age (18.0 years) in both female participants (8.16 seconds and 17.2 repetitions) and male participants (8.02 seconds and 17.7 repetitions). Test performances were lowest for all tests at the oldest age in the database. Predictors of better test performance included lower age and higher self-reported physical functioning and appendicular skeletal muscle mass, to name a few. White participants had better performance than Black participants on the STS tests. The generated centile curves reveal the pattern of change in muscle strength for tests recommended to identify probable sarcopenia. The curves can be used in rehabilitation to assess an individual's performance relative to sex- and age-specific norms. To aid use of the data, a downloadable Excel-based calculator is provided to compute participant-specific percentiles, z scores, and t scores for each outcome and plot performance on the centile curves. Physical therapists have an important role in identifying and treating individuals with sarcopenia and other causes of muscle weakness. The reference data provided for common clinical muscle strength tests provide therapists an ability to assess an individual's relative performance. Knowing the normal or expected strength for an individual's age and sex is essential to identifying muscle weakness. This study provides age- and sex-specific normal values for hand grip strength and sit-to-stand tests in adults aged 18 to 80 years.


A multicenter, randomized, double-blind, comparative study of a multiphasic hyaluronic acid filler and existing hyaluronic acid fillers for temporary restoration of the midface volume of Asian individuals.
Giselleligne is the world's first multiphasic gel product that evenly surrounds particles. In the current study, Giselleligne was compared with other existing fillers to evaluate their clinical use, safety, and ability to improve midface volume deficits of Asian individuals. A comparative experiment was conducted to gain an understanding of the physical properties of Giselleligne, which is a multilayered hyaluronic acid filler, and to compare its properties with those of existing hyaluronic acid fillers. The primary outcome of this study was a Midface Volume Deficit Scale (MFVDS) score improvement at 24 weeks after the procedure. The secondary outcomes were as follows: MFVDS score improvement after the procedure; MFVDS score changes after the procedure; Global Esthetic Improvement Scale (GAIS) scores as evaluated by the operator after the procedure; the operator's satisfaction with the product; evaluation of the GAIS scores by the patient after the procedure; and pain level of the patient on the day of the procedure. Giselleligne exhibited properties that are expected to result in significantly superior clinical outcomes compared to existing products. Giselleligne was superior not only to the existing products but also in terms of global esthetic improvement, effect duration, and operator satisfaction. Furthermore, Giselleligne was found significantly safer than the existing products. Giselleligne is a safer, more user-friendly, and more effective alternative to existing products for improving the midfacial volume.


The dynamic relationship between cerebellar Purkinje cell simple spikes and the spikelet number of complex spikes.
Purkinje cells are the sole output of the cerebellar cortex and fire two distinct types of action potential: simple spikes and complex spikes. Previous studies have mainly considered complex spikes as unitary events, even though the waveform is composed of varying numbers of spikelets. The extent to which differences in spikelet number affect simple spike activity (and vice versa) remains unclear. We found that complex spikes with greater numbers of spikelets are preceded by higher simple spike firing rates but, following the complex spike, simple spikes are reduced in a manner that is graded with spikelet number. This dynamic interaction has important implications for cerebellar information processing, and suggests that complex spike spikelet number may maintain Purkinje cells within their operational range. Purkinje cells are central to cerebellar function because they form the sole output of the cerebellar cortex. They exhibit two distinct types of action potential: simple spikes and complex spikes. It is widely accepted that interaction between these two types of impulse is central to cerebellar cortical information processing. Previous investigations of the interactions between simple spikes and complex spikes have mainly considered complex spikes as unitary events. However, complex spikes are composed of an initial large spike followed by a number of secondary components, termed spikelets. The number of spikelets within individual complex spikes is highly variable and the extent to which differences in complex spike spikelet number affects simple spike activity (and vice versa) remains poorly understood. In anaesthetized adult rats, we have found that Purkinje cells recorded from the posterior lobe vermis and hemisphere have high simple spike firing frequencies that precede complex spikes with greater numbers of spikelets. This finding was also evident in a small sample of Purkinje cells recorded from the posterior lobe hemisphere in awake cats. In addition, complex spikes with a greater number of spikelets were associated with a subsequent reduction in simple spike firing rate. We therefore suggest that one important function of spikelets is the modulation of Purkinje cell simple spike firing frequency, which has implications for controlling cerebellar cortical output and motor learning.


Decreased colonic peptide histidine-methionine in idiopathic inflammatory bowel diseases.
The sequence for peptide histidine-methionine is present within the same preprohormone as vasoactive intestinal polypeptide. Since our previous study using radioimmunoassay had demonstrated significantly decreased colonic concentrations of vasoactive intestinal polypeptide in ulcerative colitis and Crohn's colitis compared to normal colon, we determined the distribution and quantitation of peptide histidine-methionine. Fresh surgical specimens were dissected into mucosal-submucosal and muscularis externa layers prior to acid extraction and specific radioimmunoassay. One immunoreactive species that appeared to coelute with peptide histidine-methionine was separated by reverse-phase high-performance liquid chromatography. Mucosal-submucosal concentrations of peptide histidine-methionine were significantly decreased in ulcerative colitis and Crohn's colitis, compared to those in normal colon. In normal ileum and colon, linear correlation analysis showed no relationship between patient age and tissue concentrations of peptide histidine-methionine. However, a parallel decrease in molar concentrations of peptide histidine-methionine and vasoactive intestinal polypeptide in ulcerative colitis and Crohn's colitis was demonstrated by linear correlation analysis. These results are consistent with the hypothesis that peptide histidine-methionine and vasoactive intestinal polypeptide are colocalized within the same neural structures that have been altered in the idiopathic inflammatory bowel diseases.


Light-dark patterns in running-wheel activity in rats during chronic administration of theophylline.
Running-wheel activity for 24 hr and activity patterns were studied during chronic theophylline administration. Theophylline altered the normal relations between activity level and illumination. Dark-time activity was decreased to approximately 50% and 24 hr activity was unaffected. These observations were consistent with previous results showing that theophylline suppressed dark-time feeding but had no effect on 24 hr food intake. A possible mechanism to account for these results may be dependent on levels and turnover of brain norepinephrine.


Effect of hypertonic dialysate and vasodilators on peritoneal dialysis clearances in the rat.
A model for performing peritoneal dialysis in the rat was established which permitted the consistent measurement of dialysis clearances. The effects on urea and inulin clearances of interperitoneal vasodilators and 4.25% dextrose were compared. Isoproterenol, nitroprusside, histamine, and bradykinin, when added to 1.5% dextrose dialysate for three consecutive exchanges, all produced approximately a 20% increase in urea and inulin dialysis clearances. These increases in clearances persisted in the three subsequent exchanges when no drugs were added to the dialysate. The addition of isoproterenol, nitroprusside, or histamine to six consecutive exchanges did not produce a further increment in clearances. The use of 4.25% dextrose dialysate for three exchanges produced approximately a 50% increase in urea and inulin clearances. Clearances remained about 35% greater than control values in the subsequent three 1.5% dextrose exchanges.


Of resilience, vulnerability, and a woman who never lived.
One day we may be able to say with some degree of confidence that Factor A over a certain level + Factor B over a certain level + Factor C under a certain level + Factor X will produce Y level of functioning in domain X--in about 80% of cases. Despite advances in our knowledge about the influence of various protective and risk factors in development, health, and functioning, however, we still have good reason to remain humble. This article examines some of the advances and some of the problems in the study of resilience and vulnerability in children and adolescents.


Tolerability assessment of a lectin fraction from Tepary bean seeds (Phaseolus acutifolius) orally administered to rats.
Our previous studies have shown that a lectin rich fraction (TBLF) extracted from Tepary bean seeds differentially inhibits cancer cells proliferation in vitro. Before testing the in vivo anticancer effect, the acute and subchronic toxicological assays in rats were conducted, where an oral dose of 50 mg/body weight kg was determined as the NOAEL. This study evaluated the resistance to digestion and complete blood count (CBC) after 24 h of the orally administered 50 mg/kg TBLF. The digestion resistance test showed lectins activity retention after 72 h and the CBC study showed a high level of eosinophils, suggesting an allergic-like response. Tolerability was assayed after 6 weeks of treatment by dosing with an intragastric cannula every third day per week. It was observed a transient reduction in food intake and body weight in the first weeks, resulting in body weight gain reduction of 10% respect to the control group at the end of the study. Additionally, organs weight, histopathological analysis and blood markers for nutritional status and for liver, pancreas and renal function were not affected. Our results suggest that 50 mg/kg TBLF administered by oral route, exhibit no toxicity in rats and it was well tolerated. Further studies will focus on long-term studies.


Efficacy and safety of once-daily ritonavir-boosted darunavir and abacavir/lamivudine for treatment-naïve patients: a pilot study.
The efficacy and safety of once-daily darunavir/ritonavir and fixed-dose abacavir/lamivudine was examined in 22 treatment-naïve patients with HIV-1 infection. Three patients discontinued antiretroviral therapy due to mild adverse events. Among 18 patients who continued therapy, 66.7% had viral load less than 50 copies/ml at week 48. Only two patients experienced virologic failure with the emergence of resistant virus. This pilot study demonstrated the viral efficacy and safety of darunavir/ritonavir and abacavir/lamivudine.


Risk factors for mortality after hospitalization for suicide attempt: results of 11-year follow-up study in Piedmont Region, Italy.
Suicide attempters are at high risk of premature death, both for suicide and for non-suicidal causes. The aim of this study is to investigate risk factors and temporal span for mortality in a cohort of cases admitted to hospital for suicide attempt. The cohort included 1489 patients resident in Piedmont Region, North West of Italy, who had been admitted to hospital or emergency department for suicide attempt between 2010 and 2020. Cox regression models were used to identify risk factors for death. The final multivariate model included gender, age, area deprivation index, family composition, psychiatric disorders, malignant neoplasms, neurological disorders, diabetes mellitus, cardiovascular diseases, chronic obstructive pulmonary disease, and intracranial injury or skull fracture. During the observation period, 7.3% of patients died. The highest mortality was observed within the first 12 months after suicide attempt, and remained elevated for many years afterwards. Male gender, older age, high deprivation index of the census area, single-parent family, mood disorders, malignant neoplasms, diabetes mellitus and intracranial injuries or skull fracture were independent predictors of death. Risk factors for natural and unnatural causes of death were also identified. The mortality risk of suicide attempters is very high, both in the months immediately following the attempt and afterwards. The identification of high-risk groups can help to plan outpatient care following the hospital discharge. Our findings urge the need to design strategies for the assistance and care of these patients at long term in order to reduce the unfavourable outcomes.


Three-dimensional finite element stress analysis of the polypropylene, ankle-foot orthosis: static analysis.
An asymmetric 3-dimensional finite element model (FEM) of the ankle-foot orthosis (AFO) together with the ankle-foot complex was developed using the computer aided design (CAD) program PATRAN. Static analysis of normal and pathological motions of the ankle-foot complex such as the "drop-foot" problem were conducted using the FEM program ADINA. A total of 313 three dimensional solid elements and 10 truss elements were used. Heel strike and toe-off condition were simulated. Results revealed that the peak compressive stress (1.6 MPa) in the AFO model occurred in the heel regions of the AFO and the maximum tensile stress (0.8 MPa) occurred in the neck region of the AFO during toe-off. Parametric analyses revealed that the model was sensitive to the elastic moduli of the AFO and of the soft tissue, but was relatively insensitive to the ligament stiffness. The results confirmed the hypothesis that peak stresses in the orthosis occur in the heal and neck regions of the orthosis.


Isolation of antibody by polymer microspheres embedded with E. coli displaying IgG-binding domain.
Antibody purification is an important aspect of quality and cost control in the production process of antibody drugs. In this study, modified E. coli was embedded into polymer microspheres (polyvinyl alcohol/alginate) for antibody separation and the IgG binding domain was displayed on the surface of E. coli. The results showed that ZZ protein (Fc binding domain of the antibody) was successfully displayed on the surface of E. coli and was embedded in polyvinyl alcohol/alginate microspheres. In addition, it has excellent specific adsorption capacity for antibodies, with a maximum adsorption capacity of 35.74 mg/g (wet microspheres). Through the adsorption isotherm and adsorption kinetics simulation, the adsorption of IgG on the microsphere matrix conforms to the Langmuir model and follows the pseudo-first-order kinetic equation. The microsphere matrix can undergo saturation adsorption at pH 7.2 and desorption at around pH 3.0. Desorption characteristics are consistent with those of rProtein A Sepharose FF®. After five cycles of the adsorption-desorption processes, the IgG adsorption capacity remains above 80%. Using polymer microspheres to separate antibodies from mouse ascites, the antibody purity reached 86.7% and the yield was 83.5%. These results provide an alternative to protein A matrix with low-cost, fast preparation and moderate efficiency.