[Study of phospholipid components in bronchoalveolar wash surfactants in laryngectomized patients].
Surfactants serve to keep the dimension of the lower airways normal. They regulate alveolar stability, guaranteeing uniform lung insufflation. In order to evaluate pulmonary surfactant modifications during chronic obstructive disorders of the airways, the phospholipid component in the surfactants was studied using the Broncho-Alveolar Wash (BAW). Ten subjects who had undergone laryngectomy and who were suffering from stable, chronic obstructive broncho-pneumopathy (COBP) with marked hypersecretion were studied along with a control group of 7 smokers showing no signs of COBP. As compared to the controls, the laryngectomy patients showed a statistically significant reduction in the total phospholipid content and a different concentration of some important phospholipid fractions. The laryngectomy patients showed varying degrees of COBP because of their previous smoking history: as in ex-smokers where a the "biochemical" damage induced by cigarette smoking is partially repaired. On the other hand, while in the group of smokers the damage, expressed as the total phospholipid content, was quite noteworthy (reduction in this content was up to 10 times that found in the non-smoking subjects), the ex-smoking laryngectomy patients revealed less marked, yet still significant, damage.


[Nosocomial Burkholderia cepacia outbreak in an intensive pediatric care unit].
We report an outbreak of Burkholderia cepacia respiratory tract infection and colonization in an intensive pediatric care unit.P PATIENTS AND METHODS: Between February and December 1999, B. cepacia was isolated from five children hospitalized in this unit. We reviewed the charts of the patients, evaluated the antiseptics use and the disinfection practices for reusable patient care equipment. An environmental study was conducted and comparison of B. cepacia was performed with genotypic method (RAPD). All patients were mechanically ventilated and had received large spectrum antibiotics. The disinfection procedure for reusable equipment was not respected and some single-dose of antiseptics solutions were used for several patients. B. cepacia was not found in 34 environmental samples. The RAPD assay revealed that all five isolates had identical DNA profiles. Despite the investigation the source of the B. cepacia clone in this nosocomial outbreak remained unknown, but antiseptics use and disinfection practices were revised. No new B. cepacia infections were identified after control measures were implemented.


Intestinal diamine oxidase and histamine release in rabbit mesenteric ischemia.
It has been suggested that histamine contributes to lethal circulatory collapse after acute superior mesenteric artery occlusion. The activity of the histamine inactivating enzyme diamine oxidase, the release of the amine, and the effect of histamine receptor antagonists was therefore studied in rabbits. The main results were: (a) Diamine oxidase activity decreased by 60% after intestinal ischemia and reperfusion. A monoexponential dose-response relationship was found between the specific diamine oxidase inhibitor aminoguanidine and reduced survival time. (b) Plasma histamine levels in the right atrium rose only slightly after ischemia, but considerably during reperfusion of the gut, and remained high for at least 20 min. In sham-operated animals the plasma histamine concentration was unchanged throughout the experiment. The histamine content in the intestinal wall did not fall significantly at any time after mesenteric artery occlusion and reperfusion. (c) The aminoguanidine-induced reduction in survival time was completely reversed by pre-treatment of the animals with the H1-receptor antagonist dimethylpyridine and the H2-receptor antagonist cimetidine. This study provides strong evidence for the protective role of intestinal diamine oxidase in intestinal ischemia.


Wide-wavelength-tunable distributed Bragg reflector laser diode with high thermal efficiency.
We proposed a thermally-tuned distributed Bragg reflector (DBR) laser diode that has a high tuning efficiency over a wide wavelength tuning range. The laser diode is composed of a gain, a phase control (PC), and a DBR region, and its wavelength is tuned coarsely and finely by the micro-heaters on the DBR and PC regions, respectively. To improve the tuning efficiency, we developed a technique for fabricating a thermal isolation structure through a reverse mesa etching process, replacing the complex process that uses an InGaAs sacrificial layer. The DBR laser diodes (DBR-LD) fabricated using this method effectively confines heat generated by the heater, resulting in an approximate tuning range of 40 nm. This technology, which has achieved nearly four times larger wavelength tuning range than the thermally-tuned DBR-LDs without a thermal isolation structure, is considered suitable for the cost-effective development of wide-wavelength-tuning DBR-LD light sources.


Catabolism of homologous murine monoclonal hybridoma IgG antibodies in mice.
Two neutralizing monoclonal hybridoma antibodies to the surface spike glycoprotein E2 of the JHM strain of murine hepatitis virus were injected into homologous BALB/c mice, and their biological half-lives were determined by sequential titration of plasma samples in a virus-specific enzyme immunoassay. Intravascular half-lives of monomeric immunoglobulins were estimated at 8.0 +/- 1.5 days for antibody 5B19.3, an IgG1, and 12.7 +/- 2.4 days for antibody 4B11.6, an IgG2a. These catabolic rates are statistically different from each other (P less than 0.001) and significantly higher than previously reported values, which were all obtained with radiolabelled polyclonal or myeloma immunoglobulins of unknown specificities. Failure to remove aggregated 4B11.6 antibodies by high-speed centrifugation yielded a statistically significant acceleration of biological turnover (half-life 9.9 +/- 1.6 days; P less than 0.01).


Real-time estimation of nephron activity with a linear measurement system (RENAL-MS) predicts postoperative estimated glomerular filtration rate.
To determine whether a simple point-of-care measurement system estimating renal parenchymal volume using tools ubiquitously available could be used to replace nuclear medicine renal scintigraphy (NMRS) in current clinical practice to predict estimated glomerular filtration rate (eGFR) after nephrectomy by estimating preoperative split renal function. We performed a retrospective review of patients who underwent abdominal cross-sectional imaging (computed tomography/magnetic resonance imaging) and mercaptoacetyltriglycine (MAG3) NMRS prior to total nephrectomy at a single institution. We developed the real-time estimation of nephron activity with a linear measurement system (RENAL-MS) method of estimating postoperative renal function via the following technique: renal parenchymal volume of the removed kidney relative to the remaining kidney was estimated as the product of renal length and the average of six renal parenchymal thickness measurements. The utility of this value was compared to the utility of the split renal function measured by MAG3 for prediction of eGFR and new onset Stage 3 chronic kidney disease (CKD) at ≥90 days after nephrectomy using uni- and multivariate linear and logistic regression. A total of 57 patients met the study criteria. The median (interquartile range [IQR]) age was 69 (61-80) years. The median (IQR) pre- and postoperative eGFR was 74 (57-89) and 46 (35-62) mL/min/1.73 m2 , respectively. Correlations between actual and predicted postoperative eGFR were similar whether the RENAL-MS or NMRS methods were used, with correlation using RENAL-MS being slightly numerically but not statistically superior (R = 0.82 and 0.76; P = 0.138). Receiver operating characteristic curve analysis using logistic regression estimates incorporating age, sex, and preoperative creatinine to predict postoperative Stage 3 CKD were similar between RENAL-MS and NMRS (area under the curve 0.95 vs 0.98). A point-of-care tool to estimate renal parenchymal volume (RENAL-MS) performed equally as well as NMRS to predict postoperative eGFR and de novo Stage 3 CKD after nephrectomy in our population, suggesting NMRS may not be necessary in this setting.


A case of Chopra-Amiel-Gordon syndrome with a novel heterozygous variant in the ANKRD17 gene: A case report.
Chopra-Amiel-Gordon syndrome (OMIM: 619504) is an autosomal dominant neurodevelopmental disorder characterized by developmental delay, intellectual disability, speech delay, epilepsy, dysmorphic craniofacial features, ophthalmological abnormalities, and recurrent infections. It is caused by heterozygous loss-of-function pathogenic variants in the ANKRD17 gene, which codes for an ankyrin repeat-containing protein. Currently, about 35 cases of Chopra-Amiel-Gordon syndrome are described in the medical literature. We report on a 4-year-old female patient with a novel heterozygous variant in the ANKRD17 gene.


Update on gingival overgrowth by cyclosporine A in renal transplants.
Severe gingival overgrowth is one of the most frequent side effects in renal transplant patients associated with assumption of cyclosporine A. Several associations with age, sex, dosage, duration of therapy or interval since transplantation have been hypothesized. The introduction of alternative immunosuppressant drugs have been suggested to permit better long-term transplant outcomes and a decrease in incidence of gingival overgrowth. The aim of the present paper is to summarize current knowledge regarding aetiology, pathogenesis and management of gingival overgrowth induced by Cyclosporine A.


Development of X-ray photoemission electron microscopy (X-PEEM) at the SRS.
The use of synchrotron radiation sources for X-ray spectroscopy is a well known and developed field. The majority of applications, however, have been limited to studies of materials containing only a single phase of the element of interest. Owing to limited availability of suitable instrumentation, the study of materials comprising intergrowths of different phases has presented difficulties in analysis. The majority of natural materials, including mineralogical samples, fall into this category. However, by applying the technique of photoemission electron microscopy (PEEM) to view the X-ray stimulated photoemission generated at an absorption edge, micro-area-selectable spectroscopy becomes possible. An instrument for X-ray PEEM (X-PEEM) is being developed at the Daresbury SRS and this paper shows how it can be used to obtain characteristic L-edge XANES spectra from finely intergrown iron oxide minerals.


Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report.
Thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20 is rare in adults, with only 16 reported cases. However, standard treatment options for this type of thymic adenocarcinoma has not yet been established. Therefore, we report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy. We report a case of thymic-enteric adenocarcinoma occurring in a 44-year-old woman. The tumor was considered unresectable owing to its invasiveness. The patient was treated with six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2 BID, days 1-14). During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) and anti-angiogenic therapy using apatinib were recommended. The primary tumor achieved partial remission based on the Response Evaluation Criteria in Solid Tumors. During follow-up, there was no evidence of disease relapse, except a high serum CA19-9 level. The patient is alive and regularly followed. Based on the previous literature and the present case, we believe that early diagnosis of thymic-enteric adenocarcinoma is important. XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an optional therapy for inoperable thymic-enteric adenocarcinoma.


Elevated levels of circulating platelet aggregates and beta-thromboglobulin in scleroderma.
Levels of circulating platelet aggregates and plasma beta-thromboglobulin reflect the degree of platelet activation in vascular injury and repair. Both values were evaluated in 38 patients with scleroderma and 18 control subjects matched for age, sex, and race. Circulating platelet aggregates (expressed as percentage of total platelet count) were 7.2 +/- 5.5% (mean +/- SD) in the control group and 31.2 +/- 13% in the scleroderma group (p less than 0.0005). Beta-thromboglobulin levels in the control groups were 20 +/- 10 ng/mL and 72.7 +/- 50 ng/mL in the group with scleroderma (p less than 0.0005). A positive correlation was found between the two values (r = 0.6, p less than 0.0005). Significant reductions in circulating platelet aggregates and beta-thromboglobulin levels were achieved in 10 patients by dipyridamole and aspirin therapy. These results show in-vivo activation of platelets in scleroderma with release of platelet granule constituents. Antiplatelet therapy in adequate doses returned both values to normal; however, its long-term effect on scleroderma is not yet known.


Prokaryote infections in the New Zealand scallops Pecten novaezelandiae and Chlamys delicatula.
Four intracellular prokaryotes are reported from the scallops Pecten novaezelandiae Reeve, 1853 and Chlamys delicatula Hutton, 1873. Elongated (1025 x 110 nm), irregular (390 x 200 nm), or toroidal (410 x 200 nm) mollicute-like organisms (M-LOs) occurred free in the cytoplasm in the digestive diverticular epithelial cells of both scallop species. Those in P. novaezelandiae bore osmiophilic blebs that sometimes connected the organisms together, and some had a rod-like protrusion, both of which resemble the blebs and tip structures of pathogenic mycoplasmas. The M-LOs in C. delicatula had a slightly denser core than periphery. Round M-LOs, 335 x 170 nm, occurred free in the cytoplasm of agranular haemocytes in P. novaezelandiae, without apparent harm to the host cell. In P. novaezelandiae, 2 types of highly prevalent (95 to 100%) basophilic inclusions in the branchial epithelium contained Rickettsia-like organisms (R-LOs). Type 1 inclusions occurred in moderately hypertrophied, intensely basophilic cells, 8 to 10 microm in diameter, containing elongate intracellular R-LOs, 2000 x 500 nm. Type 2 inclusions were elongated and moderately basophilic in markedly hypertrophic branchial epithelial cells, 50 x 20 microm in diameter, containing intracellular organisms 500 x 200 nm in diameter. The possible roles of these organisms in pathogenesis is discussed.


Integrating machine learning with pharmacokinetic models: Benefits of scientific machine learning in adding neural networks components to existing PK models.
Recently, the use of machine-learning (ML) models for pharmacokinetic (PK) modeling has grown significantly. Although most of the current approaches use ML techniques as black boxes, there are only a few that have proposed interpretable architectures which integrate mechanistic knowledge. In this work, we use as the test case a one-compartment PK model using a scientific machine learning (SciML) framework and consider learning an unknown absorption using neural networks, while simultaneously estimating other parameters of drug distribution and elimination. We generate simulated data with different sampling strategies to show that our model can accurately predict concentrations in extrapolation tasks, including new dosing regimens with different sparsity levels, and produce reliable forecasts even for new patients. By using a scenario of fitting PK data with complex absorption, we demonstrate that including known physiological structure into an SciML model allows us to obtain highly accurate predictions while preserving the interpretability of classical compartmental models.


Wnt'er in liver: expression of Wnt and frizzled genes in mouse.
The Wnt signaling pathway is essential for a wide array of developmental and physiological processes. Wnts are extracellular ligands that bind to frizzled (Fz) receptors at the membrane, canonically inducing beta-catenin nuclear translocation and activation. Although beta-catenin has been shown to be critical in liver biology, the expression of the 19 Wnt and 10 Fz genes in liver remains undetermined. We report comprehensive analysis of Wnt and Fz expression in whole liver as well as individual cell types: freshly isolated and plated hepatocytes, biliary epithelial cells, normal and activated stellate and Kupffer cells, and sinusoidal endothelial cells (SECs). Oligonucleotides for the 19 Wnt, 10 frizzled receptors genes, and secreted Frizzled-related protein-1 (sFRP or Fzb) were synthesized based on the available sequences. A total of 11 Wnts and 8 Fz genes and Fzb were expressed in normal liver. Although only 6 Wnt and 5 Fz genes were expressed in freshly isolated hepatocytes, 8 Wnt genes, 7 Fz genes, and Fzb were expressed in plated hepatocytes. Although 12 Wnt and 7 Fz genes were expressed in biliary tree, additional Fz9 and Fzb were only expressed in cultured biliary epithelial cells. The same 14 Wnt and 7 Fz genes were expressed in both activated and normal stellate and Kupffer cells; only Fzb was expressed in their activated state. Also, 11 Wnt, seven Fz, and Fzb genes were expressed in SECs. These data indicate that most Wnt and frizzled genes are expressed in the liver and might be playing important roles in liver pathobiology via canonical and noncanonical pathways.


Catalytic removal of sulfur dioxide from dibenzothiophene sulfone over Mg-Al mixed oxides supported on mesoporous silica.
Dibenzothiophene sulfone (DBTS), one of the products of the oxidative desulfurization of heavy oil, can be removed through extraction as well as by an adsorption process. It is necessary to utilize DBTS in conjunction with catalytic cracking. An object of the present study is to provide an Mg-Al-mesoporous silica catalyst for the removal of sulfur dioxide from DBTS. The characteristics of the Mg-Al-mesoporous silica catalyst were investigated through N2 adsorption, XRD, ICP, and XRF. An Mg-Al-mesoporous silica catalyst formulated in a direct incorporation method showed higher catalytic performance compared to pure MgO during the catalytic removal of sulfur dioxide from DBTS. The higher dispersion of Mg as well as the large surface area of the Mg-Al-mesoporous silica catalyst strongly influenced the catalyst basicity in DBTS cracking.


Pediatric chronic myeloid leukemia: A single-center experience.
The rationale of this study is to reveal the statistics of pediatric chronic myeloid leukemia (CML) patients. It is a retrospective analysis conducted to assess pediatric CML data from January 1998 to December 2014. There are 65 (3.2%) pediatric CML patients out of entire 2008 patients of CML. Data were analyzed regarding epidemiological characteristics, clinical presentations, response and side effects of imatinib, event-free survival, and overall survival of the pediatric CML patients. The median age of diagnosis was 11.84 years, and 76.9% patients were male and 23.07% patients were female. Sixty (92.3%) patients were in CML-chronic phase, 3 (4.6%) patients in CML-accelerated phase, and 2 (3.07%) patients in CML-blastic crisis. Most common initial symptoms and signs are weakness (60.0%), abdominal pain (55.38%), splenomegaly (100%), and hepatomegaly (86.5%). 67.3% of patients have white blood counts <100 × 109/L and 92.3% had platelets >150 × 109/L. In the initial months of 2002, imatinib was available and utilized in 54 patients. Of 54 patients, complete hematological response at 3 months, partial cytogenetic response at 6 months, complete cytogenetic response at 12 months, and major molecular response (MMR) at 18 months were 77.77%, 59.2%, 48.14%, and 40.74%, respectively. MMR at 36 months was 62.96% ( n = 34). Most common imatinib-related side effects are gastrointestinal upset and myelosuppression. Pediatric CML in India is comparable with Western countries regarding epidemiological characteristic, clinical presentations, and tolerance of imatinib. As there is a paucity of universal literature regarding pediatric CML (especially data from Southeast Asian region), this article may fill up that space.


Decision ecology: foraging and the ecology of animal decision making.
In this article, I review the approach taken by behavioral ecologists to the study of animal foraging behavior and explore connections with general analyses of decision making. I use the example of patch exploitation decisions in this article in order to develop several key points about the properties of naturally occurring foraging decisions. First, I argue that experimental preparations based on binary, mutually exclusive choice are not good models of foraging decisions. Instead, foraging choices have a sequential foreground-background structure, in which one option is in the background of all other options. Second, behavioral ecologists view foraging as a hierarchy of decisions that range from habitat selection to food choice. Finally, data suggest that foraging animals are sensitive to several important trade-offs. These trade-offs include the effects of competitors and group mates, as well as the problem of predator avoidance.


Endotoxin, cerebral blood flow, amino acids and brain damage in young rabbits.
The effects of bacterial endotoxin (lipopolysaccharide; LPS) on the cerebral blood flow (CBF), amino acid levels and brain histology were studied in young rabbits. The CBF was slightly decreased in the cerebral cortex and markedly decreased in the cerebral white matter at 60 and 120 min after LPS administration. Histological examination revealed only slightly pyknotic neurons around small vessels at 24 hours, and multifocal necrosis in the deep cerebral cortex and white matter at 72 hours. Some amino acids were increased in the plasma and brain regions at 24 hours after LPS administration, most of which were essential amino acids. GABA in the cerebral white matter was decreased at 24 hours. At 72 hours, most non-essential and glucogenic amino acids were decreased. These results suggest that the brain histological changes are related mainly to hypoperfusion and vascular damage in the brain. The amino acid changes may also be related to inappropriate amino acid metabolism associated with brain cell damage.


Carbon Nanotubes Activate Limulus Amebocyte Lysate Coagulation by Interface Adsorption.
Limulus amebocyte lysate (LAL) assay is worldwide requested in the assessment of endotoxin contamination for biomaterials. As carbon nanotubes are one major nanomaterial with multiple potentials in biomedical application, here we investigate whether oxidized multiwalled carbon nanotubes (O-MWCNT) interferes the assessment by LAL assays. We showed that the endotoxin free O-MWCNT dispersing in aqueous solutions could activate both the gel-clotting and the end-point chromogenic LAL assay by converting coagulogen into coagulin through interfacial interactions between O-MWCNT and enzymes in the assays. In conclusion, the O-MWCNT could induce false positive results by activating the enzyme cascade of LAL.


Studies on the synthesis of derivatives of marine-derived bostrycin and their structure-activity relationship against tumor cells.
A series of new derivatives (5-29) of marine-derived bostrycin (1) were synthesized. The in vitro cytotoxic activities of all compounds were evaluated against MCF-7, MDA-MB-435, A549, HepG2, HCT-116 and MCF-10A cells using the MTT method. The compounds 7, 8, 22, 23, 25, 28 and 29 of the total showed comparable activity to epirubicin, the positive control, against the tested cancer cell lines. However, these compounds also exhibited cytotoxicity towards MCF-10A cells. The structure-activity relationship (SAR) of bostrycin derivatives was also discussed based on the obtained experimental data.


Sample preparation improvement in polycyclic aromatic hydrocarbons determination in olive oils by gel permeation chromatography and liquid chromatography with fluorescence detection.
The determination of 15 polycyclic aromatic hydrocarbons (PAHs) in olive oil samples has been improved in order to obtain a fast methodology with a low limit of detection through the combination of liquid-liquid extraction with acetonitrile and preparative gel permeation chromatography (GPC) prior to the injection of purified extracts into a C18 column. Acetonitrile-water was used as the mobile phase with a gradient from 50 to 95%, w/w, acetonitrile in 30 min. The oven temperature was maintained at 15 degrees C, and fluorometric detection was made at a fixed excitation wavelength of 264 nm and variable, optimal emission wavelength for each analyte ranging from 352 nm for 11-H-benzo(b)fluorene to 500 nm for indeno(1,2,3-cd)pyrene. Recovery for all the compounds studied varied from 75 to 111%, and limit of detection values from 0.05 ng/g for benzo(k)fluoranthene to 0.48 ng/g for indeno(1,2,3-cd)pyrene, corresponding to 0.09 ng/g benzo(a)pyrene. Results were compared with those obtained by liquid-liquid extraction followed by a cleanup on silica and a direct GPC treatment of oil samples diluted in dichloromethane, 2 other methodologies that are appropriate for quantifying PAHs in olive oils. However, the proposed method improves the determination limits, reduces the time of analysis, and provides a highly stable baseline for sample chromatograms.


Maximal Fusion Capacity and Efficient Replenishment of the Dense Core Vesicle Pool in Hippocampal Neurons.
Neuropeptides and neurotrophins, stored in dense core vesicles (DCVs), are together the largest currently known group of chemical signals in the brain. Exocytosis of DCVs requires high-frequency or patterned stimulation, but the determinants to reach maximal fusion capacity and for efficient replenishment of released DCVs are unknown. Here, we systematically studied fusion of DCV with single vesicle resolution on different stimulation patterns in mammalian CNS neurons. We show that tetanic stimulation trains of 50-Hz action potential (AP) bursts maximized DCV fusion, with significantly fewer fusion event during later bursts of the train. This difference was omitted by introduction of interburst intervals but did not increase total DCV fusion. Interburst intervals as short as 5 s were sufficient to restore the fusion capacity. Theta burst stimulation (TBS) triggered less DCV fusion than tetanic stimulation, but a similar fusion efficiency per AP. Prepulse stimulation did not alter this. However, low-frequency stimulation (4 Hz) intermitted with fast ripple stimulation (200 APs at 200 Hz) produced substantial DCV fusion, albeit not as much as tetanic stimulation. Finally, individual fusion events had longer durations with more intense stimulation. These data indicate that trains of 50-Hz AP stimulation patterns triggered DCV exocytosis most efficiently and more intense stimulation promotes longer DCV fusion pore openings.SIGNIFICANCE STATEMENT Neuropeptides and neurotrophins modulate multiple regulatory functions of human body like reproduction, food intake or mood. They are packed into dense core vesicles (DCVs) that undergo calcium and action potential (AP) fusion with the plasma membrane. In order to study the fusion of DCVs in vitro, techniques like perfusion with buffer containing high concentration of potassium or electric field stimulation are needed to trigger the exocytosis of DCVs. Here, we studied the relationship between DCVs fusion properties and different electric field stimulation patterns. We used six different stimulation patterns and showed that trains of 50-Hz action potential bursts triggered DCV exocytosis most efficiently and more intense stimulation promotes longer DCV fusion pore openings.


Patient-controlled analgesia versus intramuscular analgesic therapy.
The pharmacy and nursing time requirements, quality of postoperative pain control, and cost of patient-controlled analgesia (PCA) and intramuscular (i.m.) analgesic therapy were studied. All timings were conducted with a stopwatch on a single nursing unit that primarily receives gynecologic surgery patients. The various work elements involved in each type of therapy were timed individually. Both quality of analgesia and cost were evaluated in a prospective, randomized study in hysterectomy patients. I.M. patients received meperidine hydrochloride 75-100 mg every three to four hours as needed. PCA patients had access to morphine sulfate 1 mg or meperidine hydrochloride 10 mg, with a six-minute lockout period. The patients scored their pain every four hours. Direct costs for PCA were calculated as drug cost plus tubing cost plus form cost plus maintenance cost plus depreciation cost. Direct costs for i.m. therapy consisted of the cost of drugs. The total mean nursing time per patient was 16.9 minutes for PCA and 10.7 minutes for i.m. therapy. Pharmacy time per patient was 5.1 minutes longer for PCA than for i.m. therapy. Thirty-six hysterectomy patients (17 i.m. and 19 PCA) were enrolled in the study of pain control and cost. Among i.m. patients, 64% of the pain scores were mild or worse, compared with 40% for PCA patients. The median pain scores were moderate for i.m. patients and mild for PCA patients. Scores tended to be lower for PCA patients at 16 and 20 hours. Although equal numbers of patients in the two groups experienced nausea, i.m. patients needed more doses of antiemetics than PCA patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Molecular mechanism of the inhibition and remodeling of human islet amyloid polypeptide (hIAPP(1-37)) oligomer by resveratrol from molecular dynamics simulation.
Natural polyphenols are one of the most actively investigated categories of amyloid inhibitors, and resveratrol has recently been reported to inhibit and remodel the human islet amyloid polypeptide (hIAPP) oligomers and fibrils. However, the exact mechanism of its action is still unknown, especially for the full-length hIAPP1-37. To this end, we performed all-atom molecular dynamics simulations for hIAPP1-37 pentamer with and without resveratrol. The obtained results show that the binding of resveratrol is able to cause remarkable conformational changes of hIAPP1-37 pentamer, in terms of secondary structures, order degree, and morphology. By clustering analysis, two possible binding sites of resveratrol on the hIAPP1-37 pentamer were found, located at the grooves of the top and bottom surfaces of β-sheet layer, respectively. After the binding free energy calculation and residue energy decomposition, it can be concluded that the bottom site is the more possible one, and that the nonpolar interactions act as the driving force for the binding of hIAPP1-37 to resveratrol. In addition, Arg11 is the most important residue for the binding of resveratrol. The full understanding of inhibitory mechanism of resveratrol on the hIAPP1-37 oligomer, and the identification of its binding sites on this protein are helpful for the future design and discovery of new amyloid inhibitors.


[Effect of ethionine on intestinal enzymatic activity in adult rats].
The activity of intestinal enzymes (dipeptidase, monoglyceride lipase, amylase, invertase) was studied in intestinal mucosa homogenates from different parts of the small intestine in adult rats 24, 48, and 72 hours after a single intraperitoneal administration of ethionine in a dose of 500 mg/kg bw. 24 hours after antimetabolite administration there was a decrease in the abrasion of the small intestinal mucosa. The enzyme-forming function of the small intestine appreciably changed throughout the observation period. The activity of invertase, dipeptidase and amylase decreased. The monoglyceride lipase activity remained unchanged. The pattern of amylase and invertase distribution in the small intestine changed at the expense of inhibition of their activity in the duodenum and rise in the distal part.


Histone Deacetylase 3 Coordinates Deacetylase-independent Epigenetic Silencing of Transforming Growth Factor-β1 (TGF-β1) to Orchestrate Second Heart Field Development.
About two-thirds of human congenital heart disease involves second heart field-derived structures. Histone-modifying enzymes, histone deacetylases (HDACs), regulate the epigenome; however, their functions within the second heart field remain elusive. Here we demonstrate that histone deacetylase 3 (HDAC3) orchestrates epigenetic silencing of Tgf-β1, a causative factor in congenital heart disease pathogenesis, in a deacetylase-independent manner to regulate development of second heart field-derived structures. In murine embryos lacking HDAC3 in the second heart field, increased TGF-β1 bioavailability is associated with ascending aortic dilatation, outflow tract malrotation, overriding aorta, double outlet right ventricle, aberrant semilunar valve development, bicuspid aortic valve, ventricular septal defects, and embryonic lethality. Activation of TGF-β signaling causes aberrant endothelial-to-mesenchymal transition and altered extracellular matrix homeostasis in HDAC3-null outflow tracts and semilunar valves, and pharmacological inhibition of TGF-β rescues these defects. HDAC3 recruits components of the PRC2 complex, methyltransferase EZH2, EED, and SUZ12, to the NCOR complex to enrich trimethylation of Lys-27 on histone H3 at the Tgf-β1 regulatory region and thereby maintains epigenetic silencing of Tgf-β1 specifically within the second heart field-derived mesenchyme. Wild-type HDAC3 or catalytically inactive HDAC3 expression rescues aberrant endothelial-to-mesenchymal transition and epigenetic silencing of Tgf-β1 in HDAC3-null outflow tracts and semilunar valves. These findings reveal that epigenetic dysregulation within the second heart field is a predisposing factor for congenital heart disease.


Measuring and evaluating school performance: an investigation of status and growth-based achievement indicators.
Several school performance indices were evaluated using achievement data from multiple longitudinally matched middle school student cohorts in a large district in the southwestern United States. Measures designed to index the within-cohort achievement status and growth of students as well as the status and growth-based changes that occur over years between different student cohorts were studied. Within- and between-cohort status and growth-based estimates of school performance were generated by applying simple and relatively complex statistical models to the longitudinal time-series data obtained on students. Results indicated that within-cohort status-based estimates were closely related to student demographics and between-cohort estimates were associated with cohort enrollment size and initial performance level. These results suggest that schools may often be rewarded and penalized on the basis of factors over which school personnel have limited or no control. Implications for the measurement and evaluation of school performance are discussed.


Salivary excretion of mexiletine in normal healthy volunteers.
To investigate the kinetics and correlation between serum and saliva levels of mexiletine, serum (total and unbound) and saliva drug concentration-time courses have been analysed in five normal healthy volunteers after administration of a single oral dose (200 mg) of the drug. Mexiletine levels in saliva were always higher than those in serum. The drug concentration-time curve in each sample was analysed according to the non-linear least squares regression program MULTI, for a two-compartment model with first-order absorption. The saliva drug concentration in the post-absorption phase was found to be well correlated with either corresponding serum total or serum unbound drug level in four of the subjects. Although there was a large inter-individual variation in the ratio of saliva to serum drug concentrations as well as in the pharmacokinetic parameters, an almost consistent ratio was obtained in each individual.


Plaque Like Giant Dermatofibroma: A Case Report.
Dermatofibroma, also known as benign fibrous histiocytoma, is a soft-tissue tumour that usually occurs in the mid-adult life and shows a slight female predominance. Giant dermatofibroma, a very rare clinical variant, is characterised by its unusually large size, benign biological behaviour despite its large size and same histopathological characteristics as conventional dermatofibroma. We report a 63-year-old woman who presented with a large tumour on the scapular region which showed histopathological features of benign dermatofibroma.


The first investigative science-based evidence of Morgellons psychogenesis.
Morgellons disease is an infrequent syndromic condition, that typically affects middle-aged white women, characterized by crawling sensations on and under the skin, associated with itchy rashes, stinging sores, fiber-like filaments emerging from the sores, severe fatigue, concentrating difficulty, and memory loss. The scientific community is prone to believe that Morgellons is the manifestation of various psychiatric syndromes (Munchausen, Munchausen by proxy, Ekbom, Wittmaack-Ekbom). Up until now, no investigative science-based evidence about its psychogenesis has ever been provided. In order to close this gap, we have analyzed the filaments extracted from the skin lesions of a 49-year-old Caucasian female patient, by using a Field Emission Gun-Environmental Electron Scanning Microscope equipped with an X-ray microprobe, for the chemico-elemental characterization of the filaments, comparing them with those collected during a detailed indoor investigation, with careful air monitoring, in her apartment. Our results prove the self-introduction under the epidermis of environmental filaments. For the first time in the literature, we have scientifically demonstrated the self-induced nature of Morgellons disease, thereby wiping out fanciful theories about its etiopathogenesis.


[Prevalence of birth defects in the Tongzhou District of Beijing between 2006 and 2012].
To study the dynamic prevalence and epidemiological characteristics of birth defects distribution in the Tongzhou District of Beijing between 2006 and 2012. Data collected from the birth defects surveillance system in the Tongzhou District of Beijing between 2006 and 2012 were used. The prevalence and trends of birth defects were analyzed, also the proportion of birth defects in prenatal diagnosis was calculated. Between 2006 and 2012, 1,165 cases of birth defects were identified among 92,340 births, with a prevalence of 12.62‰. The prevalence of birth defects showed an increased trend during the seven years (χ2=6.77, P<0.01). The prevalence in the flowing population (13.27‰) was higher than that in the permanent residents (11.55‰), and the former showed an upward trend during the seven years (χ2=25.02, P<0.01). The top five birth defects were congenital heart defects, polydactyly, cleft lip and/or palate, neural tube defects, and external ear malformation in turn. The prevalence of congenital heart defects and the unspecified congenital malformation increased while that of neural tube defects decreased. There was also an upward trend of the prenatal diagnosis for congenital heart defects (χ2=14.80, P<0.01). The prevalence of birth defects increased in the Tongzhou District of Beijing from 2006 to 2012, and it was mainly caused by the increased prevalence of birth defects in the flowing population, the increased number of unspecified birth defects and the improvement of diagnosis technology for congenital heart defects.


Pathology Results at Autopsy in Brain-Dead Patients with Brain Tumors.
Brain tumors are the most challenging causes of brain deaths due to the lack of pathology results in many cases. It is not uncommon to find a brain tumor in a brain-dead patient with no pathology results or neuroradiology reports available; this would exclude the deceased from organ donation. The mortality that occurs while patients are on transplant wait lists motivated us to find a solution to prevent losing brain-dead patients as potential donors. We present our experiences in autopsy examinations of brain tumors and the results of frozen-section pathology. We performed autopsy examinations of 8 brain-dead patients who were suspected of having highly malignant brain tumors and in whom there were no pathology or radiology reports available. The autopsy process began at the conclusion of organ retrieval. First, we performed a complete brain dissection; the tumor was then removed with its adjacent brain tissue and sent for examination by an expert pathologist. Organ transplant was deferred until the pathology examination was completed. Organ transplant was cancelled if the frozen sections revealed a high-grade tumor. For all other results, the transplant was performed. If a medulloblastoma was confirmed, only the heart was transplanted. The duration of the delay for pathologic examination was 30 to 45 minutes. A total of 21 organs were donated that would otherwise have been rejected. It is worth performing an autopsy and frozen-section pathology examination to prevent losing potential organs from donors with brain tumors who are suspected of having a high-grade neoplasm but have no pathology or neuroradiology reports. This process is simple and has the potential to save lives.


Glycogen synthase kinase-3β is a pivotal mediator of cancer invasion and resistance to therapy.
Tumor cell invasion and resistance to therapy are the most intractable biological characteristics of cancer and, therefore, the most challenging for current cancer research and treatment paradigms. Refractory cancers, including pancreatic cancer and glioblastoma, show an inextricable association between the highly invasive behavior of tumor cells and their resistance to chemotherapy, radiotherapy and targeted therapies. These aggressive properties of cancer share distinct cellular pathways that are connected to each other by several molecular hubs. There is increasing evidence to show that glycogen synthase kinase (GSK)-3β is aberrantly activated in various cancer types and this has emerged as a potential therapeutic target. In many but not all cancer types, aberrant GSK3β sustains the survival, immortalization, proliferation and invasion of tumor cells, while also rendering them insensitive or resistant to chemotherapeutic agents and radiation. Here we review studies that describe associations between therapeutic stimuli/resistance and the induction of pro-invasive phenotypes in various cancer types. Such cancers are largely responsive to treatment that targets GSK3β. This review focuses on the role of GSK3β as a molecular hub that connects pathways responsible for tumor invasion and resistance to therapy, thus highlighting its potential as a major cancer therapeutic target. We also discuss the putative involvement of GSK3β in determining tumor cell stemness that underpins both tumor invasion and therapy resistance, leading to intractable and refractory cancer with dismal patient outcomes.


Determination of grade and receptor status from the primary breast lesion by magnetic resonance spectroscopy.
Magnetic resonance spectra (MRS) from fine needle aspiration biopsies (FNAB) from primary breast lesions were analysed using a pattern recognition method, Statistical Classification Strategy, to assess tumor grade and oestrogen receptor (ER) and progesterone receptor (PgR) status. Grade 1 and 2 breast cancers were separated from grade 3 cancers with a sensitivity and specificity of 96% and 95%, respectively. The ER status was predicted with a sensitivity of 91% and a specificity of 90%, and the PgR status with a sensitivity of 91% and a specificity of 86%. These classifiers provide rapid and reliable, computerized information and may offer an objective method for determining these prognostic indicators simultaneously with the diagnosis of primary pathology and lymph node involvement.


Risk and Protective Factors for Childhood Asthma: What Is the Evidence?
To summarize the principal findings on risk and protective factors for childhood asthma, we retrieved systematic reviews on these topics in children (aged 1 to 18 years), up to January 2016, through MEDLINE, EMBASE, CINAHL, SCOPUS, and CDSR. A total of 227 studies were searched from databases. Among those, 41 systematic reviews (SRs) were included: 9 focused on prenatal factors, 5 on perinatal factors, and 27 on postnatal factors. Of these 41 SRs, 83% had good methodological quality, as determined by the Assess Systematic Reviews tool. After reviewing all evidence, parental asthma, prenatal environmental tobacco smoke, and prematurity (particularly very preterm birth) are well-established risk factors for childhood asthma. Current findings do suggest mild-to-moderate causal effects of certain modifiable behaviors or exposures during pregnancy (maternal weight gain or obesity, maternal use of antibiotics or paracetamol, and maternal stress), the perinatal period (birth by Caesarean delivery), or postnatal life (severe respiratory syncytial virus infection, overweight or obesity, indoor exposure to mold or fungi, and outdoor air pollution) on childhood asthma, but this suggestive evidence must be confirmed in interventional studies or (if interventions are not feasible) well-designed prospective studies.


In situ measurements of velocity dispersion and attenuation in New Jersey Shelf sediments.
The existence of acoustic velocity dispersion and frequency dependence of attenuation in marine sediments is investigated using in situ measurements from a wideband acoustic probe system during the Shallow Water 2006 experiment. Direct-path pulse propagation measurements show evidence of velocity dispersion within the 10-80 kHz frequency band at two silty-sand sites on the New Jersey Shelf. The measured attenuation in dB/m shows linear frequency dependency within the 10-80 kHz frequency band. The measured velocity dispersion and attenuation curves are in good agreement with those predicted by an extended Biot theory [Yamamoto and Turgut, J. Acoust. Soc. Am. 83, 1744-1751 (1988)] for sediments with a distribution of pore sizes.


Drosophila Morgue is an F box/ubiquitin conjugase domain protein important for grim-reaper mediated apoptosis.
In Drosophila melanogaster, apoptosis is controlled by the integrated actions of the Grim-Reaper (Grim-Rpr) and Drosophila Inhibitor of Apoptosis (DIAP) proteins (reviewed in refs 1 4). The anti-apoptotic DIAPs bind to caspases and inhibit their proteolytic activities. DIAPs also bind to Grim-Rpr proteins, an interaction that promotes caspase activity and the initiation of apoptosis. Using a genetic modifier screen, we identified four enhancers of grim-reaper-induced apoptosis that all regulate ubiquitination processes: uba-1, skpA, fat facets (faf), and morgue. Strikingly, morgue encodes a unique protein that contains both an F box and a ubiquitin E2 conjugase domain that lacks the active site Cys required for ubiquitin linkage. A reduction of morgue activity suppressed grim-reaper-induced cell death in Drosophila. In cultured cells, Morgue induced apoptosis that was suppressed by DIAP1. Targeted morgue expression downregulated DIAP1 levels in Drosophila tissue, and Morgue and Rpr together downregulated DIAP1 levels in cultured cells. Consistent with potential substrate binding functions in an SCF ubiquitin E3 ligase complex, Morgue exhibited F box-dependent association with SkpA and F box-independent association with DIAP1. Morgue may thus have a key function in apoptosis by targeting DIAP1 for ubiquitination and turnover.


[A case of adenomatous polyps with prostatic type epithelium].
A 41-year-old male presented with gross hematuria and was found to have a polypoid lesion of the prostatic urethra. This proved to be an adenomatous polyp with prostatic type epithelium. Transurethral resection was performed on August 3, 1985. He had no evidence of recurrence following the operation. Previously reported cases of relevance are briefly discussed.


The in vitro effect of albendazole, ivermectin, diethylcarbamazine, and their combinations against infective third-stage larvae of nocturnally subperiodic Brugia malayi (Narathiwat strain): scanning electron microscopy.
Scanning electron microscopy (SEM) was employed to observe the effects of ivermectin (IVM), diethylcarbamazine (DEC), and albendazole (ALB) alone, and the drugs in combination (ALB+IVM and ALB+DEC) against infective third stage larvae (L3) of nocturnally subperiodic (NSP) Brugia malayi (Narathiwat strain) in vitro. IVM, at a concentration of 10(-4) M, killed L3 within 1-2 h. The SEM data showed damage to the L3 surface and loss of regular cuticular annulations. The cuticles were grooved in the middle region of the body. In comparison with normal L3 before treatment with IVM, the cuticular surface showed transversed striations with periodic annulations. The result demonstrated that IVM showed a larvicidal activity against L3 of NSP B. malayi cultivated in vitro. Compared with those larvae in the control group, the treated larvae had no morphological changes in the cuticular surface at the head, body, and tail regions after cultivation with all drugs alone, and in their combinations at a concentration of 10(-5) M for 7 d. In this system, and at that concentration, only the larvae cultured with ALB alone remained highly motile. Although no morphological changes had been observed by SEM, those drugs used alone (IVM and DEC) and in combinations (ALB+IVM and ALB+DEC), reduced larval motility throughout the experiments at a concentration of 10(-5) M. The minimum lethal concentration (MIC) of IVM against NSP B. malayi was 10(-4) M.


Design and Rationale of the APELOT Trial: A Randomized, Open-Label, Multicenter, Phase IV Study to Evaluate the Antiplatelet Effect of Different Loading Dose of Ticagrelor in Patients With Non-ST Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention.
Ticagrelor is a direct acting on the P2Y12 receptor blocker, which provides faster and greater platelet inhibition than clopidogrel. However, several studies suggested that in ST-segment elevation myocardial infarction patients undergoing percutaneous coronary intervention (PCI), ticagrelor exhibits initial delay in the onset of antiplatelet action. Unlike ST-segment elevation myocardial infarction, in non-ST-segment elevation acute coronary syndrome (NSTE-ACS), management pathways are highly variable, and some patients may require surgery. Effect of higher loading dose (LD) of ticagrelor in patients with NSTE-ACS in providing faster and stronger inhibition of platelet aggregation is unknown and needs to be explored further.The AntiPlatelet Effect of different Loading dOse of Ticagrelor trial is an interventional, randomized, open-label, multicenter, phase IV trial designed to evaluate whether a high LD (360 mg) of ticagrelor compared with the conventional LD (180 mg) will result in a higher inhibition of platelet aggregation without increasing bleeding events in NSTE-ACS participants undergoing PCI.A total of 250 NSTE-ACS participants will be randomized to receive a ticagrelor LD (360 or 180 mg), followed by a maintenance dose of 90 mg twice a day (bid) starting 12 hours after the LD. The primary endpoint is platelet reactivity index measured by vasodilator-stimulated phosphoprotein phosphorylation 2 hours after the LD, and the secondary endpoints include occurrence of periprocedural myocardial infarction and bleeding events.The AntiPlatelet Effect of different Loading dOse of Ticagrelor trial will provide important information on the risks and benefits of a high LD (360 mg) of ticagrelor in achieving a faster and stronger platelet inhibition compared with the conventional LD (180 mg) in NSTE-ACS patients undergoing PCI.


[The search for optimal decision in the treatment of multiple sclerosis: to improve adherence not reducing the efficacy].
Long-term disease modifying therapy (DMD) therapy is the basis of modern MS treatment, effiecacy of which is modulated by the patient's adherence to therapy. One of the possible solutions of low adherence improvement is the use of innovative drugs and the development of more convenient regimens of injectable medications. This article gives a brief review of peg-interferon β-1a clinical trials.


The roles of ethylene and transcription factors in the regulation of onset of leaf senescence.
Leaf senescence is the last stage of leaf development and is accompanied by cell death. In contrast to senescence in individual organisms that leads to death, leaf senescence is associated with dynamic processes that include the translocation of nutrients from old leaves to newly developing or storage tissues within the same plant. The onset of leaf senescence is largely regulated by age and internal and external stimuli, which include the plant hormone ethylene. Earlier studies have documented the important role of ethylene in the regulation of leaf senescence. The production of ethylene coincides with the onset of leaf senescence, whereas the application of ethylene to plants induces precocious leaf senescence. Recently, many studies have described the components of ethylene signaling and biosynthetic pathways that are involved in modulating the onset of leaf senescence. Particularly, transcription factors (TFs) integrate ethylene signals with those from environmental and developmental factors to accelerate or delay leaf senescence. This review aims to discuss the regulatory cascade involving ethylene and TFs in the regulation of onset of leaf senescence.


The role of the forensic pathologist in quality assurance and safety of patient care.
During this past half century, there has been remarkable increase in the role of forensic pathologists and medical examiners in the determination of cause and manner of deaths in health care facilities and investigations of quality of patient care. Autopsy data are an essential part of this quality assurance (QA) program in patient care, especially in trauma centers' QA programs. Forensic pathologists participate in evaluating appropriateness of patient care where death occurs during or following therapeutic and diagnostic procedures. Continuous quality improvement programs now extend into data sharing in child and elder abuse, monitoring of defective medical devices and consumer products which contributed to deaths. In recent years, forensic pathologists are increasingly requested directly by family members to conduct private autopsies to provide independent opinions as to quality of patient care. Thus forensic pathologists are contributing expertise to an ever widening circle of influence in prevention of unnecessary deaths with quality assurance programs and peer review processes.


Dust charge fluctuations in a magnetized dusty plasma.
Charging currents of electrons and ions to a spherical dust grain in a uniform magnetized dusty plasma have been examined. It is found that the external magnetic field reduces the charging currents, thereby decreasing the dust charge fluctuation damping of a low-frequency electrostatic wave in a dusty plasma.


Online RPLC-GC via TOTAD method to isolate (+)-methyl epijasmonate from lemon (Citrus limon Burm.).
Pure (+)-methyl epijasmonate was isolated from lemon ( Citrus limon Burm.) for the first time. To that aim, two commercial essential oils and one homemade extract were included in the present paper. First, a study on the appropriate chromatographic conditions to avoid the epimerization from methyl epijasmonate to the more stable methyl jasmonate was accomplished. The results obtained are discussed. The presence of (+)-methyl epijasmonate in the three samples studied was initially established through the direct injection into GC-MS. However, the overlapping of (+)-methyl epijasmonate with other matrix components made it necessary to employ a multidimensional technique. RPLC-GC analysis via through-oven transfer adsorption-desorption (TOTAD) provided the selectivity and sensitivity required, reflecting that the homemade lemon extract was an adequate natural source to obtain pure (+)-methyl epijasmonate by means of the collection of the corresponding RPLC fraction.


Intramolecular Energy Transfer in Dithienogermole Derivatives.
Dithienogermole (DTG) has been applied as a useful building unit of optical/semiconducting materials for organic optoelectronic devices because of its extended conjugation, high chemical stability, and good emissive properties. Although DTG has two substituents on the Ge atom, the substituents have been limited to simple alkyl and aryl groups in previous work. In this work, to further uncover the new functionalities of this useful building unit, various π-conjugated groups were introduced on Ge of DTG. It was expected that the introduction of π-conjugated groups would give rise to efficient energy transfer between the substituents and the DTG core, which are in proximity and linked by a Ge atom. The thus-prepared DTG compounds with fluorene, terthiophene, and pyrene units on Ge possessed well-separated frontier orbitals on the substituents and the DTG core, as proved by the absorption spectra and DFT calculations. The substituted DTG derivatives showed clear emission only from the energy acceptor even though the energy donor was photoexcited. This indicated the highly efficient energy transfer in these compounds. We also prepared more π-extended compound DTGFl2-Ph with phenyl groups on the DTG thiophene rings. DTGFl2-Ph showed strong emission in the visible region with efficient energy transfer properties. These results clearly indicate the potential application of the present DTG system as optical functional materials.


A clinical study of type 1 neurofibromatosis in north west England.
A clinical study of patients on the North West Regional Genetic Register with neurofibromatosis type 1 (NF1) identified 523 affected cases from 304 families. In those for whom relevant information was available, 86.7% (383 of 442) had more than six café au lait patches, 83.8% (310 of 370) had axillary freckling, 42.3% (151 of 357) had inguinal freckling, and 63% (157 of 249) had Lisch nodules. Cutaneous neurofibromas were present in 59.4% (217 of 365) and 45.5% (150 of 330) were noted to have subcutaneous tumours. Plexiform neurofibromas were present in 15.3% (80 of 523). A positive family history of NF1 was found in 71.2% (327 of 459) and 28.8% (132 of 459) of affected patients were considered to be the result of a new mutation. Learning difficulties of varying severity occurred in 62% (186 of 300). CNS tumours associated with NF1 were reported in 9.4% (49) of patients, optic gliomas occurring in 25 of these, 4.8% of patients. Some degree of scoliosis was reported for 11.7% (61), 1.9% (10) had pseudoarthrosis, 4.3% (23) had epilepsy, and 2.1% (11) had spinal neurofibromas. Actuarial analyses were carried out for both optic glioma and malignant nerve sheath tumours and the data are presented.


Thermodynamics of ferredoxin binding to ferredoxin:NADP+ reductase and the role of water at the complex interface.
The association of ferredoxin with ferredoxin:NADP+ reductase (both proteins from spinach chloroplasts) was characterized by isothermal titration calorimetry and fluorescence quenching titration. The formation of the complex is mainly driven by a positive entropy change (delta S = 125 +/- 8 J mol-1 K-1). The calorimetric enthalpy of binding is small between 10 and 37 degrees C and either negative or positive, with an inversion temperature near 25 degrees C. The pH dependence of the association constant [Batie, C. J., & Kamin, H. (1981) J. Biol. Chem. 256, 7756-7763] was shown to correlate with the uptake of a single proton by a group exhibiting a heat of protonation of -26 kJ mol-1. This value agrees with the protonation of an imidazole group. Possible residues to become protonated in the complex are His-19 or His-90 of ferredoxin:NADP+ reductase. The temperature dependence of the free energy of binding, delta G, is weak because of the enthalpy-entropy compensation caused by a heat capacity change, delta Cp, of -680 +/- 44 J mol-1 K-1. The favorable binding entropy and the negative delta Cp indicate a large contribution to binding from hydrophobic effects, which seem to originate from dehydration of the protein-protein interface. Dehydration was demonstrated by osmotic stress experiments in which the association constant was found to increase by 2-4-fold in the presence of 52% (w/w) glycerol. The increase in the association constant with osmotic pressure points to the release of several water molecules from the complex interface.


The study of establishment of an in vivo tumor model by three-dimensional cells culture systems methods and evaluation of antitumor effect of biotin-conjugated pullulan acetate nanoparticles.
In this study, three-dimensional (3D) hydrogels were used for human hepatocellular carcinoma (HepG2) cells culture systems in vitro and establishment of an in vivo xenografted tumor model. Based on our previous work on the biotin-conjugated pullulan acetate nanoparticles (Bio-PA NPs) as anticancer drug carriers, we further studied the anti-tumor effect of the NPs in two-dimensional (2D) and 3D cell culture system. When embedded in 3D hydrogels, HepG2 cells formed tumor spheroids and the cytoplasmic actin microfilamentrates were rearranged over a period of 7 days. In vitro cytotoxicity results indicated that HepG2 cells in 3D hydrogels were more resistant to Bio-PA NPs treatments compared to the 2D system. The tumor formation rate of in vivo xenografted tumor model using 3D culture systems method was 98.2%, which was significantly higher than that using of 2D cultured cells (76.4%). Then we injected the 3D HepG2 cells systems in the right anterior axillary of female Balb/c nude mice, and evaluate the in vivo anti-tumor efficacy of Bio-PA NPs. In summary, these results suggested that HepG2 cells in 3D hydrogel system has shown the potential to provide an in vitro and in vivo model and for the evaluation of Bio-PA NPs.


Comparison of lipid profile in type-2 obese diabetics and obese non-diabetic individuals. a hospital based study from Western Nepal.
Type-2 diabetes mellitus is an independent risk factor for coronary artery disease and risk of coronary disease is three to four fold increased in patients with diabetes compared with non-diabetic population and 60-80% 0f type-2 diabetics are obese. This study was conducted in Nepalgunj Teaching Hospital, Kohalpur, Banke, Nepal, between 1st March, 2011 and 28th February, 2012. A total of 150 samples were taken to assess the lipid profile in type-2 diabetic patients associated with obesity and 25 obese controls for their lipid profile. Venous blood samples were taken from all the subjects in the morning after fasting overnight. Exclusion criteria included pregnancy, chronic infectious disease, heart failure; renal failure and drug allergy were confirmed from the subject's personal physician report and a detailed history. The data was analyzed using Excel 2003, R 2.8.0 Statistical Package for the Social Sciences (SPSS) for Windows Version 16.0 (SPSS Inc; Chicago, IL, USA) and the EPI Info 3.5.1 Windows Version. The mean ± SD age of diabetic patients with obesity was 53.76± 6.23 while the mean ± SD age of control was 49.61 ± 4.8. Out of 150 patients 105 (70%) were males and 45 (30%) were females. Among control subjects 16 (64%) were males and 9 (36%) were females. Obese type-2 diabetic patients when compared to obese control subjects showed statistically significant increase in the levels of serum total cholesterol (p < 0.001), serum triglycerides (p < 0.001), serum LDL-cholesterol (p < 0.001) while serum HDL-cholesterol levels did not show statistically significant difference in the two group (p > 0.05). This study showed obese diabetic individuals have dyslipidemia and more prone to develop cardiovascular diseases.


Impact of nausea and vomiting on quality of life in cancer patients during chemotherapy.
It is commonly claimed that the nausea and vomiting accompanying cytotoxic chemotherapy have a negative impact on health-related quality of life. While this may seem self-evident, until a few years ago there was little empirical data demonstrating that the failure to control postchemotherapy emesis affects aspects of quality of life. In spite of their limitations, several observational studies showed that nausea and vomiting associated with chemotherapy induced a decrease in health-related quality of life with respect to patients without nausea and vomiting. This has also been demonstrated after the adjustment for health-related quality of life before chemotherapy that is an important prognostic factor of chemotherapy-induced nausea and vomiting. Furthermore, one study suggests that the optimal time of assessment of quality of life to evaluate the impact of chemotherapy-induced nausea and vomiting is day 4 if a 3-day recall period is used or day 8 when the recall period is 7 days. In double-blind studies the efficacy, tolerability and impact on quality of life of the 5-HT3 receptor antagonists was superior with respect to metoclopramide, alizapride and prochlorperazine. Similar results have been achieved with the combination of ondansetron with dexamethasone, the standard treatment for the prevention of acute emesis induced by moderately emetogenic chemotherapy, with respect to the metoclopramide plus dexamethasone combination. Instead, in another double-blind study, in patients submitted to moderately emetogenic chemotherapy, a 5-HT3 antagonist did not seem to significantly increase complete protection from delayed emesis and the patients' quality of life with respect to dexamethasone alone. In conclusion, the evaluation of quality of life in randomized trials comparing different antiemetic drugs for the prevention of chemotherapy-induced nausea and vomiting can add important information useful for the choice of the optimal antiemetic treatment.


[Development of gene delivery system using PLGA nanospheres].
The development of nonviral vectors for the efficient and safe delivery to cells has long been awaited to facilitate gene therapy. Recently, many nonviral vectors modified with cationic lipids, cationic polymers, etc. have been reported. However, those nonviral vectors with cationic materials require improved stability, longer duration of gene expression, and reduced cytotoxicity. We successfully prepared mucoadhesive poly (lactide-co-glycolide) nanospheres (PLGA NS) by modifying the nanoparticulate surface with chitosan to improve mucosal peptide absorption after oral and pulmonary administration. Furthermore, we found that nucleic acid, which was not dispersed in the organic solvent, could be dispersed by forming a complex with cationic lipid. Using this phenomenon, polynucleic acids for gene therapy (plasmid DNA, antisense oligonucleotide, small interfering RNA, etc.) can be encapsulated into the matrix of the polymer particles with the emulsion solvent diffusion method. The advantages of this preparation method are its simple process and avoidance of an ultrasonication process for submicronization of particles. The resultant nanospheres show better cellular uptake and different gene therapeutic effects compared with conventional vectors due to their improved adherence to cells and sustained release of polynucleic acid in the cells. In conclusion, chitosan-coated PLGA NS can possibly be applied in nonviral vectors for gene therapy.


Application of HPLC with a metal-free column to the analysis of cyclosporin in whole blood samples from cardiac transplant patients.
A simplified, reverse-phase HPLC method utilizing a metal-free column was developed for the analysis of cyclosporin (CYA) in whole blood in humans. The average intra and inter assay variation at the low end of the therapeutic range are less than or equal to 4.5 and 8.8% respectively. The procedure was successfully applied to the measuring of CYA in whole blood collected from cardiac transplant patients over a one year period.


Association between Mediterranean Diet and Type 2 Diabetes: Multiple Cross-Sectional Analyses.
To assess whether the Mediterranean diet (MD) is associated with lower levels of type 2 diabetes (T2D) in a non-Mediterranean population. Cross-sectional analysis of follow-ups 1 (FU1, 2009-2012, n = 4398, 45.7% men, 57.7 ± 10.5 years), 2 (FU2, 2014-2017, n = 3154, 45.0% men, 61.7 ± 9.9 years), and 3 (FU3, 2018-2021, n = 2394, 45.2% men, 65.0 ± 9.6 years) of the Colaus|PsyCoLaus study (Lausanne, Switzerland). Two MD scores (Trichopoulou, noted MD1, and Sofi, noted MD2) were calculated using participants' dietary data. T2D was defined as a fasting plasma glucose ≥7 mmol/L and/or the presence of an antidiabetic drug treatment. Participants with the highest MD adherence had a higher educational level, a lower BMI, were less frequent smokers, presented less frequently with hypertension, and were more frequent alcohol consumers. After multivariable adjustment, no differences were found between participants with and without T2D regarding MD scores: 3.93 ± 0.07 vs. 3.97 ± 0.02; 4.08 ± 0.10 vs. 3.98 ± 0.03, and 3.83 ± 0.11 vs. 3.97 ± 0.03, respectively, for the MD1 score in FU1, FU2, and FU3. In addition, no association was found between adherence to MD and T2D: odds ratio (and 95% confidence interval) for medium and high relative to low adherence to MD1: 0.87 (0.68-1.10) and 0.89 (0.64-1.24) in FU1, 1.04 (0.76-1.42) and 1.07 (0.68-1.67) in FU2, and 0.73 (0.53-1.03) and 0.61 (0.37-1.02) in FU3, respectively. Corresponding results for MD2 were 0.90 (0.70-1.15) and 1.03 (0.69-1.53) in FU1, 1.16 (0.82-1.63) and 1.40 (0.81-2.41) in FU2, and 0.93 (0.65-1.34) and 0.55 (0.28-1.08) in FU3. We found no association between Mediterranean diet adherence and T2D in a non-Mediterranean population.


Diagnostic dilemmas in patients with cystic neoplasms of the pancreas.
Cystic neoplasms of the pancreas (CNP) are rare lesions that can be difficult to diagnose preoperatively. Twenty patients with cystic neoplasms of the pancreas including five microcystic adenomas, six benign mucinous cystic neoplasms, three malignant mucinous cystic neoplasms, two solid and papillary epithelial neoplasms, and four cystic neuroendocrine tumors were treated at a single institution between 1962 and 1987. The average duration of symptoms prior to diagnosis was 10 months. Five patients were asymptomatic. Forty percent of patients presented with an abdominal mass. Plain abdominal x-rays and UGI barium contrast studies were never diagnostic. Ultrasonography, computerized tomography (CT) and visceral angiography aided in the correct diagnosis in 28%, 36%, and 75% of patients studied, respectively. Overall a correct diagnosis was made preoperatively in only 35% of patients. Twelve of 13 patients were correctly diagnosed at laparotomy with intraoperative biopsy. Without biopsy the mass was misdiagnosed at laparotomy in five of six cases. CNP must be suspected in any patients who present with an upper abdominal mass with or without abdominal pain and no history of pancreatitis. CT may be diagnostic in up to one third of cases and should be obtained routinely to demonstrate the proximity of the lesion to other structures. Visceral angiography should also be obtained prior to operation. A generous incisional biopsy should be obtained of all pancreatic cysts that are not to be resected.


Digital imaging in periodontal radiography. A review.
The development and the potential impact of digital imaging techniques for the analysis of dental radiographs are reviewed with emphasis on periodontal diagnosis. The introduction of video-based computer-assisted image analysis systems for the evaluation of standardized dental radiographs offered increased diagnostic accuracy in the detection of subtle density changes over interpretation of conventional radiographs. Digital subtraction images were interpreted qualitatively on a video monitor or quantitatively by applying programs which measure the density differences stored in digital format. Recently, these methods, which have been extensively tested in vitro, were applied to clinical trials for the assessment of alveolar bone density changes due to progression of disease or healing following therapy. The application of digital image analysis methods offers objective, quantitative and non-invasive ways to obtain additional diagnostic information from standardized radiographs in clinical trials.


Differences in responsiveness of clonally derived AXC/SSh rat prostate cancer cells to secreted or prototypic mitogens.
AXC/SSh rat prostate cancer cells elaborate heat-sensitive, heparin-binding mitogens which include members of the fibroblast growth factor (FGF)-like family of growth factors. The quantity of FGF-like growth factors, relative to total growth factor production, was cell line specific as was prostate cancer cell response to secreted or the prototypic mitogens basic FGF (bFGF), acidic FGF (aFGF), or epidermal growth factor (EGF). C3 cell proliferation, assayed either by cell counting or thymidine incorporation, was not affected by mitogens secreted by C3, D1, T1, or T5 prostate cancer cells or by bFGF, aFGF, or EGF. In contrast, C3, D1, T1, or T5 cell-secreted mitogens enhanced proliferation of T1 and T5 cells, and proliferation of D1, T1, and T5 cells was enhanced by bFGF, aFGF, and EGF. D1 cell response to prototypic mitogens was 3- to 12-fold less than that of T1 or T5 cells. By comparison, the NRKF cell response to prototypic mitogens was qualitatively comparable but quantitatively greater than that of rat prostate cancer cells. The relative and absolute bFGF or aFGF concentrations necessary for half-maximum stimulation of prostate cancer or normal rat kidney fibroblast cell thymidine incorporation were comparable to that known to effect half-maximum increase in proliferation of mesoderm-derived cells. Similarly, the EGF concentration required for half-maximum prostate cancer or normal rat kidney fibroblast cell thymidine incorporation was comparable to that known to effect half-maximum fibroblast thymidine incorporation or granulosa cell proliferation. Our data establish that prostate cancer cell response to prototypic mitogens is representative of that of nonneoplastic cells and imply that C3 cell insensitivity to prostate cancer cell or prototypic mitogens represents defects in cellular response mechanisms. The basis for C3 cell unresponsiveness or D1 cell-diminished responsiveness remains to be elaborated.


Design and synthesis of resveratrol-salicylate hybrid derivatives as CYP1A1 inhibitors.
Resveratrol and aspirin are known to exert potential chemopreventive effects through modulation of numerous targets. Considering that the CYP450 system is responsible for the activation of environmental procarcinogens, the aim of this study was to design a new class of hybrid resveratrol-aspirin derivatives possessing the stilbene and the salicylate scaffolds. Using HepG2 cells, we evaluated (a) the inhibition of TCDD-mediated induction of CYP1A1 exerted by resveratrol-aspirin derivatives using the EROD assay, and (b) CYP1A1 mRNA in vitro. We observed significant inhibition (84%) of CYP1A1 activity and a substantial decrease in CYP1A1 mRNA with compound 3, compared to control. Resveratrol did not exert inhibition under the same experimental conditions. This inhibitory profile was supported by docking studies using the crystal structure of human CYP1A1. The potential effect exerted by compound 3 (the most active), provide preliminary evidence supporting the design of hybrid molecules combining the chemical features of resveratrol and aspirin.


Bonding of autopolymerizing denture base resin to cast Type IV gold alloy.
To evaluate the shear bond strengths of an autopolymerizing denture base resin to cast Type IV gold alloy using four metal conditioners. Type IV gold alloy discs were cast. The disc surfaces were sandblasted with 50 microm alumina particles and primed with four metal conditioners (Metaltite; Alloy Primer; Metal Primer II; and V-Primer). An autopolymerizing denture base resin was applied on an area of the discs defined by a hole punched in a piece of sticky tape and by a Teflon ring. All the specimens were immersed in 37 degrees C distilled water for 24 hours. Half of the specimens were thermocycled up to 20,000 cycles in water between 4 degrees C and 60 degrees C with a dwell time of 1 minute at each temperature. The shear bond strengths were determined at a crosshead speed of 1.0 mm/minute. The data was analyzed using a 2-way ANOVA (P < 0.05). The shear bond strengths of the autopolymerizing denture base resin to cast Type IV gold alloy specimens primed with the four metal conditioners (P < 0.05) were significantly enhanced. However, the bond strength was reduced for all thermocycled groups (P < 0.01). Metaltite exhibited the greatest pre- and post-thermocycling bond strength (27.5 and 22.4 MPa) compared to the other groups (P < 0.05).


Extra dissipation and flow uniformization due to elastic instabilities of shear-thinning polymer solutions in model porous media.
We study flows of hydrolized polyacrylamide solutions in two dimensional porous media made using microfluidics, for which elastic effects are dominant. We focus on semi-dilute solutions (0.1%-0.4%) which exhibit a strong shear thinning behavior. We systematically measure the pressure drop and find that the effective permeability is dramatically higher than predicted when the Weissenberg number is greater than about 10. Observations of the streamlines of the flow reveal that this effect coincides with the onset of elastic instabilities. Moreover, and importantly for applications, we show using local measurements that the mean flow is modified: it appears to be more uniform at high Weissenberg number than for Newtonian fluids. These observations are compared and discussed using pore network simulations, which account for the effect of disorder and shear thinning on the flow properties.


ESLpred2: improved method for predicting subcellular localization of eukaryotic proteins.
The expansion of raw protein sequence databases in the post genomic era and availability of fresh annotated sequences for major localizations particularly motivated us to introduce a new improved version of our previously forged eukaryotic subcellular localizations prediction method namely "ESLpred". Since, subcellular localization of a protein offers essential clues about its functioning, hence, availability of localization predictor would definitely aid and expedite the protein deciphering studies. However, robustness of a predictor is highly dependent on the superiority of dataset and extracted protein attributes; hence, it becomes imperative to improve the performance of presently available method using latest dataset and crucial input features. Here, we describe augmentation in the prediction performance obtained for our most popular ESLpred method using new crucial features as an input to Support Vector Machine (SVM). In addition, recently available, highly non-redundant dataset encompassing three kingdoms specific protein sequence sets; 1198 fungi sequences, 2597 from animal and 491 plant sequences were also included in the present study. First, using the evolutionary information in the form of profile composition along with whole and N-terminal sequence composition as an input feature vector of 440 dimensions, overall accuracies of 72.7, 75.8 and 74.5% were achieved respectively after five-fold cross-validation. Further, enhancement in performance was observed when similarity search based results were coupled with whole and N-terminal sequence composition along with profile composition by yielding overall accuracies of 75.9, 80.8, 76.6% respectively; best accuracies reported till date on the same datasets. These results provide confidence about the reliability and accurate prediction of SVM modules generated in the present study using sequence and profile compositions along with similarity search based results. The presently developed modules are implemented as web server "ESLpred2" available at http://www.imtech.res.in/raghava/eslpred2/.


Proteins of the mineral compartment of bovine fetal enamel share common antigenic determinants with serum proteins.
Two fractions were separated from the proteins of the mineral compartment of bovine developing enamel on the basis of their affinity for the lectin concanavalin-A. A monoclonal antibody was prepared by the hybridoma technique against the Con-A-binding fraction. This antibody and a commercial polyclonal antibody against bovine serum albumin were used to examine the relationship between those proteins, serum albumin and alpha-2HS glycoprotein, two proteins concentrated within dentin and bone matrices. The Con-A-unbound fraction reacted with the anti-albumin antibody and the antibody against the Con-A-binding fraction recognized the alpha-2HS glycoprotein. These data fully support the presence of significant levels of proteins related to serum components in the mineral compartment of developing enamel matrix.


Quality Evaluation of Ethambutol Hydrochloride Tablet Batches Available in Governmental Health Facilities of Jimma Town, Southwest Ethiopia.
The availability of poor-quality drugs on the drug market might favor the ineffectiveness of the drug and/antimicrobial resistance. To evaluate the quality of similar batches of ethambutol hydrochloride tablets available in different governmental health facilities of Jimma town, southwest Ethiopia. The World Health Organization checklist was used to inspect the storage area of health facilities and check medicines for the sign of counterfeit. The test was conducted as per the United States Pharmacopeia on six similar batches of ethambutol hydrochloride sampled from different governmental health facilities. Data were analyzed using SPSS version 20, and one-way ANOVA was used for comparing the dissolution profile and weight variation of batches. Three health facilities did not comply with the storage area specifications for pharmaceuticals. No batches have shown any sign of counterfeit. All of the tablet batches tested complied with USP specifications for weight variation, percentage purity, and dissolution test. Conclusions and Recommendation. The entire tablet batches complied with the World Health Organization specification for packaging and labelling of pharmaceuticals. All tablet batches complied with the test for weight variation, purity of drug substance, and dissolution. Since some health facilities did not comply with at least one specification for storage of pharmaceuticals, regulatory agencies and stack holders are advised to inspect the health facilities to ensure appropriate storage of pharmaceuticals in health facilities.


Deciphering the Differential Effective and Toxic Responses of Bupleuri Radix following the Induction of Chronic Unpredictable Mild Stress and in Healthy Rats Based on Serum Metabolic Profiles.
The petroleum ether fraction of Bupleuri Radix which is contained in the traditional Chinese medicine prescription of Xiaoyaosan (XYS) may have a therapeutic effect in depressed subjects based on the results of our previous study. It has been reported that Bupleuri Radix can cause liver toxicity following overdosing or long-term use. Therefore, this study aimed to decipher the differential effective and toxic responses of Bupleuri Radix in chronic unpredictable mild stress (CUMS) (with depression) and healthy rats based on serum metabolic profiles. Serum metabolic profiles were obtained using the UHPLC- Q Exactive Orbitrap-MS technique. Our results demonstrated that the petroleum ether fraction of Bupleuri Radix (PBR) produces an antidepressant effect through regulating glycometabolism, amino acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, and fatty acid metabolism. It also induces more severe toxic reactions in the liver or kidney in healthy rats than in CUMS rats, which exhibited a comparatively mild drug-induced toxic reaction. The altered lysine degradation, sphingolipid metabolism, glycerophospholipid metabolism, fatty acid metabolism, and bile acid metabolism could be at least partly responsible for the PBR toxic responses in healthy rats. The differential effective and toxic response of PBR in CUMS rats and healthy rats provide a new standard for the more rational and safer application of clinical drugs in the future.


[Research progress of the objective voice assessment].
The voice is a complex multidimensional phenomenon. It is a drive through the lung airflow to vibrate the vocal cords, and then be perceived by the listeners. A multidimensional set of minimal basic measurements suitable for the voice diseases are proposed by the Committee on Phoniatrics of the European Laryngological Society in 2000. It includes five different aspects: the subjective physician perception (grade, roughness, breathiness), and subjective rating by the patient, videostroboscopy (closure, regularity, mucosal wave and symmetry), acoustics analysis and aerodynamics measurements. The first three are the subjective assessment of voice, these are not to be discussed in tis article. Only objective assessments of the voice and the latest research progress are summarized below.


Maternal and Neonatal Outcomes in Intrahepatic Cholestasis of Pregnancy.
The aims of our study were to evaluate the maternal and fetal outcomes of intrahepatic cholestasis of pregnancy (ICP). In this observational, retrospective case-control study, we included all pregnant women who gave birth with a diagnosis of ICP between January 2010 and December 2020 at the Unit of Obstetrics and Gynecology, University Hospital of Messina. The data were compared with those from a control group of pregnant women who did not have ICP. One hundred twenty-nine and eighty-five patients were included, respectively, in the study and in the control group. There was a significant difference between the two groups in the incidence of hypothyroidism, thrombophilia, gestational diabetes, gestational hypertension, postpartum hemorrhage, and preterm delivery, which were more frequent in the ICP patients. No neonatal adverse events were recorded, although a significant difference in the meconium-stained amniotic fluid condition was noted. After a 24-month follow-up, 48/129 patients with ICP accepted to be reassessed by liver ultrasound, elastographic examination, and liver function blood tests. No patient showed signs of chronic liver disease. This study confirmed a higher probability of adverse short-term maternal outcomes in ICP pregnant patients, but a lower probability of adverse short-term fetal outcomes and the absence of a long-term maternal risk of chronic liver disease.


[Next GINA report. What could be expected?].
The advantages, certain drawbacks and future problems of the next GINA (Global Initiative for Asthma Management and Prevention) elaboration are presented. It is suggested that the next issue is to arrive in 2004 or 2005.


Heterochromatin assembly and transcriptome repression by Set1 in coordination with a class II histone deacetylase.
Histone modifiers play essential roles in controlling transcription and organizing eukaryotic genomes into functional domains. Here, we show that Set1, the catalytic subunit of the highly conserved Set1C/COMPASS complex responsible for histone H3K4 methylation (H3K4me), behaves as a repressor of the transcriptome largely independent of Set1C and H3K4me in the fission yeast Schizosaccharomyces pombe. Intriguingly, while Set1 is enriched at highly expressed and repressed loci, Set1 binding levels do not generally correlate with the levels of transcription. We show that Set1 is recruited by the ATF/CREB homolog Atf1 to heterochromatic loci and promoters of stress-response genes. Moreover, we demonstrate that Set1 coordinates with the class II histone deacetylase Clr3 in heterochromatin assembly at prominent chromosomal landmarks and repression of the transcriptome that includes Tf2 retrotransposons, noncoding RNAs, and regulators of development and stress-responses. Our study delineates a molecular framework for elucidating the functional links between transcriptome control and chromatin organization.


In vitro expression of a 22-kilodalton Yersinia pestis polypeptide immunologically related to the 25-kilodalton plasmid-encoded protein of the three pathogenic Yersinia species.
Antibodies raised against the 25-kilodalton (p25) plasmid-encoded polypeptide of Yersinia enterocolitica recognized the homologous protein in the three Yersinia species grown in vitro. This polypeptide was recovered from whole cells as well as from the fluid supernatant of bacteria grown at 37 degrees C in a Ca2+-deficient medium. Furthermore, a 22-kilodalton (p22) plasmid-encoded polypeptide immunologically related to p25 was found only in Y. pestis during early growth. After 30 h of culture, the Y. pestis p25 and p22 were completely degraded, whereas the intensity of the Y. enterocolitica p25 was decreased, but the protein was still detectable in the fluid supernatant. This proteolytic activity was independent of the presence of the virulence plasmid. Some disulfide bonds are probably involved in the quaternary structure of the p25 of the three pathogenic species and of the Y. pestis p22.


Synthesis and screening of N-acyl thiolated chitosans for antibacterial applications.
Low-molecular weight chitosan-thioglycolic acid has shown significant antibacterial properties against different microorganisms. In order to explore the potential and structure-activity relationships of newly synthesized alkyl thiomers, chitosan has been functionalized with a series of thio-acids with increasing alkyl chain length. All thiomers were characterized with special emphasis on the determination of their degree of deacetylation and substitution, as well as on their molecular weight and amount of thiol groups. The pre-screened chitosan-thiomers were further investigated with plate counting on Pseudomonas aeruginosa, Streptococcus sobrinus and Streptococcus mutans. Furthermore, LIVE/DEAD assays supported the efficiency of chitosan-thiomers against the above microorganisms. All fully characterized chitosan-thiomers showed comparable or enhanced antimicrobial activity compared to pristine chitosan. Our comprehensive approach paves the way to detailed explorations of much sought-after structure activity relationships in the complex chitosan parameter room, starting from correlations between alkyl chain length and antimicrobial activity.


Fusion proteins of Hsp70 with tumor-associated antigen acting as a potent tumor vaccine and the C-terminal peptide-binding domain of Hsp70 being essential in inducing antigen-independent anti-tumor response in vivo.
Hsp70s are a family of ATP-dependent chaperones of relative molecular mass around 70 kDa. Immunization of mice with Hsp70 isolated from tumor tissues has been proved to elicit specific protective immunity against the original tumor challenge. In this work, we investigated whether Hsp70 can be used as vehicle to elicit immune response to its covalence-accompanying antigen. A recombinant protein expression vector was constructed that permitted the production of recombinant protein fusing tumor-associated antigen (eg, Mela) to the C terminus of Hsp70. We found that the Hsp70-Mela fusion protein can elicit strong cellular immune responses against murine tumor B16, which expresses protein Mela. The Hsp70 peptide-binding domain deletion mutant of the fusion protein was sufficient for inducing Mela-specific cytotoxic T lymphocyte but was not sufficient for engendering potent anti-tumor immunity against B16. We also found that host natural killer (NK) cells were stimulated in vivo by C-terminal domain of Hsp70. We thus presume that Hsp70 fusion proteins suppress tumor growth via at least 2 distinct pathways: one is covalence-accompanying antigen dependent; another is antigen independent. The C-terminal domain of Hsp70 seemed to be the crucial part in eliciting antigen-independent responses, including NK cell stimulation, against tumor challenges. Furthermore, we found that immunization with multiple Hsp70 fusion proteins resulted in a better anti-tumor effect.


Bilateral isolated submandibular gland mumps.
Isolated submandibular swellings pose a diagnostic challenge to the practising otolaryngologist. We report an unusual case of mumps isolated to bilateral submandibular glands. We discuss the case and the literature surrounding this condition and remind clinicians that mumps should be considered as a diagnosis in the presence of submandibular gland swelling in the absence of typical parotid swelling associated with mumps. Early consideration of this differential diagnosis, serological testing and a multidisciplinary approach may help to clinch the diagnosis earlier and prevent spread of the virus.


Escherichia coli gene purR encoding a repressor protein for purine nucleotide synthesis. Cloning, nucleotide sequence, and interaction with the purF operator.
The Escherichia coli gene purR, encoding a repressor protein, was cloned by complementation of a purR mutation. Gene purR on a multicopy plasmid repressed expression of purF and purF-lacZ and reduced the growth rate of host cells by limiting the rate of de novo purine nucleotide synthesis. The level of a 1.3-kilobase purR mRNA was higher in cells grown with excess adenine, suggesting that synthesis of the repressor may be regulated. The chromosomal locus of purR was mapped to coordinate 1755-kb on the E. coli restriction map (Kohara, Y., Akiyama, K., and Isono, K. (1987) Cell 50, 495-508). Pur repressor bound specifically to purF operator DNA as determined by gel retardation and DNase I footprinting assays. The amino acid sequence of Pur repressor was derived from the nucleotide sequence. Pur repressor subunit contains 341 amino acids and has a calculated Mr of 38,179. Pur repressor is 31-35% identical with the galR and cytR repressors and 26% identical with the lacI repressor. These four repressors are likely homologous. Amino acid sequence similarity is greatest in an amino-terminal region presumed to contain a DNA-binding domain. A similarity is also noted in the operator sites for these repressors.


Assessment of Retention of CAD-CAM Milled PEKK vs PEEK Double Crown-retained Removable Partial Dentures: A Randomized Clinical Trial.
To assess and compare the dislodging force of double crown-retained removable partial dentures (RPDs) made from polyetherketoneketone (PEKK) and polyetheretherketone (PEEK) at insertion (baseline) and one year after clinical functional use. A total of 18 patients with maxillary symmetrical Kennedy class I with the second premolars being the last standing abutment were selected. The patients were randomly assigned into two groups according to the materials used for the construction of the double crown-retained RPD. Group I: Double crown-retained RPDs were made from PEKK. Group II: Double crown-retained RPDs were made from PEEK. For both groups, the primary copings were made from zirconia (ZrO2). The dislodging force was measured using a digital force gauge at baseline and one year after clinical functional use. An independent t-test was used for intergroup comparisons and a paired t-test for intragroup comparisons. when comparing both groups at baseline, there was no significant difference between the two groups, but after one year, Group I had a significantly higher dislodging force value than Group II. Individually, there was an increase in dislodging force in both groups one year after clinical functional use, which was statistically significant for Group I. After clinical functional use, double crown-retained RPDs made from PEEK in combination with ZrO2 primary copings demonstrate a minimal increase in dislodging force, while those made of PEKK demonstrate a significant increase in dislodging force. All patients were satisfied with the retention and esthetics of their dentures. Polyetherketoneketone double crown-retained RPDs demonstrate better retention one year after clinical functional use.


AMPA glutamate receptors and neuropathic pain.
Glutamate receptors are implicated in many actions in the central nervous system, as an excitatory amino acid, and one of the more relevant is its role in excitotoxicity. Apart from this, it also has a role as pro-nociceptive agent, so that antagonizing its actions could be of interest for developing new analgesic agents. Furthermore, between the analgesics agents, it is of outstanding interest the fact that there is no specific therapy against the neuropathic pain, and glutamate receptor subunits have elicited as new potential targets for this disturbance.


[Multichannel cochlear implantation in a deaf child].
A multichannel cochlear implantation was performed in an 8-year-old child and the following results were obtained. The surgical procedures were not particularly difficult as compared to cochlear implantation for adults. Postoperative rehabilitation requires a longer time than in adult patients. Cochlear implants are useful not only for the recognition of environmental sound but also for the recognition of speech. Cooperation with the medical facility, as well teachers and family members, is essential.


Estimating the Effects of PM2.5 on Life Expectancy Using Causal Modeling Methods.
Many cohort studies have reported associations between PM2.5 and the hazard of dying, but few have used formal causal modeling methods, estimated marginal effects, or directly modeled the loss of life expectancy. Our goal was to directly estimate the effect of PM2.5 on the distribution of life span using causal modeling techniques. We derived nonparametric estimates of the distribution of life expectancy as a function of PM2.5 using data from 16,965,154 Medicare beneficiaries in the Northeastern and mid-Atlantic region states (129,341,959 person-years of follow-up and 6,334,905 deaths). We fit separate inverse probability-weighted logistic regressions for each year of age to estimate the risk of dying at that age given the average PM2.5 concentration at each subject's residence ZIP code in the same year, and we used Monte Carlo simulations to estimate confidence intervals. The estimated mean age at death for a population with an annual average PM2.5 exposure of 12 μg/m3 (the 2012 National Ambient Air Quality Standard) was 0.89 y less (95% CI: 0.88, 0.91) than estimated for a counterfactual PM2.5 exposure of 7.5 μg/m3. In comparison, life expectancy at 65 y of age increased by 0.9 y between 2004 and 2013 in the United States. We estimated that 23.5% of the Medicare population would die before 76 y of age if exposed to PM2.5 at 12 μg/m3 compared with 20.1% if exposed to an annual average of 7.5 μg/m3. We believe that this is the first study to directly estimate the effect of PM2.5 on the distribution of age at death using causal modeling techniques to control for confounding. We find that reducing PM2.5 concentrations below the 2012 U.S. annual standard would substantially increase life expectancy in the Medicare population. https://doi.org/10.1289/EHP3130.