Evaluation of Dose-Painting in the Dominant Intraprostatic Lesions by Radiobiological Parameters using 68Ga- PSMA PET/CT.
Patients diagnosed with dominant intraprostatic lesions (DIL) may need radiation doses over than 80 Gy. Dose-painting by contours (DPC) is a useful technique which helps the patients. Dose-painting approach need to be evaluated. To evaluate the DCP technique in the case of boosting the DILs by radiobiological parameters, tumor control probability (TCP), and normal tissue complication probability (NTCP) via PET/CT images traced by 68Ga-PSMA. In this analytical study, 68Ga-PSMA PET/CT images were obtained from patients with DILs that were delineated using the Fuzzy c-mean (FCM) algorithm and thresholding methods. The protocol of therapy included two phases; at the first phase (ph1), a total dose of 72 Gy in 36 fractions were delivered to the planning target volume (PTV1); the seconds phase consisted of the application of variable doses to the PTV2. Moreover, two concepts were also considered to calculate the TCP using the Zaider-Minerbo model. The lowest volume in DILs belonged to the DIL1 extracted by the FCM method. According to dose-volume parameters of the rectum and bladder, by the increase in the PTV dose higher than 92 Gy, the amounts of rectum and bladder doses are increased. There was no difference between the TCPs of DILs at doses higher than 86 Gy and 100 Gy for ordinary and high clone density, respectively. Consequently, our dose-painting approach for DILs, extracted by the FCM method via PET/CT images, can reduce the total dose for prostate radiation with 100% tumor control and less normal tissue complications.


GdmCl-induced unfolding studies of human carbonic anhydrase IX: a combined spectroscopic and MD simulation approach.
Carbonic anhydrase IX (CAIX) is a transmembrane glycoprotein, associated with tumor, acidification which leads to the cancer, and is considered as a potential biomarker for hypoxia-induced cancers. The overexpression of CAIX is linked with hypoxia condition which is mediated by the transcription of hypoxia-induced factor (HIF-1). To understand the biophysical properties of CAIX, we have carried out a reversible isothermal denaturation of CAIX-induced by GdmCl at pH 8.0 and 25°C. Three different spectroscopic probes, the far-UV CD at 222 nm ([θ]222), Trp fluorescence emission at 342 nm (F342) and difference molar absorption coefficient at 287 nm (Δε287) were used to estimate stability parameters, [Formula: see text] (Gibbs free energy change in the absence of GdmCl; Cm (midpoint of the denaturation curve), i.e. molar GdmCl concentration ([GdmCl]) at which ΔGD = 0; and m, the slope (=∂ΔGD/∂[GdmCl])). GdmCl induces a reversible denaturation of CAIX. Coincidence of the normalized transition curves of all optical properties suggests that unfolding/refolding of CAIX is a two-state process. We further performed molecular dynamics simulation of CAIX for 40 ns to see the dynamics of protein structure in different GdmCl concentrations. An excellent agreement was observed between in silico and in vitro studies.


The study of a possible correlation between serum levels of interleukin 17 and clinical severity in patients with allergic rhinitis.
Allergic rhinitis (AR) is one of the most common allergic diseases, which affects ∼20% of the world's population. T-helper (Th) type 2 cells produce interleukin (IL) 4 and IL-13, and mediate allergic responses, and these cytokines have been extensively studied as key players in the atopic airway diseases. However, the involvement of Th17 cells and IL-17 in AR has not been clearly examined. To reevaluate AR clinical severity with serum IL-17, whether IL-17 affects the disease alone or in contribution with the atopic predisposition. During an 18-month period, 39 individuals were divided into three groups: A, (13 control), B (13 with mild-to-moderate AR), and C (13 with severe AR). Both group B and group C patients (26) were subjected to clinical examination and allergy skin testing, and to measurement of both total serum immunoglobulin E (IgE) and IL-17 levels. Eleven patients with AR then were exposed to 6 months of cluster immunotherapy, whereas the rest of the patients were not exposed. Revealed a significant elevation of serum IL-17 levels with an associated increase in serum IgE in the patients with AR compared with controls and revealed that the serum levels of both total serum IgE and IL-17 decreased significantly after cluster immunotherapy. These preliminary results added new data about the use of injective immunotherapy as well as reported on the use of sublingual immunotherapy.


Does Risk Mitigation Reduce 90-Day Complications in Patients Undergoing Total Knee Arthroplasty?: A Cohort Study.
With ever-increasing demand for total knee arthroplasty (TKA), most healthcare systems around the world are concerned about its socioeconomic burden. Most centers have universally adopted well-defined clinical care pathways to minimize adverse outcomes, maximize volume, and limit costs. However, there are no prospective comparative trials reporting benefits of these risk mitigation (RM) strategies. This is a prospective cohort study comparing post-TKA 90-day complications between patients undergoing RM before surgery and those following a standard protocol (SP). In the RM group, we used a 20-point checklist to screen for modifiable risk factors and evaluate the need for optimizing non-modifiable comorbidities. Only when optimization goals were achieved, patients were offered TKA. TKA was performed in 811 patients in the SP group and in 829 in the RM group, 40% of which were simultaneous bilateral TKA. In both groups, hypertension was the most prevalent comorbidity (48%), followed by diabetes (20%). A total of 43 (5.3%) procedure-related complications were seen over the 90-day postoperative period in the SP group, which was significantly greater than 26 (3.1%) seen in the RM group (p = 0.039). The commonest complication was pulmonary thromboembolic, 6 in each group. Blood transfusion rate was higher in the SP group (6%) than in the RM group (< 1%). Screening and RM can reduce 90-day complications in patients undergoing TKA.


Impacts of Agriculture on the Environment and Soil Microbial Biodiversity.
Agriculture represents an important mechanism in terms of reducing plant, animal, and microbial biodiversity and altering the environment. The pressure to cope with the increasing food demands of the human population has intensified the environmental impact, and alternative ways to produce food are required in order to minimize the decrease in biodiversity. Conventional agricultural practices, such as floods and irrigation systems; the removal of undesired vegetation by fires, tilling, and plowing; the use of herbicides, fertilizers, and pesticides; and the intensification of these practices over the last 50 years, have led to one of the most important environmental threats-a major loss of biodiversity. In this study, we review the impact that agriculture and its intensification have had on the environment and biodiversity since its invention. Moreover, we demonstrate how these impacts could be reduced through the use of microorganisms as biostimulants.


Incorporation of a Phenanthrene Subunit into a Sapphyrin Framework: Synthesis of Expanded Aceneporphyrinoids.
32-Hetero-5,6-dimethoxyphenanthrisapphyrins-macrocycles that link structural features of polycylic aromatic hydrocarbons and expanded porphyrins-were obtained in a straightforward [3+1] condensation reaction of dimethoxyphenanthritripyrrane and 2,5-bis(arylhydroxymethyl)heterocyclopentadienes. The highly folded conformation of formally 4 n π-electron macrocycles causes them to manifest only limited macrocyclic π conjugation as explored by means of NMR spectroscopic and X-ray structural analyses, and supported by DFT calculations. Although protonation does not change their π-conjugation characteristics, the cleavage of ether groups at the phenanthrenylene moiety yields nonaromatic 32-hetero-5,6-dioxophenanthrisapphyrins.


Adult perspectives on growing up following uxoricide.
The purpose of this article is to provide an overview of the state of the science on uxoricide, including qualitative findings on 47 survivors. Two qualitative interviews were conducted between January 2004 and January 2005 with 47 convenience sample adult survivors of uxoricide. Data were analyzed using hermeneutic analysis. A number of themes emerge, such as later experiences with violence, including sexual abuse as a child; family difficulties in speaking about the death; the need to learn about the homicide as an adult as well as a need to reconnect with and forgive the assailant; and the importance of a caring adult to provide stability.


Malignant Peripheral Nerve Sheath Tumor of the Cervical Spine Treated with Surgical Resection Followed by X-ray Radiotherapy or Carbon Ion Radiotherapy: A Report of Three Cases.
Spinal malignant peripheral nerve sheath tumors (MPNSTs) are extremely rare. Because of vital surroundings, en bloc resection can be difficult in MPNSTs of the cervical spine. Herein, we report three cases of MPNST followed by radiotherapy or carbon ion radiotherapy (CIRT) after surgery. In case 1, the patient underwent subtotal resection from both a posterior and anterior approach following by adjuvant X-ray radiotherapy. The patient died 13 years after surgery due to liver cancer unrelated to MPNST. In case 2, recurrence spread to the spinal canal in 10 months after primary CIRT. The patient underwent resection of the spinal canal lesion with the residual lesion treated by additional CIRT. Recurrence could be controlled for at least 1 year. In case 3, the patient underwent partial resection for the spinal canal lesion with the residual lesion treated by CIRT. Intradural and extradural recurrences from outside of the CIRT field were observed at 3 years after surgery. Complete resection and adjuvant X-ray radiotherapy would be an effective treatment for MPNST of the cervical spine, even if en bloc resection with a wide margin is impossible. CIRT for the residual tumor after incomplete resection may have the potential to be an additional treatment option; however, further investigation is warranted.


The nutrient requirements of horses: historical perspectives.
The National Research Council (NRC) published the Recommended Nutrient Allowances for Horses in 1949. The subsequent publication was renamed the Nutrient Requirements of Horses and the 6th revised edition was published in 2007. The document has increased in size and scope from the initial publication in 1949 that contained 29 pages to the most recent version with 341 pages. Several formats for expressing requirements (dietary concentrations or daily amounts) have been utilized. In addition, a variety of methods have been employed to determine the nutrient requirements of horses since 1949. Many of the requirement estimates are based on research studies with the target class of horse. However, some estimates have been derived from practical experience or extrapolated from other species and there is ample opportunity for future research related to many nutrients. Equine nutritionists may also explore additional methods to express the recommended daily nutrient intakes of horses.


Resveratrol improves muscle function but not oxidative capacity in young mdx mice.
Patients with Duchenne muscular dystrophy (DMD) have reduced muscle function due to chronic muscle damage, inflammation, oxidative stress, and reduced oxidative capacity. Resveratrol reduces inflammation and oxidative stress, and increases oxidative capacity in other disease models. The purpose of this study was to determine the effects of resveratrol on muscle function, muscle pathology, and oxidative capacity in young mdx mice. For this, 4- to 5-week-old male mdx mice were randomized into control or resveratrol-treated groups and given resveratrol (100 mg/kg body mass) or an equal volume of water by gavage every other day for 8 weeks. Muscle function was assessed pre- and post-treatment. Central nucleation, total immune cell infiltrate, oxidative stress, and oxidative capacity were measured post-treatment. Resveratrol mediated substantial improvements in rotarod performance and in-situ peak tension by 53% and 17%, respectively, and slight improvements in central nucleation and oxidative stress. Resveratrol did not affect total immune cell infiltrate at 12 weeks of age, and had no effect on oxidative capacity. Resveratrol improves muscle function in mdx mice despite small changes in muscle pathology. The likely mechanism is a resveratrol-mediated reduction in immune cell infiltrate at the early stages of this disease, as previously reported by our laboratory.


Triple trouble--macrophage activation syndrome in a case of severe leptospirosis and scrub typhus co-infection.
Macrophage activation syndrome is a potentially life threatening phenomenon characterised by aggressive proliferation of macrophages and T lymphocytes leading to haemophagocytosis of other blood cells and multi organ failure. Here we present a very unusual combination of leptospirosis and scrub typhus infection leading to macrophage activation syndrome. Scrub typhus associated with macrophage activation syndrome has rarely been reported in India. A 40 year old female presented with high grade fever, seizures, bodyache, arthralgia and severe breathlessness. Investigations revealed persistent thrombocytopenia, impaired liver function tests, renal dysfunction, leptospiral IgM ELISA positive and a positive Weil Felix test. There was evidence of haemophagocytosis in bone marrow. Macrophage activation syndrome if left untreated has been associated with rapidly fatal outcome and early treatment can help us save that one precious thing..called life..!


Disposition of the opioid antagonist, nalmefene, in rat and dog.
1. The disposition of nalmefene in rat and dog was studied using in vitro and in vivo methodology. In vitro metabolite profiles were obtained following incubation of nalmefene with liver microsomes and biological fluids were assayed to profile in vivo metabolites. Characterization of metabolites was accomplished using hplc, co-chromatography with synthetic standards, or LC/MS. 2. In rat, tissue distribution and metabolite plasma concentration-time data were obtained following intravenous bolus dosing of nalmefene. 3. The results indicate that the primary phase I metabolite of nalmefene from liver microsome incubations was the N-dealkylated metabolite, nornalmefene. Quantitative metabolite production was rat >> dog. In vivo, nornalmefene glucuronide was the major metabolite in rat urine, whereas nalmefene glucuronide(s) were predominant in dog urine. 4. More than 90% of the radioactive dose was recovered in the rat excreta and tissues 24 h after an intravenous bolus dose of 14C-nalmefene, with no apparent organ-specific retention of radioactivity. 5. Pharmacokinetic analysis of the rat plasma metabolite data indicated that terminal half-lives for nalmefene and nornalmefene were comparable (approximately 1 h). However, Cmax and AUC of nornalmefene were < or = 7% that of corresponding nalmefene values.


Glutaraldehyde cross-linked chitosan microspheres as a long acting biodegradable drug delivery vehicle: studies on the in vitro release of mitoxantrone and in vivo degradation of microspheres in rat muscle.
Chitosan microspheres were prepared from 74% deacetylated chitin by the glutaraldehyde cross-linking of an aqueous acetic acid dispersion of chitosan in a mixture of liquid paraffin and petroleum ether stabilized using sorbitan sesquioleate as the surfactant. Cross-linking and hardening of the spherical particles were achieved by the addition of glutaraldehyde-saturated toluene through the organic phase. A relatively novel antineoplastic agent, mitoxantrone, was incorporated into the microspheres and the drug release was studied in vitro into phosphate buffer for over 4 weeks at 27 degrees C. Drug release was found to be effectively controlled by the extent of cross-linking. Only about 25% of the incorporated drug was released over 36 days from microspheres of high cross-linking density. Implantation of placebo chitosan microspheres in the skeletal muscle of rats was carried out in order to assess the biocompatibility and biodegradability of the microspheres. Histological analysis showed that the microspheres were well tolerated by the living tissue. However, no significant biodegradation of the material was noticed over a period of 3 months in the skeletal muscle of rats. Data obtained indicate the possibility of using cross-linked chitosan microspheres as a drug carrier for sustained drug release for very long periods.


Assessing proportionate and disproportionate functional mitral regurgitation with individualized thresholds.
The concept of proportionate/disproportionate functional mitral regurgitation (FMR) has been limited by the lack of a simple way to assess it and by the paucity of data showing its prognostic superiority. The aim of this study was to evaluate the prognostic value of an individualized method of assessing FMR proportionality. We retrospectively identified 572 patients with at least mild FMR and reduced left ventricular ejection fraction (<50%) under medical therapy. To determine FMR proportionality status, we used an approach where a simple equation determined the individualized theoretical regurgitant volume (or effective regurgitant orifice area) threshold associated with haemodynamically significant FMR. Then, we compared the measured with the theoretical value to categorize the population into non-severe, proportionate, and disproportionate FMR. The primary endpoint was all-cause mortality. During a median follow-up of 3.8 years (interquartile range: 1.8-6.2), 254 patients died. The unadjusted mortality incidence per 100 persons-year rose as the degree of FMR disproportionality worsened. On multivariable analysis, disproportionate FMR remained independently associated with all-cause mortality [adjusted hazard ratio: 1.785; 95% confidence interval (CI): 1.249-2.550; P = 0.001]. The FMR proportionality concept showed greater discriminative power (C-statistic 0.639; 95% CI: 0.597-0.680) than the American (C-statistic 0.583; 95% CI: 0.546-0.621; P for comparison <0.001) and European guidelines (C-statistic 0.584; 95% CI: 0.547-0.620; P for comparison <0.001). When added to any of the before-mentioned guidelines, FMR proportionality also improved risk stratification by reclassifying patients into lower and higher risk subsets. Disproportionate FMR is independently associated with all-cause mortality and improves the risk stratification of current guidelines.


Effect of atorvastatin on aldosterone production induced by glucose, LDL or angiotensin II in human renal mesangial cells.
Nephropathy is a major complication of diabetes mellitus, thus development of rational therapeutic means is critical for improving public health. It was previously reported that human mesangial cells locally produced aldosterone, a steroid hormone that plays an important role in the development of diabetic nephropathy. The present experiments clarified the effect of glucose, LDL and angiotensin II, the molecules frequently elevated in patients with diabetic nephropathy, on aldosterone production in human primary mesangial cells. These cells expressed the CYP11B2 mRNA, a rate-limiting enzyme in the aldosterone biosynthesis. LDL and angiotensin II stimulated CYP11B2 mRNA expression in these cells, while a high concentration of glucose, angiotensin II and/or LDL increased aldosterone production. Importantly, atorvastatin (CAS 134523-03-8), an HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitor, strongly suppressed their effects on aldosterone production. Atorvastatin also suppressed positive effects of these compounds on the mRNA expression of the angiotensin II receptor type 1, thus atorvastatin exerted its negative effect in part through changing expression of this receptor. Since elevated levels of glucose and LDL, and increased action of the renin-angiotensin-aldosterone system is known to participate in the progression of diabetic nephropathy, it is speculated that the mesangial endocrine system that produces aldosterone locally is a promising therapeutic target for diabetic nephropathy where HMG-CoA reductase inhibitors provide a beneficial effect.


Isolation of bacteria, transforming bacteria, and bacteroids from soybean nodules.
Postnuclei supernatant of soybean (Glycine max cv. Chippewa 64) nodule homogenate was fractionated by stepwise sucrose density gradient centrifugation into supernatant, endoplasmic reticulum and mitochondria, and three distinct bands with 1.22, 1.25, and 1.27 g/cm(3) of peak density. Based on their enzymic activities, composition of electron transport components, and ultrastructural characteristics, the lightest band appears to be the mature bacteroids; the intermediate band the transforming bacteria; and the heaviest, the bacteria. The isolation procedure separates nodule symbionts into different functional and developmental fractions, and it may be a valuable tool for studies involving development, regulation, and senescence of bacteroids in the nodule.


Adherence to Barcelona Clinic Liver Cancer guidelines in field practice: Results of Progetto Epatocarcinoma Campania.
The Barcelona Clinic Liver Cancer (BCLC) algorithm is the standard system for clinical management of hepatocellular carcinoma (HCC). Data on adherence to this therapeutic paradigm are scarce. This field practice study aimed to provide a description of HCC cirrhotic patients in Southern Italy, to evaluate the adherence to BCLC guidelines and its impact on patients' survival. We analyzed the region-wide Italian database of Progetto Epatocarcinoma Campania, which includes data of HCC cirrhotic patients, prospectively collected from January 2013 to December 2015 in 16 regional centers. Overall, 1008 HCC patients were enrolled: 70.6% patients received therapies recommended by BCLC algorithm, while 29.4% underwent different treatments. Among patients who were treated in adherence to guidelines, a higher rate of diagnosis on surveillance programs, better liver function, lower rate of alpha-fetoprotein > 200 ng/mL, more early-stage and monofocal HCC, lower frequency of nodules > 5 cm, portal vein thrombosis and metastases were observed. The overall survival was evaluated according to HCC stage and no differences between groups and patients managed differently were found. The multivariate analysis showed that non-adherence to treatment guidelines was independently associated to the BCLC stage B, Child-Pugh classes B and C, and the presence of neoplastic thrombosis and metastases. Adherence to BCLC algorithm in field practice was high in early and end-stage HCC patients, but it was poor in intermediate and advanced patients.


Adsorption and Flame Retardant Properties of Bio-Based Phytic Acid on Wool Fabric.
Bio-based phytic acid (PA) as a nontoxic naturally occurring compound is a promising prospect for flame-retardant (FR) modifications to polymers. In this work, PA was applied to wool fabric using an exhaustion technique, and the adsorption and FR properties of PA on wool fabric were studied. The flame retardancy of the treated wool fabrics depended greatly on the adsorption quantity of PA, which was related to the pH of treatment solution, immersing temperature and initial PA concentration. The Langmuir adsorption of PA took place due to electrostatic interactions between PA and wool fiber. The limiting oxygen index, vertical burning and pyrolysis combustion flow calorimetry tests revealed that the treated wool fabrics exhibited good flame retardancy. The measurements of the phosphorus content of the burned fabric residues and thermogravimetric analyses suggested that a significant condensed-phase FR action was applicable to the PA treated fabrics. PA treatment was found to have little adverse effect on the whiteness and mechanical performance of wool. Additionally, the washing resistance of the FR fabrics should be further improved.


A case of arteriovenous fistula after renal biopsy in an IgA nephropathy patient with macroscopic hematuria.
Macroscopic hematuria is a common symptom in IgA nephropathy and is also one of the most frequent complications after a percutaneous renal biopsy. Here, we describe a patient with IgA nephropathy and recurrent macroscopic hematuria who developed an arteriovenous fistula after renal biopsy.


Effect of physician ownership of specialty hospitals and ambulatory surgery centers on frequency of use of outpatient orthopedic surgery.
Physician-owned specialty hospitals and ambulatory surgery centers have become commonplace in many markets throughout the United States. Little is known about whether the financial incentives linked to ownership affect frequency of outpatient surgery. To evaluate if financial incentives linked to physician ownership influence frequency of outpatient orthopedic surgical procedures. We analyzed 5 years of claims data from a large private insurer in Idaho to compare frequency by orthopedic surgeon owners and nonowners of surgical procedures that could be performed in either ambulatory surgery centers or hospital outpatient surgery departments. Frequency of use, calculated as number of patients treated with the specific diagnoses who received the surgical procedure of interest divided by the number of patients with such diagnoses treated by each physician. Age- and sex-adjusted odds ratios indicate that the likelihood of having carpal tunnel repair was 54% to 129% higher for patients of surgeon owners compared with surgeon nonowners. For rotator cuff repair, the adjusted odds ratios of having surgery were 33% to 100% higher for patients treated by physician owners. The age- and sex-adjusted probability of arthroscopic surgery was 27% to 78% higher for patients of surgeon owners compared with surgeon nonowners. The consistent finding of higher use rates by physician owners across time clearly suggests that financial incentives linked to ownership of either specialty hospitals or ambulatory surgery centers influence physicians' practice patterns.


[Observation of the anastomoses of intrahepatic veins in normal men].
The purpose of this study is to identify the existence of hepatovenous intrahepatic anastomosis in normal men. A total of thirteen livers were investigated during the early autopsies of normal men who died in accidents. Perfusion venography of branches of hepatic veins using meglucamine diatrizoate was done in six cases; this method we used had not been reported in the literature. In one case, portal venography was performed. And in the other six cases, liver substance staining was done by injecting the ink through the middle hepatic vein, and such staining of the liver was observed by light microscope. The results show, (1) there are intrahepatic anastomoses between the hepatic veins within the liver; (2) there are anastomoses between the middle hepatic vein and the accessory hepatic veins; and (3) shunts exist between portal veins and hepatic veins. The above findings provide an anatomical basis for the performance of irregular hepatectomy and the rationale for one or two hepatic veins ligation should such veins were traumatized or invaded by liver cancer.


Conformational and amino acid residue requirements for the saposin C neuritogenic effect.
Prosaposin is the precursor of four activator proteins, termed saposins A, B, C, and D, that are required for much of glycosphingolipid hydrolysis. The intact precursor also has neurite outgrowth activity ex vivo and in vivo that is localized to amino acid residues 22-31 of saposin C. Across species, this saposin C region has a high degree of identity and similarity with amino acids in the analogous region of saposin A. Wild-type and mutant saposins C and A from human and mouse were expressed in E. coli. Pure proteins, synthetic peptide analogues, conformation-specific antibodies, and CD spectroscopy were used to evaluate the basis of the ex vivo neuritogenic effect. Wild-type saposin A had no neuritogenic activity whereas reduced and alkylated saposin A did. Introduction of the conserved saposin A Tyr 30 (Y30) into saposin C at the analogous position 31, a conserved Ala(A)/Gly(G)31, diminished neuritogenic activity by 50-60%. Nondenatured saposin A with an introduced A30 acquired substantial neuritogenic activity. Polyclonal antibodies directed against the NH2-terminus of saposin C cross-reacted well with reduced and alkylated saposins C and A, wild-type saposin C, and saposin A [Y30A], poorly with saposin C [A31Y], and not at all with wild-type saposin A. CD spectra of wild-type and mutant saposins C and A, the corresponding neuritogenic region of saposin C, and the analogous region of saposin A showed that more "saposin C-like" molecules had neuritogenic properties. Those with more "saposin A-like" spectra did not. These studies show that the neuritogenic activity of saposin C requires specific placement of amino acids, and that Y30 of saposin A significantly alters local conformation in this critical region and suppresses neuritogenic activity.


The second 100,000 cases of acquired immunodeficiency syndrome--United States, June 1981-December 1991.
The first cases of acquired immunodeficiency syndrome (AIDS) were reported in June 1981. From 1981 through December 1987, 50,000 AIDS cases had been reported to CDC, and by August 1989, 100,000 cases had been reported. From September 1989 through November 1991, state and territorial health departments reported 100,000 additional cases. By December 31, 1991, a cumulative total of 206,392 cases had been reported (Figure 1), and the cumulative number of reported deaths associated with AIDS was 133,232. This report presents characteristics of the first and second 100,000 persons with AIDS.


[Investigation on two family clusters of COVID-19 in a county of Baotou city in Inner Mongolia Autonomous Region].
Objective: To investigate the epidemiological characteristics and transmission chain of COVID-19 in two families, and to provide scientific evidence for effective prevention and control measures. Methods: Field epidemiological investigation was conducted for the COVID-19 cases occurred in two families and the close contacts in a county of Baotou city in Inner Mongolia Autonomous Region. Descriptive statistical analysis on epidemiological data was conducted. Results: The infection source of the COVID-19 cases in the two families was a man who had living history in Wuhan. After his return, his parents were infected by him. A few days later, the members of a neighbor family were found to be infected, and relatives of this family were also infected after dining together repeatedly. Finally, ten confirmed cases and three suspected cases of COVID-19 were detected in the two families. Conclusions: Human-to-human transmission of COVID-19 can occur not only in a family but also in neighborhoods. The cases in two families had close relationship, indicating the necessity to strengthen the health education about COVID-19 prevention and control and the management of groups at high risk to reduce the incidence of COVID-19 in families and neighborhoods.


Essential hypertension: racial/ethnic differences in pathophysiology.
Essential hypertension is a complex polygenetic disorder with different "intermediate phenotypes" among diverse racial/ethnic groups. Differences have been identified in the renin-angiotensin system, prevalence of salt sensitivity, ion-transport mechanisms, and calcium homeostasis, yet no unifying hypothesis as to the genetic mechanisms responsible for the excess prevalence and severity of hypertension among African Americans has emerged. Environmental factors, such as access to health care, socioeconomic status, stress, diet, and obesity, account for some of the differences in the prevalence of hypertension worldwide.


[Effect of growth differentiation factor 7 on tenogenic differentiation of bone marrow mesenchymal stem cells of rat in vitro].
To investigate the effect of growth differentiation factor 7 (GDF-7) on the tenogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in vitro, to provide evidence for improving the efficacy of BMSCs on tendon repair. BMSCs were isolated from bone marrow tissue of green fluorescent protein rats by density gradient centrifugation method. Chondrogenic, osteogenic, and adipogenic differentiation assays were used to demonstrate the multi-differentiation potential of the BMSCs. BMSCs at passage 3 were cultured and divided into 4 groups according to different concentrations of GDF-7 (0, 12.5, 25.0, and 50.0 ng/mL): group A, B, C, and D, respectively. After cultured for 2 weeks in vitro, the mRNA expressions of scleraxis, tenomodulin, tenascin C, and collagen type I were detected by real-time fluorescent quantitative PCR method, the protein expressions of tenomodulin, tenascin C, and collagen type I by immunocytochemistry staining in 4 groups, and the protein expressions of tenomodulin by Western blot in groups A and C. BMSCs had osteogenic, chondrogenic, and adipogenic differentiation potentials. The mRNA expressions of tenomodulin in groups B, C, and D were 2.85, 3.41, and 3.07 times higher than that in group A, respectively; the mRNA expressions of scleraxis in groups B, C, and D were 2.13, 1.50, and 2.56 times higher than that in group A, respectively; and the mRNA expressions of tenascin C in groups B, C, and D were 2.45, 2.86, and 1.88 times higher than that in group A, respectively. There were significant differences between groups B, C, D and group A (P < 0.05), while there was no significant difference among groups B, C, and D (P > 0.05). The mRNA expressions of collagen type I in groups B and C were 1.92 and 2.45 times higher than that in group A, showing significant differences between groups B, C and group A (P < 0.05), but no significant difference between groups A and D (P > 0.05). Immunocytochemistry staining showed that the protein expressions of tenomodulin, tenascin C, and collagen type I were detected in groups B, C, and D but not in group A. The results were further confirmed by Western blot results which showed higher protein expression of tenomodulin in group C than in group A. GDF-7 can be used to promote tenogenic differentiation of rat BMSCs in vitro.


Effect of oral diseases on mothers giving birth to preterm infants.
To determine the association between preterm birth (PTB) and maternal oral diseases during pregnancy. This prospective study was performed by the neonatal and dental departments at Jordan University Hospital. The study included 100 women who gave birth to preterm singleton infants (born less than 37 complete weeks from last menstrual period) between January and July 2009. The control group included an equal number of women who delivered singleton, full-term infants on the same day or the day after the women in the study. The mothers' demographic data were collected using a questionnaire, and an oral examination was conducted for each participant. Statistical analysis was performed using SPSS for Windows release 16.0 (SPSS Inc., Chicago, Ill., USA). Factors related to PTB were studied in univariate and multivariate logistic regression analyses. Significantly higher DMFT (decayed, missing, filled teeth) index scores, Silness and Loe plaque index scores and Mühlemann tooth mobility index scores were associated with PTB. Mothers who did not have prepregnancy dental checkups had a significantly higher incidence of PTB. Fewer mothers in the PTB group visited dentists during their last pregnancy compared with controls. Oral health, especially healthy periodontium, is one reliable indicator for predicting a safe pregnancy outcome.


Comparison of plateletpheresis with two different cell separators using 100 identical donors.
Plateletpheresis with the cell separator COBE Spectra and Fenwal CS 3000 was compared in 100 identical donors. The Spectra was significantly superior with regard to collection efficiency (53% vs. 42%, p less than .001) and leukocyte contamination of the platelet products (.1 x 10(8) vs. 1.4 x 10(8), p less than .001). Additionally, it offers a selectable volume of the concentrate and a better control of the ACD infusion. The Spectra standard procedure needs more ACD, resulting in more citrate dependent donor reactions (5% vs. 1%). In conclusion, the Spectra system shows a more efficient and pure platelet separation compared with the CS 3000.


Clinical and biologic features of the AIDS dementia complex.
Human immunodeficiency virus type 1 infection is frequently associated with complications of the nervous system, involving all levels of the neuraxis. Many of these represent focal disorders, such as toxoplasmosis, lymphoma, and progressive multifocal leukoencephalopathy. This article reviews the salient clinical and biological features of these disorders.


Role of osteoclasts in regulating hematopoietic stem and progenitor cells.
Bone marrow (BM) cavities are utilized for hematopoiesis and to maintain hematopoietic stem cells (HSCs). HSCs have the ability to self-renew as well as to differentiate into multiple different hematopoietic lineage cells. HSCs produce their daughter cells throughout the lifespan of individuals and thus, maintaining HSCs is crucial for individual life. BM cavities provide a specialized microenvironment termed "niche" to support HSCs. Niches are composed of various types of cells such as osteoblasts, endothelial cells and reticular cells. Osteoclasts are unique cells which resorb bones and are required for BM cavity formation. Loss of osteoclast function or differentiation results in inhibition of BM cavity formation, an osteopetrotic phenotype. Osteoclasts are also reportedly required for hematopoietic stem and progenitor cell (HSPC) mobilization to the periphery from BM cavities. Thus, lack of osteoclasts likely results in inhibition of HSC maintenance and HSPC mobilization. However, we found that osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization by using three independent osteoclast-less animal models. In this review, I will discuss the roles of osteoclasts in hematopoietic stem cell maintenance and mobilization.


The nature and significance of behavioural genetic information.
In light of the human genome project, establishing the genetic aetiology of complex human diseases has become a research priority within Western medicine. However, in addition to the identification of disease genes, numerous research projects are also being undertaken to identify genes contributing to the development of human behavioural characteristics, such as cognitive ability and criminal tendency. The permissibility of this research is obviously controversial: will society benefit from this research, or will it adversely affect our conceptions of ourselves and each other? When assessing the permissibility of this research, it is important to consider the nature and deterministic significance of behavioural genetic information. Whilst to date there has been much discussion and debate about the properties of genetic information per se and genetic determinism, this has not been applied to behavioural genetic research and its ethical implications. Therefore, this paper elucidates how behavioural genetic information can be distinguished from other types of genetic and non-genetic information and also synthesizes the determinative significance of genetic factors for the development of human behavioural traits. Undertaking this analysis enables the ethical issues raised by this research to be debated in an appropriate context and indicates that separate policy considerations are warranted.


[Effect of ketogenic diet on obesity asthma].
Recently investigators pay more attention to the relationship between obesity and bronchial asthma (asthma).Obesity is increasingly recognized as a possible risk factor for childhood asthma, and 70% of patients with difficult-to-treat asthma are overweight or obese. In recent years, ketogenic diet, as one of the natural therapies, has been shown to have positive effects on weight loss process; and recent studies showed that ketogenic diet reduced airway inflammation in asthma. This review summarized the mechanisms of associations between obesity and asthma, and described the potential mechanisms of ketogenic diet affecting obese asthma, such as controlling body weight, reducing inflammatory response, regulating intestinal flora and modifying epigenetics, to provide new ideas for the prevention and treatment of obesity asthma.


Systemically induced vasculitis in children.
Vascular diseases can be quite grave in children. Common diseases in children that cause a generalized vasculitis include Kawasaki disease, Henoch-Schonlein purpura, and Rocky Mountain spotted fever. Rheumatic fever, though preventable, is increasing in incidence and may cause arteritis, and therefore is discussed as a vascular disease. Developmental considerations should be considered when providing adequate care. Play therapy is a crucial part of every day in a child's life, even when ill with a vascular illness. Play helps a child gain control over the stress of a serious illness and hospitalization.


Reporting hospital adverse events using the Alfred Hospital's morbidity data.
Hospital morbidity data were analysed to determine their usefulness for reporting adverse events. The entire ICD-10-AM classification system was reviewed in conjunction with the Australian Coding Standards to identify external cause codes and code prefixes associated with adverse events. For the 50,712 separations registered at The Alfred from July 2000-June 2001, 4,740 external cause codes were associated with adverse events. Place of occurrence code CY92.22 was considered the best indicator of the number of separations associated with adverse events. Approximately 4% of all separations were associated with adverse events occurring during an episode of care. Results suggest that hospital morbidity data are useful for monitoring adverse events at hospital level. Reliable reporting across the health care industry requires consistent reporting requirements at state and national levels and the adoption of standard code prefixes nationally.


Uncommon otological manifestations of nasopharyngeal carcinoma.
Nasopharyngeal carcinoma (NPC) is significant for the otologist although the nasopharynx is located outside the anatomical confines of the ear. Middle-ear effusion resulting from NPC is well-known. There are however, other less common ear symptoms of NPC that many physicians are not sufficiently aware of. A personal series of patients with NPC presenting with uncommon symptoms relating to the ear is presented. These include NPC presenting as a) haemotympanum b) a peri-auricular mass c) referred sensation to the ear d) blocked ear e) barotrauma f) an ear polyp g) sudden sensorineural hearing loss. These symptoms may pose diagnostic difficulties, resulting in the diagnosis of NPC being delayed. It was concluded that a high index of suspicion for NPC is warranted in high risk patients presenting with unexplained otological symptoms.


Psychological outcomes of a pulmonary rehabilitation program.
This study assessed physiologic, psychological, and cognitive functioning in outpatients with COPD. Sixty-four subjects, 53 to 82 years of age, participated in the 30-day exercise rehabilitation program. The program consisted of exercise, education and psychosocial counselling. Participants were assessed prior to beginning the program and at the end of 30 days. Assessments at both times included physiologic functioning (bicycle ergometry testing, pulmonary function tests, 12-min walk), psychological well-being (anxiety, depression, psychiatric symptoms, perceived well-being) and an abbreviated neuropsychological test battery. Results indicate significant improvement in physical endurance and pulmonary function, significant reductions in symptoms of depression and anxiety, and improvement in measures of general well-being and neuropsychological functioning. The study suggests that exercise rehabilitation of older adults with COPD contributes not only to improvements in physical functioning and endurance, but also to enhanced cognitive functioning and psychological well-being.


Unusual cause of intraoperative hypotension diagnosed with transoesophageal echocardiography in a patient with renal cell carcinoma.
Transoesophageal echocardiography (TOE) is not commonly used in the management of non-cardiac cases. We report a case where the use of TOE played a major role in the intraoperative diagnosis and subsequent management of a patient exhibiting severe hypotension whilst undergoing a nephrectomy. The rare diagnosis of a secondary intraventricular tumour would not have been evident with more conventional monitoring techniques.


Involvement of C-jun NH2-terminal kinase and apoptosis induced factor in apoptosis induced by deglycosylated bleomycin in laryngeal carcinoma cells.
In our previous studies, we demonstrated that the deglycosylation of bleomycin-A2 (BLM-A2) does not affect the capacity of this drug to induce cell death by apoptosis in a caspase-independent manner in laryngeal cancer cells (HEp-2), but suppresses the ability of BLM-A2 to induce ROS formation. We have now investigated the consequence of BLM-A2 deglycosylation in terms of the involvement of apoptotic pathways in HEp-2 cells. Apoptosis induced by bleomycin-A2 and deglyco-BLM-A2 is associated with the release of cytochrome c and AIF. Only Bax was oligomerized with BLM-A2-induced HEp-2 cell death. BLM-A2 and deglyco-BLM-A2-induced apoptosis depended on JNK activation but was independent of death receptors expression. In contrast, both of these drugs would sensitize HEp-2 cells to death receptor ligand-induced cell death. These observations indicate that the deglycosylation of BLM does not impair the ability of the drug to trigger cell death through activation of the intrinsic pathway by the release of AIF responsible for mitochondrial permeability and chromatin condensation independent of caspases activation.


Escharotic agents: a Victorian remedy in the 21st century.
A 72-year-old woman had a warty growth 'burnt off' with a herbal remedy by a local farmer in rural Ireland. We saw the patient a number of years later in clinic and she brought the specimen with her, which was processed by the pathology department. We report her case and some interesting background information regarding escharotic agents.


Variation in crown and root formation and eruption of human deciduous teeth.
The aim of this study was to document variation of deciduous tooth formation and eruption. The material comprises 121 individuals of known or estimated age (using tooth length) from Spitalfields in London, and radiographs of 61 healthy living children aged 2-5 years. Other skeletal material from two medieval Scottish archaeological sites (Whithorn, N=74; Newark Bay, N=59) was also examined. Stages of crown and root formation as well as eruption (alveolar, midway, and occlusal levels) were assessed for each developing maxillary and mandibular tooth from radiographs or direct vision. Age of attainment for individual stages was calculated by probit analysis, and these data were also adapted for use in estimating age. The timing of crown completion was similar to previously reported studies, but apex completion times were later. Analysis of data relative to the first and second molars at the two stages D (crown complete) and F (root length > or =crown height) allowed comparison with the Scottish material. No significant differences were observed between population groups for tooth formation or eruption. These data fill several gaps in the literature, and will be useful in assessing maturity and predicting age during early childhood.


Antepartum fetal surveillance: the biophysical profile.
In summary, it appears, based on a cumulative experience of more than 15,000 patients from several centers, that fetal biophysical profile scoring holds promise as an improved method of fetal risk detection. Antepartum detection, classification, determination of severity, and ultimately, treatment of the fetus at risk for death and damage in utero form the basis of modern perinatal medicine. It remains to be determined whether addition of further variables or refinement of existing variables will improve accuracy still further. The assessment of multiple biophysical variables and responses to intrinsic and extrinsic stimuli is helpful in differentiating a normal sleeping fetus from an asphyxiated one.


Control of cardiomyocyte orientation on a microscaffold fabricated by photopolymerization with laser beam interference.
We fabricate scaffolds with a fine linear grating (periodicity of 1 to 8 microm and height of 1 microm) on a glass substrate for controlling cardiomyocyte orientation. The fabrication is done by the solidification of a liquid photopolymerizable material using two laser beam interference. As the photopolymerizable material, we use acrylated trimethylene-carbonate-based oligomers initiated with trimethylolpropane (T/TMP), followed by acrylation at terminal ends. Rat cardiomyocytes cultured on the fabricated scaffolds exhibit cell elongation, orientation, and contraction along the scaffold grating. Fluorescence observation of bundles of actin filaments of the cultured cells show that the cytoskeleton of the cells is also generated and oriented parallel to the grating. With a change in grating periodicity from 8 to 1 microm, the percentage of the cells that show orientation along the grating increase from approximately 40 to 70%. The cell orientation along the grating is observed 18 h after seeding the cells on the scaffold. This result implies that the attachment between a cell and a well-defined microarchitectural substrate at an early stage of culture is a significant determinant of cell morphology.


Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and Alzheimer's disease pathology.
Chronic neuroinflammation is a pathogenic component of Alzheimer's disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune-cell checkpoint receptor/ligand pair PD-1/PD-L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD-L1 and PD-1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD-L1 from astrocytes, which may mediate ectodomain signaling to PD-1-expressing microglia. Deletion of microglial PD-1 evoked an inflammatory response and compromised amyloid-β peptide (Aβ) uptake. APP/PS1 mice deficient for PD-1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD-1/PD-L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD.


Joint effects of polymorphisms in the HTRA1, LOC387715/ARMS2, and CFH genes on AMD in a Caucasian population.
To estimate the joint effects of single nucleotide polymorphisms (SNPs) in the genes complement factor H (CFH), HtrA serine peptidase 1 (HTRA1), and age-related maculopathy susceptibility 2 (LOC387715/ARMS2) in a Caucasian age related macular degeneration (AMD) case-control cohort. We genotyped three SNPs, rs1061170 (exon 9, CFH), rs11200638 (HTRA1 promoter, -512 bp), and rs10490924 (6.6 kb upstream of HTRA1 in LOC387715/ARMS2) in 333 cases with advanced AMD (choroidal neovascularization [CNV] and geographic atrophy) and 171 age-matched examined controls. Association tests were performed for individual SNPs and jointly with the CFH SNP Y402H. Analyses for interaction were also performed. The linkage disequilibrium measure for two SNPs on 10q26, rs10490924 and rs11200638, is D'=0.8 and all four possible haplotypes of the two SNPs were detected in the samples. The allelic association test for rs11200638 on the promoter of HTRA1 yielded p-values less than 10(-10) for geographic atrophy, less than 10(-16) for neovascularization, and less than 10(-19) for the pooled phenotypes (with an odds ration [OR] of 3.973; 95% confidence interval [CI] 2.928, 5.390). Disease risk is conferred in a dosage-dependent fashion. Similar figures were observed for the LOC387715/ARMS2 SNP. No interaction was detected between either between the 10q26 SNPs or the CFH SNP. This is the first analysis to show that the two 10q26 SNPs are not in complete linkage disequilibrium. Our studies however show that both the HTRA1 and LOC387715/ARMS2 SNP appear to contribute equally to disease risk (both geographic atrophy and choroidal neovascularization) with no evidence of interaction with CFH.


Analysis of heat-induced disassembly process of three different monomeric forms of the major light-harvesting chlorophyll a/b complex of photosystem II.
The temperature-dependent disassembly process of three monomeric isoforms, namely Lhcb1, Lhcb2, and Lhcb3, of the major light-harvesting chlorophyll (Chl) a/b complexes of photosystem II (LHCIIb) were characterized by observing the changes of absorption spectra, circular dichroism (CD), and dissociation processes of the bound pigments to the in vitro reconstituted complexes subjected to high temperatures. Our results suggest that the three isoforms of LHCIIb undergo conformational rearrangements, structural changes, and dissociations of the bound pigments when the ambient temperature increases from 20 to 90°C. The conformation of the complexes changed sensitively to the changing temperatures because the absorption peaks in the Soret region (436 and 471 nm) and the Qy region (650-660 and 680 nm) decreased immediately upon elevating the ambient temperatures. Analyzing temperature-dependent denaturing and pigment dissociation process, we can divide the disassembly process into three stages: The first stage, appeared from 20°C to around 50-60°C, was characterized by the diminishment of the absorption around 650-660 and 680 nm, accompanied by the blue-shift of the peak at 471 nm and disappearance of the absorbance at 436 nm, which is related to changes in the transition energy of the Chl b cluster, and the red-most Chl a cluster in the LHCIIb. The second stage, beginning at about 50-60°C, was signified by the diminishment of the CD signal between (+)483 nm and (-)490 nm, which implied the disturbance of dipole-dipole interaction of pigments, and the onset of the pigment dissociation. The last stage, beginning at about 70-80°C, indicates the complete dissociation of the pigments from the complex. The physiological aspects of the three stages in the denaturing process are also discussed.


Complementation of a p300/CBP defective-binding mutant of adenovirus E1a by human papillomavirus E6 proteins.
Previous studies have shown that the human papillomavirus type 16 (HPV-16) E6 protein binds to p300/CBP and abrogates its transcriptional co-activator function. However, there is little information on the biological consequences of this interaction and discrepancy as to whether the interaction is high-risk E6 specific or not. We performed a series of studies to compare the interactions of HPV-18 and HPV-11 E6 with p300, and showed that both high- and low- risk E6 proteins bind p300. In addition, using a transformation-deficient mutant of adenovirus E1a, which cannot interact with p300, we demonstrated that HPV-16, HPV-18 and, to a lesser extent, HPV-11 E6, can complement this mutant in cell transformation assays. In contrast, a mutant of HPV-16 E6 which does not bind p300 failed to rescue the E1a mutant. These results suggest that the E6-p300 interaction may be important for the ability of HPV E6 to contribute towards cell transformation.


[Medullary mechanism of the inhibition on renal sympathetic efferent activities by stimulation of the cervical vagal afferent nerve in rabbits].
Experiments were performed on 63 rabbits anesthetized with pentobarbital, paralyzed with gallamine triethiodide and ventiled artifically. Ipsilateral renal sympathetic nerve discharge (RSND), unit discharges of rostral ventrolateral medulla (RVL), caudal ventrolateral medulla (CVL) and blood pressure (BP) were recorded. The sympatho-inhibitory response were evoked by stimulation of the central end of vagal nerve (CVN) (731/788 exp.). The inhibitory duration is 3.6 +/- 0.185 s. The responses vary with the functional state of the CNS. The RSND inhibitory duration could be shortened or prolonged, depending on the excitatory background of RSND or the basal sympathetic tonic activity. The results indicate that CVN-induced inhibitory of RSND may be mediated, at least partly, by excitation of NTS and CVL, which results, in turn, in depressing RVL and final reduction of sympathetic efferent activity.


Successful Resection of a Giant Pulmonary Colloid Adenocarcinoma via Median Sternotomy.
We report on a giant pulmonary colloid adenocarcinoma successfully resected using a median sternotomy approach. A 69-year-old woman visited our hospital owing to a giant mass detected on chest radiography. A giant cystic mass measuring 115 × 90 mm was detected in the right upper lung using computed tomography. We suspected mucinous adenocarcinoma and performed right upper lobectomy and mediastinal lymph node dissection with median sternotomy. The surgical field of view for the tumor and superior vena cava was satisfactory, and compression but not invasion of the superior vena cava and chest wall by the tumor was observed. The tumor was pathologically diagnosed as a colloid adenocarcinoma of stage IIIA with pT4N0M0. The postoperative course was uneventful, with no signs of recurrence at one and a half years after operation. Thus, this case demonstrates that for giant lung tumor surgery, median sternotomy is useful and safe for improving the surgical field of view.


In situ engineering of the lymph node microenvironment via intranodal injection of adjuvant-releasing polymer particles.
Recent studies have demonstrated a simple, potentially universal strategy to enhance vaccine potency, via intralymph node (i.LN) injection. To date, intranodal immunization studies have focused on the delivery of unadjuvanted vaccines (e.g., naked DNA, peptide, or protein). We hypothesized that combining i.LN vaccination with controlled release biomaterials permitting sustained dosing of molecular adjuvants to the local tissue microenvironment would further enhance this promising vaccination strategy. To test this idea, we encapsulated the Toll-like receptor-3 ligand poly(inosinic:cytidylic acid) (polyIC) in biodegradable poly(lactide-co-glycolide) microparticles (MPs) designed to remain extracellular and release polyIC in the LN over several days. Intranodal injection of MPs increased persistence of polyIC in LNs compared to the same dose of soluble polyIC or polyIC formulated in nanoparticles, leading to increased accumulation of Toll-like receptor agonist in LN-resident antigen presenting cells and more enduring dendritic cell activation. Intralymph node injection of ovalbumin mixed with polyIC-releasing MPs enhanced the humoral response and expanded ovalbumin-specific T cells to frequencies as high as 18% among all CD8(+) cells following a single injection (8.2-fold greater than the same vaccine given i.m.), a response that could not be matched by antigen mixed with polyIC-loaded nanoparticles or a 10-fold greater dose of soluble polyIC. Thus, i.LN immunization with slow release-formulated adjuvants may be a broadly applicable strategy to enhance therapeutic or prophylactic vaccines.


Model-Free Adaptive Optimal Control for Unknown Nonlinear Multiplayer Nonzero-Sum Game.
In this article, an online adaptive optimal control algorithm based on adaptive dynamic programming is developed to solve the multiplayer nonzero-sum game (MP-NZSG) for discrete-time unknown nonlinear systems. First, a model-free coupled globalized dual-heuristic dynamic programming (GDHP) structure is designed to solve the MP-NZSG problem, in which there is no model network or identifier. Second, in order to relax the requirement of systems dynamics, an online adaptive learning algorithm is developed to solve the Hamilton-Jacobi equation using the system states of two adjacent time steps. Third, a series of critic networks and action networks are used to approximate value functions and optimal policies for all players. All the neural network (NN) weights are updated online based on real-time system states. Fourth, the uniformly ultimate boundedness analysis of the NN approximation errors is proved based on the Lyapunov approach. Finally, simulation results are given to demonstrate the effectiveness of the developed scheme.


Importance of free actin filament barbed ends for Arp2/3 complex function in platelets and fibroblasts.
We investigated the effect of actin filament barbed end uncapping on Arp23 complex function both in vivo and in vitro. Arp23 complex redistributes rapidly and uniformly to the lamellar edge of activated wild-type platelets and fibroblasts but clusters in marginal actin filament clumps in gelsolin-null cells. Treatment of gelsolin-null platelets with the negative dominant N-WASp C-terminal CA domain has no effect on their residual actin nucleation activity, placing gelsolin actin filament severing, capping, and uncapping function upstream of Arp23 complex nucleation. Actin filaments capped by gelsolin or the gelsolin homolog CapG fail to enhance Arp23 complex nucleation in vitro, but uncapping of the barbed ends of these actin filaments restores their ability to potentiate Arp23 complex nucleation. We conclude that Arp23 complex contribution to actin filament nucleation in platelets and fibroblasts importantly requires free barbed ends generated by severing and uncapping.


The biomechanical stability of miniplate osteosynthesis configurations in bilateral mandibular angle fractures.
The present study investigated the biomechanical stability of three miniplate osteosynthesis configurations used for internal fixation of bilateral mandibular angle fracture (BMAF). Standard fracture lines were created in 72 polyurethane mandibles and stabilized with 2.0-mm, 4-hole standard titanium miniplates and monocortical screws. The group descriptions and miniplate configurations were: 2Plates (1-1), 3Plates (1-2) and 4Plates (2-2). The mandibles were subjected to either incisal or molar loads (from both sides in the 3Plates group) up to a force of 120 N. The displacements of the constructs were recorded at each force increment of 10 N. ANOVA and Tukey's post-hoc tests were used for statistical analysis. The 2Plates group showed higher displacement under both loading conditions (P < 0.05 for each). The same group reached displacement levels of 1 mm and 3 mm during molar loading and 1 mm, 3 mm, and 5 mm during incisal loading at lower force magnitudes relative to others (P < 0.05 for each). Bone-plate constructs for BMAFs stabilized with three or four standard miniplates are more likely to provide similar resistance when subjected to incisal or molar loads, in contrast to the two-miniplate configuration, which is relatively more prone to displacement.


The Sir Mark Oliphant Conferences: international frontiers of science and technology.
The Vaccines and Immunotherapy Technologies Conference was organized by Professor Ian Frazer FAA, FTSE (Chair)(Centre for Immunology and Cancer Research, University of Queensland), Professor Peter Gray FTSE (Australian Institute for Bioengineering and Nanotechnology, University of Queensland), Professor Ian Gust FTSE, (Department of Microbiology and Immunology, University of Melbourne), Professor Graham Mitchell FAA, (Foursight Associates Pty Ltd), Professor Ian Ramshaw (John Curtin School of Medical Research, Australian National University) and held at The Shine Dome in Canberra, 9-11 April. The conference was funded by the Australian Department of Innovation, Industry, Science and Research.


Cultured arterial smooth muscle cells maintain distinct phenotypes when implanted into carotid artery.
Cultured arterial smooth muscle cells (SMCs) with distinct phenotypic features have been described by several laboratories; however, it is not presently known whether this phenotypic heterogeneity can be maintained within an in vivo environment. To answer this question, we have seeded into the intima of denuded rat carotid artery 2 SMC populations with well-established distinct biological features, ie, spindle-shaped, not growing in the absence of serum, and well differentiated versus epithelioid, growing in the absence of serum, and relatively undifferentiated, derived from the aortic media of newborn rats (aged 4 days) and old rats (aged >18 months), respectively. We show that these 2 populations maintain their distinct biochemical features (ie, expression of alpha-smooth muscle actin, smooth muscle myosin heavy chains, and cellular retinol binding protein-1) in the in vivo environment. The old rat media-derived SMCs continue to produce cellular retinol binding protein-1 but little alpha-smooth muscle actin and smooth muscle myosin heavy chains, whereas the newborn rat media-derived SMCs continue to express alpha-smooth muscle actin and smooth muscle myosin heavy chains but no cellular retinol binding protein-1. Our results reinforce the notion of arterial SMC phenotypic heterogeneity and suggest that in our model, heterogeneity is controlled genetically and not by the local environment.


Reclassification of non-pigmented Erwinia herbicola strains from trees as Erwinia billingiae sp. nov.
Twenty-two Erwinia-like strains, isolated from trees since the late fifties and belonging to a distinct phenotypic group with resemblance to Pantoea agglomerans, were further characterized by conventional biochemical tests, the BIOLOG metabolic fingerprinting system and fatty acid analysis. Their phylogenetic positions were determined by comparing the 16S rRNA gene sequence of a representative strain to available sequences of Erwinia, Pantoea, Pectobacterium and Brenneria species. The strains were shown to belong to the genus Erwinia, with Erwinia rhapontici and Erwinia persicina as the closest phylogenetic relatives. The name Erwinia billingiae sp. nov. is proposed (type strain LMG 2613T) and a description of the species is given.


Viral infections of the newborn.
Viral infections of the newborn result in significant morbidity and mortality each year. The fetus and newborn are particularly vulnerable to viral infection. The range of expression may vary from no clinical disease to devastating illness and infection occurring before, during, or after birth. Nursing management is determined by the specific viral infection, the severity of the illness, and the unique conditions of the newborn and his/her family. Promising new therapies are on the horizon that may lessen the severity of viral disease. Until such time, the major thrusts of management of neonatal viral disease are prevention of infection and supportive care for the acutely ill newborn.


Maternal sensitivity throughout infancy: continuity and relation to attachment security.
Relations among different measures of maternal sensitivity were assessed longitudinally by examining maternal behavior when infants were 4 months, 15 months, and 2.5 years. At each time period, two measures of maternal sensitivity were scored (4 months: maternal vocal and smiling contingency in face-to-face interactions; 15 months: maternal scaffolding and following of infants' play within joint attention; 2.5 years: maternal facilitative and collaborative play within joint attention). When infants were 2.5 years, attachment security was assessed. Mothers' scores on each maternal sensitivity measure within each time period were correlated with their maternal sensitivity scores in another time period, suggesting individual measures of maternal sensitivity were tapping similar aspects across the time periods. Maternal vocal contingency at 4 months was the strongest predictor of infants' attachment security over 2 years later.


The ISL LIM-homeobox 2 transcription factor is negatively regulated by circadian adrenergic signaling to repress the expression of Aanat in pinealocytes of the rat pineal gland.
Melatonin is synthesized in the pineal gland during nighttime in response to nocturnal increase in the activity of the enzyme aralkylamine N-acetyltransferase (AANAT), the transcription of which is modulated by several homeodomain transcription factors. Recent work suggests that the homeodomain transcription factor ISL LIM homeobox 2 (ISL2) is expressed in the pineal gland, but its role is currently unknown. With the purpose of identifying the mechanisms that control pineal expression of Isl2 and the possible function of Isl2 in circadian pineal biology, we report that Isl2 is specifically expressed in the pinealocytes of the rat pineal gland. Its expression exhibits a 24 h rhythm with high transcript and protein levels during the day and a trough in the second half of the night. This rhythm persists in darkness, and lesion studies reveal that it requires intact function of the suprachiasmatic nuclei, suggesting intrinsic circadian regulation. In vivo and in vitro experiments show that pineal Isl2 expression is repressed by adrenergic signaling acting via cyclic AMP; further, Isl2 is negatively regulated by the nocturnal transcription factor cone-rod homeobox. During development, pineal Isl2 expression is detectable from embryonic day 19, preceding Aanat by several days. In vitro knockdown of Isl2 is accompanied by an increase in Aanat transcript levels suggesting that ISL2 represses its daytime expression. Thus, rhythmic expression of ISL2 in pinealocytes is under the control of the suprachiasmatic nucleus acting via adrenergic signaling in the gland to repress nocturnal expression, while ISL2 itself negatively regulates daytime pineal expression of Aanat and thereby suggestively enhances the circadian rhythm in melatonin synthesis.


Synthesis, biological evaluation, QSAR and molecular dynamics simulation studies of potential fibroblast growth factor receptor 1 inhibitors for the treatment of gastric cancer.
Accumulating evidence suggests that fibroblast growth factor receptor 1 (FGFR1) is an attractive target in gastric cancer therapy. Based on our previous discovery of two non-ATP competitive FGFR1 inhibitors, A114 and A117, we designed and screened a series of compounds with the framework of bisaryl-1,4-dien-3-one. Among them, D12 and D15 exhibited the most potent FGFR1 inhibitory activity, which was ATP-independent. Furthermore, a quantitative structure-activity relationship analysis of 41 analogs demonstrated that the specific structural substitutions alter their bioactivities. Molecular docking and dynamics simulation analysis indicated the hydrophobic interaction at the FGFR1-D12/D15 interaction was dominant. Evaluation for anti-gastric cancer efficacy of D12 and D15 indicated effective inhibition of cell proliferation, apoptosis induction and cell cycle arrest. Thus, these two FGFR1 inhibitors have therapeutic potential in the treatment of gastric cancer, and this study provides will contribute to the rational design of novel non-ATP competitive FGFR1 inhibitors.


[Reconstruction of the medial canthus in oncology. Apropos of 105 cases over 9 years].
Without forgetting that resection of a malignant tumour must always take priority over the problems of reconstruction, based on a series of 105 cases of medial canthus lesions, the authors believe that: for tumours with a reserved prognosis, particularly sclerodermiform basal cell carcinomas of the orbit, full thickness skin graft is the most appropriate technique; for cases with a good prognosis, the cosmetic result takes priority. An intersuperciliary island flap is currently the method of choice; for advanced cancers of the medial canthus, the combination of frontal flaps and nasolabial flaps is the procedure which gives the best aesthetic and functional results. This series includes three cases of radical orbital exenteration, including two because of sclerodermiform basal cell carcinomas, and the authors stress the very serious prognosis of these tumours in the orbit, especially in the presence of a recurrence in an irradiated territory.


Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria.
Nosocomial pneumonia is a notable cause of morbidity and mortality and leads to increases in lengths of hospital stays and institutional expenditures. Aminoglycosides are used to treat patients with these infections, but few data on the doses and schedules required to achieve optimal therapeutic outcomes exist. We analyzed aminoglycoside treatment data for 78 patients with nosocomial pneumonia to determine if optimization of aminoglycoside pharmacodynamic parameters results in a more rapid therapeutic response (defined by outcome and days to leukocyte count resolution and temperature resolution). Cox proportional hazards, Classification and Regression Tree (CART), and logistic regression analyses were applied to the data. By all analyses, the first measured maximum concentration of drug in serum (Cmax)/MIC predicted days to temperature resolution and the second measured Cmax/MIC predicted days to leukocyte count resolution. For days to temperature resolution and leukocyte count resolution, CART analyses produced breakpoints, with an 89% success rate at 7 days of therapy for a Cmax/MIC of > 4.7 and an 86% success rate at 7 days of therapy for a Cmax/MIC of > 4.5, respectively. Logistic regression analyses predicted a 90% probability of temperature resolution and leukocyte count resolution by day 7 if a Cmax/MIC of > or = 10 is achieved within the first 48 h of aminoglycoside therapy. Aggressive aminoglycoside dosing immediately followed by individualized pharmacokinetic monitoring would ensure that Cmax/MIC targets are achieved early in therapy. This would increase the probability of a rapid therapeutic response for pneumonia caused by gram-negative bacteria and potentially decreasing durations of parenteral antibiotic therapy, lengths of hospitalization, and institutional expenditures, a situation in which both the patient and the institution benefit.


Ovalbumin Delivery by Guanidine-Terminated Dendrimers Bearing an Amyloid-Promoting Peptide via Nanoparticle Formulation.
Development of protein delivery systems is important for biomedical applications such as immunotherapy. Ovalbumin (OVA) is a major component of egg whites, and is a possible cause of egg allergy. In this study, OVA was used as a model protein to develop a delivery system using guanidine-terminated dendrimers (Gdn-den) bearing an amyloid-promoting peptide derived from the helix B (hB) region of OVA (hB-Gdn-den). OVA nanoparticles (NPs) were prepared by heat treatment of OVA/hB-Gdn-den mixtures. The NP size and the surface charge were controlled by adjusting the ratio of hB-Gdn-den to OVA. The NPs were around 200 nm in diameter and stably dispersed, and their encapsulation efficiency for OVA was more than 80%. Although OVA NPs were also prepared using Gdn-den, the NPs aggregated readily. Complexation with hB-Gdn-den induced conformational changes in the OVA, and the hB peptide promoted digestion of OVA. These suggest that the hB peptide of the Gdn-den works as a possible anchor to OVA. The positively charged OVA NPs effectively associated with RAW264 cells. Thus, the amyloid-promoting Gdn-den, when mixed with OVA at a suitable molar ratio to form NPs, could act as a carrier for delivery of antigen proteins to immune cells.


Interactions between growth hormone and nutrition in hypophysectomized rats: body composition and production of insulin-like growth factor-I.
Hypophysectomy of adult rats results in a loss of body growth which can be reversed by treatment with GH. The increased growth caused by administration of GH is accompanied by an increase in food consumption. The effects of GH and interactions with nutrition were investigated by treating hypophysectomized rats with GH and either providing unrestricted food or preventing the increased food consumption by pair-feeding with the same intake as that of the hypophysectomized animals. Over the 7-day experimental period, the GH-treated animals grew significantly when food was available ad libitum but did not gain body weight when an increase in food intake was prevented. However, there was a significant interaction between GH and nutrition on body composition; GH significantly decreased body fat and increased the protein: fat ratio only in the animals with the restricted intake. Gastrocnemius muscle weight was increased by GH regardless of food intake, but heart weight did not increase and liver weight was actually decreased by GH treatment when food intake was restricted. Serum concentrations of insulin and insulin-like growth factor-I (IGF-I) were increased by GH in the rats with food available ad libitum but not in the pair-fed rats. However, the liver concentration of IGF-I and its mRNA were increased by GH although the increase in IGF-I mRNA was modulated by the restricted food intake. The decreased weight of the liver in the pair-fed GH-treated rats, despite the increase in IGF-I mRNA, suggests that IGF-I does not influence liver growth. In the gastrocnemius muscle, however, GH increased IGF-I mRNA concentration similarly in both rats with food available ad libitum and in pair-fed rats. Decreased nutrition therefore modulated the action of GH but emphasized its nutrient partitioning effect, thus increasing the anabolic drive towards skeletal muscle growth; this appeared to be mediated by the local production of IGF-I within the muscle.


Biliary complications among live donors following live donor liver transplantation.
In live donor liver transplantation (LDLT), bile duct division is a critical step in donor hepatectomy. Biliary complications hence are a feared sequelae even among donors. Long term data on biliary complications in donors from India are sparse. Prospective evaluation of 452 live donors over 10 years was performed to ascertain the incidence & risk factors of clinically significant biliary complications. Of the 452 donor hepatectomies (M: F = 114:338, median age = 38), 66.2% (299) were extended right lobe grafts, 24.1% (109) modified right lobe and 9.7% (44) were left lobe grafts. Portal vein anatomy was Type-I in 85% (386), Type-II in 7.5% (34) and Type-III in 7.1% (32). Following donor hepatectomy, a single bile duct opening occurred only in 46.5% (210) of the grafts. Of the remaining 53.5% grafts, 2 ductal openings were noted in 217 (48%) and three ductal openings in 25 (5.5%). Incidence of multiple openings in the duct were more commonly noted in Type II (70.6%) and III (75%) portal vein anatomy than in grafts with Type I (50.4%) portal anatomy (P = 0.001) Bile leak was noted in 15 (3.3%) donors which included one broncho-biliary fistula and bilio-pleural fistula. Analysis revealed no association between post-operative biliary complications and type of graft, portal vein anatomy or biliary anatomy. There was a single mortality in this series secondary to biliary sepsis. On long term follow, there were no biliary strictures in any of the patients. Biliary complications although rare (3.3%), present significant peri-operative morbidity to the donors.


Dimensional Changes in Alveolar Ridge Following Extraction of Teeth in the Maxillary Premolar Area in Subjects with Thick and Thin Gingival Biotypes: A Pilot Study.
This study investigated changes in residual ridge dimensions after tooth extraction among thin and thick gingival biotypes. Fifteen patients who required extraction of maxillary premolars were classified according to gingival biotypes (10 teeth in 9 participants were included in the thick group, and 6 teeth in 6 participants were included in the thin group). Minimally traumatic extractions were carried out using periotomes and rotational movement of teeth. At the time of extraction an osteometer was used to measure the thickness of the labial plate and the bony alveolar ridge at the extraction site by penetrating the tissues until bone was reached 5 mm, 7 mm, and 10 mm below the midpoint of the crest of the facial and palatal gingival margins. Standardized radiographs were taken immediately and after 3 months. The results of this study show minimal differences in dimensional changes following extraction of premolar teeth in thick and thin gingival biotypes. Significantly greater bone loss was detected in both gingival biotypes when the labial plate thickness was less than 1.5 mm, especially in alveolar ridge height.


Retinopathy Induced by Zinc Oxide Nanoparticles in Rats Assessed by Micro-computed Tomography and Histopathology.
Nanotechnology has advanced at an extremely rapid pace over the past several years in numerous fields of research. However, the uptake of nanoparticles (NPs) into the body after administration through various routes may pose a risk to human health. In this study, we investigated the potential ocular toxicity of 20-nm, negatively- charged zinc oxide (ZnO) NPs in rats using micro-computed tomography (micro-CT) and histopathological assessment. Animals were divided into four groups as control group, ZnO NPs treatment group (500 mg/kg/day), control recovery group, and ZnO NPs treatment and recovery group. Ocular samples were prepared from animals treated for 90 days (10 males and 10 females, respectively) and from recovery animals (5 males and 5 females, respectively) sacrificed at 14 days after final treatment and were compared to age-matched control animals. Micro-CT analyses represented the deposition and distribution of foreign materials in the eyes of rats treated with ZnO NPs, whereas control animals showed no such findings. X-ray fluorescence spectrometry and energy dispersive spectrometry showed the intraocular foreign materials as zinc in treated rats, whereas control animals showed no zinc signal. Histopathological examination revealed the retinopathy in the eyes of rats treated with ZnO NPs. Neuronal nuclei expression was decreased in neurons of the ganglion cell layer of animals treated with ZnO NPs compared to the control group. Taken together, treatment with 20-nm, negatively-charged ZnO NPs increased retinopathy, associated with local distribution of them in ocular lesions.


[Focal segmental glomerulosclerosis].
Focal segmental glomerulosclerosis (FSGS) is one of the major causes of nephrotic syndrome in adult as well as in the children. Untreated or steroid-resistant primary FSGS often shows a progressive renal insufficiency and reaches to end-stage renal failure. Concerning the treatment for such patients, the combined immunosuppressive therapy with corticosteroid and other cytotoxic drugs (cyclophosphamide, cyclosporine and tacrolimus etc.) is recommended. Since podocyte injury seems to be the most important primary events in FSGS, the extensive studies have been focused on the role of podocyte-related molecules. Recently slit membrane-associated molecules (CD2AP, alpha-actinin 4 and podocin) and angiotensin II type I receptor in the podocyte have been clearly shown to be relevant for the pathogenesis of FSGS.


GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma.
Cerebellar development requires regulated proliferation of cerebellar granule neuron progenitors (CGNPs). Inadequate CGNP proliferation causes cerebellar hypoplasia whereas excessive CGNP proliferation can cause medulloblastoma, the most common malignant pediatric brain tumor. Although sonic hedgehog (SHH) signaling is known to activate CGNP proliferation, the mechanisms downregulating proliferation are less defined. We investigated CGNP regulation by GSK-3, which downregulates proliferation in the forebrain, gut and breast by suppressing mitogenic WNT signaling in mouse. In striking contrast to these systems, we found that co-deleting Gsk3a and Gsk3b blocked CGNP proliferation, causing severe cerebellar hypoplasia. The GSK-3 inhibitor CHIR-98014 similarly downregulated SHH-driven proliferation. Transcriptomic analysis showed activated WNT signaling and upregulated Cdkn1a in Gsk3a/b-deleted CGNPs. Ctnnb co-deletion increased CGNP proliferation and rescued cerebellar hypoproliferation in Gsk3a/b mutants, demonstrating physiological control of CGNPs by GSK-3, mediated through WNT. SHH-driven medulloblastomas similarly required GSK-3, as co-deleting Gsk3a/b blocked tumor growth in medulloblastoma-prone SmoM2 mice. These data show that a GSK-3/WNT axis modulates the developmental proliferation of CGNPs and the pathological growth of SHH-driven medulloblastoma. The requirement for GSK-3 in SHH-driven proliferation suggests that GSK-3 may be targeted for SHH-driven medulloblastoma therapy.


A novel germline PALB2 deletion in Polish breast and ovarian cancer patients.
PALB2 protein was recently identified as a partner of BRCA1 and BRCA2 which determines their proper function in DNA repair. Initially, the entire coding sequence of the PALB2 gene with exon/intron boundaries was evaluated by the PCR-SSCP and direct sequencing methods on 70 ovarian carcinomas. Sequence variants of interest were further studied on enlarged groups of ovarian carcinomas (total 339 non-consecutive ovarian carcinomas), blood samples from 334 consecutive sporadic and 648 consecutive familial breast cancer patients, and 1310 healthy controls from central Poland. Ten types of sequence variants were detected, and among them four novel polymorphisms: c.2996+58T>C in intron 9; c.505C>A (p.L169I), c.618T>G (p.L206L), both in exon 4; and c.2135C>T (A712V) in exon 5 of the PALB2 gene. Another two polymorphisms, c.212-58A>C and c.2014G>C (E672Q) were always detected together, both in cancer (7.5% of patients) and control samples (4.9% of controls, p = 0.2). A novel germline truncating mutation, c.509_510delGA (p.R170fs) was found in exon 4: in 2 of 339 (0.6%) unrelated ovarian cancer patients, in 4 of 648 (0.6%) unrelated familial breast cancer patients, and in 1 of 1310 controls (0.08%, p = 0.1, p = 0.044, respectively). One ovarian cancer patient with the PALB2 mutation had also a germline nonsense mutation of the BRCA2 gene. The c.509_510delGA is a novel PALB2 mutation that increases the risk of familial breast cancer. Occurrence of the same PALB2 alteration in seven unrelated women suggests that c.509_510delGA (p.R170fs) is a recurrent mutation for Polish population.


Comparison of Serum Adipocytokine Levels according to Metabolic Health and Obesity Status.
Metabolic health is an emerging concept that is highly correlated with various metabolic complications, and adipocytokines have been causally linked to a wide range of metabolic diseases. Thus, this study compared serum adipocytokine levels according to metabolic health and obesity status. Four hundred and fifty-six nondiabetic subjects (mean age, 40.5 years) were categorized into four groups according to metabolic health and obesity status: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUHNO), and metabolically unhealthy obese (MUHO). Being metabolically healthy was defined as the presence of fewer than two of the following five metabolic abnormalities: high blood pressure, high fasting blood glucose, high triglyceride, low high density lipoprotein cholesterol, and being in the highest decile of the homeostatic model assessment of insulin resistance index. Obesity status was assessed using body mass index (BMI), with obesity defined as a BMI higher than 25 kg/m². Levels of serum interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α (TNF-α), and adipocyte fatty acid binding protein (A-FABP) were also evaluated. Of the 456 subjects, 247 (54.2%) were in the MHNO group, 66 (14.5%) were in the MHO group, 66 (14.5%) were in the MUHNO group, and 77 (16.9%) were in the MUHO group. There were no significant differences in IL-6 or MCP-1 levels among the groups, but levels of TNF-α and A-FABP were significantly higher in the MUHNO group compared to the MHNO group. High TNF-α and A-FABP levels are significantly associated with metabolically unhealthiness in nonobese Korean individuals.


Hemosuccus pancreaticus: CT manifestations.
A case of severe gastrointestinal bleeding due to rupture of a splenic artery aneurysm into the pancreatic duct (hemosuccus pancreaticus) was encountered. Contrast enhanced CT revealed a low-density mass containing an enhancing central area in the pancreatic tail. Arteriography demonstrated a splenic artery aneurysm. Postoperative pathological review revealed a communication between the ruptured splenic artery aneurysm and the pancreatic duct.


Possible Acute Poisoning by Sinapis arvensis in Sheep: Clinical, Laboratory and Necropsy Findings.
An outbreak of possible acute poisoning by Sinapis arvensis occurred in a flock of 50 fat-tailed sheep located in the Semnan province of Iran. Sinapis arvensis is an annual or winter annual plant of the genus Sinapis in the family Brassicaceae, commonly known as field mustard, wild mustard or charlock. The poisonous constituents are volatile oil of mustard, the alkaloid sinapin, and the alkaloidal glucoside sinalbin. The flock was grazing in land containing high amounts of wild mustard (Sinapis arvensis) in late spring. Seven sheep (aged between 1 and 5 years) died within approximately 3 days. The affected animals displayed signs of depression, reluctance to move, tachycardia, tachypnea, mucoid and hemorrhagic nasal discharges, pale conjunctiva, ataxia, abdominal pain, bruxism, and anorexia. Rectal temperature in these animals was normal to high (39-41.5 °C). Ruminal movements were reduced (1-2/min). Serum biochemical levels in affected sheep showed marked increases of blood urea nitrogen (BUN), Gamma glutamyl transferase (GGT), magnesium (Mg), and phosphorous (P) and a marked decrease in calcium (Ca). In urinalysis, marked hemoglobinuria and proteinuria were observed. Necropsy findings included congestion in lungs and hemorrhage on the epicardial and endocardial heart surfaces, on the surface and medulla of the kidneys, and abomasal mucosa. The liver was also congested with a nutmeg pattern. Rumen contents included digested materials and large quantities of seeds and stems of wild mustard. For the first time, our findings confirmed wild mustard toxicosis in sheep in Iran.


CD105 (endoglin) expression as a prognostic marker of angiogenesis in squamous cell cervical cancer treated with radical radiotherapy.
Increased levels of endoglin may represent a new reagent of active neovascularization and angiogenesis process in various cancer types. The prognostic value of tumor CD105 (endoglin) expression in cervical squamous cell cancer (CSCC) patients treated with radical radiotherapy (RT) ± chemotherapy was investigated. CD105 (endoglin) expression was assessed by immunohistochemical methods in seventy patients, who were treated with radical RT ± chemotherapy for CSCC. The prognostic effects of CD105 on patient and treatment characteristics, local-regional control, and survival were assessed. The median follow-up was 24 (5-99) months for the whole cohort. The median CD105 microvessel density was 55.5 (range; 12-136). Age (≤61 vs. >61 years; P = 0.015), lymph node metastasis status (absent vs. present; P = 0.028), International Federation of Gynecology and Obstetrics stage (Ib-IIa vs. IIb-IVa; P = 0.036), cycles of concurrent chemotherapy (1-3 vs. 4-6 cycles; P = 0.001), and hemoglobin levels (≤10 g/dL vs. >10 g/dL; P = 0.006) appeared to associate significantly with overall survival on univariate analysis. No correlation was identified between the tumor CD105 (endoglin) expression and survival in CSCC patients treated with radical RT ± chemotherapy.


Haptoglobin as an early serum biomarker of virus-induced autoimmune type 1 diabetes in biobreeding diabetes resistant and LEW1.WR1 rats.
Proteomic profiling of serum is a powerful technique to identify differentially expressed proteins that can serve as biomarkers predictive of disease onset. In this study, we utilized two-dimensional (2D) gel analysis followed by matrix-assisted-laser desorption/ionization time-of-flight mass spectrometry analysis to identify putative serum biomarkers for autoimmune type 1 diabetes (T1D) in biobreeding diabetes resistant (BBDR) rats induced to express the disease. Treatment with toll-like receptor 3 ligand, polyinosinic:polycytidilic acid (pIC), plus infection with Kilham rat virus (KRV), a rat parvovirus, results in nearly 100% of young BBDR rats becoming diabetic within 11-21 d. Sera collected from prediabetic rats at early time points following treatment with pIC + KRV were analyzed by 2D gel electrophoresis and compared with sera from control rats treated with phosphate-buffered saline, pIC alone or pIC + H1, a non-diabetogenic parvovirus. None of the latter three control treatments precipitates T1D. 2D gel analysis revealed that haptoglobin, an acute phase and hemoglobin scavenger protein, was differentially expressed in the sera of rats treated with pIC + KRV relative to control groups. These results were confirmed by Western blot and enzyme-linked immunosorbent assay studies, which further validated haptoglobin levels as being differentially increased in the sera of pIC + KRV-treated rats relative to controls during the first week following infection. Early elevations in serum haptoglobin were also observed in LEW1.WR1 rats that became diabetic following infection with rat cytomegalovirus. The identification and validation of haptoglobin as a putative serum biomarker for autoimmune T1D in rats now affords us the opportunity to test the validity of this protein as a biomarker for human T1D, particularly in those situations where viral infection is believed to precede the onset of disease.


New insights on the phytochemical intervention for the treatment of neuropsychiatric disorders using the leaves of Michelia champaca: an in vivo and in silico approach.
Michelia champaca L. (Magnoliaceae) has been known since ancient times for its rich medicinal properties. The ethanol extract of Michelia champaca leaves (EEMC) was evaluated on depression and anxiety using in vivo and in silico studies. Swiss albino mice were divided into control, standard, 100 and 200 mg/kg b.w. EEMC groups and for drug administration using oral gavage. The antidepressant activity was evaluated using forced swim test (FST) and tail suspension test (TST) whereas the anxiolytic activity through elevated plus maze and light and dark tests. The in silico studies included molecular docking against human potassium channel KCSA-FAB and human serotonin transporter, and ADME/T analysis. Open arm duration and entries were comparable between 200 mg/kg b.w. group (184.45 ± 1.00 s and 6.25 ± 1.11, respectively) and that of diazepam treated group (180.02 s ± 0.40 and 6.10 ± 0.05, respectively). Time spent in the light cubicle was higher (46.86 ± 0.03%), similar to that of diazepam (44.33 ± 0.64%), suggesting its potent anxiolytic activity. A delayed onset of immobility and lowered immobility time was seen at both the treatment doses (FST: 93.7 ± 1.70 and 89.1 ± 0.40 s; TST: 35.05 ± 2.75 and 38.50 ± 4.10 s) and the standard drug imipramine (FST: 72.7 ± 3.72 and TST: 30.01 ± 2.99 s), indicative of its antidepressant ability. In silico studies predicted doripenem to induce anxiolytic and antidepressant activity by inhibiting human potassium channel KCSA-FAB and human serotonin transporter proteins, respectively. EEMC is a rich source of bioactive compounds with strong antidepressant and anxiolytic properties.


Universal and differential transcriptional regulatory pathways involved in the preparation of summer and winter diapauses in Pieris melete.
Much progress has been made in understanding the environmental and hormonal systems regulating winter diapause. However, transcriptional regulation of summer diapause is still largely unknown, making it difficult to understand an all-around regulation profile of seasonal adaptation. To bridge this gap, comparison RNA-seq to profile the transcriptome and to examine differential gene expression profiles between non-diapause, summer diapause, and winter diapause groups were performed. A total number of 113 million reads were generated and assembled into 79,117 unigenes, with 37,492 unigenes categorized into 58 functional gene ontology groups, 25 clusters of orthologous group categories, and 256 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. KEGG analysis mapped 2108 differentially expressed genes to 48 and 67 pathways for summer and winter diapauses, respectively. Enrichment statistics showed that 11 identical pathways similarly overlapped in the top 20 enriched functional groups both related to summer and winter diapauses. We also identified 35 key candidate genes for universal and differential functions related to summer and winter diapause preparation. Furthermore, we identified some genes involved in the signaling and metabolic pathways that may be the key drivers to integrate environmental signals into the summer and winter diapause preparation. The current study provided valuable insights into global molecular mechanisms underpinning diapause preparation.