Effect of renovating an office building on occupants' comfort and health.
An intervention study was performed in a mechanically ventilated office building in which there were severe indoor climate complaints among the occupants. In one part of the building a new heating and ventilation strategy was implemented by renovating the HVAC system, and a carpet was replaced with a low-emitting vinyl floor material; the other part of the building was kept unchanged, serving as a control. A comprehensive indoor climate investigation was performed before and after the intervention. Over a 2-week period, the occupants completed a daily questionnaire regarding their comfort and health. Physiological examinations of eyes, nose and lungs were performed on each occupant. Physical, chemical and sensory measurements were performed before and after the intervention. The renewal of the flooring material was performed after a sensory test of alternative solutions in the laboratory. Before the floor material was installed in the office building, a full-scale exposure experiment was performed in the laboratory. The new ventilation strategy and renovation of the HVAC system were selected on the basis of laboratory experiments on a full-scale mock-up of a cellular office. The severity of occupants' environmental perceptions and symptoms was significantly reduced by the intervention.


Vibrio vulnificus: new insights into a deadly opportunistic pathogen.
Vibrio vulnificus is a Gram-negative aquatic bacterium first isolated by the United States (US) Centers for Disease Control and Prevention (CDC) in 1964. This bacterium is part of the normal microbiota of estuarine waters and occurs in high numbers in molluscan shellfish around the world, particularly in warmer months. Infections in humans are derived from consumption of seafood produce and from water exposure. Vibrio vulnificus is a striking and enigmatic human pathogen, yet many aspects related to its biology, genomics, virulence capabilities and epidemiology remain elusive and poorly understood. This pathogen is responsible for over 95% of seafood-related deaths in the United States, and carries the highest fatality rate of any food-borne pathogen. Indeed, infections associated with this pathogen that progress to primary septicaemia have a similar case fatality rate to category BSL 3 and 4 pathogens, such as anthrax, bubonic plague, Ebola and Marburg fever. Interestingly, V. vulnificus infections disproportionately affect males (∼85% of cases) and older patients (> 40 years), especially those with underlying conditions such as liver diseases, diabetes and immune disorders. New insights from molecular studies and comparative genomic approaches have offered tantalising insights into this pathogen. A recent increase and geographical spread in reported infections, in particular wound cases, underlines the growing international importance of V. vulnificus, particularly in the context of coastal warming. We outline and explore here a range of current data gaps regarding this important pathogen, and provide some current thoughts on approaches to elucidate key aspects associated with this bacterium.


Comparison of inverse scattering algorithms for designing ultrabroadband fibre Bragg gratings.
We compare different inverse scattering (IS) algorithms used to calculate profiles of fibre Bragg gratings (FBGs) and analyse their robustness, speed and implementation difficulties. We analyse sources of IS algorithm errors and discuss their relative importance. We discuss the optimal choice of IS algorithm for inverse-direct iterative optimisation schemes for grating design. We find that our time-domain layer-peeling method is an order of magnitude faster and more robust than the spectral domain algorithms considered here. We demonstrate that our method is essential to solving highly complex FBG designs demanded by astronomical applications.


The primary structures of two leghemoglobin genes from soybean.
We present the complete nucleotide sequences of two leghemoglobin genes isolated from soybean DNA. Both genes contain three intervening sequences which interrupt the two coding sequences in identical positions. The 5' and 3' flanking sequences in both genes contain conserved sequences similar to those found in corresponding positions in other eukaryotic genes. Thus, the general DNA sequence organization of these plant genes is similar to that of other eukaryotic genes.


Modern antihypertensive treatment and the progression of renal disease.
In animal models of hypertension, the resistance state of the preglomerular (afferent) and postglomerular (efferent) capillary arterioles may determine whether a particular form of antihypertensive therapy will spare the kidney from hemodynamic-mediated glomerular injury. In experimental models of renal disease with impaired autoregulation, control of systemic blood pressure is a prerequisite for normalizing glomerular capillary hydraulic pressure. In humans, effective blood pressure control reverses renal hemodynamic abnormalities in hypertensive patients, reduces microalbuminuria in essential hypertensive, nondiabetic, and diabetic renal diseases, and attenuates but does not prevent the progression of nondiabetic and diabetic renal disease. Although some researchers have concluded that angiotensin converting enzyme inhibitors are the renal protective drugs of choice, these pronouncements are not based on clinical trials correlating specific drug-mediated changes in albumin or protein excretion with the longitudinal assessment of glomerular filtration rate (GFR), permitting derivation of a slope-defining change in GFR, and/or the longitudinal assessment of renal structure (i.e. renal biopsy). Definitive clinical trials have not been reported. It is important to recognize that an elevated serum creatinine is a powerful predictor of mortality and that, in most patients, death is caused by a cardiovascular or cerebrovascular event, rather than by renal failure. Because morbidity and mortality of essential hypertension and nondiabetic or diabetic renal disease is related primarily to cardiovascular or cerebrovascular events, the antihypertensive 'drugs of choice' should be those that reduce these risks, prevent or regress target-organ damage, and optimize treatment of concomitant diseases.


Description and initial evaluation of an educational and psychosocial support model for adults with congenitally malformed hearts.
Various programmes for adults with congenitally malformed hearts have been developed, but detailed descriptions of content, rationale and goals are often missing. The aim of this study was to describe and make an initial evaluation of a follow-up model for adults with congenitally malformed hearts, focusing on education and psychosocial support by a multidisciplinary team (EPS). The model is described in steps and evaluated with regards to perceptions of knowledge, anxiety and satisfaction. The EPS model included a policlinic visit to the physician/nurse (medical consultation, computer-based and individual education face-to-face as well as psychosocial support) and a 1-month telephone follow-up. Fifty-five adults (mean age 34, 29 women) with the nine most common forms of congenitally malformed hearts participated in the EPS model as well as the 3-months follow-up. Knowledge about congenital heart malformation had increased in 40% of the participants at the 3-months follow-up. This study describes and evaluates a model that combines a multidisciplinary approach and computer-based education for follow-up of adults with congenitally malformed hearts. The EPS model was found to increase self-estimated knowledge, but further evaluations need to be conducted to prove patient-centred outcomes over time. The model is now ready to be implemented in adults with congenitally malformed hearts.


Sirtuin-1 and Its Relevance in Vascular Calcification.
Vascular calcification (VC) is highly associated with cardiovascular disease and all-cause mortality in patients with chronic kidney disease. Dysregulation of endothelial cells and vascular smooth muscle cells (VSMCs) is related to VC. Sirtuin-1 (Sirt1) deacetylase encompasses a broad range of transcription factors that are linked to an extended lifespan. Sirt1 enhances endothelial NO synthase and upregulates FoxOs to activate its antioxidant properties and delay cell senescence. Sirt1 reverses osteogenic phenotypic transdifferentiation by influencing RUNX2 expression in VSMCs. Low Sirt1 hardly prevents acetylation by p300 and phosphorylation of β-catenin that, following the facilitation of β-catenin translocation, drives osteogenic phenotypic transdifferentiation. Hyperphosphatemia induces VC by osteogenic conversion, apoptosis, and senescence of VSMCs through the Pit-1 cotransporter, which can be retarded by the sirt1 activator resveratrol. Proinflammatory adipocytokines released from dysfunctional perivascular adipose tissue (PVAT) mediate medial calcification and arterial stiffness. Sirt1 ameliorates release of PVAT adipokines and increases adiponectin secretion, which interact with FoxO 1 against oxidative stress and inflammatory arterial insult. Conclusively, Sirt1 decelerates VC by means of influencing endothelial NO bioavailability, senescence of ECs and VSMCs, osteogenic phenotypic transdifferentiation, apoptosis of VSMCs, ECM deposition, and the inflammatory response of PVAT. Factors that aggravate VC include vitamin D deficiency-related macrophage recruitment and further inflammation responses. Supplementation with vitamin D to adequate levels is beneficial in improving PVAT macrophage infiltration and local inflammation, which further prevents VC.


Alcohol hangover: mechanisms and mediators.
Hangovers are a frequent, though unpleasant, experience among people who drink to intoxication. Despite the prevalence of hangovers, however, this condition is not well understood scientifically. Multiple possible contributors to the hangover state have been investigated, and researchers have produced evidence that alcohol can directly promote hangover symptoms through its effects on urine production, the gastrointestinal tract, blood sugar concentrations, sleep patterns, and biological rhythms. In addition, researchers postulate that effects related to alcohol's absence after a drinking bout (i.e., withdrawal), alcohol metabolism, and other factors (e.g., biologically active, nonalcohol compounds in beverages; the use of other drugs; certain personality traits; and a family history of alcoholism) also may contribute to the hangover condition. Few of the treatments commonly described for hangover have undergone scientific evaluation.


Serious lower extremity venous injury management with ligation: prospective overview of 63 patients.
Management of lower extremity venous trauma using repair or ligation has been an area of controversy during the past decades. However, in unstable patients or if primary repair is technically impossible as a result of extensive disruption of the vein, ligation is recommended. This study investigated the effects of venous ligation on major veins in the lower extremities when primary repair is impossible as a result of extensive laceration of the vein. Between January 2001 and April 2004, 63 patients with Grade III and IV venous injuries were observed prospectively. Compression ultrasonography was performed postoperatively on the fifth day, once before discharge, and at the 3-month visit to assess deep vein thrombosis (DVT) and the patency of arterial repair. If DVT was present, the patient was given an oral anticoagulant (warfarin Na) for 3 months (international normalized ratio, 2.0-3.0), and Class II compression stockings (Sigvaris-212, Ganzoni, Switzerland) were used for 1 year. Follow-up visits occurred at 1, 3, 6, and 12 months and at 6-month intervals thereafter. Combined arterial and venous injuries were present in 50 (79.4%) patients and pure venous injuries were present in 13 (20.6%) patients. DVT developed in 49 patients (77.7%; postoperative n = 37 [58.7%], late n = 12 [19%]). Three arterial restenoses (4.7%) and one pseudoaneurysm (1.6%) of the superficial femoral artery developed. Five early (prophylactic) and two late (compartment syndrome) fasciotomies were performed. Postoperative edema was seen in 56 (88.8%) patients and wound infection was seen in 19 patients (30.1%; n=18 superficial, n=1 deep). Two amputations (3.2%) were performed. One patient (1.7%) died as a result of irreversible shock. After a median of 18 months, 25 patients were classified with Clinical Etiology, Anatomy, Pathology classification: 10 legs C-0, seven legs C-2, and eight legs C-3. No severe postthrombophlebitic syndrome was observed. Early leg swelling after venous ligation was the most common morbidity. We observed no significant sequelae of chronic venous insufficiency, and venous ligation had no detrimental effect on associated arterial repair. In cases of DVT, anticoagulation with low-molecular-weight heparin and oral anticoagulants should begin immediately and continue for 3 months along with compression stocking support for 1 year.


Signs and symptoms at diagnosis of amyotrophic lateral sclerosis: a population-based study in southern Italy.
Amyotrophic lateral sclerosis (ALS) diagnostic criteria are used to select patients for clinical trials based on different levels of diagnostic certainty, according to the spread of upper (UMN) and lower motoneuron (LMN) signs in different anatomic regions. However, the clinical presentation of ALS patients is extremely variable and this can delay the time to diagnosis and decrease the likelihood for trial entry. The aims of the study were to describe the signs and symptoms of diagnosis in a population-based incident cohort of ALS cases, using the El Escorial (EEC) and the Revised Airlie Diagnostic Criteria (AHC). The source of the study was a prospective population-based registry established in Puglia, southern Italy, in 1997. The diagnosis and the classification of the cases were based on EEC and AHC. All incident ALS cases during the period 1998-1999 were enrolled and followed up. During the surveillance period, we identified 130 ALS incident cases, and bulbar-ALS represented 20% of our cohort. The highest risk for bulbar onset was among subjects aged >75 years [RR: 20.1, 95% confidence interval (CI) 3.4-118.0] compared with subjects aged <55 years and among females compared with males (Relative risk (RR): 2.75, 95% CI: 1-7.3). The vast majority of patients (72%) referred progressive muscle weakness in the limbs as the presenting symptom. Eighty percent of cases presented contemporary bulbar or spinal involvement; UMN signs in the bulbar region were present in 24% of cases and any motoneuronal sign in thoracic region in only 15% of the cases. In this population-based series, progressive muscle weakness was the most common presenting sign; bulbar onset was associated with advanced age and female sex. UMN signs in the bulbar region and any motoneuronal sign in the thoracic region were observed in 20% of our case series. This may represent the main limitation to show the spread of signs during diagnostic assessment for inclusion in epidemiological studies and clinical trials.


Quantification of Wear and Deformation in Different Configurations of Polyethylene Acetabular Cups Using Micro X-ray Computed Tomography.
Wear is currently quantified as mass loss of the bearing materials measured using gravimetric methods. However, this method does not provide other information, such as volumetric loss or surface deviation. In this work, we validated a technique to quantify polyethylene wear in three different batches of ultrahigh-molecular-polyethylene acetabular cups used for hip implants using nondestructive microcomputed tomography. Three different configurations of polyethylene acetabular cups, previously tested under the ISO 14242 parameters, were tested on a hip simulator for an additional 2 million cycles using a modified ISO 14242 load waveform. In this context, a new approach was proposed in order to simulate, on a hip joint simulator, high-demand activities. In addition, the effects of these activities were analyzed in terms of wear and deformations of those polyethylenes by means of gravimetric method and micro X-ray computed tomography. In particular, while the gravimetric method was used for weight loss assessment, microcomputed tomography allowed for acquisition of additional quantitative information about the evolution of local wear and deformation through three-dimensional surface deviation maps for the entire cups' surface. Experimental results showed that the wear and deformation behavior of these materials change according to different mechanical simulations.


Anthrax toxin blocks priming of neutrophils by lipopolysaccharide and by muramyl dipeptide.
We studied the pretreatment of human polymorphonuclear neutrophils (PMN) with purified preparations of the anthrax toxin components--protective antigen (PA), edema factor (EF), and lethal factor (LF)--and their effects on release of superoxide anion (O-2) after stimulation with the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (FMLP). PMN isolated in the absence of lipopolysaccharide (LPS) (less than 0.1 ng/ml) released only small amounts of O-2 after FMLP stimulation; pretreatment with anthrax toxin had little effect. The release of O-2 was increased fivefold by prior treatment with 3 ng/ml LPS for 1 h at 37 degrees C, an effect referred to as priming. PMN were primed to an equivalent extent by treatment with 100 ng/ml N-acetyl-muramyl-L-alanyl-D-isoglutamine (muramyl dipeptide [MDP]). Pretreatment of PMN with anthrax toxin components PA plus EF or PA plus LF inhibited priming by LPS or MDP, as shown by the reduction in the release of O-2 up to 90% relative to controls not treated with toxin; single toxin components were inactive. The inhibition was markedly reduced when priming with LPS or MDP was carried out before exposure to toxin. O-2 release after stimulation by phorbol myristate acetate was not increased by priming, and pretreatment with toxin did not inhibit O-2 release after this stimulus. Evidently, anthrax toxin inhibits the priming that is normally induced in PMN by bacterial products and is necessary for the full expression of antimicrobial effects.


Single-nucleotide polymorphisms link gout with health-related lifestyle factors in Korean cohorts.
Gout-a very painful inflammatory arthritis caused by the deposition of monosodium urate crystals in the joints-is influenced by several factors. We identified the association of single- nucleotide polymorphisms (SNPs) that link gout with health-related lifestyle factors using genomic data from the Korean Genome and Epidemiology Study. We conducted a genome-wide association study (GWAS) on 18,927 samples of 438 Korean patients with gout and 18,489 controls for the discovery stage. For the replication stage, another batch containing samples of 326 patients with gout and 2,737 controls were analyzed. Lastly, a meta-analysis was performed using these two cohorts. We analyzed the effects of health-related lifestyle factors, including eating habits, physical activity, drinking behavior, and smoking behavior, on gout. After identifying the association between GWAS-derived SNPs and health-related lifestyle factors, we confirmed the interaction between the polygenic risk score (PRS) and health-related lifestyle factors. We identified 15 SNPs related to gout, among which rs1481012 of ABCG2 located on chromosome 4 has been newly discovered (P = 2.46e-11). On examining the interaction between SNPs and health-related lifestyles, rs3109823-located in ABCG2-was found to be associated with smoking status. In addition, rs11936395-located in SLC2A9-was significantly associated with the average momentum of exercise per session, whereas rs11066325 located in PTPN11, showed a significant association with the number of exercise sessions per week, smoking status, drinking status, and amount of soju drink per session. rs9421589-located in FAM35A-was significantly associated with the duration of smoking. In addition, we verified that the association between PRS and duration of smoking affects gout. Thus, in this study, we identified novel SNPs that link gout with health-related lifestyle factors in the Korean population.


Minimal Invasive Surgical Treatment of Fragility Fractures of the Pelvis.
The incidence of fragility fractures of the pelvis is increasing quickly. The characteristics of these fractures are different from pelvic ring disruptions in adults. Fragility fractures of the pelvis are the consequence of a low-energy trauma which occurs in a patient with an important decrease of bone mineral density. Due to a consistent pattern of alteration of bone mass distribution in the sacrum, other fracture morphologies occur than in younger adults. The leading symptom is immobilizing pain in the lower back, in the buttocks, in the inguinal region and/or at the pubic symphysis. Conventional radiographs and CT will show the presence and localization of the fractures in the anterior and posterior pelvic ring. A new, comprehensive classification system distinguishes four categories of instability. This first criterion is most important, because it also gives hints for the preferred type of treatment. The second criterion, leading to the subtypes in the four categories, is the localization of the instability in the posterior pelvic ring. This criterion points the way towards the type of the surgical procedure to be used. When a surgical treatment is chosen, the procedure should be as minimal invasive as possible. Different techniques for percutaneous or less invasive fixation of the posterior pelvic ring have been developed. Their advantages and limitations are presented: sacroplasty, iliosacral screw osteosynthesis, cement augmentation, transiliac internal fixation, trans-sacral osteosynthesis, lumbopelvic fixation. Fractures of the anterior pelvic ring also need special attention. Retrograde transpubic screw fixation is recommended for pubic rami fractures. Fractures of the pubic body and instabilities of the pubic symphysis need bridging plate osteosynthesis. We do not recommend anterior pelvic external fixation in elderly because of the risk of pin track infection and pin loosening.


Differential Brain and Muscle Tissue Oxygenation Responses to Exercise in Tibetans Compared to Han Chinese.
The Tibetans' better aerobic exercise capacity at altitude remains ill-understood. We tested the hypothesis that Tibetans display better muscle and brain tissue oxygenation during exercise in hypoxia. Using near-infrared spectrometry (NIRS) to provide indices of tissue oxygenation, we measured oxy- and deoxy-hemoglobin ([O2Hb] and [HHb], respectively) responses of the vastus lateralis muscle and the right prefrontal cortex in ten Han Chinese and ten Tibetans during incremental cycling to exhaustion in a pressure-regulated chamber at simulated sea-level (air at 1 atm: normobaric normoxia) and 5,000 m (air at 0.5 atm: hypobaric hypoxia). Hypoxia reduced aerobic capacity by ∼22% in both groups (d = 0.8, p < 0.001 vs. normoxia), while Tibetans consistently outperformed their Han Chinese counterpart by ∼32% in normoxia and hypoxia (d = 1.0, p = 0.008). We found cerebral [O2Hb] was higher in Tibetans at normoxic maximal effort compared Han (p = 0.001), while muscle [O2Hb] was not different (p = 0.240). Hypoxic exercise lowered muscle [O2Hb] in Tibetans by a greater extent than in Han (interaction effect: p < 0.001 vs. normoxic exercise). Muscle [O2Hb] was lower in Tibetans when compared to Han during hypoxic exercise (d = 0.9, p = 0.003), but not during normoxic exercise (d = 0.4, p = 0.240). Muscle [HHb] was not different between the two groups during normoxic and hypoxic exercise (p = 0.778). Compared to Han, our findings revealed a higher brain tissue oxygenation in Tibetans during maximal exercise in normoxia, but lower muscle tissue oxygenation during exercise in hypoxia. This would suggest that the Tibetans privileged oxygenation of the brain at the expense of that of the muscle.


Muscle glycogen synthesis in recovery from intense exercise in humans.
The present study examined the role of lactate and glucose as substrates for glyconeogenesis in muscle in recovery from high-intensity exercise in humans. Seven subjects performed approximately 100 min of intense intermittent one-legged knee extensor exercise on two occasions: with [high lactate (HL)] and without [control (C)] intense arm exercise between the leg exercise bouts, leading to end exercise arterial plasma lactate concentrations of 16.0 +/- 1.6 and 9.2 +/- 1.6 mmol/l, respectively (P < 0.05). At the end of exercise, muscle lactate and glycogen were similar in HL and C (20.5 +/- 1.3 vs. 17.3 +/- 2.0 mmol/kg wet wt and 48.1 +/- 11.3 vs. 56.3 +/- 8.6 mmol/kg wet wt, respectively). Muscle glycogen increased (P < 0.05) during the first 5 min of recovery only in HL, but after 90 min of recovery the muscle glycogen concentration was the same in C and HL (61.2 +/- 12.0 vs. 71.5 +/- 10.9 mmol/kg wet wt). Muscle lactate not released to the blood could maximally account for 28 (C) and 54% (HL) of the increase in muscle glycogen during 90 min of recovery or < 10% of glycogen synthesis after full recovery. The total net glucose uptake corresponded to 84 (C) and 57% (HL) of the glycogen synthesized. Apparently, muscle glyconeogenesis may occur in humans, but the role of lactate as a substrate is minor. Instead, blood glucose appears to be the most important precursor for muscle glycogen synthesis after intense exercise.


Passive infrared sensors: limitations on performance.
The performance of passive sensors for surveillance, radiometry, spectroscopy, astronomy is analyzed using idealizations of engineering features. Sensors are characterized by a finite number of degrees of freedom in each of two angles, wavelength, and time. An optimum number of degrees of freedom is found to sense a target field in four dimensions. Degrees of freedom are quite freely interchangeable between dimensions of different kinds. An optimum number of output states is related to the sensing or measurement requirment. An optimum weighting is found for averaging degrees of freedom into output states. Simple equations relate performance to an index of cost. Examples apply the results to estimate limits to sensor performance for several applications.


Variability of the honey bee mite Varroa destructor in Serbia, based on mtDNA analysis.
Only two mitochondrial haplotypes (Korea and Japan) of Varroa destructor, the ectoparasitic honey bee mite, are known to be capable of infesting and successfully reproducing in Apis mellifera colonies worldwide. Varroa destructor (then called Varroa jacobsoni) was observed in Serbia for the first time in 1976. In order to obtain insight into the genetic variability of the mites parasitizing A. mellifera we analyzed 45 adult female mites sampled from nine localities dispersed throughout Serbia. Four fragments within cox1, atp6, cox3 and cytb mtDNA genes were sequenced. The Korea haplotype of V. destructor was found to be present at all localities, but also two new haplotypes (Serbia 1 and Peshter 1) were revealed, based on cox1 and cytb sequence variability. The simultaneous occurrence of Korea and Serbia 1 haplotypes was observed at five localities, whereas Peshter 1 haplotype was identifed at only one place.


[Assessment of the nutritional status of a group of people older than 50 years by means of dietary and body composition parameters].
To assess the nutritional status of elder adults by means of dietary and body composition parameters. The sample comprised 49 adults, older than 50 years (23 men and 26 women) with a mean age of 54.84±4.56 years, working at a private university. The body composition was analyzed by using anthropometric parameters. The energy and nutrients intake was gathered by means of a registry of all the foods and beverages consumed during 3 days that was filled-up by each (previously instructed) participant and estimating the amounts through photographic models. Total energy requirements were estimated by the Harris-Benedict and FAO/WHO calculations. The body mass index was similar (p=0.018) in both men and women (26.1±1.9 and 24.4±2.8 kg/m²). The percentage of fat obtained by anthropometrics was 29.6±3.6 and 36.8±3.1% (p=0.000) in men and women, respectively. The level of physical activity was very light to light. Daily energy intake was appropriate for total energy demands when these were calculated by the calculations proposed by FAO/WHO. The caloric profile indicated an unbalance with high proteins and lipids and low carbohydrates intake. As for the micronutrients, the diets assessed indicated a deficient intake of folic acid and vitamins D and E, in both genders, and zinc and selenium also in women. We have found overweight problems according to the BMI and the waist circumference, and obesity according to the body fat percentage, with the potential risk for the development of an associated complication. It would be advisable to improve the quality of the diets consumed by increasing the amount of some micronutrients and fiber, and by promoting an increase in the physical activity.


Inhibition of DNA topoisomerase II alpha gene expression by the p53 tumor suppressor.
DNA topoisomerase II (topo II) is an essential nuclear enzyme involved in major cellular functions such as DNA replication, transcription, recombination, and mitosis. While an elevated level of topo II alpha is associated with cell proliferation, wild-type (wt) p53 inhibits the expression of various growth-stimulatory genes. To determine if p53 downregulates topo II alpha gene expression, a murine cell line, (10)1val, that expresses a temperature-sensitive p53 was utilized. The (10)1val cells had significantly lower levels of topo II alpha mRNA and protein following incubation for 24 h at 32 degrees C (p53 with wt conformation) than at 39 degrees C (p53 with mutant conformation). The effect of p53 on the human topo II alpha gene promoter was determined by using luciferase reporter plasmids containing varying lengths of the topo II alpha promoter transiently cotransfected into p53-deficient (10)1 cells together with wt or mutant p53 expression plasmids. Transcription from the full-length (bp -557 to +90) topo II alpha promoter was decreased 15-fold by wt p53 in a concentration-dependent manner, whereas mutant p53 exerted much weaker inhibition. Consecutive deletion of the five inverted CCAAT elements (ICEs) from the topo II alpha promoter reduced both the basal promoter activity and wt p53-induced suppression. Transcription of the minimal promoter (-32 to +90), which contains no ICE, was slightly stimulated by wt or mutant p53 expression. When point mutations were introduced into the most proximal ICE (-68), the inhibitory effect of wt p53 was alleviated and stimulation of topo II alpha expression resulted. Our study suggests that wt p53 functions as a transcriptional repressor of topo II alpha gene expression, possibly through a functional interaction with specific ICEs. Inactivation of wt p53 may reduce normal regulatory suppression of topo II alpha and contribute to abortive cell cycle checkpoints, accelerated cell proliferation, and alterations in genomic stability associated with neoplasia.


N-acetylcysteine inhibits RhoA and promotes apoptotic cell clearance during intense lung inflammation.
The resolution of pulmonary inflammation seen in various inflammatory lung conditions depends on the clearance of apoptotic cells to prevent permanent tissue damage or progressive disease. Uptake of apoptotic cells by alveolar macrophages is suppressed by oxidants through the activation of Rho signaling. We hypothesized that antioxidant exposure would increase the ability of alveolar macrophages to clear pulmonary apoptotic cells through the inhibition of RhoA. The effects of the antioxidant N-acetylcysteine (NAC) on the pulmonary immune response were seen in mice treated intratracheally with LPS, LPS + NAC, or saline. Apoptotic cell clearance, RhoA activity, and changes in the lung inflammatory responses were analyzed in vivo or ex vivo. Neutrophil accumulation, apoptosis, necrosis, and oxidant production peaked at 3 days post LPS treatment. NAC enhanced the clearance of apoptotic cells and inhibited RhoA activity in alveolar macrophages at 3 days post LPS treatment. NAC suppressed LPS-induced proinflammatory mediators, enhanced the production of transforming growth factor-beta1, reduced the accumulation of inflammatory cells, and reduced levels of protein and lactate dehydrogenase in bronchoalveolar lavage fluid. In the presence of ex vivo apoptotic cells, alveolar macrophages exposed to LPS or LPS + NAC had reduced tumor necrosis factor-alpha levels and increased transforming growth factor-beta1 levels. A Rho kinase inhibitor mimicked the effects of NAC on the clearance of apoptotic cells and the inflammatory responses. These results indicate that NAC can expedite the resolution of LPS-induced pulmonary inflammation through the inhibition of RhoA activity and the enhancement of apoptotic cell clearance.


[Mesenteric panniculitis: experience in our center].
Although several etiological factors have been associated with mesenteric panniculitis, the exact etiology in some cases remains unknown. Herein, we present a retrospective analysis of 8 patients affected with this disorder performed between May 2000 and December 2006. In our series the mean age at which patients presented was 63 years. The majority of the patients were male (with a male: female ratio of 3:1). The most common clinical manifestations were abdominal pain (n = 4) and asthenia (n = 4). Three cases presented with obstructive symptoms and three had a history of abdominal surgery. Notably, seven had a background of tobacco use (five smokers and two ex-smokers) and one patient developed follicular lymphoma. A literature research was carried out to analyze our results and formulate a new hypothesis. In our opinion, we believe that the study of causal factors such as tobacco and its components is required due to the strong association found in this study.


Trends in long-term survival of patients with chronic lymphocytic leukemia from the 1980s to the early 21st century.
Although chronic lymphocytic leukemia (CLL) has remained incurable with standard treatments, newer therapeutic approaches, such as chemoimmunotherapy or stem cell transplantation, bear the potential for prolonged survival. We estimated trends in age-specific 5- and 10-year absolute and relative survival of CLL patients in the United States between 1980-1984 and 2000-2004 from the 1973 to 2004 database of the Surveillance, Epidemiology, and End Results Program. Period analysis was used to disclose recent developments with minimum delay. Overall, 5- and 10-year absolute survival from diagnosis increased from 54.2% to 60.2% (+6 percentage points; P < .0001) and from 27.8% to 34.8% (+7 percentage points; P < .0001), respectively. Despite a strong age gradient in prognosis, increases in 5-year absolute and relative survival over time were rather homogeneous across age groups. In contrast, increases in 10-year absolute and relative survival close to or well above 10% units were observed for all patients younger than 80 years of age at diagnosis compared with no increase at all for older patients. Long-term survival expectations of patients with CLL have substantially improved over the past 2 decades except for patients 80 years of age or older at the time of diagnosis. Future studies are needed to confirm and expand our findings.


Depression in multiple sclerosis: a review.
Several studies have reported high rates of depression in multiple sclerosis (MS) with a lifetime prevalence of approximately 50% and an annual prevalence of 20% not uncommon. Concern about the potential of new drug treatments to exacerbate or precipitate depression in MS has led to increased interest in the relation between MS and depression. This review on MS and depression identifies the following key issues: How common is depression in people with MS? Is depression in MS associated with lesions in specific regions of the central nervous system? Is there an increased risk of suicide in MS? Is there a higher than expected incidence of anxiety disorders in MS? Are fatigue and depressed mood related in MS? Is there a relation between depression and cognitive impairment in MS? Which psychosocial variables affect the development of depression in MS? Does treatment with interferon increase the risk of depression? How effective are treatments for MS patients with depression? Each of these issues is briefly reviewed with critical commentary, and some priorities for future research are suggested.


Imaging: how to recognise idiopathic pulmonary fibrosis.
It is well known that high-resolution computed tomography (HRCT) is an essential component of the diagnostic pathway in idiopathic pulmonary fibrosis (IPF). Honeycombing, a common feature of IPF seen on HRCT, is crucial for an accurate diagnosis. Unfortunately, identification of honeycombing is not always straightforward, and there is some disagreement regarding its imaging features. It can be difficult to distinguish honeycombing from traction bronchiectasis and emphysema, although several imaging characteristics can be helpful. Recently, there has been an interest in expanding the use of HRCT beyond diagnosis for disease monitoring and prognostication, and several studies have provided valuable contributions in this regard. Traction bronchiectasis and the extent of fibrosis, for example, have been reported to be powerful prognostic predictors for mortality. Finally, considering the difficulties in diagnosis of "possible usual interstitial pneumonia", clinicians should always be aware that clinical factors must be considered together with HRCT in order to reach an accurate diagnosis and provide appropriate treatment.


Total Outflow of High-Density Lipoprotein-Cholesteryl Esters from Plasma Is Decreased in a Model of 3/4 Renal Mass Reduction.
(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins.


CREB is a novel nuclear target of PTEN phosphatase.
PTEN phosphatase is a potent tumor suppressor that regulates multiple cellular functions. In the cytoplasm, PTEN dephosphorylates its primary lipid substrate, phosphatidylinositol 3,4,5-trisphosphate, to antagonize the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway. It has also become increasingly evident that PTEN functions in the nucleus and may play an important part in transcription regulation, but its nuclear targets remain elusive. In this report, we demonstrate the transcription factor cyclic AMP response element-binding protein (CREB) is a protein target of PTEN phosphatase and that PTEN deficiency leads to CREB phosphorylation independent of the PI3K/AKT pathway. Using confocal immunofluorescence and reciprocal immunoprecipitation, we further show that PTEN colocalizes with CREB and physically interacts with CREB. Moreover, we use both in vitro and in vivo experiments to show PTEN can dephosphorylate CREB in a phosphatase-dependent manner, suggesting that CREB is a substrate of PTEN nuclear phosphatase. Loss of Pten results in an elevated RNA level of multiple CREB transcriptional targets and increased cell proliferation, which can be reversed by a nonphosphorylatable CREB mutant or knockdown of CREB. These data reveal a mechanism for PTEN modulation of CREB-mediated gene transcription and cell growth. Our study thus characterizes PTEN as a nuclear phophatase of a transcription factor and identifies CREB as a novel protein target of PTEN phosphatase, which contributes to better understanding of PTEN function in the nucleus.


Energy and macronutrient content of human milk during early lactation from mothers giving birth prematurely and at term.
The lactose, lipid, protein, and total energy content of milk produced during the first 4 wk of lactation was determined in milk from mothers giving birth prematurely and at term. Milk samples analyzed were representative of complete 24-h expressions. Over the first 4 wk of lactation lactose concentration increased, but nitrogen concentration decreased by an average of 25%. Lipid and total energy concentration increased by 25% from the 1st to 2nd wk and then remained stable in both groups. Although these changes with duration of lactation were similar in both groups, premature compared to full term milk was consistently 20 to 30% higher in total energy and lipid concentration, 15 to 20% higher in total protein and, after the 1st wk, approximately 10% lower in lactose. By comparing predicted nutrient intakes to estimated requirements of premature infants fed 150 to 200 ml/kg/day of their own mothers' milk, we predict that the quantities of protein and energy provided would be adequate to meet the needs of the infant during the early weeks of life.


The Relationship Between Tobacco Smoke Exposure and Airflow Obstruction in US Children: Analysis of the National Health and Nutrition Examination Survey (2007-2012).
It has been difficult to determine the individual impact of prenatal and postnatal tobacco smoke exposure (TSE) on childhood lung function, as children are often exposed to both. The goal of this study was to determine the association between current TSE and airflow obstruction while adjusting for self-reported prenatal TSE. Children aged 6 to 11 years who participated in the National Health and Nutrition Examination Survey (2007-2012) who had serum cotinine levels measured and spirometry performed were included. Logistic regression was used to determine the association between log-transformed serum cotinine level and airflow obstruction while adjusting for confounders; the analysis was then stratified according to asthma status. The final model included both log-transformed serum cotinine level and prenatal exposure as covariates. The sample consisted of 2,070 children; 9.6% had airflow obstruction. The association between cotinine levels and airflow obstruction was significant in an unadjusted analysis (OR, 1.12 [95% CI, 1.02-1.23]). In the multivariate analysis with both exposures included as covariates, serum cotinine level was not significantly associated with airflow obstruction (ORadj, 1.07 [95% CI, 0.94-1.21]), and no association was seen in children with asthma and nonasthmatic children. Prenatal smoking was associated with airflow obstruction in children with asthma (ORadj, 2.51 [95% CI, 1.08-5.79]) but not in nonasthmatic children (ORadj, 1.08 [95% CI, 0.53-2.18]). Current TSE was not independently associated with airflow obstruction in school-aged children. Prenatal TSE was associated with airflow obstruction in children with asthma. Repeated studies into potential mediators and confounders of this relationship are needed.


Global dispersal reduces local diversity.
Metapopulation models and stepping-stone models in genetics are based on very different underlying dispersal structures, yet it can be difficult to distinguish the behaviour of the two kinds of models. We demonstrate a striking qualitative difference in the equilibrium behaviour possible with these two kinds of dispersal. If, in a local patch, there are multiple stable equilibria (and consequently an unstable equilibrium), we demonstrate that, for the spatial system with a metapopulation structure, at equilibrium every patch has to be near one of the stable equilibria. This contrasts with the clinal structure possible with a stepping-stone or continuous space model; thus the result can be used to deduce qualitative information about the form of dispersal from observations of allele frequencies.


Escherichia coli capsule bacteriophages. V. Lysozyme 29.
In addition to the spike-associated host capsule depolymerase, infection by Escherichia coli capsule bacteriophage no. 29 also induces the synthesis of a large bacteriolytic enzyme which has been purified to homogeneity. On incubation of isolated host murein sacculi with this enzyme, no amino groups but reducing sugar groups were liberated, and muraminitol, but no glucosaminitol, was found in the degraded sacculi after subsequent reduction with NaBH4. The bacteriolytic enzyme is thus another lysozyme (mucopeptide N-acetylmuramylhydrolase; EC 22.214.171.124). Electron optical visualization of negatively stained lysozyme specimens showed oblong particles of roughly 4.5 to 5.5 nm in diameter and 15 to 19 nm in length. Although the material tended to dissociate, a crude estimate of its molecular weight (270,000 plus or minus 30,000) could be obtained from these dimensions, from its sedimentation equilibrium, and from its behavior in gel chromatography. After disintegration of homogeneous lysozyme 29 by heating in solution with sodium dodecyl sulfate and dithiothreitol, polypeptides of one size only (about 46,000 dalton, probably six copies per molecule) were found in sodium dodecyl sulfate-polyacrylamide electrophoresis. The amino acid analysis of the enzyme accounted for more than 90% of its dry weight. One percent or less of the bacteriolytic activity in phage 29 lysates was found to be associated with the intact or disrupted virus particles, and a polypeptide of 46,000 daltons was not detected in the virions. These results strongly suggest that, in contrast to the host capsule depolymerase also induced by the same phage, and in spite of its comparatively large size, "lysozyme 29" does not constitute an integral part also of the homologous bacteriophage particles.


Laryngeal chondritis as a differential for upper airway diseases in German sheep.
Ovine laryngeal chondritis is a rare entity of sheep in the USA, Great Britain, New Zealand and Iceland, but has not been reported in Germany so far. Here, two German cases are reported. Two rams showed severe and progressive signs of dyspnea. Endoscopically, a severe bilateral swelling of the larynx was identified in both rams. Due to poor prognosis and progression of clinical signs one ram was euthanized, while the other ram died overnight. In both cases, a necrosuppurative laryngitis and chondritis of arytenoid cartilages was found at necropsy. Fusobacterium necrophorum and Streptococcus ovis were isolated from the laryngeal lesion in one animal. This is the first report of ovine laryngeal chondritis in continental Europe. This entity should be considered a differential diagnosis for upper airway disease in sheep.


When Stars Do Not Align: Overall Hospital Quality Star Ratings and the Volume-Outcome Association.
Volume-outcome relationships are well established for coronary artery bypass grafting and total joint arthroplasty surgery. Although the U.S. Centers for Medicare & Medicaid Services (CMS) Overall Hospital Quality Star Ratings program includes outcome quality measures for these procedures, these outcome quality measures are not counted toward the star ratings for low-volume hospitals. We sought to assess whether excluding low-volume hospitals from surgical quality measures with known volume-outcome relationships affects the star ratings. We identified quality measures used in CMS's star ratings that are related to surgical procedures with a known volume-outcome relationship and tested for the presence of the volume-outcome association for each of these measures. We then imputed missing values for low-volume hospitals for each measure and otherwise identically repeated the CMS calculations in order to assess the percentages of hospitals with the same, better, or worse ratings. Among the measures used to calculate star ratings, we identified 4 quality measures (2 related to coronary artery bypass grafting and 2 related to total joint arthroplasty) with known volume-outcome relationships that were excluded from the calculations of the star ratings for low-volume hospitals. We confirmed a volume-outcome association in the CMS data for all 4 measures. When total joint arthroplasty complications were imputed for low-volume hospitals and then included in the calculation of the star ratings, over one-third of hospitals received a different rating; both low-volume and other hospitals were more often hurt than helped. Imputing the other 3 quality measures among low-volume hospitals left the ratings unchanged. The CMS star ratings do not fully represent the risks of undergoing procedures at low-volume hospitals, potentially misrepresent quality across facilities, and hence are of uncertain utility to consumers.


Human cerebral malaria: a pathological study.
The following report using light and electron microscopic and immunological techniques is based on a series of 19 Burmese patients who died of cerebral malaria. The principal change was blockage of cerebral capillaries by Plasmodium falciparum-infected erythrocytes. Ring hemorrhages and segmental necrosis of cerebral capillaries were common. Cerebral edema was variable in these cases. Electron-dense knobs, 40 X 80 nm in size, which protruded from the membrane of infected erythrocytes, formed focal junctions between endothelial cells and erythrocytes. These junctions resulted in the entrapment of erythrocytes and caused blockage in the capillary lumen. Immunoperoxidase study revealed that P. falciparum antigens and IgG deposits in the capillary basement membrane. This implies that damage to the cerebral capillary could be related to immune mechanisms.


Rapid platelet inhibition after a single capsule of Aggrenox: challenging a conventional full-dose aspirin antiplatelet advantage?
Aggrenox is a novel combination of 25 mg of aspirin with 200 mg of sustained release dipyridamole. In a recent large trial (ESPS-2), Aggrenox was twice as effective for secondary stroke prevention as either aspirin or dipyridamole alone, suggesting superior platelet inhibition for combination therapy. We sought to compare the time course of platelet inhibition with Aggrenox compared with escalating doses of non-enteric coated aspirin. Data from 10 healthy volunteers were analyzed. Fasting subjects sequentially ingested aspirin in the following order: 325 mg, 81 mg, 25 mg, and then one pill of Aggrenox after a 3-week interval for aspirin washout. Platelet function was assessed at baseline, 15, 30, 60, and 120 min post-medication with 5 microM epinephrine and 5 microM ADP using conventional aggregometry. Aspirin provided significant (P < 0.01) reduction of platelet aggregation at 15 min post 325 mg, 30 min post 81 mg, and unexpectedly within 60 min after taking 25 mg of aspirin. A single pill of Aggrenox also inhibited platelet aggregation within 1 hr after administration. Aspirin inhibits platelets remarkably fast. Both Aggrenox and a matching dose of aspirin (25 mg) exhibit significant antiplatelet properties within 60 min after ingestion. These findings could be relevant for the optimal balance between the reduction of vascular events via sufficient and rapid platelet inhibition and low risk of bleeding complications associated with the Aggrenox therapy.


Cystic and cavitary lung diseases: focal and diffuse.
Cysts and cavities are commonly encountered abnormalities on chest radiography and chest computed tomography. Occasionally, the underlying nature of the lesions can be readily apparent as in bullae associated with emphysema. Other times, cystic and cavitary lung lesions can be a diagnostic challenge. In such circumstances, distinguishing cysts (wall thickness < or = 4 mm) from cavities (wall thickness > 4 mm or a surrounding infiltrate or mass) and focal or multifocal disease from diffuse involvement facilitates the diagnostic process. Other radiological characteristics, including size, inner wall contour, nature of contents, and location, when correlated with the clinical context and tempo of the disease process provide the most helpful diagnostic clues. Focal or multifocal cystic lesions include blebs, bullae, pneumatoceles, congenital cystic lesions, traumatic lesions, and several infectious processes, including coccidioidomycosis, Pneumocystis carinii pneumonia, and hydatid disease. Malignant lesions including metastatic lesions may rarely present as cystic lesions. Focal or multifocal cavitary lesions include neoplasms such as bronchogenic carcinomas and lymphomas, many types of infections or abscesses, immunologic disorders such as Wegener granulomatosis and rheumatoid nodule, pulmonary infarct, septic embolism, progressive massive fibrosis with pneumoconiosis, lymphocytic interstitial pneumonia, localized bronchiectasis, and some congenital lesions. Diffuse involvement with cystic or cavitary lesions may be seen in pulmonary lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, honeycomb lung associated with advanced fibrosis, diffuse bronchiectasis, and, rarely, metastatic disease. High-resolution computed tomography of the chest frequently helps define morphologic features that may serve as important clues regarding the nature of cystic and cavitary lesions in the lung.


Photothermally tunable Fabry-Pérot fiber interferometer for photoacoustic mesoscopy.
An optical fiber based Fabry-Pérot interferometer whose resonant wavelength can be dynamically tuned was designed and realized for photoacoustic mesoscopy. The optical path length (OPL) of the Fabry-Pérot cavity can be modulated by a photothermal heating process, which was achieved by adjusting the power of a 650 nm heating laser. The optical heating process can effectively change the thickness and refractive index of the polymer spacer of the sensor cavity. The robustness of the sensor can be greatly improved by proper packaging. The interferometer was interrogated by a relatively cheap wavelength-fixed 1550 nm laser for broadband and sensitive ultrasound detection, eliminating the requirement for an expensive tunable interrogation laser. The sensing module was then integrated into a photoacoustic mesoscopic imaging system. Two phantom imaging experiments and an ex vivo imaging experiment demonstrated the capability of such a miniature sensor. The interferometer has an acoustic detection bandwidth of up to 30 MHz and a noise equivalent pressure of 40 mPa/Hz1/2 (i.e., 220 Pa over the full detection bandwidth). The new tuning mechanism and the batch-production compatibility of the sensor holds promises for commercialization and parallelized detection.


[Infectious complications after arthroscopic replacement of the cruciate ligaments].
Infection following replacement of the cruciate ligaments of the knee joint may result in not only graft failure but also complete destruction of the joint. The aim of this study was to report the authors' experience with the diagnosis and therapy of this, fortunately occasional, complication. In the period from October 1999 till June 2003, a total of 2372 arthroscopic operations of the knee joint were carried out; of these, 908 were cruciate ligament replacements. Three surgeons using the same technique were involved. An autologous graft taken from the ligamentum patellae and fixed with interference screws was used in 857 knees, and a graft derived from the tendon of the semitendinosus or the gracilis muscle, with "endobutton" fixation, was employed. Two kinds of inflammatory complications were recorded in the early post-operative period, i. e., infection of the articular cavity and infected subcutaneous hematoma at site of graft collection. When infection of the articular cavity was suspected because of severe pain, perspiration, motion restriction, articular exudate and increased temperature, arthrocentesis was performed and a sample of the fluid withdrawn was sent for cultivation; laboratory tests (blood counts, erythrocyte sedimentation rate, C-reactive protein) were carried out and antibiotic therapy was started. When there was no subsidence of signs within 24 h, revision surgery was carried out without waiting for the results of laboratory examination. Coagula from inside of the cavity were removed through a short incision on the lateral side of the suprapatellar recess and, after repeated thorough irrigation, a suction drain was inserted. Antibiotic therapy was administered parenterally. Infected subcutaneous hematoma, associated with edema, reddening and tension of the skin, pain, fluctuation and, in some cases, high temperature, was treated by disintegration of the wound, removal of the hematoma, debridement and thorough irrigation. After drain insertion, the wound was closed by suture. The development of infectious complications was assessed in relation to the risk factors described in the literature, namely, patient's age, operating room time and tourniquet application, previous infections of the upper respiratory or urinary tracts, previous surgery on the same joint and the season in which the operation was performed. A total of 37 revision operations following replacement of the cruciate ligaments of the knee joint were carried out; of these, 29 involved the articular cavity. An infectious agent was found in six cases (0.7 % of the total number of cruciate ligament replacements). Eight knees were treated for hematoma in the wound at site of graft collection and, in seven of them, Staphylococcus aureus was isolated (0.8 % of the total number of crucial ligament replacements). For recurrent problems the distal fixation material had to be removed in two patients at 6 and 12 months, respectively. Afterwards the patients were free from symptoms. The only risk factor for the development of infection was found to be previous surgery on the same joint. The authors prefer early revision surgery in the cases showing signs of developing infection in the articular cavity or hematoma in the wound after graft collection. Therefore the results of positive cultivation were fewer in comparison with other relevant reports. In revision surgery on the articular cavity, the authors made a 2-cm incision on the lateral side of the suprapatellar recess, which enabled them to wash out all coagula, in comparison to other authors who recommend irrigation with the use of arthroscopic apparatus only. The early intervention made it possible to keep all grafts in situ. The only factor associated with a higher occurrence of complications in our patients was a previous operation on the same joint. On the basis of their experience with arthroscopic replacement of the cruciate ligaments, the authors recommend an active approach if the development of infectious complications is suspected. In our patients, no persisting sequelae were recorded.


EndoBarrier®: a Safe and Effective Novel Treatment for Obesity and Type 2 Diabetes?
Obesity associated with diabetes mellitus is a significant worldwide problem associated with considerable health care costs. Whilst surgical intervention is effective, it is invasive, costly and associated with complications. This study aims to evaluate the safety and efficacy of the EndoBarrier®, a duodenal-jejunal sleeve bypass as an alternative treatment of diabetes mellitus in obese patients. This was a multi-centre, non-randomised trial recruiting obese patients with type 2 diabetes from three sites in the UK. Eligible participants had a BMI of 30-50 kg/m2 and HbA1c levels of 7.5-10%. The study comprised a 12-month period with the EndoBarrier® inserted and a 6-month follow-up period after it had been explanted. The primary study outcomes were weight, BMI, HbA1c levels and fasting insulin and glucose levels. Forty-five patients were recruited and 31 patients (69%) completed the 12-month study period. Significant reductions in weight (95%CI 0.62-29.38; p < 0.05) and BMI (95%CI 1.1-8.7; p < 0.005) were documented 12 months after device insertion. The mean HbA1c was significantly reduced (95%CI 0.1-1.6; p < 0.05) after the device insertion period and reductions in metabolic parameters (fasting insulin and glucose levels) were also documented during the study. Adverse events were also assessed in all patients, the vast majority of which were reported as mild. The EndoBarrier® appears to be a safe and effective treatment strategy in overweight patients with poor glycaemic control despite medical therapy, or in those who are eligible but decline bariatric surgery.


Improved detection of canine Angiostrongylus vasorum infection using real-time PCR and indirect ELISA.
This study reports the development of a real-time PCR assay and an indirect ELISA to improve on current detection of canine Angiostrongylus vasorum infection. A highly specific fluorescent probe-based, real-time PCR assay was developed to target the A. vasorum second internal transcribed spacer region and detected DNA in EDTA blood, lung tissue, broncho-alveolar larvage fluid, endotracheal mucus, pharyngeal swabs and faecal samples. PCR was fast (∼1 h), highly efficient when using EDTA blood samples, consistently detected a single molecule of parasite DNA and did not amplify DNA from other parasitic nematodes or definitive host species. An indirect ELISA was also developed using the soluble protein fraction from adult A. vasorum worms. Some cross-reactive antigen recognition was observed when tested against sera from dogs infected with Crenosoma vulpis (n = 8), Toxocara canis (n = 5) and Dirofilaria immitis (n = 5). This was largely overcome by setting the cut-off for a positive result at an appropriately high level. Field evaluation of the real-time PCR and ELISA was conducted by testing sera and EDTA blood from dogs with suspected A. vasorum infection (n = 148) and compared with the Baermann's larval migration test in faeces. Thirty-one dogs were positive by at least one test. Of these, 20 (65%) were detected by the Baermann method, 18 (58%) by blood PCR, 24 (77%) by ELISA and 28 (90%) by blood PCR and ELISA together. Combined testing using real-time PCR and ELISA therefore improved the detection rate of A. vasorum infection and holds promise for improved clinical diagnosis and epidemiological investigation.


Voxel Level Survival Analysis of Grey Matter Volume and Incident Mild Cognitive Impairment or Alzheimer's Disease.
The purpose of this study was to identify, at the voxel level, brain regions associated with the time to develop mild cognitive impairment (MCI) or Alzheimer's disease (AD) from normal cognition. We analyzed incident MCI (n = 58) or AD (n = 151) in 292 cognitively normal participants in the Cardiovascular Health Study-Cognition Study (mean age = 79.2 ± 3.6 years). We used segmented, modulated grey matter maps from 3D (spoiled gradient echo) MRI scans obtained in 1998/99 (with clinical follow-up through 2012) that were smoothed with a 3-D 4 mm Gaussian filter. We fit approximately 1.92 million voxel-level Cox proportional hazard models to examine the grey matter volume effect on time to event, adjusting for age, sex, and diabetes. We used the significance threshold of p < 0.005 with contiguity threshold of at least 68 voxels (false detection probability <2.5×10 -8). Areas within the mesial temporal lobe (MTL), anterior temporal lobe, hippocampus, and posterior cingulate gyrus were associated with time to MCI or AD. The presence of white matter lesions (a marker of small vessel disease in the brain) was associated with the volumes of the MTL and precuneus; MRI-identified infarcts also predicted MTL volume. These findings are important because we identified critical brain regions that predict a person's increased likelihood of developing MCI or AD over a decade prior to the onset of clinical symptoms; these critical brain regions were themselves affected by the presence of vascular disease.


Early neuromodulation prevents the development of brain and behavioral abnormalities in a rodent model of schizophrenia.
The notion that schizophrenia is a neurodevelopmental disorder in which neuropathologies evolve gradually over the developmental course indicates a potential therapeutic window during which pathophysiological processes may be modified to halt disease progression or reduce its severity. Here we used a neurodevelopmental maternal immune stimulation (MIS) rat model of schizophrenia to test whether early targeted modulatory intervention would affect schizophrenia's neurodevelopmental course. We applied deep brain stimulation (DBS) or sham stimulation to the medial prefrontal cortex (mPFC) of adolescent MIS rats and respective controls, and investigated its behavioral, biochemical, brain-structural and -metabolic effects in adulthood. We found that mPFC-DBS successfully prevented the emergence of deficits in sensorimotor gating, attentional selectivity and executive function in adulthood, as well as the enlargement of lateral ventricle volumes and mal-development of dopaminergic and serotonergic transmission. These data suggest that the mPFC may be a valuable target for effective preventive treatments. This may have significant translational value, suggesting that targeting the mPFC before the onset of psychosis via less invasive neuromodulation approaches may be a viable preventive strategy.


Exosomal miRNAs in central nervous system diseases: biomarkers, pathological mediators, protective factors and therapeutic agents.
Exosomes are small bilipid layer-enclosed extracellular vesicles that can be found in tissues and biological fluids. As a key cell-to-cell and distant communication mediator, exosomes are involved in various central nervous system (CNS) diseases, potentially through transferring their contents such as proteins, lipids and nucleic acids to the target cells. Exosomal miRNAs, which are small non-coding RNAs in the exosomes, are known to be more stable than free miRNAs and therefore have lasting effects on disease-related gene expressions. There are distinct profiles of exosomal miRNAs in different types of CNS diseases even before the onset of irreversible neurological damages, indicating that exosomal miRNAs within tissues and biological fluids could serve as promising biomarkers. Emerging evidence has also demonstrated the pathological effects of several exosomal miRNAs in CNS diseases via specific modulation of disease-related factors. Moreover, exosomes carry therapeutically beneficial miRNAs across the blood-brain-barrier, which can be exploited as a powerful drug delivery tool to help alleviating multiple CNS diseases. In this review, we summarize the recent progress made in understanding the biological roles of exosomal miRNAs as potential diagnostic biomarkers, pathological regulators, and therapeutic targets/drugs for CNS diseases. A comprehensive discussion of the main concerns and challenges for the applications of exosomal miRNAs in the clinical setting is also provided.


What works for whom? Moderators in parental reflective functioning intervention.
The DUET program (a group intervention) aims to enhance parental reflective functioning (PRF). We examined whether pretreatment levels of key outcomes as well as individual parental and family-environment characteristics predicted improvement after intervention with the DUET program. One hundred forty-two parents (native Israelis; mean age = 34.84 years) of preschool children (n = 107; mean child age = 4.3 years; 53% female) were assessed before, after, and 6 months following the intervention. Results indicated significant associations between lower levels of key outcomes at the pretreatment assessment and greater improvement after treatment in PRF, child self-regulation, and child self-distraction strategies. Furthermore, two subgroups of families were uncovered based on individual parental and family-environment characteristics: low-distress and high-distress parents. Following intervention, the high-distress group showed greater improvement in parental sensitivity and child problem behavior, whereas the low-distress group reported greater improvement in locus of control. Clinical and future directions are discussed.


Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study.
Recent small studies on hepatorenal syndrome (HRS) indicate some clinical benefit after transjugular intrahepatic portosystemic stent-shunt (TIPS) but sufficient long term data are lacking. We studied prospectively feasibility, safety, and long term survival after TIPS in 41 non-transplantable cirrhotics with HRS (phase II study). HRS was diagnosed using current criteria (severe (type I) HRS, n=21; moderate (type II) HRS, n=20). Thirty one patients (14 type I, 17 type II) received TIPS (8-10 mm) while advanced liver failure excluded shunting in 10. During follow up (median 24 months) we analysed renal function and survival (Kaplan-Meier). TIPS markedly reduced the portal pressure gradient (21 (5) to 13 (4) mm Hg (mean (SD)); p<0.001) with one procedure related death (3.2%). Renal function deteriorated without TIPS but improved (p<0.001) within two weeks after TIPS (creatinine clearance 18 (15) to 48 (42) ml/min; sodium excretion 9 (16) to 77 (78) mmol/24 hours) and stabilised thereafter. Following TIPS, three, six, 12, and 18 month survival rates were 81%, 71%, 48%, and 35%, respectively. As only 10% of non-shunted patients survived three months, total survival rates were 63%, 56%, 39%, and 29%, respectively. Multivariate Cox regression analysis revealed bilirubin (p<0.001) and HRS type (p<0.05) as independent survival predictors after TIPS. TIPS provides long term renal function and probably survival benefits in the majority of non-transplantable cirrhotics with HRS. These data warrant controlled trials evaluating TIPS in the management of HRS.


Placental Growth Factor Reduces Blood Pressure in a Uteroplacental Ischemia Model of Preeclampsia in Nonhuman Primates.
An imbalance in the angiogenesis axis during pregnancy manifests as clinical preeclampsia because of endothelial dysfunction. Circulating soluble fms-like tyrosine kinase 1 (sFLT-1) increases and placental growth factor (PlGF) reduces before and during disease. We investigated the clinical and biochemical effects of replenishing the reduced circulating PlGF with recombinant human PlGF (rhPlGF) and thus restoring the angiogenic balance. Hypertensive proteinuria was induced in a nonhuman primate (Papio hamadryas) by uterine artery ligation at 136 days gestation (of a 182-day pregnancy). Two weeks after uteroplacental ischemia, rhPlGF (rhPlGF, n=3) or normal saline (control, n=4) was administered by subcutaneous injection (100 μg/kg per day) for 5 days. Blood pressure was monitored by intra-arterial radiotelemetry and sFLT-1 and PlGF by ELISA. Uteroplacental ischemia resulted in experimental preeclampsia evidenced by increased blood pressure, proteinuria, and endotheliosis on renal biopsy and elevated sFLT-1. PlGF significantly reduced after uteroplacental ischemia. rhPlGF reduced systolic blood pressure in the treated group (-5.2±0.8 mm Hg; from 132.6±6.6 mm Hg to 124.1±7.6 mm Hg) compared with an increase in systolic blood pressure in controls (6.5±3 mm Hg; from 131.3±1.5 mm Hg to 138.6±1.5 mm Hg). Proteinuria reduced in the treated group (-72.7±55.7 mg/mmol) but increased in the control group. Circulating levels of total sFLT-1 were not affected by the administration of PlGF; however, a reduction in placental sFLT-1 mRNA expression was demonstrated. There was no significant difference between the weights or lengths of the neonates in the rhPlGF or control group; however, this study was not designed to assess fetal safety or outcomes. Increasing circulating PlGF by the administration of rhPlGF improves clinical parameters in a primate animal model of experimental preeclampsia.


Negativism, equivocation, and wobbly assent: public "support" for the prochoice platform on abortion.
Although disapproval of all justifications for abortion is rare in the United States, our analysis of numerous surveys taken in the 1960s and 1970s shows that support for the full prochoice platform is also rare. This means that respondents who endorse some justifications for abortion and reject others typically constitute about 50 percent of these samples. If forced to choose politically between polar positions, would these people be more likely to side with a positive or a negative extreme? Using Multiple Classification Analysis as a form of discriminant analysis, we examine whether people who appear to form a "middle" group actually are closer in their characteristics to those who are positive, or to those who are negative. Finally, we test to see whether those respondents who endorse all four justifications for abortion (health, child defect, financial stress, and elective abortion) also endorse additional prochoice positions, such as government payments for abortion, abortion without the husband's or the parent's consent, and abortion after the first trimester.


[Cleaning and disinfection: tips for the practice].
Cleaning (removal of visible dirt) and disinfection (reduction of the number of micro-organisms to an acceptable level) are necessary to limit 'carry over' of infections agents between patients and people as much as possible. Loose dirt should be removed prior to the use of a detergent. Apart from cases of contamination of an otherwise clean surface or in case of a highly infectious agent, thorough cleaning should always precede disinfection. Several active ingredients are approved for disinfection of animal accommodation. From the point of view of safety and effectiveness, individual chemicals should never be mixed or added to detergents. Queries about the use of chemical agents can be addressed to the College voor de Toelating van Bestrijdingsmiddelen or the manufacturer of the product.


Production of phenylpropanoids and flavonolignans from glycerol by metabolically engineered Escherichia coli.
Phenylpropanoids are a group of plant natural products with medicinal importance derived from aromatic amino acids. Here, we report the production of two representative phenylpropanoids-coniferyl alcohol (CA) and dihydroquercetin (DHQ)-from glycerol by engineered Escherichia coli. First, an E. coli strain capable of producing 187.7 mg/L of CA from glycerol was constructed by the introduction of hpaBC from E. coli and OMT1, 4CL4, and CCR1 from Arabidopsis thaliana to the p-coumaric acid producer. Next, an E. coli strain capable of producing 239.4 mg/L of DHQ from glycerol was constructed by the introduction of F3H, TT7, and CPR from A. thaliana to the naringenin producer, followed by engineering the signal peptide of a cytochrome P450 TT7. Furthermore, to demonstrate the production of flavonolignans, a group of heterodimeric phenylpropanoids, from glycerol, ascorbate peroxidase 1 from Silybum marianum was employed and engineered to produce 0.04 μg/L of silybin and 1.29 μg/L of isosilybin from glycerol by stepwise culture. Finally, a single strain harboring all the 16 necessary genes was constructed, resulting in 0.12 μg/L of isosilybin production directly from glycerol. The strategies described here will be useful for the production of pharmaceutically important yet complex natural products.


The Q41R mutation in the HCV-protease enhances the reactivity towards MAVS by suppressing non-reactive pathways.
Recent experimental findings pointed out a new mutation in the HCV protease, Q41R, responsible for a significant enhancement of the enzyme's reactivity towards the mitochondrial antiviral-signaling protein (MAVS). The Q41R mutation is located rather far from the active site, and its involvement in the overall reaction mechanism is thus unclear. We used classical molecular dynamics and QM/MM to study the acylation reaction of HCV NS3/4A protease variants bound to MAVS and the NS4A/4B substrate and uncovered the indirect mechanism by which the Q41R mutation plays a critical role in the efficient cleavage of the substrate. Our simulations reveal that there are two major conformations of the MAVS H1'(p) residue for the wild type protease and only one conformation for the Q41R mutant. The conformational space of H1'(p) is restricted by the Q41R mutation due to a π-π stacking between H1'(p) and R41 as well as a strong hydrogen bond between the backbone of H57 and the side chain of R41. Further QM/MM calculations indicate that the complex with the conformation ruled out by the Q41R substitution is a non-reactive species due to its higher free energy barrier for the acylation reaction. Based on our calculations, we propose a kinetic mechanism that explains experimental data showing an increase of apparent rate constants for MAVS cleavage in Q41R mutants. Our model predicts that the non-reactive conformation of the enzyme-substrate complex modulates reaction kinetics like an uncompetitive inhibitor.


Resilience as resistance to the new managerialism: portraits that reframe nursing through quotes from the field.
This paper acknowledges the relationship between resilience and the new managerialism of contemporary nursing. Qualitative portraiture methodology. The new managerialism in hospital settings results in a rapidly increasing turnover of acutely ill or comorbid patients, which directly relates to retention and quality service. In education settings, the management imperative to recruit more students into the profession combined with financial cutbacks leads to similar tensions. In aged care the trend equates care directly with funding, with the same effect. Yet despite this, many registered nurses remain working. Portraiture explored 'why' nurses remain in workplaces often described as awful. The resilience of nurses is seen through their stories and reframed to highlight resilience as a form of resistance to the new managerialism inherent in contemporary healthcare. This paper describes some of the hallmarks of new managerialism where workforce pressures force practices that do not value the 'human resource'. The quotes from the field give insight into the nurse's world view and have implications for managers, educators and employers, as well as for consumers of nursing care.


Commercially manufactured engineered nanomaterials for environmental and health studies: important insights provided by independent characterization.
Environmental and health studies on nanomaterials are appearing in the literature at a rapid pace. These studies will address important issues related to the environmental health and safety (EHS) of nanomaterials. As noted in many recent workshop and agency reports, studies devoted toward the environmental fate and transport, nanomaterial-biological interactions, toxicity, and overall risk assessment of nanomaterials should have nanomaterial characterization as a central component of the study design. This aspect of the study design is necessary so that risks associated with nanomaterials can be fully understood and related to specific material properties. For studies that use commercially manufactured nanomaterials, the company often provides characterization data (e.g., chemical composition, phase, and size) of the purchased materials. One question is, how good are these data? Another is, what methods of analysis are used to characterize the properties of commercial nanomaterials? In the present study, some examples are presented that show marked differences between independent characterization of commercially manufactured nanomaterials and that provided by the company. Furthermore, information provided by the manufacturer may be incomplete and nonrepresentative of the entire sample and, in some cases, the information can, in fact, be wrong. Thus, the current study demonstrates an important need for independent characterization data in EHS studies of purchased materials.


Rule learning by seven-month-old infants.
A fundamental task of language acquisition is to extract abstract algebraic rules. Three experiments show that 7-month-old infants attend longer to sentences with unfamiliar structures than to sentences with familiar structures. The design of the artificial language task used in these experiments ensured that this discrimination could not be performed by counting, by a system that is sensitive only to transitional probabilities, or by a popular class of simple neural network models. Instead, these results suggest that infants can represent, extract, and generalize abstract algebraic rules.


Management of Parenteral Nutrition in Hospitalized Adult Patients [Formula: see text].
Despite the high prevalence of malnutrition in adult hospitalized patients, surveys continue to report that many clinicians are undertrained in clinical nutrition, making targeted nutrition education for clinicians essential for best patient care. Clinical practice models also continue to evolve, with more disciplines prescribing parenteral nutrition (PN) or managing the cases of patients who are receiving it, further adding to the need for proficiency in general PN skills. This tutorial focuses on the daily management of adult hospitalized patients already receiving PN and reviews the following topics: (1) PN basics, including the determination of energy and volume requirements; (2) PN macronutrient content (protein, dextrose, and intravenous fat emulsion); (3) PN micronutrient content (electrolytes, minerals, vitamins, and trace elements); (4) alteration of PN for special situations, such as obesity, hyperglycemia, hypertriglyceridemia, refeeding, and hepatic/renal disease; (5) daily monitoring and adjustment of PN formula; and (6) PN-related complications (PN-associated liver disease and catheter-related complications).


Combining optogenetics with sensitive FRET imaging to monitor local microtubule manipulations.
Optogenetic methods for switching molecular states in cells are increasingly prominent tools in life sciences. Förster Resonance Energy Transfer (FRET)-based sensors can provide quantitative and sensitive readouts of altered cellular biochemistry, e.g. from optogenetics. However, most of the light-inducible domains respond to the same wavelength as is required for excitation of popular CFP/YFP-based FRET pairs, rendering the techniques incompatible with each other. In order to overcome this limitation, we red-shifted an existing CFP/YFP-based OP18 FRET sensor (COPY) by employing an sYFP2 donor and mScarlet-I acceptor. Their favorable quantum yield and brightness result in a red-shifted FRET pair with an optimized dynamic range, which could be further enhanced by an R125I point mutation that stimulates intramolecular interactions. The new sensor was named ROPY and it visualizes the interaction between the microtubule regulator stathmin/OP18 and free tubulin heterodimers. We show that through phosphorylation of the ROPY sensor, its tubulin sequestering ability can be locally regulated by photo-activatable Rac1 (PARac1), independent of the FRET readout. Together, ROPY and PARac1 provide spatiotemporal control over free tubulin levels. ROPY/PARac1-based optogenetic regulation of free tubulin levels allowed us to demonstrate that depletion of free tubulin prevents the formation of pioneer microtubules, while local upregulation of tubulin concentration allows localized microtubule extensions to support the lamellipodia.


Validity and Reliability of Kinematics Measured with PUSH Band vs. Linear Encoder in Bench Press and Push-Ups.
The aim of this study was to compare the validity and reliability of a PUSH band device with a linear encoder to measure movement velocity with different loads during the push-up and bench press exercises. Twenty resistance-trained athletes performed push-up and bench press exercises with four different loads: without weight vest, 10-20-30 kg weight vest, bench press: 50-82% of their assumed 1 repetition maximum (1 RM) in steps of 10 kg. A linear encoder (Musclelab) and the PUSH band measured mean and peak velocity during both exercises. Several statistical analyses were used to investigate the validity and reliability of the PUSH band with the linear encoder. The main findings of this study demonstrated only moderate associations between the PUSH band and linear encoder for mean velocity (r = 0.62, 0.70) and peak velocity (r = 0.46, 0.49) for both exercises. Furthermore, a good level of agreement (peak velocity: ICC = 0.60, 0.64; mean velocity: ICC = 0.77, 0.78) was observed between the two measurement devices. However, a significant bias was found with lower velocity values measured with the PUSH band in both exercises. In the push-up, both the linear encoder and PUSH band were deemed very reliable (ICC > 0.98; the coefficient of variation (CV): 5.9-7.3%). Bench press reliability decreased for the PUSH band (ICC < 0.95), and the coefficient of variance increased to (12.8-13.3%) for the velocity measures. Calculated 1 RM with the two devices was the same for the push-up, while in bench press the PUSH band under-estimated the 1 RM by 14 kg compared to the linear encoder. It was concluded that the PUSH band will show decreased reliability from velocity measures in a bench press exercise and underestimate load-velocity based 1 RM predictions. For training, the PUSH band can be used during push-ups, however caution is suggested when using the device for the purposes of feedback in bench press at increasing loads.


Novel protein-lipid composite nanoparticles with an inner aqueous compartment as delivery systems of hydrophilic nutraceutical compounds.
Food protein and lipid based nanoparticles have attracted recent interest as a means of delivering nutraceuticals. Nanoparticle encapsulation of nutraceuticals faces challenges to overcome for it to be readily applied in the food industry, such as low encapsulation efficiency for hydrophilic compounds and poor stability once in the gastrointestinal tract. This research introduces a new protein-lipid composite nanoparticle with a three-layered structure (a barley protein layer, α-tocopherol layer and phospholipid layer) and an inner aqueous compartment to load hydrophilic nutraceuticals. This delivery system showed efficient encapsulation of vitamin B12 (69%) and controlled release behavior in simulated gastrointestinal media. An in vitro cell evaluation demonstrated that nanoparticles could internalize into Caco-2 cells via energy-dependent endocytosis and significantly increase the uptake and transport efficiency of vitamin B12 in this model. In vivo, the developed vitamin B12 loaded nanoparticle showed increased serum vitamin B12 levels upon oral administration and reduced the methylmalonic acid level more efficiently than the free form in rats. A 14-day in vivo toxicity study showed no evidence of toxicity in rats implying the safety of the developed nanoparticles in long term use. Overall, the results of this study show the great potential of the developed nanoparticles in increasing the absorption of vitamin B12 upon oral administration.


Curcumin is an APE1 redox inhibitor and exhibits an antiviral activity against KSHV replication and pathogenesis.
Curcumin, a polyphenol, is the main bioactive compound in dietary spice turmeric curcuma longa. It possesses anti-inflammatory, anti-oxidant and anti-neoplastic properties and shows potentials in treating or preventing particular diseases such as oxidative and inflammatory conditions, metabolic syndrome, arthritis, anxiety, hyperlipidemia and cancers. The diverse range and potential health beneficial effects has generated enthusiasm leading to intensive investigation into the phytochemical. However, a concern has been also raised if curcumin has a promiscuous bioassay profile and is a Pan-Assay INterference compound (PAINS). Here we present evidence indicating that curcumin is not a PAINS, but an inhibitor to APE1 redox function that affects many genes and pathways. This discovery explains the wide range of effects of curcumin on diverse human diseases and predicts a potential application in treatment of viral infection and virus-associated cancer. As a proof-of-concept, we demonstrated that curcumin is able to efficiently block Kaposi's sarcoma-associated herpesvirus replication and inhibit the pathogenic processes of angiogenesis and cell invasion.


Central and peripheral mechanisms contribute to the hypoglycemia induced by interleukin-1.
The impact that neuroendocrine effects of cytokines have on general host homeostasis is reflected by the profound metabolic changes observed in parallel. The effect of interleukin-1 beta (IL-1 beta) on glucose blood levels serves as an example. Although IL-1 beta stimulates glucocorticoid output and decreases hepatic glycogen content, hypoglycemia is concomitantly detected in adult and newborn mice. This effect is observed even during fasting and is probably due to increased glucose transport into tissues. Even after a glucose load, IL-1-treated animals remain hypoglycemic, suggesting that central mechanisms that control the set point of glucose homeostasis are affected. Low doses of IL-1 beta injected i.c.v. can also induce hypoglycemia. Furthermore, central blockade of IL-1 receptors partially inhibits the hypoglycemia induced by peripheral administration of IL-1 beta. On the other hand, central depletion of catecholamines exacerbates IL-1-induced hypoglycemia. IL-1-mediated effects on glucose levels might be directed at providing more energy supply to tissues during processes with high metabolic demands.


Murine cell surface glycoproteins. Identification, purification, and characterization of a major glycosylated component of 110,000 daltons by use of a monoclonal antibody.
A 110,000-dalton plasma membrane glycoprotein of mouse cells has been identified, purified, and characterized by use of a xenogeneic monoclonal antibody. The glycoprotein was a major component of the NIH/3T3 cell surface. It contained 15% of [3H]glucosamine incorporated into cell proteins and was composed of at least 16 isomorphic variants with apparent molecular weights from 100,000 to 120,000 and isoelectric points between 6.5 and 8.1. The glycoprotein constituted 0.1% of total cell protein, as measured by the yield of purified protein, and there were over 10(6) antibody-binding sites/cell. Immunoprecipitation from pulse-chase labeled cells showed that the 110,000-dalton glycoprotein was initially synthesized as a 92,000-dalton microsomal polypeptide which gradually was converted to the mature surface form. The turnover time of the surface form was at least 20 h. The antigenic determinant recognized by the monoclonal antibody was species-specific and nonpolymorphic. It was present in high concentration on most dividing murine cells in culture, whereas the concentration in normal mouse tissues differed widely. Among lymphoid tissues, antigen concentration was enriched in bone marrow as compared to spleen and thymus. Among nonlymphoid tissues, antigen concentration was 10-fold greater in kidney than in brain, liver, and skeletal muscle. The glycoprotein was purified without loss of antigenic activity by antibody affinity chromatography. The single step procedure yielded 3 mg of pure glycoprotein from 3 g of crude cell extract. The purification and characterization of this major membrane protein provide a basis for further study of its cell surface structure and function.


Effect of temperature on the degree of conversion and working time of dual-cured resin cements exposed to different curing conditions.
This study evaluated the degree of conversion (DC) and working time (WT) of two commercial, dual-cured resin cements polymerized at varying temperatures and under different curing-light accessible conditions, using Fourier transformed infrared analysis (FTIR). Calibra (Cal; Dentsply Caulk) and Variolink II (Ivoclar Vivadent) were tested at 25°C or preheated to 37°C or 50°C and applied to a similar-temperature surface of a horizontal attenuated-total-reflectance unit (ATR) attached to an infrared spectrometer. The products were polymerized using one of four conditions: direct light exposure only (600 mW/cm(2)) through a glass slide or through a 1.5- or 3.0-mm-thick ceramic disc (A2 shade, IPS e.max, Ivoclar Vivadent) or allowed to self-cure in the absence of light curing. FTIR spectra were recorded for 20 min (1 spectrum/s, 16 scans/spectrum, resolution 4 cm(-1)) immediately after application to the ATR. DC was calculated using standard techniques of observing changes in aliphatic-to-aromatic peak ratios precuring and 20-min postcuring as well as during each 1-second interval. Time-based monomer conversion analysis was used to determine WT at each temperature. DC and WT data (n=6) were analyzed by two-way analysis of variance and Tukey post hoc test (p=0.05). Higher temperatures increased DC regardless of curing mode and product. For Calibra, only the 3-mm-thick ceramic group showed lower DC than the other groups at 25°C (p=0.01830), while no significant difference was observed among groups at 37°C and 50°C. For Variolink, the 3-mm-thick ceramic group showed lower DC than the 1-mm-thick group only at 25°C, while the self-cure group showed lower DC than the others at all temperatures (p=0.00001). WT decreased with increasing temperature: at 37°C near 70% reduction and at 50°C near 90% for both products, with WT reduction reaching clinically inappropriate times in some cases (p=0.00001). Elevated temperature during polymerization of dual-cured cements increased DC. WT was reduced with elevated temperature, but the extent of reduction might not be clinically acceptable.


Fatty Acids in Some Cooking Oils as Agents of Hormonal Manipulation in a Rat Model of Benign Prostate Cancer.
Anti-androgenic substances, mainly prostate 5α-reductase inhibitors, used in the treatment of benign prostatic hyperplasia (BPH) have been associated with side effects in man and animals. To reduce these side effects as well as suppress BPH development, the management of the condition has come to include dietary interventions. This study investigated the effect of some cooking oils on testosterone-induced hyperplasia of the prostate in rats. Male Sprague-dawley rats were distributed into eighteen groups (n=6) as A-R. A negative control group was injected subcutaneously with soya oil; while prostatic hyperplasia was induced subcutaneously in groups B-R with 3mg/kg testosterone daily for 14days. Group B was the positive control (BPH group) while groups C-R were also administered orally 800mg/kg of coconut, castor, canola, cottonseed, pomegranate, blackseed, sheabutter, olive oil, codliver, sardine, palm, repeatedly heated palm (RHPO), vegetable, repeatedly-heated vegetable (RHVO), sesame, and groundnut oils respectively, daily, for 14 days. Blood sample was drawn via retro-orbital sinus for the estimation of serum testosterone(T) and dihydrotestosterone (DHT) level and rats were thereafter euthanized to obtain the prostates for T and DHT determination as well as tissue weights. Data are mean ± SEM, compared by ANOVA. The oils significantly reduced the increase in prostate weight (PW) to body weight (BW) ratio induced by testosterone. Apart from the fact that all the oils reduced the PW:BW ratio, the blackseed, sheabutter, sardine, vegetable and groundnut oils suppressed the DHT level in the serum, while pomegranate, olive, RHPO reduced DHT level in the prostate compared to the BPH rats. This study suggests that blackseed, sheabutter, sardine, vegetable, groundnut, pomegranate, olive, and RHPO oils could inhibit testosterone-induced hyperplasia of the prostate and therefore may be beneficial in the management of BPH.


Surgical Antibiotic Prophylaxis Administration Improved after introducing Dedicated Guidelines: A Before-and-After Study from Dhulikhel Hospital in Nepal (2019-2023).
(1) Background: Surgical antibiotic prophylaxis (SAP) is important for reducing surgical site infections. The development of a dedicated hospital SAP guideline in the Dhulikhel Hospital was a recommendation from a baseline study on SAP compliance. Compliance with this new guideline was enhanced through the establishment of a hospital committee, the establishment of an antibiotic stewardship program and the funding and training of healthcare professionals. Using the baseline and a follow-up study after introducing dedicated hospital SAP guidelines, we compared: (a) overall compliance with the SAP guidelines and (b) the proportion of eligible and non-eligible patients who received initial and redosing of SAP; (2) Methods: A before-and-after cohort study was conducted to compare SAP compliance between a baseline study (July 2019-December 2019) and a follow-up study (January 2023-April 2023); (3) Results: A total of 874 patients were in the baseline study and 751 in the follow-up study. Overall SAP compliance increased from 75% (baseline) to 85% in the follow-up study (p < 0.001). Over 90% of those eligible for the initial dose of SAP received it in both studies. Inappropriate use for those not eligible for an initial dose was reduced from 50% to 38% (p = 0.04). For those eligible for redosing, this increased from 14% to 22% but was not statistically significant (p = 0.272); (4) Conclusions: Although there is room for improvement, introduction of dedicated SAP guidelines was associated with improved overall SAP compliance. This study highlights the role of operational research in triggering favorable interventions in hospital clinical care.