Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP).
This report updates the 2001 recommendations by the Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza vaccine and antiviral agents (MMWR 2001;50 [No. RR-4]:1-44). The 2002 recommendations include new or updated information regarding 1) the timing of influenza vaccination by risk group; 2) influenza vaccine for children aged 6-23 months; 3) the 2002-2003 trivalent vaccine virus strains: A/Moscow/10/99 (H3N2)-like, A/New Caledonia/20/99 (H1N1)-like, and B/Hong Kong/330/2001-like strains; and 4) availability of certain influenza vaccine doses with reduced thimerosal content. A link to this report and other information related to influenza can be accessed at the website for the Influenza Branch, Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, CDC, at http://www.cdc.gov/ncidod/diseases/flu/fluvirus.htm.


Synthesis of a hexagonal nanosized macrocyclic fluorophore with integrated endotopic terpyridine metal-chelation sites.
A rigid nanosized hexagonal phenylethynyl cyclophane 5 has been prepared, which incorporates two 2,2':6',2"-terpyridines as integral structural units, for the purpose of binding metal ions. Macrocycle 5 was obtained by a 14-step synthesis in an overall yield of 11 %, and was characterised by spectroscopic techniques. The efficiency and ease of all transformations, and the relatively enhanced yield of the final macrocyclisation suggests that the entire synthetic pathway should be amenable to scale-up. Cyclophane 5 possesses four bulky triisopropylsilyl(TIPS)-protected ethyne substituents which serve a dual role. Firstly, they solubilise the structure thereby facilitating purification and subsequent handling. Secondly, they enable post-synthetic modification in which additional functionality may be attached to the periphery of the ring. Significantly, 5 was found to be a fluorescent chromophore, and may therefore potentially function as a new sensory platform for the detection of metal ions and H-bond donating biological substrates. The structurally well-defined nanosized morphology of 5, coupled with its interesting spectroscopic properties, supports the expectation that 5 and related architectures will attain a wealth of future applications within the developing fields of nanochemistry and nanoscience.


Synthesis and Characterization of Constrained Geometry Oxygen and Sulphur Functionalized Cyclopentadienylchromium Complexes and Their Use in Catalysis for Olefin Polymerization.
A series of constrained geometry O-functionalized cyclopentadienylchromium complexes (1-6) and a S-functionalized cyclopentadienylchromium complex (7) were first synthesized, characterized, and tested as catalyst precursors for the olefin polymerization. In the presence of MAO, the complexes exhibited high catalytic activity for the polymerization of ethylene. It is shown that ligand variations can have a substantial effect on catalyst activity and stability. The effect of Al/Cr ratio on catalytic activity was also studied.


Parametric and non-parametric masking of randomness in sequence alignments can be improved and leads to better resolved trees.
Methods of alignment masking, which refers to the technique of excluding alignment blocks prior to tree reconstructions, have been successful in improving the signal-to-noise ratio in sequence alignments. However, the lack of formally well defined methods to identify randomness in sequence alignments has prevented a routine application of alignment masking. In this study, we compared the effects on tree reconstructions of the most commonly used profiling method (GBLOCKS) which uses a predefined set of rules in combination with alignment masking, with a new profiling approach (ALISCORE) based on Monte Carlo resampling within a sliding window, using different data sets and alignment methods. While the GBLOCKS approach excludes variable sections above a certain threshold which choice is left arbitrary, the ALISCORE algorithm is free of a priori rating of parameter space and therefore more objective. ALISCORE was successfully extended to amino acids using a proportional model and empirical substitution matrices to score randomness in multiple sequence alignments. A complex bootstrap resampling leads to an even distribution of scores of randomly similar sequences to assess randomness of the observed sequence similarity. Testing performance on real data, both masking methods, GBLOCKS and ALISCORE, helped to improve tree resolution. The sliding window approach was less sensitive to different alignments of identical data sets and performed equally well on all data sets. Concurrently, ALISCORE is capable of dealing with different substitution patterns and heterogeneous base composition. ALISCORE and the most relaxed GBLOCKS gap parameter setting performed best on all data sets. Correspondingly, Neighbor-Net analyses showed the most decrease in conflict. Alignment masking improves signal-to-noise ratio in multiple sequence alignments prior to phylogenetic reconstruction. Given the robust performance of alignment profiling, alignment masking should routinely be used to improve tree reconstructions. Parametric methods of alignment profiling can be easily extended to more complex likelihood based models of sequence evolution which opens the possibility of further improvements.


A Novel Hyaluronic Acid Filling Technique for Restoring Volume of the Labia Majora.
Vulvar rejuvenation, which includes both functional and aesthetic aspects, has received a lot of attention in recent years. Despite the fact that surgical interventions have proven to be effective, the development of minimally invasive techniques for restoring volume and tissue function remains a top priority. This case study describes a novel method for vulvar volumization and collagen stimulation of the labia majora using a hyaluronic acid filling technique. The procedure begins with a meticulous assessment of each patient's anatomical characteristics and specific concerns, followed by hyaluronic acid retroinjections using a microcannula. The current article describes the use of this technique on a single patient and emphasizes its potential benefits in addressing various vulvar concerns, with a focus on minimal downtime and high patient satisfaction. The case report adds to the ongoing search for optimal vulvar rejuvenation strategies by providing valuable insights into the efficacy and utility of this novel approach.


Gallstone pancreatitis after laparoscopic cholecystectomy.
This case report describes the rare presentation of an unknown dumbbell shaped (or hourglass with diaphragmatic membrane) gallbladder presenting as gallstone pancreatitis 5 months after laparoscopic cholecystectomy for cholelithiasis and our management strategy. This case highlights the importance of ensuring adequate exposure at the time of operation to prevent such presentations.


An investigation into local government plans for public health emergencies in China.
A cross-sectional investigation was designed to assess the quality of local government plans for public health emergencies and to determine whether relevant regulations for emergency plans are in place. Sixty-six municipalities were selected randomly using stratified sampling, and a questionnaire investigation on emergency plans was conducted in these municipalities. The findings show that approximately 50% of emergency plans omitted important content; less than 50% of municipalities had established three regulations for emergency plans. Based on the analysis, the quality of existing public health emergency plans is not sufficient. More than 50% of municipalities lack regulations for emergency plans. Suggestions regarding the responsibility of government at different levels are made. First, central government should draw up a set of standard development procedures and a standard template for emergency plans. Secondly, local governments should revise their plans. Thirdly, local governments should establish regulations for emergency plans as soon as possible.


Interhemispheric memory transfer in the intracarotid amobarbital procedure.
The authors examined interhemispheric memory transfer in 32 patients with lateralized temporal lobe complex partial epilepsy (15 right onsets, 17 left onsets). Visually presented verbal, nonverbal, and two types of dually encodable stimuli were displayed during amobarbital anesthesia, and recognition memory was tested with verbal and nonverbal (pointing) response modalities. No relationship was found between the material specificity of stimuli and response modality. The only significant findings were for poorer recognition memory after injection of the hemisphere contralateral to the seizure focus. Visual information presented predominantly to one hemisphere during anesthesia is available to the other hemisphere for recognition memory on clearing.


Worker brain development and colony organization in ants: Does division of labor influence neuroplasticity?
Brain compartment size allometries may adaptively reflect cognitive needs associated with behavioral development and ecology. Ants provide an informative system to study the relationship of neural architecture and development because worker tasks and sensory inputs may change with age. Additionally, tasks may be divided among morphologically and behaviorally differentiated worker groups (subcastes), reducing repertoire size through specialization and aligning brain structure with task-specific cognitive requirements. We hypothesized that division of labor may decrease developmental neuroplasticity in workers due to the apparently limited behavioral flexibility associated with task specialization. To test this hypothesis, we compared macroscopic and cellular neuroanatomy in two ant sister clades with striking contrasts in worker morphological differentiation and colony-level social organization: Oecophylla smaragdina, a socially complex species with large colonies and behaviorally distinct dimorphic workers, and Formica subsericea, a socially basic species with small colonies containing monomorphic workers. We quantified volumes of functionally distinct brain compartments in newly eclosed and mature workers and measured the effects of visual experience on synaptic complex (microglomeruli) organization in the mushroom bodies-regions of higher-order sensory integration-to determine the extent of experience-dependent neuroplasticity. We demonstrate that, contrary to our hypothesis, O. smaragdina workers have significant age-related volume increases and synaptic reorganization in the mushroom bodies, whereas F. subsericea workers have reduced age-related neuroplasticity. We also found no visual experience-dependent synaptic reorganization in either species. Our findings thus suggest that changes in the mushroom body with age are associated with division of labor, and therefore social complexity, in ants. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 77: 1072-1085, 2017.


Experimental and DFT studies on competitive heterocyclic rearrangements. 3. A cascade isoxazole-1,2,4-oxadiazole-oxazole rearrangement.
The thermal rearrangements of 3-acylamino-5-methylisoxazoles 1 have been investigated under basic and neutral conditions and interpreted with the support of computational data. The density functional theory (DFT) study on the competitive routes available for the base-catalyzed thermal rearrangement of isoxazoles 1 showed that the Boulton-Katritzky (BK) rearrangement, producing the less stable 3-acetonyl-1,2,4-oxadiazoles 5, is a much more favored process than either the migration-nucleophilic attack-cyclization (MNAC) or the ring contraction-ring expansion (RCRE). In turn, an increase in reaction temperature will promote the MNAC of oxadiazoles 5, producing the more stable 2-acylaminooxazoles 8. The thermal rearrangement of 3-acylaminoisoxazoles 1 into oxazoles 8 can therefore be interpreted in terms of a cascade BK-MNAC rearrangement involving 3-acetonyl-1,2,4-oxadiazoles 5 as ancillary intermediates.


The ORION guidelines: raising research standards for the control of antimicrobial-resistant pathogens and healthcare-associated infection.
The ORION (Outbreak Reports and Intervention studies Of Nosocomial Infection) guidelines were recently published with the aim of raising methodological standards and the clarity of reporting of intervention studies in hospital infection control. The guidelines provide advice on use of appropriate statistical analysis techniques and the measures necessary to prevent bias, with the aim of ensuring complete transparency in reports of such interventions, their epidemiological context and potential confounders. CMI authors and reviewers should consider these helpful proposals when designing, reporting and assessing intervention and outbreak studies. Use of these guidelines should contribute to the construction of a solid evidence base for control of antimicrobial resistance and healthcare-associated infection.


Review: immunologic response to protease inhibitor-based highly active antiretroviral therapy: a review.
A substantial body of evidence indicates that CD4 cell count is an important independent prognostic indicator for progression of HIV disease. Consequently, in addition to plasma HIV RNA levels, CD4 cell count change is considered to be a key surrogate marker for disease progression in clinical practice and in clinical studies. Given the relationship between changes in CD4 count and disease progression, it is notable that protease inhibitor (PI)-based highly active antiretroviral therapy (HAART) can rapidly increase CD4 cell count early in treatment in both therapy-naïve and -experienced patients, and can sustain clinically relevant levels beyond 24 weeks. A number of trials with a follow-up of more than 3 years allow us to conclude that the gains in CD4 counts are maintained in a durable manner. This review evaluated randomized studies of PI-based and PI-boosted HAART (published between January 1996 and February 2006) to determine the effect of PI-based therapy on CD4 cell count. Only studies that assessed CD4 response in the overall patient population were included. Four mechanisms have been proposed to account for the rapid increase in CD4 cell count that occurs with HAART: CD4 cell redistribution from lymphatic tissues, increased CD4 cell production, reduction of apoptotic CD4 cells and the recovery of hematopoietic activity in bone marrow. Further research is required to clarify the relative importance of these mechanisms and ways in which they might be enhanced.


Early valve replacement in active infective endocarditis.
Infective endocarditis is associated with a high mortality, but previous studies have suggested that the major complications of the condition might be prevented by early surgery. Of 50 patients treated for infective endocarditis at the Montreal Heart Institute from 1977 to 1982, 30 were treated nonsurgically and the remaining 20 underwent early valve replacement before preoperative antibiotic therapy was completed. Of these 20, 14 had native valve endocarditis and 6 prosthetic valve endocarditis. The organisms involved were Streptococcus sp in 11, Staphylococcus aureus in 2, gram-negative organisms in 3 and Candida parapsilosis in 1. Blood cultures remained negative in three patients. There were three early deaths (15%) following operation and one late death (5%). Infection on implanted prostheses did not recur, but reoperation was required in one patient because of prosthetic dehiscence 7 months after initial implantation. All resected valves displayed evidence of infection. Follow-up was obtained in all survivors. After an average follow-up of 26 months, 12 patients remained in functional class I and 4 in class II (New York Heart Association classification). Early valve replacement has resulted in improved survival of patients with infective endocarditis and is now associated with a low operative mortality and morbidity.


PTH and PTHR1 in osteocytes. New insights into old partners.
Parathyroid hormone receptors are present in bone cells and play a crucial role in the maintenance of skeletal integrity, bone homeostasis and regulation of calcium and phosphate metabolism. Although the function of these receptors has long being recognized in the cells of the osteoblastic lineage regulating directly osteoblast differentiation and function and indirectly osteoclastogenesis, recent findings demonstrate their functional presence in osteocytes participating in the co-ordination of bone remodelling. In this review we focus on the key roles of these receptors in osteoblasts and osteocytes, combining what is known and what is new regarding these interesting pleiotropic hormone receptors.


Nonunion of a type II odontoid fracture after an apparent radiographic fusion: case report.
The type II odontoid fracture, initially described by Anderson and D'Alonzo, is the most common axis fracture. Several factors that predict the need for operative intervention have been discussed in the literature; however, the initial treatment remains somewhat controversial. We present the case of a 20-year-old woman who suffered a Type II odontoid fracture during a skiing accident. She was managed initially with halo-vest immobilization, and after 12 weeks, bony fusion was documented by plain spine radiographs and tomography. Routine follow-up cervical spine films at 8 months after her injury revealed no union at the previous fracture site and resultant atlantoaxial instability. A posterior C1-C2 fusion was therefore performed, leading to a long-term solid bony fusion. There are no previous reports in the literature describing a nonunion after radiographically documented healing of a Type II odontoid fracture. We present this case in order to emphasize the importance of scheduled follow-up examinations, including cervical spine films, for at least 12 months after a documented fusion. Further reports of similar cases may generate a more thorough understanding of the pathogenesis of delayed nonunion and may elicit factors that will predict its development.


Early Pars Plana Vitrectomy for Treatment of Acute Infective Endophthalmitis.
To evaluate the efficacy and safety of early pars plana vitrectomy (PPV) for the treatment of acute infective endophthalmitis, and identify prognostic factors for better visual outcome. Retrospective cohort study. Consecutive patients who underwent early PPV within 72 hours of presentation for the treatment of acute infective bacterial endophthalmitis and presented to a large tertiary referral center in New South Wales, Australia, between January 2009 and December 2013 were included. Changes in best-corrected visual acuity (VA) from baseline to 1 year were examined. A total of 64 patients were included. The inciting events were cataract surgery (53%), intravitreal injection (36%), trabeculectomy (3%), and endogenous (3%). The mean VA improved from 3.1 logMAR (hand motion) at baseline to 1.02 (approximately 20/200) at 1 year, with 42% achieving final VA equal to or better than 0.477 logMAR (20/60) following early PPV. Positive prognostic factors were negative microbial cultures (P < 0.01) and etiology of post-cataract surgery (P < 0.01). In multivariable analyses adjusting for age and prognostic factors, patients with baseline VA of light perception and hand motion achieved greater visual gains than those with counting fingers, with gains of logMAR of -2.68, -2.09, and -0.85, respectively (P < 0.0001). Most patients who undergo early PPV experience substantial VA improvement. Negative microbial cultures and endophthalmitis after cataract surgery were associated with better final visual outcome. Patients with presenting VA of light perception or hand motion achieved higher visual gains than those with counting fingers, suggesting the possibility that early PPV may be beneficial in both groups.


Effects of environmental complexity and deprivation on brain chemistry and physiology: a review.
Within the last two decades it has become evident that the brain exhibits a wide range of chemical and physiological responses to its sensory environment. Comparison of the brains of animals reared in relatively complex as opposed to deprived sensory environments has yielded significant insight into the nature of these effects, which are reviewed in this paper. Greater complexity of the sensory environment results in increased total cholinesterase and acetylcholinesterase enzyme activity, while other neurotransmitter related substances, the catecholamines, show more variable responses. RNA concentration is slightly greater as is DNA transcriptional activity, while protein precursor uptake shows a variety of regional and temporal patterns. In general, responses for most substances tend to show regional and temporal specificity with the largest effects most often in the occipital cortex. Electrophysiological measures have revealed shorter visual cortex evoked potential latencies and greater amounts of sleep in the complexity-reared subjects. The wide range of environmentally responsive parameters is consistent with an adaptive functioning of brain chemistry and physiology and with recent models in the physical sciences which view the universe as composed of dynamic webs of relationships rather than isolated independent units.


Epidemiological study of the lung function of workers at a factory manufacturing polyvinylchloride.
A preliminary epidemiological study has been carried out to investigate a report that some men working in a factory manufacturing polyvinylchloride (PVC) had abnormally low values of the single breath diffusing capacity for carbon monoxide (TLCO). All monoxide (TLCO). All 265 present and past employees of the PVC factory were studied, together with 219 men from the workforce of a nearby foundry. Each man's TLCO was measured and a smoking history and detailed occupational history obtained. The distribution of standardised TLCO results from all persons examined was symmetrical and did not indicate an unexpectedly high proportion of men with having allowed for age, height, weight, and smoking habit, TLCO was associated with a history of working in the PVC factory before 1975 (when levels of vinylchloride monomers (VCM) were much higher than subsequently), and slightly associated with working in jobs where exposure to VCM was likely to have been highest. The men with low TLCO also tended to have smoked more heavily than controls. The relative importance of occupational factors and smoking in relation to low TLCO is not clear, but the results give some support to the hypothesis that work in the PVC factory before 1975 entailed exposure to a substance that caused impairment of lung function in a small number of men.


Centers for Disease Control and Prevention guidelines for preventing central venous catheter-related infection: results of a knowledge test among 3405 European intensive care nurses.
To determine European intensive care unit (ICU) nurses' knowledge of guidelines for preventing central venous catheter-related infection from the Centers for Disease Control and Prevention. Multicountry survey (October 2006-March 2007). Twenty-two European countries. ICU nurses. Using a validated multiple-choice test, knowledge of ten recommendations for central venous catheter-related infection prevention was evaluated (one point per question) and assessed in relation to participants' gender, ICU experience, number of ICU beds, and acquisition of a specialized ICU qualification. We collected 3405 questionnaires (70.9% response rate); mean test score was 44.4%. Fifty-six percent knew that central venous catheters should be replaced on indication only, and 74% knew this also concerns replacement over a guidewire. Replacing pressure transducers and tubing every 4 days, and using coated devices in patients requiring a central venous catheter >5 days in settings with high infection rates only were recognized as recommended by 53% and 31%, respectively. Central venous catheters dressings in general are known to be changed on indication and at least once weekly by 43%, and 26% recognized that both polyurethane and gauze dressings are recommended. Only 14% checked 2% aqueous chlorhexidine as the recommended disinfection solution; 30% knew antibiotic ointments are not recommended because they trigger resistance. Replacing administration sets within 24 hrs after administering lipid emulsions was recognized as recommended by 90%, but only 26% knew sets should be replaced every 96 hrs when administering neither lipid emulsions nor blood products. Professional seniority and number of ICU beds showed to be independently associated with better test scores. Opportunities exist to optimize knowledge of central venous catheter-related infection prevention among European ICU nurses. We recommend including central venous catheter-related infection prevention guidelines in educational curricula and continuing refresher education programs.


Microsolvation effects on the excited-state dynamics of protonated tryptophan.
To better understand the complex photophysics of the amino acid tryptophan, which is widely used as a probe of protein structure and dynamics, we have measured electronic spectra of protonated, gas-phase tryptophan solvated with a controlled number of water molecules and cooled to approximately 10 K. We observe that, even at this temperature, the bare molecule exhibits a broad electronic spectrum, implying ultrafast, nonradiative decay of the excited state. Surprisingly, the addition of two water molecules sufficiently lengthens the excited-state lifetime that we obtain a fully vibrationally resolved electronic spectrum. Quantum chemical calculations at the RI-CC2/aug-cc-pVDZ level, together with TDDFT/pw based first-principles MD simulations of the excited-state dynamics, clearly demonstrate how interactions with water destabilize the photodissociative states and increase the excited-state lifetime.


The importance of colonoscopy bowel preparation for the detection of colorectal lesions and colorectal cancer prevention.
Background and study aims Colonoscopy for colorectal cancer (CRC) screening has reduced CRC incidence and mortality and improved prognosis. Optimal bowel preparation and high-quality endoscopic technique facilitate early CRC detection. This review provides a narrative on the clinical importance of bowel preparation for colonoscopy and highlights available bowel preparations. Methods A PubMed search was conducted through June 2019 to identify studies evaluating clinical outcomes, efficacy, safety, and tolerability associated with bowel preparation for CRC screening-related colonoscopy. Results Selecting the optimal bowel preparation regimen is based on considerations of efficacy, safety, and tolerability, in conjunction with individual patient characteristics and preferences. Available bowel preparations include high-volume (4 L) and low-volume (2 L and 1 L), polyethylene glycol (PEG) solutions, sodium sulfate, sodium picosulfate/magnesium oxide plus anhydrous citric acid, sodium phosphate tablets, and the over-the-counter preparations magnesium citrate and PEG-3350. These preparations may be administered as a single dose on the same day or evening before, or as two doses administered the same day or evening before/morning of colonoscopy. Ingesting at least half the bowel preparation on the day of colonoscopy (split-dosing) is associated with higher adequate bowel preparation quality versus evening-before dosing (odds ratio [OR], 2.5; 95 % confidence interval [CI], 1.9-3.4). Conclusions High-quality bowel preparation is integral for optimal CRC screening/surveillance by colonoscopy. Over the last 30 years, patients and providers have gained more options for bowel preparation, including low-volume agents with enhanced tolerability and cleansing quality that are equivalent to 4 L preparations. Split-dosing is preferred for achieving a high-quality preparation.


Brain Metabolism Changes in Patients Infected with HTLV-1.
The Human T-cell leukemia virus type-I (HTLV-1) is the causal agent of HTLV-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). HAM/TSP is the result of demyelination and cell death in the spinal cord and disruption of the blood-brain barrier (BBB), mediated by a virus-induced inflammatory response. In this study, we applied Positron Emission Tomography with 18F-fluordeoxyglucose (18F-FDG PET) to evaluate brain metabolism in a group of 47 patients infected with HTLV-1, and 18 healthy controls. Patients were divided into three groups according to their neurological symptoms. A machine learning (ML) based Gaussian Processes classification algorithm (GPC) was applied to classify between patient groups and controls and also to organize the three patient groups, based on gray and white matter brain metabolism. We found that GPC was able to differentiate the HAM/TSP group from controls with 85% accuracy (p = 0.003) and the asymptomatic seropositive patients from controls with 85.7% accuracy (p = 0.001). The weight map suggests diffuse cortical hypometabolism in both patient groups when compared to controls. We also found that the GPC could separate the asymptomatic HTLV-1 patients from the HAM/TSP patients, but with a lower accuracy (72.7%, p = 0.026). The weight map suggests a diffuse pattern of lower metabolism in the asymptomatic group when compared to the HAM/TSP group. These results are compatible with distinctive patterns of glucose uptake into the brain of HTLV-1 patients, including those without neurological symptoms, which differentiate them from controls. Furthermore, our results might unveil surprising aspects of the pathophysiology of HAM/TSP and related diseases, as well as new therapeutic strategies.


Hepatocytes contribute to residual glucose production in a mouse model for glycogen storage disease type Ia.
It is a long-standing enigma how glycogen storage disease (GSD) type I patients retain a limited capacity for endogenous glucose production despite the loss of glucose-6-phosphatase activity. Insight into the source of residual endogenous glucose production is of clinical importance given the risk of sudden death in these patients, but so far contradictory mechanisms have been proposed. We investigated glucose-6-phosphatase-independent endogenous glucose production in hepatocytes isolated from a liver-specific GSD Ia mouse model (L-G6pc-/- mice) and performed real-time analysis of hepatic glucose fluxes and glycogen metabolism in L-G6pc-/- mice using state-of-the-art stable isotope methodologies. Here we show that G6pc-deficient hepatocytes are capable of producing glucose. In vivo analysis of hepatic glucose metabolism revealed that the hepatic glucokinase flux was decreased by 95% in L-G6pc-/- mice. It also showed increased glycogen phosphorylase flux in L-G6pc-/- mice, which is coupled to the release of free glucose through glycogen debranching. Although the ex vivo activities of debranching enzyme and lysosomal acid maltase, two major hepatic α-glucosidases, were unaltered in L-G6pc-/- mice, pharmacological inhibition of α-glucosidase activity almost completely abolished residual glucose production by G6pc-deficient hepatocytes. Our data indicate that hepatocytes contribute to residual glucose production in GSD Ia. We show that α-glucosidase activity, i.e. glycogen debranching and/or lysosomal glycogen breakdown, contributes to residual glucose production by GSD Ia hepatocytes. A strong reduction in hepatic GCK flux in L-G6pc-/- mice furthermore limits the phosphorylation of free glucose synthesized by G6pc-deficient hepatocytes, allowing the release of glucose into the circulation. The almost complete abrogation of GCK flux in G6pc-deficient liver also explains the contradictory reports on residual glucose production in GSD Ia patients. (Hepatology 2017;66:2042-2054).


Short-term overfeeding increases resting energy expenditure in patients with HIV lipodystrophy.
HIV lipodystrophy and other lipodystrophy syndromes are characterized by extensive loss of subcutaneous adipose tissue. Lipodystrophy syndromes are also associated with increased resting energy expenditure (REE). This hypermetabolism may be an adaptive response to an inability to store triacylglycerol fuel in a normal manner. This study was done to determine whether REE increases significantly after short-term overfeeding in patients with HIV lipodystrophy. REE was measured in HIV-infected patients with lipodystrophy (n = 9) and in HIV-infected (n = 10) and healthy (n = 9) controls after 3 d on a eucaloric diet and again after 3 d on a diet of similar composition but increased in calories by 50%. After 3 d of eucaloric feeding, REE was significantly higher in patients with HIV lipodystrophy [33.2 +/- 0.27 kcal/kg lean body mass (LBM)] than for both HIV-infected and healthy controls (29.9 +/- 0.26 and 29.6 +/- 0.27 kcal/kg LBM, respectively; P < 0.01). Furthermore, after 3 d of overfeeding, REE increased significantly in patients with HIV lipodystrophy but not in the control groups (33.2 +/- 0.27 vs 34.7 +/- 0.27 kcal/kg LBM; P < 0.01). Finally, postprandial thermogenesis did not differ among the groups after a "normal" test meal but tended to be higher in patients with HIV lipodystrophy than in healthy controls after a large test meal. Adaptive thermogenesis in the resting component of total daily energy expenditure and in the postprandial period may be a feature of the HIV lipodystrophy syndrome and may be due to an inability to store triacylglycerol fuel in a normal manner.


Kallikrein concentrations in the plasma, lymph, thoracic, and cerebrospinal fluid of rabbits.
Since there is not an established method for selective assay of kallikrein, it is still unsettled whether kallikrein is absorbed from the intestine or not. Kallikrein was injected into the duodenum of rabbits which had been fasted for 24 hr and the concentrations of the drug in the plasma, lymph and cerebrospinal fluid were determined by an enzymatic method using substrate TAME or Peptide-MCA (hereafter, briefly as TAME method or Peptide-MCA method). An unknown substance, which splits the substrate TAME, appeared in the plasma, lymph and cerebrospinal fluid after injection of kallikrein into the rabbit duodenum. In rabbits which underwent pancreatectomy, kallikrein was not absorbed from the intestine and the unknown substance was not detected in any of the plasma, lymph and cerebrospinal fluid.


Airways obstruction from asbestos exposure. Effects of asbestosis and smoking.
To define the apparent steps in developing airways obstruction vs restrictive lung disease in men exposed to asbestos for more than 20 years who had never smoked vs cigarette smokers. Physiologic signs of asbestosis were studied in cross-sectional age-matched groups of never, current, and ex-cigarette smoking workers. The study included 8,720 asbestos-exposed construction and shipyard workers in the United States. FVC, FEV1, FEF25-75, and FEF75-85 were measured by spirometry and total lung capacity (TLC) by planimetry of standard chest radiographs and adjusted for height, age, and duration of cigarette smoking and expressed as percentage of predicted. TLC minus FVC yielded RV. We compared means and mean residuals (measurement minus group mean) expiratory flows and lung volumes in 1,146 men with pulmonary asbestosis age matched to 1,146 without asbestosis who had similar durations of asbestos exposure and to 370 men without asbestos exposure. Next, flows and volumes were regressed against the International Labour Office (ILO) profusion scale of irregular opacities on chest radiographs (PIO) and the duration of asbestos exposure for 1,777 never smokers (NS), 4,550 current smokers, and 2,393 ex-smokers. Asbestos exposure in NS men decreased expiratory flows and increased TLCs compared with unexposed NS men. Further reductions in flows and FVC and increases RV/TLC with radiographic asbestosis were not statistically significant. As the PIO increased from 1/1 to 3/3, obstruction and air trapping increased significantly but TLC did not. Asbestos exposure reduced flows and produced air trapping after 20 years in workers who never smoked. Smoking increased these abnormalities.


Doxazosin gastrointestinal therapeutic system: a review of its use in benign prostatic hyperplasia.
Doxazosin, a well established treatment in patients with bothersome lower urinary tract symptoms from benign prostatic hyperplasia (BPH), is available in a new controlled-release formulation, doxazosin gastrointestinal therapeutic system (GITS). Doxazosin GITS (Cardura XL, Cardular PP Uro, Diblocin PP Uro) has an altered pharmacokinetic profile, which allows a higher initial dosage to be used than with the standard formulation and less titration steps to reach a clinically effective dosage. In two large, double-blind, randomised studies (one was placebo-controlled) in patients with BPH, doxazosin GITS (4-8 mg once daily) was as effective as the standard formulation (2-8 mg once daily), and both were more effective than placebo, after 13 weeks' treatment in improving symptom scores, health-related quality of life (HR-QOL), and maximum urinary flow rate (Qmax). Doxazosin GITS was at least as well tolerated as the standard formulation of doxazosin in clinical studies in patients with BPH.


Photochemical generation and reversible cycloaromatization of a nine-membered ring cyclic enediyne.
Irradiation of the nine-membered ring enediyne precursor, which has one of its triple bonds masked as cyclopropenone, efficiently (Phi = 0.34) generates the reactive 4,5-benzocyclonona-2,6-diynol. The latter rapidly equilibrates with the corresponding 1,4-didehydronaphthalene diradical and then undergoes rate-limiting hydrogen abstraction to produce the ultimate product of the Bergman cyclization, benz[f]indanol.


Endogenous assessment of chronic myocardial infarction with T(1ρ)-mapping in patients.
Detection of cardiac fibrosis based on endogenous magnetic resonance (MR) characteristics of the myocardium would yield a measurement that can provide quantitative information, is independent of contrast agent concentration, renal function and timing. In ex vivo myocardial infarction (MI) tissue, it has been shown that a significantly higher T(1ρ) is found in the MI region, and studies in animal models of chronic MI showed the first in vivo evidence for the ability to detect myocardial fibrosis with native T(1ρ)-mapping. In this study we aimed to translate and validate T(1ρ)-mapping for endogenous detection of chronic MI in patients. We first performed a study in a porcine animal model of chronic MI to validate the implementation of T(1ρ)-mapping on a clinical cardiovascular MR scanner and studied the correlation with histology. Subsequently a clinical protocol was developed, to assess the feasibility of scar tissue detection with native T(1ρ)-mapping in patients (n = 21) with chronic MI, and correlated with gold standard late gadolinium enhancement (LGE) CMR. Four T1ρ-weighted images were acquired using a spin-lock preparation pulse with varying duration (0, 13, 27, 45 ms) and an amplitude of 750 Hz, and a T(1ρ)-map was calculated. The resulting T(1ρ)-maps and LGE images were scored qualitatively for the presence and extent of myocardial scarring using the 17-segment AHA model. In the animal model (n = 9) a significantly higher T(1ρ) relaxation time was found in the infarct region (61 ± 11 ms), compared to healthy remote myocardium (36 ± 4 ms) . In patients a higher T(1ρ) relaxation time (79 ± 11 ms) was found in the infarct region than in remote myocardium (54 ± 6 ms). Overlap in the scoring of scar tissue on LGE images and T(1ρ)-maps was 74%. We have shown the feasibility of native T(1ρ)-mapping for detection of infarct area in patients with a chronic myocardial infarction. In the near future, improvements on the T(1ρ)-mapping sequence could provide a higher sensitivity and specificity. This endogenous method could be an alternative for LGE imaging, and provide additional quantitative information on myocardial tissue characteristics.


Dopaminergic medication reduces striatal sensitivity to negative outcomes in Parkinson's disease.
Reduced levels of dopamine in Parkinson's disease contribute to changes in learning, resulting from the loss of midbrain neurons that transmit a dopaminergic teaching signal to the striatum. Dopamine medication used by patients with Parkinson's disease has previously been linked to behavioural changes during learning as well as to adjustments in value-based decision-making after learning. To date, however, little is known about the specific relationship between dopaminergic medication-driven differences during learning and subsequent changes in approach/avoidance tendencies in individual patients. Twenty-four Parkinson's disease patients ON and OFF dopaminergic medication and 24 healthy controls subjects underwent functional MRI while performing a probabilistic reinforcement learning experiment. During learning, dopaminergic medication reduced an overemphasis on negative outcomes. Medication reduced negative (but not positive) outcome learning rates, while concurrent striatal blood oxygen level-dependent responses showed reduced prediction error sensitivity. Medication-induced shifts in negative learning rates were predictive of changes in approach/avoidance choice patterns after learning, and these changes were accompanied by systematic striatal blood oxygen level-dependent response alterations. These findings elucidate the role of dopamine-driven learning differences in Parkinson's disease, and show how these changes during learning impact subsequent value-based decision-making.


Examining the influence of working memory on updating mental models.
The ability to accurately build and update mental representations of our environment depends on our ability to integrate information over a variety of time scales and detect changes in the regularity of events. As such, the cognitive mechanisms that support model building and updating are likely to interact with those involved in working memory (WM). To examine this, we performed three experiments that manipulated WM demands concurrently with the need to attend to regularities in other stimulus properties (i.e., location and shape). That is, participants completed a prediction task while simultaneously performing an n-back WM task with either no load or a moderate load. The distribution of target locations (Experiment 1) or shapes (Experiments 2 and 3) included some level of probabilistic regularity, which, unbeknown to participants, changed abruptly within each block. Moderate WM load hampered the ability to benefit from target regularities and to adapt to changes in those regularities (i.e., the prediction task). This was most pronounced when both prediction and WM requirements shared the same target feature. Our results show that representational updating depends on free WM resources in a domain-specific fashion.


Microfluidic device as a new platform for immunofluorescent detection of viruses.
A bead-based microfluidic device was developed and demonstrated to achieve rapid and sensitive enzyme-linked immunosorbent assay (ELISA) with quantum dots as the labeling fluorophore for virus detection. In comparison to standard ELISA performed on the same virus, the minimal detectable concentration of the target virus was improved from 360 to 22 ng mL-1, the detection time was shortened from >3.25 h to <30 min, and the amount of antibody consumed was reduced by a factor of 14.3.


Being disconnected from life: meanings of existential loneliness as narrated by frail older people.
This study illuminated the meanings of existential loneliness (EL) as narrated by frail older people. Data were collected through individual narrative interviews with 23 people 76-101 years old receiving long-term care and services. A phenomenological hermeneutical analysis was performed, including a naïve reading and two structural analyses as a basis for a comprehensive understanding of EL. Four themes were identified related to meanings of EL: (1) being trapped in a frail and deteriorating body; (2) being met with indifference; (3) having nobody to share life with; and (4) lacking purpose and meaning. These intertwined themes were synthesized into a comprehensive understanding of EL as 'being disconnected from life'. Illness and physical limitation affects access to the world. When being met with indifference and being unable to share one's thoughts and experiences of life with others, a sense of worthlessness is reinforced, triggering an experience of meaninglessness and EL, i.e. disconnection from life. It is urgent to develop support strategies that can be used by health care professionals to address older people in vulnerable situations, thereby facilitating connectedness.


Light microscopic, ultrastructural, and immunohistochemical examinations of two calcifying epithelial odontogenic tumors (CEOT) in a dog and a cat.
Two calcifying epithelial odontogenic tumors from a 10-year-old cross-breed dog and a 9-year-old cat were characterized histologically and electron microscopically. Important characteristics were plexiform to squamous epithelial structure, amyloid in the tumor tissue with partial calcification (Liesegang's rings), and a low rate of mitosis. The amyloid found in the tumors was subjected to immunohistochemical examination, using a series of antibodies (anti-AA, -AL, -AF, -ASc1, -AB, -cytokeratin, -vimentin, -desmin, -laminin). The exclusive reaction to anti-cytokeratin and anti-laminin suggests that the amyloid is of epithelial origin.


Next-generation metabolomics in lung cancer diagnosis, treatment and precision medicine: mini review.
Lung cancer is the leading cause of cancer-related death. Next-generation metabolomics is becoming a powerful emerging technology for studying the systems biology and chemistry of health and disease. This mini review summarized the main platforms of next-generation metabolomics and its main applications in lung cancer including early diagnosis, pathogenesis, classifications and precision medicine. The period covers between 2009 and August, 2017. The major issues and future directions of metabolomics in lung cancer research and clinical applications were also discussed.


Gene-disease association with human IFNL locus polymorphisms extends beyond hepatitis C virus infections.
Interferon (IFN) lambda (IFN-λ or type III IFN) gene polymorphisms were discovered in the year 2009 to have a strong association with spontaneous and treatment-induced clearance of hepatitis C virus (HCV) infection in human hosts. This landmark discovery also brought renewed interest in type III IFN biology. After more than half a decade since this discovery, we now have reports that show that genetic association of IFNL gene polymorphisms in humans is not limited only to HCV infections but extends beyond, to include varied diseases such as non-alcoholic fatty liver disease, allergy and several other viral diseases including that caused by the human immunodeficiency virus. Notably, all these conditions have strong involvement of host innate immune responses. After the discovery of a deletion polymorphism that leads to the expression of a functional IFN-λ4 as the prime 'functional' variant, the relevance of other polymorphisms regulating the expression of IFN-λ3 is in doubt. Herein, I seek to critically address these issues and review the current literature to provide a framework to help further understanding of IFN-λ biology.


Effects Of Interferon Therapy On Heart.
Hepatitis C virus (HCV) infection is a major health problem worldwide. Around 185 million people are suffering from HCV infection all over the world, out of which 10 million people are residing in Pakistan. 4.7% (2-14% by different studies) of Pakistanis are suffering from this deadly disease. Interferon+Ribavarin IFN/RIB is the mainstay of treatment for this infection. Various cardiovascular adverse reactions have been reported of this therapy. We conducted this study at Punjab Institute of cardiology to look for the cardiac safety of interferon therapy in our population. We studied HCV infected patients planned for interferon therapy between 21st of November 2012 to 20th of August 2014. Echocardiography was performed before, during and after the completion of therapy. Pegylated interferon once a week plus ribavirin therapy was given to the patients. Patients received 16-40 injections of pegylated interferon depending upon the decision of hepatologist. Patients with prior structural heart disease, patients who did not start the treatment or patients who did not turn up on follow up were excluded from the study. A total of 102 patients planned to have interferon therapy were screened echocardiographically. One patient died after 5 injections due to infection (a non-cardiac cause). 46 patients completed the treatment and the follow up. None of the patients had any acute cardiac event. All patients had normal biventricular systolic function at the end of study. None of the patients had significant valvular heart disease or pulmonary hypertension. Reversal of E/A ratio or E/A ratio>2, parameters of diastolic dysfunction and mild pericardial effusion were noted in a statistically significant number of patients. Interferon therapy for HCV infection is cardiac safe in patients who have structurally normal heart. Female patients have propensity of adverse events like severe diastolic dysfunction and mild pericardial effusion. The safety of drug in patients already having cardiac ailment needs to be studied. Moreover HCV infection itself is not injurious to the heart.


Sensorimotor neurotoxicity associated with high-dose deferoxamine treatment.
We report a reversible sensorimotor neurotixicity that developed in two beta-thalassemic patients treated with high-dose deferoxamine (DFO) for iron overload. Two patients were treated with high-dose (120 mg/kg/day) intravenous DFO for iron overload. Sensorimotor toxicity developed after 5 and 6 months of treatment, respectively. The development of the neurotoxicity did not correlate with the serum ferritin or the ratio of DFO dose to serum ferritin. Symptoms resolved in both patients with discontinuation of DFO treatment. In 1 patient, symptoms recurred with resumption of DFO treatment. These cases demonstrate that a reversible sensorimotor neurotoxicity, a previously unreported toxicity, may complicate DFO therapy, this complements the previously reported auditory and visual neurotoxicity associated with DFO therapy. Discontinuation of therapy at the time of onset of neurotoxicity is recommended, with possible resumption at lower doses.


Performance of the piezoelectric microbalance respirable aerosol sensor.
A battery-portable respirable aerosol sensor has been experimentally evaluated. Calibration procedures are described. For instruments calibrated with welding smoke, test results show agreement within +/- 15% of parallel filter samples for 10 laboratory and industrial aerosols including welding and tobacco smoke, oil mist, cotton and asbestos mill dusts, powdered metal and walnut shell dusts, and atmospheric urban aerosol in the 0.05-5.5 mg/m3 range. Results show that an average of several piezobalance measurements can accurately simulate a time-integrated filter sample in many industrial environments.


Reaction-Cattaneo systems with fluctuating relaxation time.
A reaction-Cattaneo equation with fluctuating relaxation time of the diffusive flux has been explored. It has been shown that depending on the strength of fluctuations, the dynamical system exhibits new oscillatory solutions as a result of Hopf and double Hopf bifurcations leading to spatiotemporal patterns. This analysis has been applied to two model nonlinear systems.


Different manifestations of Class II Division 2 incisor retroclination: a morphologic study.
The aims of this study were to investigate whether there is a different transverse morphologic pattern of dental arches among patients with different manifestations of Class II Division 2 incisor retroclination and to evaluate to what extent the pattern of smaller-than-average teeth in Class II Division 2 malocclusion is common to all groups studied. This information might clarify whether different Class II Division 2 phenotypes represent a single etiology or multiple etiologies. The sample comprised 108 subjects with Class II Division 2 malocclusions, divided into 2 groups according to the type of incisor retroclination: group I included 43 Class II Division 2 subjects with retroclination exclusively of the maxillary central incisors, and group II included 65 Class II Division 2 subjects with retroclination of the 4 maxillary incisors. Maxillary and mandibular intercanine and intermolar widths as well as mesiodistal crown dimensions of the 4 maxillary and mandibular incisors were determined from the patients' initial study models. Mean values of all variables were compared between the 2 groups by sex with analysis of variance. From the comparison between these 2 groups, no statistically significant differences were found for all transverse measurements (P >0.05). For all mesiodistal measurements analyzed, statistically significant differences between the groups were only found for the mean value of both maxillary lateral incisors' mesiodistal dimensions in both sexes (P <0.05). It is not possible to attribute a characteristic pattern of dental arch-width and incisor mesiodistal dimensions to the different manifestations of incisor retroclination in Class II Division 2 malocclusion.


Research on the speed thresholds of trucks in a sharp turn based on dynamic rollover risk levels.
Truck rollover is a problem that seriously endangers the safety of human life. Under special conditions, when the driver takes a sharp turn, the truck is most prone to rollover. Speed seriously affects the driving stability of the truck in a sharp turn, but the calculation of the safe speed is not accurate enough at present. The aim of this paper is to develop a more accurate safe speed calculation method to avoid the truck rollover in a sharp turn. Firstly, the calculation formula of the rollover threshold was derived based on a theoretical model, then, the simulation tests were carried out. We selected a 4-axle truck with a total weight of 30t as the subject, simulated the dynamic process of the truck rollover in a sharp turn with TruckSim, evaluated the dynamic rollover risk levels of the truck during this process, and verified the accuracy of the simulation results by results of the theoretical model. Finally, by analyzing the steering principle of the vehicle, the safe speed threshold and the limit speed threshold of the truck in a sharp turn were calculated according to the lateral acceleration corresponding to the rollover risk levels. The results show that no matter what the loading condition of the truck is, when the rollover margin is reduced to about 0.15g, the truck just reaches the risk level of critical rollover; the result provides an accurate algorithm for speed thresholds of the truck when turning radius is less than 250 m. The research provides a calculation method for safe speed of trucks from a dynamic perspective. The research results can be applied to the speed warning system of trucks, which can make drivers better control the rollover risk of trucks in the process of driving and improve driving safety.


Leishmania donovani targets tumor necrosis factor receptor-associated factor (TRAF) 3 for impairing TLR4-mediated host response.
Intramacrophage pathogen Leishmania donovani escapes host immune response by subverting Toll-like receptor (TLR) signaling, which is critically regulated by protein ubiquitination. In the present study, we identified tumor necrosis factor receptor-associated factor (TRAF) 3, degradative ubiquitination of which is essential for TLR4 activation, as a target for Leishmania to deactivate LPS-mediated TLR4 signaling. We used LPS-treated RAW 264.7 cells and compared the TLR4-mediated immune response in these cells with L. donovani and L. donovani + LPS costimulated macrophages. TRAF3, which was ubiquitinated (2.1-fold over control) at lys 48 position and subsequently degraded following LPS treatment, persisted in L. donovani and L. donovani + LPS costimulated cells due to defective lys 48 ubiquitination. Lys 63-linked ubiquitination of upstream proteins in the cascade (cIAP1/2 and TRAF6), mandatory for TRAF3 degradation, was also reduced postinfection. This may be attributed to reduced association between ubiquitin-conjugating enzyme Ubc13 and TRAF6 during infection. Inhibition of TRAF3 before infection by shRNA in Balb/c mice showed enhanced IL-12 and TNF-α (10.8- and 8.1-fold over infected control) and decreased spleen parasite burden (61.3% suppression, P<0.001), thereby marking reduction in disease progression. Our findings identified TRAF3 as a novel molecular regulator exploited by Leishmania for successful infection.


Endoscopic intranasal reduction of the orbit in isolated blowout fractures.
Endoscopic intranasal reduction of the orbital floor with a detachable temporary balloon, or of the medial orbital wall with a silastic sheet and Merocel packing, provided good functional results and definite advantages. We suggest that these techniques are another surgical alternative for isolated orbital floor or medial wall blowout fractures that do not accompany any associated fractures of the orbital rim. Extended applications of endoscopic sinus surgery have reported endoscopic intranasal reduction or reconstruction of the orbital wall with good functional and cosmetic results. We present our experience with endoscopic intranasal reduction of the orbit in isolated orbital floor and/or medial wall blowout fractures, treated by reduction of the orbital floor with a detachable temporary balloon, or of the medial orbital wall with a silastic sheet and Merocel packing. Floor reduction: After creating a wide middle meatal antrostomy, herniated orbital contents and fracture-displaced floor are mobilized and reduced. The orbital floor is supported by a saline filled balloon, which is connected with an infant feeding catheter and passed through the middle meatal antrostoma. After confirming the reduction of the orbital floor by postoperative CT, the catheter is ligated and cut in short to keep it in the nasal cavity. Medial wall reduction: After completing an intranasal ethmoidectomy, herniated orbital contents and fractured lamina papyracea are mobilized and reduced. The shape of the medial orbital wall is fixed by a silastic sheet and Merocel packing saturated with an antibiotic solution. Surgery was performed when the eye function could be accurately assessed, usually at 7 to 10 days following the injury. Temporary supporting of the orbital wall with a detachable temporary balloon, or a silastic sheet and Merocel packing was removed 4 weeks after surgery in the out-patient clinic. We have experienced 40 cases of endoscopic intranasal reduction of the orbit in blowout fractures. CT scan confirmed isolated orbital floor fracture in 11 patients, isolated medial wall fracture in 17 patients, and combined fractures of the orbital floor and the medial wall in 12 patients. Twenty five patients had diplopia, 20 patients had limitation of eye movement, and 14 patients developed enophthalmos. Thirty three of the 40 patients recovered completely without any residual eye symptoms or complications.


A model averaging approach for estimating propensity scores by optimizing balance.
Many approaches, including traditional parametric modeling and machine learning techniques, have been proposed to estimate propensity scores. This paper describes a new model averaging approach to propensity score estimation in which parametric and nonparametric estimates are combined to achieve covariate balance. Simulation studies are conducted across different scenarios varying in the degree of interactions and nonlinearities in the treatment model. The results show that, based on inverse probability weighting, the proposed propensity score estimator produces less bias and smaller standard errors than existing approaches. They also show that a model averaging approach with the objective of minimizing the average Kolmogorov-Smirnov statistic leads to the best performing IPW estimator. The proposed approach is also applied to a real data set in evaluating the causal effect of formula or mixed feeding versus exclusive breastfeeding on a child's body mass index Z-score at age 4. The data analysis shows that formula or mixed feeding is more likely to lead to obesity at age 4, compared to exclusive breastfeeding.


Inhibition of substance P-mediated responses in NG108-15 cells by netupitant and palonosetron exhibit synergistic effects.
Netupitant is a potent and selective NK(1) receptor antagonist under development in combination with a fixed dose of palonosetron for the prevention of chemotherapy induced nausea and vomiting. Palonosetron is a 5-HT(3) receptor antagonist approved for both the prevention of acute and delayed chemotherapy induced nausea and vomiting after moderately emetogenic chemotherapy. Accumulating evidence suggests that substance P (SP), a ligand acting largely on tachykinin (NK(1)) receptors, is the dominant mediator of delayed emesis. Interestingly, palonosetron does not bind to the NK(1) receptor so that the mechanism behind palonosetron's unique efficacy against delayed emesis is not clear. Palonosetron exhibits a distinct ability among 5-HT(3) receptor antagonists to inhibit crosstalk between NK(1) and 5-HT(3) receptor signaling pathways. The objective of the current work was to determine if palonosetron's ability to inhibit receptor signaling crosstalk would influence netupitant's inhibition of the SP-mediated response when the two drugs are dosed together. We first studied the inhibition of SP-induced Ca(2+) mobilization in NG108-15 cells by palonosetron, ondansetron and granisetron. Unexpectedly, in the absence of serotonin, palonosetron inhibited the SP-mediated dose response 15-fold; ondansetron and granisetron had no effect. Netupitant also dose-dependently inhibited the SP response as expected from an NK1 receptor antagonist. Importantly, when both palonosetron and netupitant were present, they exhibited an enhanced inhibition of the SP response compared to either of the two antagonists alone. The results further confirm palonosetron's unique pharmacology among 5-HT(3) receptor antagonists and suggest that it can enhance the prevention of delayed emesis provided by NK(1) receptor antagonists.


Serological survey of Rickettsia japonica infection in dogs and cats in Japan.
Antibodies against Rickettsia japonica in 20 of 1,207 dogs and 5 of 584 cats in Japan were detected using immunofluorescence. Some antibody-positive animals were detected in Niigata and Kagawa Prefectures, areas in which Japanese spotted fever in human patients has never been identified. Some animals were positive for antibodies against other new Rickettsia species.


Successful treatment of a case with pancreatic neuroendocrine carcinoma with focal hepatoid differentiation: a case report and literature review.
A 33-year-old Chinese woman was admitted to our hospital because of an elevated serum alpha-fetoprotein (AFP) level (300 ng/mL) found in a regular medical checkup. Computed tomography imaging of the abdomen revealed a 1.6 × 2.2 cm low-attenuation mass in the head of the pancreas, with no enlarged lymph nodes and no metastatic liver nodules, and a pancreaticoduodenectomy was performed and the tumor was completely removed. The tumor was solid, unencapsulated and poorly demarcated, measuring 2 × 1.4 × 1.8 cm, and the cut surface was grey-yellowish. Histologically, most of the areas of the tumor were composed of small monotonous and round shaped neuroendocrine cells, and approximately 20% of the areas were cells with indistinct cytoplasmic borders, large oval nuclei, prominent nucleoli and abundant eosinophilic cytoplasm, resembling the appearance of HCC. Immunohistochemical stains revealed that the neuroendocrine areas were diffusely positive for chromogranin, and the hepatoid areas showed diffuse and strong positive reaction to AFP. After surgery the AFP level reduced to normal. She received six cycles of postoperative chemotherapy and three years after the surgery was found to have an elevated serum AFP level again which gave rise to the suspicion of tumor recurrence, and a positron emission tomography-computed tomography confirmed the speculation by showing a hypermetabolic lymph node behind the body of the pancreas. She then underwent radiotherapy and the AFP level reduced to normal. Up till now she has survived 46 months since the initial diagnosis. This case and previous cases suggest that the serum AFP could be a useful marker for early detection of the disease, but careful differential diagnosis should be performed, and AFP could also be a marker for evaluation of therapeutic response and recurrence of the AFP-producing hepatoid carcinomas of pancreas.


Width of sulcus and thickness of gyrus in patients with cerebral atherosclerosis: a new tool for the prevention of vascular cognitive impairment.
Cerebral atherosclerosis is the main cause of lesions that contribute to vascular cognitive impairment and vascular dementia, followed by arteriosclerosis of small vessels and cerebral amyloid angiopathy. The purpose of this study was to compare the post-mortem radiological alterations of autopsied adults with the macroscopic alterations in the posterior region of these brains in order to establish a relationship between the two forms of analysis and to discuss the relevance of the prevention of vascular cognitive impairment in patients with encephalic atherosclerosis. Thirteen brains were analysed macroscopically to assess the degree of atherosclerosis of the basilar and the posterior cerebral arteries. The patients were autopsied in the Subject of General Pathology at General Hospital of Triângulo Mineiro Federal University in Uberaba, state of Minas Gerais, Brazil. The qualitative analysis of atherosclerosis was performed with classification into mild, moderate or severe. In the posterior region of the brains, width of sulcus and thickness of gyrus were measured by macroscopic analysis and by tomographic analysis. There was a decrease in calcarine sulcus width and an increase in medial temporal occipital gyrus thickness in patients with a higher degree of atherosclerosis, macroscopically and in tomography, respectively. Low oxygenation caused by atherosclerosis probably leads to an encephalic parenchyma inflammation that causes microglial cells hypertrophy provoking increase in the gyrus thickness and decrease in the sulcus width, as observed in the present study.


How Can Gastric Cancer Molecular Profiling Guide Future Therapies?
Gastric cancer is the third greatest global cause of cancer-related deaths. Despite its high prevalence, only recently have comprehensive genomic surveys shed light on its molecular alterations. As surgery is the only curative treatment strategy and chemotherapy has shown limited efficacy, new treatments are urgently needed. Many molecular therapies for gastric cancer have entered clinical trials but-apart from Trastuzumab and Ramucirumab-all have failed. We analyze the current knowledge of the genetic 'landscape' of gastric cancers, elaborating on novel, preclinical approaches. We posit that this knowledge lays the basis for identifying bona fide molecular targets and developing solid therapeutic approaches, requiring accurate patient selection and taking advantage of preclinical models to assist clinical development of novel combination strategies.


Barriers to spirometry in Australian general practice: A systematic review.
The reasons for the underutilisation of spirometry are unclear. We undertook a systematic review assessing barriers to correct spirometry in Australian general practice. PRISMA guidelines were followed. Six databases (MEDLINE, EMBASE, CINAHL, Scopus, PubMed, Google Scholar) were searched using terms 'primary health care', 'family physicians', 'family practice', 'general practice', 'primary care', 'Australia' and 'spirometry'. The 11 included studies reported multiple barriers to the use of spirometry in Australian general practice. Barriers for clinicians included spirometry having limited clinical utility in general practice (six studies), a reported low confidence with spirometry (six studies) and demonstrated poor spirometry interpretation skills (two studies). Practice-related barriers were time (six studies), cost (four studies), lack of trained staff (four studies), poor availability (four studies) and poor technique/calibration (two studies). Patient reluctance to attend for spirometry (four studies) was also reported as a barrier. To reduce barriers to correct spirometry, its perceived low clinical utility and patient reluctance require remediation. Issues of cost, confidence and competence might be addressed by reimbursement settings and ongoing training.


Fraught with the utmost danger: the object relations of mothers who kill their children.
The author explores the psychodynamics of maternal filicide from an object relations perspective. Among psychotic women, the murder of the child reflects a critical interplay among the mother's neurobiology, constitution, developmental experiences, and complex internal object world. Two types of personality structure are discussed. For the disorganized type, the psychodynamic scenario involves attempts to contend with the danger of massive internal breakdown. For the organized type, the scenario involves attempts to contend with the danger of persecution and annihilation. For these women, physical violence is used because of failures in mentalization, and is an enactment of catastrophic internal anxieties.


[Short-term effectiveness of arthroscopic single-bundle reconstruction of anterior cruciate ligament being centered within native ligament's tibial and femoral insertions].
To evaluate the short-term effectiveness of arthroscopic single-bundle reconstruction of anterior cruciate ligament (ACL) being centered within the native ligament's tibial and femoral insertions with independent drilling of tibial and femoral tunnels. Between September 2008 and September 2010, 33 patients with chronic ACL ruptures underwent arthroscopic reconstruction with four-stranded hamstring tendons in single-bundle. There were 19 males and 14 females, aged 22-33 years (mean, 26.4 years). Injuries were caused by traffic accident in 15 cases, by falling in 13 cases, and by sports in 5 cases. The location was the left knee in 20 cases and the right knee in 13 cases. The average time from injury to surgery was 6 months (range, 2-20 months). ACL reconstruction could be optimized when single-bundle grafts were centered within the native ligament's tibial and femoral insertions with independent drilling of tibial and femoral tunnels. KT-1000 test, Lachman test, and pivot-shift test were used to evaluate the knee stability, and the International Knee Documentation Committee (IKDC) and Lysholm scores to assess the knee function. Primary healing of incision was obtained in all patients, who had no complications of intra-articular infection, deep venous thrombosis of the lower extremity, and injury of blood vessels and nerves. All the patients were followed up 18.6 months on average (range, 13-24 months). At 1 year after operation, the results of Lachman test were negative in 31 cases and I degree positive in 2 cases, showing significant difference when compared with preoperative results (I degree positive in 4, II degree positive in 26, and III degree positive in 3) (Z = -5.42, P = 0.00). The results of pivot-shift test were negative in 31 cases, I degree positive in 2 cases, showing significant difference when compared with preoperative results (I degree positive in 15 and II degree positive in 18) (Z = -5.17, P = 0.00). The KT-1000 results of examination (134 N) showed that the side difference of anterior laxity was (1.2 +/- 0.7) mm at 25 degrees flexion and (0.8 +/- 0.6) mm at 70 degrees flexion, showing significant differences when compared with preoperative ones [(7.8 +/- 2.1) mm and (5.0 +/- 1.8) mm] (t = 16.19, P = 0.00; t = 13.28, P = 0.00). The IKDC score was significantly increased from 39.6 +/- 4.5 at preoperation to 95.1 +/- 1.6 at postoperation (t = - 78.88, P = 0.00), and Lysholm score was significantly increased from 48.3 +/- 3.6 at preoperation to 92.0 +/- 2.5 at postoperation (t = -42.00, P = 0.00). It is a reliable procedure to restore the stability of the knee that arthroscopic single-bundle reconstruction of ACL is centered within the native ligament's tibial and femoral insertions with independent drilling of tibial and femoral tunnels.


Crosstalk between NRF2 and HIPK2 shapes cytoprotective responses.
Homeodomain interacting protein kinase-2 (HIPK2) is a member of the HIPK family of stress-responsive kinases that modulates cell growth, apoptosis, proliferation and development. HIPK2 has several well-characterised tumour suppressor roles, but recent studies suggest it can also contribute to tumour progression, although the underlying mechanisms are unknown. Herein, we have identified novel crosstalk between HIPK2 and the cytoprotective transcription factor NRF2. We show that HIPK2 is a direct transcriptional target of NRF2, identifying a functional NRF2 binding site in the HIPK2 gene locus and demonstrating for the first time a transcriptional mode of regulation for this kinase. In addition, HIPK2 is required for robust NRF2 responsiveness in cells and in vivo. By using both gain-of-function and loss-of-function approaches, we demonstrate that HIPK2 can elicit a cytoprotective response in cancer cells via NRF2. Our results have uncovered a new downstream effector of HIPK2, NRF2, which is frequently activated in human tumours correlating with chemoresistance and poor prognosis. Furthermore, our results suggest that modulation of either HIPK2 levels or activity could be exploited to impair NRF2-mediated signalling in cancer cells, and thus sensitise them to chemotherapeutic drugs.


Effect of Piper chaba Hunter, Piper sarmentosum Roxb. and Piper interruptum Opiz. on natural killer cell activity and lymphocyte proliferation.
Immune system is the most important system ofhuman body. Thaifolk doctors have used some medicinal plants as an adaptogenic drug or immunomodulatory agent. Piper chaba Hunter, Piper sarmentosum Roxb. and Piper interruptum Opiz. are used by folk doctors to activate immune response in cancer patients. To investigate the effect on natural killer cell activity and on lymphocyte proliferation activity of water extract of P chaba Hunter P. sarmentosum Roxb. and P interruptum Opiz. MATERIAL ANDMETHOD: Plant materials were extracted by decoction method. All extracts were testedfor an immunomodulatory effect using PBMCs from twelve healthy donors by chromium release assay. Lymphocyte proliferation was also determined by 3H-thymidine uptake assay. The degree of activation was expressed as the stimulation index. The water extract of P chaba Hunter significantly increased lymphocyte proliferation at concentrations ofl ng/ml, 10 ng/ml, 1 μg/ml, 5 μg/ml, 10 μg/ml and 100 μg/ml. P sarmentosum Roxb., and P interruptum Opiz. extracts at those concentrations significantly stimulated lymphocyteproliferation. P sarmentosum Roxb. extractsignificantly increased natural killer (NK) cell activity at a concentration of 100 μg/ml but P chaba Hunter and P interruptum Opiz. extracts did not significantly stimulate natural killer cell activity. P chaba Hunter, P interruptum Opiz. andP sarmentosum Roxb. have an immunomodulatory effect especially for P sarmentosum Roxb. extract which can activate both lymphocyte proliferation and NK cell activity.


Myelophil ameliorates brain oxidative stress in mice subjected to restraint stress.
We evaluated the pharmacological effects of Myelophil, a 30% ethanol extract of a mix of Astragali Radix and Salviae Radix, on oxidative stress-induced brain damage in mice caused by restraint stress. C57BL/6 male mice (eight weeks old) underwent daily oral administration of distilled water, Myelophil (25, 50, or 100mg/kg), or ascorbic acid (100mg/kg) 1h before induction of restraint stress, which involved 3h of immobilization per day for 21days. Nitric oxide levels, lipid peroxidation, activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione redox system enzymes), and concentrations of adrenaline, corticosterone, and interferon-γ, were measured in brain tissues and/or sera. Restraint stress-induced increases in nitric oxide levels (serum and brain tissues) and lipid peroxidation (brain tissues) were significantly attenuated by Myelophil treatment. Restraint stress moderately lowered total antioxidant capacity, catalase activity, glutathione content, and the activities of glutathione reductase, glutathione peroxidase, and glutathione S-transferase; all these responses were reversed by Myelophil. Myelophil significantly attenuated the elevated serum concentrations of adrenaline and corticosterone and restored serum and brain interferon-γ levels. Moreover, Myelophil normalized expression of the genes encoding monoamine oxidase A, catechol-O-methyltransferase, and phenylethanolamine N-methyltransferase, which was up-regulated by restraint stress in brain tissues. These results suggest that Myelophil has pharmacological properties protects brain tissues against stress-associated oxidative stress damage, perhaps in part through regulation of stress hormones.


Regulation of Smad activities.
TGF-beta (Transforming Growth Factor-beta) cytokines employ Smad proteins as the intracellular mediator of signaling. Upon TGF-beta stimulation, the cytoplasmic Smads become phosphorylated and consequently accumulate in the nucleus to regulate target gene expression. The cytoplasm-to-nucleus redistribution of Smads, as well as the ability of Smads to activate or repress gene transcription, is under multiple layers of regulation by factors not limited to TGF-beta. With recent advance in the knowledge of regulatory factors impinged on Smads, we are beginning to understand the complexity in cellular responses to TGF-beta.


Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M.
The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo.


CC genotype at rs12979860 of IL28B is associated with lower risk of new-onset diabetes after transplantation in adult patients with liver transplantation for hepatitis C cirrhosis.
New-onset diabetes mellitus after transplantation (NODAT) in patients undergoing liver transplantation (LT) for hepatitis C virus (HCV)-related cirrhosis is associated with more aggressive HCV recurrence on the graft, rapid progression of fibrosis, and lower rate of sustained viral response to antiviral therapy. The CC genotype at rs12979860 of the IL28B is associated with greater rates of spontaneous clearance of HCV and response to antiviral therapy. IL28B acts on the interferon-stimulated genes through the JAK-STAT pathway, which is related to the development of insulin resistance. The aim of this study was to investigate whether IL28B rs12979860 polymorphism is associated with the development of NODAT after LT for cirrhosis owing to HCV infection. We analyzed 99 patients (age, 52.7 ± 9.4 years; 70% male) who underwent LT for HCV-related cirrhosis, with ≥1 year of follow-up and with available DNA sample. NODAT was defined starting from the sixth month after LT, according to the international consensus guidelines. Genotyping was carried out by real-time polymerase chain reaction and analysis of the melting temperature with the LightCycler 480 system. Twenty-eight patients (28.3%) developed NODAT. CC genotype at rs12979860 of IL28B was associated with a lesser incidence of NODAT versus non-CC genotypes (P = .05; odds ratio, 0.31; 95% CI, 0.11-0.92). We did not find any association between NODAT and age at transplantation, gender, pretransplant body mass index, presence of hepatocellular carcinoma, type of initial immunosuppression (cyclosporine, tacrolimus or corticosteroids) or acute rejection treated with steroids. The CC genotype at rs12979860 of IL28B is a protective factor for NODAT in patients with LT for HCV-related cirrhosis.


Pharmacokinetics and echocardiographic effects of digoxin in low birth weight infants with left-to-right shunting due to patent ductus arteriosus.
Serum digoxin (DIG) levels, timed urine and M-mode echocardiograms were performed in 9 low birth weight infants with left-to-right shunting due to patent ductus arteriosus treated with DIG (40 micrograms/kg in 3 and 20 micrograms/kg in 6). Half the DIG was given initially and a quarter at 8-hourly intervals. Serum DIG levels at 24 h (1.8-7.0 ng/ml) were similar in both dose groups. One infant in the 40 micrograms/kg dose group developed Wenckebach phenomenon. Left atrial to aortic root ratio fell within 30 min and remained reduced during the ensuing 24 h (p less than 0.025). There were no significant changes in the other echocardiographic measurements. Half-life of distribution and elimination of DIG were 1.04 +/- 0.46 and 15.25 +/- 0.36 h. The alpha-phase volumes of distribution (VD) differed between the 40 and 20 micrograms/kg dose groups (2.28 +/- 0.05 vs. 1.33 +/- 0.66 liters/kg, p less than 0.025). The beta-phase VD (4.25 +/- 0.61 and 2.76 +/- 0.99, respectively) were similar. Mean urinary DIG clearance was 13.1 +/- 3.2 ml/min/1.73(2).


Proximate Composition, Amino Acid Profile, and Oxidative Stability of Slow-Growing Indigenous Chickens Compared with Commercial Broiler Chickens.
The increased demand for chicken meat products has led to chickens with increased growth rates and heavier slaughter weights. This has had unintentional negative effects on the genetics of these animals, such as spontaneous, idiopathic muscle abnormalities. There has also been a shift in customer preference towards products from alternative farming systems such as organic and free-range. Indigenous purebred chickens, such as the Polverara, show potential in these systems as they are adapted to more extensive systems. The aim of the present study was to characterize the meat quality traits of the Polverara, by comparing the proximate composition and amino acid profile with that of a commercial Hybrid. In addition, the lipid and protein oxidation was analyzed after eight days of storage. A total of 120 leg meat samples, 60 Polverara and 60 Hybrid were analyzed. Polverara exhibited higher protein content, lower lipid content, and a better amino acid profile. These results indicate that the Polverara has better nutritional meat quality. However, Polverara also showed higher levels of lipid and protein oxidation. Therefore, further research is needed, especially in regards to the fatty acid profile and mineral content of the meat, which is known to affect oxidative stability.


Extracting protein regulatory networks with graphical models.
During the last decade the development of high-throughput biotechnologies has resulted in the production of exponentially expanding quantities of biological data, such as genomic and proteomic expression data. One fundamental problem in systems biology is to learn the architecture of biochemical pathways and regulatory networks in an inferential way from such postgenomic data. Along with the increasing amount of available data, a lot of novel statistical methods have been developed and proposed in the literature. This article gives a non-mathematical overview of three widely used reverse engineering methods, namely relevance networks, graphical Gaussian models, and Bayesian networks, whereby the focus is on their relative merits and shortcomings. In addition the reverse engineering results of these graphical methods on cytometric protein data from the RAF-signalling network are cross-compared via AUROC scatter plots.


Ordinal scaling of timbre-related spectral audio descriptors.
A psychophysical experiment was conducted to perceptually validate several spectral audio features through ordinal scaling: spectral centroid, spectral spread, spectral skewness, odd-to-even harmonic ratio, spectral slope, and harmonic spectral deviation. Several sets of stimuli per audio feature were synthesized at different fundamental frequencies and spectral centroids by controlling (wherever possible) each spectral feature independently of the others, thus isolating the effect that each feature had on the stimulus rankings within each sound set. Listeners were overall able to order stimuli varying along all the spectral features tested when presented with an appropriate spacing of feature values. For specific cases of stimuli in which the ordering task partially failed, psychophysical interpretations are provided to explain listeners' confusions. The results of the ordinal scaling experiment outline trajectories of spectral features that correspond to listeners' perceptions and suggest a number of sound synthesis parameters that could carry timbral contour information.


Informatics for mouse genetics and genome mapping.
Bioinformatics has become an essential part of biological research. The rapid pace of technology development and the ability to carry out biological experimentation in large scale require computerized systems for data management, analysis, and display. Experimentation with the mouse, a major model organism of the Human Genome Initiative, has intensified the need for bioinformatics tools for mouse mapping and genome analysis. This article describes the Mouse Genome Database in the United States, a primary resource for mouse genomic data, as well as resources at the Mammalian Genetics Unit in the United Kingdom and the Animal Genome Database of Japan. Internet addresses are provided for major genetic and physical mapping resources, major genome data sites, and resources of molecular information.


Comparative study of the developmental patterns of vasopressin, glucagon, angiotensin II, and alpha 1-adrenergic receptors in the liver of developing and adult hypothyroid rats.
The effects of propylthiouracil (PTU) treatment on vasopressin, angiotensin II, glucagon and alpha 1-adrenergic receptors in both developing and adult rats were studied in liver membrane preparations by measuring the binding of the following ligands: [3H][8-lysine]vasopressin, [3H]Sar-angiotensin II, [125I]glucagon and [3H]prazosin, and in the case of glucagon, by measuring adenylate cyclase activation. Whatever the ligand used, in young as well as in adult animals, PTU treatment led to a similar reduction (about 50%) in the maximal number of binding sites (Bmax), without significant changes in the apparent dissociation constant (KD) of labeled hormone for its specific receptor. In normal adult animals, thyroxine treatment, i.e. hyperthyroidism, had an opposite effect on the Bmax (25-50% increase), without changes in the KD. In developing PTU-treated rats, the abnormalities completely disappeared after therapy with increasing physiological doses of thyroxine; consequently they were directly related to thyroid deficiency and not to toxic effects of PTU. Moreover, the abnormalities resulting from induced hypothyroidism were reversible. In developing and adult hypothyroid rats, neither basal, NaF-, nor Gpp(NH)p-stimulated adenylate cyclase activities were significantly affected. Glucagon-sensitive adenylate cyclase activity seemed to be slightly increased (by about 15%), without changes in the apparent activation constant (Kact). These results are considered in parallel with findings on plasmatic glucagon and vasopressin levels, compared with similar previous reports related to renal vasopressin receptors, and discussed with respect to unpublished observations concerning hepatic responsiveness to glycogenolytic hormones in young and adult rats with induced hypothyroidism.


TSH secretory responses to prolonged infusion of TRH in hypothyroid rats.
Continuous infusion of 0.1-10 micrograms/ml of TRH was performed through chronic i.v. cannulas in unrestrained, unanesthetized hypothyroid rats. Infusion of a constant concentration of TRH induced a peak in the plasma TSH concentration within 5-15 min which declined to the baseline within 1 h. The refractory period lasted 20-40 min after stopping the continuous TRH infusion. A second burst of TSH secretion was induced by increasing the TRH concentration during the refractory period while TRH was being continuously infused. These data indicate that in hypothyroid rats TSH secretion rapidly becomes refractory to continuous exposure to the same concentration of TRH but is stimulated by a higher TRH concentration. This suggests there is heterogeneity in TSH secretory units, which may consist of a constellation of thyrotrophs or of discrete intracellular secretory units, each with a threshold of specific response to TRH.


A case of acute pancreatitis - does step-up protocol always indicated?
Acute pancreatitis (AP) is still one of the most frequent cause of hospitalization. Grading severity of AP due to revised Atlanta classification differentiate: mild, moderately severe and severe AP. Mortality ranges from occasional tomild,8% in moderate, 36%-59% in severe AP. 59-year-old man was hospitalized due to severe acute pancreatitis. Biliary duct obstruction was determined as a reason of AP and intensive treatment was started. The CT scan showed infected post-inflammatory pancreatic cyst. For this reason, endoscopic drainage of the pancreatic cyst to the stomach was performed first and then Jurasz operation. Severe postoperative course required treatment in the Intensive Care Unit (ICU). During the next hospitalization due to the patient's condition deterioration, endoscopic cyst drainage was performed again. Because of ineffectiveness of the performed treatment, the patient was reoperated. Post-operative multi-organ failure, lack of response to the intensive therapy and cachexia because of long-lasting illness, lead into patient's death. This case demonstrates problem with severe complications of AP which despite of multidisciplinary treatment combining endoscopy, surgery and pharmacology can finally lead to death.


Proteomics of traumatic brain injury and regeneration.
Despite the enormous medical and economic consequences of traumatic brain injury (TBI), little is known about the proteins involved in the resulting pathology. Major advances in the identification of such proteins have been made in recent years through application of differential proteome analysis. Such an approach has revealed a number of novel proteins as potential regulators of the degenerative and regenerative processes that take place in the mammalian brain after a traumatic insult. Some of these proteins may serve as diagnostic and prognostic markers to assess the severity of the brain damage. Comparative proteome analysis of brain systems differing in their intrinsic regenerative potential are likely to provide new insights into the cellular signals that could be targeted for therapeutic intervention to increase the repair capacity of the human brain.


Aortic rupture due to radiation injury successfully treated with thoracic endovascular aortic repair.
Thoracic endovascular aortic repair (TEVAR) has been reported to be an effective treatment option for aortic emergencies. However, there are few reports about TEVAR for aortic rupture due to radiation injury. A 54-year-old man presented with haemoptysis. He had a history of lung cancer, which had been treated with chemotherapy and radiation therapy (72 Gy/16 times) 3 years previously, and the cancer lesion did not progress. On chest radiography, pneumonia was suspected in the radiated lesion. However, after admission, he presented with back pain, progressive anaemia and hypotension. Enhanced computed tomography revealed extravasation of contrast medium in the distal aortic arch. He was diagnosed with aortic rupture due to radiation injury. TEVAR was performed. He was extubated one day after the operation, and the haemoptysis disappeared. He was discharged from the hospital without any complications. He is well 1 year after the surgery, without aortic disease progression or lung cancer recurrence.


Quantitative testing of liver function compared to prognostic scores in patients with primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a slowly progressive liver disease which can lead to cirrhosis. We investigated if quantitative tests of liver function (QTLF) and serum levels of a surrogate marker of hepatic fibrogenesis (PIIINP) provide information in addition to established prognostic scores. In 34 PBC patients PIIINP, PBC-relevant parameters, histological staging and QTLF at entry and at 2 years were determined and compared with the Christensen (CPS I, CPS II) and Mayo prognosis score. QTLF included aminopyrine breath test, galactose elimination capacity, sorbitol and indocyanine green clearance. Bilirubin, serum IgM and PIIINP were elevated at both time points, whereas albumin and prothrombin time remained normal. Clinical findings (ascites, cirrhosis, central cholestasis) and histological staging worsened after 2 years, as did the CPS II. However, QTLF, PIIINP, CPS I and the Mayo score revealed no significant changes. Only CPS II changed after 2 years, whereas CPS I and the Mayo score remained unaltered. QTLF and PIIINP did not provide any further information on progression of PBC, suggesting that QTLF cannot predict prognosis of PBC patients in a two-year interval and that CPS II is superior to CPS I and the Mayo score in short-term studies for PBC.


Strategies of collateral blood flow assessment in ischemic stroke: prediction of the follow-up infarct volume in conventional and dynamic CTA.
Collateral blood flow is an important prognostic marker in the acute stroke situation but approaches for assessment vary widely. Our aim was to compare strategies of collateral blood flow assessment in dynamic and conventional CTA in their ability to predict the follow-up infarction volume. We retrospectively included all patients with an M1 occlusion from an existing cohort of 1912 consecutive patients who underwent initial multimodal stroke CT and follow-up MR imaging or nonenhanced CT. Collateralization was assessed in both conventional CT angiography and dynamic CT angiography by using 3 different collateral grading scores and segmentation of the volume of hypoattenuation. Arterial, arteriovenous, and venous phases were reconstructed for dynamic CT angiography, and all collateral scores and the volume of hypoattenuation were individually assessed for all phases. Different grading systems were compared by using the Bayesian information criterion calculated for multivariate regression analyses (Bayesian information criterion difference = 2-6, "positive"; Bayesian information criterion difference = 6-10, "strong"; Bayesian information criterion difference = >10, "very strong"). One hundred thirty-six patients (mean age, 70.4 years; male sex, 41.2%) were included. In the multivariate analysis, models containing the volume of hypoattenuation showed a significantly better model fit than models containing any of the 3 collateral grading scores in conventional CT angiography (Bayesian information criterion difference = >10) and dynamic CT angiography (Bayesian information criterion difference = >10). All grading systems showed the best model fit in the arteriovenous phase. For the volume of hypoattenuation, model fit was significantly higher for models containing the volume of hypoattenuation as assessed in the arteriovenous phase of dynamic CT angiography compared with the venous phase (Bayesian information criterion difference = 6.2) and the arterial phase of dynamic CT angiography (Bayesian information criterion difference = >10) and in comparison with conventional CT angiography (Bayesian information criterion difference = >10). The use of dynamic CT angiography within the arteriovenous phase by using quantification of the volume of hypoattenuation is the superior technique for assessment of collateralization among the tested approaches.


Model free audit methodology for bias evaluation of tumour progression in oncology.
Many oncology studies incorporate a blinded independent central review (BICR) to make an assessment of the integrity of the primary endpoint, progression free survival. Recently, it has been suggested that, in order to assess the potential for bias amongst investigators, a BICR amongst only a sample of patients could be performed; if evidence of bias is detected, according to a predefined threshold, the BICR is then assessed in all patients, otherwise, it is concluded that the sample was sufficient to rule out meaningful levels of bias. In this paper, we present an approach that adapts a method originally created for defining futility bounds in group sequential designs. The hazard ratio ratio, the ratio of the hazard ratio (HR) for the treatment effect estimated from the BICR to the corresponding HR for the investigator assessments, is used as the metric to define bias. The approach is simple to implement and ensures a high probability that a substantial true bias will be detected. In the absence of bias, there is a high probability of accepting the accuracy of local evaluations based on the sample, in which case an expensive BICR of all patients is avoided. The properties of the approach are demonstrated by retrospective application to a completed Phase III trial in colorectal cancer. The same approach could easily be adapted for other disease settings, and for test statistics other than the hazard ratio.