[Innovative technologies in the complex treatment of patients with rheumatoid arthritis].
The treatment of rheumatoid arthritis (RA) remains a difficult task since the current therapy does not always result in the disease remission. The search for and development of new methods and principles for the complex therapy of RA have been underway. 144 RA patients aged 22 to 65, disease duration--72.4 +/- 7.3 months, have been investigated. A majority of them (62.3%) had stage 2 RA, and 77.4% had RA stages 2-3. The patients who were taking methotrixate for 5 years were found to respond better and longer to the traditional-therapy drugs versus drugs of other basic groups. An intensification of treatment (by methilprednizolone combined with cyclophosphamide) in a group of stage 1 RA patients) improperly responding to the therapy (resulted in a disease remission for as long as 2.5 months. An intensification of therapy in stage 2 RA (by cyclophosphamide, vincristin and prednizolone) entailed a 13.2-month remission in 23 patients. A big number of contraindications restrict the use of such intense therapy which should be replaced, in such cases, by anticytokine drugs. Remission and improvements were ensured after remicade in 4 and 2 of 7 RA patients respectively. DMARS provided a significantly lower RA intensity that lasted, however, only for 2 weeks, which necessitates further research related with higher drug's doses and with extending its effect. Stem-cells transplantations were used in RA, after which remission and improvements were observed in 80% of patients.


Do stigma, blame and stereotyping contribute to unsafe sexual behaviour? A test of claims about the spread of HIV/AIDS arising from social representation theory and the AIDS risk reduction model.
In the context of social representation theory and the AIDS risk reduction model, it has been claimed that stigmatizing, blaming and stereotyping attitudes make people feel less at risk of contracting HIV/AIDS, and that this, in turn, results in them taking fewer precautions in their sexual behaviour. Previous research has failed to provide convincing evidence to support these claims. The present study provided a test of the claims that addressed some of the methodological issues identified in the earlier research. A sample of 460 young people from Ghana, ranging in age from 15 to 28 years (mean=18), completed a questionnaire that measured the relevant constructs. The results supported the claims in relation to stigmatizing and intended sexual risk behaviour, but not stigmatizing and actual sexual risk behaviour. Although the latter two were correlated, this was not mediated by reduced perceptions of vulnerability. Claims in relation to blaming and stereotyping were not supported. Contrary to expectation, specific blaming and stereotyping attitudes that constructed HIV/AIDS as a sexual disease were associated with safer intended sexual behaviour, and this relationship was mediated by feeling at greater risk.


Heavy Drinking Habits Are Associated with Worse In-Hospital Outcomes in Patients with Acute Coronary Syndrome: An Insight from the AMIS Plus Registry.
The association between alcohol consumption and the occurrence of coronary heart disease is well described in the literature, while data regarding the impact of regular alcohol consumption on in-hospital outcomes in the setting of acute coronary syndrome (ACS) are lacking. We aimed to evaluate the impact of self-reported alcohol consumption on in-hospital outcomes in patients with ACS. Data derived from patients enrolled between 2007 and 2019 in the Acute Myocardial Infarction in Switzerland (AMIS) Plus registry were retrospectively analyzed. Patients were stratified based on alcohol drinking pattern. Primary outcome was all-cause in-hospital mortality, while secondary outcomes were set as incidence of major adverse cardiac and cerebrovascular events (MACCEs). Outcome comparisons according to quantity of daily alcohol intake were also performed. Records concerning alcohol consumption were available in 25,707 patients; 5,298 of them (21%) fulfilled the criteria of regular alcohol consumption. Regular drinkers were predominantly male, younger, smokers, more comorbid and with a worse clinical presentation as compared with abstainers/occasional drinkers. Daily alcohol intake was reported in 4,059 (77%) of these patients (regular drinkers). Among them, 2,640 were light drinkers (≤2 drinks/day) and 1,419 heavy drinkers (>2 drinks/day). In-hospital mortality and MACCEs of heavy drinkers were significantly higher compared with those of light drinkers (5.4 vs. 3.3% and 7.0 vs. 4.4%, both p = 0.001). When tested together with Global Registry of Acute Coronary Events risk score parameters, heavy alcohol consumption was independently associated with in-hospital mortality (p = 0.004). Our results support that heavy alcohol consumption is an independent predictor of in-hospital mortality in patients presenting with ACS.


Leishmaniasis in Saudi Arabia: Current situation and future perspectives.
Leishmaniasis is endemic in Saudi Arabia with cases reported in many regions. This review refers to publications on leishmaniasis in Saudi Arabia and discusses issues related to parasite species, clinical manifestation and diagnosis. This research was done at Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia by systematic literature search on PubMed and Google Scholar databases from 1989 to 2018. Selection criteria included original articles reporting on visceral leishmaniasis (VL) or cutaneous leishmaniasis (CL) in Saudi Arabia. The search identified 16 eligible articles, six for VL and 10 for CL. VL was reported in areas known to be non-endemic. Leishmania donovani was the main cause for human VL while Leishmania infantum seemed to cause the disease in animals. Dogs were considered the main reservoir hosts and black rats (Rattus rattus) were potential hosts. VL mainly affected infants and young children. It is important to note that VL diagnosis was based on either invasive parasite detection procedures or serologically using indirect hemagglutination test. CL represented the most frequent clinical form with the main endemic foci reported in the South-West and Eastern regions. CL appeared to have no demographic or socioeconomic restriction; it affected both rural and urban citizens, with the majority occurring among farmers. Travelling was recognized as an important risk factor. Leishmania tropica and Leishmania major were recognized as the main causes for CL. This report summarizes the potential risks for VL and CL in Saudi Arabia in areas known to be non-endemic. There are substantial gaps in knowledge and practices in regard to leishmaniasis in Saudi Arabia, highlighting the need for more research and medical surveillance targeting the disease in humans and animals.


Remote platelet function testing using P-selectin expression in patients with recent cerebral ischaemia on clopidogrel.
Antiplatelet agents reduce recurrence after cerebral ischaemia but are not effective in all patients, in part because of treatment resistance. The primary aim was to assess the proportion of patients who are insensitive to clopidogrel. The secondary aim was to assess the association between insensitivity to clopidogrel and recurrent cerebrovascular events. Following written informed consent, independent patients with a recent non-cardioembolic ischaemic stroke or transient ischaemic attack, and taking clopidogrel, were enrolled. Platelet function was assessed with remote measurement of surface expression of P-selectin (CD62P) using commercial kits sensitive to aspirin or clopidogrel. Participants' general practitioners provided details on recurrent vascular events at least 90 days later. Data are mean (SD) and median [IQR]. Resistance was defined as: aspirin median fluorescence (MF) >500 units, clopidogrel MF >860 units. Non-parametric descriptors and tests were used. 63 patients were recruited: mean age 64 (13.7) years, women 47%. At baseline, 59 (95%) patients were taking clopidogrel alone with 3 (5%) on combined clopidogrel and aspirin. Assessment of platelet surface P-selectin revealed: aspirin test 528 [317, 834], >500 54.8%; clopidogrel test 429 [303, 656], >860 11.3%. No participants on aspirin and clopidogrel showed aspirin resistance. Thirteen (20.6%) patients had a recurrent cerebrovascular event; those with an ischaemic stroke had a non-significantly higher baseline P-selectin using the clopidogrel test as compared with those with no recurrence: 626 [380, 801] versus 406 [265, 609], p=0.08. Remote measurement of platelet function assessed using the platelet surface expression of P-selectin is feasible. 11% of patients taking clopidogrel showed resistance. No significant associations were noted between clopidogrel resistance and recurrent ischaemic events.


Role of the beet western yellows virus readthrough protein in virus movement in Nicotiana clevelandii.
Luteoviruses such as beet western yellows polerovirus (BWYV) are confined to and multiply within the phloem compartment of their hosts. The readthrough domain (RTD) of the minor BWYV capsid protein P74 is required for efficient virus accumulation in Nicotiana clevelandii. Experiments were carried out to determine if the low virus titres observed following agro-inoculation of whole plants with certain RTD mutants are due to a defect in virus multiplication in the nucleate cells of the phloem compartment or to inefficient virus movement to new infection sites. Immuno-localization of wild-type and an RTD-null mutant virus in thin sections of petioles and in phloem cells of leaf lamina, as well as electron microscopy observations, were all consistent with the conclusion that the RTD is not essential for efficient virus multiplication in the nucleate phloem cells but intervenes in virus movement to increase the rate at which new infection foci are established and expand.


Total joint replacement for neglected posterior knee dislocation following septic arthritis after arthroscopy.
This report presents the first case of a knee dislocation following septic arthritis after arthroscopy. A 65-year-old woman had an arthroscopy with irrigation and debridement (I&D) of the joint and microfracture for the chondral lesions. She had complaints of postarthroscopic infection but non-steroidal anti-inflammatory medication and local ice compression was recommended. She revisited her physician twice and at the last visit she had a large purulent effusion in her knee. The gram stain of the joint fluid aspirate demonstrated gram-positive cocci and the cultures grew methicilline-sensitive Staphylococcus aureus. She underwent arthroscopic assisted I&D and received intravenous antibiotics. I&D was repeated after two weeks. Intravenous antibiotherapy was continued for one more week and was changed to oral antibiotherapy for six weeks. At the third month visit's physical examination, a deformity at the knee was noticed and was referred to us for further treatment. A posterior knee dislocation with no neurovascular deficit was detected. The patient had a history of knee sprain but did not seek medical advice immediately. The blood samples showed no abnormality. The patient underwent a surgery with a cemented hinged revision total knee prosthesis following the exclusion of the active knee joint infection. Intraoperative frozen sections were also taken to exclude the active infection. The patient's knee is pain-free with full range of motion after 3 years. The objective of this report was to highlight the importance of early diagnosis, prompt appropriate treatment of septic arthritis following arthroscopy and the awareness of the knee dislocation as a rare dreadful complication of postarthroscopic infection particularly in elderly patients.


Effect of weight cycling on susceptibility to dietary obesity.
Weight cycling, defined as repeated episodes of weight loss followed by weight regain, has been suggested to make rats more energy efficient and produce a state of energy balance favoring accumulation of excess body fat. In addition, weight cycling may favor accumulation of fat in central vs. peripheral adipose depots. In the present study, we gave two groups of female Wistar rats ad libitum access to an obesity-producing high-fat diet (60% of calories from fat). Both groups had previously eaten a low-fat stock diet, but one group had been subjected to three bouts of weight cycling. Rats that were previously weight cycled gained less body weight and body fat when given the high-fat diet than did controls. The lower rate of weight gain was due to a lesser increase in food intake, since daily energy expenditure was significantly lower in previously cycled rats than in controls. In summary, weight cycling does not appear to predispose rats to becoming obese on a high-calorie diet and apparently produces some effect on food intake that reduces, at least in the short run, weight gain on the high-calorie diet.


Polymorphisms of inflammation-related genes and colorectal cancer risk: a population-based case-control study in China.
The previous studies found that chronic inflammation related to an increased risk of colorectal cancer (CRC). This study aims to explore the associations of polymorphisms in inflammation-related genes (IL10, IL10RA, IL6R, TNFRSF1A, TNFRSF1B, LTA and IL4) and their interactions with the risk of colorectal cancer among Chinese population. A population-based case-control study including 299 cases and 296 controls was conducted from January 2001 to December 2009. Multivariate unconditional logistic regression was used to analyse the association of nine SNPs in inflammation-related genes with the risk of CRC, colon cancer and rectal cancer, respectively. Generalized multifactor dimensionality reduction (GMDR) was implemented to explore the gene-gene interactions among all SNPs on CRC. A decreased risk of colorectal cancer in subjects with rs1800872 AC genotype of IL10 (OR = 0.643, 95%CI = 0.453, 0.912) or AC/CC genotype (OR = 0.636, 95%CI = 0.457, 0.885) was observed, compared with those with AA genotype. Meanwhile, similar associations were observed between rs1800872 and rectal cancer. Additionally, in rs1061624 of TNFRSF1B gene, AG genotype (OR=0.566; 95% CI= 0.362, 0.885) and AG/GG genotype (OR=0.638; 95% CI=0.420, 0.971) were significantly associated with a decreased risk of rectal cancer, respectively. Our findings indicated that mutants in IL10 and TNFRSF1B genes may change the CRC risk. However, there is no interaction between inflammation-related genes on CRC risk.


Ethnicity as a predictor of detention under the Mental Health Act.
There has been major concern about the 'over-representation' of Black and ethnic minority groups amongst people detained under the Mental Health Act (MHA). We explored the effect of patient ethnicity on detention following an MHA assessment, once confounding variables were controlled for. Prospective data were collected for all MHA assessments over 4-month periods in the years 2008, 2009, 2010 and 2011 each in three regions in England: Birmingham, West London and Oxfordshire. Logistic regression modelling was conducted to predict the outcome of MHA assessments - either resulting in 'detention' or 'no detention'. Of the 4423 MHA assessments, 2841 (66%) resulted in a detention. A diagnosis of psychosis, the presence of risk, female gender, level of social support and London as the site of assessment predicted detention under the MHA. Ethnicity was not an independent predictor of detention. There is no evidence for that amongst those assessed under the MHA, ethnicity has an independent effect on the odds of being detained.


Radiological predictors of recurrent lumbar disc herniation: a systematic review and meta-analysis.
Lumbar discectomy for the management of lumbar radiculopathy is a commonly performed procedure with generally excellent patient outcomes. However, recurrent lumbar disc herniation (rLDH) remains one of the most common complications of the procedure, often necessitating repeat surgery. rLDH is known to be influenced by a variety of factors, and in this systematic review the authors aimed to explore the radiological predictors of recurrence. A systematic review and meta-analysis was conducted to identify studies analyzing radiological predictors of recurrent herniation, both ipsilateral and contralateral. A search was conducted on Medline and EMBASE. Both retrospective and prospective comparative studies were included, measuring radiological parameters of lumbar discectomy patients. All factors were considered irrespective of imaging modality, and a meta-analysis of the data was performed in which 5 or more studies were identified analyzing the same parameter. In total, 1626 reported studies were screened, with 23 being included in this review, of which 13 were appropriate for meta-analysis. Three factors, namely disc height index, Modic changes, and sagittal range of motion, were determined to be significantly correlated with an increased rate of rLDH. Some variables were considered in only 1 or 2 different studies, and the authors have included a narrative review of these novel findings. The findings of associations between the radiological parameters and rLDH implicates the role of instability in the development of recurrence. Understanding the physiological factors associated with instability is important, because although early degenerative disc changes may predispose patients to herniation recurrence, more advanced degeneration likely reduces segmental motion and concurrently risk of recurrence.


Synthetic strategies for aryl/heterocyclic selenides and tellurides under transition-metal-catalyst free conditions.
Aryl and heteroaryl selenides and tellurides are found to have broad applications in the diverse fields such as medicine, biology, materials science, pharmaceutical etc. and thus their synthesis remains a challenging field for synthetic chemists in last decade. Although a large no of methodologies have been developed based on metal catalyzed C-Se/Te coupling, a large number of researches has been focused on developing metal catalyst free protocols due to their sustainability in recent times. This review covers all the recent developments in last decade on their synthesis under metal catalyst free conditions by using different sustainable techniques e.g. greener reagents and solvents, ball milling, visible light photocatalysis, microwave, ultrasound etc.


Bioinspired RGD-Engineered Bacteriophage Nanofiber Cues against Oxidative Stress.
Instructive tissue engineering biomaterials provide a vascular niche and protect oxidative stress in injured tissue. In this study, we exploited bioinspired bacteriophage nanofibers, previously recognized by their biochemical and structural cues inducing angiogenesis, as an antioxidant tissue engineering material. We demonstrated that topological cues of Arg-Gly-Asp (RGD)-engineered bacteriophage nanofibers provide angiogenic niches and cytoprotective functions against cellular oxidative stress with increased expression of antioxidant enzymes heme oxygenase-1 (HO-1) and NAD(P)H-quinone oxidoreductase 1 (NQO1) via the extracellular-signal-regulated kinase (ERK)-nuclear factor erythroid 2-related factor2 (Nrf2)-mediated signaling pathway, where a high density of RGD cues on the phage body support efficient interaction of cells with phage cues. These bioinspired RGD-engineered bacteriophage nanofibers can serve as a novel therapeutic platform for curing ischemic diseases.


Early Cancer Detection in Blood Vessels Using Mobile Nanosensors.
In this paper, we propose using mobile nanosensors (MNSs) for early stage anomaly detection. For concreteness, we focus on the detection of cancer cells located in a particular region of a blood vessel. These cancer cells produce and emit special molecules, so-called biomarkers, which are symptomatic for the presence of anomaly, into the cardiovascular system. Detection of cancer biomarkers with conventional blood tests is difficult in the early stages of a cancer due to the very low concentration of the biomarkers in the samples taken. However, close to the cancer cells, the concentration of the cancer biomarkers is high. Hence, detection is possible if a sensor with the ability to detect these biomarkers is placed in the vicinity of the cancer cells. Therefore, in this paper, we study the use of MNSs that are injected at a suitable injection site and can move through the blood vessels of the cardiovascular system, which potentially contain cancer cells. These MNSs can be activated by the biomarkers close to the cancer cells, where the biomarker concentration is sufficiently high. Eventually, the MNSs are collected by a fusion center (FC), where their activation levels are read and exploited to declare the presence of anomaly. We analytically derive the biomarker concentration in a network of interconnected blood vessels as well as the probability mass function of the MNSs' activation levels and validate the obtained results via particle-based simulations. Then, we derive the optimal decision rule for the FC regarding the presence of anomaly assuming that the entire network is known at the FC. Finally, for the FC, we propose a simple sum detector that does not require knowledge of the network topology. Our simulations reveal that while the optimal detector achieves a higher performance than the sum detector, both proposed detectors significantly outperform a benchmark scheme that uses fixed nanosensors at the FC.


Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice.
Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a polyglutamine repeat within the disease protein, ataxin 1. To elucidate cellular pathways involved in SCA1, we used DNA microarrays to determine the pattern of gene expression in SCA1 transgenic mice at two specific times in the disease process; 5 weeks, a timepoint prior to onset of pathology, and 12 weeks, at the midpoint of the disease progression. Taking advantage of the availability of three SCA1 transgenic mouse lines, each expressing a different form of ataxin-1, we utilized a strategy that resulted in the identification of a limited number of genes with an altered pattern of expression specific to the development of disease. By comparing the pattern of gene expression in the SCA1 ataxic B05-ataxin-1[82Q] transgenic mouse line with those seen in two non-ataxic lines, A02-ataxin-1[30Q] and K772T-[82Q], nine genes were identified whose expression was consistently altered in the cerebellum of B05[82Q] mice at 5 and 12 weeks of age. Interestingly, five of the genes in this group form a biological cohort centered on glutamate signaling pathways in Purkinje cells.


Antibiotics in the treatment of chronic staphylococcal osteomyelitis.
Fourteen patients with chronic osteomyelitis were treated with oral penicillin, oxacillin, or cloxacillin at a dose of 5 gm/day, plus 0.5 gm of probenecid (Benemid) three or four times per day. Treatment was continued for 2 1/2 to six months. In ten patients, evidence of osteomyelitis disappeared and there has been no recurrence during follow-up periods varying from six months to 2 1/2 years. Significant hepatotoxicity was encountered in two patients; one similar patient, not in this series but receiving a similar regimen of antibiotic, developed leukipenia. Thus, patients with chronic osteomyelitis appear to benefit from such a therapeutic program, but they must be monitored closely for hepatic or hematologic toxicity.


Psoriasis image representation using patch-based dictionary learning for erythema severity scoring.
Psoriasis is a chronic skin disease which can be life-threatening. Accurate severity scoring helps dermatologists to decide on the treatment. In this paper, we present a semi-supervised computer-aided system for automatic erythema severity scoring in psoriasis images. Firstly, the unsupervised stage includes a novel image representation method. We construct a dictionary, which is then used in the sparse representation for local feature extraction. To acquire the final image representation vector, an aggregation method is exploited over the local features. Secondly, the supervised phase is where various multi-class machine learning (ML) classifiers are trained for erythema severity scoring. Finally, we compare the proposed system with two popular unsupervised feature extractor methods, namely: bag of visual words model (BoVWs) and AlexNet pretrained model. Root mean square error (RMSE) and F1 score are used as performance measures for the learned dictionaries and the trained ML models, respectively. A psoriasis image set consisting of 676 images, is used in this study. Experimental results demonstrate that the use of the proposed procedure can provide a setup where erythema scoring is accurate and consistent. Also, it is revealed that dictionaries with large number of atoms and small patch sizes yield the best representative erythema severity features. Further, random forest (RF) outperforms other classifiers with F1 score 0.71, followed by support vector machine (SVM) and boosting with 0.66 and 0.64 scores, respectively. Furthermore, the conducted comparative studies confirm the effectiveness of the proposed approach with improvement of 9% and 12% over BoVWs and AlexNet based features, respectively.


Research Directions in Genetic Predispositions to Stevens-Johnson Syndrome / Toxic Epidermal Necrolysis.
Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is one of the most devastating of adverse drug reactions (ADRs) and was, until recently, essentially unpredictable. With the discovery of several risk alleles for drug-induced SJS/TEN and the demonstration of effectiveness of screening in reducing incidence, the stage is set for implementation of preventive strategies in populations at risk. Yet much remains to be learned about this potentially fatal complication of commonly used drugs.


PHASES and ELAPSS Scores Are Associated with Aneurysm Growth: A Study of 431 Unruptured Intracranial Aneurysms.
Understanding risk factors for intracranial aneurysm growth is important for patient management. We performed a retrospective study examining risk factors for the growth of unruptured intracranial aneurysms followed at our institution, evaluating both traditional risk factors and the PHASES (Population, Hypertension, Age, Size, Earlier Subarachnoid Hemorrhage, Site) score. We retrospectively reviewed a consecutive series of unruptured intracranial aneurysms followed at our institution for a minimum of 6 months over a 15-year period. The primary outcome of this study was aneurysm growth, defined as a ≥1-mm increase in maximum diameter. Risk factors studied included PHASES score, ELAPSS (Earlier Subarachnoid Hemorrhage, Location of Aneurysm, Age, Population, Size, and Shape) score, demographics, multiple aneurysms, previous subarachnoid hemorrhage, family history of aneurysm or subarachnoid hemorrhage, smoking, hypertension, and aneurysm shape, size, and location. The χ2 test was used for comparison of categorical variables, and the Student t test was used for continuous variables. The study cohort comprised 352 patients with a total of 431 unruptured intracranial aneurysms. The mean duration of follow-up was 4.8 years, and there was a total of 2100 aneurysm-years of follow-up. Forty aneurysms (9.3%) grew, for an annualized growth rate of 2.0% of aneurysms/year. Current smoking status was the sole modifiable risk factor associated with growth (growth rate of 5.1%/year compared with 1.5%/year for never smokers; P = 0.0004). Increasing size (odds ratio [OR], 1.22; 95% confidence interval [CI], 1.11-1.33; P < 0.0001), ELAPSS score (OR, 1.10; 95% CI, 1.09-1.11; P < 0.0001), and PHASES score (OR, 1.24; 95% CI, 1.20-1.28; P < 0.0001) were associated with growth as well. Age, location, previous subarachnoid hemorrhage, and hypertension were not independently associated with aneurysm growth. Our retrospective study suggests that aneurysm size, smoking status, PHASES score, and ELAPSS score are associated with aneurysm growth.


Higher body mass index may be a predictor of extrathyroidal extension in patients with papillary thyroid microcarcinoma.
Recently, higher body mass index (BMI) has been associated with aggressive pathologic features of papillary thyroid carcinoma. The aim of this study was to clarify the relationship between BMI and aggressive pathologic features of papillary thyroid microcarcinoma (PTMC) and to evaluate whether the BMI can be a prognostic factor of PTMC. This retrospective study included 612 PTMC patients who underwent surgical excision at a referral center between April 2006 and December 2007. Patients were grouped according to BMI (<25 or ≥25 kg/m2). Multivariable logistic regression analysis was performed to determine independent predictors of aggressive pathologic features (advanced stage, extrathyroidal extension, and lymph node metastasis), with adjustment for age, gender, tumor size, multifocality, thyroid stimulating hormone (TSH) level, and BMI (value/group). PTMC patients with a BMI≥25 kg/m2 showed significantly higher prevalences of extrathyroidal extension, advanced pathologic TNM stage, and male gender, compared to those of patients with a BMI<25 kg/m2. Lymph node metastasis and mean TSH level were not significantly different between the two BMI subgroups. In multivariable analysis, the BMI≥25 kg/m2 group was positively associated with the presence of extrathyroidal extension (adjusted odds ratio 1.49, P=0.05). Higher BMI was associated with extrathyroidal extension in PTMC patients. This study suggests that the BMI could be considered as a prognostic factor for predicting the presence of extrathyroidal extension and it may help decide the appropriate surgical extent for PTMC patients.


Distinct amino acids in the C-linker domain of the Arabidopsis K+ channel KAT2 determine its subcellular localization and activity at the plasma membrane.
Shaker K(+) channels form the major K(+) conductance of the plasma membrane in plants. They are composed of four subunits arranged around a central ion-conducting pore. The intracellular carboxy-terminal region of each subunit contains several regulatory elements, including a C-linker region and a cyclic nucleotide-binding domain (CNBD). The C-linker is the first domain present downstream of the sixth transmembrane segment and connects the CNBD to the transmembrane core. With the aim of identifying the role of the C-linker in the Shaker channel properties, we performed subdomain swapping between the C-linker of two Arabidopsis (Arabidopsis thaliana) Shaker subunits, K(+) channel in Arabidopsis thaliana2 (KAT2) and Arabidopsis thaliana K(+) rectifying channel1 (AtKC1). These two subunits contribute to K(+) transport in planta by forming heteromeric channels with other Shaker subunits. However, they display contrasting behavior when expressed in tobacco mesophyll protoplasts: KAT2 forms homotetrameric channels active at the plasma membrane, whereas AtKC1 is retained in the endoplasmic reticulum when expressed alone. The resulting chimeric/mutated constructs were analyzed for subcellular localization and functionally characterized. We identified two contiguous amino acids, valine-381 and serine-382, located in the C-linker carboxy-terminal end, which prevent KAT2 surface expression when mutated into the equivalent residues from AtKC1. Moreover, we demonstrated that the nine-amino acid stretch 312TVRAASEFA320 that composes the first C-linker α-helix located just below the pore is a crucial determinant of KAT2 channel activity. A KAT2 C-linker/CNBD three-dimensional model, based on animal HCN (for Hyperpolarization-activated, cyclic nucleotide-gated K(+)) channels as structure templates, has been built and used to discuss the role of the C-linker in plant Shaker inward channel structure and function.


Endothelial progenitor cells for vascular regeneration.
The basis for native as well as therapeutic neovascularization is not restricted to angiogenesis but includes postnatal vasculogenesis. Our laboratory and others' have established that bone marrow-derived endothelial progenitor cells (EPCs) are present in the systemic circulation, are augmented in response to certain cytokines and/or tissue ischemia, and home to as well as incorporate into sites of neovascularization. Given the background, EPCs have been investigated as therapeutic agents in these studies of supply-side angiogenesis under pathological as well as physiological conditions. This review discusses the therapeutic potential of EPCs for cardiovascular ischemic diseases.


DRhoGEF2 encodes a member of the Dbl family of oncogenes and controls cell shape changes during gastrulation in Drosophila.
We have identified a gene, DRhoGEF2, which encodes a putative guanine nucleotide exchange factor belonging to the Dbl family of oncogenes. DRhoGEF2 function is essential for the coordination of cell shape changes during gastrulation. In the absence of maternal DRhoGEF2 gene activity, mesodermal and endodermal primordia fail to invaginate. The phenotype seen in DRhoGEF2 mutants is more severe than the defects associated with mutations in two previously identified gastrulation genes, folded gastrulation and concertina, suggesting that DRhoGEF2 acts in a signaling pathway independent of these genes. Expression of dominant-negative DRhoA during gastrulation results in phenocopies of the DRhoGEF2 mutant, suggesting that a signaling cascade involving DRhoGEF2 and the small GTPase DRhoA is responsible for the regulation of cell shape changes during early Drosophila morphogenesis.


The 'Netflix plus model': can subscription financing improve access to medicines in low- and middle-income countries?
At present, pay for prescription models are insufficient at containing costs and improving access to medicines. Subscription financing through tenders, licensing fees and unrestricted or fixed volumes can benefit stakeholders across the supply chain. Pharmaceutical manufacturers can reduce the need for marketing expenses and gain certainty in revenue. This will decrease costs, improve predictability in budget expenditure for payers and remove price as a barrier of access from patients. Inherently, low- and middle-income countries lack the purchasing power to leverage price discounts through typical price arrangements. These markets can realise substantial savings for branded and generic medicines through subscription financing. Procuring of on-patent and off-patent drugs requires separate analysis for competition effects, the length of contract and encouraging innovation in the medicine pipeline. Prices of competitive on-patent medicines and orphan drugs can be reduced through increased competition and volume. Furthermore, pooling expertise and resources through joint procurement has the potential for greater savings. Incentivising research and development within the pharmaceutical industry is essential for sustaining a competitive market, preventing monopolies and improving access to expensive treatments. However, technical capacity, forecasting demand and the quality of generic medicines present limitations which necessitate government support and international partnerships. Ultimately, improving access requires progressive financing mechanisms with patients and cost containment in mind.


Effect of terlipressin (Glypressin) on hepatorenal syndrome in cirrhotic patients: results of a multicentre pilot study.
Hepatorenal syndrome (HRS) is a severe complication of cirrhosis, leading to death in more than 90% of cases in the absence of liver transplantation. Several treatments have been attempted as a bridge to liver transplantation. Among such treatments, terlipressin has been studied in several reports, two prospective pilot studies and a double-blind, short-term, controlled haemodynamic study. Promising results have been shown with this drug. The purpose of this multicentre retrospective study was to evaluate the effects of terlipressin on renal function and survival of patients with HRS. Eighteen patients recruited in three liver units with type 1 HRS in 16 cases and type 2 HRS in two cases were given 4 mg/day terlipressin (range 1.5-12) for 7 days (range 2-16). Electrolytes, renal function, mean urinary output, natriuresis, liver function tests, and tolerance of the treatment were monitored regularly. A total of 13/18 (72%) patients responded with a mean decline in serum creatinine ranging from 31 to 75% from day 0 to day 5. Eight of these 13 patients had a normal serum creatinine level at day 5. Liver function tests remained unaffected by terlipressin administration. Three local necrosis complications were noted in patients receiving terlipressin continuously via an infusion pump. Two responder patients survived: one of these underwent orthotopic liver transplantation with a follow-up of 24 months; the other is alive with a follow-up of more than 36 months. Patients who responded to terlipressin had lower baseline serum bilirubin and significantly higher serum sodium concentrations than patients who did not respond. In this pilot study, improvement in renal function was noted in 72% of cases after administration of terlipressin, and was associated with long-term survival in two patients. Parameters associated with response to terlipressin and increased survival should be defined better in a large cohort of cirrhotic patients with HRS.


Transcriptional profiling of Mycoplasma hyopneumoniae during iron depletion using microarrays.
Mycoplasma hyopneumoniae, the causative agent of swine enzootic pneumonia and a major component of the porcine respiratory disease complex, continues to confound swine producers despite control programmes worldwide. The disease is chronic and self-limiting, but the host is subject to immunopathological changes that potentiate respiratory disease associated with other pathogens. The response of M. hyopneumoniae to environmental stress is of interest because of its relevance to virulence mechanisms in other bacterial pathogens. One of these stressors, iron deprivation, is a prominent feature of the host innate immune response, and most certainly impacts growth of mycoplasmas in vivo. To study this, microarray technology was applied to the transcriptome analysis of M. hyopneumoniae during iron deprivation. An array consisting of 632 of the 698 ORFs in the genome was used to compare the mRNA isolated from organisms grown under normal laboratory conditions with that from organisms subjected to iron deprivation with the chelator 2,2'-dipyridyl. This analysis identified 27 genes that were either up- or down-regulated in response to low-iron growth conditions (P<0.01), with an estimated false discovery rate below 10 %. These included genes encoding transport proteins, enzymes involved in energy metabolism, and components of the translation process. Ten of the 27 identified genes had no assigned function. These studies indicate that M. hyopneumoniae can respond to changes in environmental conditions, but the mechanism employed remains unknown.


Infectious bronchitis virus 3a protein localizes to a novel domain of the smooth endoplasmic reticulum.
All coronaviruses possess small open reading frames (ORFs) between structural genes that have been hypothesized to play important roles in pathogenesis. Infectious bronchitis virus (IBV) ORF 3a is one such gene. It is highly conserved among group 3 coronaviruses, suggesting that it has an important function in infection. IBV 3a protein is expressed in infected cells but is not detected in virions. Sequence analysis predicted that IBV 3a was a membrane protein; however, only a fraction behaved like an integral membrane protein. Microscopy and immunoprecipitation studies demonstrated that IBV 3a localized to the cytoplasm in a diffuse pattern as well as in sharp puncta in both infected and transfected cells. These puncta did not overlap cellular organelles or other punctate structures. Confocal microscopy demonstrated that IBV 3a puncta lined up along smooth endoplasmic reticulum (ER) tubules and, in a significant number of instances, were partially surrounded by these tubules. Our results suggest that IBV 3a is partially targeted to a novel domain of the smooth ER.


Susceptibility of aldehyde and aldose reductases of human tissues to aldose reductase inhibitors.
The effect of aldose reductase inhibitors such as sorbinil, alrestatin, and quercitrin has been studied on the aldose reductase purified from human brain and lens, and aldehyde reductase I purified from human liver, and aldehyde reductase II purified from human brain, liver, and red cells. None of the aldose reductase inhibitors have been found to be specific for aldose reductase. Fifty micromolar sorbinil besides inhibiting aldose reductase, completely inhibits aldehyde reductase II from the brain, liver and red cells. Similarly, alrestatin and quercitrin also are potent inhibitors of aldehyde reductase I and aldehyde reductase II.


Drug therapy recommendations from the 2005 ACC/AHA guidelines for treatment of chronic heart failure.
To review and discuss key aspects of the drug therapy recommendations in the American College of Cardiology (ACC)/American Heart Association (AHA) 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure (HF) in the Adult. Data were obtained from the ACC/AHA 2005 Guideline Update for Chronic HF. English-language clinical trials, observational studies, and pertinent review articles evaluating the pharmacotherapy of chronic HF were identified, based on MEDLINE searches through January 2006. Articles presenting information that impacts the evidence base for recommendations regarding the use of various drug therapies in patients with chronic HF were evaluated. The ACC/AHA 2005 Guideline Update for HF provides revised, evidence-based recommendations for the treatment of chronic HF. The new guidelines are based on a staging system that recognizes both the development and progression of HF. Recommendations are provided for 2 stages of patients (A and B) who do not yet have clinical HF but are clearly at risk and 2 stages (C and D) that include patients with symptomatic HF. The guidelines continue to emphasize the important role of neurohormonal blockade with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-adrenergic blockers, and aldosterone antagonists. Based on recent trials, updated recommendations address the roles of combination therapy and the selective addition of hydralazine and isosorbide dinitrate. Along with specific drug recommendations, information on the practical use of various drugs is provided. Although the guidelines primarily focus on HF due to systolic dysfunction, general recommendations are also provided for patients with preserved systolic function. The ACC/AHA 2005 Guideline Update provides evidence-based recommendations for healthcare professionals involved in the care of adults with chronic HF. Recent clinical trial findings have further clarified the evolving role of neurohormonal-blocking drugs in the prevention and treatment of HF.


Compound Zhebei granules combined with chemotherapy for the treatment of refractory acute leukemia: a randomized clinical trial.
To observe the effect of compound Zhebei granules (CZBG) with chemotherapy in the treatment of refractory acute leukemia. In this multicenter, double-blind, placebo-controlled clinical trial, we used a central (online) randomization system to assign 235 patients to two treatment groups. A total of 118 patients received chemotherapy combined with CZBG (4 g, twice daily) and 117 patients received chemotherapy plus placebo. The clinical efficacy was evaluated at the end of one chemotherapeutic cycle. In the full analysis set, in which deaths due to disease progression were regarded as inefficacy, the rates of complete remission (CR) and partial remission (CR + PR) were 32.35% and 50.00% , respectively, for the chemotherapy combined with CZBG group, and 23.08% and 35.58%, respectively, for the chemotherapy plus placebo group. There was a statistically significant difference between the two groups according to a χ2 test (P < 0.05). In the per protocol analysis set (PPS), the CR (33.67%), CR+PR (52.04%) response rates for the chemotherapy plus CZBG group were significantly different from the response rates of the control group (CR: 24.24% and CR+PR: 37.37%), respectively (P < 0.05). CZBG plus chemotherapy can improve the clinical remission rate of refractory acute leukemia after one just one therapeutic cycle.


A supramolecular platform for controlling and optimizing molecular architectures of siRNA targeted delivery vehicles.
It requires multistep synthesis and conjugation processes to incorporate multifunctionalities into a polyplex gene vehicle to overcome numerous hurdles during gene delivery. Here, we describe a supramolecular platform to precisely control, screen, and optimize molecular architectures of siRNA targeted delivery vehicles, which is based on rationally designed host-guest complexation between a β-cyclodextrin-based cationic host polymer and a library of guest polymers with various PEG shape and size, and various density of ligands. The host polymer is responsible to load/unload siRNA, while the guest polymer is responsible to shield the vehicles from nonspecific cellular uptake, to prolong their circulation time, and to target tumor cells. A series of precisely controlled molecular architectures through a simple assembly process allow for a rapid optimization of siRNA delivery vehicles in vitro and in vivo for therapeutic siRNA-Bcl2 delivery and tumor therapy, indicating the platform is a powerful screening tool for targeted gene delivery vehicles.


Gonococcal infection and human fertility in sub-Saharan Africa.
An analysis is presented of the influence of Neisseria gonorrhoeae on human population growth in regions of sub-Saharan Africa where gonococcal infections are prevalent in sexually active adults. Combining epidemiological and demographic data within the framework of a mathematical model, we show that gonorrhoea has a major impact on fertility and, concomitantly, on net population growth in areas with a high prevalence of untreated infections. Specifically, a 20% prevalence in sexually active adults is predicted to induce a 50% reduction in net population growth. Model predictions are in good agreement with observed data from Uganda, and the sensitivity of the prediction to various complications, such as heterogeneity in sexual behaviour, is assessed. The analysis suggests that the predicted increase in fertility arising from expanded sexually transmitted disease (STD) control programmes in Africa to help combat the spread of human immunodeficiency viruses (HIV-1 and HIV-2) will help to offset the predicted demographic impact of AIDS in the worst afflicted areas. In other areas the rise in fertility associated with effective STD control will need to be countered by the linkage of STD control programmes with family planning initiatives.


Rational clinical immunotherapy for multiple sclerosis.
In this article, we assess the roles and the efficacy of immunopharmacologic agents in the treatment of multiple sclerosis (MS) and other demyelinating disease syndromes. The initial clinical manifestations of demyelinating disease, immunotherapeutic goals, efficacy of individual agents, and specific immunopharmacologic recommendations are discussed. MS and other idiopathic demyelinating disease syndromes can be effectively managed with immunotherapy. Exacerbations are treatable, and the frequency and severity of exacerbations can be reduced. Although some agents have a minor effect on progression of disability, current approaches have not proved to have a major influence on treatment of progressive MS. Immunotherapy for inflammatory demyelinating disease necessitates a high degree of clinical certainty about the diagnosis. Because all available therapeutic agents have limitations and significant toxic effects, careful consideration is necessary before use. Treatment should be individualized on the basis of the clinical course of the disease and the degree of patient disability.


Comparative effectiveness of long-acting injectable risperidone vs. long-acting injectable first-generation antipsychotics in bipolar disorder.
The aim of this study was to compare the treatment effectiveness between long-acting injectable risperidone and long-acting injectable first-generation antipsychotics among patients with bipolar disorder. We conducted a retrospective cohort study using Taiwan's National Health Insurance Research Database. Patients with bipolar disorder aged 15 years or higher, who were newly administered long-acting injectable antipsychotics between June 1, 2004 and December 31, 2011 were included. The clinical outcome indexes were hospitalization for any mood, manic/mixed, or depressive episodes. In addition, the all-cause discontinuation of long-acting injectable antipsychotic treatment was also assessed. A total of 3916 patients with bipolar disorder were extracted. Compared with risperidone, the use of first-generation antipsychotics was associated with a higher rate of hospitalization for any mood episode and major depressive episode. However, there was no statistically significant difference in treatment discontinuation rate between risperidone and first-generation antipsychotics. Information for the severity of mood symptoms, social support, life style, neurological and metabolic adverse effect was not available in this database. In addition, we only measured severe mood episodes with hospitalization as our outcome index. It may not be possible to generalize our findings to mild mood episodes. Our findings suggested that patients treated with long-acting injectable risperidone might be superior to first-generation antipsychotics in the rate of psychiatric hospitalization.


Effects of ocean acidification over successive generations decrease resilience of larval European sea bass to ocean acidification and warming but juveniles could benefit from higher temperatures in the NE Atlantic.
European sea bass (Dicentrarchus labrax) is a large, economically important fish species with a long generation time whose long-term resilience to ocean acidification (OA) and warming (OW) is not clear. We incubated sea bass from Brittany (France) for two generations (>5 years in total) under ambient and predicted OA conditions (PCO2: 650 and 1700 µatm) crossed with ambient and predicted OW conditions in F1 (temperature: 15-18°C and 20-23°C) to investigate the effects of climate change on larval and juvenile growth and metabolic rate. We found that in F1, OA as a single stressor at ambient temperature did not affect larval or juvenile growth and OW increased developmental time and growth rate, but OAW decreased larval size at metamorphosis. Larval routine and juvenile standard metabolic rate were significantly lower in cold compared with warm conditioned fish and also lower in F0 compared with F1 fish. We did not find any effect of OA as a single stressor on metabolic rate. Juvenile PO2,crit was not affected by OA or OAW in both generations. We discuss the potential underlying mechanisms resulting in the resilience of F0 and F1 larvae and juveniles to OA and in the beneficial effects of OW on F1 larval growth and metabolic rate, but contrastingly in the vulnerability of F1, but not F0 larvae to OAW. With regard to the ecological perspective, we conclude that recruitment of larvae and early juveniles to nursery areas might decrease under OAW conditions but individuals reaching juvenile phase might benefit from increased performance at higher temperatures.


Safety and efficacy of microsurgical treatment of previously coiled aneurysms: a systematic review and meta-analysis.
We conducted a systematic review of the literature to evaluate the safety and efficacy of surgical treatment of previously coiled aneurysms. A comprehensive review of the literature for studies on surgical treatment of previously coiled aneurysms was conducted. For each study, the following data were extracted: patient demographics, initial clinical status, location and size of aneurysms, time interval between initial/last endovascular procedure and surgery, surgical indications, and microsurgical technique. We performed subgroup analyses to compare direct clipping versus coil removal and clipping versus parent vessel occlusion, early (<4 weeks post-coiling) versus late surgery and anterior versus posterior circulation. Twenty-six studies with 466 patients and 471 intracranial aneurysms were included. All of the studies were retrospective and non-comparative case-series. Patients undergoing direct clipping had lower perioperative morbidity (5.0 %, 95 % CI = 2.6-7.4 %) when compared to those undergoing coil removal and clipping (11.1 %, 95 % CI = 5.3-17.0 %) or parent vessel occlusion (13.1 %, 95 % CI = 4.6-21.6 %) (p = 0.05). Patients receiving early surgery (<4 weeks post-coiling) had significantly lower rates of good neurological outcome (77.1 %, 95 % CI = 69.3-84.8 %) when compared to those undergoing late surgery (92.1 %, 95 % CI = 89.0-95.2 %) (p < 0.01). There were higher rates of long-term neurological morbidity in the posterior circulation group (23.1 vs. 4.7 %, p < 0.01) as well as long-term neurological mortality (4.4 vs. 2.8 %, p < 0.01). Our meta-analysis suggests that surgical treatment is safe and effective. Our data indicate that aneurysms that are amenable to direct clipping have superior outcomes. Late surgery was also associated with better clinical outcomes. Surgery of recurrent posterior circulation aneurysms was associated with high rates of morbidity and mortality. Given the characteristics of the included studies, the quality of evidence of this meta-analysis is limited.


Differential effects of cyclic nucleotide analogues and GnRH on LH synthesis and release.
We compared the effects of gonadotropin-releasing hormone (GnRH) and cyclic nucleotides on biosynthesis and release of luteinizing hormone (LH) by rat anterior pituitary glands (APs). APs from ovariectomized rats were incubated in the presence of test compounds, [3H]glucosamine, and [14C]alanine. GnRH significantly (P less than 0.01) increased both incorporation of [3H]glucosamine into LH (glycosylation) and release of immunoreactive LH (IR-LH) and [3H]LH. None of the cyclic nucleotides alone at 5 mM significantly stimulated release of IR-LH. Adenosine 3',5'-cyclic monophosphate (cAMP), N6,O2'-dibutyryl cAMP (DBcAMP), and 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP) stimulated (P less than 0.01) glycosylation, whereas 8-Br-AMP, 8-bromoguanosine 5'-monophosphate (8-Br-GMP), cGMP, and 8-Br-cGMP had no detectable effect. Release of [3H]LH was increased by GnRH, 8-Br-cAMP, and DBcAMP, but not by other nucleotides. None of the cyclic nucleotides elevated [14C]LH, whereas GnRH elevated it (P less than 0.01) in the medium. Dose-response curves for glycosylation in response to 8-Br-cAMP and GnRH were parallel. In contrast, dose-response curves for release of both [3H]LH and IR-LH were nonparallel. It appears that cAMP can mimic the action of GnRH on LH glycosylation, but may have little direct effect on LH release.


PROFILE OF PATIENTS WHO SEEK THE BARIATRIC SURGERY.
Nowadays obesity is a chronic disease considered one of the greatest problems in public healthy. Showing to be effective in a short and long term, the bariatric surgery has emerged as an optional treatment for morbid obesity. Identify the profile of patients seeking bariatric surgery. Were interviewed 100 patients in preoperative nutritional monitoring of bariatric surgery. The study was conducted by applying a questionnaire prepared according to the research objectives. From the individuals that were seeking bariatric surgery, 78% were female, 62% were married and 69% reported physical activity. The average age of those surveyed was 37±10.83 years and mean body mass index (BMI) was 43.51± 6.25 kg/m². The comorbidity more prevalent in this group was high blood pressure (51%). In previous treatments for weight reduction, 92% have already done hypocaloric diet followed by anorectic drug (83%). The success of these treatments was reported by 92% of patients; however, the weight lost was recovered in less than one year of 75%. Patients with diabetes mellitus and dyslipidemia had higher BMI values. The patients with comorbidities showed lower levels of BMI. The profile of patients who sought surgical treatment for their obesity were predominantly women with a family background of obesity and obesity-related comorbidities, especially hypertension and diabetes mellitus.


Infections in Patients with Systemic Lupus Erythematosus: The Contribution of Primary Immune Defects Versus Treatment-Induced Immunosuppression.
Patients with systemic lupus erythematosus experience high rates of infections. The use of immunosuppressive drugs to treat the disease, along with the fact that both the innate and adaptive branches of the immune system are compromised, account for the development of infections. In this communication, we briefly discuss the aberrant function of the immune system in patients with systemic lupus erythematosus and review the occurrence of infections that have been reported in clinical trials conducted to develop new therapeutics. Understanding the immune dysfunction in patients with systemic lupus erythematosus and the appearance of infections while trying to control the disease using immunosuppressive or immunomodulatory drugs should help limit infections and mitigate the associated morbidity and mortality.


Cardiac function in spontaneously hypertensive diabetic rats.
The isolated perfused working heart was used to study hypertensive diabetes-induced alterations in cardiac function at 6 and 12 wk after diabetes was induced. At 6 wk after diabetes induction, cardiac performance was depressed in the diabetic animals. However, there was no difference in cardiac function between normotensive Wistar and spontaneously hypertensive (SHR) diabetic rats. Wistar-Kyoto (WKY) rats were also included as normotensive controls in our 12-wk study. Hearts from 12-wk SHR and Wistar diabetic animals exhibited a depressed left ventricular developed pressure and positive and negative dP/dt when compared with control animals. However, this depression was not seen in the WKY diabetic animals. In addition, quantitation of various parameters of heart function revealed highly significant differences between SHR diabetic animals and all other groups associated with an increased mortality. Serum lipids were elevated in SHR and Wistar and were unaffected in WKY diabetic rats. Furthermore, thyroid hormone levels were not depressed in WKY diabetic rats as seen in the other two diabetic groups. This normal lipid metabolism and thyroid status could, in part, explain the lack of cardiac dysfunction in these animals. The data provide further evidence that the combination of hypertension and diabetes mellitus produces greater myocardial dysfunction than with either disease alone and is associated with a significant mortality.


Modulation of rat liver 3-hydroxy-3-methylglutaryl-CoA reductase activity by reversible phosphorylation.
We have previously reported that the enzymic activity of rat liver-3-hydroxy-3-methyl-glutaryl-CoA reductase (NADPH) (HMG-CoA reductase) is modulated in vitro by a phosphorylation-dephosphorylation reaction sequence. The in vitro phosphorylation of HMG-CoA reductase was further studied by utilizing purified HMG-CoA reductase and reductase kinase. Analysis of 32P-labeled HMG-CoA reductase revealed 1 mol of phosphate per subunit. Purified [32P]HMG-CoA reductase could be dephosphorylated with phosphoprotein phosphatase. To demonstrate the in vivo phosphorylation, rats were injected with 32P and hepatic HMG-CoA reductase was isolated by immunoprecipitation and also by purification of the enzyme to homogeneity. Analysis of [32P]HMG-CoA reductase by sodium dodecyl sulfate gel electrophoresis revealed a single peak of radioactivity comigrating with HMG-CoA reductase. Administration of glucagon enhances the in vivo phosphorylation of both HMG-CoA reductase and reductase kinase. In response to glucagon, HMG-CoA reductase activity is decreased whereas reductase kinase activity is increased. These results support our concept that the enzymic activity of HMG-CoA reductase is modulated by a bicyclic cascade system involving phosphorylation-dephosphorylation. The enzymic activity of HMG-CoA reductase has also been shown to be modulated by cholesterol and mevalonolactone by both short-term and long-term mechanisms. The effects of cholesterol and mevalonolactone are twofold. Rapid inhibition of HMG-CoA reductase activity is due to increased phosphorylation of the enzyme; the long-term effect of HMG-CoA reductase is achieved by reduction in enzyme concentration by modulation of enzyme synthesis and/or degradation. Regulation of HMG-CoA reductase by mevalonolactone is of major importance in cellular metabolism because mevalonate serves as precursor for four separate metabolic pathways, including the formation of cholesterol, ubiquinone, dolichols, and isopentenyl tRNA.


Magnetic Resonance Imaging and Spectroscopy to Assess Leg Muscle Macrostructure and Microstructure in Healthy Older Women: A Feasibility Assessment.
Advanced magnetic resonance (MR) scanning techniques, such as diffusion tensor imaging (DTI) and proton MR spectroscopy (1H-MRS) permit microstructural evaluation of water diffusivity and intramyocellular lipid content, respectively. We aimed to determine the feasibility of performing advanced MR scanning (proton density [PD] weighted imaging, DTI, and 1H-MRS) to evaluate properties of leg muscles in older women with respect to: (1) participant recruitment using three community-based strategies; (2) participant tolerance to the MRI scan acquisition protocol; and (3) scan acquisition and analyses protocols. Recruitment feasibility was evaluated based on the number of participants enrolled using various strategies. Participant tolerance was feasible if the scanning session was uninterrupted and image artifacts were absent. Optimal PD imaging, DTI, and 1H-MRS acquisition and analyses protocols were established. Nine women (mean age = 71 years) were recruited over four months. The acquisition protocol was well tolerated by all participants. Adaptations were required for women with short stature and vertebral fracture risk. PD-weighted image analyses were improved by using the phased array uniformity enhancement filter to increase tissue contrast. It is feasible to use a combination of MR scanning methods to evaluate muscle macrostructure and microstructure in the leg of older women. Our findings suggest that advanced MR scanning methods can be used for future studies interested in quantifying components of muscle structure in older women, but prospective studies are needed to confirm whether change in microstructure can be detected in response to an intervention.


Postprandial hypertriglyceridemia and cardiovascular disease: current and future therapies.
Exaggerated postprandial hypertriglyceridemia is a risk factor for cardiovascular disease. This metabolic abnormality is principally due to overproduction and/or decreased catabolism of triglyceride-rich lipoproteins (TRLs) and is a consequence of pathogenic genetic variations and other coexistent medical conditions, particularly obesity and insulin resistance. Accumulation of TRL in the postprandial state promotes the formation of small, dense low-density lipoproteins, as well as oxidative stress, inflammation, and endothelial dysfunction, all of which compound the risk of cardiovascular disease. The cardiovascular benefits of lifestyle modification (weight loss and exercise) and conventional lipid-lowering therapies (statins, fibrates, niacin, ezetimibe, and n-3 fatty acid supplementation) could involve their favorable effects on TRL metabolism. New agents, such as dual peroxisome-proliferator-activated receptor α/δ agonists, diacylglycerol, inhibitors of diacylglycerol acyltransferase 1 and microsomal triglyceride transfer protein, antisense oligonucleotides for apolipoprotein B-100 and apolipoprotein C-III, and incretin-based therapies, may enhance the treatment of postprandial lipemia, but their efficacy needs to be tested in clinical end point trials. Further work is required to develop a simple clinical protocol for investigating postprandial lipemia, as well as internationally agreed management guidelines for this type of dyslipidemia.


Polypoidal choroidal vasculopathy - a type I polypoidal subretinal neovasculopathy.
This 47 year old female developed the new onset of a polypoidal subretinal neovascular membrane in the left eye 13 years after having polypoidal choroidal vasculopathy (PCV) treated in the right eye. The indocyanine green (ICG) angiography of the left eye at initial presentation showed a normal choroidal vascular pattern without PCV. The new development of a PCV complex on ICG angiography demonstrates that PCV is truly a type of subretinal neovascularization, and not a choroidal vascular abnormality. The optical coherence tomography shows that the polypoidal vascular complex lies above Bruch's membrane and beneath the retinal pigment epithelium, and not within the choroid. Treatment with high dose ranibizumab (2.0 mg) resulted in excellent polyp closure and regression of the branching vascular network. The documented new development of polypoidal subretinal vessels on ICG angiography and the response to ranibizumab supports that PCV is a polypoidal neovasculopathy (PNV).


Detection of APC gene deletions in colorectal malignancies using quantitative PCR in a Chinese population.
The adenomatous polyposis coli (APC) gene has been shown to be involved in genetic instability and to be downregluated in several human carcinomas. The chromosome locus of APC, 5q21-22, is frequently deleted in colorectal cancers (CRCs). The functional impact of such regions needs to be extensively investigated in large amount of clinical samples. Case-matched tissues of CRC and adjacent normal epithelium (n = 134) were included in this study. Quantitative PCR was carried out to examine the copy number as well as mRNA expression of APC gene in colorectal malignancies. Our results showed that copy number deletions of APC were present in a relatively high percentage of colorectal cancer samples (26.1%, 35 out of 134). There was a positive correlation between copy number decrease of APC and tumor progression in CRCs. Furthermore, copy number loss of APC was correlated with decreased mRNA expression. However, mRNA levels of APC were also impaired in CRC samples with unaltered copy numbers, indicating that sporadic CRCs exhibit different mechanisms of APC regulation.


Gastroprotective properties of Myristica malabarica against indometacin-induced stomach ulceration: a mechanistic exploration.
The healing activity of the methanol extract of the spice rampatri, Myristica malabarica, (RM) and omeprazole against indometacin-induced stomach ulceration has been studied in a mouse model. Treatment with RM (40 mg kg(-1) per day) and omeprazole (3 mg kg(-1) per day) for 3 days could effectively heal the stomach ulceration, as revealed from the ulcer indices and histopathological studies. Compared with the ulcerated group, treatment with RM and omeprazole for 3 days reduced the macroscopic damage score by approximately 72% and 76%, respectively (P<0.001), establishing the efficacy of RM. The extent of ulcer healing offered by 3 days' treatment with RM or omeprazole was better than that observed with natural recovery over 5 and 7 days (P<0.05). The healing capacities of RM and omeprazole could be attributed to their antioxidant activity as well as the ability to enhance the mucin content of the gastric tissues. Both drugs reduced lipid peroxidation (by 42-44%) and protein carbonyl content (by 34%), and augmented non-protein thiol levels beyond normal values. Furthermore, RM improved the mucin level beyond the normal value, while omeprazole restored it to near normalcy.


[Ways of inserting physicians into the healthcare production process: case of study of basic healthcare units in Belo Horizonte, Brazil].
The main purpose of this paper is to describe and analyze the ways of inserting physicians into the health production process. This subject is justified by a belief that that this way of working may be a problem but at the same time may well be the key to implementing healthcare models that are ethically and politically committed to the lives of public health system users. Initially, the problem is presented through the construction of an archetype physician and his historical and social and cultural conditioning factors, taking the work processes of physicians at Basic Healthcare Units in Belo Horizonte as an example that is built up through interviews and participative observations. Some possibilities for intervention are indicated through the introduction of new concepts and technologies that could transform the work of these practitioners in ways that would build up links with more responsibility for the care and lives of users of public healthcare services.


Quantitative Evaluation of the Function of the Sensory Nerve Fibers of the Palate in Patients With Obstructive Sleep Apnea.
To quantitatively evaluate the functional integrity of sensory nerve fibers of the palate in patients with obstructive sleep apnea (OSA) using the Neurometer system. A total of 32 patients with OSA and 18 healthy control patients were included in the study. All participants were selected based on medical history, physical examination, and nocturnal polysomnography (PSG) and divided into two groups. The palatal sensory status of participants was examined with a Neurometer current perception threshold (CPT) system. The system was used to deliver an electrical stimulus at three different frequencies (2,000 Hz, 250 Hz, and 5 Hz) by an investigator blinded to the PSG results. There were no significant differences in the CPT values of the hard palate between the patients with OSA and control patients at any of the three stimulation frequencies. The differences in the CPT values of the soft palate between these groups failed to show any statistical significance at 250 Hz and 5 Hz. However, the patients with OSA showed significantly higher CPT values of the soft palate at 2,000 Hz than the age-matched healthy control patients (256.56 ± 129.34 versus 372.13 ± 152.06; P = .009). Our study revealed an impairment of 2,000 Hz-related sensory nerve function of the soft palate among patients with OSA. The CPT test could be a useful tool for the quantitative and selective assessment of the sensory nerve function in patients with OSA. Additional research is required to evaluate the different types of sensory nerve dysfunctions among such patients. Registry: ClinicalTrials.gov; Title: The Effects of Nasal Airflow on Upper Airway Dilator Muscles During Sleep; Identifier: NCT03506178; URL: https://clinicaltrials.gov/ct2/show/NCT03506178. An Y, Li Y, Chang W, Gao F, Ding X, Xu W, Han D. Quantitative evaluation of the function of the sensory nerve fibers of the palate in patients with obstructive sleep apnea. J Clin Sleep Med. 2019;15(9):1347-1353.


Crystal-plane-controlled surface chemistry and catalytic performance of surfactant-free Cu2 O nanocrystals.
Surfactant-free Cu2 O nanocrystals, including cubes exposing {100} crystal planes, octahedra exposing {111} crystal planes, and rhombic dodecahedra exposing {110} crystal planes, were used as model catalysts to study the effect of the crystal plane on the surface chemistry and catalytic performance for CO oxidation of Cu2 O nanocrystals. The catalytic performance follows the order of octahedra rhombic dodecahedra>cubes; this suggests that Cu2 O(111) is most active in catalyzing CO oxidation among Cu2 O (111), (110), and (100) surfaces. CO temperature-programmed reduction results demonstrate that Cu2 O octahedra are the most easily reduced of the Cu2 O cubes, octahedra, and rhombic dodecahedra. Diffuse reflectance FTIR spectra show that CO chemisorption on Cu2 O nanocrystals depends on their shape and the chemisorption temperature. CO chemisorption is strongest on rhombic dodecahedra at 30°C, but at 150°C on octahedra. Both the reducibility and chemisorption ability of various Cu2 O nanocrystals toward CO are consistent with their catalytic performance in CO oxidation. The observed surface chemistry and catalytic performance in CO oxidation of various Cu2 O nanocrystals can be well correlated with their exposed crystal plane and surface composition/structure. Cu2 O octahedra expose the {111} crystal plane with coordinated, unsaturated Cu(I) sites, and thus, are most active in chemisorbing CO and catalyzing CO oxidation. These results nicely demonstrate the crystal-plane-controlled surface chemistry and catalytic performance of oxide catalysts.


The Impairment of Number Transcoding Abilities in Individuals with Amnestic Mild Cognitive Impairment and Alzheimer Disease: Associations With Attentional and Executive Functions.
Studies have shown that number transcoding abilities (ie, translating numbers from one numerical code to another) are affected early in the development of Alzheimer disease (AD). However, no study has extensively explored how these abilities are affected in individuals with mild cognitive impairment (MCI). To determine the contribution that number transcoding tasks make to the identification of MCI, and to pinpoint the cognitive correlates of performance in these tasks. We compared the performance of 20 individuals with the amnestic subtype of MCI, eight individuals with AD, and 20 healthy controls on three number transcoding tasks. The results confirmed the presence of number transcoding impairment in the individuals with AD. The individuals with MCI were found to be impaired in two of the transcoding tasks; these individuals produced perseverations of the input code-the most noteworthy error type in individuals with AD. In addition, the relationship between impairment in attentional and executive functions and impairment in number transcoding was supported by the correlational analyses. This study confirmed that number transcoding abilities are impaired in individuals with MCI, although less severely than in individuals with AD. Our results provide evidence for the clinical value of including number transcoding tasks in the assessment of cognitive deficits associated with pathological aging.


Astaxanthin uptake in domestic dogs and cats.
Research on the uptake and transport of astaxanthin is lacking in most species. We studied the uptake of astaxanthin by plasma, lipoproteins and leukocytes in domestic dogs and cats. Mature female Beagle dogs (18 to 19 mo old; 11 to 14 kg BW) were dosed orally with 0, 0.1, 0.5, 2.5, 10 or 40 mg astaxanthin and blood taken at 0, 3, 6, 9, 12, 18 and 24 h post-administration (n = 8/treatment). Similarly, mature domestic short hair cats (12 mo old; 3 to 3.5 kg body weight) were fed a single dose of 0, 0.02, 0.08, 0.4, 2, 5, or 10 mg astaxanthin and blood taken (n = 8/treatment) at the same interval. Both dogs and cats showed similar biokinetic profiles. Maximal astaxanthin concentration in plasma was approximately 0.14 mumol/L in both species, and was observed at 6 h post-dosing. The plasma astaxanthin elimination half-life was 9 to 18 h. Astaxanthin was still detectable by 24 h in both species. In a subsequent study, dogs and cats were fed similar doses of astaxanthin daily for 15 to 16 d and astaxanthin uptake by plasma, lipoproteins, and leukocytes studied. In both species, plasma astaxanthin concentrations generally continued to increase through d 15 or 16 of supplementation. The astaxanthin was mainly associated with high density lipoprotein (HDL). In blood leukocytes, approximately half of the total astaxanthin was found in the mitochondria, with significant amounts also associated with the microsomes and nuclei. Dogs and cats absorb astaxanthin from the diet. In the blood, the astaxanthin is mainly associated with HDL, and is taken up by blood leukocytes, where it is distributed to all subcellular organelles. Certain aspects of the biokinetic uptake of astaxanthin in dogs and cats are similar to that in humans.


Anatomy of language impairments in primary progressive aphasia.
Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by progressive decline in language function but relative sparing of other cognitive domains. There are three recognized PPA variants: agrammatic, semantic, and logopenic. Although each PPA subtype is characterized by the nature of the principal deficit, individual patients frequently display subtle impairments in additional language domains. The present study investigated the distribution of atrophy related to performance in specific language domains (i.e., grammatical processing, semantic processing, fluency, and sentence repetition) across PPA variants to better understand the anatomical substrates of language. Results showed regionally specific relationships, primarily in the left hemisphere, between atrophy and impairments in language performance. Most notable was the neuroanatomical distinction between fluency and grammatical processing. Poor fluency was associated with regions dorsal to the traditional boundaries of Broca's area in the inferior frontal sulcus and the posterior middle frontal gyrus, whereas grammatical processing was associated with more widespread atrophy, including the inferior frontal gyrus and supramarginal gyrus. Repetition performance was correlated with atrophy in the posterior superior temporal gyrus. The correlation of atrophy with semantic processing impairment was localized to the anterior temporal poles. Atrophy patterns were more closely correlated with domain-specific performance than with subtype. These results show that PPA reflects a selective disruption of the language network as a whole, with no rigid boundaries between subtypes. Further, these atrophy patterns reveal anatomical correlates of language that could not have been surmised in patients with aphasia resulting from cerebrovascular lesions.


Predictors of physical functioning after a cardiac event.
An increased understanding of the factors that promote or hinder patients' return to optimal activity levels after a cardiac event is necessary to help them achieve this goal. Accordingly, the purpose of this study was to examine psychologic resources, depression, physical recovery, and illness severity for their relationships with subjective and objective physical functioning (exercise data). A correlational survey design was used to assess patients' (n = 46) illness responses 9 weeks after the cardiac event. Patients also participated in a symptom-limited exercise test. The findings suggested that the individual's return to greater activity levels after a cardiac illness was associated with less depression and illness severity, and higher levels of objective physical functioning, physical recovery, and self-esteem. Further, patients' objective physical functioning was associated not only with greater subjective physical functioning but also with greater levels of physical recovery and mastery.


Unbalanced oxidant-induced DNA damage and repair in COPD: a link towards lung cancer.
Chronic obstructive pulmonary disease (COPD) is characterised by oxidative stress and increased risk of lung carcinoma. Oxidative stress causes DNA damage which can be repaired by DNA-dependent protein kinase complex. To investigate DNA damage/repair balance and DNA-dependent protein kinase complex in COPD lung and in an animal model of smoking-induced lung damage and to evaluate the effects of oxidative stress on Ku expression and function in human bronchial epithelial cells. Protein expression was quantified using immunohistochemistry and/or western blotting. DNA damage/repair was measured using colorimetric assays. 8-OH-dG, a marker of oxidant-induced DNA damage, was statistically significantly increased in the peripheral lung of smokers (with and without COPD) compared with non-smokers, while the number of apurinic/apyrimidinic (AP) sites (DNA damage and repair) was increased in smokers compared with non-smokers (p = 0.0012) and patients with COPD (p < 0.0148). Nuclear expression of Ku86, but not of DNA-PKcs, phospho-DNA-PKcs, Ku70 or γ-H2AFX, was reduced in bronchiolar epithelial cells from patients with COPD compared with normal smokers and non-smokers (p < 0.039). Loss of Ku86 expression was also observed in a smoking mouse model (p < 0.012) and prevented by antioxidants. Oxidants reduced (p < 0.0112) Ku86 expression in human bronchial epithelial cells and Ku86 knock down modified AP sites in response to oxidative stress. Ineffective DNA repair rather than strand breakage per se accounts for the reduced AP sites observed in COPD and this is correlated with a selective decrease of the expression of Ku86 in the bronchiolar epithelium. DNA damage/repair imbalance may contribute to increased risk of lung carcinoma in COPD.


Brain-heart interaction in perseverative cognition.
The move from the concept of homeostasis to that of allostasis has led reactivity stress research to widen the object of its investigation: from the brief physiological response that occurs when one is facing a stressor to what happens when one is anticipating or recovering from a stressor. A paradigmatic example is represented by perseverative cognition, during which human beings react "as if" they were constantly facing a concrete stressor. The core idea behind this review is that the cognitive inflexibility that characterizes perseverative cognition is reflected in both our body (by increased autonomic nervous system rigidity assessed by heart rate variability; HRV) and our brain (by reduced prefrontal-amygdala functional connectivity). This is a review of studies conducted in different settings (laboratory, daily life), populations (healthy, major depression, generalized anxiety), location (United States, Europe), and age groups (children, adults) that consistently replicated the association between autonomic, subjective, and behavioral measures of cognitive inflexibility during perseverative cognition. Moreover, compelling neuroimaging data suggest that HRV reduction from pre- to post-induction of perseverative cognition is associated with both structural and functional brain abnormalities reflecting impaired prefrontal inhibitory control over subcortical structures (e.g., diminished prefrontal-amygdala functional connectivity). The integration of neuroscience techniques with clinical autonomic research has advanced our understanding of the neurobiology of brain-heart interaction during perseverative cognition, potentially yielding to more effective treatment packages. This is clinically relevant if one considers that perseverative cognition is a pervasive transdiagnostic factor that carries prognostic risk for both psychological and somatic health.


Platelet-rich plasma exhibits beneficial effects for rheumatoid arthritis mice by suppressing inflammatory factors.
Platelet-rich plasma (PRP) is a multifunctional blood product containing highly concentrated platelets, and various cell growth factors which promote cell proliferation and differentiation. PRP exhibited benefits in injurious articular cartilage repair and the removal of inflammatory factors in clinical studies. Rheumatoid arthritis (RA) is an autoimmune disease manifesting primarily as inflammatory arthritis, which is associated with notable morbidity in humans. In the present study, the therapeutic effects and primary mechanism of PRP on a type II collagen‑induced arthritis (CIA) mouse model was investigated. Inflammatory factors interleukin (IL)‑6, IL‑8, IL‑17, IL‑1β, tumor necrosis factor (TNF)‑α and interferon (IFN)‑γ were analyzed in PRP and PBS‑treated groups. Vascular endothelial growth factor (VEGF), platelet‑derived growth factor (PDGF), insulin‑like growth factor (IGF)‑1 and transforming growth factor (TGF)‑β expression in peripheral whole blood was additionally analyzed. The therapeutic efficacy of PRP for RA mice was evaluated using clinical arthritis scores. The results of the present study demonstrated that treatment with PRP alleviated arthritis, and reduced humoral and cellular immune responses, leading to beneficial effects on histological parameters as observed using joint tissue histological staining. CIA mice treated with PRP exhibited downregulated expression of IL‑6, IL‑8, IL‑17A, IL‑1β, TNF‑α, receptor activator for nuclear factor‑κB and IFN‑γ in inflammatory tissue. In addition, VEGF, PDGF, IGF‑1 and TGF‑β expression in peripheral whole blood was increased following treatment with PRP. The serum concentration of anti‑collagen antibody was decreased in PRP‑treated CIA mice. In conclusion, CIA mice treated with PRP exhibited beneficial effects, including decreased joint inflammation, cartilage destruction and bone damage, and increased repair of joint tissue. The results of the present study suggested that PRP may be an effective therapeutic agent for RA.


Polyamines in pancreatic islets of obese-hyperglycemic (ob/ob) mice of different ages.
To further evaluate the role of polyamines in insulin production and cell replication in diabetic pancreatic islets, we have studied hyperplastic islets of obese-hyperglycemic mice of different ages and normal islets of the same strain. The aims of the study were to investigate the impact of the diabetic state and aging on polyamine contents and requirements in these islets. Cultured islets from lean and obese animals contained significantly less polyamines than freshly isolated islets. Spermine-to-spermidine ratio was elevated in freshly isolated islets from young obese mice compared with those from lean mice. In islets from old obese animals, spermidine content was decreased, whereas the content of spermine was not different from that of young obese mice. The physiological significance of polyamines was investigated by exposing islets in tissue culture to inhibitors of polyamine synthesis. This treatment caused a partial polyamine depletion in whole islets but failed to affect polyamine content of cell nuclei. Insulin content was not affected in polyamine-deficient islets of obese mice, irrespective of age, in contrast to decreased islet insulin content in polyamine-depleted young lean animals. Polyamine depletion depressed DNA synthesis rate in obese mouse islets; in lean mice it actually stimulated DNA synthesis. We concluded that important qualitative and quantitative differences exist between islets from obese-hyperglycemic and normal mice with respect to polyamine content and requirements of polyamines for regulation of insulin content and cell proliferation. The results suggest that spermine may be involved in mediating the rapid islet cell proliferation noted early in obese-hyperglycemic syndrome, but changes in spermine concentration do not seem to account for the decline in islet cell DNA synthesis in aged normoglycemic animals.


Longterm Survival and Cost-Effectiveness of Immunosuppression Withdrawal After Liver Transplantation.
Lifelong immunosuppression (IS) after liver transplantation is associated with severe adverse effects and increased recipients' morbidity and mortality. Clinical operational tolerance has been reported in up to 40% in very well-selected recipients. Longterm survival and cost savings within the Italian national health system in operational tolerant recipients is reported. Seventy-five liver recipients were enrolled for IS withdrawal at our institution during the period from April 1998 to December 2015. The study population comprised 32 (42.7%) tolerant patients; 41 (54.7%) nontolerant patients needing uptake of IS after clinical or biopsy-proven rejection; and 2 (2.7%) immediate nontolerant patients who developed early rejection after the first drug reduction. The primary endpoint of the study was to assess the longterm patients and graft outcome; the secondary endpoint was the assessment of cost savings in the context of IS withdrawal. The follow-up was 95.0 months (interquartile range, 22.5-108.5 months). IS withdrawal did not result in patient nor graft loss and resulted in a major cost savings reaching about €630,000. In conclusion, longterm IS withdrawal represents a remarkable cost savings in the health care of liver recipients without exposing them to graft loss.


Bradykinin B2 receptors mediate contraction in the normal and inflamed human gallbladder in vitro.
The components of the kinin system, including kinongens, kininogenases, and B(2) and B(1) receptors, are expressed and activated during inflammation. Here, we investigated the expression of the kinin B(2) receptor messenger RNA, kininogen and kallikrein immunoreactivity, and the ability of kinins to contract control and inflamed gallbladders in vitro. Human gallbladders, obtained from patients undergoing cholecystectomy either for acute cholecystitis secondary to gallstone disease or during elective gastro-entero-pancreatic surgery (controls), were processed for reverse-transcription polymerase chain reaction analysis, kallikrein and kininogen immunohistochemistry, binding studies, and in vitro contractility studies. Tissue expression of B(2) receptor messenger RNA and specific binding of [(3)H]-bradykinin increased significantly in acute cholecystitis compared to controls. Kallikrein immunoreactivity was detected in the epithelium and infiltrating leukocytes, whereas kininogen immunoreactivity in the lumen of blood vessels and interstitial space. Bradykinin contracted isolated strips of control and acute cholecystitis gallbladders. In acute cholecystitis tissue, efficacy of bradykinin was higher than that of control gallbladders and similar to that of cholecystokinin. The contraction induced by bradykinin was significantly attenuated by B(2) receptor antagonism but not by cyclooxygenase inhibition and B(1), muscarinic, or tachykinin receptor antagonism. All the components of the kinin system are expressed in the human gallbladder. Bradykinin is a powerful spasmogen via B(2) receptor activation in the normal and, especially, in the inflamed human gallbladder.


Central stimulants in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents. A naturalistic study of the prescription in Sweden, 1977-2007.
An increased prescription of central stimulants (CS) for treatment of attention-deficit hyperactivity disorder (ADHD) in children and adolescents has been reported in Sweden. To follow-up the treatment with CS as concerns total as well as regional differences in prescription rate. Efficacy and side-effects reported and gender differences in prescription over time also have been summarized. Data from the Swedish Medical Products Agency (MPA) of individual licences, annual reports about patients on individual or clinic licences from the MPA and sales statistics from the National Pharmacy (Apoteket AB) have been used. The number of new licences and prescriptions increased dramatically from 1992 to 2007 and a change of preparations was seen. Great differences (fivefold) between the 21 counties of Sweden were noticed. In the follow-up reports to the MPA, a good/moderate treatment effect was reported in 92% and adverse effects were reported in 4% leading to discontinuation of medication in 46% of them. Abuse/misuse of the preparation was suspected in 0.2% of the reports. A tendency of a reduction of the proportion of boys to girls treated through individual licences has been seen. The study, although observational, supports good efficacy, limited adverse effects and a low degree of misuse in clinical use of CS for children and adolescents with ADHD.


Stable implantation of orthogonal sensor circuits in Gram-negative bacteria for environmental release.
A broad host range, orthogonal genetic platform has been developed to format sensor circuits in the chromosome of Gram-negative microorganisms destined for environmental release as bioindicators of toxic or perilous compounds (e.g. explosives) in soil. The genetic scheme includes the generation of a genomic landing pad for the sensor module with a Tn5-mini-transposon bearing an optimal attTn7 sequence and a choice of reporter systems with optical and enzymatic outputs. The array of functional elements thereby inserted in the chromosome match that of a cognate plasmid vector which delivers the transcription factors and the promoters to a frame that places the regulatory parts in front of the reporters. Site-specific recombination sites allow the deletion of antibiotic resistances and enables reporter output prior to deliberate release. The system thus allows the production and maintenance of cells in a pre-release state and its intentional conversion in deliverable strains that fulfil all safety, stability and performance criteria. The combination of such a genetic platform with a variant of the transcriptional regulator XylR of Pseudomonas putida that responds to 2,4-dinitrotoluene has been the basis for the production of strains that emit light upon exposure to residues of explosives in a soil microcosm.


Functional near-infrared spectroscopy can detect low-frequency hemodynamic oscillations in the prefrontal cortex during steady-state visual evoked potential-inducing periodic facial expression stimuli presentation.
Brain oscillations are vital to cognitive functions, while disrupted oscillatory activity is linked to various brain disorders. Although high-frequency neural oscillations (> 1 Hz) have been extensively studied in cognition, the neural mechanisms underlying low-frequency hemodynamic oscillations (LFHO) < 1 Hz have not yet been fully explored. One way to examine oscillatory neural dynamics is to use a facial expression (FE) paradigm to induce steady-state visual evoked potentials (SSVEPs), which has been used in electroencephalography studies of high-frequency brain oscillation activity. In this study, LFHO during SSVEP-inducing periodic flickering stimuli presentation were inspected using functional near-infrared spectroscopy (fNIRS), in which hemodynamic responses in the prefrontal cortex were recorded while participants were passively viewing dynamic FEs flickering at 0.2 Hz. The fast Fourier analysis results demonstrated that the power exhibited monochronic peaks at 0.2 Hz across all channels, indicating that the periodic events successfully elicited LFHO in the prefrontal cortex. More importantly, measurement of LFHO can effectively distinguish the brain activation difference between different cognitive conditions, with happy FE presentation showing greater LFHO power than neutral FE presentation. These results demonstrate that stimuli flashing at a given frequency can induce LFHO in the prefrontal cortex, which provides new insights into the cognitive mechanisms involved in slow oscillation.


Peripheral lymphadenopathy: approach and diagnostic tools.
Peripheral lymph nodes, located deep in the subcutaneous tissue, clean antigens from the extracellular fluid. Generally, a normal sized lymph node is less than one cm in diameter. Peripheral lymphadenopathy (LAP) is frequently due to a local or systemic, benign, self-limited, infectious disease. However, it could be a manifestation of underlying malignancy. Seventy-five percent of all LAPs are localized, with more than 50% being seen in the head and neck area. LAP may be localized or generalized. Cervical lymph nodes are involved more often than the other lymphatic regions. Generally, it is due to infections, but most of the supraclavicular lymphadenopathies are associated with malignancy. Based on different geographical areas, the etiology is various. For example, in tropical areas, tuberculosis (TB) is a main benign cause of LAP in adults and children. Complete history taking and physical examination are mandatory for diagnosis; however, laboratory tests, imaging diagnostic methods, and tissue samplings are the next steps. Tissue diagnosis by fine needle aspiration biopsy or excisional biopsy is the gold standard evaluation for LAP. We concluded that in patients with peripheral LAP, the patient's age and environmental exposures along with a careful history taking and physical examination can help the physician to request step by step further work-up when required, including laboratory tests, imaging modalities, and tissue diagnosis, to reach an appropriate diagnosis.


Enhancement of the efficacy of cancer chemotherapy by the pineal hormone melatonin and its relation with the psychospiritual status of cancer patients.
The anti-oxidant and immunomodulating natural agents may enhance the efficacy of cancer chemotherapy. One of the most important agents is the pineal hormone melatonin (MLT) which may exert both anti-oxidant and antiproliferative immunostimulating anticancer effects. This study was performed to evaluate the efficacy of a biochemotherapeutic regimen in metastatic cancer patients, and its therapeutic activity in relation to the psychospiritual status of patients. The study included 50 metastatic non-small cell lung cancer (NSCLC) patients and a control group of 100 patients. Chemotherapy consisted of cisplatin plus gemcitabine. MLT was given orally at 20 mg/day in the evening. Patients were subdivided into 5 psychic profiles, as follows: spiritual faith, rationale faith, anxiety, apathy, and accusation behavior. Tumor response rate was significantly higher in patients treated by chemotherapy plus MLT than in those treated by chemotherapy alone (21/50 vs. 24/100, p < 0.001). However, the percentage of objective tumor regressions obtained in patients with spiritual faith was significantly higher than that found in the overall other patients concomitantly treated by chemotherapy plus MLT (6/8 vs. 15/42, p < 0.01). In conclusion, the efficacy of chemotherapy may be enhanced by the pineal hormone MLT, by representing a new promising biochemotherapeutic combination; also despite its objective ability to enhance chemotherapy efficacy, the activity of MLT is depending at least in part on the psychospiritual status of cancer patients, and it is maximal in the presence of a real spiritual faith.