Impact of Crisis Line Volunteering on Mental Wellbeing and the Associated Factors: A Systematic Review.
Crisis line services, operated by volunteers, have been proven to be effective in decreasing psychological pain and preventing suicidality. Although working at the crisis line may be rewarding, for some the confrontation with highly complex topics (i.e., suicidality, abuse, and loneliness) in combination with inappropriate calls (i.e., sexually abusive calls), may lead to distress or vicarious trauma. The aim of this paper is to systematically review the studies that have examined mental wellbeing of crisis line volunteers and the factors associated with it. Thirteen published empirical studies on the topic were found. These showed that crisis line volunteers are at increased risk of declined mental wellbeing. However, a wide range of operationalizations were used and most studies did not use validated instruments. On the other hand, studies showed that many volunteers experience satisfaction and gratification from their work. This review gives insight into some of the work-related, organization-related, and volunteer-related factors that may be associated with the decrease of mental wellbeing. More high quality, comprehensive, and quantitative research using validated instruments is urgently needed to assess the impact of the work on mental wellbeing and the relative impact of influencing factors.


A multicentre study of 95 biopsy-proven cases of renal disease in primary Sjögren's syndrome.
Renal involvement is a rare event during primary SS (pSS). We aimed to describe the clinico-biological and histopathological characteristics of pSS-related nephropathy and its response to treatment. We conducted a French nationwide, retrospective, multicentre study including pSS patients fulfilling American-European Consensus Group criteria or enlarged American-European Consensus Group criteria, and with biopsy-proven renal involvement. A total of 95 patients were included (median age 49 years). An estimated glomerular filtration rate (eGFR) of <60 ml/min was found in 82/95 patients (86.3%). Renal biopsy demonstrated tubulointerstitial nephritis (TIN) in 93 patients (97.9%), and frequent (75%) plasma cell infiltrates. Glomerular lesions were found in 22 patients (23.2%), mainly related to cryoglobulin. The presence of anti-SSA (76.8%) and anti-SSB (53.8%) antibodies was particularly frequent among patients with TIN and was associated with a worse renal prognosis. Eighty-one patients (85.3%) were treated, with CSs in 80 (98.8%) and immunosuppressive agents (mostly rituximab) in 21 cases (25.9%). Despite marked interstitial fibrosis at initial biopsy, kidney function improved significantly during the 12-month period following diagnosis (final eGFR 49.9 vs 39.8 ml/min/1.73 m 2 at baseline, P < 0.001). No proven benefit of immunosuppressive agents over steroid therapy alone was found in this study. Renal involvement of pSS is mostly due to TIN with marked T, B and especially plasma cell infiltration. Renal dysfunction is usually isolated but can be severe. Use of CSs can improve the eGFR, but further studies are needed to define the best therapeutic strategy in this disease.


[Better adaptation of the Tunisian adolescent health care system].
Classical health indicators are insufficient to account for adolescent health. With the majority of young people's health problems being linked to social and behavioural factors, the compartmentalised and biomedical approaches to their health are inept. Can the totality of adolescents' health needs receive an appropriate response in a health care system which articulates itself based upon a parceled vision of health? Health professionals seem to experience difficulties in situating themselves above the expressed symptom, and therefore become aware of the real needs linked to the emotional, familial and educational contexts and integrate a global, multi-disciplinary approach to adolescent and young adult health into their everyday practice. Their reduced consumption of care is not only linked to the fact that adolescents in general enjoy good health, but it is also linked to the difficulties of the health care system to recognise their true health needs. It thus emphasises the need to develop competencies in the field of adolescent health and organise the work in a multi-disciplinary network. In order to accomplish this, it is essential that the medical schools and public health schools offer a multi-disciplinary approach to adolescent health allowing for future health professionals to be able to address fields which are not uniquely bio-medically dependent. Furthermore, the regional medical study and university centres must evolve to become welcome centers and care centers for adolescents, adopting a multi-disciplinary approach going beyond the simple juxtaposition of diverse disciplines.


A Study of the Reliability and Concurrent Validity of the Chinese Version of the Pain Medication Attitude Questionnaire (ChPMAQ) in a Sample of Chinese Patients with Chronic Pain.
The Pain Medication Attitude Questionnaire (PMAQ) was designed to assess concerns about pain medication among patients with chronic nonmalignant pain. The instrument has been demonstrated to be a reliable measure with good psychometric properties, yet its validity among Chinese has not been evaluated. This study aimed to translate the English-language version of the PMAQ into Chinese (ChPMAQ) and to evaluate its reliability and concurrent validity. A total of 201 Chinese patients with chronic pain attending two multidisciplinary pain clinics in Hong Kong completed the ChPMAQ, the Chronic Pain Grade (CPG) questionnaire, the mental health subscale of the SF-12 (QoL-Mental), and questions assessing sociodemographic and pain characteristics. Our results showed that the seven ChPMAQ scales possessed good internal consistency. Except for the correlation between Withdrawal and Mistrust (r = 0.13), all ChPMAQ scales were significantly correlated with each other (all p < 0.01). The scales also correlated with two concurrent criterion measures, QoL-Mental and Pain Disability, in a predictable direction. Results of hierarchical multiple regression analyses showed that the ChPMAQ scales predicted concurrent QoL-Mental (F(7,190) = 2.75, p < 0.05) and pain disability (F(7,188) = 3.00, p < 0.01). Need (std β = -0.23, p<0.05) and Side effects (std β = 0.27, p < 0.01) emerged as independent predictors of concurrent QoL-Mental and pain disability, respectively. Despite the current preliminary findings for the reliability and concurrent validity of the ChPMAQ, more research is needed to substantiate the reliability, validity and other psychometric properties of the instrument.


Effects of keratinocyte growth factor-2 (KGF-2) on wound healing in an ischaemia-impaired rabbit ear model and on scar formation.
Keratinocyte growth factor-2 (KGF-2), also described as fibroblast growth factor-10 (FGF-10), is a member of the fibroblast growth factor family. KGF-2 shares 57 per cent sequence homology to previously reported KGF-1 (FGF-7). In skin, both growth factors are expressed in the dermal compartment. KGF-1 and KGF-2 bind to the same receptor with high affinity, the KGFR isoform of FGFR2, which is exclusively expressed by epithelial cells. This study examines the in vivo function of topically applied KGF-2 on wound healing using an ischaemia-impaired rabbit dermal ulcer model, in young and aged animals. Histological analysis of the wounds showed that KGF-2 significantly promoted re-epithelialization in both young and old animals. Similar results have been observed with KGF-1 in this model. In addition, KGF-2 enhanced granulation tissue formation in both young and old rabbits, a biological effect not found with KGF-1, suggesting a possible indirect mechanism which enhances neo-granulation tissue formation. Immunohistological staining of day 7 wounds with proliferating cell nuclear antigen (PCNA) antibody demonstrated a significant increase of dermal cell proliferation in KGF-2-treated wounds compared with placebo wounds. These results suggest a mesenchymal-epithelial interaction that is mediated by a paracrine feedback loop of KGF-2. Because of the wound healing impairment observed with ageing, the wound healing response to KGF-2 was also studied in ischaemic wounds of aged animals. Administration of KGF-2 led to significant stimulation of epithelial growth and granulation tissue formation. The effects seen in the old animals were delayed compared with the young animals. Lastly, the effect of KGF-2 was examined in a rabbit model of scar formation. Quantification of scar elevation index showed no significant differences in scar formation when KGF-2 was compared with buffer placebo. Compared with other growth factors, including KGF-1 and TGF-beta which have previously been examined in these models, KGF-2 is the most effective and causes no obvious scarring.


Lithium Reduces Migration and Collagen Synthesis Activity in Human Cardiac Fibroblasts by Inhibiting Store-Operated Ca2+ Entry.
Cardiac fibrosis plays a vital role in the pathogenesis of heart failure. Fibroblast activity is enhanced by increases in store-operated Ca2+ entry (SOCE) and calcium release-activated calcium channel protein 1 (Orai1) levels. Lithium regulates SOCE; however, whether therapeutic concentrations of lithium can be used to inhibit cardiac fibrogenesis is unknown. Migration and proliferation assays, Western blotting, real-time reverse-transcription polymerase chain reaction analysis, and calcium fluorescence imaging were performed in human cardiac fibroblasts treated with or without LiCl at 1.0 mM (i.e., therapeutic peak level) or 0.1 mM (i.e., therapeutic trough level) for 24 h. Results showed that LiCl (0.1 mM, but not 1.0 mM) inhibited the migration and collagen synthesis ability of cardiac fibroblasts. Additionally, thapsigargin-induced SOCE was reduced in fibroblasts treated with LiCl (0.1 mM). The expression level of Orai1 was lower in LiCl (0.1 mM)-treated fibroblasts relative to the fibroblasts without LiCl treatment. Fibroblasts treated with a combination of LiCl (0.1 mM) and 2-APB (10 μM, an Orai1 inhibitor) demonstrated similar migration and collagen synthesis abilities as those in LiCl (0.1 mM)-treated fibroblasts. Altogether, lithium at therapeutic trough levels reduced the migration and collagen synthesis abilities of human cardiac fibroblasts by inhibiting SOCE and Orai1 expression.


Classification of obsessive compulsive disorder by EEG complexity and hemispheric dependency measurements.
In the present study, both single channel electroencephalography (EEG) complexity and two channel interhemispheric dependency measurements have newly been examined for classification of patients with obsessive-compulsive disorder (OCD) and controls by using support vector machine classifiers. Three embedding entropy measurements (approximate entropy, sample entropy, permutation entropy (PermEn)) are used to estimate single channel EEG complexity for 19-channel eyes closed cortical measurements. Mean coherence and mutual information are examined to measure the level of interhemispheric dependency in frequency and statistical domain, respectively for eight distinct electrode pairs placed on the scalp with respect to the international 10-20 electrode placement system. All methods are applied to short EEG segments of 2 s. The classification performance is measured 20 times with different 2-fold cross-validation data for both single channel complexity features (19 features) and interhemispheric dependency features (eight features). The highest classification accuracy of 85 ±5.2% is provided by PermEn at prefrontal regions of the brain. Even if the classification success do not provided by other methods as high as PermEn, the clear differences between patients and controls at prefrontal regions can also be obtained by using other methods except coherence. In conclusion, OCD, defined as illness of orbitofronto-striatal structures [Beucke et al., JAMA Psychiatry70 (2013) 619-629; Cavedini et al., Psychiatry Res.78 (1998) 21-28; Menzies et al., Neurosci. Biobehav. Rev.32(3) (2008) 525-549], is caused by functional abnormalities in the pre-frontal regions. Particularly, patients are characterized by lower EEG complexity at both pre-frontal regions and right fronto-temporal locations. Our results are compatible with imaging studies that define OCD as a sub group of anxiety disorders exhibited a decreased complexity (such as anorexia nervosa [Toth et al., Int. J. Psychophysiol.51(3) (2004) 253-260] and panic disorder [Bob et al., Physiol. Res.55 (2006) S113-S119]).


Evidence of Intermediate Hydrogen States in the Formation of a Complex Hydride.
A complex hydride (LaMg2NiH7) composed of La3+, two Mg2+, [NiH4]4- with a covalently bonded hydrogen, and three H- was formed from an intermetallic LaMg2Ni via an intermediate phase (LaMg2NiH4.6) composed of La, Mg, NiH2, NiH3 units, and H atoms at tetrahedral sites. The NiH2 and NiH3 units in LaMg2NiH4.6 were reported as precursors for [NiH4]4- in LaMg2NiH7 [ Miwa et al. J. Phys. Chem. C 2016 , 120 , 5926 - 5931 ]. To further understand the hydrogen states in the precursors (the NiH2 and NiH3 units) and H atoms at the tetrahedral sites in the intermediate phase, LaMg2NiH4.6, we observed the hydrogen vibrations in LaMg2NiH4.6 and LaMg2NiH7 by using inelastic neutron scattering. A comparison of the hydrogen vibrations of the NiH2 and NiH3 units with that of [NiH4]4- shows that the librational modes of the NiH2 and NiH3 units were nonexistent; librational modes are characteristic modes for complex anions, such as [NiH4]4-. Furthermore, the hydrogen vibrations for the H atoms in the tetrahedral sites showed a narrower wavenumber range than that for H- and a wider range than that for typical interstitial hydrogen. The results indicated the presence of intermediate hydrogen states before the formation of [NiH4]4- and H-.


Longitudinal relationship of diet and oxidative stress with depressive symptoms in patients with metabolic syndrome after following a weight loss treatment: the RESMENA project.
Metabolic syndrome and depression seem to share some common underlying mechanisms, although less is known about the impact of metabolic syndrome dietary treatments on depression. This study examined the association between a hypocaloric treatment designed to reduce metabolic syndrome features in self-perceived depression and the potential involvement of dietary components and oxidative stress changes. Analyses were based on volunteers (n = 55) with metabolic syndrome (age 50 ± 1 y.o.; 38M/17F), where depressive symptoms were assessed using the Beck Depression Inventory. Participants followed two hypocaloric diets (control diet and RESMENA diet) with the same energy restriction (-30% TCV) for six months. Depressive symptoms, dietary records, anthropometrical measurements, biochemical parameters and oxidative stress levels were analysed. Both diets improved self-perceived depression similarly (p = 0.528). Participants with lower depressive symptoms at baseline reported a significantly higher intake of omega-3 polyunsaturated fatty acids (p trend = 0.002). Interestingly, after adjusting for potential confounders, the increase in folate consumption (p = 0.011) and the decrease in plasma malondialdehyde levels (p = 0.012) throughout the intervention, were associated with the improvement in depressive symptoms. A higher intake of folate and a decline in malondialdehyde plasma levels during a weight loss intervention, were related to improvements in manifestations of depression (www.clinicaltrials.gov; NCT01087086).


Enhancement of antiproliferative activity by phototautomerization of anthrylphenols.
An antiproliferative investigation was conducted on 3 human cancer cell lines, HCT 116 (colon), MCF-7 (breast), and H 460 (lung), on a series of 4 anthrylphenols in the dark and upon exposure to light (350 nm). 9-(2-Hydroxyphenyl)anthracene (1) moderately inhibited proliferation, but irradiation considerably enhanced the effect. The other anthracenes 4–6 exhibited antiproliferative activity in the dark, which was not enhanced upon irradiation. The enhancement of the antiproliferative effect on the irradiation of 1 was rationalized as being due to the formation of quinone methide (QM 2) by excited state proton transfer. QM 2 acts as an electrophilic species capable of reacting with biological molecules. Although QM 2 reacts with nucleotides, the adducts could not be isolated. On the contrary, cysteine adduct 8 was isolated and characterized, whereas the adducts with glycine, serine and tripeptide glutathione were characterized by MS. Non-covalent binding of 1 to DNA and bovine serum albumin was demonstrated by UV-vis, fluorescence and CD spectroscopy. However, a straightforward conclusion regarding the DNA or protein alkylating (damaging) ability of 2 could not be drawn. The results obtained by the irradiation of 1 in the presence of DNA, amino acids and peptides, cell cycle perturbation analysis, and in vitro translation of GFP suggest that the effect is not only due to the damage of DNA but also due to the impact on the cellular proteins. Considering that to date all QM agents were assumed to target DNA dominantly, this is an important finding with an impact on the further development of anticancer agents based on QMs.


Weather and land cover influences on mosquito populations in Sioux Falls, South Dakota.
This study compared the spatial and temporal patterns of Culex tarsalis Coquillett and Aedes vexans Meigen populations and examined their relationships with land cover types and climatic variability in Sioux Falls, SD. Between 24 and 30 CDC CO2-baited light traps were set annually in Sioux Falls from May to September 2005-2008. Land cover data were acquired from the 2001 National Land Cover Dataset and the percentages of selected land cover types were calculated within a 600-m buffer zone around each trap. Meteorological information was summarized from local weather stations. Cx. tarsalis exhibited stronger spatial autocorrelation than Ae. vexans. Land cover analysis indicated that Cx. tarsalis was positively correlated with grass/hay, and Ae. vexans was positively correlated with wetlands. No associations were identified between irrigation and the host-seeking population of each species. Higher temperature in the current week and 2 wk prior and higher precipitation 3-4 wk before collection of host-seeking adult mosquitoes had positive influences on Cx. tarsalis abundance. Temperature in the current week and rainfall 2-3 wk before sampling had positive influences on Ae. vexans abundance. This study revealed the different influences of weather and land cover on important mosquito species in the Northern Great Plains region, which can be used to improve local vector control strategies and West Nile virus prevention efforts.


Are sites with multiple single nucleotide variants in cancer genomes a consequence of drivers, hypermutable sites or sequencing errors?
Across independent cancer genomes it has been observed that some sites have been recurrently hit by single nucleotide variants (SNVs). Such recurrently hit sites might be either (i) drivers of cancer that are postively selected during oncogenesis, (ii) due to mutation rate variation, or (iii) due to sequencing and assembly errors. We have investigated the cause of recurrently hit sites in a dataset of >3 million SNVs from 507 complete cancer genome sequences. We find evidence that many sites have been hit significantly more often than one would expect by chance, even taking into account the effect of the adjacent nucleotides on the rate of mutation. We find that the density of these recurrently hit sites is higher in non-coding than coding DNA and hence conclude that most of them are unlikely to be drivers. We also find that most of them are found in parts of the genome that are not uniquely mappable and hence are likely to be due to mapping errors. In support of the error hypothesis, we find that recurently hit sites are not randomly distributed across sequences from different laboratories. We fit a model to the data in which the rate of mutation is constant across sites but the rate of error varies. This model suggests that ∼4% of all SNVs are errors in this dataset, but that the rate of error varies by thousands-of-fold between sites.


Urocortin 3 transgenic mice exhibit a metabolically favourable phenotype resisting obesity and hyperglycaemia on a high-fat diet.
Urocortins are the endogenous ligands for the corticotropin-releasing factor receptor type 2 (CRFR2), which is implicated in regulating energy balance and/or glucose metabolism. We determined the effects of chronic CRFR2 activation on metabolism in vivo, by generating and phenotyping transgenic mice overproducing the specific CRFR2 ligand urocortin 3. Body composition, glucose metabolism, insulin sensitivity, energy efficiency and expression of key metabolic genes were assessed in adult male urocortin 3 transgenic mice (Ucn3(+)) under control conditions and following an obesogenic high-fat diet (HFD) challenge. Ucn3(+) mice had increased skeletal muscle mass with myocyte hypertrophy. Accelerated peripheral glucose disposal, increased respiratory exchange ratio and hypoglycaemia on fasting demonstrated increased carbohydrate metabolism. Insulin tolerance and indices of insulin-stimulated signalling were unchanged, indicating these effects were not mediated by increased insulin sensitivity. Expression of the transgene in Crfr2 (also known as Crhr2)-null mice negated key aspects of the Ucn3(+) phenotype. Ucn3(+) mice were protected from the HFD-induced hyperglycaemia and increased adiposity seen in control mice despite consuming more energy. Expression of uncoupling proteins 2 and 3 was higher in Ucn3(+) muscle, suggesting increased catabolic processes. IGF-1 abundance was upregulated in Ucn3(+) muscle, providing a potential paracrine mechanism in which urocortin 3 acts upon CRFR2 to link the altered metabolism and muscular hypertrophy observed. Urocortin 3 acting on CRFR2 in skeletal muscle of Ucn3(+) mice results in a novel metabolically favourable phenotype, with lean body composition and protection against diet-induced obesity and hyperglycaemia. Urocortins and CRFR2 may be of interest as potential therapeutic targets for obesity.


Modulation of Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines.
2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in approximately 500 currently available structures, and present in nearly 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in such molecules can give rise to two distinct chemical environments. Here we demonstrate, using NMR studies and density functional theory modeling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amide E:Z equilibrium is affected by non-covalent interactions between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amide conformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis of the available X-ray data of a variety of published N-acyl-piperidine-containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures.


Failure of temporal lobe resection for epilepsy in patients with mesial temporal sclerosis: results and treatment options.
The purpose of this study was to identify the causes of failed temporal lobe resection in patients with mesial temporal sclerosis (MTS) and the role of repeat surgery for seizure control. This is a retrospective study of 105 patients who underwent temporal lobe resection for MTS with unilateral electroencephalographic findings. The mean follow-up duration was 36 months (range 24-84 months). Surgeries were all performed by the senior author (F.L.V.). Following initial surgical intervention, 97 patients (92%) improved to Engel Class I or II (Group A), and 8 (8%) did not have significant improvement (Engel Class III or IV; Group B). These 8 patients were restudied using video-electroencephalography (EEG) and MR imaging. All major surgical failures occurred within 1 year after initial intervention. Reevaluation demonstrated 3 patients (37.5%) with contralateral temporal EEG findings. Five patients (62.5%) had evidence of ipsilateral recurrent discharges. Four patients underwent extended neocortical resection along the previous resection cavity. Their outcomes ranged from Engel Class I to Class III. Only 1 patient (12.5%) who failed to improve after initial surgery was found to have incomplete resection of mesial structures. This last patient underwent reoperation to complete the resection and improved to Engel Class I. Failure of temporal lobe resection for MTS is multifactorial. The cause of failure lies in the pathological substrate of the epileptogenic area. Complete seizure control cannot be predicted solely by conventional preoperative workup. Initial surgical failures from temporal lobe resection often benefit from reevaluation, because reoperation may be beneficial in selected patients. Based on this work, the authors have proposed a management and treatment algorithm for these patients.


Mutation to herbicide resistance maps within the psbA gene of Anacystis nidulans R2.
A psbA gene encoding the target of photosystem II herbicide inhibition, the 32,000-dalton thylakoid membrane protein, has been cloned from a mutant of Anacystis nidulans R2, which is resistant to 3-(3,4-dichlorophenyl)-1,1-dimethylurea-(diuron). A cloned DNA fragment from within the coding region of this gene transforms wild-type cells to herbicide resistance, proving that mutation within psbA is responsible for that phenotype. The mutation consists of a single nucleotide change that replaces serine at position 264 of the wild-type protein with alanine in that of the diuron-resistant mutant.


Effect of intracellular and extracellular pH on contraction in isolated, mammalian cardiac muscle.
1. Intracellular pH (pHi) and Na+ activity were recorded (ion-selective microelectrodes) in guinea-pig papillary muscle and the sheep cardiac Purkinje fibre while simultaneously recording twitch tension. The effects of intracellular acidosis and alkalosis upon contraction were investigated. 2. A fall of pHi produced by reducing pHo was associated with a fall of twitch tension. Similarly, a rise of pHi produced by raising pHo produced a rise of twitch tension. The time course of the changes in tension correlated with the time course of changes of pHi rather than pHo. These results are consistent with previous work showing that acidosis inhibits contraction and that the inhibition depends upon a fall of pHi. 3. Changes of pHi were produced while maintaining pHo constant at 7.4. Removal of NH4Cl or addition of sodium acetate (pHo 7.4) reduced pHi but this gave either an increase of tension (papillary muscle) or an initial fall followed by a subsequent recovery of tension (Purkinje fibre). The increase or recovery of tension occurred despite the fact that there was an intracellular acid load. Thus, reducing pHi at constant pHo can increase tension whereas reducing pHi at low pHo (6.4, see paragraph 2) inhibits tension. 4. The increase of recovery of tension during intracellular acidosis produced at a constant pHo (7.4) was associated with a rise of intracellular sodium activity (aiNa). Amiloride (1.5 mmol/l), an inhibitor of Na(+)-H+ exchange, prevented the rise of aiNa during intracellular acidosis and also prevented the recovery of tension. It is concluded that the increase or recovery of tension at low pHi is secondary to a rise of aiNa caused by stimulation of Na(+)-H+ exchange. A rise of aiNa will elevate Ca2+ via sarcolemmal Na(+)-Ca2+ exchange and thus will elevate tension. 5. An intracellular acidosis produced by reducing pHo (6.4) does not elevate aiNa in the Purkinje fibre. In papillary muscle, aiNa rises but this occurs slowly and the rise is 50% smaller than that seen when the same intracellular acidosis is induced at normal pHo (7.4). The net depression of tension under these conditions thus correlates with the lack of a large rise of aiNa. 6. Knowing the quantitative dependence of tension upon both aiNa and pHi in the two tissues it is possible to predict the recovery of twitch tension during intracellular acidosis at constant pHo (7.4), using the changes of pHi and aiNa measured under these conditions.(ABSTRACT TRUNCATED AT 400 WORDS)


Estradiol-17 beta affects estrogen receptor distribution and elevates progesterone receptor content in baboon aorta.
We used the synthetic estrogen R2858 (moxestrol) and estradiol-17 beta, respectively, to characterize the estrogen receptor in baboon (Papio sp.) aortic or myocardial cytoplasmic and nuclear preparations. We observed regional differences in the cytoplasmic fraction estrogen and progesterone receptor content of aortic arch, thoracic aorta, and abdominal aorta when tissues from either oophorectomized or oophorectomized estradiol-17 beta-treated subjects were compared. The estrogen receptor content was highest in the abdominal aorta and lowest in the aortic arch. In contrast, the cytoplasmic fraction progesterone receptor content was highest in the aortic arch and lowest in the abdominal aorta. The nuclear fraction estrogen receptor could not be demonstrated in preparations from cardiovasculature of oophorectomized female baboons. The use of Silastic implants to administer a physiologic concentration of estradiol-17 beta to oophorectomized female baboons caused a 20% to 50% reduction in cytoplasmic fraction estrogen receptor content, which was quantitatively accounted for by the appearance of estrogen receptor in the corresponding nuclear aortic or myocardial preparation. Estrogen administration caused a 20% to 40% increase in cytoplasmic fraction progesterone receptor content in both myocardium and aorta; however, differences were significant only for abdominal aorta (p less than 0.05). Estradiol-17 beta treatment caused a tenfold increase in uterine cytoplasmic fraction progesterone receptor content in treated as compared to oophorectomized control females, suggesting that baboon cardiovasculature is less sensitive to changes in endogenous estrogen concentration than is uterus. The ability of estradiol-17 beta to affect apparent intracellular distribution of baboon cardiovascular estrogen receptors and to elevate cytoplasmic fraction progesterone receptor content suggests that these estrogen receptors are physiologically functional and indicates that estrogen may directly regulate primate cardiovascular cell function.


Parvalbumin- and calbindin D-28k-immunoreactive innervation of orofacial tissues in the rat.
Parvalbumin- and calbindin D-28k-immunoreactive (-ir) innervation was examined in orofacial tissues of the rat. Labial and facial skins were devoid of the calcium-binding protein (CaBP)-ir nerve endings, while the infraorbital and mental nerves contained numerous parvalbumin-ir axons. Labial and gingival mucosae were also devoid of the CaBP-ir nerve endings. The buccal mucosa and incisive papilla contained both encapsulated and unencapsulated endings, while the hard palate mucosa excluding the incisive papilla contained only unencapsulated endings. Encapsulated endings were found just beneath the epithelium or attached to the cartilaginous core of the incisive papilla. Unencapsulated endings in the lamina propria were subdivided into two types: simple (unramified) and complex (ramified). Neurites of simple endings were straight, curved, or coiled, while those of complex endings exhibited a bush-like appearance due to the ramification. In addition, palatal rugae contained intraepithelial endings. The unencapsulated complex endings in palatal rugae coexpressed parvalbumin- and calbindin D-28k-irs, whereas other endings were immunoreactive for parvalbumin alone. The pterygopalatine ganglion contained calbindin D-28k-ir pericellular fibers but not the ir cell bodies. A subpopulation of trigeminal ganglion neurons coexpressed both CaBPs. CaBP-ir encapsulated and unencapsulated endings in the oral mucosa probably include low-threshold mechanoreceptors, while parvalbumin-ir intraepithelial endings in the palatal mucosa may be involved in nociception.


Evaluation of antiparkinsonian drugs in pharmacy records as a marker for Parkinson's disease.
The aim of this study was to determine whether use of antiparkinsonian drugs in pharmacy records can be used as a marker for patients with Parkinson's disease (PD). Data were obtained from the Rotterdam Study, a community-based prospective cohort study among people aged 55 years or older who were all screened for PD. For 5510 persons, of whom 74 had PD, pharmacy records were available. Stepwise logistic regression analysis was used to evaluate whether age, sex and use of the antiparkinsonian drugs amantadine, anticholinergics, dopamine agonists, levodopa and selegiline, were predictive variables for PD. For each individual a probability for having PD was calculated. Sensitivity, specificity and positive predictive value (PPV) were calculated at different cut-off values based on calculated probabilities. More than 90% of the users of levodopa, bromocriptine, selegiline, and users of at least two different antiparkinsonian drugs had PD. Age, use of amantadine, anticholinergics, bromocriptine, levodopa, and selegiline were predictive variables for PD. After application of different cut-off values, sensitivity was at most 66.2%, and specificity was at least 99.8%. A PPV of higher than 90% was obtained at higher probabilities. Based on the high PPV of our predictive model, antiparkinsonian drugs can be used as a reliable marker for PD in pharmacy records. Because sensitivity is low, pharmacy records cannot be used to estimate prevalence of PD.


Surufatinib in advanced pancreatic neuroendocrine tumours (SANET-p): a randomised, double-blind, placebo-controlled, phase 3 study.
Surufatinib showed superior efficacy in extrapancreatic neuroendocrine tumours (NETs) in the phase 3 SANET-ep study. In SANET-p, we aimed to assess the efficacy and safety of surufatinib in patients with advanced pancreatic NETs. SANET-p was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study, done in 21 hospitals across China. Eligible patients were adults (aged 18 years or older) with progressive, advanced, well differentiated pancreatic NETs, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and progression on up to two kinds of previous systemic regimens for advanced disease. Patients were randomly assigned (2:1) via an interactive web response system to receive 300 mg of surufatinib or placebo, taken orally once per day in consecutive 4-week treatment cycles until disease progression, intolerable toxicity, withdrawal of consent, poor compliance, use of other antitumour medication, pregnancy, loss to follow-up, or if the investigator deemed discontinuation in the patient's best interest. Randomisation was done centrally using stratified block randomisation (block size three), stratified by pathological grade, previous systemic antitumour treatment, and ECOG performance status score. Patients, investigators, research staff, and the sponsor study team were masked to treatment allocation. Crossover to surufatinib was permitted for patients in the placebo group with disease progression. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, which included all patients in randomisation. A pre-planned interim analysis was done at 70% of the predicted progression-free survival events. This study is registered at ClinicalTrials.gov, NCT02589821. Between Feb 18, 2016, and Nov 11, 2019, of 264 patients who were screened, 172 (65%) patients were randomly assigned to receive surufatinib (n=113) or placebo (n=59). The median follow-up was 19·3 months (95% CI 9·3-19·4) in the surufatinib group and 11·1 months (5·7-35·9) in the placebo group. The median investigator-assessed progression-free survival was 10·9 months (7·5-13·8) for surufatinib versus 3·7 months (2·8-5·6) for placebo (hazard ratio 0·49, 95% CI 0·32-0·76; p=0·0011). The trial met the early stopping criteria at the interim analysis and was terminated on recommendation from the independent data monitoring committee. The most common grade 3 or worse treatment-related adverse events were hypertension (43 [38%] of 113 with surufatinib vs four [7%] of 59 with placebo), proteinuria (11 [10%] vs one [2%]), and hypertriglyceridaemia (eight [7%] vs none). Treatment-related serious adverse events were reported in 25 (22%) patients in the surufatinib group and four (7%) patients in the placebo group. There were three on-treatment deaths in the surufatinib group, including two deaths due to adverse events (gastrointestinal haemorrhage [possibly treatment-related] and cerebral haemorrhage [unlikely to be treatment-related]), and one death attributed to disease progression. One on-treatment death in the placebo group was attributed to disease progression. Surufatinib significantly improves progression-free survival and has an acceptable safety profile in patients with progressive, advanced pancreatic NETs, and could be a potential treatment option in this patient population. Hutchison MediPharma.


The molecular dimension of microbial species: 3. Comparative genomics of Synechococcus strains with different light responses and in situ diel transcription patterns of associated putative ecotypes in the Mushroom Spring microbial mat.
Genomes were obtained for three closely related strains of Synechococcus that are representative of putative ecotypes (PEs) that predominate at different depths in the 1 mm-thick, upper-green layer in the 60°C mat of Mushroom Spring, Yellowstone National Park, and exhibit different light adaptation and acclimation responses. The genomes were compared to the published genome of a previously obtained, closely related strain from a neighboring spring, and differences in both gene content and orthologous gene alleles between high-light-adapted and low-light-adapted strains were identified. Evidence of genetic differences that relate to adaptation to light intensity and/or quality, CO2uptake, nitrogen metabolism, organic carbon metabolism, and uptake of other nutrients were found between strains of the different putative ecotypes. In situ diel transcription patterns of genes, including genes unique to either low-light-adapted or high-light-adapted strains and different alleles of an orthologous photosystem gene, revealed that expression is fine-tuned to the different light environments experienced by ecotypes prevalent at various depths in the mat. This study suggests that strains of closely related PEs have different genomic adaptations that enable them to inhabit distinct ecological niches while living in close proximity within a microbial community.


GPU accelerated numerical simulations of viscoelastic phase separation model.
We introduce a complete implementation of viscoelastic model for numerical simulations of the phase separation kinetics in dynamic asymmetry systems such as polymer blends and polymer solutions on a graphics processing unit (GPU) by CUDA language and discuss algorithms and optimizations in details. From studies of a polymer solution, we show that the GPU-based implementation can predict correctly the accepted results and provide about 190 times speedup over a single central processing unit (CPU). Further accuracy analysis demonstrates that both the single and the double precision calculations on the GPU are sufficient to produce high-quality results in numerical simulations of viscoelastic model. Therefore, the GPU-based viscoelastic model is very promising for studying many phase separation processes of experimental and theoretical interests that often take place on the large length and time scales and are not easily addressed by a conventional implementation running on a single CPU.


Cancer survivors' experiences with breakdowns in patient-centered communication.
This study analyzed cancer survivors' communication experiences that fell short of being patient-centered. Patients' descriptions of communication "breakdowns" were analyzed according to domain (eg, information exchange, fostering relationships, and managing emotions), whether it was a breakdown of commission (what was communicated) or omission (what should have been communicated) and whether it involved a clinician or the health care organization. Cancer survivors (from an online panel of patients) completed the Patients Assessment of Communication Experience measure. Ratings less than "excellent" elicited a prompt asking where communication fell short. Communication breakdowns were categorized as one of commission/omission, if it involved a clinician/health care system, and within which communication domain. Thematic analysis explored how communication breakdowns affected respondents' cancer care experiences. Overall communication was rated as less than excellent by 153 respondents, of which 79 identified a specific communication breakdown. Over half (n = 43, 54%) were problems of omission, mostly attributed to interaction with health care organizations (n = 25). Breakdowns of commission (n = 36, 46%) occurred primarily within clinical encounters (n = 32). Most breakdowns were problems of information exchange (49%) or fostering relationships (27%). Three overarching themes emerged-emotional fallout from unmet information needs, inattention to patient perspective, and uncertainty about navigation and team communication. Patient-centered communication breakdowns create distress that worsens patients' cancer care experiences. Communication skills training for clinicians should address listening, perspective taking, and assessing/satisfying patients' information and emotional needs. Health care organizations should enhance processes to provide timely, useful information to patients.


Biomechanical effects of passive hip springs during walking.
Passive spring-like structures can store and return energy during cyclic movements and thereby reduce the energetic cost of locomotion. That makes them important components of the human body and wearable assistive devices alike. This study investigates how springs placed anteriorly across the hip joint affect leg joint angles and powers, and leg muscle activities during level walking at 0.5 to 2.1 m/s. We hypothesized that the anterior hip springs (I) load hip extension, (II) support hip flexion and (III) affect ankle muscle activity and dynamics during walking. Effects at the ankle were expected because hip and ankle redistribute segmental power in concert to achieve forward progression. We observed that the participants' contribution to hip power did not increase during hip extension as the spring stored energy. Simultaneously, the activities of plantarflexor muscles that modulate energy storage in the Achilles tendon were reduced by 28% (gastrocnemius medialis) and 9% (soleus). As the spring returned energy with the onset of hip flexion, the participants' contribution to hip power was reduced by as much as 23%. Soleus activity before push-off increased by up to 9%. Instead of loading hip extension, anterior hip springs seem to store and return parts of the energy normally exchanged with the Achilles tendon. Thereby, the springs support hip flexion but may reduce elastic energy storage in and hence recoil from the Achilles tendon. This interaction should be considered during the design and simulation of wearable assistive devices as it might - depending on user characteristics - enhance or diminish their overall functionality.


Vascular protection by angiotensin receptor antagonism involves differential VEGF expression in both hemispheres after experimental stroke.
We identified that the angiotensin receptor antagonist, candesartan, has profound neurovascular protective properties when administered after ischemic stroke and was associated with a proangiogenic state at least partly explained by vascular endothelial growth factor A (VEGFA). However, the spatial distribution of vascular endothelial growth factor (VEGF) isoforms and their receptors remained unknown. Protein analysis identified a significant increase in vascular endothelial grow factor B (VEGFB) in the cerebrospinal fluid (CSF) and the ischemic hemispheres (with increased VEGF receptor 1 activation) of treated animals (p<0.05) which was co-occurring with an increase in protein kinase B (Akt) phosphorylation (p<0.05). An increase in VEGFA protein in the contralesional hemisphere corresponded to a significant increase in vascular density at seven days (p<0.01) after stroke onset. Vascular restoration by candesartan after stroke maybe related to differential regional upregulation of VEGFB and VEGFA, promoting a "prosurvival state" in the ischemic hemisphere and angiogenesis in the contralesional side, respectively. These vascular changes in both hemispheres after effective treatment are likely to contribute to enhanced recovery after stroke.


Behavioral plasticity allows short-term adjustment to a novel environment.
Many species are currently experiencing anthropogenically driven environmental changes. Among these changes, increasing noise levels are specifically a problem for species relying on acoustic communication. Recent evidence suggests that some species adjust their acoustic signals to man-made noise. However, it is unknown whether these changes occur through short-term and reversible adjustments by behavioral plasticity or through long-term adaptations by evolutionary change. Using behavioral observations and playback experiments, we show that male reed buntings (Emberiza schoeniclus) adjusted their songs immediately, singing at a higher minimum frequency and at a lower rate when noise levels were high. Our data showed that these changes in singing behavior were short-term adjustments of signal characteristics resulting from behavioral plasticity, rather than a long-term adaptation. However, more males remained unpaired at a noisy location than at a quiet location throughout the breeding season. Thus, phenotypic plasticity enables individuals to respond to environmental changes, but whether these short-term adjustments are beneficial remains to be seen.


Assessing data availability and research reproducibility in hydrology and water resources.
There is broad interest to improve the reproducibility of published research. We developed a survey tool to assess the availability of digital research artifacts published alongside peer-reviewed journal articles (e.g. data, models, code, directions for use) and reproducibility of article results. We used the tool to assess 360 of the 1,989 articles published by six hydrology and water resources journals in 2017. Like studies from other fields, we reproduced results for only a small fraction of articles (1.6% of tested articles) using their available artifacts. We estimated, with 95% confidence, that results might be reproduced for only 0.6% to 6.8% of all 1,989 articles. Unlike prior studies, the survey tool identified key bottlenecks to making work more reproducible. Bottlenecks include: only some digital artifacts available (44% of articles), no directions (89%), or all artifacts available but results not reproducible (5%). The tool (or extensions) can help authors, journals, funders, and institutions to self-assess manuscripts, provide feedback to improve reproducibility, and recognize and reward reproducible articles as examples for others.


The Endocannabinoid/Endovanilloid System in Bone: From Osteoporosis to Osteosarcoma.
Bone is a dynamic tissue, whose homeostasis is maintained by a fine balance between osteoclast (OC) and osteoblast (OB) activity. The endocannabinoid/endovanilloid (EC/EV) system's receptors are the cannabinoid receptor type 1 (CB1), the cannabinoid receptor type 2 (CB2), and the transient receptor potential cation channel subfamily V member 1 (TRPV1). Their stimulation modulates bone formation and bone resorption. Bone diseases are very common worldwide. Osteoporosis is the principal cause of bone loss and it can be caused by several factors such as postmenopausal estrogen decrease, glucocorticoid (GC) treatments, iron overload, and chemotherapies. Studies have demonstrated that CB1 and TRPV1 stimulation exerts osteoclastogenic effects, whereas CB2 stimulation has an anti-osteoclastogenic role. Moreover, the EC/EV system has been demonstrated to have a role in cancer, favoring apoptosis and inhibiting cell proliferation. In particular, in bone cancer, the modulation of the EC/EV system not only reduces cell growth and enhances apoptosis but it also reduces cell invasion and bone pain in mouse models. Therefore, EC/EV receptors may be a useful pharmacological target in the prevention and treatment of bone diseases. More studies to better investigate the biochemical mechanisms underlining the EC/EV system effects in bone are needed, but the synthesis of hybrid molecules, targeting these receptors and capable of oppositely regulating bone homeostasis, seems to be a promising and encouraging prospective in bone disease management.


A procedure-specific systematic review and consensus recommendations for analgesia after total hip replacement.
Total hip replacement is a major surgical procedure usually associated with significant pain in the early postoperative period. Several anaesthetic and analgesic techniques are in common clinical use for this procedure but, to date, clinical studies of pain after total hip replacement have not been systematically assessed. Using the Cochrane protocol, we have conducted a systematic review of analgesic, anaesthetic and surgical interventions affecting postoperative pain after total hip replacement. In addition to the review, transferable evidence from other relevant procedures and clinical practice observations collated by the Delphi method were used to develop evidence-based recommendations for the treatment of postoperative pain. For primary total hip replacement, PROSPECT recommends either general anaesthesia combined with a peripheral nerve block that is continued after surgery or an intrathecal (spinal) injection of local anaesthetic and opioid. The primary analgesic technique should be combined with a step-down approach using paracetamol plus conventional non-steroidal anti-inflammatory drugs, with strong or weak opioids as required.


Aetiology and antibiotic resistance patterns of urinary tract infections in the elderly: a 6-month study.
Urinary tract infections (UTIs) are a common cause of bacteraemia in the elderly and are associated with a high probability of hospitalization. Despite the impact of UTIs on health status and quality of life, a limited number of studies have evaluated their aetiology in this population. This study aimed to evaluate the microbial aetiology and pattern of susceptibility of bacteria causing UTIs in the elderly. For this purpose, a retrospective cohort study of elderly residents (n = 472, aged >65 years) in 14 nursing homes in Milan (Italy) and its province was performed. Globally, 393 micro-organisms from 328 samples were isolated: Escherichia coli was the most prevalent (44.8 %), followed by Proteus mirabilis (20.4 %), Providencia spp. (8.9 %), Klebsiella spp. (6.4 %) and Pseudomonas aeruginosa (4.6 %). Enterococci were the most frequently isolated Gram-positive organisms (7.4 %). Almost all Enterobacteriaceae were susceptible to nitrofurantoin, carbapenems and amikacin. Extended-spectrum β-lactamases were detected in 42.1 % of isolates. The most active antibiotics against P. aeruginosa were colistin, amikacin and piperacillin/tazobactam. All Gram-positive organisms were susceptible to glycopeptides and linezolid, and 90 % were susceptible to nitrofurantoin. Fluoroquinolones showed a limited activity against all the tested micro-organisms. Escherichia coli remains the major micro-organism responsible for UTIs in older people, although to a lesser extent than in a younger population. The high rates of resistance observed in this study make careful use of antibiotics advisable to limit further development of resistance.


Studying Nestin and its Interrelationship with Cdk5.
Current research utilizes the specific expression pattern of intermediate filaments (IF) for identifying cellular state and origin, as well as for the purpose of disease diagnosis. Nestin is commonly utilized as a specific marker and driver for CNS progenitor cell types, but in addition, nestin can be found in several mesenchymal progenitor cells, and it is constitutively expressed in a few restricted locations, such as muscle neuromuscular junctions and kidney podocytes. Alike most other members of the IF protein family, nestin filaments are dynamic, constantly being remodeled through posttranslational modifications, which alter the solubility, protein levels, and signaling capacity of the nestin filaments. Through its interactions with kinases and other signaling executors, resulting in a complex and bidirectional regulation of cell signaling events, nestin has the potential to determine whether cells divide, differentiate, migrate, or stay in place. In this review, the broad and similar roles of IFs as dynamic signaling scaffolds, is exemplified by observations of nestin functions and its interaction with the cyclin- dependent kinase 5, the atypical kinase in the family of cyclin-dependent kinases.


Thermal and metabolic responsiveness of Japanese quail embryos following periodic exposure to 2,450 MHz microwaves.
Two studies were performed to determine if repeated exposure of the avian egg to microwaves can alter metabolism, temperature, and growth rate of embryos. Another aim was to supplement conventional heating with microwave heating and provide an optimal temperature for growth. Japanese quail (Coturnix coturnix japonica) eggs were exposed from day 1 through 15 of incubation (8 h/day) to sham or microwave (2,450 MHz) irradiation. Microwave exposures were at two power densities, 5 or 20 mW/cm2, and at three ambient temperatures (Tas), 30.0, 33.1, or 35.4 degrees C. Specific absorption rates for unincubated and 15-day-old incubated eggs were, respectively, 0.76 and 0.66 W kg-1 mW-1 cm-2 (i.e., 3.8 and 3.3 W/kg at 5 mW/cm2 and 15.2 and 13.2 W/kg at 20 mW/cm2). Eggs were concurrently sham exposed at each of five Tas, ranging from 27.9 to 37.5 degrees C. Tests were conducted during the 16th day of incubation (i.e., 1 day post-treatment), in the absence of microwaves, to determine metabolic rate of embryos and internal and external egg temperatures at different Tas. Repeated exposures to microwaves at 5 and 20 mW/cm2 at the same Ta (30 degrees C) increased wet-embryo mass on the 16th day by an average, respectively, of 9% and 61% when compared with predicted masses for embryos exposed at the same Ta in the absence of microwave radiation. There was no reliable indication, from post-treatment tests and comparisons with control embryos of similar mass, that repeated exposure to microwave radiation resulted in abnormal physiological development. Microwave radiation can be used to increase egg temperature and embryonic growth rate at Tas below normal incubation level without altering basic metabolic and thermal characteristics of the developing bird.


Elucidating the Ramularia eucalypti species complex.
The genus Ramularia includes numerous phytopathogenic species, several of which are economically important. Ramularia eucalypti is currently the only species of this genus known to infect Eucalyptus by causing severe leaf-spotting symptoms on this host. However, several isolates identified as R. eucalypti based on morphology and on nrDNA sequence data of the ITS region have recently been isolated from other plant hosts, from environmental samples and also from human clinical specimens. Identification of closely related species based on morphology is often difficult and the ITS region has previously been shown to be unreliable for species level identification in several genera. In this study we aimed to resolve this species-complex by applying a polyphasic approach involving morphology, multi-gene phylogeny and matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS). Six partial genes (ITS, ACT, TEF1-α, HIS3, GAPDH and RPB2) were amplified and sequenced for a total of 44 isolates representing R. eucalypti s.lat. and closely related species. A multi-gene Bayesian phylogenetic analysis and parsimony analysis were performed, and both the resulting trees showed significant support for separation of seven species in R. eucalypti s.lat., including two previously described (R. eucalypti and R. miae), four novel species here described (R. haroldporteri, R. glennii, R. mali and R. plurivora) and one undescribed Ramularia species (sterile). Additionally, Mycosphaerella nyssicola is newly combined in Ramularia as R. nyssicola. Main mass spectra (MSPs) of several R. eucalypti s.lat. strains were generated using MALDI-TOF MS and were compared through a Principal Component Analysis (PCA) dendogram. The PCA dendrogram supported three clades containing R. plurivora, R. glenni/R. mali and R. eucalypti/R. miae. Although the dendrogram separation of species differed from the phylogenetic analysis, the clinically relevant strains were successfully identified by MALDI-TOF MS.


Control of diarrhoeal disease in Tonga 1978-83.
Tonga, like many developing countries, suffers from a shortage of medical staff and a high morbidity and mortality from paediatric diarrhoeal disease. In 1980 a programme was started to train medical assistants and village administrators in the correct use of oral rehydration salt solution for rehydration. The effect on morbidity, mortality, and admission to hospital over the six years 1978-83 was assessed. After the introduction of the scheme the number of deaths due to diarrhoea fell considerably and the state of hydration in children admitted to hospital with diarrhoea greatly improved. It is recommended that similar programmes be adopted where clinical problems of diarrhoea with dehydration persist. Instruction in the use of oral rehydration fluid was most effectively given by non-medical staff to groups of mothers, rather than by paediatricians in their inevitably brief, although important, explanation given in hospital.


Plasma free fatty acids and peroxisome proliferator-activated receptor alpha in the control of myocardial uncoupling protein levels.
Diabetic patients have abnormal cardiac energy metabolism associated with high plasma free fatty acid (FFA) concentrations. We investigated whether high plasma FFAs increase mitochondrial uncoupling protein (UCP) levels in the mouse heart by activating the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR)alpha. We used Western blotting to measure UCP protein levels in isolated cardiac mitochondria from PPARalpha-/- and diabetic mice. Cardiac UCP2 and UCP3 were significantly lower in the PPARalpha-/- mouse than in the wild type. Treatment with the PPARalpha-specific agonist, WY-14,643, increased cardiac UCP2 and UCP3 levels in wild-type mice but did not alter UCP levels in PPARalpha-/- mice. Inhibition of beta-oxidation with etomoxir increased cardiac UCP2 and UCP3 levels in wild-type mice and UCP2 levels in PPARalpha-/- mice but did not alter UCP3 levels in PPARalpha-/- mice. Streptozotocin treatment, which increased circulating FFAs by 91%, did not alter cardiac UCP2 levels in wild-type or PPARalpha-/- mice but increased UCP3 levels in wild-type, and not in PPARalpha-/-, mice. The diabetic db/db mouse had 50% higher plasma FFA concentrations and elevated cardiac UCP2 and UCP3 protein levels. We conclude that high plasma FFAs activated PPARalpha to increase cardiac UCP3 levels, but cardiac UCP2 levels changed via PPARalpha-dependent and -independent mechanisms.


Subperiosteal midface lift with or without a hard palate mucosal graft for correction of lower eyelid retraction.
To compare functional and surgical outcomes of a subperiosteal midface lift with and without the placement of a hard palate mucosal graft (HPMG) in patients with lower eyelid retraction. Retrospective, comparative, interventional case series. Thirty-four patients with lower eyelid retractions who underwent surgery at the Jules Stein Eye Institute in a 5-year period. Medical record review of all patients who underwent surgery for lower eyelid retraction by a subperiosteal midface lift with or without an HPMG. Preoperative and postoperative digital photographs were taken in all patients. Change in margin reflex distance 2 (MRD2), measured from the pupillary margin to the upper margin of the lower eyelid; patient discomfort; and surgical complications. Thirty-four patients (20 female; mean age, 64 years) participated in the study; 11 underwent bilateral surgery, with overall 43 surgeries performed. Eighteen patients (42%) had lower eyelid retraction secondary to previous transcutaneous lower eyelid blepharoplasty. Postoperatively, patients attained a better lower eyelid position, with improvement of lower eyelid height of 1.4 mm (P<0.001, 1-sample t test). Patients operated using an HPMG (12 surgeries) achieved a greater reduction in MRD2 postoperatively as compared with patients operated by subperiosteal midface lift alone (31 surgeries; 2.2 mm vs. 1.1 mm, respectively; P = 0.02, Wilcoxon Mann-Whitney). One patient needed reoperation secondary to symptomatic lower eyelid retraction postoperatively. The subperiosteal midface lift is effective in correction of lower eyelid retraction of various causes. The use of an HPMG spacer may enhance surgical outcomes and results in a better lower eyelid position.


SUPERFAMILY: HMMs representing all proteins of known structure. SCOP sequence searches, alignments and genome assignments.
The SUPERFAMILY database contains a library of hidden Markov models representing all proteins of known structure. The database is based on the SCOP 'superfamily' level of protein domain classification which groups together the most distantly related proteins which have a common evolutionary ancestor. There is a public server at http://supfam.org which provides three services: sequence searching, multiple alignments to sequences of known structure, and structural assignments to all complete genomes. Given an amino acid or nucleotide query sequence the server will return the domain architecture and SCOP classification. The server produces alignments of the query sequences with sequences of known structure, and includes multiple alignments of genome and PDB sequences. The structural assignments are carried out on all complete genomes (currently 59) covering approximately half of the soluble protein domains. The assignments, superfamily breakdown and statistics on them are available from the server. The database is currently used by this group and others for genome annotation, structural genomics, gene prediction and domain-based genomic studies.


Dogs recognize dog and human emotions.
The perception of emotional expressions allows animals to evaluate the social intentions and motivations of each other. This usually takes place within species; however, in the case of domestic dogs, it might be advantageous to recognize the emotions of humans as well as other dogs. In this sense, the combination of visual and auditory cues to categorize others' emotions facilitates the information processing and indicates high-level cognitive representations. Using a cross-modal preferential looking paradigm, we presented dogs with either human or dog faces with different emotional valences (happy/playful versus angry/aggressive) paired with a single vocalization from the same individual with either a positive or negative valence or Brownian noise. Dogs looked significantly longer at the face whose expression was congruent to the valence of vocalization, for both conspecifics and heterospecifics, an ability previously known only in humans. These results demonstrate that dogs can extract and integrate bimodal sensory emotional information, and discriminate between positive and negative emotions from both humans and dogs.


The Validity of Rapid Malaria Test and Microscopy in Detecting Malaria in a Preelimination Region of Egypt.
Background. Malaria is a leading cause of morbidity and mortality worldwide. Rapid and accurate diagnosis of malaria would improve control measures and reduce morbidity and mortality. Objective. The aim of this study was to assess the prevalence of malaria in high risk foci in Egypt and the effectiveness of rapid diagnostic tests in diagnosis and subsequently control of malaria. Methodology. A total number of 600 cases of both sexes with different ages were included in the present study. Cases were included in 2 groups; first group (500 cases) were randomly selected from households in Fayoum Governorate and second group (100 cases) were admitted to Fayoum Fever Hospital with signs suggestive of malaria. Cases were subjected to detailed history taking, clinical examination, microscopic examination of thin and thick blood films, and immunological test to detect plasmodial antigens. Results. A total of 3 positive cases were detected by rapid diagnostic tests (RDTs). Out of these 3 cases, one case was positive for malaria parasite by microscopic examination of blood films. All positive cases in the study had history of travel to malaria endemic areas. Conclusion. RDTs are simple and effective for rapid diagnosis of malaria to help in implication of control measures in different localities.


Resistance to Foliar Diseases in a Mini-Core Collection of Sorghum Germplasm.
Anthracnose, leaf blight, and rust are important biotic constraints to grain and forage sorghum production worldwide and are best managed through host plant resistance. A sorghum mini-core collection, consisting of 242 germplasm accessions developed from a core collection of 2,246 landrace accessions originating from 58 countries, was evaluated to identify sources of resistance to foliar diseases. The mini-core accessions were evaluated in anthracnose- and leaf-blight-screening nurseries under artificial inoculation in the rainy and late rainy seasons, respectively, during 2009 and 2010. For rust resistance, screening was done under artificial inoculation in the greenhouse as well as in the field under natural infection. In all, 13 accessions were found resistant (score ≤3.0 on a 1-to-9 scale) to anthracnose and 27 to leaf blight in both 2009 and 2010. Six accessions exhibited resistance to rust in both the greenhouse and the field. In the resistant accessions, a wide range of diversity was observed for agronomic traits such as days to 50% flowering, plant height, and grain yield/plant, and morphological characteristics such as grain or glume color, glume coverage, endosperm texture, and panicle type (ear head compactness). Three mini-core accessions (IS 473, IS 23684, and IS 23521) exhibited resistance to all three diseases. These accessions with multiple disease resistance will be useful in sorghum disease resistance breeding programs.


Purification and characterization of human lung fibroblast motility-stimulating factor for human soft tissue sarcoma cells: identification as an NH2-terminal fragment of human fibronectin.
Paracrine motogenic factors, including motility cytokines and extracellular matrix molecules secreted by normal cells, can stimulate metastatic cell invasion. Both intact extracellular matrix molecules and their degradative products may exhibit these activities. We have found that human lung fibroblasts produce paracrine motility-stimulating factors for recently established human sarcoma cell strains. We purified the major fibroblast motility-stimulating factor (FMSF) from human lung fibroblast-conditioned medium by sequential heparin affinity chromatography and DEAE anion exchange chromatography. Lysylendopeptidase C digestion of FMSF and sequencing of peptides purified by reverse-phase high-pressure liquid chromatography identified FMSF as an NH2-terminal fragment of human fibronectin. Using SYN-1 sarcoma cells, FMSF predominantly stimulated chemotaxis and some chemokinesis, and it was chemotactic for a variety of human sarcoma cells, including fibrosarcoma, leiomyosarcoma, liposarcoma, synovial sarcoma, and neurofibrosarcoma cells. The FMSF activity present in human lung fibroblast-conditioned medium was completely eliminated by either neutralization or immunodepletion with a rabbit antihuman-fibronectin antibody, thus further confirming that the NH2-terminal fibronectin fragment was the FMSF responsible for the motility stimulation of human soft tissue sarcoma cells. Because human soft tissue sarcomas have a distinctive hematogenous metastatic pattern (predominantly lung), and lung-derived fibroblasts secrete large amounts of FMSF, FMSF and fibronectin may play a role in stimulating sarcoma invasion into lung tissue.


GTP binding controls complex formation by the human ROCO protein MASL1.
The human ROCO proteins are a family of multi-domain proteins sharing a conserved ROC-COR supra-domain. The family has four members: leucine-rich repeat kinase 1 (LRRK1), leucine-rich repeat kinase 2 (LRRK2), death-associated protein kinase 1 (DAPK1) and malignant fibrous histiocytoma amplified sequences with leucine-rich tandem repeats 1 (MASL1). Previous studies of LRRK1/2 and DAPK1 have shown that the ROC (Ras of complex proteins) domain can bind and hydrolyse GTP, but the cellular consequences of this activity are still unclear. Here, the first biochemical characterization of MASL1 and the impact of GTP binding on MASL1 complex formation are reported. The results demonstrate that MASL1, similar to other ROCO proteins, can bind guanosine nucleotides via its ROC domain. Furthermore, MASL1 exists in two distinct cellular complexes associated with heat shock protein 60, and the formation of a low molecular weight pool of MASL1 is modulated by GTP binding. Finally, loss of GTP enhances MASL1 toxicity in cells. Taken together, these data point to a central role for the ROC/GTPase domain of MASL1 in the regulation of its cellular function.


Reinforcement-related regulation of AMPA glutamate receptor subunits in the ventral tegmental area enhances motivation for cocaine.
Chronic cocaine use produces numerous biological changes in brain, but relatively few are functionally associated with cocaine reinforcement. Here we show that daily intravenous cocaine self-administration, but not passive cocaine administration, induces dynamic upregulation of the AMPA glutamate receptor subunits GluR1 and GluR2 in the ventral tegmental area (VTA) of rats. Increases in GluR1 protein and GluR1(S845) phosphorylation are associated with increased GluR1 mRNA in self-administering animals, whereas increased GluR2 protein levels occurred despite substantial decreases in GluR2 mRNA. We investigated the functional significance of GluR1 upregulation in the VTA on cocaine self-administration using localized viral-mediated gene transfer. Overexpression of GluR1(WT) in rat VTA primarily infected dopamine neurons (75%) and increased AMPA receptor-mediated membrane rectification in these neurons with AMPA application. Similar GluR1(WT) overexpression potentiated locomotor responses to intra-VTA AMPA, but not NMDA, infusions. In cocaine self-administering animals, overexpression of GluR1(WT) in the VTA markedly increased the motivation for cocaine injections on a progressive ratio schedule of cocaine reinforcement. In contrast, overexpression of protein kinase A-resistant GluR1(S845A) in the VTA reduced peak rates of cocaine self-administration on a fixed ratio reinforcement schedule. Neither viral vector altered sucrose self-administration, and overexpression of GluR1(WT) or GluR1(S845A) in the adjacent substantia nigra had no effect on cocaine self-administration. Together, these results suggest that dynamic regulation of AMPA receptors in the VTA during cocaine self-administration contributes to cocaine addiction by acting to facilitate subsequent cocaine use.


Temperature-sensitive defects in paramyotonia congenita mutants R1448C and T1313M.
The biophysical origins of paramyotonia congenita and its exacerbation in cold temperatures were examined. Human skeletal muscle voltage-gated sodium channels were expressed in Xenopus oocytes and macroscopic currents were recorded from cell-attached patches. Wild-type (hNaV1.4) channels were compared to two mutant channel isoforms, T1313M and R1448C. The voltage dependence and temperature sensitivity of activation, fast-inactivation onset and recovery, and deactivation were studied. Although activation and the onset of fast-inactivation were temperature sensitive in all three isoforms, and although these properties in mutant channels differed from those in wild-type channels, they did not account for cold-exacerbation. Deactivation, however, was disproportionately slower in R1448C, but not in T1313M, than in hNaV1.4. These defects may, at least in part, account for the clinical symptoms of paramyotonia congenita and its exacerbation by cold, and provide a basis for studies into the therapeutic alleviation of these symptoms.


Conventional and Novel Lipid Measures and Risk of Peripheral Artery Disease.
The aim of this study was to comprehensively assess the association of multiple lipid measures with incident peripheral artery disease (PAD). Approach and Results: We used Cox proportional hazards models to characterize the associations of each of the fasting lipid measures (total cholesterol, LDL-C [low-density lipoprotein cholesterol], HDL-C [high-density lipoprotein cholesterol], triglycerides, RLP-C [remnant lipoprotein cholesterol], LDL-TG [LDL-triglycerides], sdLDL-C [small dense LDL-C], and Apo-E-HDL [Apo-E-containing HDL-C]) with incident PAD identified by pertinent International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) hospital discharge codes (eg, 440.2) among 8330 Black and White ARIC (Atherosclerosis Risk in Communities) participants (mean age 62.8 [SD 5.6] years) free of PAD at baseline (1996-1998) through 2015. Since lipid traits are biologically correlated to each other, we also conducted principal component analysis to identify underlying components for PAD risk. There were 246 incident PAD cases with a median follow-up of 17 years. After accounting for potential confounders, the following lipid measures were significantly associated with PAD (hazard ratio per 1-SD increment [decrement for HDL-C and Apo-E-HDL]): triglycerides, 1.21 (95% CI, 1.08-1.36); RLP-C, 1.18 (1.08-1.29); LDL-TG, 1.18 (1.05-1.33); HDL-C, 1.39 (1.16-1.67); and Apo-E-HDL, 1.27 (1.07-1.51). The principal component analysis identified 3 components (1: mainly loaded by triglycerides, RLP-C, LDL-TG, and sdLDL-C; 2: by HDL-C and Apo-E-HDL; and 3: by LDL-C and RLP-C). Components 1 and 2 showed independent associations with incident PAD. Triglyceride-related and HDL-related lipids were independently associated with incident PAD, which has implications on preventive strategies for PAD. However, none of the novel lipid measures outperformed conventional ones. Graphic Abstract: A graphic abstract is available for this article.


Prenatal diagnosis of beta-thalassaemia in Pakistan: experience in a Muslim country.
A service for prenatal diagnosis of beta-thalassaemia was introduced in Pakistan in May 1994. Two renowned Islamic scholars, consulted before the service was introduced, ruled that a pregnancy can be terminated if the fetus is affected by a serious genetic disorder, and if termination is before 120 days (17 weeks) of gestation. During the first 3(1/2) years of the service 300 couples requested the test. Almost all the couples had been informed by their treating doctors. Most diagnoses were made between 10 and 16 weeks of gestation, and only 15 (5%) were reached after the 16th week. DNA analysis was by the amplification refractory mutation system (ARMS). A multiplex ARMS was developed in which three primer combinations identified the mutations in 91.5% of the couples. In 13 couples (4. 3%) linkage analysis was required for the fetal diagnosis. In 47/53 (88.7%) women carrying an affected fetus the pregnancy was terminated. In six cases it was declined principally on religious grounds. Postnatal confirmation of the prenatal diagnosis was possible in 117 unaffected children. One year after the start of the service, interviews with 141 couples with an affected child showed that 72% knew of the availability of prenatal diagnosis. Thirty-two of the informed couples had had a pregnancy, but only 18 (56%) used prenatal diagnosis. The main reasons for non-utilization of prenatal diagnosis were the cost of the test and fear of undergoing the test, though some gave no clear explanation. This study demonstrates that prenatal diagnosis is feasible and acceptable in a Muslim country such as Pakistan.


Adverse associations of increases in television viewing time with 5-year changes in glucose homoeostasis markers: the AusDiab study.
Television viewing time is associated cross-sectionally with abnormal glucose tolerance and diabetes risk; however, the impact of changes in television viewing time on glycaemic measures is less understood. We examined relationships of 5-year change in television viewing time with 5-year change in glucose homeostasis markers. Participants in the Australian Diabetes, Obesity and Lifestyle study with data available at the 1999-2000 baseline and the 2004-2005 follow-up were included (4870; 45% men). Television viewing time (h/week) was assessed by questionnaire. Fasting plasma glucose, serum insulin and 2-h plasma glucose were obtained from an oral glucose tolerance test. Beta-cell function and insulin resistance were ascertained using the homeostasis model assessment 2-calculator. Associations of change in television viewing time with changes in glucose homeostasis markers were examined using linear regression models [β-coefficients (95% CI)]. Adjustments included baseline measures of age, television viewing time and glycaemic marker, and baseline and 5-year change in diet quality, energy intake, physical activity and waist circumference. For every 5-h per week increase in television viewing time from baseline to 5-year follow-up, changes in glucose homeostasis markers were observed: among women there was a significant increase in fasting plasma glucose [0.01 (0.00-0.02) mmol/l] insulin resistance [0.03 (0.01-0.05)] and insulin secretion [1.07 (0.02-2.12) %]; insulin levels increased [men: 1.20 (0.30-2.09); women: 1.06 (0.32-1.80) pmol/l]; in men, 2-h plasma glucose levels increased [0.06 (0.01-0.1) mmol/l]. Five-year increases in television viewing time were associated adversely with changes in glucose homeostasis markers. These findings add to earlier cross-sectional evidence that television viewing time can be associated with biomarkers of diabetes risk.


The ins and outs of secretion from pancreatic beta-cells: control of single-vesicle exo- and endocytosis.
Exocytosis of insulin-containing secretory vesicles in pancreatic beta-cells is crucial to maintenance of plasma glucose levels. They fuse with the plasma membrane in a regulated manner to release their contents and are subsequently recaptured either intact or through conventional clathrin-mediated endocytosis. Here, we discuss these mechanisms in beta-cells at the single-vesicle level.


Quantitative Visualization of the Interaction between Complement Component C1 and Immunoglobulin G: The Effect of CH1 Domain Deletion.
Immunoglobulin G (IgG) adopts a modular multidomain structure that mediates antigen recognition and effector functions, such as complement-dependent cytotoxicity. IgG molecules are self-assembled into a hexameric ring on antigen-containing membranes, recruiting the complement component C1q. In order to provide deeper insights into the initial step of the complement pathway, we report a high-speed atomic force microscopy study for the quantitative visualization of the interaction between mouse IgG and the C1 complex composed of C1q, C1r, and C1s. The results showed that the C1q in the C1 complex is restricted regarding internal motion, and that it has a stronger binding affinity for on-membrane IgG2b assemblages than C1q alone, presumably because of the lower conformational entropy loss upon binding. Furthermore, we visualized a 1:1 stoichiometric interaction between C1/C1q and an IgG2a variant that lacks the entire CH1 domain in the absence of an antigen. In addition to the canonical C1q-binding site on Fc, their interactions are mediated through a secondary site on the CL domain that is cryptic in the presence of the CH1 domain. Our findings offer clues for novel-modality therapeutic antibodies.


The degree of p70 S6k and S6 phosphorylation in human skeletal muscle in response to resistance exercise depends on the training volume.
Regular performance of resistance exercise induces an increase in skeletal muscle mass, however, the molecular mechanisms underlying this effect are not yet fully understood. The purpose of the present investigation was to examine acute changes in molecular signalling in response to resistance exercise involving different training volumes. Eight untrained male subjects carried out one, three and five sets of 6 repetition maximum (RM) in leg press exercise in a random order. Muscle biopsies were taken from the vastus lateralis both prior to and 30 min after each training session and the effect on protein signalling was studied. Phosphorylation of Akt was not altered significantly after any of the training protocols, whereas that of the mammalian target of rapamycin was enhanced to a similar extent by training at all three volumes. The phosphorylation of p70S6 kinase (p70(S6k)) was elevated threefold after 3 × 6 RM and sixfold after 5 × 6 RM, while the phosphorylation of S6 was increased 30- and 55-fold following the 3 × 6 RM and 5 × 6 RM exercises, respectively. Moreover, the level of the phosphorylated form of the gamma isoform of p38 MAPK was enhanced three to fourfold following each of the three protocols, whereas phosphorylation of ERK1/2 was unchanged 30 min following exercise. These findings indicate that when exercise is performed in a fasted state, the increase in phosphorylation of signalling molecules such as p70(S6k) and the S6 ribosomal protein in human muscle depends on the exercise volume.


Gender differences in dementia management plans of spousal caregivers: implications for occupational therapy.
Occupational therapists treating older people with Alzheimer disease know that they must also consider the others who are affected by the disease, the informal caregivers. Intervention is most effective when it enables both the impaired person and the primary caregiver to manage the secondary symptoms of dementia. Unfortunately, little is understood about how caregivers approach and carry out their tasks and about why male and female caregivers respond differently to their caregiving role in terms of depression, burden, stress, and substance abuse. This paper discusses the effects of gender on dementia management plans of spousal caregivers. Husbands and wives have different approaches to caregiving; each approach has consequences. Male caregivers adopt a task-oriented approach to their duties and carry out their activities in a linear fashion; female caregivers use a parent-child approach and nest activities inside one another in a constant stream of work. Two cases are presented to illustrate gender differences in dementia management plans. Implications for occupational therapy include suggestions for supporting men and women in their caregiving role, modulating the negative consequences of caregiving, and conducting research to demonstrate the efficacy of an occupational therapy approach.


Catheter-directed thrombolysis for iliofemoral venous thrombosis.
The combination of catheter-directed thrombolytic therapy and endovascular stenting is a new and promising approach for treating acute and chronic thrombotic iliofemoral venous occlusions on the basis of the authors' initial experience in a small group of patients. In acute DVT, catheter-directed techniques provide more complete lysis than systemic infusions and early, aggressive interventional therapy may spare the patient from the life-long disability associated with the postphlebitic syndrome, by preserving valve function and eliminating the venous outflow obstruction. Immediate postthrombolysis venography can evaluate the underlying vein and assess the need for adjunctive treatment with angioplasty and/or stents. Urokinase has a high degree of safety with few complications when a catheter-directed approach rather than systemic infusion is used. Even patients with chronic DVT can benefit by reducing the obstruction to venous outflow if the occlusion is limited to the iliac vein and/or the inferior vena cava. Long-term follow-up studies are necessary to evaluate patency rates of the treated veins, determine whether successfully treated limbs have a lower frequency of recurrent DVT, and ascertain the frequency of chronic venous insufficiency compared with that in patients treated with anticoagulation alone. Based on our initial experience, a National Venous Thrombosis Registry was established in October 1994. The purpose of this multidisciplinary Registry is to prospectively document the long-term results of catheter-directed thrombolytic therapy for patients with iliofemoral DVT, with data now being collected from 40 leading medical centers around the United States. We hope that endovascular techniques for iliofemoral DVT will significantly reduce the immediate and long-term complications commonly associated with this difficult and often misunderstood clinical problem.


Machine Learning for Screening Microvascular Complications in Type 2 Diabetic Patients Using Demographic, Clinical, and Laboratory Profiles.
Microvascular complications are one of the key causes of mortality among type 2 diabetic patients. This study was sought to investigate the use of a novel machine learning approach for predicting these complications using only the patient demographic, clinical, and laboratory profiles. A total of 96 Bangladeshi participants with type 2 diabetes were recruited during their routine hospital visits. All patient profiles were assessed by using a chi-squared (χ2) test to statistically determine the most important markers in predicting three microvascular complications: cardiac autonomic neuropathy (CAN), diabetic peripheral neuropathy (DPN), and diabetic retinopathy (RET). A machine learning approach based on logistic regression, random forest (RF), and support vector machine (SVM) algorithms was then developed to ensure automated clinical testing for microvascular complications in diabetic patients. The highest prediction accuracies were obtained by RF using diastolic blood pressure, albumin-creatinine ratio, and gender for CAN testing (98.67%); microalbuminuria, smoking history, and hemoglobin A1C for DPN testing (67.78%); and hemoglobin A1C, microalbuminuria, and smoking history for RET testing (84.38%). This study suggests machine learning as a promising automated tool for predicting microvascular complications in diabetic patients using their profiles, which could help prevent those patients from further microvascular complications leading to early death.


Effect of stretch positions on hamstring muscle length, lumbar flexion range of motion, and lumbar curvature in healthy adults.
Hamstring stretching is a common practice in physical therapy to change not only hamstring muscle length (HML), but also lumbar flexion range of motion (LROM) or lumbar curvature (LC). Yet limited published research compares the effectiveness of two commonly used hamstring stretch positions, sitting and standing. The purposes of this study were to determine the effect of (1) stretch position on HML; and 2) HML on LROM and LC. Thirty-six participants (M=44.8 years, SD=17.1) with short HML (i.e., with shortness for men ≥45° and for women ≥ 24° of active knee flexion with 90° hip flexion) were measured for HML, LROM, and LC; randomly allocated to one of three groups: (1) hamstring stretching in sitting (SI); (2) standing (ST); or (3) no stretching (control); and remeasured after 4 weeks. Participants in the stretching groups performed two 30-second static stretches 4 days per week for 4 weeks. Multivariate analysis of covariance (MANCOVA) showed significance between the stretching groups and nonstretching group for HML only. Nonsignificance was shown for HML between the stretch positions (i.e., SI-active knee extension (AKE) and ST-AKE), indicating that both were equally effective for increasing HML. However, there was no change in LROM or in LC even though HML increased.


Overcoming multidrug resistance using folate receptor-targeted and pH-responsive polymeric nanogels containing covalently entrapped doxorubicin.
Multidrug resistance (MDR) contributes to failure of chemotherapy. We here show that biodegradable polymeric nanogels are able to overcome MDR via folic acid targeting. The nanogels are based on hydroxyethyl methacrylamide-oligoglycolates-derivatized poly(hydroxyethyl methacrylamide-co-N-(2-azidoethyl)methacrylamide) (p(HEMAm-co-AzEMAm)-Gly-HEMAm), covalently loaded with the chemotherapeutic drug doxorubicin (DOX) and subsequently decorated with a folic acid-PEG conjugate via copper-free click chemistry. pH-Responsive drug release is achieved via the acid-labile hydrazone bond between DOX and the methacrylamide polymeric network. Cellular uptake and cytotoxicity analyses in folate receptor-positive B16F10 melanoma versus folate receptor-negative A549 lung carcinoma cells confirmed specific uptake of the targeted nanogels. Confocal microscopy demonstrated efficient internalization, lysosomal trafficking, drug release and nuclear localization of DOX. We also show that DOX resistance in 4T1 breast cancer cells results in upregulation of the folate receptor, and that folic acid targeted nanogels can be employed to bypass drug efflux pumps, resulting in highly efficient killing of resistant cancer cells. In conclusion, folic acid functionalized nanogels with pH-controlled drug release seem to hold significant potential for treating multidrug resistant malignancies.


Vasodilating drugs: contrasting haemodynamic effects.
1. We investigated the haemodynamic effects of intravenously administered hydrallazine, diazoxide and nitroprusside and orally administered minoxidil to determine whether vasodilators (such as nitroprusside) which do not increase cardiac output might be better treatment for hypertensive complications associated with, or caused by, myocardial failure than those that do. 2. Hydrallazine and diazoxide caused increases in heart rate, cardiac output, cardiopulmonary blood volume, the ratio of cardiac output to cardiopulmonary volume, and pulmonary artery pressure. Nitroprusside, although decreasing pressure and vascular resistance, caused no significant change in the other functions except for reducing pulmonary artery pressure. Minoxidil, when given orally, had the potential for causing pulmonary hypertension. This seemed explained by increased flow (hyperdynamic type) in some but by congestive cardiac failure in others; the latter condition was probably intensified by the marked fluid retention that the drug can cause. 3. On the basis of these results a classification of vasodilators was constructed which depends on the presence or absence of a venodilating effect. Vasodilators which produce no (or little) venodilatation, increase heart rate, cardiac output, cardiopulmonary blood volume and pulmonary artery pressure. In this class are diazoxide, hydrallazine and minoxidil. Those that cause venodilatation do not stimulate the heart nor do they cause pulmonary hypertension. Nitroprusside and nitroglycerine are drugs of this type. 4. These results suggest that drugs producing both venodilatation and arteriolar dilatation may be more specific therapy for hypertensive complications associated with cardiac failure than those that cause only arteriolar dilatation.


The HIF1 target gene NOX2 promotes angiogenesis through urotensin-II.
Urotensin-II (U-II) has been considered as one of the most potent vasoactive peptides, although its physiological and pathophysiological role is still not finally resolved. Recent evidence suggests that it promotes angiogenic responses in endothelial cells, although the underlying signalling mechanisms are unclear. Reactive oxygen species derived from NADPH oxidases are major signalling molecules in the vasculature. Because NOX2 is functional in endothelial cells, we investigated the role of the NOX2-containing NADPH oxidase in U-II-induced angiogenesis and elucidated a possible contribution of hypoxia-inducible factor-1 (HIF-1), the master regulator of hypoxic angiogenesis, in the response to U-II. We found that U-II increases angiogenesis in vitro and in vivo, and these responses were prevented by antioxidants, NOX2 knockdown and in Nox2(-/-) mice. In addition, U-II-induced angiogenesis was dependent on HIF-1. Interestingly, U-II increased NOX2 transcription involving HIF-1, and chromatin immunoprecipitation confirmed NOX2 as a target gene of HIF-1. In support, NOX2 levels were greatly diminished in U-II-stimulated isolated vessels derived from mice deficient in endothelial HIF-1. Conversely, reactive oxygen species derived from NOX2 were required for U-II activation of HIF and upregulation of HIF-1. In line with this, U-II-induced upregulation of HIF-1 was absent in Nox2(-/-) vessels. Collectively, these findings identified HIF-1 and NOX2 as partners acting in concert to promote angiogenesis in response to U-II. Because U-II has been found to be elevated in cardiovascular disorders and in tumour tissues, this feed-forward mechanism could be an interesting anti-angiogenic therapeutic option in these disorders.


Hydrogen gas treatment prolongs replicative lifespan of bone marrow multipotential stromal cells in vitro while preserving differentiation and paracrine potentials.
Cell therapy with bone marrow multipotential stromal cells/mesenchymal stem cells (MSCs) represents a promising approach in the field of regenerative medicine. Low frequency of MSCs in adult bone marrow necessitates ex vivo expansion of MSCs after harvest; however, such a manipulation causes cellular senescence with loss of differentiation, proliferative, and therapeutic potentials of MSCs. Hydrogen molecules have been shown to exert organ protective effects through selective reduction of hydroxyl radicals. As oxidative stress is one of the key insults promoting cell senescence in vivo as well as in vitro, we hypothesized that hydrogen molecules prevent senescent process during MSC expansion. Addition of 3% hydrogen gas enhanced preservation of colony forming early progenitor cells within MSC preparation and prolonged the in vitro replicative lifespan of MSCs without losing differentiation potentials and paracrine capabilities. Interestingly, 3% hydrogen gas treatment did not decrease hydroxyl radical, protein carbonyl, and 8-hydroxydeoxyguanosine, suggesting that scavenging hydroxyl radical might not be responsible for these effects of hydrogen gas in this study.


Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain.
New neurons are continuously generated in restricted regions of the adult mammalian brain. Although these adult-born neurons have been shown to receive synaptic inputs, little is known about their synaptic outputs. Using retrovirus-mediated birth-dating and labeling in combination with serial section electron microscopic reconstruction, we report that mossy fiber en passant boutons of adult-born dentate granule cells form initial synaptic contacts with CA3 pyramidal cells within 2 weeks after their birth and reach morphologic maturity within 8 weeks in the adult hippocampus. Knockdown of Disrupted-in-Schizophrenia-1 (DISC1) in newborn granule cells leads to defects in axonal targeting and development of synaptic outputs in the adult brain. Together with previous reports of synaptic inputs, these results demonstrate that adult-born neurons are fully integrated into the existing neuronal circuitry. Our results also indicate a role for DISC1 in presynaptic development and may have implications for the etiology of schizophrenia and related mental disorders.


Decreasing rates of cervical cancer among American Indians and Hispanics in New Mexico (United States).
Minority women in New Mexico (United States)--including American Indian and Hispanic women--have shown disproportionately high incidence rates of invasive cervical cancer during the 1960s and 1970s. Several public health programs in New Mexico were directed toward early detection of cervical cellular abnormalities, particularly targeting the state's minority women. To evaluate the effectiveness of these programs, we examined the New Mexico Surveillance, Epidemiology, and End Results (SEER) data collected from 1969-92, and calculated average annual, age-specific, and age-adjusted incidence rates by ethnic group (American Indian, Hispanic, and non-Hispanic White) for five-year time intervals. We also calculated age-adjusted mortality rates for cervical cancer in the same ethnic groups using state vital records. Age-adjusted incidence rates for invasive cervical cancer show substantial temporal decreases, especially for minority women in the state. The age-adjusted incidence rate decreased by 66 percent, from 30.3 to 10.3 per 100,000 for American Indian women, and by 61 percent, from 26.1 to 10.2 per 100,000 for Hispanic women. A stage shift to earlier stages of cervical neoplasia occurred over the study period, with a substantially higher proportion of in situ compared with invasive cancers diagnosed in the most recent cf the most remote time period. The ratio of incidence rates of in situ to invasive cancers changed dramatically for both American Indian and Hispanic women. Cervical cancer mortality rates decreased steadily among Hispanic women from 1958 to 1992; the decrease among American Indian women was less stable and fluctuated due to small numbers. Ongoing targeted screening programs should help to reduce cervical cancer incidence and mortality further in New Mexico.