In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls.
Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed.


Proteasome versus Thioredoxin Reductase Competition as Possible Biological Targets in Antitumor Mixed Thiolate-Dithiocarbamate Gold(III) Complexes.
New mixed gold(III) derivatives with dithiocarbamate and thiolate ligands have been synthesized and characterized. They display high anticancer activity against colon cancer cell lines without affecting to differentiated enterocytes, high stability in phosphate-buffered saline solution, and resistance to gold reduction in the presence of reducing agents in the majority of the derivatives. Some of them show interaction with thioredoxin reductase as derived from in vitro analysis and computational studies. However, a competition between this enzyme and proteasome is detected in cells, which is corroborated by the determination of proteasomal chymotrypsin-like activity inhibition. In addition, some of these dithiocarbamate gold(III) derivatives reduce cell viability and proliferation by intrinsic apoptotic pathway, with changes in mitochondrial membrane potential, cytochrome c release and caspase-3 activation. Consequently, our results show new complexes with proteasome as possible target in colorectal cancer.


A New Cost-effective Method of NPWT in Diabetic Foot Wound.
Diabetic foot wounds present a great challenge to surgeons. They are difficult to heal and are a significant risk factor for non-traumatic foot amputation besides being a huge financial burden. NPWT systems commercially available (VAC™ system, KCI Inc., USA) are costly precluding widespread use. To determine whether negative-pressure wound therapy (NPWT) would afford quicker wound recovery as compared to saline-moistened gauze in the treatment of diabetic foot wounds. Sixty patients were randomized into either the experimental NPWT group or conventional dressing group (control). All patients were given medical therapy for diabetes and antibiotics given according to culture and sensitivity patterns. All foot ulcers were surgically debrided prior to initiation of NPWT or conventional treatment. In the NPWT group, dressings were changed every 48-72 h. In the control group, conventional dressings were applied at the time of surgical debridement and changed twice a day thereafter. End point of study was when wound was ready for either skin grafting or secondary suturing. End point was achieved in the NPWT group in 17.2(SD ± 3.55) days, compared to 34.9 (SD ± 5.96) days in the control group (p < 0.001). Number of dressing applied were 7.46(SD ± 2.25) in NPWT group versus 69.8(SD ± 11.93) in conventional dressing group (p < 0.001). Ninety percent cases were successfully treated in NPWT Group as compared to 76.6 % in conventional group. Rate of healing of ulcer is faster in NPWT group as compared to conventional group. Economically modified NPWT is more cost-effective to the patients in our setup.


Ab Initio Molecular Dynamics Investigation of the Solvation States of Hydrated Ions in Confined Water.
Ionic transport in nanoscale channels with a critical size comparable to that of ions and solutes exhibits exceptional performance in water desalination, ion separation, electrocatalysts, and supercapacitors. However, the solvation states (SSs), i.e., the hydration structures and probability distribution, of hydrated ions in nanochannels differ from those in the bulk and the perspective of continuum theory. In this work, we conduct ab initio enhanced-sampling atomistic simulations to investigate the ion-specific SSs of monovalent ions (including Li+, Na+, K+, F-, Cl-, and I-) in the graphene channel with a width of 1 nm. Our findings highlight that the SSs of those ions are primarily determined by ion-water hydration, where ion-wall interactions play a minor role. The distribution of ions in layered confined water is a result of ion-specific hydration, which arises from the synergy of entropy and enthalpy. The free energy barriers for transitions between SSs are on the order of 1kBT, allowing for modulation through applying external fields or modifying surface properties. As the ion-wall interaction strengthens, as observed in vermiculite and carbides and nitrides of transition metal channels, the probability of near-wall SSs increases. These results help to improve the performance of nanofluidic devices and provide crucial insights for developing accurate force fields of molecular simulations or advanced theoretical approaches for ion dynamics in confined channels.


Evolution of novel genes in three-spined stickleback populations.
Eukaryotic genomes frequently acquire new protein-coding genes which may significantly impact an organism's fitness. Novel genes can be created, for example, by duplication of large genomic regions or de novo, from previously non-coding DNA. Either way, creation of a novel transcript is an essential early step during novel gene emergence. Most studies on the gain-and-loss dynamics of novel genes so far have compared genomes between species, constraining analyses to genes that have remained fixed over long time scales. However, the importance of novel genes for rapid adaptation among populations has recently been shown. Therefore, since little is known about the evolutionary dynamics of transcripts across natural populations, we here study transcriptomes from several tissues and nine geographically distinct populations of an ecological model species, the three-spined stickleback. Our findings suggest that novel genes typically start out as transcripts with low expression and high tissue specificity. Early expression regulation appears to be mediated by gene-body methylation. Although most new and narrowly expressed genes are rapidly lost, those that survive and subsequently spread through populations tend to gain broader and higher expression levels. The properties of the encoded proteins, such as disorder and aggregation propensity, hardly change. Correspondingly, young novel genes are not preferentially under positive selection but older novel genes more often overlap with FST outlier regions. Taken together, expression of the surviving novel genes is rapidly regulated, probably via epigenetic mechanisms, while structural properties of encoded proteins are non-debilitating and might only change much later.


Lactose nutrition in lactase nonpersisters.
Lactose handling by the human gut by most people, beyond being breast-fed, has been considered a disorder rather than physiological. A non-human mammalian milk source is novel for the majority. During the first 6 months of life, when neonates and infants are best breast-fed, lactose along with other macronutrients, provides energy, but may have other functions as well. At birth, babies are endowed with their mother's vaginal microbiome, but not if they are born by Caesarean section. How much maternal milk lactose survives the infant's small intestine and is processed by this unique gut microbiome and to what end is still uncertain, but no lactose or galactose appears in the faeces. Once intestinal lactase activity declines in most infants, lactose may enhance innate immunity through the cathelicidin antimicrobial peptide (CAMP), which is best achieved by lactose synergy with other colonic fermentation metabolites such as butyrate. It is of interest whether this lactose function or a variant of it persists. It might not be evident when lactase is persistent, as it is in most people of northern European ancestry. Population genomics indicate that lactase persistence became prevalent only about 3000-1000 BC, the Bronze Age of Eurasia. Gastrointestinal symptoms (GIS) in lactase nonpersisters who consume dairy foods are partly dose dependent and not usually evident with single lactose intakes≤25 g per day. Spreading intake across the day reduces the risk as can various dietary patterns. Nevertheless, individual differences in GIS lactose sensitivity may merit public health and clinical consideration.


A Case of a Large Intraabdominal Abscess in a Patient with Cirrhosis Misdiagnosed as Spontaneous Bacterial Peritonitis.
Spontaneous bacterial peritonitis is a known complication of patients with decompensated cirrhosis and ascites. It is differentiated from secondary bacterial peritonitis by the absence of an intraabdominal source of infection. We present a 56-year-old man with alcoholic cirrhosis who underwent multiple paracenteses that yielded fluid with progressively increasing neutrophil counts and several different organisms, recurring despite numerous treatments for SBP. Eventually, a computed tomography (CT) of the abdomen and the pelvis revealed a large intraabdominal abscess (22 × 13 cm) treated with an ultrasound-guided drain and IV antibiotics. Recurrent episodes of SBP despite appropriate antibiotics should raise suspicion for secondary bacterial peritonitis. It is crucial to differentiate SBP from secondary bacterial peritonitis as the mortality of the latter is much higher without prompt treatment. Appropriate antibiotic regimens, prompt surgical treatment, and postoperative care are crucial to improving clinical outcomes in these patients.


Effect of phosphatidylcholine on explicit memory.
Previous studies have not demonstrated a consistent relationship between precursors to acetylcholine (ACh) and memory function in normal human subjects. This experiment (N = 80, college students) employed a double-blind mixed design to test the effect of phosphatidylcholine (PCh) on explicit memory. Dose of placebo and PCh was compared at two levels (10 and 25 g) as was time of testing postingestion (60 and 90 min). With 25 g of PCh, which supplies 3.75 g of choline, significant improvement in explicit memory, as measured by a serial learning task, was observed at 90 min postingestion and slight improvement was observed at 60 min postigestion. Further analyses indicated that this improvement may have been due to the responses of slow learners. This is the first study to test the relationship between a single dose of PCh and explicit memory on normal human subjects.


Fatigue in patients with ankylosing spondylitis: A comparison with the general population and associations with clinical and self-reported measures.
To investigate 1) levels of fatigue in patients with ankylosing spondylitis (AS) compared with the general population; 2) the relationships between fatigue and demographic, self-reported, and clinical measures; and 3) the performance of both a generic and a disease-specific measure of fatigue. Patients with AS (n = 152) were compared with people from the general population (n = 2,323). Fatigue was assessed by the Short Form 36 (SF-36) vitality scale and the fatigue item of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Other measures of self-reported health included BASDAI for disease activity, Bath Ankylosing Spondylitis Functional Index for functional abilities, and the SF-36 for mental health. Clinical measures comprised Bath Ankylosing Spondylitis Metrology Index for joint mobility and erythrocyte sedimentation rate and C-reactive protein as inflammatory markers. The explanatory power of demographic, self-reported, and clinical measures was examined in a block regression model. The mean +/- SD SF-36 vitality score was 43 +/- 24 in the patients and 60 +/- 21 in the general population (P < 0.001). The SF-36 vitality and the BASDAI fatigue scores were consistently associated with measures of mental health and disease activity. Clinical measures did not show explanatory power. A cutoff at 70 mm on the BASDAI fatigue item implied specificity of 0.77 and sensitivity of 0.82. Self-reported measures of disease activity and mental health contributed significantly to explain fatigue, whereas clinical measures of inflammation and joint mobility did not. The BASDAI fatigue item reached acceptable sensitivity and specificity with a cutoff at 70 mm when using the low vitality scores of SF-36 as an external indicator.


Implementation and Impacts of Surface and Blowing Snow Sources of Arctic Bromine Activation Within WRF-Chem 4.1.1.
Elevated concentrations of atmospheric bromine are known to cause ozone depletion in the Arctic, which is most frequently observed during springtime. We implement a detailed description of bromine and chlorine chemistry within the WRF-Chem 4.1.1 model, and two different descriptions of Arctic bromine activation: (1) heterogeneous chemistry on surface snow on sea ice, triggered by ozone deposition to snow (Toyota et al., 2011 https://doi.org/10.5194/acp-11-3949-2011), and (2) heterogeneous reactions on sea salt aerosols emitted through the sublimation of lofted blowing snow (Yang et al., 2008, https://doi.org/10.1029/2008gl034536). In both mechanisms, bromine activation is sustained by heterogeneous reactions on aerosols and surface snow. Simulations for spring 2012 covering the entire Arctic reproduce frequent and widespread ozone depletion events, and comparisons with observations of ozone show that these developments significantly improve model predictions during the Arctic spring. Simulations show that ozone depletion events can be initiated by both surface snow on sea ice, or by aerosols that originate from blowing snow. On a regional scale, in spring 2012, snow on sea ice dominates halogen activation and ozone depletion at the surface. During this period, blowing snow is a major source of Arctic sea salt aerosols but only triggers a few depletion events.


Maxillary reconstruction with a fibula osteoseptocutaneous free flap and simultaneous insertion of osseointegrated dental implants.
The fibula osteoseptocutaneous flap is a good option for reconstruction of three-dimensional composite maxillary defects. This flap provides both bone and soft-tissue reconstruction and allows osseointegrated dental implantation, either simultaneously or in a second-stage procedure. Simultaneous placement of osseointegrated dental implants reduces operative sessions and allows faster oral rehabilitation for properly selected patients. The defects may result from trauma or resection of benign tumors or low-grade malignancies. Between August of 1999 and July of 2001, three patients underwent maxillary reconstruction with the fibula osteoseptocutaneous flap and simultaneous osseointegrated dental implants. The cause of the defect was trauma in two cases and resection of an adenoid cystic carcinoma in the other. The mean length of the fibula used for bony reconstruction was 4.7 cm. One osteotomy was performed in one case and no osteotomy was necessary in the other two. Skin islands of 8 x 2.5 cm and 16 x 3.5 cm were used for two patients. For the other patient, a double skin island was used for both nasal (6 x 4 cm) and oral (6 x 5 cm) reconstructions. Two osseointegrated implants were inserted into the fibular bone for each patient. Six months after the first-stage procedure, palatal rotation flaps or mucosa grafts were used to cover the exposed implant necks and prepare the implants for prostheses. One month after the second-stage procedure, prostheses were placed. An implant-supported prosthesis was used for one patient and implant/tissue-supported prostheses were used for the others. At a mean follow-up time of 30 months (range, 16 to 38 months), all patients were able to use the dental prosthesis for chewing (beginning 6 weeks after the final procedure) and all patients were satisfied with the cosmetic results.


Effects of tai chi on pain and muscle activity in young males with acute low back pain.
[Purpose] This study was to examine the effects of tai chi on low back pain in young males. [Subjects and Methods] Forty males in their 20s with low back pain were randomly assigned to two groups. Tai chi was applied to one group, and stretching was applied to the other group. The subjects conducted exercise for one hour, three times per week for four weeks. They performed warm-up exercises for 10 min at the beginning and end of the sessions and conducted the main exercise for 40 minutes. Wireless surface electromyography (sEMG) and a visual analogue scale (VAS) were employed to measure muscle activity and pain, respectively. [Results] There were significant differences between the two groups in pain and muscle activity. The tai chi group's VAS decreased from 3.1 to 2.1, and its muscle activity decreased from 21.5% maximum voluntary isomeric contraction (MVIC) to 16.4% MVIC. The stretching group's VAS decreased from 3.4 to 2.8, and its muscle activity decreased from 24.1% MVIC to 22.1% MVIC. [Conclusion] Tai chi is more effective for low back pain in males in their 20s than stretching. Tai chi can be considered an effective method to reduce low back pain in males in their 20s.


[Electro-ophthalmologic studies in HIV patients].
We examined 44 HIV-positive patients in different disease stages with electroretinogram (ERG), pattern-electroretinogram (PERG), and visually evoked cortical potentials (VECP). Sixty-eight of the 88 eyes examined had a normal fundus and full central vision. Twelve eyes showed cotton-wool ecudates and 8 eyes CMV retinitis. Fifty-four eyes with normal fundus were examined by ERG. Of these 28 (52%) showed marked reduction of the amplitude. In the PERG, 20 eyes out of 50 examined (40%) showed an amplitude reduction. In the VECP, 12 out of 65 eyes (19%) had a reduced amplitude. In the ERG, 7 of 11 eyes (64%) with cotton-wool exudates showed marked pathological findings, as opposed to 4 of 10 cases (40%) in the PERG and 3 of 12 (12%) in the VECP. Seventy-five percent of the eyes with CMV retinitis (6 of 8 cases) showed pathological findings in the ERG and VECP and 100% (all 7 cases examined) in the PERG. These electrophysiological findings suggest that there are diffuse disorders in the retina of HIV-positive patients. It is possible that these findings are based on direct infection of the retina with HIV, or that they represent a vascular disorder, subclinical infection or are related to side effects of the drugs used for the HIV infection.


Different mutation patterns of atovaquone resistance to Plasmodium falciparum in vitro and in vivo: rapid detection of codon 268 polymorphisms in the cytochrome b as potential in vivo resistance marker.
Resistance of Plasmodium falciparum to atovaquone in vitro and in vivo has been associated to mutations in the parasite cytochrome b gene. Cultures were sequentially subjected to increasing doses of atovaquone alone or in combination with cycloguanil and the cytochrome b gene was sequenced. Additionally, we investigated the parasite cytochrome b gene of a patient returning from Mali with Malarone treatment failure in vivo. All strains that survived atovaquone concentrations in vitro of 2 x 10(-8) to 2 x 10(7) M showed the M133I mutation and one strain with the highest atovaquone concentration the additional mutation L171F. Sequencing of the in vivo treatment failure revealed a point mutation at codon 268 resulting in an amino acid change from tyrosine to serine. Based on the repeated emergence of mutations at codon 268, but no detection of alterations at codon 133 in vivo, we developed a detection method for the diagnostic of codon 268 polymorphisms as a potential atovaquone/proguanil resistance marker. A nested PCR with 3 different pairs of primers for the second round was designed. Each product was digested with restriction enzymes, capable to distinguish the wild type from the two reported mutations at codon 268. Mutations at codon 268 of the parasite cytochrome bc1 gene are associated with atovaquone/proguanil treatment failure in vivo and can be used as potential resistance marker This method provides a novel and robust tool to investigate the relevance of codon 268 polymorphisms as resistance marker and to monitor the further emergence of atovaquone/proguanil resistance.


MicroRNA-221 promotes proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) by targeting tissue inhibitor of metalloproteinases-3 (TIMP3).
Aberrant vascular smooth muscle cell (VSMC) proliferation and migration play an important role in the development of cardiovascular diseases including pulmonary arterial hypertension (PAH). MicroRNAs (miRNAs, miRs) have been considered to be implicated in the progression of PAH pathogenesis. In this study, we aim to clarify the role of miR-221 on proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs) and identify the target genes involved in this biological process. PASMCs were isolated from the pulmonary arteries of male Sprague-Dawley (SD) rats. Cell proliferation of PASMCs was detected by 5-ethynyl-2'-deoxyuridine (EdU) assay. Cell migration was determined by a scratch wound assay. Quantitative real-time PCR was used to determine the expression of miR-221 while western blot analysis was used to determine the expression of TIMP3. Luciferase assay was used to confirm that TIMP3 was a direct target gene of miR-221. Monocrotaline (MCT) induced-PAH rat model was established and miR-221 and TIMP3 levels were checked in lung tissue and PASMCs from PAH rats. miR-221 was able to promote the proliferation and migration PASMCs. TIMP3 were negatively regulated by miR-221 at the protein level in PASMCs. In addition, TIMP3 was identified to be a direct target gene of miR-221 in PASMCs based on luciferase assays. TIMP3 knockdown abolished the inhibitory effect of miR-221 inhibitor on PASMCs proliferation and migration, suggesting TIMP3 mediated the effects of miR-221 in PASMCs. Finally, we found that miR-221 was increased while TIMP3 was down-regulated in PASMCs in MCT-treated rats. In conclusion, miR-221 promotes PASMCs proliferation and migration by targeting TIMP3. MiR-221 and TIMP3 could be potential therapeutic targets for the treatment of PAH.


Carcinogenicity of N-phenyl-1-naphthylamine and N-phenyl-2-naphthylamine in mice.
Technical N-phenyl-1-naphthylamine ( PANA ), which is an optic isomer of N-phenyl-2-naphthylamine ( PBNA ), has been used as a rubber additive without suspicion of its being carcinogenic. When male ICR mice were given repeated s.c. injections of both technical and pure PANA in dimethyl sulfoxide, it resulted in high percentage of malignant tumors similar to that in mice given technical PBNA . PANA had a tendency to induce hemangiosarcoma. Similar injections of PANA and PBNA into male TA-1 mice gave similar results. Previous unilateral nephrectomy enhanced both PANA and PBNA induction of renal hemangiosarcomas. The similar carcinogenic potency of PANA and PBNA suggests other routes of metabolic activation besides dephenylation for both chemicals in mice.


Practice innovation: a methodological maze.
Practice innovation is an inevitable feature of a health culture preoccupied with evidence-based practice. The cyclical process of defining best practice, implementing and evaluating change represents an unparalleled opportunity for nurse researchers to engage in, and develop, practice through 'realistic evaluation'. However, the methodological dilemmas and challenges inherent in evaluation research which informs policy should not be under-estimated. This paper seeks to introduce and wrestle with some of the political tensions and methodological issues surrounding practice innovation when it is undertaken within an evaluative research framework. A critical pathway is presented to stimulate discussion and guide novice evaluators through this often perplexing methodological maze. A case study in audiological rehabilitation in elder care is used to illustrate the issues raised.


Imaging of Angiogenesis in White Matter Hyperintensities.
Background White matter hyperintensities (WMHs) are areas of increased signal intensity on T2-weighted magnetic resonance imaging (MRI). WMH penumbra may be a potential target for early intervention in WMHs. We explored the relationship between angiogenesis and WMH penumbra in patients with WMHs. Methods and Results Twenty-one patients with confluent WMHs of Fazekas grade ≥2 were included. All the participants underwent 68Ga-NOTA-PRGD2 positron emission tomography/magnetic resonance imaging. WMH penumbra was analyzed with masks created for the WMH and 7 normal-appearing white matter layers; each layer was dilated away from the WMH by 2 mm. Angiogenesis array and ELISA were used to detect the serum levels of angiogenic factors, inflammatory factors, HIF-1 alpha, and S100B. Fourteen patients with increased 68Ga-NOTA-PRGD2 maximum standardized uptake (>0.17) were classified into group 2. Seven patients with maximum standardized uptake ≤0.17 were classified as group 1. WMH volume and serum levels of integrin αvβ3, vascular endothelial growth factor receptor 22, and interleukin-1β tended to be higher in group 2 than in group 1. In group 2, 68Ga-NOTA-PRGD2 uptake was significantly increased at the border between the WMH and normal-appearing white matter than in WMHs (P=0.004). The structure penumbra, defined by fractional anisotropy, was wider in group 2 (8 mm) than in group 1 (2 mm). The cerebral blood flow penumbra was 12 mm in both groups. Angiogenesis showed a correlation with reduced cerebral blood flow and microstructure integrity. Conclusions Our study provides evidence that angiogenesis occurs in the WMH penumbra. Further studies are warranted to verify the effect of angiogenesis on WMH growth.


Cadmium and Lead Concentration in Drinking Instant Coffee, Instant Coffee Drinks and Coffee Substitutes: Safety and Health Risk Assessment.
The presence of heavy metals in food is a global problem. The paper aimed to examine the content of cadmium (Cd) and lead (Pb) in instant coffee and instant coffee substitutes. The safety of consumption of the beverages by adult Poles was estimated based on the following parameters: tolerable weekly intake (TWI) %, benchmark dose lower confidence limit (BMDL) %, chronic daily intake (CDI), target hazard quotient (THQ) and hazard index (HI), for three beverage consumption patterns-one, two or three servings a day. Forty-nine samples of coffee, instant coffee drinks and coffee substitutes were analysed. The content of cadmium and lead was determined by ICP (inductively coupled plasma) analysis. The maximum level of Cd in the analysed beverages was 3.2 µg, and that of Pb was 82.6 µg per 1 kg. The tolerable level of intake of Cd (TWI) and Pb (BMDL) with the analysed beverages did not exceed 2.5%. The value of CDI, THQ and HI was not higher than 1, which means that the risk of diseases related to chronic exposure to Cd and Pb consumed with coffee should be evaluated as very low. However, special note should be taken of Pb, as the level of this metal was higher than that of Cd, and for beverages with a higher weight per serving (e.g. Cappuccino), the intake of Pb can exceed consumer-safe levels if they are consumed on a regular basis. Therefore, it should be considered whether it is advisable for flavoured multi-ingredient instant coffee drinks to be consumed from time to time only, and natural coffee with optional milk and/or sugar be the choice of regular coffee drinkers.


Denervation increases myogenic tone in a resistance artery in the growing rabbit ear.
The effect of chronic sympathetic and sensory denervation of the growing rabbit ear vasculature on myogenic tone in a resistance artery was studied. Unilateral superior cervical ganglionectomy and section of greater and anterior auricular nerves were performed at 4 wk of age. Compared with the contralateral control, 2 and 6 wk later, the denervated artery developed greater stretch-dependent myogenic tone. This phenomenon may partially account for the return of tone described in the denervated ear vasculature.


A Bayesian approach to analyze energy balance data from lactating dairy cows.
The objective of the present investigation was to develop a Bayesian framework for updating and integrating covariate information into key parameters of metabolizable energy (ME) systems for dairy cows. The study addressed specifically the effects of genetic improvements and feed quality on key parameters in current ME systems. These are net and metabolizable energy for maintenance (NE(M) and ME(M), respectively), efficiency of utilization of ME for milk production (k(L)) and growth (k(G)), and efficiency of utilization of body stores for milk production (k(T)). Data were collated from 38 studies, yielding 701 individual cow observations on milk energy, ME intake, and tissue gain and loss. A function based on a linear relationship between milk energy and ME intake and correcting for tissue energy loss or gain served as the basis of a full Bayesian hierarchical model. The within-study variability was modeled by a Student t-distribution and the between-study variability in the structural parameters was modeled by a multivariate normal distribution. A meaningful relationship between genetic improvements in milk production and the key parameters could not be established. The parameter k(L) was linearly related to feed metabolizability, and the slope predicted a 0.010 (-0.0004; 0.0210) change per 0.1-unit change in metabolizability. The effect of metabolizability on k(L) was smaller than assumed in present feed evaluation systems and its significance was dependent on collection of studies included in the analysis. Three sets of population estimates (with 95% credible interval in parentheses) were generated, reflecting different degrees of prior belief: (1) Noninformative priors yielded 0.28 (0.23; 0.33) MJ/(kg(0.75)d), 0.55 (0.51; 0.58), 0.86 (0.81; 0.93) and 0.66 (0.58; 0.75), for NE(M), k(L), k(G), and k(T), respectively; (2) Introducing an informative prior that was derived from a fasting metabolism study served to combine the most recent information on energy metabolism in modern dairy cows. The new estimates of NE(M), k(L), k(G) and k(T) were 0.34 (0.28; 0.39) MJ/(kg(0.75)d), 0.58 (0.54; 0.62), 0.89 (0.85; 0.95), and 0.69 (0.60; 0.79), respectively; (3) finally, all informative priors were used that were established from literature, yielding estimates for NE(M), k(L), k(G), and k(T) of 0.29 (0.11; 0.46) MJ/(kg(0.75)d), 0.60 (0.54; 0.70), 0.70 (0.50; 0.88), and 0.80 (0.67; 0.97), respectively. Bayesian methods are especially applicable in meta-analytical studies as information can enter at various stages in the hierarchical model.


[Implantation of the artificial heart].
This article gives some methods of implanting an artificial heart to calves. The non-invasive method used to control the central hemodynamic parameters in the post-operative period showed high stability and informative value in operation. It has been shown that the heart prosthesis is well placed in the thoracic cavity of the human cadaver of different weight and constitution. The further development of the artificial heart problem in many respects depends upon the progress in the field of chemistry and the technology of polymers as well as precision equipment.


Economic Evaluations of Pathology Tests, 2010-2015: A Scoping Review.
Concerns about pathology testing such as the value provided by new tests and the potential for inappropriate utilization have led to a greater need to assess costs and benefits. Economic evaluations are a formal method of analyzing costs and benefits, yet for pathology tests, questions remain about the scope and quality of the economic evidence. To describe the extent and quality of published evidence provided by economic evaluations of pathology tests from 2010 to 2015. Economic evaluations relating to pathology tests from 2010 to 2015 were reviewed. Eight databases were searched for published studies, and details recorded for the country, clinical focus, type of testing, and consideration of sensitivity, specificity, and false test results. The reporting quality of studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist and cost-effectiveness ratios were analyzed for publication bias. We found 356 economic evaluations of pathology tests, most of which regarded developed countries. The most common economic evaluations were cost-utility analyses and the most common clinical focus was infectious diseases. More than half of the studies considered sensitivity and specificity, but few studies considered the impact of false test results. The average Consolidated Health Economic Evaluation Reporting Standards checklist score was 17 out of 24. Cost-utility ratios were commonly less than $10,000/quality-adjusted life-year or more than $200,000/quality-adjusted life-year. The number of economic evaluations of pathology tests has increased in recent years, but the rate of increase has plateaued. Furthermore, the quality of studies in the past 5 years was highly variable, and there is some question of publication bias in reporting cost-effectiveness ratios.


[Analysis of the clinical features and outcome of ventilator-associated Pseudomonas aeruginosa-related pneumonia in an intensive care unit].
The occurrence, the course, and outcome of ventilator-associated pneumonia (VAP) related to Pseudomonas aeruginosa were prospectively followed up in 51 patients treated at an intensive care unit. The characteristic feature of P. aeruginosa-induced VAP was its severe course and poor prognosis (mortality was 38%). More than half of cases were found to have bilateral lung injury with the upper left lung being involved. Lung tissue destruction and edema were rather frequent complications. The predictors of death in VAP caused by P. aeruginosa are admission to an intensive care unit, septic shock, and infection.


Glucocorticoid-inducible expression of a bacterial avirulence gene in transgenic Arabidopsis induces hypersensitive cell death.
Pathogenic strains of Pseudomonas syringae pv. tomato carrying the avrRpt2 avirulence gene specifically induce a hypersensitive cell death response in Arabidopsis plants that contain the complementary RPS2 disease resistance gene. Transient expression of avrRpt2 in Arabidopsis plants having the RPS2 gene has been shown to induce hypersensitive cell death. In order to analyze the effects of conditional expression of avrRpt2 in Arabidopsis plants, transgenic lines were constructed that contained the avrRpt2 gene under the control of a tightly regulated, glucocorticoid-inducible promoter. Dexamethasone-induced expression of avrRpt2 in transgenic lines having the RPS2 gene resulted in a specific hypersensitive cell death response that resembled a Pseudomonas syringae-induced hypersensitive response and also induced the expression of a pathogenesis-related gene (PR1). Interestingly, high level expression of avrRpt2 in a mutant rps2-101C background resulted in plant stress and ultimately cell death, suggesting a possible role for avrRpt2 in Pseudomonas syringae virulence. Transgenic RPS2 and rps2 plants that contain the glucocorticoid-inducible avrRpt2 gene will provide a powerful new tool for the genetic, physiological, biochemical, and molecular dissection of an avirulence gene-specified cell death response in both resistant and susceptible plants.


Effects of chronic treprostinil treatment on experimental right heart hypertrophy and failure.
Right heart function is an important predictor of morbidity and mortality in pulmonary arterial hypertension and many CHD. We investigated whether treatment with the prostacyclin analogue treprostinil could prevent pressure overload-induced right ventricular hypertrophy and failure. Male Wistar rats were randomised to severe pulmonary trunk banding with a 0.5-mm banding clip (n=41), moderate pulmonary trunk banding with a 0.6-mm banding clip (n=36), or sham procedure (n=10). The banded rats were randomised to 6 weeks of treatment with a moderate dose of treprostinil (300 ng/kg/minute), a high dose of treprostinil (900 ng/kg/minute), or vehicle. Pulmonary trunk banding effectively induced hypertrophy, dilatation, and decreased right ventricular function. The severely banded animals presented with decompensated heart failure with extracardial manifestations. Treatment with treprostinil neither reduced right ventricular hypertrophy nor improved right ventricular function. In the pulmonary trunk banding model of pressure overload-induced right ventricular hypertrophy and failure, moderate- and high-dose treatment with treprostinil did not improve right ventricular function neither in compensated nor in decompensated right heart failure.


A Comparison of Different Prerace Warm-Up Strategies on 1-km Cycling Time-Trial Performance.
Ischemic preconditioning (IPC) and postactivation potentiation (PAP) are warm-up strategies proposed to improve high-intensity sporting performance. However, only few studies have investigated the benefits of these strategies compared with an appropriate control (CON) or an athlete-selected (SELF) warm-up protocol. Therefore, this study examined the effects of 4 different warm-up routines on 1-km time-trial (TT) performance with competitive cyclists. In a randomized crossover study, 12 well-trained cyclists (age 32 [10] y, mass 77.7 [4.6] kg, peak power output 1141 [61] W) performed 4 different warm-up strategies-(CON) 17 minutes CON only, (SELF) a self-determined warm-up, (IPC) IPC + CON, or (PAP) CON + PAP-prior to completing a maximal-effort 1-km TT. Performance time and power, quadriceps electromyograms, muscle oxygen saturation (SmO2), and blood lactate were measured to determine differences between trials. There were no significant differences (P > .05) in 1-km performance time between CON (76.9 [5.2] s), SELF (77.3 [6.0] s), IPC (77.0 [5.5] s), or PAP (77.3 [5.9] s) protocols. Furthermore, there were no significant differences in mean or peak power output between trials. Finally, electromyogram activity, SmO2, and recovery blood lactate concentration were not different between conditions. Adding IPC or PAP protocols to a short CON warm-up appears to provide no additional benefit to 1-km TT performance with well-trained cyclists and is therefore not recommended. Furthermore, additional IPC and PAP protocols had no effect on electromyograms and SmO2 values during the TT or peak lactate concentration during recovery.


Cognitive effect of antiseizure medications in medial temporal lobe epilepsy.
The specific effects of antiseizure medications (ASMs) on cognition are a rich field of study, with many ongoing questions. The aim of this study was to evaluate these effects in a homogeneous group of patients with epilepsy to guide clinicians to choose the most appropriate medications. We retrospectively identified 287 refractory patients with medial temporal lobe epilepsy associated with hippocampal sclerosis. Scores measuring general cognition (global, verbal and performance IQ), working memory, episodic memory, executive functions, and language abilities were correlated with ASM type, number, dosage and generation (old vs. new). We also assessed non-modifiable factors affecting cognition, such as demographics and epilepsy-related factors. Key parameters were total number of ASMs and specific medications, especially topiramate (TPM) and sodium valproate (VPA). Four cognitive profiles of the ASMs were identified: (i) drugs with an overall detrimental effect on cognition (TPM, VPA); (ii) drugs with negative effects on specific areas: verbal memory and language skills (carbamazepine), and language functions (zonisamide); (iii) drugs affecting a single function in a specific and limited area: visual denomination (oxcarbazepine, lacosamide); and (iv) drugs without documented cognitive side effects. Non-modifiable factors such as age at testing, age at seizure onset, and history of febrile seizures also influenced cognition and were notably influenced by total number of ASMs. We conclude that ASMs significantly impact cognition. Key parameters were total number of ASMs and specific medications, especially TPM and VPA. These results should lead to a reduction in the number of drugs received and the avoidance of medications with unfavorable cognitive profiles.


Blood pressure ranges in premature infants: II. The first week of life.
To examine the arterial blood pressure in the first week of life in a healthy premature population. Population-based cohort study. Three intensive care nurseries in central New Jersey. Premature infants with birth weights less than 2000 g. We documented daily maximum and minimum systolic and maximum and minimun diastolic blood pressures during the first 7 days of life. To examine the effects on the ranges of blood pressure, we identified four groups of infants: (1) healthy infants without any of the major risk factors (n = 193); (2) infants who were mechanically ventilated but free of any of the other conditions (n = 225); (3) infants with histories of maternal hypertension or preeclampsia (n = 38) and (4) infants with low Apgar scores (less than 3 at 1 minute and less than 6 at 5 minutes) regardless of the presence of other conditions (n = 86). Blood pressure increased steadily in the first week of life in all four groups. There was no relationship between any of the four blood pressure variables, or trends in blood pressure over time, with birth weight, gender, or race. Regression equations (based on all infants with available data) for blood pressure ranges by day of life revealed that the maximum systolic blood pressure increased by 2.6 mm Hg/d, the minimum systolic blood pressure increased by 1.8 mm Hg/d,the maximum diastolic blood pressure increased by 2.0 mm HHg/d, and the minimum diastolic blood pressure increased by 1.3 Hg/d. Infants with birth asphyxia and ventilated infants had significantly lower systolic and diastolic blood pressures than healthy infants.


Retinal ganglion cells: properties, types, genera, pathways and trans-species comparisons.
This article attempts to develop an empirical foundation for the notion of 'cell type', and to use this notion to clarify the issues involved in the classification, pathways, and trans-species comparisons of retinal ganglion cells.


Structural requirements for intracellular targeting of SP-C proprotein.
Rat surfactant protein (SP) C is synthesized as a 194-amino acid proprotein that is proteolytically processed to a 35-amino acid mature form in subcellular compartments distal to the medial Golgi compartment. To identify domains of SP-C proprotein (proSP-C) necessary for endoplasmic reticulum translocation and for targeting to cytosolic processing compartments, we characterized expression patterns of heterologous SP-C fusion proteins in A549 lung epithelial cells and in the rat pheochromocytoma cell line PC-12. cDNA constructs were produced; these constructs encoded fusion proteins consisting of enhanced green fluorescent protein (EGFP) and wild-type proSP-C (EGFP/SP-C(1-194)), mature SP-C (EGFP/SP-C(24-59)), or progressive deletions of the NH(2)- or COOH-terminal flanking domains. By fluorescence microscopy, EGFP/SP-C(1-194) transfected into A549 cells was translocated and expressed in acidic cytoplasmic vesicles. By deletional analysis, a functional signal peptide was mapped to the domain Phe(24) to His(59), whereas a motif for targeting to cytosolic vesicular compartments was localized to the NH(2) flanking domain Met(10) to Gln(23). Truncations of the distal COOH terminus were retained in the endoplasmic reticulum/Golgi compartment; however, the COOH flanking region alone was insufficient for targeting. In PC-12 cells, EGFP/SP-C(1-194) was expressed in peripheral cytosolic vesicles, whereas EGFP/SP-C(24-194) and EGFP/SP-C(24-59) were each translocated but not targeted. We conclude that two domains in the proSP-C sequence are required for targeting: mature SP-C (Phe(24) to Leu(58)) contains a functional signal sequence active in epithelial and nonepithelial cells, whereas Met(10) to Gln(23), but not the COOH flanking peptide, is required for targeting to late vesicular compartments.


hnRNP K Is a Novel Internal Ribosomal Entry Site-Transacting Factor That Negatively Regulates Foot-and-Mouth Disease Virus Translation and Replication and Is Antagonized by Viral 3C Protease.
Cap-independent translation initiation on picornavirus mRNAs is mediated by an internal ribosomal entry site (IRES) in the 5' untranslated region. The regulation of internal initiation requires the interaction of IRES-transacting factors (ITAFs) with the IRES. In this study, we identified a novel ITAF, heterogeneous nuclear ribonucleoprotein K (hnRNP K), which negatively regulates foot-and-mouth disease virus (FMDV) translation and viral replication. Further investigation revealed that the KH2 and KH3 domains of hnRNP K directly bind to domains II, III, and IV of the FMDV IRES, resulting in the inhibition of IRES-mediated translation by interfering with the recognition of another positive ITAF, polypyrimidine tract-binding protein (PTB). Conversely, hnRNP K-mediated inhibition was antagonized by the viral 3C protease through the cleavage of hnRNP K at the Glu-364 residue during FMDV infection. Interestingly, the N-terminal cleavage product, hnRNP K1-364, retained partial inhibitory effects on IRES activity, whereas the C-terminal cleavage product, hnRNP K364-465, became a positive regulator of FMDV replication. Our findings expand the current understanding of virus-host interactions concerning viral recruitment and the modulation of ITAFs, providing new insights into translational control during viral infection.IMPORTANCE The translation of picornaviral genome RNA mediated by the internal ribosomal entry site (IRES) is a crucial step for virus infections. Virus-host interactions play a critical role in the regulation of IRES-dependent translation, but the regulatory mechanism remains largely unknown. In this study, we identified an ITAF, hnRNP K, that negatively regulates FMDV replication by inhibiting viral IRES-mediated translation. In addition, we describe a novel translational regulation mechanism involving the proteolytic cleavage of hnRNP K by FMDV protease 3C. The cleavage of hnRNP K yields two cleavage products with opposite functions: the cleavage product hnRNP K1-364 retains a partial inhibitory effect on IRES activity, and the cleavage product hnRNP K364-465 becomes a positive regulator of FMDV replication. Our findings shed light on the effect of a novel ITAF on the translational regulation of picornavirus and provide new insights into translational control during viral infection.


[Role of Toll-like receptor 2/4-nuclear factor-κB signaling pathway in invasion of Mycobacterium tuberculosis to mouse dendritic cells].
To investigate the mechanism of Mycobacterium tuberculosis invasion to mouse dendritic cells (DC). Mycobacterium tuberculosis strain H37Rv was co-cultured with mouse DC2.4 cells.The mRNA expression of Toll-like receptor 2/4(TLR2/4) in DC2.4 cells was detected by fluorescent quantitative real-time PCR and the protein expression of nuclear factor κB(NF-κB) was assessed by Western blotting.The extracellular concentration of tumor necrosis factor α(TNF-α) was measured by ELISA methods during Mycobacterium Tuberculosis invasion.Indirect immunofluorescent staining and flow cytometry assay were used to detect the expression of CD80 and CD86 on DC2.4 cells before and after invasion. The invasion of Mycobacterium tuberculosis in DC2.4 cells was observed after 2 h of co-incubation.The rates of invasion were (37.9±5.6)%,(51.2±7.6)%,(57.2±8.9)% and(63.9±6.8)% at 6,8,10 and 12 h after co-incubation,respectively.The mRNA expression level of TLR2 /4 was significantly increased at 6 h but decreased at 10 h after co-incubation.The expressions of NF-κB p65 and TNF-α were higher in DC2.4 cells after being invaded by 6,8,and 10 h and then gradually decreased.CD80 and CD86 expression were increased on DC2.4 at 6 h after co-incubation. Invasion of Mycobacterium tuberculosis strain H37Rv to DC might enhance its antigen-presenting function through activation of TLR2/4-NF-kB signaling pathway.


Simultaneous Morphology and Band Structure Manipulation of BiOBr by Te Doping for Enhanced Photocatalytic Oxygen Evolution.
The photocatalytic oxygen evolution of bismuth oxybromide (BiOBr) is greatly hindered by its low visible-light response and high electron-hole recombination. Nonmetal doping can effectively alleviate these issues, leading to improvement in photocatalytic performance. Herein, Bi2Te3 was introduced as both the Te doping source and the morphology-control template to improve the photocatalytic performance of BiOBr. Appropriate amounts of Te are critical to maintain the ultrathin plate-like structure of BiOBr, whereas excessive Te results in the formation of a flower-like architecture. Oxygen evolution activity disclosed that a plate-like structure is essential for realizing higher performance owing to sufficient light utilization and efficient charge separation. An optimal oxygen evolution rate of 368.0 μmol h-1 g-1 was achieved for the Te-doped sample, which is 2.3-fold as that of the undoped BiOBr (158.9 μmol h-1 g-1). Theoretical calculations demonstrated that Te doping can induce impurity levels above the valence band of BiOBr, which slightly narrowed the band gap and strengthened the light absorption in the range of 400-800 nm. More importantly, Te dopants could act as shallow traps for confining the excited electrons, thus prolonging the carrier lifetime. This work provides a novel strategy to prepare highly efficient photocatalysts by simultaneously realizing morphology manipulation and nonmetal doping.


The possible effects of a change to master's entry level in occupational therapy.
One of the most challenging debates facing the profession of occupational therapy centers on whether or not the standard for entry level into the field should be upgraded. The occupational therapy baccalaureate degree has been viewed as too limited in scope and professional training, and the master's degree has been forwarded as the standard for entry into the profession. However, upgrading the entry level standard raises several questions. This study considered 25 areas that would be affected by upgrading the entry level from the baccalaureate to the master's level in occupational therapy and in related health professions. A model was developed to provide a framework for analyzing how a change in entry level will affect the current status of occupational therapy as a profession. Although the parallel material is drawn from other health professions, the considerations are similar to the ones faced by occupational therapy. This comparison is especially important because a major change in entry level education has far-reaching repercussions that must be considered before any groundwork is laid for upgrading educational requirements.


Influence of the interval between primary tumor removal and chemotherapy on kinetics and growth of metastases.
In many animal models, primary tumor removal produces increased proliferation of cells in metastatic foci. The present investigations using a murine mammary tumor were carried out to determine how a variation in the time interval between primary tumor removal and administration of a single dose of cyclophosphamide (CY) affected labeling indices of residual tumor cells, their growth, and animal survival. The CY (240 mg/kg) had a more favorable effect when given on the day of tumor removal than 3 days after, a time when the labeling index (LI) of metastases was at a peak. It was least effective if given at 7 days following primary tumor excision, when the LI had returned to the preoperative level. The greatest effect occurred when the CY was given prior to operation. It completely prevented the increase in LI resulting from tumor removal, more effectively suppressed the growth of residual tumor, and prolonged survival to a greater extent than was noted under any other circumstance. The interval between tumor removal and administration of a relatively small amount of CY (60 mg/kg) was critical. When given on the day of tumor removal, an increase in LI of the residual focus occurred which was greater than that occurring as a result of tumor removal. When given 3 days after tumor removal, the smaller dose was almost as effective in suppressing LI as was the larger. From a kinetic standpoint, there was no advantage in reducing the tumor burden prior to the use of chemotherapy. The tumor response in this model suggests that, for the most effective control of metastases, the largest tolerable dose of chemotherapy would best be used at the time of or before primary tumor removal. The results provide a biological rationale for the use of perioperative adjuvant chemotherapy.


Modulation of rat testes lipid composition by hormones: effect of PRL and hCG.
The effect of prolactin (PRL) and human chorionic gonadotropin (hCG) administration for 7 days on the composition and function of rat testicular plasma membrane was investigated. Refractory state in Leydig cells desensitized by hCG decreased the binding capacity for 125I-labeled hCG and also luteinizing hormone (LH)-induced adenosine 3',5'-cyclic monophosphate (cAMP) and testosterone production. In testicular membranes of hCG-treated animals, a depletion of cholesterol and an increase in total phospholipid content was observed after gonadotropin injection, thereby decreasing the cholesterol-to-phospholipid ratio. Injection of high doses of PRL had no effect on the binding capacity or affinity of the LH-hCG receptor but decreased the response of Leydig cells to LH in terms of cAMP and testosterone synthesis. PRL also increased total and esterified cholesterol and decreased free cholesterol and membrane phospholipid content. The fatty acid composition of testicular lipids was significantly and selectively influenced by both hormonal treatments. These observations suggest that metabolism of cholesterol and long-chain polyunsaturated fatty acids in testicular tissue is affected by chorionic gonadotropin and PRL and may provide the mechanism for regulating steroidogenic functions.


Liver metastasis of breast carcinoma: An unusual presentation and growth pattern.
Breast carcinoma is one of the tumors that frequently metastasize to the liver. Extramedullary hematopoiesis (EMH) usually occurs due to insufficient medullary hematopoiesis. In this case report, we present a female patient with sinusoidal breast carcinoma metastasis and extramedullary hematopoiesis in liver biopsy. A 63-year-old female patient with history of breast carcinoma was admitted to our center with respiratory distress. Pleural effusion was detected and thoracentesis was planned. Treatment was given after detection of non-mycobacterial tuberculosis bacillus in the thoracentesis fluid. Antibiotherapy was terminated due to elevation of liver enzymes and bilirubin. The patient's clinical status was evaluated and treatment was re-initiated. The patient did not have any mass lesion in the liver. Tru-cut biopsy was performed to evaluate a possible tuberculosis involvement in the liver. The diagnosis of metastatic breast carcinoma located in the sinusoidal area and cholestatic liver with extramedullary hematopoiesis foci was given using the histomorphological, immunohistochemical and histochemical findings. Radiological evaluation has an important role in staging of malignancies. However, it should be kept in mind that hepatic metastases may present without formation of a mass lesion, and unexpected laboratory results of cases without abnormal radiological features should raise the suspicion of a metastasis. Such materials should be evaluated in detail by making multiple serial sections in the pathology laboratory. Rare metastatic tumor growth patterns not causing a mass lesion such as sinusoidal or portal pattern, should also be kept in mind.


Comparative cell wall analyses of morphological forms within the genus Actinomyces.
Comparative cell wall analyses were made of mycelial and smooth forms of Actinomyces bovis and A. israelii to determine the changes which occur in the cell wall composition concurrent with a change in morphology, and to evaluate cell wall analyses as a criterion for taxonomic identification within the genus Actinomyces. Cell walls of the spider forms of A. boyis had little or no aspartic acid and a high hexosamine concentration; cell walls of the smooth forms had a high aspartic acid content and low concentrations of hexosamine. Both forms had large amounts of glutamic acid, alanine, and lysine, as previously reported. A strain of Actinomyces, previously identified as A. naeslundii on the basis of morphology and aerobic growth characteristics, was found to have the basic cell wall composition of A. israelii. When transferred from the Actinomyces maintenance broth to a thioglycolate broth, the cells of this strain passed from a mycelial form through a transient filamentous morphology to become diphtheroidal with continued incubation. Concomitantly, the concentrations of glutamic acid relative to alanine decreased, and the hexosamine content increased. Variation in morphology within the species A. israelii and A. bovis could not be related to any mutual chemical change of their cell walls.


In-vitro differential metabolism and activity of 5-fluorouracil between short-term, high-dose and long-term, low-dose treatments in human squamous carcinoma cells.
Although continuous infusion of 5-fluorouracil (5-FU) has been clinically demonstrated to be superior to bolus administration, the mechanistic difference between the treatments still remains unclear. Here, we investigated in vitro whether there were any differences in the metabolism and activity of 5-FU between these schedules. To simulate bolus and infusional treatments of 5-FU, HST-1 human squamous carcinoma cells were treated with short-term, high-doses and long-term, low-doses so that the area under the curve (AUC) of 5-FU became equivalent between both schedules, and compared the cytotoxicity, fluorinated RNA (F-RNA) levels, 5-fluorodeoxyuridine monophosphate (FdUMP) content and thymidylate synthase (TS) activity. F-RNA and FdUMP were measured by capillary gas chromatography-mass spectrometry and competitive ligand-binding assay, respectively. The [H]FdUMP binding site in TS was determined as an index of the amount of TS using the radio-binding assay. Long-term, low-dose treatment of 5-FU was found to be 1.3-1.7 times more cytotoxic than the short-term, high-dose treatment. F-RNA content increased as the AUC of 5-FU was increased and was 2-4 times significantly higher in the cells treated with the long-term, low-dose than those with the short-term, high-dose schedule, indicating that the levels of F-RNA are AUC and schedule dependent. In contrast, there were no significant differences in FdUMP levels, TS activity and TS inhibition rate between the schedules. These data suggest that the superior activity of 5-FU administered long-term, low-dose over short-term, high-dose could be explained by more 5-FU incorporated into RNA during a long-term, low-dose exposure, thus providing a strategic rationale for the clinical advantage of continuous infusion over bolus administration.


Genetic Diagnosis in Hereditary Hemochromatosis: Discovering and Understanding the Biological Relevance of Variants.
Hereditary hemochromatosis (HH) is a genetic disease, leading to iron accumulation and possible organ damage. Patients are usually homozygous for p. Cys282Tyr in the homeostatic iron regulator gene but may have mutations in other genes involved in the regulation of iron. Next-generation sequencing is increasingly being utilized for the diagnosis of patients, leading to the discovery of novel genetic variants. The clinical significance of these variants is often unknown. Determining the pathogenicity of such variants of unknown significance is important for diagnostics and genetic counseling. Predictions can be made using in silico computational tools and population data, but additional evidence is required for a conclusive pathogenicity classification. Genetic disease models, such as in vitro models using cellular overexpression, induced pluripotent stem cells or organoids, and in vivo models using mice or zebrafish all have their own challenges and opportunities when used to model HH and other iron disorders. Recent developments in gene-editing technologies are transforming the field of genetic disease modeling. In summary, this review addresses methods and developments regarding the discovery and classification of genetic variants, from in silico tools to in vitro and in vivo models, and presents them in the context of HH. It also explores recent gene-editing developments and how they can be applied to the discussed models of genetic disease.


Animal- and plant-food-based diets and iron status: benefits and costs.
Fe seems to be the only nutrient deficiency that industrialized and low-income countries have in common. Thus, Fe is one of the most critical nutrition requirements to be met in most diets in human subjects. Fe deficiency is caused not only by too low an intake, but is also the result of low bioavailability, as well as an increased Fe requirement due to physiological variables or clinical problems which are not met by an increased dietary intake of Fe. In low-income countries poor dietary quality rather than Fe intake seems to be the key determinant of impaired Fe status. Sometimes the Fe intake even exceeds that in populations of industrialized countries. The interaction of all enhancers (e.g. ascorbic acid and meat), as well as inhibitors (such as bran, polyphenols, egg yolk, soyabean products, Ca, Ca3(PO4)2 and phytic acid (or phytate)) is what determines the bioavailability of non-haem-Fe in the meal. Dietary composition seems to be particularly important when Fe reserves are low, or in the presence of Fe deficiency. Furthermore, the development of anaemia as a result of Fe deficiency, secondary to Fe-stress situations, is dependent on the Fe balance in the host. With respect to the dietary intake of Fe, other products in the food consumed as well as previous treatment of the product (e.g. heat treatment and processing) may also influence bioavailability. Despite all efforts to counteract Fe deficiency it still represents one of the dominant problems in the micronutrient sphere. It is apparent that there is no simple solution to the problem, and the fact that Fe deficiency still occurs in affluent societies consuming a mixed diet speaks for itself a more holistic view of total dietary composition and the role of enhancers and inhibitors is needed.


Nutcracker syndrome mimicking new daily persistent headache: A case report.
Compression of the duodenum and left renal vein between the aorta and superior mesenteric artery usually leads to symptoms of proximal bowel obstruction or hematuria and, more rarely, nonspecific mild headaches. A young woman presented with new daily persistent headache refractory to numerous pharmacological treatments, onabotulinumtoxinA, nerve blocks, and occipital nerve stimulation. Following several years of daily severe headache, worsening abdominal pain and intolerance for food intake led to the discovery of aortomesenteric compression. Surgical treatment gave prompt improvement in gastric symptoms but also essentially resolved the headache. This is the first description of new daily persistent headache in association with aortomesenteric compression as well as marked improvement of headache following aortomesenteric decompression. In patients with new daily persistent headache and orthostatic symptoms one may consider a differential diagnosis of Nutcracker syndrome, especially in patients with comorbid hypermobility syndromes, hematuria or gastric symptoms.


Evaluation of three-dimensional acromiohumeral distance in the standing position and comparison with its conventional measuring methods.
Narrowing of the acromiohumeral distance (AHD) implies a rotator cuff tear. However, conventional AHD measurements using two-dimensional (2D) imaging or with the patient in the supine position might differ from that while standing during daily activity. This study aimed to evaluate the three-dimensional (3D) actual distance between the acromion and humeral head in the standing position and compare the AHD values with those obtained using conventional measuring methods. Computed tomography (CT) images of 166 shoulders from 83 healthy volunteers (31 male and 52 female; mean age 40.1 ± 5.8 years; age range, 30-49 years) were prospectively acquired in the supine and standing positions using conventional and upright CT scanners, respectively. The minimum distance between the acromion and humeral head on the 3D surface models was considered as the 3D AHD. We measured the 2D AHD on anteroposterior digitally reconstructed radiographs. The AHD values were compared between the supine and standing positions and between the 2D and 3D measurements. The mean values of 2D AHD were 8.8 ± 1.3 mm (range, 5.9-15.4 mm) in the standing position and 8.1 ± 1.2 mm (range, 5.3-14.3 mm) in the supine position. The mean values of 3D AHD were 7.3 ± 1.4 mm (range, 4.7-14.0 mm) in the standing position and 6.6 ± 1.2 mm (range, 4.4-13.7 mm) in the supine position. The values of 3D AHD were significantly lower than those of 2D AHDs in both the standing and supine positions (P < 0.001). The values of 2D and 3D AHDs were significantly lower in the supine position than in the standing position (P < 0.001). This study evaluated the 3D AHD of normal shoulders in the standing position using an upright CT scanner. The present results indicated that assessments in the supine position can underestimate the value of the AHD compared with those made in the standing position and that assessments using 2D analysis can overestimate the value.


Frequent occurrence of rapid as well as delayed gastric emptying of a corn flakes and milk meal in clinical patients with gastrointestinal symptoms.
Early satiety, nausea and vomiting have traditionally been associated with delayed gastric emptying (GE). A study was performed to determine the frequency of rapid/delayed GE in 100 patients sequentially referred for scintigraphic GE using a corn flakes and milk meal. A retrospective review of 100 consecutive GE studies at the University Hospital, San Antonio, Texas, was performed. Each patient received a semisolid meal containing corn flakes, milk, and sugar (200 kcal, 6 g fat, 7 g protein, and 30 g carbohydrates) and 37.0 MBq (1 mCi) of Tc-99m sulfur colloid according to a standard clinical protocol followed by dynamic 1-minute planar acquisitions for 60 minutes. Gastric emptying times were classified based on the 50% emptying time as follows: 30 to 60 minutes for normal, abnormally delayed as >60 minutes, and abnormally rapid as <30 minutes. Twenty-eight patients demonstrated rapid GE, 25 delayed GE, and 45 normal GE. Fifteen (54%) patients with rapid GE were diabetic, 4 (14%) had impaired fasting glucose values, and 9 (32%) were normoglycemic. Fourteen (56%) patients with delayed GE were diabetic, one (4%) had impaired fasting glucose, and 10 (40%) were normoglycemic. Both patients with delayed and those with rapid GE had nausea as the most common symptom followed by early satiety (rapid GE) and vomiting (delayed GE). Of 28 patients with rapid GE, 26 were on promotility agents. The number of patients with rapid GE of the corn flakes, milk, and sugar meal is appreciably greater (28%) than previously reported with other meals. This relative large number is likely related to the meal composition and the homogeneous dispersal of the label within the meal.


Diversity of rickettsiae in ticks (Acari: Ixodidae) collected from wild vertebrates in part of the Amazon, Cerrado, and Pantanal biomes in Brazil.
Ticks parasitizing 102 wild animals in the states of Mato Grosso and Goiás, Brazil were collected between 2015 and 2018. A total of 2338 ticks (865 males, 541 females, 823 nymphs, and 109 larvae) belonging to four genera (Amblyomma, Dermacentor, Haemaphysalis, and Rhipicephalus) and at least 21 species were identified. DNA extraction and a molecular survey for rickettsial agents were performed on 650 ticks. The results revealed parasitism by the following species: Rickettsia amblyommatis in Amblyomma cajennense s.s., A. cajennense s.l., Amblyomma coelebs, Amblyomma humerale, Amblyomma longirostre, Amblyomma nodosum, Amblyomma scalpturatum, Amblyomma sculptum, and Amblyomma romitii; Rickettsia parkeri in Amblyomma nodosum, Amblyomma ovale, Amblyomma scalpturatum, and Amblyomma triste; Rickettsia rhipicephali in Haemaphysalis juxtakochi; Rickettsia sp. in A. cajennense s.s., A. nodosum, and A. sculptum, and lastly, 'Candidatus Rickettsia andeanae' in Amblyomma parvum and Rhipicephalus microplus. This study expands the body of knowledge about tick parasitism among wild animals, including new data concerning tick-host associations, and provides information about the epidemiology of tick-borne pathogens in the Center-West region of Brazil.


Pediatric Chronic Rhinosinusitis Management in Rhinologists and Pediatric Otolaryngologists.
To compare the management of pediatric chronic rhinosinusitis (PCRS) between members of the American Rhinologic Society (ARS) and the American Society of Pediatric Otolaryngology (ASPO). Comparison of surveys. A web-based survey was distributed to ASPO membership twice in September-October 2016. Data were compared to previously published data from ARS membership in March-April 2016. ASPO survey completion rate was 22%. ARS members were more likely to employ oral steroids in initial ( P = .025) and maximal medical management ( P = .001). ASPO members more commonly performed adenoidectomy before computed tomography (CT) ( P < .001). Both groups commonly included adenoidectomy as part of initial surgical management (90% vs 94%, P = .316), while ASPO members more frequently performed adenoidectomy alone (70% vs 43%, P = .001). If initial surgical treatment failed, both groups commonly performed endoscopic sinus surgery (ESS; 81% vs 88%, P = .56) with a similar extent including frontal ( P ≥ .207) and sphenoid ( P ≥ .304) surgery. Pediatric chronic rhinosinusitis management is similar between groups, yet there are differences including oral steroid use, relative order of CT versus adenoidectomy, and performing concomitant procedures with adenoidectomy. Both groups commonly perform ESS with similar surgical extent if prior surgical treatment fails. Management by both groups is largely in agreement with published consensus statements.


Use of the theoretical domains framework and behaviour change wheel to develop a novel intervention to improve the quality of multidisciplinary cancer conference decision-making.
Multidisciplinary Cancer Conferences (MCCs) are prospective meetings involving cancer specialists to discuss treatment plans for patients with cancer. Despite reported gaps in MCC quality, there have been few efforts to improve its functioning. The purpose of this study was to use theoretically-rooted knowledge translation (KT) theories and frameworks to inform the development of a strategy to improve MCC decision-making quality. A multi-phased approach was used to design an intervention titled the KT-MCC Strategy. First, key informant interviews framed using the Theoretical Domains Framework (TDF) were conducted with MCC participants to identify barriers and facilitators to optimal MCC decision-making. Second, identified TDF domains were mapped to corresponding strategies using the COM-B Behavior Change Wheel to develop the KT-MCC Strategy. Finally, focus groups with MCC participants were held to confirm acceptability of the proposed KT-MCC Strategy. Data saturation was reached at n = 21 interviews. Twenty-seven barrier themes and 13 facilitator themes were ascribed to 11 and 10 TDF domains, respectively. Differences in reported barriers by physician specialty were observed. The resulting KT-MCC Strategy included workshops, chair training, team training, standardized intake forms and a synoptic discussion checklist, and, audit and feedback. Focus groups (n = 3, participants 18) confirmed the acceptability of the identified interventions. Myriad factors were found to influence MCC decision making. We present a novel application of the TDF and COM-B to the context of MCCs. We comprehensively describe the barriers and facilitators that impact MCC decision making and propose strategies that may positively impact the quality of MCC decision making.


CT Findings of Central Airway Lesions Causing Airway Stenosis-Visualization and Quantification: A Pictorial Essay.
The tracheobronchial tree is a system of airways that allows the passage of air to aerate the lungs and entire body. Several pathological conditions can affect this anatomical region. Multidetector CT (MDCT) helps identify and characterize various large airway diseases. Post-processing tools, such as virtual bronchoscopy and automatic lung analysis, can help enhance the performance of imaging studies. In this pictorial essay review, we provide imaging findings of various bronchial lesions manifested as wall thickening and endoluminal nodules on conventional MDCT and advanced image visualization and analysis.


A single antigenomic open reading frame of the hepatitis delta virus encodes the epitope(s) of both hepatitis delta antigen polypeptides p24 delta and p27 delta.
On the basis of the complete nucleotide sequence of the single-stranded, covalently closed circular hepatitis delta virus RNA genome (K.-S. Wang, Q.-L. Choo, A. J. Weiner, J.-H. Ou, R. C. Najarian, R. M. Thayer, G. T. Mullenbach, K. J. Denniston, J. L. Gerin, and M. Houghton, Nature [London] 323:508-514, 1986 [Author's correction, 328:456, 1987]), five long open reading frames (ORFs) encoding polypeptides containing a methionine proximal to the amino terminus were expressed in bacteria. Only polypeptides encoded by the antigenomic ORF5 cross-reacted with antisera obtained from patients with hepatitis delta virus infections. Immunological analysis of viral extracts and the recombinant ORF5 polypeptides synthesized in bacteria and yeast cells revealed that ORF5 encodes the immunogenic epitope(s) shared by both hepatitis delta viral polypeptides p27 delta and p24 delta and probably represents the complete structural gene for p27 delta and p24 delta. We also present evidence that ORF5 encodes the hepatitis delta antigen, an antigen originally found in the nuclei of hepatocytes of infected individuals (M. Rizzetto, M. G. Canese, S. Arico, O. Crivelli, F. Bonino, C. G. Trepo, and G. Verme, Gut 18:997-1003, 1977). A comparison of the primary structure of the predicted hepatitis delta antigen polypeptides with that of the core antigen of the hepatitis B virus shows that these polypeptides are very dissimilar.


Cleaved Caspase-3 Transcriptionally Regulates Angiogenesis-Promoting Chemotherapy Resistance.
Caspases are well known for their role in apoptosis. Recently, nonapoptotic roles of caspases have been identified, however, these noncanonical roles are not well documented and the mechanisms involved are not fully understood. Here, we studied the role of cleaved caspase-3 using human- and mouse-proficient caspase-3 cancer cell lines and human-deficient caspase-3 cancer cells. Cleaved caspase-3 functioned as a transcription factor and directly bound to DNA. A DNA-binding domain was identified in the small subunit of caspase-3 and an active conformation was essential for caspase-3 transcriptional activity. Caspase-3 DNA binding enhanced angiogenesis by upregulating the expression of proangiogenic genes and by activating pathways that promoted endothelial cell activation. Some proapoptotic genes were downregulated in caspase-3-proficient cells. Inhibiting caspase-3 increased the efficacy of chemotherapy and decreased spontaneous tumor development. These data highlight a novel nonapoptotic role of caspase-3 and suggest that cleaved caspase-3 could be a new therapeutic target in cancer. SIGNIFICANCE: These findings report a noncanonical function of caspase-3 by demonstrating its ability to transcriptionally regulate the VEGFR pathway.


[Oral antibiotic treatment of exacerbation of COPD. Beyond COVID-19].
COPD (chronic obstructive pulmonary disease) includes patients with chronic bronchitis and / or emphysema who have in common the presence of a chronic and progressive airflow obstruction, with symptoms of dyspnea and whose natural history is modified by acute episodes of exacerbations. Exacerbation (EACOPD) is defined as an acute episode of clinical instability characterized by a sustained worsening of respiratory symptoms. It is necessary to distinguish a new EACOPD from a previous treatment failure or a relapse. EACOPD become more frequent and intense over time, deteriorating lung function and quality of life. The diagnosis of EACOPD consists of 3 essential steps: a) differential diagnosis; b) establish the severity, and c) identify its etiology. The main cause of exacerbations is infection, both bacterial and viral. Antibiotics are especially indicated in severe EACOPD and the presence of purulent sputum. Beta-lactams (amoxicillin-clavulanate and cefditoren) and fluoroquinolones (levofloxacin) are the most widely used antimicrobials. This review updates the problem of acute exacerbation with infectious origin from the perspective of etiology, antimicrobial resistance, microbiological studies, risk stratification, and antimicrobial management. The risk, prognosis and characteristics of COPD patients who develop COVID19 are analyzed.


[Herpes simplex virus type 1: a possible sexually transmitted agent among college students].
To study the factors associated with the presence of antibodies against herpes simplex virus type 1 (HSV-1) and to screen for HSV-1 in genital samples. Students answered a survey and provided biological samples (blood and genital discharge). The detection of IgG and IgM antibodies against HSV-1 was performed by an ELISA test. From IgM positive samples we sought and extracted genital DNA and identified a beta-globulin gene and HSV-1. Eight hundred and fifteen students participated. IgG/HSV-1 seroprevalence was 56.7%, HSV-1 infection was associated with number of sexual partners, exchanging sex for money, same sex relationships and occasional partners. IgM/HSV-1 seroprevalence was 18.2%, 91 samples were positive for human beta-globuline but none for HSV-1 DNA. Epidemiological evidence suggests that HSV-1 could be transmitted by sexual contact among college students; however, HSV-1 was not detected in any of the genital samples analyzed. To further test our hypothesis we need to study HSV-1 among high risk groups or increase our sample size.


Exome sequencing identification of a GJB1 missense mutation in a kindred with X-linked spinocerebellar ataxia (SCA-X1).
We undertook a gene identification and molecular characterization project in a large kindred originally clinically diagnosed with SCA-X1. While presenting with ataxia, this kindred also had some unique peripheral nervous system features. The implicated region on the X chromosome was delineated using haplotyping. Large deletions and duplications were excluded by array comparative genomic hybridization. Exome sequencing was undertaken in two affected subjects. The single identified X chromosome candidate variant was then confirmed to co-segregate appropriately in all affected, carrier and unaffected family members by Sanger sequencing. The variant was confirmed to be novel by comparison with dbSNP, and filtering for a minor allele frequency of <1% in 1000 Genomes project, and was not present in the NHLBI Exome Sequencing Project or a local database at the BCM HGSC. Functional experiments on transfected cells were subsequently undertaken to assess the biological effect of the variant in vitro. The variant identified consisted of a previously unidentified non-synonymous variant, GJB1 p.P58S, in the Connexin 32/Gap Junction Beta 1 gene. Segregation studies with Sanger sequencing confirmed the presence of the variant in all affected individuals and one known carrier, and the absence of the variant in unaffected members. Functional studies confirmed that the p.P58S variant reduced the number and size of gap junction plaques, but the conductance of the gap junctions was unaffected. Two X-linked ataxias have been associated with genetic loci, with the first of these recently characterized at the molecular level. This represents the second kindred with molecular characterization of X-linked ataxia, and is the first instance of a previously unreported GJB1 mutation with a dominant and permanent ataxia phenotype, although different CNS deficits have previously been reported. This pedigree has also been relatively unique in its phenotype due to the presence of central and peripheral neural abnormalities. Other X-linked SCAs with unique features might therefore also potentially represent variable phenotypic expression of other known neurological entities.


Defect of TIMP4 Is Associated with High Myopia and Participates in Rat Ocular Development in a Dose-Dependent Manner.
Thinning of the sclera happens in myopia eyes owing to extracellular matrix (ECM) remodeling, but the initiators of the ECM remodeling in myopia are mainly unknown. The matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) regulate the homeostasis of the ECM. However, genetic studies of the MMPs and TIMPs in the occurrence of myopia are poor and limited. This study systematically investigated the association between twenty-nine genes of the TIMPs and MMPs families and early-onset high myopia (eoHM) based on whole exome sequencing data. Two TIMP4 heterozygous loss-of-function (LoF) variants, c.528C>A in six patients and c.234_235insAA in one patient, were statistically enriched in 928 eoHM probands compared to that in 5469 non-high myopia control (p = 3.7 × 10-5) and that in the general population (p = 2.78 × 10-9). Consequently, the Timp4 gene editing rat was further evaluated to explore the possible role of Timp4 on ocular and myopia development. A series of ocular morphology abnormalities in a dose-dependent manner (Timp4-/- < Timp4+/- < Timp4+/+) were observed in a rat model, including the decline in the retinal thickness, the elongation in the axial length, more vulnerable to the form deprivation model, morphology changes in sclera collagen bundles, and the decrease in collagen contents of the sclera and retina. Electroretinogram revealed that the b-wave amplitudes of Timp4 defect rats were significantly reduced, consistent with the shorter length of the bipolar axons detected by HE and IF staining. Heterozygous LoF variants in the TIMP4 are associated with early onset high myopia, and the Timp4 defect disturbs ocular development by influencing the morphology and function of the ocular tissue.


Definition of three serotypes of Hantaviruses by a double sandwich ELISA with biotin-avidin amplification system.
A total of seven different isolates of Hantaviruses from five mammalian species and six geographical areas were examined by a double sandwich ELISA with biotin-avidin amplification system. Three serotypes were recognized by comparing antigen titres to homologous and heterologous antibody and blocking antibody titres to homologous and heterologous antigens. Serotype 1 included four strains: Hantaan virus isolated from Apodemus agrarius in South Korea, Hupei-I isolated from acute-phase serum from a patient with epidemic haemorrhagic fever (EHF) in China, SR-11 isolated from a laboratory rat associated with an EHF outbreak in Sapporo, Japan, and Tchoupitoulas isolated from a wharf rat (Rattus norvegicus) trapped in New Orleans, La., U.S.A. Serotype 2 included two strains of nephropathia epidemica virus, Hällnäs-I and Puumala, isolated from Clethrionomys glareolus trapped in nephropathia epidemica foci in Sweden and Finland, respectively. Serotype 3 included one strain, Prospect Hill-I, isolated from Microtus pennsylvanicus, trapped in Frederick, Md., U.S.A.


Molecular biology of the renin-angiotensin system.
This paper reviews the molecular biology of the renin-angiotensin system. The renin gene structure is analyzed in detail, including an examination of the putative regulatory regions. The combined action of these regulatory sequences would result in the complex, tissue-specific expression and regulation observed in vivo. The expression of the tissue renin-angiotensin systems, which may have important physiological functions, is also described. In addition, the pathway of renin biosynthesis and secretion is reviewed. This includes speculation on the fate of circulating prorenin and the physiological role of multiple renin forms and secretory pathways. The molecular approaches described in this paper have greatly advanced our knowledge of the biology of the renin-angiotensin system. Future studies using these and other approaches should provide further insight into this complex system.


Biowaiver monographs for immediate release solid oral dosage forms: furosemide.
Literature and new experimental data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing furosemide are reviewed. The available data on solubility, oral absorption, and permeability are sufficiently conclusive to classify furosemide into Class IV of the Biopharmaceutics Classification System (BCS). Furosemide's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions and reported BE/bioavailability (BA) problems are also taken into consideration. In view of the data available, it is concluded that the biowaiver procedure cannot be justified for either the registration of new multisource drug products or major postapproval changes (variations) to existing drug products.


Physical Activity Levels in Individuals with Cystic Fibrosis-Related Diabetes.
Purpose: The literature on physical activity (PA) in adults with cystic fibrosis, particularly in those with cystic fibrosis-related diabetes (CFRD), is limited. PA may be an important part of blood glucose management in CFRD. The purpose of this study was to describe PA levels in adults with CFRD and determine their adherence to the Canadian Diabetes Association (CDA) aerobic exercise training guidelines. Methods: Adults with CFRD were recruited from a hospital-based CF clinic. PA was measured using the Seven-Day Physical Activity Recall (telephone interview), adherence to CFRD management with the Self-Care Inventory-Revised (questionnaire), and blood glucose control from glycated hemoglobin levels documented in participants' medical chart within 3 months. Results: Eighteen adults (mean age 41 [SD 9] y) with diagnosed CFRD participated in the study. They varied in volume of PA (range 13,080-17,362 metabolic equivalent min/wk). Of the study participants, 12 (67%) met the CDA guidelines of 150 minutes of moderate to vigorous PA per week with no more than 2 consecutive days without exercise. No differences were found in clinical factors between those who met the aerobic exercise guidelines and those who did not. Conclusion: The majority of individuals with CFRD are meeting the recommended amount of aerobic PA. The factors influencing PA and blood glucose control in adults with CFRD require further investigation.


Berberine sensitizes nasopharyngeal carcinoma cells to radiation through inhibition of Sp1 and EMT.
Nasopharyngeal carcinoma (NPC) is a tumor of epithelial origin with radiotherapy as its standard treatment. However, radioresistance remains a critical issue in the treatment of NPC. This study aimed to investigate the effect of berberine on the proliferation, cell cycle regulation, apoptosis, radioresistance of NPC cells and whether specificity protein 1 (Sp1) is a functional target of berberine. Our results showed that treatment with berberine reduced the proliferation and viability of CNE-2 cells in a dose- and time‑dependent manner. Berberine induced cell cycle arrest in the G0/G1 phase and apoptosis. In CNE-2 cells exposed to gamma‑ray irradiation, berberine reduced cell viability at various concentrations (25, 50, 75 and 100 µmol/l). Berberine significantly decreased mRNA and protein expression of Sp1 in the CNE-2 cells. Mithramycin A, a selective Sp1 inhibitor, enhanced the radiosensitivity and the rate of apoptosis in the CNE-2 cells. Berberine inhibited transforming growth factor-β (TGF-β)-induced tumor invasion and suppressed epithelial-to-mesenchymal transition (EMT) process, as evidenced by increased E-cadherin and decreased vimentin proteins. Sp1 may be required for the TGF-β1-induced invasion and EMT by berberine. In conclusion, berberine demonstrated the ability to suppress proliferation, induce cell cycle arrest and apoptosis, and enhance radiosensitivity of the CNE-2 NPC cells. Sp1 may be a target of berberine which is decreased during the radiosensitization of berberine.


A Mobile Health App for Facilitating Disease Management in Children With Atopic Dermatitis: Feasibility and Impact Study.
Inadequate control of atopic dermatitis (AD) increases the frequency of exacerbations and reduces the quality of life. Mobile health apps provide information and communication technology and may increase treatment adherence and facilitate disease management at home. The mobile health app, Atopic App, designed for patients and their caregivers, and the associated web-based patient education program, Atopic School, provide an opportunity for improving patients' and caregivers' engagement and adherence to the management of AD. This noninterventional, observational study aimed to explore the feasibility and potential impact on the management of AD in children by caregivers using the Atopic App mobile health app. The patient-oriented eczema measure (POEM) and numerical rating scale for the grading of pruritus were used as severity scores (scale range: 0-28). The artificial intelligence model of the app was used to assess the severity of AD based on the eczema area and severity index approach. The deidentified data enabled the analysis of the severity of AD, treatment plan history, potential triggers of flare-ups, usage of available features of the app, and the impact of patient education. During a 12-month period, of the 1223 users who installed the app, 910 (74.4%) registered users were caregivers of children with AD. The web-based Atopic School course was accessed by 266 (29.2%) caregivers of children with AD, 134 (50.4%) of whom completed the course. Usage of the app was significantly more frequent among those who completed the Atopic School program than among those who did not access or did not complete the course (P<.001). Users who completed a second POEM 21 to 27 days apart exhibited a significant improvement of AD severity based on the POEM score (P<.001), with an average improvement of 3.86 (SD 6.85) points. The artificial intelligence severity score and itching score were highly correlated with the POEM score (r=0.35 and r=0.52, respectively). The Atopic App provides valuable real-world data on the epidemiology, severity dynamics, treatment patterns, and exacerbation-trigger correlations in patients with AD. The significant reduction in the POEM score among users of the Atopic App indicates a potential impact of this tool on health care engagement by caregivers of children with AD.


Gap junction communication mediates transforming growth factor-beta activation and endothelial-induced mural cell differentiation.
During blood vessel assembly, endothelial cells recruit mesenchymal progenitors and induce their differentiation into mural cells via contact-dependent transforming growth factor-beta (TGF-beta) activation. We investigated whether gap junction channels are formed between endothelial cells and recruited mesenchymal progenitors and whether intercellular communication is necessary for endothelial-induced mural cell differentiation. Mesenchymal progenitors from Cx43-/- murine embryos and Cx43+/+ littermates were cocultured with prelabeled endothelial cells. Intracellular dye injection and dual whole-cell voltage clamp revealed that endothelial cells formed gap junction channels with Cx43+/+ but not Cx43-/- progenitors. In coculture with endothelial cells, Cx43-/- progenitors did not undergo mural cell differentiation as did Cx43+/+ cells. Stable reexpression of Cx43 in Cx43-/- cells (reCx43) restored their ability to form gap junctions with endothelial cells and undergo endothelial-induced mural cell differentiation. Cocultures of endothelial cells and either Cx43+/+ or reCx43 mesenchymal cells produced activated TGF-beta; endothelial-Cx43-/- cocultures did not. However, Cx43-/- cells did produce latent TGF-beta and undergo mural cell differentiation in response to exogenous TGF-beta1. These studies indicate that gap junction communication between endothelial and mesenchymal cells mediates TGF-beta activation and subsequent mural cell differentiation.


Detection of anti-Ro/SSA and anti-La/SSB autoantibody-producing cells in salivary glands from patients with Sjögren's syndrome.
To investigate and identify the presence of cells producing anti-Ro/SSA and anti-La/SSB autoantibodies in salivary glands from patients with Sjögren's syndrome (SS). Submucosal salivary gland biopsy samples from 10 SS patients (8 with and 2 without circulating Ro and La autoantibodies) and 14 control subjects were evaluated. Frozen tissue sections were immunostained by an avidin-biotin complex technique, using biotinylated recombinant Ro and La proteins as detection reagents. Autoantibody levels in SS patient sera were analyzed by enzyme-linked immunosorbent assay. Cells producing autoantibodies to the Ro 52-kd, Ro 60-kd, and La proteins were recorded in 8, 6, and 7 of the 10 SS patient biopsy samples, respectively. Samples from the 2 SS patients without circulating Ro and La autoantibodies were negative for these autoantibody-producing cells, as were all control biopsy samples. A strong positive correlation between the presence of autoantibodies in sera and the presence of autoantibody-producing cells in glandular biopsy tissues was evident. The number of autoantibody-producing cells and the serum autoantibody levels were also correlated (r(s)=0.94, P < 0.0001). Using a novel technique, we have demonstrated the presence of Ro and La autoantibody-producing cells in salivary gland biopsy tissues from patients with SS. These findings indicate that anti-Ro/ SSA and anti-La/SSB autoantibodies are produced and are present at sites of inflammation and indicate their potential involvement in the autoimmune exocrinopathy of this disease.


The Pillar Effect of Large-Size Alkaline Ions on the Electrochemical Stability of Sodium Manganese Hexacyanoferrate for Sodium-Ion Batteries.
Sodium manganese hexacyanoferrate (NaMnHCF) is an attractive candidate as a cathode material for sodium-ion batteries due to its low cost and high energy density. However, its practical application is hindered by poor electrochemical stability caused by the Jahn-Teller effect of Mn and the unstable structure of NaMnHCF. Here, this paper aims to address this issue by introducing highly stable AMnHCF (where A = K, Rb, or Cs) through a facile method to composite with NaMnHCF. The findings reveal that all AMnHCFs have a "pillar effect" on the crystal structure of NaMnHCF. It is observed that the degree of pillar effect varies depending on the specific AMnHCF used. The less electrochemically inactive the alkaline ion is and the greater the degree of compositing with NaMnHCF, the more dramatic the pillar effect. KMnHCF shows limited pillar effect due to its rough composition with NaMnHCF and the loss of K+ upon (de)intercalation. RbMnHCF has lower electrochemical activity and can be better composited with NaMnHCF. On the other hand, CsMnHCF exhibits the strongest pillar effect due to the inactivation of Cs+ and the excellent coherent structure formed by CsMnHCF and NaMnHCF. This research provides a new perspective on stabilizing NaMnHCF with other alkaline elements.


A Query Tool for Investigator Access to the Data and Images of the National Lung Screening Trial.
The National Cancer Institute (NCI), in conjunction with blinded university, provides a mechanism to enable public access to the study data, CT radiology images, and pathology images from the National Lung Screening Trial (NLST). Access to the data and images is through the NCI-sponsored, blinded university-hosted The Cancer Imaging Archive (TCIA), a repository of more than 40 study collections of cancer images. Once access to the NLST data has been granted by NCI, a Query Tool within TCIA is used to access the NLST data and images. The Query Tool is a simple-to-use menu-driven database application designed to quickly pose queries and retrieve/save results (from 53,452 NLST participants), download CT images (~20 million available), and view pathology images (~1200 available). NLST study data are contained in 17 Query Tool tables with ~370 variables to query. This paper describes Query Tool design, functionality, and usefulness for researchers, clinicians, and software developers to query data, save query results, and download/view images.