The Effect of a Pediatric Intensive Care Severity-Tiered Pathway for Status Asthmaticus on Quality Measures and Outcomes.
Background: Patients with status asthmaticus admitted to the hospital contribute tremendous costs to the healthcare system. Treatment protocols directed at improving care to pediatric inpatients have improved both clinical and financial outcomes; however, there are limited data demonstrating the impact of goal-driven therapy for patients with status asthmaticus in the pediatric intensive care unit (PICU). The purpose of this initiative was to standardize care of children with status asthmaticus in the PICU to improve clinical outcomes. Materials and Methods: A goal-directed clinical pathway using a validated pediatric asthma severity score was developed. A pre-post intervention assessed patients 2-17 years of age admitted to the PICU with status asthmaticus. The effect of the protocol was measured from October 2015 to October 2016. The primary outcome was the transition time interval from continuous nebulized bronchodilator therapy to every 2 hourly intermittent treatments. Secondary outcomes related to treatment options and clinical complications were also assessed. Results: Postintervention patient (n = 124) demographics were similar to those in the preintervention group (n = 130). Compared with baseline, there was a 4.9-h decrease in the mean transition time from continuous to intermittent bronchodilator use (31.9 versus 27.0, P = 0.033) following the intervention. The mean and median hospital length of stay (LOS) was significantly decreased in the postintervention group by 14.76 h (P = 0.011) and 16.68 h (P = 0.003). There were no readmissions to the PICU in the postintervention group. The use of rescue BiPAP (Bi-level positive airway pressure ventilation) was significantly higher in the preintervention group compared with the postintervention group (42% versus 28%, P = 0.036). Conclusions: A severity-tiered, goal-driven treatment pathway for pediatric patients admitted to the PICU with status asthmaticus reduced the time required to transition from continuous to intermittent inhaled bronchodilator use. As a result, overall hospital LOS was significantly decreased with no increase in clinical complications.


The Effect of a Pre-Colonoscopy Education Program on Fear and Anxiety of Patients: A Randomized Clinical Trial Study.
Due to the increasing prevalence of intestinal diseases, colonoscopy is considered a safe and fast diagnostic and treatment method for these patients. According to studies, most patients waiting for a colonoscopy experience fear and anxiety. This study aimed to investigate the effect of a pre-colonoscopy education program on the fear and anxiety of patients undergoing colonoscopy. This randomized clinical trial study was conducted on patients undergoing colonoscopy in hospitals in southeast Iran. A total of 90 participants were selected by convenient sampling and randomly assigned to two groups control (n = 45) and intervention (n = 45). The patients in the intervention group received nursing interventions before colonoscopy, while the patients in the control group received only routine care. The data were collected using a researcher-made fear of colonoscopy scale, its Cronbach's alpha coefficient (0.92), and the Spielberger State-Trait Anxiety Inventory. The data were analyzed with a Chi-square t-test and pair t-test. The data showed that anxiety and fear of colonoscopy in the patients in the intervention group significantly decreased compared to the patients in the control group (p < 0.001). Using non-pharmacological methods before colonoscopy can reduce the fear and anxiety in patients who are candidates for this procedure and similar invasive procedures. The intervention performed in this study can be used together with other methods to control patients' fear and anxiety. Especially for nurses, It is recommended to do pre-colonoscopy education programs for these clients.


Item validity of the Myers-Briggs Type Indicator.
The present study presents a brief summary of four extensive psychometric analyses of the Myers-Briggs Type Indicator (MBTI) items. Positive empirical evidence supports the MBTI item validity. However, several measurement issues on item construction were raised to caution the future users.


Low diet quality in older adults: a population-based study in southern Brazil.
The aim of this study was to identify the factors associated with low diet quality in older adults from the city of Pelotas, Southern Brazil. Information on food consumption was collected using a reduced food frequency questionnaire, and diet quality was assessed by the Elderly Diet Quality Index DQI-E ("Índice de Qualidade da Dieta de Idosos - IQD-I"), devised by the authors. Points were attributed to each food evaluated according to frequency of consumption. Higher consumption frequency of healthy foods received higher scores whilst unhealthy foods received lower scores. Scores were divided into tertiles classified as: low quality, intermediate quality, and good quality. Multinomial logistic regression was used to assess the association between diet quality and the independent variables. The factors associated with low diet quality were: male gender, age < 80 years, low education, problems affording food, underweight, mouth or teeth problems, and having less than four meals a day. Important barriers to the consumption of a good quality diet were observed, highlighting the importance of considering these aspects in the promotion of healthy eating among older adults.


Norisoprenoids, Sesquiterpenes and Terpenoids Content of Valpolicella Wines During Aging: Investigating Aroma Potential in Relationship to Evolution of Tobacco and Balsamic Aroma in Aged Wine.
During wine aging, tobacco and balsamic aroma notes appear. In this paper, volatile compounds directly or potentially related to those aromas have been investigated in Corvina and Corvinone wines during aging. Corvina and Corvinone are two northern-Italy autochthonous red grape varieties, used to produce Valpolicella Classico and Amarone wines, both characterized by tobacco and balsamic aroma notes. Wines were analyzed shortly after bottling or following model aging at 60°C for 48, 72, and 168 h. Volatile compounds were analyzed by HS-SPME-GC-MS. Results showed that compounds related to tobacco aroma [β-damascenone, 3-oxo-α-ionol, (E)-1-(2,3,6-Trimethylphenyl)-buta-1,3-diene (TPB), and megastigmatrienones] increased in relationship to storage time with different patterns. β-Damascenone and 3-oxo-α-ionol rapidly increased to reach a plateau in the first 48-72 h of model aging. Instead, TPB and megastigmatrienones concentration showed a linear correlation with aging time. During model aging, several cyclic terpenes tended to increase. Among them 1,8-cineole and 1,4-cineole, previously reported to contribute to red wine eucalyptus notes increased proportionally to storage time, and this behavior was clearly associated with reactions involving α-terpineol, limonene, and terpinolene, as confirmed by studies with model wine solutions. Among other relevant volatile compounds, sesquiterpenes appear to contribute potentially balsamic and spicy aroma notes. In this study, linear sesquiterpenes (nerolidol, farnesol) underwent acid hydrolysis during long wine aging, while cyclic sesquiterpenes seemed to increase with time. The chemical pathways associated with evolution of some of the compounds investigated have been studied in model wine.


Lamellar corneal lenticule graft to treat keratolysis after AlphaCor keratoprosthesis implantation.
Clinical assessment of AlphaCor keratoprosthesis and evaluation of surgical method to treat keratolysis in case of stromal necrosis occurrence. This is a noncomparative, retrospective, interventional case series. The medical records of 12 eyes of 12 patients who underwent consecutive AlphaCor keratoprosthesis implantations were reviewed. Patients with severe bilateral corneal pathology unsuitable for a conventional corneal graft, a best-corrected visual acuity (BCVA) from light perception (LP) to 20/200, with no active ocular surface inflammation, controlled intraocular pressure prior to the surgery, and an unstimulated Schirmer test of >2.5 mm at 5 minutes were included. Postoperative medications included topical dexamethasone, ciprofloxacin, and 2% cyclosporine A. Main outcome measures included BCVA and complications occurrence. After a mean follow-up of 25 ± 12.3 months (range 2-38 months), 8 (66.7%) AlphaCor devices were retained. Postoperative BCVA ranged from LP to 20/63 (mean gain of 2.5 ± 3.1 lines). Seven cases of stromal melt (58.3%) occurred. Three were reversed to penetrating keratoplasty and 3 had a donor corneal layer fixated over the AlphaCor with satisfactory results (mean follow-up 23 ± 1.6 months). There were no instances of endophthalmitis, retinal detachment, or glaucoma exacerbation. AlphaCor showed a low incidence of the classic keratoprosthesis complications but a high occurrence of recipient cornea necrosis. Corneal melts were successfully managed in 3 cases by lamellar corneal lenticule graft, thereby increasing the retention of AlphaCor and maintaining BCVA.


Prolonged after-effects of pneumonia in children.
Sixty-two black children were prospectively followed up for 1-7 years after pneumonia contracted at a median age of 17 months. In 55% of cases the pneumonia was measles-associated and 27% had serological evidence of infection with other respiratory viruses. Recurrence of cough or wheeze for more than 6 months occurred in 85% with just over 50% having recovered during the follow-up period. While the highest incidence of persistent symptoms occurred in children after measles superinfected with another virus, this was not significant. Abnormal radiographic features persisted in 53% of children and consisted of peribronchial and/or parenchymal lesions. Abnormal large and small airway calibre and/or bronchial hyperreactivity were found in one-third of children, and were significantly more common in those children whose main symptom was recurrent wheezing. Clinical and lung function abnormalities years after lower respiratory tract infection in this group of disadvantaged children compare with reports from more privileged groups. Recognition that long-term sequelae occur may prevent inappropriate subsequent management of symptomatic children.


COVID-19 pandemic: is it time for shared surgical guidelines? A systematic review of the literature.
The recent COrona Virus Disease 2019 (COVID-19) pandemic caused a massive disruption of surgical activity and after a year from its first outbreak surgeons still struggle to keep their regular activity coexisting with the virus exhausting requests of healthcare resources. The aim of this paper is to offer a comprehensive overview of the most important recommendations by the International Guidelines about general surgery, and possibly to invite building common shared guidelines to preserve the potential to provide surgical assistance despite the pandemic. This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. PubMed, Embase, Cochrane and Web of Science databases were searched. The searches revealed a total of 18579 articles published up to the end of February 2021. Five articles published between March and May 2020, were included in the present study: Guidelines from The European Society of Trauma and Emergency Surgery (ESTES), The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and The European Association for Endoscopic Surgeons (EAES), The Endoscopic and Laparoscopic Surgeons of Asia (ELSA), The European Hernia Society (EHS) and The International Organization for the Study of Inflammatory Bowel Disease (IOS-IBD). In the likely scenario that the SARS-CoV-2 pandemic will become an endemic chronic problem, we should not be forced to choose between COVID-19 or surgery in the future and find a way to make both coexisting.


Small-Fiber Polyneuropathy Is Prevalent in Patients With Interstitial Cystitis/Bladder Pain Syndrome.
The pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) is imperfectly understood. Recent studies reported that small-fiber polyneuropathy (SFPN) is common in fibromyalgia, a condition commonly comorbid with IC/BPS. The objective of this study was to determine the prevalence of SFPN in a large cohort of IC/BPS patients. Adults diagnosed with IC/BPS scheduled to undergo either therapeutic hydrodistention (n = 97) or cystectomy with urinary diversion (n = 3) were prospectively recruited to this study. A skin biopsy obtained from the lower leg was used for intraepidermal nerve fiber density measurement. Small-fiber polyneuropathy (+/-) status was determined by comparing linear intraepidermal nerve fiber density (fibers/mm2) with normative reference values. Demographic information, medical history, and diagnoses for 14 conditions (both urologic and nonurologic) known to co-occur with IC/BPS were documented from self-report and electronic medical record. In this large cohort of patients with IC/BPS, 31% (31/100) were positive for SFPN. Intraepidermal nerve fiber density was below the median for age and sex in 81% (81/100) of patients. Approximately one-third (31%) of SFPN+ patients reported co-occurring chronic fatigue syndrome, compared with 10.6% of the SFPN- group (P = 0.034). Small-fiber polyneuropathy-positive patients reported significantly fewer allergies than SFPN- patients (37.9% vs 60.6%; P = 0.047). There were no significant differences in bladder capacity or Hunner lesion status between the SFPN+ and SFPN- subgroups. Small-fiber polyneuropathy is a common finding in patients with IC/BPS, and SFPN status is significantly correlated with co-occurring chronic fatigue syndrome and negatively correlated with the presence of allergies in this population.


Inducible Costimulator Gene-Transduced Bone Marrow-Derived Mesenchymal Stem Cells Attenuate the Severity of Acute Graft-Versus-Host Disease in Mouse Models.
In murine allogeneic transplantation models, ICOS gene-transduced bone marrow-derived mesenchymal stem cells (MSCs(ICOS-EGFP)) were evaluated for their effects on GvHD severity and long-term survival. Lethally irradiated BALB/c or first filial generation of BALB/c and C57BL/6 (CB6F1) mice were transplanted with bone marrow cells and splenocytes from C57BL/6 mice to establish acute GvHD models. Recipient mice were injected with MSCs(ICOS-EGFP), MSCs, MSCs(EGFP), ICOS-Ig fusion protein, MSCs + ICOS-Ig, or PBS (control group). Long-term survival, GvHD rates and severity, CD4(+) T-cell apoptosis and proliferation, and Th1/Th2/Th17 effecter cell polarization were evaluated. In the C57BL/6 → CB6F1 HSCT model, the long-term survival in the MSC(ICOS-EGFP) group was higher than that in the GvHD group (74.29 ± 7.39% vs. 0, p < 0.01), and this survival rate was also higher than that in the MSC, ICOS-Ig, or MSC + ICOS-Ig groups (42.86 ± 8.36%, p = 0.004; 48.57 ± 8.45%, p = 0.03; or 50.43 ± 8.45% p = 0.04, respectively). The survival advantages of MSC(ICOS-EGFP)-treated group were confirmed in the C57BL/6 → BALB/c HSCT model. In both HSCT models, the low mortality in the MSC(ICOS-EGFP) group was associated with lower incidence and severity of acute GvHD. Treatment with MSCs(ICOS-EGFP) induced more CD4(+) T-cell apoptosis compared with that in the GvHD group. The effect on CD4(+) T cells was shown as early as day 2 and maintained until day 14 (p < 0.05 on days 2, 3, 7, and 14). Furthermore, we demonstrated that MSCs(ICOS-EGFP) were able to suppress Th1 and Th17 polarization and promote Th2 polarization on both protein expression and gene transcription levels. Higher serum levels of IL-4, IL-10, and lower levels of IFN-γ, IL-2, IL-12, and IL-17A were detected in the MSC(ICOS-EGFP) group. The MSCs(ICOS-EGFP) could also induce GATA-3, STAT6 expression and inhibit T-bet, STAT4, ROR-γt expression. Our results showed that injection of MSCs(ICOS-EGFP) is a promising strategy for acute GvHD prevention and treatment. It provides synergistic benefits of MSC immune modulation and ICOS-B7h pathway blockage.


Copper-mediated direct C(sp3)-H and C(sp2)-H acetoxylation.
A copper-mediated terminal position-selective C(sp(3))-H acetoxylation using a bidentate directing group and AgOAc as an oxidant was achieved. This reaction has high functional group tolerance and is not affected by steric hindrance. The reaction proceeds in excellent yield, even in gram scale, and the directing group can be removed after the reaction. Aromatic C(sp(2))-H acetoxylation also proceeded under similar reaction conditions.


Acute neuroinflammation, sickness behavior and working memory responses to acute systemic LPS challenge following noradrenergic lesion in mice.
Locus coeruleus (LC)-derived noradrenaline is important in cognition and decreases with age, but the impact of prior noradrenaline deficiency on vulnerability to inflammation-induced acute cognitive dysfunction is unclear. Here we assessed whether noradrenergic depletion, in female mice, impacted upon inflammation, locomotor activity and working memory directly after acute systemic immune challenge with bacterial lipopolysaccharide (LPS), a paradigm we have previously used to capture delirium-like acute cognitive deficits. Mice received 2 doses of the LC-selective noradrenergic toxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg i.p.) and were challenged, 2 weeks later, with LPS (100 μg/kg i.p.). DSP-4 dramatically reduced noradrenaline concentrations and tyrosine hydroxylase-positive afferents in the frontal cortex and hippocampus. This did not significantly alter numbers of Pu.1-positive microglia, Iba1-positive microglial morphology or mRNA expression of microglia-associated gene transcripts (Tyrobp, Sall1, Cd68, Sra2, Clec7a) in the hippocampus or frontal cortex and produced modest reductions in Cx3cr1 and P2ry12. LPS induced blood and brain cytokine levels, cFOS activation and locomotor responses that were highly similar in DSP-4- and vehicle-treated mice, although LPS-induced plasma TNF-α was significantly reduced in those treated with DSP-4. Importantly, prior noradrenergic depletion did not predispose to LPS-induced T-maze working memory deficits. The data demonstrate that significant depletion of noradrenaline in the hippocampus and frontal cortex does not prompt acutely exaggerated neuroinflammation or leave the brain vulnerable to acute, transient working memory deficits upon low dose LPS challenge. These findings have implications for our understanding of the impact of systemic inflammation on the aging and vulnerable brain during septic encephalopathy and delirium.


Multicomponent 1,3-Bifunctionalization of Donor-Acceptor Cyclopropanes with Arenes and Nitrosoarenes.
AlBr3-mediated multicomponent 1,3-bifunctionalization of donor-acceptor cyclopropanes using arenes and nitrosoarenes as coupling partners is presented. In the cascade, a C-C, a C-N, and a C-Br bond is formed. Reactions are easy to conduct and proceed under mild conditions. The γ,γ-disubstituted N-arylated α-amino esters obtained as products are readily further chemically modified rendering the method valuable.


An Outbreak of Aeromonas hydrophila Infection in Turtles (Pseudemis scripta).
An outbreak of Aeromonas hydrophila infection with a high rate of mortality (95%) in turtles (Pseudemis scripta) in Italy is reported. Pure cultures of the pathogen were isolated from liver, lung, kidney, and heart specimens of the turtles. The A. hydrophila isolate was resistant to amoxicillin, ampicillin, cephalothin, and trimethoprim-sulfamethoxazole but was sensitive to a number of other antibiotics tested. The study indicates that pet turtles can act as reservoirs of this pathogen and may play an important role in the etiology of Aeromonas-associated human infections.


Guidelines for Working Heights of the Lower-Limb Exoskeleton (CEX) Based on Ergonomic Evaluations.
The aim of this study was to evaluate the muscle activities and subjective discomfort according to the heights of tasks and the lower-limb exoskeleton CEX (Chairless EXoskeleton), which is a chair-type passive exoskeleton. Twenty healthy subjects (thirteen males and seven females) participated in this experiment. The independent variables were wearing of the exoskeleton (w/ CEX, w/o CEX), working height (6 levels: 40, 60, 80, 100, 120, and 140 cm), and muscle type (8 levels: upper trapezius (UT), erector spinae (ES), middle deltoid (MD), triceps brachii (TB), biceps brachii (BB), biceps femoris (BF), rectus femoris (RF), and tibialis anterior (TA)). The dependent variables were EMG activity (% MVC) and subjective discomfort rating. When wearing the CEX, the UT, ES, RF, and TA showed lower muscle activities at low working heights (40-80 cm) than not wearing the CEX, whereas those muscles showed higher muscle activities at high working heights (100-140 cm). Use of the CEX had a positive effect on subjective discomfort rating at lower working heights. Generally, lower discomfort was reported at working heights below 100 cm when using the CEX. At working heights of 100-140 cm, the muscle activity when wearing the CEX tended to be greater than when not wearing it. Thus, considering the results of this study, the use of the lower-limb exoskeleton (CEX) at a working height of 40-100 cm might reduce the muscle activity and discomfort of whole body and decrease the risk of related disorders.


Application of environmental sampling to investigate a case of avian chlamydiosis in a pet store and breeding facility leading to mass bird exposures.
Chlamydia psittaci is a bacterium that causes chlamydiosis in birds and can cause zoonotic psittacosis in people. In November 2017, we received notification of a suspected case of avian chlamydiosis in a captive cockatiel (Nymphicus hollandicus) that was sold by an online pet bird retail and breeding facility in Washington State. We describe the investigation with emphasis on how environmental sampling was used to guide veterinary and public health interventions. Bird samples were collected either from pooled droppings, pooled plumage or individual nasal and choanal swabs. Environmental samples were obtained by swabbing cleaning mops, tables and cage structures. All samples were tested by polymerase chain reaction and positive samples underwent genotyping. Approximately 1000 birds representing four taxonomic orders were kept within an open-space warehouse. Eight of 14 environmental samples and one of two pooled faecal samples were positive for Chlamydia spp. The contaminating strain of Chlamydia spp. was identified as genotype A. The facility was closed for environmental disinfection, and all psittacines were treated with oral doxycycline for 45 days. Ten of 10 environmental and two of two pooled faecal samples were negative for C. psittaci 11 months after the completion of environmental disinfection and antimicrobial treatment. This investigation highlights the importance of preventing and mitigating pathogen incursion in an online pet retail and breeding facility. Environmental sampling is valuable to guide animal and public health interventions for control of C. psittaci, particularly when large numbers of birds are exposed to the pathogen.


[Renal amyloidosis: uncommon complication of sickle cell disease].
Type AA amyloidosis is a rare complication of sickle cell anemia. The purpose of this report is to describe the case of a 30-year-old man with heterozygous sickle cell disease who was referred to our unit with nephritic syndrome and microscopic hematuria. Light microscopy on a renal biopsy specimen demonstrated AA amyloidosis. After elimination of other causes, it was concluded that amyloidosis was the result of recurrent acute inflammation secondary to sickle cell disease. To our knowledge, this is the fifth that renal amyloidosis as a complication of sickle cell disease has been described in the literature.


Hepatoprotective effect of myristicin from nutmeg (Myristica fragrans) on lipopolysaccharide/d-galactosamine-induced liver injury.
To evaluate the hepatoprotective activity of spices, 21 different spices were fed to rats with liver damage caused by lipopolysaccharide (LPS) plus d-galactosamine (D-GalN). As assessed by plasma aminotranferase activities, nutmeg showed the most potent hepatoprotective activity. Bioassay-guided isolation of the active compound from nutmeg was carried out in mice by a single oral administration of the respective fractions. Myristicin, one of the major essential oils of nutmeg, was found to possess extraordinarily potent hepatoprotective activity. Myristicin markedly suppressed LPS/D-GalN-induced enhancement of serum TNF-alpha concentrations and hepatic DNA fragmentation in mice. These findings suggest that the hepatoprotective activity of myristicin might be, at least in part, due to the inhibition of TNF-alpha release from macrophages. However, further studies are needed to elucidate the hepatoprotective mechanism(s) of myristicin.


The MXCXXC class of metallochaperone proteins: model studies.
Transition metal ions can be both beneficial and harmful to biological systems if not carefully regulated. A family of proteins that include a conserved sequence in their binding site of MXCXXC is responsible for delivery and homeostasis of different metals. Model studies present an effective tool for studying the parameters governing metal affinity, selectivity and other mechanistic aspects. Small-molecule, peptide-based, and advanced models will be presented, as well as functional models of potential industrial applications.


Local recurrence of the atypical fibrous histiocytoma - a case report.
Atypical fibrous histiocytoma (AFH) is an uncommon variant of benign skin neoplasm, fibrous histiocytoma. Despite having pseudosarcomatous histological features, atypical fibrous histiocytoma is characterized by a benign clinical course. The aim of the study was to present the case of local recurrence of atypical fibrous histiocytoma in scar after the primary excision. A 28-year-old woman was admitted due to a slowgrowing 10 mm skin tumor of the left elbow, which has been observed for 18 months. Physical examination revealed that the tumor was covered by normal skin, firm, painless and movable. Tumor was excised and the wound was healed properly. Histopathological examination revealed AFH with normal tissue margins below 1 mm. It was decided to increase the excision. After 4 months patient was admitted for an extended resection. Physical examination showed no abnormalities within the scar. Despite this the primary procedure was radicalized and the scar with margins was excised. Histopathological examination reveals a subcuticular, single-site, 2 mm recurrent atypical fibrous histiocytoma with a surrounding of 2-10 mm normal tissue margin. The patient remains in follow-up the scar reveals no irregularities. The excisional biopsy followed by an extended resection makes a complete recovery. The probability of a too small surgical margin (<1 mm) could contribute to the local recurrence of atypical fibrous histiocytoma.


Risk factors for post-pancreaticoduodenectomy bleeding and finding an innovative approach to treatment.
This study is to determine the risk factors and outcome for post-pancreaticoduodenectomy bleeding, and to assess the roles of surgery and intravascular intervention in its management. Post-pancreaticoduodenectomy data of 628 patients were analyzed with regards to post-pancreaticoduodenectomy bleeding. Post-pancreaticoduodenectomy bleeding occurred in 58 patients (9.2%) and led to death in 23 patients. Pancreatic leakage and intra-abdominal abscess were independent risk factors for both extraluminal and intraluminal post-pancreaticoduodenectomy bleeding. The most common source of bleeding was the gastroduodenal artery (n = 9, 24.3%), and 8 of these patients (88.9%) experienced gastroduodenal artery bleeding in late post-pancreaticoduodenectomy bleeding. Hemostasis for post-pancreaticoduodenectomy bleeding was achieved by surgery in 22 patients (78.6%) and intravascular intervention in 7 patients (58.3%). Transarterial embolization for gastroduodenal artery bleeding did not deteriorate liver function in most patients except for 1 who died of hepatic failure. The placement of metallic clips on the gastroduodenal artery stump during a pancreaticoduodenectomy is helpful in identifying overlooked intermittent sentinel bleeding during angiography. Transarterial embolization for gastroduodenal artery bleeding could not guarantee against hepatic failure. The intravascular placement of a covered stent is the preferred procedure to avoid the complete interruption of arterial blood supply to the liver.


Targeted high throughput sequencing of a cancer-related exome subset by specific sequence capture with a fully automated microarray platform.
Sequence capture methods for targeted next generation sequencing promise to massively reduce cost of genomics projects compared to untargeted sequencing. However, evaluated capture methods specifically dedicated to biologically relevant genomic regions are rare. Whole exome capture has been shown to be a powerful tool to discover the genetic origin of disease and provides a reduction in target size and thus calculative sequencing capacity of >90-fold compared to untargeted whole genome sequencing. For further cost reduction, a valuable complementing approach is the analysis of smaller, relevant gene subsets but involving large cohorts of samples. However, effective adjustment of target sizes and sample numbers is hampered by the limited scalability of enrichment systems. We report a highly scalable and automated method to capture a 480 Kb exome subset of 115 cancer-related genes using microfluidic DNA arrays. The arrays are adaptable from 125 Kb to 1 Mb target size and/or one to eight samples without barcoding strategies, representing a further 26 - 270-fold reduction of calculative sequencing capacity compared to whole exome sequencing. Illumina GAII analysis of a HapMap genome enriched for this exome subset revealed a completeness of >96%. Uniformity was such that >68% of exons had at least half the median depth of coverage. An analysis of reference SNPs revealed a sensitivity of up to 93% and a specificity of 98.2% or higher.


The BIMDA shuttle flight mission: a low cost microgravity payload.
This paper presents the design, operation and experiment protocol of the Bioserve sponsored flights of the ITA Materials Dispersion Apparatus Payload (BIMDA) flown on the Space Shuttle on STS-37. The BIMDA payload represents a joint effort between ITA (Instrumentation Technology Associates, Inc.) and Bioserve Space Technologies, a NASA Center for the Commercial Development of Space, to investigate the methods and commercial potential of biomedical and fluid science applications in the microgravity environment of space. The BIMDA payload, flown in a Refrigerator/Incubator Module (R/IM) in the Orbiter middeck, consists of three different devices designed to mix fluids in space; four Materials Dispersion Apparatus (MDA) Minilabs developed by ITA, six Cell Syringes, and six Bioprocessing Modules both developed by NASA JSC and Bioserve. The BIMDA design and operation reflect user needs for late access prior to launch (<24 h) and early access after landing (<2 h). The environment for the payload is temperature controlled by the R/IM. The astronaut crew operates the payload and documents its operation. The temperature of the payload is recorded automatically during flight. The flight of the BIMDA payload is the first of two development flights of the MDA on the Space Shuttle. Future commercial flights of ITA's Materials Dispersion Apparatus on the Shuttle will be sponsored by NASA's Office of Commercial Programs and will take place over the next three years. Experiments for the BIMDA payload include research into the following areas: protein crystal growth, thin film membrane casting, collagen formation, fibrin clot formation, seed germination, enzymatic catalysis, zeolite crystallization, studies of mixing effects of lymphocyte functions, and solute diffusion and transport.


Retinal and choroidal expression of BMP-2 in lens-induced myopia and recovery from myopia in guinea pigs.
The present study investigated the retinal and choroidal expression of bone morphogenetic protein-2 (BMP-2) in myopia and in myopia recovery in a guinea pig model. For this investigation, two groups of guinea pigs, lens‑induced myopia and recovery from myopia, were used, and defocused myopia was induced the guinea pigs wearing ‑4.00 D lenses on the right eyes for 3 weeks, with the left eyes serving as the contralateral. In the following week, the lenses of the guinea pigs in the recovery group were removed, and the refractive power and axial length were measured. The expression of BMP‑2 in the eyeballs was observed using immunohistochemistry and analyzed using Western blot analysis. After 3 weeks, the eyes acquired relative myopia and longer axial lengths in the two groups of guinea pigs. After 1 week without lenses in the recovery group, the myopia and axial lengths regressed. Immunofluorescence staining showed that BMP‑2 was expressed in the posterior retina, RPE, choroid and sclera. The expression of BMP‑2 decreased in the myopic retina of the guinea pigs. Following the regression of myopia in the recovery group, no difference in the expression of BMP‑2 was observed between the recovered treated eyes and the contralateral eyes. The choroidal expression level of BMP‑2 in the treated eyes showed no significant changes in either group. Therefore, BMP‑2 may be involved in the development of myopia, however, it does not have a primary role in the retinal and choroidal signals regulating scleral remodeling.


Semi-automated micro-computed tomography lung segmentation and analysis in mouse models.
Computed Tomography (CT) is a standard clinical tool utilized to diagnose known lung pathologies based on established grading methods. However, for preclinical trials and toxicity investigations in animal models, more comprehensive datasets are typically needed to determine discriminative features between experimental treatments, which oftentimes require analysis of multiple images and their associated differential quantification using manual segmentation methods. Furthermore, for manual segmentation of image data, three or more readers is the gold standard of analysis, but this requirement can be time-consuming and inefficient, depending on variability due to reader bias. In previous papers, microCT image manual segmentation was a valuable tool for assessment of lung pathology in several animal models; however, the manual segmentation approach and the commercial software used was typically a major rate-limiting step. To improve the efficiency, the semi-manual segmentation method was streamlined, and a semi-automated segmentation process was developed to produce:•Quantifiable segmentations: using manual and semi-automated analysis methods for assessing experimental injury and toxicity models,•Deterministic results and efficiency through automation in an unbiased and parameter free process, thereby reducing reader variance, user time, and increases throughput in data analysis,•Cost-Effectiveness: portable with low computational resource demand, based on a cross-platform open-source ImageJ program.


A Flexible Three-in-One Microsensor for Real-Time Monitoring of Internal Temperature, Voltage and Current of Lithium Batteries.
Lithium batteries are widely used in notebook computers, mobile phones, 3C electronic products, and electric vehicles. However, under a high charge/discharge rate, the internal temperature of lithium battery may rise sharply, thus causing safety problems. On the other hand, when the lithium battery is overcharged, the voltage and current may be affected, resulting in battery instability. This study applies the micro-electro-mechanical systems (MEMS) technology on a flexible substrate, and develops a flexible three-in-one microsensor that can withstand the internal harsh environment of a lithium battery and instantly measure the internal temperature, voltage and current of the battery. Then, the internal information can be fed back to the outside in advance for the purpose of safety management without damaging the lithium battery structure. The proposed flexible three-in-one microsensor should prove helpful for the improvement of lithium battery design or material development in the future.


The SHI-3 iron transport island of Shigella boydii 0-1392 carries the genes for aerobactin synthesis and transport.
In Shigella boydii 0-1392, genes encoding the synthesis and transport of the hydroxamate siderophore aerobactin are located within a 21-kb iron transport island between lysU and the pheU tRNA gene. DNA sequence analysis of the S. boydii 0-1392 island, designated SHI-3 for Shigella island 3, revealed a conserved aerobactin operon associated with a P4 prophage-like integrase gene and numerous insertion sequences (IS). SHI-3 is present at the pheU tRNA locus in some S. boydii isolates but not in others. The map locations of the aerobactin genes vary among closely related species. The association of the aerobactin operon with phage genes and mobile elements and its presence at different locations within the genomes of enteric pathogens suggest that these virulence-enhancing genes may have been acquired by bacteriophage integration or IS element-mediated transposition. An S. boydii aerobactin synthesis mutant, 0-1392 iucB, was constructed and was similar to the wild type in tissue culture assays of invasion and intercellular spread.


[Effects of Huangpu Tongqiao capsule on apoptosis of Alzheimer's disease cell model].
The loss of hippocampal neurons is one of the main pathological features of Alzheimer's disease (AD), which is related to the apoptosis of hippocampal neurons. Huangpu Tongqiao capsule is used for the treatment of AD, but the underlying mechanism is still unclear. This study is to investigate the mechanism of neuroprotective effect of Huangpu Tongqiao capsule in the treatment of AD, through observing the effect of Huangpu Tongqiao capsule containing serum on cell injury of primary cultured hippocampal neurons induced by Aβ₂₅₋₃₅ via inhibiting the cell apoptosis. Primary cultured hippocampal neurons were cultured and identified by MAP-2 immunofluorescence staining, and cell growth state was observed by inverted microscope. The Huangpu Tongqiao capsule containing serum was prepared using the method of serum pharmacology. MTT assays were used to measure the optimum concentration range of Huangpu Tongqiao capsule containing serum, and optimum Aβ concentration for establishing the AD model. After primary cultured hippocampal neurons AD cell model was induced by Aβ₂₅₋₃₅, cell survival rate was detected by MTT, cell apoptosis rate was assayed by flow cytometry, and protein expressions of Bax, Cyt C and caspase-3 were determined by Western blot analysis. The results showed that the primary cultured hippocampal neurons were cultured successfully, and cells grew mature at seventh days; Compared with normal group, the survival rate of hippocampal neurons in AD cell model group was decreased, the apoptosis rate of hippocampal neurons was increased, and the protein expressions of Bax, Cyt C and caspase-3 were increased (P<0.05, P<0.01); Compared with AD cell model group, the survival rate of hippocampal neurons in Huangpu Tongqiao capsule containing serum group was increased, the apoptosis rate of hippocampal neurons was decreased, and the protein expressions of Bax, Cyt C and caspase-3 were decreased (P<0.05, P<0.01). These findings suggest that Huangpu Tongqiao capsule containing serum has a neuroprotective effect on cell injury of the primary cultured hippocampal neurons induced by Aβ₂₅₋₃₅, and its effect on the treatment of AD is associated with the inhibition the apoptosis of hippocampal neurons.


The role of WNT5A and Ror2 in peritoneal membrane injury.
Patients on peritoneal dialysis are at risk of developing peritoneal fibrosis and angiogenesis, which can lead to dysfunction of the peritoneal membrane. Recent evidence has identified cross-talk between transforming growth factor beta (TGFB) and the WNT/β-catenin pathway to induce fibrosis and angiogenesis. Limited evidence exists describing the role of non-canonical WNT signalling in peritoneal membrane injury. Non-canonical WNT5A is suggested to have different effects depending on the receptor environment. WNT5A has been implicated in antagonizing canonical WNT/β-catenin signalling in the presence of receptor tyrosine kinase-like orphan receptor (Ror2). We co-expressed TGFB and WNT5A using adenovirus and examined its role in the development of peritoneal fibrosis and angiogenesis. Treatment of mouse peritoneum with AdWNT5A decreased the submesothelial thickening and angiogenesis induced by AdTGFB. WNT5A appeared to block WNT/β-catenin signalling by inhibiting phosphorylation of glycogen synthase kinase 3 beta (GSK3B) and reducing levels of total β-catenin and target proteins. To examine the function of Ror2, we silenced Ror2 in a human mesothelial cell line. We treated cells with AdWNT5A and observed a significant increase in fibronectin compared with AdWNT5A alone. We also analysed fibronectin and vascular endothelial growth factor (VEGF) in a TGFB model of mesothelial cell injury. Both fibronectin and VEGF were significantly increased in response to Ror2 silencing when cells were exposed to TGFB. Our results suggest that WNT5A inhibits peritoneal injury and this is associated with a decrease in WNT/β-catenin signalling. In human mesothelial cells, Ror2 is involved in regulating levels of fibronectin and VEGF.


Variation of serum and urinary neutrophil gelatinase associated lipocalin (NGAL) after strenuous physical exercise.
Strenuous exercise may trigger acute complications, such as exertional rhabdomyolysis and gastrointestinal complaint. As less is known about the potential renal impairment after long distance running, we assessed creatinine and neutrophil gelatinase associated lipocalin (NGAL) in serum (sNGAL) and urine (uNGAL) before and after an ultramarathon. The study population consisted of 16 trained male athletes who ran a 60 km ultramarathon. Blood and spot urine samples were collected 20 min before and immediately after the run. Creatinine was assessed by Jaffe assay on Beckman Coulter AU5800 and renal function was expressed as estimated glomerular filtration rate (eGFR) by MDRD formula. NGAL was measured by fully-automated immunoassay NGAL Test™ on AU 5800. Serum and urinary creatinine increased significantly by 38% and 78%, respectively. The eGFR contextually decreased by 31%. sNGAL, uNGAL and uNGAL/creatinine ratio increased by 1.6-fold, 7.7-fold and 2.9-fold. In six of 16 athletes (38%), the acute post-exercise increase of serum creatinine met the criteria of acute kidney injury. No significant relationship was found between pre-exercise, post-exercise values and post-exercise variation of sNGAL, uNGAL and uNGAL/creatinine ratio. A significant correlation was found between pre- and post-exercise changes of serum creatinine and sNGAL, but not with either uNGAL or uNGAL/creatinine ratio. The acute variations of serum creatinine and uNGAL attest that renal impairment is likely to develop after long distance running. The uNGAL seems more independent from creatinine variation and extra-renal sources, and thereby more reliable for monitoring the renal involvement in these types of kidney impairment.


Fluorene-Based Copolymers Containing Dinaphtho-s-indacene as New Building Blocks for High-Efficiency and Color-Stable Blue LEDs.
By incorporating a new building block, 7,7,15,15-tetraoctyldinaphtho-s-indacene (NSI), into the backbone of poly(9,9-dioctylfluorene) (PFO), a novel series of blue light-emitting copolymers (PFO-NSI) have been developed. The insertion of the NSI unit into the PFO backbone leads to the increase of local effective conjugation length, to form low-energy fluorene-NSI-fluorene (FNF) segments that serve as exciton trapping sites, to which the energy transfers from the high-energy PFO segments. This causes these copolymers to show red-shifted emissions compared with PFO, with a high efficiency and good color stability and purity. The best device performance with a luminance efficiency of 3.43 cd · A(-1) , a maximum brightness of 6 539 cd · m(-2) , and CIE coordinates of (0.152, 0.164) was achieved.


[Sex correction in testicular feminization syndrome].
From 1993 to 2000 the authors observed 10 patients with testicular feminization. In spite of existent highly informative methods, early diagnosis of the genesis of abnormal sexual differentiation is not easy, it requires time. Treatment policy varied with the form of testicular feminization. In a complete form (6 patients), bilateral ventrofixation of the gonads (ovotestis) was made, in incomplete form (4 patients) male gonads were removed with subsequent replacement hormonotherapy. Correction of the external genitalia consisted in amputation of the hypertrophic clitoris with creation of the female-type external genitalia. It is emphasized that in incomplete testicular feminization surgical correction should be started before the appearance of secondary sexual characters to raise effectiveness of hormone treatment in formation of a female genotype.


The Microbiome of the Meibum and Ocular Surface in Healthy Subjects.
The purpose of this study was to investigate the microbiome in the meibum, conjunctival sac, and eyelid skin in young and elderly healthy subjects, and analyze the effect that age, sex, and region have on microbiome composition. This study involved 36 healthy subjects (young-age subjects: 9 men/9 women, age range: 20-35 years; elderly age subjects: 9 men/9 women, age range: 60-70 years). In all subjects, lower-eyelid meibum, lower conjunctival sac, and lower-eyelid skin specimens were collected from one eye, and then stored at -20°C. Taxonomic composition of the microbiome was obtained via 16S rRNA gene sequencing, and then analyzed. The meibum microbiome showed a high α-diversity (within-community diversity), particularly in the young subjects. However, in approximately 30% of the elderly subjects, a low-diversity microbiome dominated by Corynebacterium sp. or Neisseriaceae was observed. In the young subjects, the microbiome of the meibum resembled that of the conjunctival-sac, yet in the elderly subjects, the microbiome of the conjunctival-sac became more similar to that of the eyelid skin. The eyelid-skin microbiome was relatively simple, and was typically dominated by Propionibacterium acnes in the young subjects, or by Corynebacterium sp. or Neisseriaceae in the elderly subjects. In both age groups, no significant difference was seen between the men and women in regard to the meibum, conjunctival-sac, and eyelid-skin microbiome. Our findings confirmed that the meibum of healthy adult-age subjects harbors highly diverse microbiota, and revealed that the meibum microbiome, especially the decrease of its diversity, alters with aging and may affect the homeostasis of the ocular surface.


Effects of dietary inclusion of lentil byproduct on performance and oxidative stability of eggs in laying quail.
One hundred and sixty-eight 11-week-old laying quails (Coturnix coturnix japonica) were fed one of the following three diets: (1) control: basal diet with no lentil (Lens culinaris L.) byproduct; (2) inclusion of 10% lentil byproduct; (3) inclusion of 20% lentil byproduct. In the recent years, colour sorting machines are used in order to separate red lentils according to their colours. The goal is to select the items which are discoloured, not as ripe as required, or still with hull even after dehulling of lentil seed. During the sorting, a new byproduct called "sorting byproduct" leftover is obtained. The byproduct is cleaner and is of a higher quality than other lentil byproducts. This experiment was conducted to study the effects of the inclusion of different levels of lentil byproduct on laying quail performance. The experimental treatment included 10% or 20% lentil byproduct in the diet, and this was fed to quails aged between 11 and 22 weeks. The inclusion of 10% and 20% levels of lentil byproduct in the diet significantly increased egg production, but feed intake and feed conversion ratio were not significantly affected. Egg weight decreased significantly following the inclusion of 20% lentil byproduct. The inclusion of lentil byproduct in the diet increased the deposition of yellow yolk pigments and decreased malonaldehyde formation in the yolk.


Interaction of vasopressin and prostaglandins in the toad urinary bladder.
Prostaglandins are important modulators of the action of vasopressin. Others researchers have proposed that vasopressin stimulates prostaglandin synthesis, completing a negative feedback loop and thereby limiting vasopressin's antidiuretic effect. We have re-examined this question, using specific radioimmunoassay and thin-layer radiochromatography to determine prostaglandin synthesis by the toad bladder. Under control conditions, the bladder synthesizes prostaglandin (PG)E2 and thromboxane (TX)B2. There was no evidence for synthesis of PGE1 or PGF2 alpha by radioimmunoassay, or of other prostaglandins by radiochromatography. Furthermore, there was no evidence for metabolism of PGE2 by the bladder. Using a variety of protocols, in isolated epithelial cells as well as intact bladders, we were unable to detect any significant increase in PGE2 or TXB2 synthesis after stimulation with arginine vasopressin (AVP) or deamino-8-D-arginine vasopressin (DDAVP). Arachidonic acid, the specific precursor of prostaglandin synthesis, increased PGE2 synthesis twofold, and significantly inhibited AVP- and DDAVP-stimulated water flow by 60 and 75%, respectively. Naproxen and acetaminophen inhibited prostaglandin synthesis and enhanced water flow in response to AVP and DDAVP (44-54%). Our findings indicate that the toad bladder produces tow prostaglandins, PGE2 and TXB2, and that vasopressin does not alter their rate of synthesis. Because agents such as acetaminophen and naproxen inhibit prostaglandin synthesis and enhance vasopressin- and DDAVP-stimulated water flow, we suggest that it is the inhibitory effect of these agents on the hormone-independent rate of prostaglandin synthesis that is responsible for their enhancement of water flow. Furthermore, because AVP appears to increase prostaglandin synthesis by the intact kidney, we suggest that cells other than those of the collecting tubule are responsible for the increased prostaglandin production.


The development of human sera tests for HDL-bound serum PON1 and its lipolactonase activity.
Serum paraoxonase (PON1) is a lipolactonase that associates with HDL-apolipoprotein A-I (HDL-apoA-I) and thereby plays a role in the prevention of atherosclerosis. Current sera tests make use of promiscuous substrates and provide no indications regarding HDL-PON1 complex formation. We developed new enzymatic tests that detect total PON1 levels, irrespective of HDL status and R/Q polymorphism, as well as the degree of catalytic stimulation and increased stability that follow PON1's tight binding to HDL-apoA-I. The tests are based on measuring total PON1 levels with a fluorogenic phosphotriester, measuring the lipolactonase activity with a chromogenic lactone, and assaying the enzyme's chelator-mediated inactivation rate. The latter two are affected by tight HDL binding and thereby derive the levels of the serum PON1-HDL complex. We demonstrate these new tests with a group of healthy individuals (n=54) and show that the levels of PON1-HDL vary by a factor of 12. Whereas the traditionally applied paraoxonase and arylesterase tests weakly reflect PON1-HDL levels (R=0.64), the lipolactonase test provides better correlation (R=0.80). These new tests indicate the levels and activity of PON1 in a physiologically relevant context as well as the levels and quality of the HDL particles with which the enzyme is associated.


Influence of glucoregulation quality on C-reactive protein, interleukin-6 and tumor necrosis factor-alpha level in patients with diabetes type 1.
Results of studies which have proved an increased inflammatory activity in diabetes type 1, have been published over recent years. One of possible mechanisms that are used to explain chronic inflammation in diabetes is the state of hyperglycemia leading to the enhanced synthesis of glycosylation end products (AGEs) which activate macrophages, increase the oxidative stress and affect the synthesis of interleukins (IL-1, IL-6), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP). The aim of the study was to determine the inflammatory markers (CRP, IL-6, TNF-alpha) in patients with diabetes type 1 and to establish their correlation with glucoregulation parameters and other cardiovascular risk factors as well as to compare them with the healthy controls. The study included 76 patients with diabetes type 1 and 30 healthy controls. We determined values of inflammatory markers (CRP, IL-6, TNF-alpha) and glucoregulation parameters (fasting glucose HbA(1c)). The values of CRP (p = 0.014), IL-6 (p = 0.020) and TNF-alpha (p = 0.037) were statistically significantly higher in the diabetic patients than in the healthy controls. There was a positive correlation between CRP with postprandial glycemia (p = 0.004); the multivariate regression analysis revealed a statistically significant correlation between CRP and age (p = 0.001), smoking (p = 0.055), fasting glucose (p = 0.021) and triglycerides (p = 0.048) as well as between IL-6 and LDL-cholesterol (p = 0.009). No statistically significant correlations were found between glycosilated hemoglobin (HbA(1c)) and the inflammatory markers (CRP, IL-6 and TNF-alpha). The patients with type 1 diabetes were found to have a low level of inflammatory activity manifested by the increased values of CRP, IL-6 and TNF-alpha.


TRPV4 increases cardiomyocyte calcium cycling and contractility yet contributes to damage in the aged heart following hypoosmotic stress.
Cardiomyocyte Ca2+ homeostasis is altered with aging via poorly-understood mechanisms. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an osmotically-activated Ca2+ channel, and there is limited information on the role of TRPV4 in cardiomyocytes. Our data show that TRPV4 protein expression increases in cardiomyocytes of the aged heart. The objective of this study was to examine the role of TRPV4 in cardiomyocyte Ca2+ homeostasis following hypoosmotic stress and to assess the contribution of TRPV4 to cardiac contractility and tissue damage following ischaemia-reperfusion (I/R), a pathological condition associated with cardiomyocyte osmotic stress. TRPV4 protein expression increased in cardiomyocytes of Aged (24-27 months) mice compared with Young (3-6 months) mice. Immunohistochemistry revealed TRPV4 localization to microtubules and the t-tubule network of cardiomyocytes of Aged mice, as well as in left ventricular myocardium of elderly patients undergoing surgical aortic valve replacement for aortic stenosis. Following hypoosmotic stress, cardiomyocytes of Aged, but not Young exhibited an increase in action-potential induced Ca2+ transients. This effect was mediated via increased sarcoplasmic reticulum Ca2+ content and facilitation of Ryanodine Receptor Ca2+ release and was prevented by TRPV4 antagonism (1 μmol/L HC067047). A similar hypoosmotic stress-induced facilitation of Ca2+ transients was observed in Young transgenic mice with inducible TRPV4 expression in cardiomyocytes. Following I/R, isolated hearts of Young mice with transgenic TRPV4 expression exhibited enhanced contractility vs. hearts of Young control mice. Similarly, hearts of Aged mice exhibited enhanced contractility vs. hearts of Aged TRPV4 knock-out (TRPV4-/-) mice. In Aged, pharmacological inhibition of TRPV4 (1 μmol/L, HC067047) prevented hypoosmotic stress-induced cardiomyocyte death and I/R-induced cardiac damage. Our findings provide a new mechanism for hypoosmotic stress-induced cardiomyocyte Ca2+ entry and cell damage in the aged heart. These finding have potential implications in treatment of elderly populations at increased risk of myocardial infarction and I/R injury.


Effect of metabolic control on cognitive functions in children and adolescents with type 1 diabetes mellitus.
Neurocognitive functions of children with type 1 diabetes mellitus (T1D) are reported to be poorer than those of healthy peers. The aim was to investigate the effects of age of onset of diabetes, metabolic control, and type of insulin regimen on neurocognitive functions in children and adolescents with T1D. Forty-seven children aged 6-18 years, with T1D for at least five years, were included. Children with a known psychiatric disorder or chronic diseases other than T1D were excluded. Intelligence via the Wechsler children's intelligence scale (WISC-R), short-term memory via the audio-auditory digits form B (GISD-B) test, visual motor perception via the Bender Gestalt test, and attention via the Moxo continuous attention and performance test, timing, hyperactivity, and impulsivity (Moxo-dCPT) were assessed. Compared with the T1D group, healthy controls had higher scores in terms of verbal intelligence quotient (IQ), performance IQ, and total IQ mean scores on WISC-R (p=0.01, p=0.05 and p=0.01, respectively). On the MOXO-dCPT test, the T1D group had higher impulsivity compared to the control group (p=0.04). Verbal IQ was better in the moderate control group than in the poorer metabolic control (p=0.01). Patients with no history of diabetic ketoacidosis (DKA) had higher performance, verbal and total intelligence scores than the group with history of DKA. Poor metabolic control and a history of DKA in children with T1D adversely affected neurocognitive functions. It would be beneficial to consider the assessment of neurocognitive functions in T1D and to take the necessary precautions in follow-up.


Deoxygenation of hydroquinones as a general route to norbornane-fused aromatic systems: an entry into substituted and functionalized dimethano- and methanoanthracenes.
A high-yielding route to substituted and functionalized dimethanoanthracenes by the Pd-catalyzed deoxyenation of the corresponding hydroquinone precursors is described. Attempts were made to deoxygenate the 9,10-dimesylate, ditosylate, and ditriflate derivatives of anti-dimethanoanthracene 1a, and it was found that under the studied conditions only the ditriflate 8a gave the corresponding deoxygenated aromatic scaffold. Optimization of the reaction conditions identified the Pd(OAc)(2)/dppf tandem as a suitable catalytic system for this transformation. The presented strategy was further extended to a novel and efficient synthetic route to methanoanthracenes employing a one-pot Pd-catalyzed deoxygenation/hydrogenation sequence.


Advantages of being diligent: lessons learnt from umbilical venous catheterisation in neonates.
Umbilical venous catheters (UVCs) are commonly used in neonatal units. Abdominal radiograph, taken soon after the insertion, is used to confirm the correct placement of the catheter. However, as demonstrated by our case series, complacency when an initial UVC is normally positioned can lead to detecting UVC-related complications very late. We describe cases of three neonates where, despite the initial UVC being confirmed to be well positioned, the patients developed life-threatening complications, including liver haematoma, left atrial thrombus and pericardial effusion causing cardiac tamponade. The routine use of point of care echocardiography helped in the early diagnosis of these complications. We suggest repeated echocardiographic screening at regular intervals in all newborn babies requiring UVCs, to ensure that the catheter is maintained in the proper position and for the early detection of catheter-related complications.


Cyclin-dependent kinases in brain development and disease.
Cyclin-dependent kinase 5 (Cdk5) is a multifaceted serine/threonine kinase protein with important roles in the nervous system. Two related proteins, p35 and p39, activate Cdk5 upon direct binding. Over the past decade, Cdk5 activity has been demonstrated to regulate many events during brain development, including neuronal migration as well as axon and dendrite development. Recent evidence also suggests a pivotal role for Cdk5 in synaptic plasticity, behavior, and cognition. Dysfunction of Cdk5 has been implicated in a number of neurological disorders and neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick type C disease, and ischemia. Hyperactivation of Cdk5 due to the conversion of p35 to p25 by the calcium-dependent protease calpain during neurotoxicity also contributes to the pathological state. This review surveys recent literature surrounding Cdk5 in synaptic plasticity and homeostasis, with particular emphasis on Cdk5 kinase activity under neurodegenerative conditions.


Localized Vibrations of Bi Bilayer Leading to Ultralow Lattice Thermal Conductivity and High Thermoelectric Performance in Weak Topological Insulator n-Type BiSe.
Realization of high thermoelectric performance in n-type semiconductors is of imperative need on account of the dearth of efficient n-type thermoelectric materials compared to the p-type counterpart. Moreover, development of efficient thermoelectric materials based on Te-free compounds is desirable because of the scarcity of Te in the Earth's crust. Herein, we report the intrinsic ultralow thermal conductivity and high thermoelectric performance near room temperature in n-type BiSe, a Te-free solid, which recently has emerged as a weak topological insulator. BiSe possesses a layered structure consisting of a bismuth bilayer (Bi2) sandwiched between two Bi2Se3 quintuple layers [Se-Bi-Se-Bi-Se], resembling natural heterostructure. High thermoelectric performance of BiSe is realized through the ultralow lattice thermal conductivity (κlat of ∼0.6 W/mK at 300 K), which is significantly lower than that of Bi2Se3 (κlat of ∼1.8 W/mK at 300 K), although both of them belong to the same layered homologous family (Bi2) m(Bi2Se3) n. Phonon dispersion calculated from first-principles and the experimental low-temperature specific heat data indicate that soft localized vibrations of bismuth bilayer in BiSe are responsible for its ultralow κlat. These low energy optical phonon branches couple strongly with the heat carrying acoustic phonons, and consequently suppress the phonon mean free path leading to low κlat. Further optimization of thermoelectric properties of BiSe through Sb substitution and spark plasma sintering (SPS) results in high ZT ∼ 0.8 at 425 K along the pressing direction, which is indeed remarkable among Te-free n-type thermoelectric materials near room temperature.


Structural basis for broad neutralization of hepatitis C virus quasispecies.
Monoclonal antibodies directed against hepatitis C virus (HCV) E2 protein can neutralize cell-cultured HCV and pseudoparticles expressing envelopes derived from multiple HCV subtypes. For example, based on antibody blocking experiments and alanine scanning mutagenesis, it was proposed that the AR3B monoclonal antibody recognized a discontinuous conformational epitope comprised of amino acid residues 396-424, 436-447, and 523-540 of HCV E2 envelope protein. Intriguingly, one of these segments (436-447) overlapped with hypervariable region 3 (HVR3), a domain that exhibited significant intrahost and interhost genetic diversity. To reconcile these observations, amino-acid sequence variability was examined and homology-based structural modelling of E2 based on tick-borne encephalitis virus (TBEV) E protein was performed based on 413 HCV sequences derived from 18 subjects with chronic hepatitis C. Here we report that despite a high degree of amino-acid sequence variability, the three-dimensional structure of E2 is remarkably conserved, suggesting broad recognition of structural determinants rather than specific residues. Regions 396-424 and 523-540 were largely exposed and in close spatial proximity at the surface of E2. In contrast, region 436-447, which overlaps with HVR3, was >35 Å away, and estimates of buried surface were inconsistent with HVR3 being part of the AR3B binding interface. High-throughput structural analysis of HCV quasispecies could facilitate the development of novel vaccines that target conserved structural features of HCV envelope and elicit neutralizing antibody responses that are less vulnerable to viral escape.


Superelastic shape recovery of mechanically twinned 3,5-difluorobenzoic acid crystals.
Generally, superelastic behavior cannot be expected in mechanically twinned crystals because there is essentially no strain on the interface that is a driving force for spontaneous shape recovery. However, we found that single crystals of 3,5-difluorobenzoic acid are superelastic organic crystals under mechanical twinning. The unexpected shape recovery can be explained by molecular distortion on the twinning interface, which suggests a new mechanism for superelasticity in molecular materials.


Influence of Water on Noncatalytic Oxidative Desulfurization of High-Sulfur Straight-Run Oil Fractions.
The noncatalytic oxidative desulfurization process of straight-run kerosene and diesel fractions with high sulfur contents due to their treatment with air without using expensive catalysts and strong oxidants is considered. The research was carried out in a periodic mode in a bubble-type reactor with a volume of 1 × 10-3 m3 under the following conditions: 180-200 °C; 2.5-3.0 MPa; the process lasted for 20-30 min; the air/raw material ratio was 1.6-2.2 m3/min per 1 m3 of raw material. The process can be used to obtain industrial jet fuels and diesel fuel components with good lubricating properties. The possibility and expediency of carrying out the process in the presence of water have been studied. The ratio of water/raw materials (vol.) varied from 0:1 to 2:1. It was proven that the water presence in the reaction medium has a positive effect on the studied process and decreases the oxidation intensity of hydrocarbon medium by 2-4 times. This is due to both the slowing of oxidation reactions by water during peroxide decomposition and chain growth and branching and the partial change in chemical oxidation with the formation of phenols and/or tertiary alcohols, which are inhibitors of oxidation reactions. On the other hand, water has almost no effect on the removal degree of sulfur compounds.


A novel, adaptable, radiographically opaque, multi-plane continuous filament marker for optimizing tissue identification, radiation planning, and radiographic follow-up.
In breast cancer treatment, marking the tumor bed is an important aspect of the surgical component of therapy. Clear delineation of the tumor bed allows radiation oncologists a defined target for planning and delivering postoperative radiation therapy (XRT). Tumor bed marking also allows radiographic follow-up of the tumor bed on subsequent breast imaging. The aim of this assessment is to evaluate the ease and feasibility of utilizing a tumor bed filament marker (VeraFormÒ, Videra Surgical inc., USA) as a marker in post-operative benign surgical sites and malignant breast surgical tumor beds in breast cancer surgery. The filament marker is a novel radiopaque surgical filament that in lieu of clips and other markers is implanted in the surgical tumor bed during breast surgery. Following development of the filament marker, the researchers used breast phantoms and radiographic images to develop a series of geometric patterns of placement options that optimize comprehensive multi-plane radiographic interpretation of the exact tumor bed or surgical margin. Three breast surgeons at 3 separate institutions then used this filament as a continuous multi-plane marker in 20 patients during breast conservation surgery. In these patients, the filament marker was thus used to mark the tumor bed (breast cancer surgery) or surgical site (benign breast disease) instead of the more traditional devices such as clips or other metallic open framework devices. We then assessed 2 important factors related to this device; (I) the ease, feasibility, and accuracy of in vivo placement with oncoplastic and non-oncoplastic breast conservation surgery techniques; (II) the radiographic footprint this device left on standard imaging protocols of post-operative mammogram (MMG), computed tomography (CT) scan, breast magnetic resonance imaging (MRI) examinations, and ultrasounds (USs) for both routine follow-up imaging and for standard radiation planning. There were no adverse events reported with the use of this device. The cases were then reviewed by a multidisciplinary team that included the original surgeon, a breast radiologist, and radiation oncologist. Their unanimous evaluation was that the filament marker clearly delineated all sides and planes of the tumor bed (cancer surgery) or surgical site (benign disease). Regardless of surgical technique utilized, this information provided precise 3D guidance for radiation planning and delivery as well as radiographic follow-up. The surgeons involved reported that delineating the bed with the filament marker was a quick and easy procedure and did not interfere with performing the planned surgical technique. Radiologists, surgeons, and radiation oncologists found that the filament marker was not only radiographically opaque on CT and MMG, but also caused no significant artifact on CT, MRI, US, or MMG. The continuous multi-plane filament marker is a new device that fulfills the heretofore unmet need for safe and improved tumor bed and tissue site marking. It is an easy to place, non-palpable continuous multi-plane radiographic opaque tissue marker that seems to better delineate the tumor bed, regardless of type of breast surgery performed, while providing a more accurate 3D image for radiation planning and radiographic follow-up on MMG MRI, CT and US.


Fluorescent probe displacement assays reveal unique nucleic acid binding properties of human nudix enzymes.
Nudix proteins are members of a large family of homologous enzymes that hydrolyze nucleoside diphosphates linked to other compounds. The substrates for a subset of Nudix enzymes are all nucleotides linked to RNA, like the m7G mRNA caps and the more recently discovered NAD(H) RNA caps. However, the RNA affinity and nucleic acid specificity of Nudix proteins has not yet been explored in depth. In this study we designed new fluorescence-based assays to examine the interaction of purified recombinant E. coli NudC and human Nudt1 (aka MTH1) Nudt3, Nudt12, Nudt16, and Nudt20 (aka Dcp2). All Nudix proteins except Nudt1 and Nudt12 bound both RNA and DNA stoichiometrically with high affinity (dissociation constants in the nanomolar range) and no clear sequence specificity. In stark contrast, Nudt12 binds RNA but not similar DNA oligonucleotides. Nudt12 also bound RNAs with 5' NAD+ caps more tightly than those with NADH or m7G cap. NudC was similarly selective against m7G caps but did not differentiate between NAD+ and NADH capped RNA. Nudt3, Nudt16, and Nudt20 bound m7G capped RNA more tightly than RNA with NADH caps.


[Amelogenesis imperfecta and hypothalamo-hypophyseal insufficiency].
Eleven patients with hypopituitarism, medio-facial hypoplasia and amelogenesis imperfecta were examined. The hypothalamo-pituitary dysfunction affected somatotrophic, gonadotrophic, corticotrophic and thyrotrophic function. The facial anomalies included medio-facial hypoplasia with hypertelorism and amelogenesis imperfecta. The latter--hypoplastic in nature--was noted in all anterior teeth and affected both dentitions. The enamel defect was confirmed on microscopic examination of an impacted tooth. The spectrum of malformation may also present as amelogenesis imperfecta in association with somatotropin deficiency. A genetic mechanism may possibly account for the clinical elements.


Stressful situations in caregiving: relations between caregiver coping and well-being.
We examined ways in which caregivers cope with stressful caregiving situations and the relations between coping strategies and caregivers' psychosocial well-being. Respondents were 58 family caregivers to patients discharged from a rehabilitation hospital. Caregivers identified a recent stressful event in caregiving and indicated strategies used to cope with this event. After controlling for patients' impairment level, analyses indicated that caregivers engaging in more escape-avoidance coping reported greater depression and more conflict in their personal relationships. Those using more positive reappraisal demonstrated greater positive affect. Younger caregivers, many of whom were women, used more avoidance strategies. Results have implications for therapeutic interventions with family caregivers.


Development and evaluation of a T1 standard brain template for Alzheimer disease.
Patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) have high variability in brain tissue loss, making it difficult to use a disease-specific standard brain template. The objective of this study was to develop an AD-specific three-dimensional (3D) T1 brain tissue template and to evaluate the characteristics of the populations used to form the template. We obtained 3D T1-weighted images from 294 individuals, including 101 AD, 96 amnestic MCI, and 97 cognitively normal (CN) elderly individuals, and segmented them into different brain tissues to generate AD-specific brain tissue templates. Demographic data and clinical outcome scores were compared between the three groups. Voxel-based analyses and regions-of-interest-based analyses were performed to compare gray matter volume (GMV) and white matter volume (WMV) between the three participant groups and to evaluate the relationship of GMV and WMV loss with age, years of education, and Mini-Mental State Examination (MMSE) scores. We created high-resolution AD-specific tissue probability maps (TPMs). In the AD and MCI groups, losses of both GMV and WMV were found with respect to the CN group in the hippocampus (F >44.60, P<0.001). GMV was lower with increasing age in all individuals in the left (r=-0.621, P<0.001) and right (r=-0.632, P<0.001) hippocampi. In the left hippocampus, GMV was positively correlated with years of education in the CN groups (r=0.345, P<0.001) but not in the MCI (r=0.223, P=0.0293) or AD (r=-0.021, P=0.835) groups. WMV of the corpus callosum was not significantly correlated with years of education in any of the three subject groups (r=0.035 and P=0.549 for left, r=0.013 and P=0.821 for right). In all individuals, GMV of the hippocampus was significantly correlated with MMSE scores (left, r=0.710 and P<0.001; right, r=0.680 and P<0.001), while WMV of the corpus callosum showed a weak correlation (left, r=0.142 and P=0.015; right, r=0.123 and P=0.035). A 3D, T1 brain tissue template was created using imaging data from CN, MCI, and AD participants considering the participants' age, sex, and years of education. Our disease-specific template can help evaluate brains to promote early diagnosis of MCI individuals and aid treatment of MCI and AD individuals.


Sirt3 Pharmacologically Promotes Insulin Sensitivity through PI3/AKT/mTOR and Their Downstream Pathway in Adipocytes.
Sirtuin-3 (Sirt3) is a major mitochondrial deacetylase enzyme that regulates multiple metabolic pathways, and its expression is decreased in diabetes type 1 and type 2 diabetes. This study aimed to elucidate Sirt3's molecular mechanism in regulating insulin sensitivity in adipocytes that can contribute to the effort of targeting Sirt3 for the treatment of obesity and type 2 diabetes. We found that the Sirt3 activator honokiol (HNK) induced adipogenesis compared to the control, in contrast to Sirt3 inhibitor, 3-TYP. Accordingly, HNK increased expression of adipocyte gene markers, gene-involved lipolysis and glucose transport (GLUT4), while 3-TYP reduced expression of those genes. Interestingly, 3-TYP caused an increase in gene expression of adipocyte-specific cytokines including IL6, resistin, and TNF-α. However, changes in adipocyte-specific cytokines in HNK treated cells were not significant. In addition, HNK stimulated insulin pathway by promoting insulin receptor beta (IRβ) and PI3K/AKT/mTOR pathways, resulting in an increase in phosphorylation of the forkhead family FoxO1/FoxO3a/FoxO4 and glycogen synthase kinase-3 (GSK-3β), opposing 3-TYP. In line with these findings, HNK increased free fatty acid and glucose uptake, contrary to 3-TYP. In conclusion, Sirt3 activator-HNK induced adipogenesis and lipolysis reduced adipocytes specific cytokines. Intriguingly, HNK activated insulin signaling pathway and increased free fatty acid as well as glucose uptake and transport, in sharp contrast to 3-TYP. These results indicate that, via insulin signaling regulation, Sirt3 activation by HNK improves insulin resistance, while Sirt3 inhibition by 3-TYP might precipitate insulin resistance.


Role of menaquinone in nitrate respiration in Staphylococcus aureus.
Two menaquinone-deficient and one aromatic-deficient mutants of Staphylococcus aureus were unable to reduce nitrate to nitrite. Reinitiation of menaquinone synthesis in the aromatic-deficient mutant by growing it with shikimic acid restored its nitrate respiratory activity. The results clearly demonstrate a role for menaquinone in nitrate respiration in Staphylococcus aureus.


Survivors of the Piper Alpha oil platform disaster: long-term follow-up study.
The long-term psychological effects of surviving a major disaster are poorly understood. We undertook a survey of survivors of the Piper Alpha oil platform disaster (1988). To examine the role of factors relating to the trauma, the survivors and the survivors' circumstances. Ten years after the disaster, 78% (46/59) of the survivors were located, of whom 72% (33/46) agreed to be interviewed. A further three individuals completed postal measures. The most stringent diagnostic criteria for post-traumatic stress disorder (PTSD) were met by 21% (7/33) of the survivors over 10 years after the disaster. Features such as physical injury, personal experience and survivor guilt were associated with significantly higher levels of post-traumatic symptoms. A narrow definition of factors affecting outcome will limit the potential for improving survivor well-being in the long-term after major disasters. Specific symptoms that are not included in the criteria for the diagnosis of PTSD, together with issues such as re-employment, need to be addressed.


Allosterically controlled single-chained maxizymes with extremely high and specific activity.
For the treatment of chronic myelogenous leukemia (CML), attempts have been made to design various ribozyme motifs that can specifically recognize and cleave BCR-ABL fusion mRNAs. In the case of L6 BCR-ABL b2a2 mRNA, it is difficult to cleave the abnormal mRNA specifically because the mRNA includes no sequences that can be cleaved efficiently by conventional hammerhead ribozymes near the BCR-ABL junction. We recently succeeded in designing a novel maxizyme, which specifically cleaves BCR-ABL fusion mRNA, as a result of the formation of a dimeric structure [Kuwabara, T.; et al. Mol. Cell 1998, 2, 617-627; Tanabe, T.; et al. Nature 2000, 406, 473-474]. Specifically, we tailored the maxizyme with molecular switching function: the maxizyme splices a cleavable GUC site, but only when it appears within a strand of mRNA that possesses the abnormal splice junction. We demonstrated that this approach is generalizable [Tanabe, T.; et al. Biomacromolecules 2000, 1, 108-117]. All the maxizymes designed in the past functioned as a result of the formation of a dimeric structure. Questions have been asked whether a similar molecular switching might be possible within a single molecule when two monomer units of the maxizyme were connected via a linker sequence. We found that an analogous conformational change could not be induced within a single molecule when two maxizyme units were simply connected via a nonregulatable linker sequence. However, an active conformation was achieved by the introduction of an antisense modulator within the linker sequence that adjusted the overall structure to the correct form. Results of studies in cultured cells suggested that the desired conformational change could indeed be induced within the modified single-chained maxizyme and such a construct caused apoptosis only in leukemic cells with the Philadelphia chromosome.


Mechanism and Effect of Polar Styrenes on Scandium-Catalyzed Copolymerization with Ethylene.
Copolymerization of ethylene (E) and polar vinyl monomers remains a problem because E propagation is hindered. Herein, for the first time, we report the copolymerization of E and polar styrenes (SR ) by using an oxophilic scandium catalyst that exhibits higher turnover frequencies than both E and SR homopolymerizations when R is an electron-withdrawing group. This positive comonomer effect was elucidated through computing reaction profiles of E/SF copolymerization at the DFT (B3PW91) level of theory. It reveals that the secondary interaction between Sc3+ and phenyl of the last and penultimate inserted SF units leads to a decrease of the E insertion barrier, because the electron-withdrawing substituent enhances the electrophilicity of Sc3+ by an inductive effect mediated by the secondary interaction. After three consecutive insertions of the E units, the secondary interaction is lost and the SF insertion is kinetically preferred over the E insertion. This process is in line with the NMR spectrum analyses which show that the resultant copolymers mainly contain SR (E)x SR sequences where x≤3.


Involvement of Autophagy in Rat Tail Static Compression-Induced Intervertebral Disc Degeneration and Notochordal Cell Disappearance.
The intervertebral disc is the largest avascular low-nutrient organ in the body. Thus, resident cells may utilize autophagy, a stress-response survival mechanism, by self-digesting and recycling damaged components. Our objective was to elucidate the involvement of autophagy in rat experimental disc degeneration. In vitro, the comparison between human and rat disc nucleus pulposus (NP) and annulus fibrosus (AF) cells found increased autophagic flux under serum deprivation rather in humans than in rats and in NP cells than in AF cells of rats (n = 6). In vivo, time-course Western blotting showed more distinct basal autophagy in rat tail disc NP tissues than in AF tissues; however, both decreased under sustained static compression (n = 24). Then, immunohistochemistry displayed abundant autophagy-related protein expression in large vacuolated disc NP notochordal cells of sham rats. Under temporary static compression (n = 18), multi-color immunofluorescence further identified rapidly decreased brachyury-positive notochordal cells with robust expression of autophagic microtubule-associated protein 1 light chain 3 (LC3) and transiently increased brachyury-negative non-notochordal cells with weaker LC3 expression. Notably, terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic death was predominant in brachyury-negative non-notochordal cells. Based on the observed notochordal cell autophagy impairment and non-notochordal cell apoptosis induction under unphysiological mechanical loading, further investigation is warranted to clarify possible autophagy-induced protection against notochordal cell disappearance, the earliest sign of disc degeneration, through limiting apoptosis.


Layer-specific response properties of the human lateral geniculate nucleus and superior colliculus.
The human LGN and SC consist of distinct layers, but their layer-specific response properties remain poorly understood. In this fMRI study, we characterized visual response properties of the magnocellular (M) and parvocellular (P) layers of the human LGN, as well as at different depths in the SC. Results show that fMRI is capable of resolving layer-specific signals from the LGN and SC. Compared to the P layers of the LGN, the M layers preferred higher temporal frequency, lower spatial frequency stimuli, and their responses saturated at lower contrast. Furthermore, the M layers are colorblind while the P layers showed robust response to both chromatic and achromatic stimuli. Visual responses in the SC were strongest in the superficial voxels, which showed similar spatiotemporal and contrast response properties as the M layers of the LGN, but were sensitive to color and responded strongly to isoluminant color stimulus. Thus, the non-invasive fMRI measures show that the M and P layers of human LGN have similar response properties as that observed in non-human primates and the superficial layers of the human SC prefer transient inputs but are not colorblind.


Caffeine consumption and serum cholesterol levels.
Caffeine consumption was significantly associated with serum cholesterol levels in women but not in men in a cross-sectional study of 4757 Australians. Use of caffeinated coffee by men, but not total caffeine consumption rate, was significantly associated with raised serum cholesterol. Potential confounding factors including age, adiposity and occupation were controlled for in this analysis. After adjusting for age and adiposity, the mean serum cholesterol level was 11 mg/dl higher for women consuming 200 mg or more of caffeine per day compared with those consuming less. The relative risk of high serum cholesterol (greater than 260 mg/dl) was greater than 2 for women consuming 200 mg or more of caffeine per day. A significant positive interaction between smoking and caffeine consumption in their association with serum cholesterol levels was found for females.


Careful considerations for mHealth app development: lessons learned from QuestExplore.
Mobile health (mHealth) applications (app) have proven to be useful in gathering symptom data for a variety of populations living with chronic and serious illnesses. These mHealth tools have been built for a variety of populations but can quickly lose their novelty over time due to the lack of changes and engagement between the mHealth tool and the user. High costs, constantly changing timelines, and difficulties in building compliant data storage systems are some of the reasons why mHealth development and implementation can be a challenge. Our team's tool, QuestExplore (QE), was built in collaboration with healthcare providers, child-life specialists, a music therapist, mobile app developers, data specialists, cyber security specialists, researchers, and children living with chronic illnesses alongside their families. Through this process, our team learned various ways to reduce costs, streamline the app development process, and build compliant data storage systems. In addition, our frequent interactions with stakeholders provided us with the ability to continuously make improvements, to build an engaging mHealth app. Based upon our findings, our team needed to include prompting, condensing, gamification, data visualizations, and an engaging user design in the remodel of QE. Through a three-stage process of redesigning our previous symptom monitoring apps, QE was developed to better communicate between our users and their providers, with the overall hope of improving symptom management of these children. In the paper, we aim to explain how our team developed QE with feedback from our stakeholders, while also continuously improving our development process through the lessons we gained through the app's development. QE is now being used in both Duke University and the University of North Carolina at Chapel Hill and will soon be implemented in Amsterdam University Medical Center.


In vivo erythrocyte sodium concentration in human hypertension is reduced, not increased.
The level of intracellular sodium concentration in hypertension is of theoretical interest. Using extensive in vitro manipulations, previous investigators have reported increased erythrocyte sodium content in human hypertension. In the present study, erythrocyte sodium (Nai) and potassium (Ki) concentrations were measured within seconds after venopuncture by centrifuging whole blood over oil to separate the erythrocytes from plasma. Labelled 125I-albumin and 57Co-EDTA were used to estimate plasma trapping. The presence of white cells and platelets in the cell pellets had no detectable effect on erythrocyte cation measurements. Twenty-eight white male hypertensives and 25 normotensive control subjects were studied. In hypertensive subjects, Nai was reduced and Ki was increased. Erythrocyte sodium and sodium: potassium ratio (Nai:Ki) of hypertensive subjects correlated inversely with their pressor responses to intravenous norepinephrine. The findings suggest increased erythrocyte Na, K-pump activity in human hypertension. Assuming that erythrocyte cation concentrations reflect those of vascular muscle, enhanced transmembrane sodium gradient does not preclude pressor hyper-responsiveness in hypertension.


Drenched Silicon Suppresses Disease and Insect Pests in Coffee Plant Grown in Controlled Environment by Improving Physiology and Upregulating Defense Genes.
Plant disease and insect pests are major limiting factors that reduce crop production worldwide. The ornamental indoor cultivation cash crop dwarf coffee Punica arabica 'Pacas' is also troubled by these issues. Silicon (Si) is one of the most abundant elements in the lithosphere and positively impacts plant health by effectively mitigating biotic and abiotic stresses. Several studies have shown that Si activates plant defense systems, although the specific nature of the involvement of Si in biochemical processes that lead to resistance is unclear. In our study, Si significantly promoted the growth and development of dwarf coffee seedlings grown in plant growth chambers. More than that, through natural infection, Si suppressed disease and insect pests by improving physiology (e.g., the strong development of the internal structures of roots, stems, and leaves; higher photosynthetic efficiency; more abundant organic matter accumulation; the promotion of root activity; the efficient absorption and transfer of mineral elements; and various activated enzymes) and up-regulating defense genes (CaERFTF11 and CaERF13). Overall, in agriculture, Si may potentially contribute to global food security and safety by assisting in the creation of enhanced crop types with optimal production as well by mitigating plant disease and insect pests. In this sense, Si is a sustainable alternative in agricultural production.


Effect of aqueous extract of Tragia involucrata Linn. on acute and subacute inflammation.
Antiinflammatory activity of aqueous extract of Tragia involucrata was tested on carrageenan-induced hind paw oedema and cotton pellet granuloma models in albino rats. In the subacute model, cotton pellet granuloma was produced by implantation of 10 mg sterile cotton in the axilla under ether anaesthesia. The animals were administered an aqueous extract at various concentrations of 50, 100, 200, 300 and 400 mg/kg. Phenyl butazone (80 mg/kg) was used as a standard drug. The paw diameter was measured at different time intervals and the dry granuloma weight was taken after the treatment. The aqueous leaf extract (400 mg/kg) showed the maximum inhibition (84.23%) of oedema at the end of 3 h following carrageenin-induced rat paw oedema. In subacute inflammation, the extract showed 76.25% reduction in granuloma weight. The results prove that the aqueous leaf extract showed highest antiinflammatory activity in acute and subacute inflammation and also support the usage of traditional claims.


Low- Versus High-Risk Rectal Cancer Based on MRI Features: Outcomes in Patients Treated Without Neoadjuvant Chemoradiotherapy.
The objective of this study was to compare the prognoses of patients with low- and high-risk rectal cancer detected by MRI who were treated without neoadjuvant chemoradiotherapy (NCRT) and to determine independent risk factors. This retrospective study included 185 patients with pathologically proven rectal adenocarcinoma who were treated without NCRT. Cancer was defined as high risk if one or more of the following factors were present: extramural depth of tumor invasion greater than 5 mm or stage T4a or T4b for tumor in the mid or high rectum; involvement of intersphincteric space, levators, or adjacent organs for tumor in the low rectum; extramural venous invasion (EMVI); or circumferential resection margin (CRM) involvement. Patients without any of those risk factors were placed in the low-risk group. The Kaplan-Meier method and Cox proportional hazards regression model were used to compare the survival outcomes between the two groups and to investigate the univariate and multivariate influences of the risk factors. Cancer was deemed to be low risk in 65 (35.1%) patients and high risk in 120 (64.9%) patients. The two patient groups had statistically significant differences in 3-year actuarial overall survival (OS; 100% vs 88.3%, p = 0.0044), disease-free survival (DFS; 92.3% vs 60.0%, p < 0.0001), and local recurrence (LR; 1.5% vs 10.0%, p = 0.0297). CRM involvement was identified as an independent risk factor for OS (hazard ratio [HR], 4.78; 95% CI, 1.24-18.45), DFS (HR, 2.44; 95% CI, 1.24-4.81), and LR (HR, 3.92; 95% CI, 1.07-14.41). Moreover, EMVI was identified as an independent risk factor for DFS (HR, 2.46; 95% CI, 1.28-4.74). The LR and long-term survival of patients in the low-risk group were more favorable than those of patients in the high-risk group. EMVI and CRM status were independent risk factors.


Predictive Value of Serum Carbohydrate Antigen 19-9 (CA19-9) for Early Mortality in Advanced Pancreatic Cancer.
Levels of carbohydrate antigen 19-9 (CA19-9) in metastatic pancreatic cancer are used in daily practice as a marker of response to chemotherapy. The association between CA19-9 levels and mortality remains uncertain. This study sought to determine the most accurate level of CA19-9 associated with early mortality, both at diagnosis and during the course of metastatic disease. This research is a retrospective analysis of 64 patients with metastatic adenocarcinoma of the pancreas evaluated from January 2010 to December 2015. A receiver-operating characteristic (ROC) curve analysis was performed to evaluate the CA19-9 value and the association with early death (death within 2 months after diagnosis of advanced disease). The survival analysis was estimated by the Kaplan-Meier method, and variables of interest were assessed by proportional hazards regression Cox models. The mortality rate was 92.2%, and the estimated median survival was 11.0 months. For the ROC curve analysis of initial CA19-9, an area under the curve of 0.868 (95% confidence interval 0.782 to 0.954) was obtained; the cutoff of 2504 U/ml had a sensitivity of 100% and specificity of 82.8% for early death. The effect of initial CA19-9 and chemotherapy contributed independently to the survival time, and every increase of 1000 CA19-9 units increased the risk of death by 9% (p = 0.0003). CA19-9 levels in advanced pancreatic adenocarcinoma are associated independently with worse prognosis and early death. CA19-9 levels could be considered as a stratification factor for future clinical trials.


Signal transducers and activators of transcription (Stat) are detectable in mouse trigeminal ganglion neurons.
We studied signal transducers and activators of transcription (Stat) expression in mouse trigeminal ganglia (TG) to gain an understanding of herpes simplex virus (HSV) infection and reactivation. Mouse TG were harvested and were either frozen for Western blot analysis or preserved in 4% paraformaldehyde for subsequent immunohistochemistry study. The thawed specimens were homogenized, and nuclear/cytoplasmic extractions were performed for Western blots and immunoprecipitation. Immunohistochemistry showed that Stat1, Stat3, Stat4, Stat5b, and phosphotyrosine Stat3 localized to TG neurons, not surrounding satellite cells. Western blot of TG nuclear and cytoplasmic extracts confirmed the presence of these Stat at the appropriate molecular weights. Stat2 was undetectable in TG by these methods. Immunoprecipitation of TG nuclear extracts did not confirm the presence of Stat-Stat dimers in these specimens. These studies show that several Stat, including phosphotyrosine Stat3, are present in TG neurons, the site of HSV latency, where they could act upon latent viral DNA to effect reactivation.


Zebrafish genome instability after exposure to model genotoxicants.
Sublethal exposure to environmental genotoxicants may impact genome integrity in affected organisms. It is therefore necessary to develop tools to measure the extent and longevity of genotoxicant-induced DNA damage, and choose appropriate model organisms for biomonitoring. To this end, markers of DNA damage were measured in zebrafish larvae and adults following exposure to model genotoxicants (benzo[a]pyrene and ethyl methanesulfonate). Specifically, we assessed primary DNA damage and the existence of potentially persistent genomic alterations through application of the comet assay, quantitative random amplified polymorphic DNA (qRAPD) and amplified fragment length polymorphism (AFLP) assays. Furthermore, expression of genes involved in DNA repair, oxidative stress response and xenobiotic metabolism was evaluated as well. Additionally, the AFLP method was applied to adult specimens 1 year after larval exposure to the genotoxicants to evaluate the longevity of the observed DNA alterations. Large numbers of DNA alterations were detected in larval DNA using the comet assay, qRAPD and AFLP, demonstrating that zebrafish larvae are a sensitive model for revealing genotoxic effects. Furthermore, some of these genomic alterations persisted into adulthood, indicating the formation of stable genomic modifications. qRAPD and AFLP methods proved to be highly sensitive to genotoxic effects, even in cases when the comet assay indicated a lack of significant damage. These results thus support the use of zebrafish larvae as a sensitive model for monitoring the impact of genotoxic insult and give evidence of the longevity of genomic modifications induced by genotoxic agents.


Theory of functional systems in the scientific school of P.K. Anokhin.
In this paper we present brief biographical data of the outstanding Russian physiologist P.K. Anokhin and the stages of formation of the theory of functional systems, proposed by him. Furthermore we will deal with the architectonics of system organization of behavioral acts, underlying principles of the theory of functional systems as a part of the general theory of systems and the evolution of the theory of functional systems in the Anokhin Scientific School.