Serum and milk folates during the first two gestations and lactations in Romanov, Finnsheep, and Suffolk ewes.
Concentrations of folates in serum and milk were determined during the first two parities in 7 Suffolk, 12 Finnsheep, and 15 Romanov ewes at 0 (mating), 60, 110, and 140 d of gestation and 1, 7, 14, 21, and 50 d of lactation. The number of lambs born at first and second parturitions was 1.38 +/- .13 and 1.71 +/- .13 for Suffolk, 2.00 +/- .32 and 2.33 +/- .57 for Finnsheep, and 2.67 +/- .24 and 3.20 +/- .22 for Romanov, respectively, and the concentration of folates at d 0 was 1.17 +/- .21, 1.87 +/- .19, and 2.14 +/- .17 ng/mL, respectively. During gestation, serum concentrations of folates declined in the three breeds, more quickly in Romanov and Finnsheep (from d 0 to 60) than in Suffolk (from d 0 to 110). This decline was followed by an increase in serum concentrations of folates from d 110 to 140 of gestation in the three breeds; the largest increase was observed in Romanov (breed x quadratic effect of time, P = .001). During lactation, Romanov had higher serum concentrations of folates than Finnsheep, which in turn had a higher concentration than Suffolk (P = .001). Colostrum of Romanov had the highest concentration of folates (164.9 +/- 11.9 ng/mL), followed by that of Finnsheep (125.0 +/- 9.5 ng/mL) and Suffolk (98.2 +/- 13.3 ng/mL). On d 7 of lactation, concentration of folates was similar in milk of Romanov (97.1 +/- 5.6 ng/mL) and Finnsheep (94.9 +/- 4.0 ng/mL) and was higher than in Suffolk (72.4 +/- 3.7 ng/mL). From d 14, the concentration of milk folates was similar among breeds and decreased slowly to approximately 40 ng/mL at d 50 (breed x quadratic effect of time, P = .005). The changes in serum concentration of folates during gestation of ewes were similar to those observed in sows, suggesting that exogenous supply of folates may not be optimal in ewes during gestation and lactation.


[Clinical evaluation of preadjusted appliance based on Chinese normal occlusion].
To evaluate the effect of the preadjusted appliance (Z1 appliance) based on Chinese normal occlusion. Thirty non-extraction patients were treated with Z1 appliance. No wire bending was made during treatment. The results of these 30 cases had been evaluated by five senior orthodontists. Models were analysed quantitatively to testify and evaluate the efficiency of the appliance. The average score for post-treatment models was 91.2 (total score was 100). The model measurements indicated that average projective distance on occlusal plane between proximal contact points of adjacent teeth was less than 0.3 mm, which demonstrated good alignment. The prominence of crowns was almost coincident with the data of Chinese normal occlusion. For the average tip of most teeth, there was no statistical difference between the study group and the normal control group. The crown torque variation tendency from anterior to posterior was similar to that in the subjects with normal occlusion. However, the cases treated with Z1 appliance achieved more negative torque in the lower posterior segment. The result of the non-extraction patients treated with Z1 appliance was quite satisfied. Wire bending could be reduced during treatment. It was necessary to adjust the crown torque values for lower posterior teeth.


Investigation of Thiocarbamates as Potential Inhibitors of the SARS-CoV-2 Mpro.
In the present study we tested, using the microscale thermophoresis technique, a small library of thionocarbamates, thiolocarbamates, sulfide and disulfide as potential lead compounds for SARS-CoV-2 Mpro drug design. The successfully identified binder is a representative of the thionocarbamates group with a high potential for future modifications aiming for higher affinity and solubility. The experimental analysis was extended by computational studies that show insufficient accuracy of the simplest and widely applied approaches and underline the necessity of applying more advanced methods to properly evaluate the affinity of potential SARS-CoV-2 Mpro binders.


Dengue Dynamics and Vaccine Cost-Effectiveness Analysis in the Philippines.
Dengue is one of the most problematic vector-borne diseases in the Philippines, with an estimated 842,867 cases resulting in medical costs of $345 million U.S. dollars annually. In December 2015, the first dengue vaccine, known as chimeric yellow fever virus-dengue virus tetravalent dengue vaccine, was approved for use in the Philippines and is given to children 9 years of age. To estimate the cost-effectiveness of dengue vaccination in the Philippines, we developed an age-structured model of dengue transmission and vaccination. Using our model, we compared two vaccination scenarios entailing routine vaccination programs both with and without catch-up vaccination. Our results indicate that the higher the cost of vaccination, the less cost-effective the dengue vaccination program. With the current dengue vaccination program that vaccinates children 9 years of age, dengue vaccination is cost-effective for vaccination costs up to $70 from a health-care perspective and up to $75 from a societal perspective. Under a favorable scenario consisting of 1 year of catch-up vaccinations that target children 9-15 years of age, followed by regular vaccination of 9-year-old children, vaccination is cost-effective at costs up to $72 from a health-care perspective and up to $78 from a societal perspective. In general, dengue vaccination is expected to reduce the incidence of both dengue fever and dengue hemorrhagic fever /dengue shock syndrome. Our results demonstrate that even at relatively low vaccine efficacies, age-targeted vaccination may still be cost-effective provided the vaccination cost is sufficiently low.


Value of routine vascular laboratory studies to identify vein graft stenosis.
Thirty-three stenotic lesions were found in 30 vein grafts (17 femoral-popliteal, 13 femoral-tibial) 3 months to 8 years postoperatively--77% appeared within 1 year of surgery. Seventeen (57%) of the patients presented with normal distal pulses, and a similar number were asymptomatic. Only eight (26%) presented with unequivocal clinical evidence of graft stenosis based on decreased pulses and return of ischemic symptoms. Forty percent were completely asymptomatic with normal distal pulses. The mean postoperative ankle systolic pressure index (ASPI) was 0.83 +%- 0.03 (SEM); it fell to 0.57 +/- 0.04 (SEM) when stenosis developed. The peripheral vascular laboratory measurements were the key factor influencing the decision for repeat arteriography in many of these patients and reinforced the need for a repeat arteriogram when the clinical diagnosis was unclear. Early diagnosis of vein graft lesions prior to graft occlusions allowed 24 of 30 of these stenotic grafts to be treated primarily by percutaneous transluminal angioplasty (PTA); 80% remained patent 24 months after PTA. Since most vein graft stenoses can be treated by such a simple, nonoperative technique (PTA), every effort should be made to diagnose and treat lesions prior to graft occlusion. Our experience indicates that frequent vascular laboratory measurements of ASPI are more sensitive then clinical examinations in detecting early vein graft stenosis.


Regulation of lymphocyte proliferation by uterine serpin: interleukin-2 mRNA production, CD25 expression and responsiveness to interleukin-2.
During pregnancy, the endometrium of the ewe secretes large amounts of a progesterone-induced protein of the serpin superfamily of serine proteinase inhibitors called ovine uterine serpin (OvUS). This protein inhibits lymphocyte proliferation in response to concanavalin A (ConA), phytohemagglutinin (PHA), or mixed lymphocyte reaction. The purpose of these experiments was to characterize the mechanism by which OvUS inhibits lymphocyte proliferation. Ovine US caused dose-dependent inhibition of lymphocyte proliferation induced by phorbol myristol acetate (PMA), an activator of protein kinase C. The PHA-induced increase in CD25 expression was inhibited in peripheral blood mononuclear leukocytes (PBML) by OvUS. However, no effect of OvUS on Con A-induced expression of CD25 was observed. Further analysis using two-color flow cytometry revealed that OvUS inhibited ConA-induced expression of CD25 in gammadelta-TCR- cells but not gammadelta-TCR+ cells. Stimulation of PBML for 14 hr with ConA resulted in an increase in steady state amounts of interleukin-2 (IL-2) mRNA that was not inhibited by OvUS. Ovine US was also inhibitory to lymphocyte proliferation induced by human IL-2. Results suggest that OvUS acts to inhibit lymphocyte proliferation by blocking the upregulation of the IL-2 receptor and inhibiting IL-2-mediated events. Lack of an effect of OvUS on ConA-stimulated CD25 expression in gammadelta-TCR+ cells may reflect a different mechanism of activation of these cells or insensitivity to inhibition by OvUS.


Decision-making style, nicotine and caffeine use and dependence.
As therapeutic interventions are being developed utilising telehealth and mobile phones, it is important to understand how substance-dependent individuals will respond to offers of online assistance. The present paper considered the following: (1) how decision-making style is associated with use and dependence upon commonly used stimulants and (2) how it influences behavioural responses to electronic offers of further information about these drugs. An online survey examined patterns of nicotine and caffeine use, administered Severity of Dependence Scales for caffeine and nicotine and assessed decision-making style using the Melbourne Decision Making Questionnaire and mood using the Kessler Distress Scale. Upon completing these scales, the 181 participants with a mean age of 28.14 years were offered further information online. Stimulant dependence was associated with psychological distress. Caffeine dependence was linked to hypervigilance (panic). Decisional self-esteem varied with stimulant dependence and Kessler Distress Scale score. Participants with high decisional self-esteem declined electronic offers of further information. Confidence rather than defensive avoidance was a factor in reducing information-seeking behaviours on the Internet.


High Medium-Term Survivorship of Cruciate-Retaining Total Knee Arthroplasties (110 Knees) for Valgus Deformity.
The main purpose of this article is to evaluate the clinical outcomes and survivorship of cruciate-retaining (CR) knee arthroplasties for valgus deformity. This article is retrospective consecutive series of 110 valgus knees using CR implants with a minimum 2-year follow-up. Deformity correction was achieved using stepwise sequential soft tissue releases (iliotibial band, popliteus tendon, lateral collateral release through sliver femoral condylar osteotomy). Demographic data, range of movement, and degrees of deformity were collected. The Oxford Knee Score (OKS) was used as patients' reported outcome measure at final follow-up. One-hundred and four patients (110 knees) were included (87 females/17 males) with mean age of 68.7 years. Primary diagnosis was osteoarthritis in 85 patients and rheumatoid arthritis in 19 patients. Mean follow-up was 5.5 years (median: 5 years; range: 2-14 years). Preoperative valgus deformity was measured radiographically using the mechanical tibiofemoral angle with a mean 18.6° (standard deviation [SD]: 7.5; range: 11-38°). At final follow-up, mechanical tibiofemoral angle was 3.8° (SD: 1.97; range: 2-8°). A p-value was <0.0001 and mean OKS was 42 (SD: 5.4; range: 36-48) suggesting satisfactory patients' reported outcomes with no implant revision for any cause. CR implants for valgus knees using staged soft tissue releases including sliver condylar osteotomy had excellent medium-term survivorship and satisfactory patient reported outcome measures. The Level of Evidence for this study is IV.


[Effect of localization of pulmonary arterial changes on echocardiographic indices of right heart function and their correlation with exercise capacity: comparison of arterial and thromboembolic pulmonary hypertension].
To assess correlation between exercise tolerance and Doppler-derived indices of right ventricular (RV)--pulmonary arterial coupling in patients with different location of vascular lesions causing pulmonary hypertension (PH). 45 patients: 21 with thromboembolic (TE-PH) and 24 with arterial PH defined as systolic pulmonary arterial pressure (SPAP) > 40 mm Hg. The two groups were similar as far as SPAP (74,8 +/- 15,2 vs 76.5 +/- 14,1 mm Hg, p = ns) and distance covered during 6 minute walk test (339 +/- 116 vs 320 +/- 127, p = ns) are concerned. Flow velocity curve in the RV outflow tract were different in the two groups. Time from onset to peak velocity of ejection (acceleration time, AcT) as well as to midsystolic deceleration were shorter in TE-PH then in arterial PH (59.0 +/- 6.3 vs 68.1 +/- 15.4 msec, p = 0.015 and 123.8 +/- 17.9 vs 137.9 +/- 29.7 msec, p = 0.071, respectively). In the whole studied group as well as in arterial PH significant correlation between exercise tolerance and Doppler-derived indices of RV--pulmonary arterial coupling were found (r = 0.51, p < 0.001 and r = 0.72, p = < 0.001, respectively). Interestingly, no such relationship was found in TE-PH, (r = 0.16, p = ns). In contrast to arterial PH, pressure wave prematurely reflected from the intraluminal thrombi seem to disturb the RV ejection pattern and its correlation with exercise tolerance in TE-PH. Whether progression or effects of treatment on arterial PH can be assessed by monitoring changes in Doppler-derived indices of RV--pulmonary arterial coupling requires further studies.


Choice-option evaluation is preserved in early Huntington and Parkinson's disease.
The ability to choose effectively when faced with potential risks and rewards is fundamental for adaptive survival. The striatum has a well-established role supporting learning from the outcomes of decisions, but it remains unclear whether this structure is also necessary for computing expected value (i.e., advantageousness of potential decisions) when all information is explicitly given. We addressed this question presenting simple monetary gambles, where all decisional parameters were given and outcome feedback was absent, to patients with early Huntington's and Parkinson's disease, taken as complementary models of striatal dysfunction. Behavioural responses and associated times were found to be unaltered. This negative finding suggests that striatal activity may not be essential for decision-making in situations where all information is provided and learning from outcomes is unnecessary.


[Disorders of the neurotransmitter system in multiple sclerosis--possibilities for a therapeutic approach?].
The type and extent of neurological deficits in multiple sclerosis depends on the localisation and size of the lesion and the type of neuropathological pattern of the lesion. The elective demyelinating process (loss of myeline sheath without axonal damage) brings, about a showing and faulty conduction of impulses and thereby a disturbed processing of information. It can finally come to a total (functional, reversible) conduction blockage. Additionally also disturbances in the synaptic transmission may be involved. The occurrence and extent of these disturbances in conduction and transmission depend on definite paristatic factors. Our presented concepts of the "therapeutic model" based on pathophysiological investigations in multiple sclerosis show the tendency towards a "marked symptomatic therapy", which does not however, influence the basis of the disease processes, but rather represents an extremely helpful suppression of symptoms for the patients concerned.


A bioimpedance sensing system for in-vivo cancer tissue identification: Design and preliminary evaluation.
Bioimpedance evaluation can provide useful information for biological tissue characterization and potentially allows the identification of pathological areas within a tissue in-vivo. In this study a new needle-based bioimpedance sensing system was designed and developed to provide such capability considering intra-operative detection of cancerous tissue in the larynx as the primary specific application. The system is small, low-power, fully embedded in a printed circuit board and based on a disposable concentric electrode needle. These characteristics make it appropriate for the envisioned clinical use. In addition, the device operates in real-time and offers functionalities allowing the tuning of its properties to maximize its sensing capabilities for different applications. This includes the possibility to perform bioimpedance measurements using a sweep of excitation frequencies or a single frequency. Here, the first functionality was used to evaluate the instrument's tissue discrimination performance at different frequencies and consequently identify the best frequency for such task. The second functionality was used to evaluate the performance of the system by obtaining repeated measurements on different locations of specific biological tissues. This was done using six different ex-vivo animal tissues and an ex-vivo porcine larynx. The bioimpedance measurements acquired were then investigated in terms of magnitude and phase. Combined analysis of these two terms suggests that it is indeed possible to discriminate between different tissues using the developed instrument. This is a highly motivating preliminary result that demonstrates the potential of the technology and justify the investment of further efforts towards a clinically usable system.


Mutations within the nuclear localization signal of the porcine reproductive and respiratory syndrome virus nucleocapsid protein attenuate virus replication.
Porcine reproductive and respiratory syndrome virus (PRRSV) is an RNA virus replicating in the cytoplasm, but the nucleocapsid (N) protein is specifically localized to the nucleus and nucleolus in virus-infected cells. A 'pat7' motif of 41-PGKK(N/S)KK has previously been identified in the N protein as the functional nuclear localization signal (NLS); however, the biological consequences of N protein nuclear localization are unknown. In the present study, the role of N protein nuclear localization during infection was investigated in pigs using an NLS-null mutant virus. When two lysines at 43 and 44 at the NLS locus were substituted to glycines, the modified NLS with 41-PGGGNKK restricted the N protein to the cytoplasm. This NLS-null mutation was introduced into a full-length infectious cDNA clone of PRRSV. Upon transfection of cells, the NLS-null full-length clone induced cytopathic effects and produced infectious progeny. The NLS-null virus grew to a titer 100-fold lower than that of wild-type virus. To examine the response to NLS-null PRRSV in the natural host, three groups of pigs, consisting of seven animals per group, were intranasally inoculated with wild-type, placebo, or NLS-null virus, and the animals were maintained for 4 weeks. The NLS-null-infected pigs had a significantly shorter mean duration of viremia than wild-type-infected pigs but developed significantly higher titers of neutralizing antibodies. Mutations occurred at the NLS locus in one pig during viremia, and four types of mutations were identified: 41-PGRGNKK, 41-PGGRNKK, and 41-PGRRNKK, and 41-PGKKSKK. Both wild-type and NLS-null viruses persisted in the tonsils for at least 4 weeks, and the NLS-null virus persisting in the tonsils was found to be mutated to either 41-PGRGNKK or 41-PGGRNKK in all pigs. No other mutation was found in the N gene. All types of reversions which occurred during viremia and persistence were able to translocate the mutated N proteins to the nucleus, indicating a strong selection pressure for reversion at the NLS locus of the N protein in vivo. Reversions from NLS-null to functional NLS in the tonsils suggest a possible correlation of viral persistence with N protein nuclear localization. These results show that N protein nuclear localization is non-essential for PRRSV multiplication but may play an important role in viral attenuation and in pathogenesis in vivo.


iCONCUR: informed consent for clinical data and bio-sample use for research.
Implementation of patient preferences for use of electronic health records for research has been traditionally limited to identifiable data. Tiered e-consent for use of de-identified data has traditionally been deemed unnecessary or impractical for implementation in clinical settings. We developed a web-based tiered informed consent tool called informed consent for clinical data and bio-sample use for research (iCONCUR) that honors granular patient preferences for use of electronic health record data in research. We piloted this tool in 4 outpatient clinics of an academic medical center. Of patients offered access to iCONCUR, 394 agreed to participate in this study, among whom 126 patients accessed the website to modify their records according to data category and data recipient. The majority consented to share most of their data and specimens with researchers. Willingness to share was greater among participants from an Human Immunodeficiency Virus (HIV) clinic than those from internal medicine clinics. The number of items declined was higher for for-profit institution recipients. Overall, participants were most willing to share demographics and body measurements and least willing to share family history and financial data. Participants indicated that having granular choices for data sharing was appropriate, and that they liked being informed about who was using their data for what purposes, as well as about outcomes of the research. This study suggests that a tiered electronic informed consent system is a workable solution that respects patient preferences, increases satisfaction, and does not significantly affect participation in research.


DNA barcoding and molecular phylogeny of Dumasia (Fabaceae: Phaseoleae) reveals a cryptic lineage.
Dumasia taxonomy and classification have long been problematic. Species within this genus have few morphological differences and plants without flowers or fruits are difficult to accurately identify. In this study, we evaluated the ability of six DNA barcoding sequences, one nuclear (ITS) and five chloroplast regions (trnH-psbA, matK, rbcL, trnL-trnF, psbB-psbF), to efficiently identify Dumasia species. Most single markers or their combinations identify obvious barcoding gaps between intraspecific and interspecific genetic variation. Most combined analyses including ITS showed good species resolution and identification efficiency. We therefore suggest that ITS alone or a combination of ITS with any cpDNA marker are most suitable for DNA barcoding of Dumasia. The phylogenetic analyses clearly indicated that Dumasia yunnanensis is not monophyletic and is separated as two independent branches, which may result from cryptic differentiation. Our results demonstrate that molecular data can deepen the comprehension of taxonomy of Dumasia and provide an efficient approach for identification of the species.


Thermostable DNA ligase-mediated PCR production of circular plasmid (PPCP) and its application in directed evolution via in situ error-prone PCR.
Polymerase chain reaction (PCR) is a powerful method to produce linear DNA fragments. Here we describe the Tma thermostable DNA ligase-mediated PCR production of circular plasmid (PPCP) and its application in directed evolution via in situ error-prone PCR. In this thermostable DNA ligase-mediated whole-plasmid amplification method, the resultant DNA nick between the 5' end of the PCR primer and the extended newly synthesized DNA 3' end of each PCR cycle is ligated by Tma DNA ligase, resulting in circular plasmid DNA product that can be directly transformed. The template plasmid DNA is eliminated by 'selection marker swapping' upon transformation. When performed under an error-prone condition with Taq DNA polymerase, PPCP allows one-step construction of mutagenesis libraries based on in situ error-prone PCR so that random mutations are introduced into the target gene without altering the expression vector plasmid. A significant difference between PPCP and previously published methods is that PPCP allows exponential amplification of circular DNA. We used this method to create random mutagenesis libraries of a xylanase gene and two cellulase genes. Screening of these libraries resulted in mutant proteins with desired properties, demonstrating the usefulness of in situ error-prone PPCP for creating random mutagenesis libraries for directed evolution.


Protracted, but not acute, hepatitis A virus infection is strongly associated with HLA-DRB*1301, a marker for pediatric autoimmune hepatitis.
HLA alleles are known to be associated with susceptibility to develop autoimmune hepatitis (AH), and hepatitis A virus (HAV) infection is postulated as a putative trigger for AH. We investigated whether HLA may influence the outcome of the HAV infection by studying 67 children with self-limited and 39 children with protracted forms of this infection. HLA typing of the uncomplicated forms showed no significant increase of any HLA class I or II alleles. In contrast, DRB1*1301 was present in 46.1% of the children with protracted forms (vs. 9.8% in healthy controls; relative risk [RR]: 7.6; chi(2) = 33.3; P = 2 x 10(-9)). In uncomplicated hepatitis, 45% developed anti-smooth muscle antibody (SMA)/actin antibodies, but only 1 child had detectable antibodies after 3 months of infection onset. In contrast, after 1 year, 69% of the patients suffering protracted forms had titers of anti-SMA/actin antibodies that ranged between 1:40 and 1:160. Within their follow-up, 2 patients developed a Hashimoto's thyroiditis, but the remaining patients showed no signs of developing autoimmune hepatitis. We conclude that the DRB1*1301 haplotype is strongly associated with the protracted forms of HAV infection and suggest that the infection allows a sustained release of liver self-antigens. However, other still-unknown susceptibility genes are required for the full development of pediatric AH.


Initial Carbon-Carbon Bond Formation during the Early Stages of the Methanol-to-Olefin Process Proven by Zeolite-Trapped Acetate and Methyl Acetate.
Methanol-to-olefin (MTO) catalysis is a very active field of research because there is a wide variety of sometimes conflicting mechanistic proposals. An example is the ongoing discussion on the initial C-C bond formation from methanol during the induction period of the MTO process. By employing a combination of solid-state NMR spectroscopy with UV/Vis diffuse reflectance spectroscopy and mass spectrometry on an active H-SAPO-34 catalyst, we provide spectroscopic evidence for the formation of surface acetate and methyl acetate, as well as dimethoxymethane during the MTO process. As a consequence, new insights in the formation of the first C-C bond are provided, suggesting a direct mechanism may be operative, at least in the early stages of the MTO reaction.


Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial.
Long-term antibiotic therapy is used to prevent exacerbations of COPD but there is uncertainty over whether this reduces airway bacteria. The optimum antibiotic choice remains unknown. We conducted an exploratory trial in stable patients with COPD comparing three antibiotic regimens against placebo. This was a single-centre, single-blind, randomised placebo-controlled trial. Patients aged ≥45 years with COPD, FEV1<80% predicted and chronic productive cough were randomised to receive either moxifloxacin 400 mg daily for 5 days every 4 weeks, doxycycline 100 mg/day, azithromycin 250 mg 3 times a week or one placebo tablet daily for 13 weeks. The primary outcome was the change in total cultured bacterial load in sputum from baseline; secondary outcomes included bacterial load by 16S quantitative PCR (qPCR), sputum inflammation and antibiotic resistance. 99 patients were randomised; 86 completed follow-up, were able to expectorate sputum and were analysed. After adjustment, there was a non-significant reduction in bacterial load of 0.42 log10 cfu/mL (95% CI -0.08 to 0.91, p=0.10) with moxifloxacin, 0.11 (-0.33 to 0.55, p=0.62) with doxycycline and 0.08 (-0.38 to 0.54, p=0.73) with azithromycin from placebo, respectively. There were also no significant changes in bacterial load measured by 16S qPCR or in airway inflammation. More treatment-related adverse events occurred with moxifloxacin. Of note, mean inhibitory concentrations of cultured isolates increased by at least three times over placebo in all treatment arms. Total airway bacterial load did not decrease significantly after 3 months of antibiotic therapy. Large increases in antibiotic resistance were seen in all treatment groups and this has important implications for future studies. clinicaltrials.gov (NCT01398072).


Ultrasound-excited hydrogen radical from NiFe layered double hydroxide for preparation of ultrafine supported Ru nanocatalysts in hydrogen storage of N-ethylcarbazole.
Highly active Ru nanoparticles (Ru NPs) supported on NiFe layered double hydroxide (Ru/NiFe-LDH) are prepared easily using ultrasound-assisted reduction method without chemical reductants and stabilizers. The plentiful hydroxyls on NiFe-LDH are excited into hydrogen radicals (H) under the action of ultrasound for reducing Ru3+ to Ru0. Ru NPs with an average particle size of 1.26 nm highly disperse on the mesopore-like surface of NiFe-LDH, which improve the catalytic performance for N-ethylcarbazole (NEC) hydrogenation. The experimental results show that 5Ru/NiFe-LDH-300-60 exhibits the best catalytic performance with 100% conversion of NEC, 98.88% yield of dodecahydro-N-ethylcarbazole (12H-NEC) and 5.77 wt% mass hydrogen storage capacity under the reaction conditions of 110 ℃, 6 MPa and mRu:mNEC = 0.15 wt% for 80 min. The kinetics study shows that the apparent activation energy is only 25.15 kJ/mol, which is the lowest in the reported literatures. Ru complexes with O-contained groups on NiFe-LDH, improving the catalytic stability in NEC hydrogenation.


Bilateral Orbital Compartment Syndrome Preceding Cerebellar Herniation in Neuropsychiatric Systemic Lupus Erythematosus.
Orbital compartment syndrome poses a significant risk for vision loss if not promptly treated. The authors report a patient with neuropsychiatric systemic lupus erythematosus presenting with bilateral orbital compartment syndrome and rapid decompensation leading to uncal and tonsillar herniation. While extremely rare, bilateral orbital compartment syndrome should prompt consideration of systemic etiologies including neuropsychiatric systemic lupus erythematosus.


The Effect of Selective Laser Trabeculoplasty on Intraocular Pressure in Patients with Dexamethasone Intravitreal Implant-Induced Elevated Intraocular Pressure.
To assess the safety and efficacy of selective laser trabeculoplasty (SLT) for ocular hypertension (OHT) induced by a dexamethasone (DEX) intravitreal implant. We performed a retrospective study of patients who underwent an SLT procedure for ocular hypertension induced by injection of a DEX intravitreal implant. Patients had, at least, one injection of the DEX-implant for symptomatic macular edema. SLT was delivered to 360° of the trabecular meshwork in two sessions. The primary outcome was a decrease in IOP, evaluated at one, three, and six months after the SLT procedure. Twenty-six eyes of 22 patients were included. The mean intraocular pressure (IOP) measured after DEX-implant injection was 25.4 ± 5.4 mmHg, and the mean increase in IOP was 35.8 ± 14.6%. The mean follow-up after SLT was 18.3 ± 7.7 months. After SLT, the mean IOP dropped by 30.9% at one month (16.9 ± 4.5 mmHg, p=0.01), 33.6% at three months (16.0 ± 2.7 mmHg, p < 0.01), and 34.9% at six months (15.6 ± 2.1 mmHg, p < 0.01). Each patient had a minimum follow-up of 6 months after SLT. Eight eyes (31%) received a second DEX-implant injection after the SLT procedure without experiencing an increase in the IOP above 21 mmHg or >20%. No glaucoma surgery was required during the follow-up. The mean number of medications (1.65 ± 1.36) was significantly reduced at one (1.19 ± 1.20, p=0.04), three (0.96 ± 1.03, p < 0.01), and six months (0.77 ± 0.95, p < 0.01) after SLT. SLT is an effective and safe procedure to control OHT following DEX-implant intravitreal injection.


Co-localization of suramin and serum albumin in lysosomes of suramin-treated human colon cancer cells.
Suramin is a polysulfonated compound currently under investigation for the treatment of various types of cancer. Pharmacokinetic studies from clinical trials in humans have shown that most of the circulating drug is associated with serum albumin. The objective of the present study was to investigate the intracellular localization of suramin and serum albumin in human colon cancer cells (HT-29-D4) upon suramin treatment. For this purpose, combined gold labeling and autoradiographic methods were performed on HT-29-D4 cells grown in serum free medium containing both [3H]suramin and colloidal gold-albumin. These morphological experiments demonstrated for the first time that suramin and serum albumin were co-localized in the same cellular compartment (i.e. the lysosomal system) of the suramin-treated HT-29-D4 cells. The albumin-directed targeting of suramin in lysosomes may allow the drug to inhibit the activity of several lysosomal hydrolases, resulting in a lysosomal storage disorder.


Attenuation of cardiovascular responses to tracheal extubation: verapamil versus diltiazem.
We studied the effect of intravenous injection of verapamil (0.05 mg/kg or 0.1 mg/kg) on cardiovascular changes during tracheal extubation and emergence from anesthesia and compared the efficacy of the drug with that of diltiazem (0.2 mg/kg). Eighty patients (ASA physical status I) who were to undergo elective gynecological surgery were randomly assigned to one of four groups (n = 20 each): saline (control), 0.05 mg/kg and 0.1 mg/kg verapamil, and 0.2 mg/kg diltiazem. These medications were given 2 min before tracheal extubation. Anesthesia was maintained with 0.5%-1.8% isoflurane and 60% nitrous oxide in oxygen. Muscle relaxation was achieved with vecuronium. Changes in heart rate (HR) and arterial blood pressure (AP) were measured during and after tracheal extubation. In the control group, the HR and systolic and diastolic AP increased significantly during tracheal extubation. Both calcium channel blockers attenuated the increases in these variables. The inhibitory effect was greatest with verapamil 0.1 mg/kg, while the alleviative effect of verapamil 0.05 mg/kg was inferior to that of diltiazem 0.2 mg/kg. These findings suggest that a bolus injection of verapamil 0.1 mg/kg given 2 min before tracheal extubation is a more effective prophylactic for attenuating the cardiovascular changes associated with extubation than is diltiazem 0.2 mg/kg.


Understanding the experiences of lesbian, bisexual and trans survivors of domestic violence: a qualitative study.
Using a participatory approach, our objectives were to understand community perspectives on domestic violence (DV) in lesbian, bisexual and trans (LBT) communities, and to assess access to and cultural appropriateness ofDVservices for LBT survivors. We used qualitative methods and conducted focus groups and semi-structured interviews with LBT survivors of DV. Nearly all participants reported that the level of awareness regarding DV in their communities was limited. Survivors reported difficulty identifying their partners' behavior as abusive. Isolation was described as central to experiences of abuse, and respondents discussed a variety of isolation tactics specific to LBT communities. Isolation also contributed to difficulty seeking help. Respondents reported that they often did not access mainstream DV services due to concerns about homophobia and transphobia. To address DV in LBT communities respondents pointed to the importance of friendship and community networks, sharing information about queer DV, and holding batterers accountable for their behavior. LBT people face challenges identifying and responding to DV that are specific to their cultural context. Services for LBT DV survivors must be culturally appropriate and accessible. Community based solutions for addressing and preventing DV should be encouraged.


Inhibition of in vitro pituitary gonadotropin secretion by 17 beta-estradiol in the frog Rana pipiens.
We tested the effects of low concentrations of 17 beta-estradiol (E2) on the in vitro pituitary responsiveness to gonadotropin-releasing hormone (GnRH) in frogs (Rana pipiens). We first showed that the pH indicator phenosulfonpthalein (phenol red, PR) at levels normally used in the culture medium did not significantly affect pituitary basal or GnRH-stimulated gonadotropin secretion in male glands, as may occur in mammals. Incubation of male glands with E2 at 10 pg/ml for 24 hr in medium lacking PR did not alter basal follicle-stimulating hormone (FSH) or luteinizing hormone (LH) secretion, but significantly attenuated responsiveness of both gonadotropins to GnRH (0.2, 1, and 5 ng/ml); E2 did not affect responses at the highest dose of GnRH (25 ng/ml). GnRH responsiveness of female pituitaries was also inhibited by E2 at all doses of GnRH; 1 ng/ml E2 had greater effects than did 10 pg/ml. The present results demonstrate that E2 at concentrations commonly found in the circulation of both sexes have a consistent direct inhibitory effect on FSH and LH secretion at the level of the pituitary.


Effects of tannic acid on spontaneous and induced somatic mutations in Drosophila melanogaster.
The effects of tannic acid (TA) alone and in combination with direct acting chemical genotoxins and gamma-radiation were investigated in Somatic Mutation and Recombination Tests (SMARTs) using Drosophila melanogaster. Treatment with TA alone (2.5-15 mmol/l) resulted in a moderate but dose dependent induction of mosaic spots in males and females, indicating that the compound possesses mutagenic and recombinogenic activity. When TA (10 mmol/l) was given simultaneously with MMS, 4-NQO and cis-DDP, a potentiating effect on their mutagenicity was observed in males whereas in females no such increase was measured. The frequency of 4-NQO induced mosaic spots in males was raised more than threefold in presence of TA, for MMS and cis-DDP the enhancement was approximately 2-fold; with gamma-radiation no synergistic effect occurred. The different response in the two sexes indicates that TA preferentially induces gene mutations and deletions but has no enhancing effect on the number of mosaic spots which are formed as a consequence of recombinogenic events.


[Amyotrophic lateral sclerosis--electrophysiologic aspects of its pathophysiology and new therapeutic options].
It is essential to perform electromyography and nerve-conduction studies for diagnosis amyotrophic lateral sclerosis (ALS), but these conventional electrophysiologic methods cannot be used for studies on the mechanism underlying ALS. The recently developed nerve-excitability test can provide new insights into the pathophysiology of this disease. Fasciculation is one of the characteristic features of ALS. Ectopic firing of motor units originates usually from the motor nerve terminals and occasionally from the motor neurons, indicating a widespread abnormality in axonal excitability. ALS is a multifactorial disease in which some genetic abnormalities and environmental factors lead to cell death through a complex cascade, which includes oxidative stress, mitochondrial dysfunction, excitotoxicity, and impaired axonal transport. It is important to elucidate the pathophysiology of axonal excitability in ALS because increased axonal excitability enhances oxidative stress and excitotoxicity, ultimately contributing to motor neuron death. To date, 2 axonal ion channel abnormalities have been identified: (1) increased persistent sodium currents and (2) reduced potassium currents; both abnormalities cause an increase in axonal excitability and are responsible for fasciculations. The results for excitability testing in such patients are characterized by the following features: (1) a prolonged strength-duration time constant, which suggests increased persistent sodium currents; (2) greater threshold changes in depolarizing threshold electrotonus; and (3) greater supernormality, which suggests impaired potassium channels. The altered axonal properties in patients with ALS may provide new insights into the pathophysiology of ALS and have implications for the development of ion channel modulators as therapeutic options for patients with ALS.


Unusual heterogeneity of the 5'-termini of human adenovirus type 2 early region E2 mRNA.
The 5'-terminal structures of human adenovirus type 2 (Ad2) early region 2 (E2) mRNA were investigated. The E2 transcription unit has several interesting properties, including the presence of a TATA-like box that matches the consensus sequence poorly, delayed transcription during early stages of infection, and a switch in promoter recognition late after infection. E2-specific RNA, 5'-labeled in vitro to high specific activity was analyzed. Purified E2 mRNA was digested with RNase A or RNase T1 and the resulting oligonucleotides were resolved by two dimensional paper electrophoresis-homochromatography. Remarkably, as many as sixteen 5'-terminal RNase A oligonucleotides were identified and their sequences were deduced. The most common 5'-termini in the RNase A digest were p(m6)AmCp, p(m6)AmA(m)Cp, pGmA(m)Cp, and p(m6)AmG(m)Cp. Two RNase A oligonucleotides originated from the E4 promoter region, consistent with electron microscopic observations. The sequence encoding these potential initiation sites covered about 90 nucleotides. Eleven of the sequences of the 5'-terminal RNase A oligonucleotides were aligned with the Ad2 DNA sequence in the Ad2 E2 promoter region. If the heterogeneous termini in the E2 promoter region were generated by a process of transcription initiation, their existence cannot be explained by stuttering of RNA polymerase II. This suggests that the transcription of Ad early region 2 has features which differ from those of other Ad2 early gene transcription units. Perhaps this is due to the absence of a conventional TATA box which is believed to position the initiation site. Alternatively, it is conceivable that the E2 promoter represents an alternate class of RNA polymerase II promoters containing different signals with different requirements for activation and/or that an E1A gene product modifies transcription initiation.


Involvement of germ cell apoptosis in the induction of testicular toxicity following hydroxyurea treatment.
The present study investigated the occurrence of apoptotic cell death in the mouse testis at various intervals following the administration of hydroxyurea (HU). The presence of apoptosis was assessed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method and by DNA fragmentation assay using ligation-mediated polymerase chain reaction. Both the incidence of apoptotic cells and the level of DNA fragmentation in the testis increased depending on the HU dose, and they were most apparent at the highest dose (400 mg/kg). The incidence of apoptotic cells in the HU-treated group increased continuously and peaked at 12 h, but then decreased gradually, reaching control levels by 48 h. After HU treatment, TUNEL-positive apoptotic cells increased in the seminiferous epithelium of the tubules, and affected cells were found synchronously in the tubules of animals treated with HU. Spermatogonia and spermatocytes were found to be affected selectively. TUNEL-positive cells were found to be stage-specific and were primarily in stage IV-VI tubules. It has been shown that in vivo HU exposure induced testicular germ cell apoptosis dose dependently in a time- and stage-specific manner, and damaged cells appeared to be eliminated by phagocytosis by neighboring cells. Apoptosis of damaged testicular germ cells is apparently a common response to various testicular toxicants therefore protecting the next generations of germ cells from the damaged cell population.


Increased plasma 8-isoprostane levels in hypertensive subjects: the Tsurugaya Project.
To examine the relationship between 8-isoprostane and blood pressure, we measured plasma 8-isoprostane concentration and home blood pressure levels in an elderly Japanese population. Our study population comprised 569 subjects aged 70 years and over who were not receiving antihypertensive medication. On the basis of their blood pressure values, the participants were classified into three groups: normotensive (home blood pressure <135/85 mmHg), hypertensive (home blood pressure 135/85-160/90 mmHg), and severely hypertensive (home blood pressure > or =160/90 mmHg). The mean plasma 8-isoprostane level in the severely hypertensive group (21.1+/-5.2 pg/ml) was significantly higher than that in the normotensive (20.2+/-4.9 pg/ml) or hypertensive (19.7+/-5.1 pg/ml) group, and this result was unchanged when we adjusted for possible confounding factors such as age, sex, use of vitamin A, C or E supplements, smoking status, drinking status, body mass index, use of non-steroidal anti-inflammatory drugs, history of diabetes, hypercholesterolemia, home heart rate and serum creatinine level. Thus, the level of plasma 8-isoprostane appears to be elevated in older subjects with severe hypertension.


Remodeling the zonula adherens in response to tension and the role of afadin in this response.
Morphogenesis requires dynamic coordination between cell-cell adhesion and the cytoskeleton to allow cells to change shape and move without losing tissue integrity. We used genetic tools and superresolution microscopy in a simple model epithelial cell line to define how the molecular architecture of cell-cell zonula adherens (ZA) is modified in response to elevated contractility, and how these cells maintain tissue integrity. We previously found that depleting zonula occludens 1 (ZO-1) family proteins in MDCK cells induces a highly organized contractile actomyosin array at the ZA. We find that ZO knockdown elevates contractility via a Shroom3/Rho-associated, coiled-coil containing protein kinase (ROCK) pathway. Our data suggest that each bicellular border is an independent contractile unit, with actin cables anchored end-on to cadherin complexes at tricellular junctions. Cells respond to elevated contractility by increasing junctional afadin. Although ZO/afadin knockdown did not prevent contractile array assembly, it dramatically altered cell shape and barrier function in response to elevated contractility. We propose that afadin acts as a robust protein scaffold that maintains ZA architecture at tricellular junctions.


Linking systemic arterial stiffness among adolescents to adverse childhood experiences.
Adverse childhood experiences (ACEs) have been linked with cardiovascular disease and early mortality among adults. Most research examines this relationship retrospectively. Examining the association between ACEs and children's cardiovascular health is required to understand the time course of this association. We examined the relationship between ACEs exposure and ECG-to-toe pulse wave velocity (PWV), a measure of systemic arterial stiffness that is strongly related to cardiovascular mortality among adults. PWV (distance/transit time; m/s) was calculated using transit times from the ECG R-wave to the pulse wave contour at the toe. Transit times were collected over 15 heartbeats and the distance from the sternal notch to the left middle toe was used. A total of 221 children (119 females) aged 10-14 years participated in data collection of PWV, hemodynamic and anthropometric variables. Parents of these children completed a modified inventory of ACEs taken from the Childhood Trust Events Survey. Multivariable regression assessed the relationship between ACEs group (<4 ACEs versus ≥4 ACEs) and PWV. Analyses yielded an ACEs group by sex interaction, with males who experienced four or more ACEs having higher PWV (p<0.01). This association was independent of hemodynamic, anthropometric and sociodemographic variables (R(2)=0.346; p<0.01). Four or more ACEs is associated with greater arterial stiffness in male children aged 10-14 years. Addressing stress and trauma exposure in childhood is an important target for public health interventions to reduce early cardiovascular risk.


A combined molecular dynamic simulation, DFT calculations, and experimental study of the eriochrome black T dye adsorption onto chitosan in aqueous solutions.
This study aims to evaluate and understand the adsorption of eriochrome black T (EB) by chitosan extracted from local shrimp shells under different experimental conditions. Chitosan samples were characterized by XRD, SEM, and FTIR. Experimental results indicate that the process was pH-dependent with a high adsorption capacity in acidic medium. The adsorption was rapid and kinetic data were suitably correlated to the pseudo-second-order kinetic model. EB molecules were adsorbed on monolayer according to the Langmuir model with an adsorption capacity of 162.3 mg/g. On the other hand, it should be noted that calculated quantum chemical parameters support the experimentally obtained results. The interaction energies calculated for (molecule/chitosan) complexes were in the order of H2EB- > HEB2- (O38) > HEB2- (O48) > EB > H3EB > EB3-, which means that the best and possible adsorption process can take place with H2EB- form. The molecular dynamics (MD) approach was performed to illuminate the nature of the relationship between the EB and the chitosan (110) surface. It was found that the chitosan (110) surface adsorbs EB molecule in a nearby parallel orientation. The higher negative adsorption energy determined for the H2EB- implies that the adsorption mechanism is the typical chemisorption.


Role of capsule endoscopy in the management of patients with obscure gastrointestinal bleeding.
The recent emergence of capsule endoscopy has entailed a relevant diagnostic imaging advance for gastrointestinal conditions, especially those involving the small bowel. Gastrointestinal haemorrhage of obscure origin is probably the most widely accepted indication for this new technique, and promising results have been reported from series extant to date. In view of data available on this new modality, and looking forward to having wide, well designed studies fr corroboration, this paper suggests a tentative algorithm for the management of this patient group.


Opioid Overdose Deaths Among Formerly Incarcerated Persons and the General Population: North Carolina, 2000‒2018.
Objectives. To compare opioid overdose death (OOD) rates among formerly incarcerated persons (FIPs) from 2016 to 2018 with the North Carolina population and with OOD rates from 2000 to 2015. Methods. We performed a retrospective cohort study of 259 861 North Carolina FIPs from 2000 to 2018 linked with North Carolina death records. We used indirectly standardized OOD mortality rates and ratios and present 95% confidence intervals (CIs). Results. From 2017 to 2018, the OOD rates in the North Carolina general population decreased by 10.1% but increased by 32% among FIPs. During 2016 to 2018, the highest substance-specific OOD rate among FIPs was attributable to synthetic narcotics (mainly fentanyl and its analogs), while OOD rates for other opioids were half or less than that from synthetic narcotics. During 2016 to 2018, the OOD risk for FIPs from synthetic narcotics was 50.3 (95% CI = 30.9, 69.6), 20.2 (95% CI = 17.3, 23.2), and 18.2 (95% CI = 15.9, 20.5) times as high as that for the North Carolina population at 2-week, 1-year, and complete follow-up after release, respectively. Conclusions. While nationwide OOD rates declined from 2017 to 2018, OOD rates among North Carolina FIPs increased by about a third, largely from fentanyl and its analogs. (Am J Public Health. 2022;112(2):300-303. https://doi.org/10.2105/AJPH.2021.306621).


Regulation of Brassinosteroid Homeostasis in Higher Plants.
Brassinosteroids (BRs) are known as one of the major classes of phytohormones essential for various processes during normal plant growth, development, and adaptations to biotic and abiotic stresses. Significant progress has been achieved on revealing mechanisms regulating BR biosynthesis, catabolism, and signaling in many crops and in model plant Arabidopsis. It is known that BRs control plant growth and development in a dosage-dependent manner. Maintenance of BR homeostasis is therefore critical for optimal functions of BRs. In this review, updated discoveries on mechanisms controlling BR homeostasis in higher plants in response to internal and external cues are discussed.


[Prevalence of internet addiction and the related factors in middle school students in Guangzhou].
To study the status of and the factors contributing to Internet addiction among middle school students in Guangzhou. Cluster sampling method was used to recruit an urban middle school, a rural junior middle school and a rural senior high school to conduct the survey with the stressful life event questionnaire, the trait-oriented coping styles questionnaire and the Internet Addiction Test. The majority of respondents were classified as normal users of the Internet (n=1392, 89.2%), with 158 (10.2%) moderately and 10 (0.6%) severely addicted to the Internet. Fifty-eight students had never used the Internet. There were significant differences in gender, the father's education, the 4 dimensions of the stressful life event questionnaire and the coping styles between students with and without Internet addiction. Binary logistic analysis showed that the factors contributing to Internet addiction included passive coping styles, male gender and stressful life event experienced in family and interpersonal communication. The incidence of Internet addiction is high among middle school students in Guangzhou. Male students with stressful life events in family and interpersonal communication, poor education on the part of the father, and frequent use of negative coping styles are more likely to develop Internet addiction.


Heparin inhibits the attachment and growth of Balb/c-3T3 fibroblasts on collagen substrata.
In investigating the role of cell-extracellular matrix interactions in cell adhesion and growth control, the effects of heparin on cell-collagen interactions were examined. Exponentially growing Balb/c-3T3 fibroblasts were radiolabelled with 3H-thymidine and detached from tissue culture surfaces using EDTA, and cell attachment to various types of collagen substrata was assayed in the presence or absence of heparin or other glycosaminoglycans (GAGs) or dextran sulfate (40 K). Cells attached readily (70-90%) to films of types I and V, but not to type III collagen. The number of cells bound to types I and V collagen films was inhibited by 10-50% when heparin was present from 0.1-100 micrograms/ml. Cell-collagen attachment was also inhibited by dextran sulfate, and to a lesser extent by dermatan sulfate, but chondroitin sulfates A and C and hyaluronic acid showed no effect. Heparin was active even at early time points in the adhesion assay, suggesting it may disrupt cell-collagen attachment. To study the effects of heparin in modulating cell growth on collagen, growth arrested cells cultured on type I collagen films were serum stimulated in the presence of heparin or other GAGs for 3 days. Growth was inhibited (greater than 40%) only by heparin and dextran sulfate. Interaction of heparin fragments (Mr less than or equal to 6KD) with type I collagen was analyzed by affinity co-electrophoresis (Lee and Lander, 1991) and showed higher affinity heparin binding to native as compared with denatured collagen. These data suggest that sites within native collagen may mediate Balb cell-collagen and heparin-collagen interactions, and such interactions may be relevant towards understanding heparin's antiproliferative activity in vivo and in vitro.


Predicting brain concentrations of drug using positron emission tomography and venous input: modeling of arterial-venous concentration differences.
In a positron emission tomography (PET) study, the concentrations of the labeled drug (radiotracer) are often different in arterial and venous plasma, especially immediately following administration. In a PET study, the transfer of the drug from plasma to brain is usually described using arterial plasma concentrations, whereas venous sampling is standard in clinical pharmacokinetic studies of new drug candidates. The purpose of the study was to demonstrate the modeling of brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform (T(av)). Brain kinetics (C(br)) was described as the convolution of arterial plasma kinetics (C(ar)) with an arterial-to-brain impulse response function (T(br)). The arterial plasma kinetics was obtained as venous plasma kinetics (C(ve)) convolved with the inverse of the arterio-venous transform (T(av) (-1)). The brain kinetics was then given by C(br)=C(ve)*T(av) (-1)*T(br). This concept was applied on data from a clinical PET study in which both arterial and venous plasma sampling was done in parallel to PET measurement of brain drug kinetics. The predictions of the brain kinetics based on an arterial input were compared with predictions using a venous input with and without an arterio-venous transform. The venous based models for brain distribution, including a biexponential arterio-venous transform, performed comparably to models based on arterial data and better than venous based models without the transform. It was also shown that three different brain regions with different shaped concentration curves could be modeled with a common arterio-venous transform together with an individual brain distribution model. We demonstrated the feasibility of modeling brain drug kinetics based on PET data in combination with venous blood sampling and an arterio-venous transform. Such a model can in turn be used for the calculation of brain kinetics resulting from an arbitrary administration mode by applying this model on venous plasma pharmacokinetics. This would be an important advantage in the development of drugs acting in the brain, and in other circumstances when the effect is likely to be closer related to the brain than the plasma concentration.


Olmesartan niosomes ameliorates the Indomethacin-induced gastric ulcer in rats: Insights on MAPK and Nrf2/HO-1 signaling pathway.
Gastric ulcer is a continuous worldwide threat that inquires protective agents. Olmesartan (OLM) has potent anti-oxidant and anti-inflammatory characters, yet having limited bioavailability. We targeted the gastro-protective potential and probable mechanism of OLM and its niosomal form against indomethacin (IND) induced-gastric ulcer in rats. we prepared OLM niosomes (OLM-NIO) with different surfactant: cholesterol molar ratios. We evaluated particle size, zeta-potential, polydispersity, and entrapment efficiency. In-vitro release study, Fourier transform infrared spectroscopy, differential scanning calorimetry, and transmission electron microscopy were performed for selected niosomes. In-vivo, we used oral Omeprazole (30 mg/kg), OLM or OLM-NIO (10 mg/kg) for 3 days before IND (25 mg/kg) ingestion. We assessed gastric lesions, oxidative and inflammatory markers. OLM-NIO prepared with span 60:cholesterol ratio (1:1) showed high entrapment efficiency 93 ± 2%, small particle size 159.3 ± 6.8 nm, low polydispersity 0.229 ± 0.009, and high zeta-potential -35.3 ± 1.2 mV, with sustained release mechanism by release data. In-vivo macroscopical and histological results showed gastro-protective effects of OLM pretreatment, which improved oxidative stress parameters and enhanced the gastric mucosal cyclooxygenase-1 (COX-1) and prostaglandin E2 (PGE2) contents. OLM pretreatment suppressed interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) contents and translocation of p38 mitogen-activated protein kinase (p38-MAPK). Besides, OLM substantially promoted the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) protective pathway. OLM-NIO furtherly improved all previous outcomes. We explored OLM anti-ulcerative effects, implicating oxidative stress and inflammation improvement, mediated by the Nrf2/HO-1 signaling pathway and p38-MAPK translocation. Meanwhile, the more bioavailable OLM-NIO achieved better gastro-protective effects compared to conventional OLM form.


Proteomics changes in adhesion molecules: a driving force for vascular smooth muscle cell phenotypic switch.
Vascular smooth muscle cells (VSMCs), if activated by growth factors as a consequence of vessel injuries, acquire the ability to proliferate and migrate thus contributing to the formation of neointima and atherosclerotic plaque. In this study, a gel-free and label-free proteomic approach was proposed to highlight factors modulated during VSMC activation. Twenty proteins, differentially expressed between quiescent and activated cells, were identified. A constellation of elements, that move together and are closely and functionally related, was visualized. The great majority of them are involved in cell migration and in adhesion formation, suggesting a pivotal role of these protein complexes on the phenotypic modulation. This study represents a first step to ascertain the precise actors of cell activation, their roles and interactions.


R. v. Morgentaler, 28 January 1988.
The appellants, physicians who had set up a clinic to perform abortions, were charged with conspiracy with intent to commit abortions contrary to Section 251(4) of the Canadian Criminal Code. Section 251(4) prohibits abortions being performed upon women who have not obtained a certificate from a therapeutic abortion committee of an accredited or approved hospital. On appeal of a lower court decision ordering a new trial for the appellants after a jury had acquitted them, the Supreme Court held (two justices dissenting) that conditioning the performance of an abortion upon certification by an abortion committee violated the right of security of the person contained in Section 7 of the Canadian Charter of Rights and Freedoms. The five justices in the majority wrote three separate opinions which pointed out, variously, that Section 251 imposed unnecessary procedures and restrictions, restricted access to hospitals, caused delays, resulted in physical, psychological and emotional risk to the woman, and forced some women to carry a fetus to term against their will.


Use of Patient-reported Outcome Measures in Pediatric Orthopaedic Literature.
Patient-reported outcomes are increasingly used as primary measures of success and impact of health care services. There is no current consensus on the efficacy of functional health status (FHS) or health-related quality of life (HRQoL) evaluation in pediatric orthopaedic surgery. The purpose of this study was to quantify and characterize the use of such patient-reported outcomes in the pediatric orthopaedic literature over the last several years. A cross-sectional review of 6 orthopaedic journals-Journal of Bone and Joint Surgery, Bone and Joint Journal, Spine, Journal of Pediatric Orthopaedics A, Journal of Pediatric Orthopaedics B, and Journal of Children's Orthopaedics, was conducted by 2 independent reviewers. Articles were analyzed for patient-reported outcome usage over the time periods of 2000 to 2001, 2007 to 2008, and 2012 to 2013. A total of 189 articles (2.7%) were identified that used patient-reported outcomes in pediatric populations. A total of 71 (37.5%) of these articles used FHS tools, 95 (50.3%) used HRQoL tools and 23 (12.2%) used a combination of both. The use of FHS and HRQoL tools has increased over time, with 8 FHS and 2 HRQoL publications in the year 2000 expanding to 19 and 28, respectively, in 2013. Journal of Bone and Joint Surgery American Volume published both the highest total number of articles containing patient-reported outcome measures (57/189) and the highest number of articles specifically using FHS measures (28/71). Spine published the highest number of articles using HRQoL measures (43/95). The most frequently used FHS and HRQoL tools were the Lysholm knee score and the Scoliosis Research Society tools, respectively. Only 33/73 identified patient-based outcome instruments had been validated in a pediatric population. Patient-reported outcome measures are underutilized in the pediatric orthopaedic literature. Instruments are frequently used that are neither designed nor validated for a pediatric population. Consequently, further work is necessary to develop, validate, and implement pediatric-specific FHS and HRQoL tools to fully understand the impact of a clinical intervention on all aspects of patient quality of life.


Economic evaluation in long-term clinical trials.
Economic endpoints have been increasingly included in long-term clinical trials, but they pose several methodologic challenges, including how best to collect, describe, analyse and interpret medical cost data. Cost of care can be measured by converting billed charges, performing detailed micro-costing studies, or by measuring use of key resources and assigning cost weights to each resource. The latter method is most commonly used, with cost weights based either on empirical regression models or administratively determined reimbursement rates. In long-term studies, monetary units should be adjusted to reflect cost inflation and discounting. The temporal pattern of accumulating costs can be described using a modification of the Kaplan-Meier curve. Regression analyses to evaluate factors associated with cost are best performed on the log of costs due to their typically skewed distribution.Cost-effectiveness analysis attempts to measure the value of a new therapy by calculating the difference in cost between the new therapy and the standard therapy, divided by the difference in benefit between the new therapy and the standard therapy. The cost-effectiveness ratio based on the results of a randomized trial may change substantially with longer follow-up intervals, particularly for therapies that are initially expensive but eventually improve survival. A model that projects long-term patterns of cost and survival expected beyond the end of completed follow-up can provide an important perspective in the setting of limited trial duration.


"Do not resuscitate" (DNR) orders and the anesthesiologist: a survey.
Anesthesiologists were surveyed to determine their experience and opinions regarding "Do Not Resuscitate" (DNR) orders in the perioperative period. Four hundred fifteen questionnaires were mailed and 193 (47%) were returned. One hundred sixty-one (87%) of 186 respondents had been requested to provide (and more than two-thirds had provided) monitored anesthesia care, regional anesthesia, or general anesthesia to a patient with a DNR order. Almost two-thirds of the respondents assume DNR suspension in the perioperative period and only half discuss this assumption with the patient/guardian. Less than 50% of respondents would require DNR suspension for a palliative procedure contrasted with > 60% for an elective procedure. After agreeing to a patient's decision to retain their DNR status, > 67%, > 58%, < 49%, and < 33% would utilize positive pressure ventilation with a mask, vasoactive drugs, endotracheal intubation, or defibrillation, respectively, in the event of a cardiopulmonary arrest in the perioperative period. These findings suggest much ambiguity regarding DNR orders in the perioperative period. Further discussion among physicians and patients is warranted.


Blocking effect of bepridil on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes.
We examined the effect of bepridil, a class IV antiarrhythmic drug, on Na+/Ca2+ exchange current (I(NCX)) in single guinea pig cardiac ventricular cells using the whole-cell voltage clamp technique. I(NCX) was recorded by ramp pulses from the holding potential of -60 mV in the presence of 140 mM Na+ and 1 mM Ca2+ in the external solution and 20 mM Na+ and 119 nM free Ca2+ (7 mM Ca2+ and 20 mM BAPTA) in the internal solution. Bepridil suppressed I(NCX) in a concentration-dependent manner. The IC50 value was 8.1 microM with a Hill coefficient of 0.8. Intracellular treatment with trypsin via the pipette solution attenuated the blocking effect of bepridil, suggesting that the inhibitory site is on the cytosolic side of the Na+/Ca2+ exchanger. In the absence of albumin in the external solution, 10 microM bepridil inhibited I(NCX) by 46+/-7% (n = 8), while bepridil blocked it by 28+/-8% (n = 6) in the presence of albumin. Bepridil inhibited I(NCX) in a supra-therapeutic concentration range.


Comparison of midazolam and diazepam as co-induction agents with ketamine for anaesthesia in sedated ponies undergoing field castration.
To compare intravenous (IV) midazolam and diazepam administered with ketamine for induction of anaesthesia in ponies, already sedated with detomidine, undergoing field castration. Prospective, randomised, 'blinded', clinical study. Twenty Welsh pony yearlings. After IV injection of detomidine (20 μg kg(-1) ) and phenylbutazone (4.4 mg kg(-1) ) ponies were allocated to receive either IV midazolam (group M) or diazepam (group D) (both 0.06 mg kg(-1) ) with ketamine (2.2 mg kg(-1) ) for induction of anaesthesia. Using simple descriptive scales, quality of sedation, induction, endotracheal intubation, surgical conditions and recovery were scored by observers blinded to treatment. Time from sedation to induction of anaesthesia, IV injection to lateral recumbency, induction to start of surgery, induction to first head lift and to standing, and total surgical time were measured. Cardiorespiratory function was assessed every 5 minutes. Time, number and total quantity of additional IV ketamine as well as any adverse effects were documented. Data were tested for normality and analysed using two-way anova with Bonferroni post hoc tests, unpaired t-tests and Mann-Whitney U tests as appropriate. Significance was set at p < 0.05. There were no significant group differences in any of the measured variables except bodyweight (mean ± SD: group M 163 ± 12 kg; group D 150 ± 7 kg; p = 0.01). One pony in group M required ketamine 15 minutes after induction of anaesthesia. Surgical conditions were good in all cases; time from induction to standing was 50 ± 11 minutes in group M and 48 ± 12 minutes in group D. There were no adverse effects. Recoveries were uneventful with minimal ataxia. Midazolam and diazepam at 0.06 mg kg(-1) can be used interchangeably in combination with ketamine for IV induction of short term anaesthesia in ponies.


The Involvement of Mig1 from Xanthophyllomyces dendrorhous in Catabolic Repression: An Active Mechanism Contributing to the Regulation of Carotenoid Production.
The red yeast X. dendrorhous is one of the few natural sources of astaxanthin, a carotenoid used in aquaculture for salmonid fish pigmentation and in the cosmetic and pharmaceutical industries for its antioxidant properties. Genetic control of carotenogenesis is well characterized in this yeast; however, little is known about the regulation of the carotenogenesis process. Several lines of evidence have suggested that carotenogenesis is regulated by catabolic repression, and the aim of this work was to identify and functionally characterize the X. dendrorhous MIG1 gene encoding the catabolic repressor Mig1, which mediates transcriptional glucose-dependent repression in other yeasts and fungi. The identified gene encodes a protein of 863 amino acids that demonstrates the characteristic conserved features of Mig1 proteins, and binds in vitro to DNA fragments containing Mig1 boxes. Gene functionality was demonstrated by heterologous complementation in a S. cerevisiae mig1- strain; several aspects of catabolic repression were restored by the X. dendrorhous MIG1 gene. Additionally, a X. dendrorhous mig1- mutant was constructed and demonstrated a higher carotenoid content than the wild-type strain. Most important, the mig1- mutation alleviated the glucose-mediated repression of carotenogenesis in X. dendrorhous: the addition of glucose to mig1- and wild-type cultures promoted the growth of both strains, but carotenoid synthesis was observed only in the mutant strain. Transcriptomic and RT-qPCR analyses revealed that several genes were differentially expressed between X. dendrorhous mig1- and the wild-type strain when cultured with glucose as the sole carbon source. The results obtained in this study demonstrate that catabolic repression in X. dendrorhous is an active process in which the identified MIG1 gene product plays a central role in the regulation of several biological processes, including carotenogenesis.


HITM-SURE: Hepatic immunotherapy for metastases phase Ib anti-CEA CAR-T study utilizing pressure enabled drug delivery.
In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.


Clinical and laboratory predictors of chronic immune thrombocytopenia in children: a systematic review and meta-analysis.
Childhood immune thrombocytopenia (ITP) is a rare autoimmune bleeding disorder. Most children recover within 6 to 12 months, but individual course is difficult to predict. We performed a systematic review and meta-analysis to identify predictors of chronic ITP. We found 1399 articles; after critical appraisal, 54 studies were included. The following predictors of chronic ITP in children, assessed in at least 3 studies, have been identified: female gender (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.04-1.31), older age at presentation (age ≥11 years; OR 2.47, 95% CI 1.94-3.15), no preceding infection or vaccination (OR 3.08, 95 CI 2.19-4.32), insidious onset (OR 11.27, 95% CI 6.27-20.27), higher platelet counts at presentation (≥20 × 10(9)/L: OR 2.15, 95% CI 1.63-2.83), presence of antinuclear antibodies (OR 2.87, 95% 1.57-5.24), and treatment with a combination of methylprednisolone and intravenous immunoglobulin (OR 2.67, 95% CI 1.44-4.96). Children with mucosal bleeding at diagnosis or treatment with intravenous immunoglobulin alone developed chronic ITP less often (OR 0.39, 95% CI 0.28-0.54 and OR 0.71, 95% CI 0.52-0.97, respectively). The protective effect of intravenous immunoglobulin is remarkable and needs confirmation in prospective randomized trials as well as future laboratory studies to elucidate the mechanism of this effect.


A severe case of oculo-ectodermal syndrome?
We describe a child with features of the oculo-ectodermal syndrome, who in addition to the cardinal manifestations of cutis aplasia and epibulbar dermoid had a number of other features. These include laryngomalacia, an anterior anus, microcephaly and significant developmental delay. The parents are of New Zealand Maori ancestry and are related as half first cousins, raising the possibility that this syndrome may be recessively inherited.


Adipose-derived mesenchymal stem cells stereotactic transplantation alleviate brain edema from intracerebral hemorrhage.
Adipose-derived mesenchymal stromal cells (ADSCs) exhibited high potential in tissue repair and regeneration, and it has been proved that ADSCs could protect brain cells from apoptosis and maintaining blood-brain barrier stability after cerebral vascular disease. In this study, we evaluated the therapeutic potential and mechanism of ADSCs stereotactic transplantation in intracerebral hemorrhage (ICH) mice model and hemin-treated astrocytes. Mice were divided into three groups: sham group, ICH + PBS group, and ICH + ADSC group. Mice in ICH + ADSC group received ADSCs cell suspension stereotactic transplantation into the area beside the bleeding region. Astrocytes were divided into three groups: control group, hemin group, and hemin + ADSC group. Astrocytes in hemin + ADSC group were cultured in ADSCs-astrocyte no-contact coculture system and treated with 30 μM hemin solution. The results showed that ADSCs stereotactic transplantation improved functional outcomes and reduced cell apoptosis after ICH. Moreover, ADSCs stereotactic transplantation could alleviate brain edema and inflammation and AQP4 protein expression contributed to the alleviation of brain edema. In addition, mitogen-activated protein kinase (MAPK) pathways, including p38/MAPK pathway and c-Jun N-terminal kinase pathway, were involved in AQP4 modulation by ADSCs transplantation in ICH. In conclusion, ADSCs transplantation could alleviate the nervous tissue injury, reduce cell apoptosis, and relieve brain edema in ICH. And the edema regulation effect of ADSCs transplantation is associated with inhibition of inflammation and AQP4 protein expression.


Stimulation of mu and delta-Opiate Receptors and Tolerance of Isolated Heart to Oxidative Stress: the Role of NO-Synthase.
Preliminary intravenous injection of delta-opiate receptor (OR) agonists DSLET (0.1 mg/kg) or DTLET (0.1 mg/kg) increased tolerance of isolated perfused myocardium to damage by oxidative stress simulated in vivo with FeSO4 + ascorbic acid. This manifested itself by a decreased level of creatine phosphokinase (CPK) in the perfusate flowing out of the heart during the oxidative exposure. The preliminary systemic injection of mu-agonists DAMGO (0.1 mg/kg) or DALDA (0.1 mg/kg) failed to affect the release of CPK from the myocardium. The cardioprotective effect of the delta-agonist DSLET was completely abolished by preliminary intravenous injection of the delta-OR antagonist ICI 174,864 (2.5 mg/kg). The intravenous injection of the NO-synthase inhibitor L-NAME (50 mg/kg) also completely abolished the cardioprotective effect of delta-OR stimulation. The preliminary injection of DSLET but not of DAMGO prevented an increase in the level of diene conjugates and a decrease in the activity of superoxide dismutase (SOD) in the isolated myocardium tissue. Thus, the in vivo stimulation of delta-OR increased the tolerance of the heart to oxidative stress through activation of NO-synthase and SOD.


Smooth pursuit eye movement preferentially facilitates motor-evoked potential elicited by anterior-posterior current in the brain.
Neural interaction between the eye and hand movement centers must be a critical part of the mechanism underlying eye-hand coordination. One of the previous findings supporting this view is smooth pursuit eye movement-induced suppression of motor-evoked potential (MEP) in the hand muscles. The purpose of this study was to determine which descending volleys contributing to MEP are preferentially modulated by smooth pursuit eye movement. MEP in the first dorsal interosseous muscle was elicited by different directions of current in the brain during the steady-state phase of smooth pursuit eye movement. Smooth pursuit eye movement facilitated MEP elicited by anterior-posterior (AP) current, but this effect was not seen in MEP elicited by lateromedial or posterior-anterior current. Latency of MEP elicited by AP current was significantly longer than latencies of MEPs elicited by other directions of current, indicating that AP current in the brain predominantly elicited later I-waves. We conclude that smooth pursuit eye movement in the steady-state phase preferentially facilitates MEP predominantly elicited by later I-waves generated by AP current in the brain.


Intestinal commensal bacteria mediate lung mucosal immunity and promote resistance of newborn mice to infection.
Immature mucosal defenses contribute to increased susceptibility of newborn infants to pathogens. Sparse knowledge of age-dependent changes in mucosal immunity has hampered improvements in neonatal morbidity because of infections. We report that exposure of neonatal mice to commensal bacteria immediately after birth is required for a robust host defense against bacterial pneumonia, the leading cause of death in newborn infants. This crucial window was characterized by an abrupt influx of interleukin-22 (IL-22)-producing group 3 innate lymphoid cells (IL-22+ILC3) into the lungs of newborn mice. This influx was dependent on sensing of commensal bacteria by intestinal mucosal dendritic cells. Disruption of postnatal commensal colonization or selective depletion of dendritic cells interrupted the migratory program of lung IL-22+ILC3 and made the newborn mice more susceptible to pneumonia, which was reversed by transfer of commensal bacteria after birth. Thus, the resistance of newborn mice to pneumonia relied on commensal bacteria-directed ILC3 influx into the lungs, which mediated IL-22-dependent host resistance to pneumonia during this developmental window. These data establish that postnatal colonization by intestinal commensal bacteria is pivotal in the development of the lung defenses of newborns.


Intracellular Assembly of Nuclear-Targeted Gold Nanosphere Enables Selective Plasmonic Photothermal Therapy of Cancer by Shifting Their Absorption Wavelength toward Near-Infrared Region.
Despite the important applications of near-infrared (NIR) absorbing nanomaterials in plasmonic photothermal therapy (PPT), their high yield synthesis and nonspecific heating during the active- and passive-targeted cancer therapeutic strategies remain challenging. In the present work, we systematically demonstrate that in situ aggregation of typical non-NIR absorbing plasmonic nanoparticles at the nuclear region of the cells could translate them into an effective NIR photoabsorber in plasmonic photothermal therapy of cancer due to a significant shift of the plasmonic absorption band to the NIR region. We evaluated the potential of nuclear-targeted AuNSs as photoabsorber at various stages of endocytosis by virtue of their inherent in situ assembling capabilities at the nuclear region of the cells, which has been considered as one of the most thermolabile structures within the cells, to selectively destruct cancer cells with minimal damage to healthy cells. Various plasmonic nanoparticles such as rods and cubes have been exploited to elucidate the role of plasmonic field coupling in assembled nanoparticles and their subsequent killing efficiency. The NIR absorbing capabilities of aggregated AuNSs have been further demonstrated both experimentally and theoretically using discrete dipolar approximation (DDA) techniques, which was in concordance with the observed results in plasmonic photothermal therapeutic studies. While the current work was able to demonstrate the utility of non-NIR absorbing plasmonic nanoparticles as a potential alternative for plasmonic photothermal therapy by inducing localized plasmonic heating at the nuclear region of the cells, these findings could potentially open up new possibilities in developing more efficient nanoparticles for efficient cancer treatment modalities.


Risk Factors for Canalicular Injury After Mohs Micrographic Surgery.
There is a paucity of literature describing risk factors for canalicular injury (CI) during periocular Mohs micrographic surgery (Mohs). This study aimed to determine factors associated with CI after Mohs. This information may inform patient counseling and surgical planning. This case-control study compared subjects with canalicular injury after Mohs with subjects requiring ophthalmologic Mohs repair without canalicular injury. All subjects who had CI after Mohs were included in the control group. CI from other causes were excluded. Basal cell carcinoma was the most common etiologic tumor (p < .00001). Canalicular injury was associated with infiltrative, morpheaform, and/or micronodular-type basal cell carcinoma. Initial tumor location involving the medial canthus was not statistically different between cases and controls (32% vs 17%, p = .22). Having a final defect involving the medial canthus region was more likely in cases versus controls (55% vs 26%, p = .01952). Although most final defects involved the medial canthal region, a substantial number of tumors resulting in CI did not initially seem to involve the medial canthus. Surgeons cannot rely simply on anatomical location when assessing risk for CI, and anticipation of need for canalicular reconstruction is challenging.


Ultrasonographic evaluation of relative gastrointestinal layer thickness in cats without clinical evidence of gastrointestinal tract disease.
The objectives of this study were (1) to measure normal thickness values of the muscularis, submucosal, mucosal and serosal layers in each gastrointestinal (GI) segment (gastric fundus, body and pyloric antrum; duodenum; jejunum; ileum; colon), and (2) to calculate a ratio of muscularis and mucosal layer thickness to aortic diameter measured at the level of the celiac artery (Musc:Ao and Muc:Ao) in each GI segment in a sample of healthy cats. Ultrasonographic examination of the GI tract was performed, and measurements of the individual layers in each GI segment were obtained in 38 healthy cats without clinical evidence of disease. The muscularis layer was significantly thickest in the ileum, compared with other segments, and it was thicker than the submucosa in all segments except the colon. The mucosa was the thickest layer in all segments, and was thickest in the duodenum and ileum. Measurements of the submucosal and serosal layers were not significantly different between all segments. Musc:Ao and Muc:Ao in each segment were 0.12 and 0.25 (gastric fundus), 0.12 and 0.18 (gastric body), 0.11 and 0.16 (pyloric antrum), 0.08 and 0.27 (duodenum), 0.08 and 0.22 (jejunum), 0.14 and 0.25 (ileum), and 0.05 and 0.08 (colon), respectively. Musc:Ao and Muc:Ao are clinically relevant values that can be used to objectively identify thickening of the muscularis and mucosal layers in response to GI diseases.


A Simple Logistic Regression Model for Predicting the Likelihood of Recurrence of Atrial Fibrillation Within 1 Year After Initial Radio-Frequency Catheter Ablation Therapy.
The clinical factors associated with the recurrence of atrial fibrillation (Af) in patients undergoing catheter ablation (CA) are still ambiguous to date. 1. To recognize preoperative serologic factors and clinical features associated with Af recurrence after the first ablation treatment. 2. To Develop a Logical Regression Model for Predicting the Likelihood of Recurrence Within 1 Year After the Initial Radio-Frequency Catheter Ablation (RFCA) Therapy. Atrial fibrillation patients undergoing RFCA at our institution from January 2016 to June 2021 were included in the analysis (n = 246). A combined dataset of relevant parameters was collected from the participants (clinical characteristics, laboratory results, and time to recurrence) (n = 200). We performed the least absolute shrinkage and selection operator (Lasso) regression with 100 cycles, selecting variables present in all 100 cycles to identify factors associated with the first recurrence of atrial fibrillation. A logistic regression model for predicting whether Af would recur within a year was created using 70% of the data as a training set and the remaining data to validate the accuracy. The predictions were assessed using calibration plots, concordance index (C-index), and decision curve analysis. The left atrial diameter, albumin, type of Af, whether other arrhythmias were combined, and the duration of Af attack time were associated with Af recurrence in this sample. Some clinically meaningful variables were selected and combined with recognized factors associated with recurrence to construct a logistic regression prediction model for 1-year Af recurrence. The receiver operating characteristic (ROC) curve for this model was 0.8695, and the established prediction model had a C-index of 0.83. The performance was superior to the extreme curve in the decision curve analysis. Our study demonstrates that several clinical features and serological markers can predict the recurrence of Af in patients undergoing RFCA. This simple model can play a crucial role in guiding physicians in preoperative evaluation and clinical decision-making.


Bone mineral density during long-term use of the progestagen contraceptive implant Implanon compared to a non-hormonal method of contraception.
An open, prospective, comparative study was done in healthy women, aged between 18 and 40 years, to study the effects of long-term etonogestrel treatment on bone mineral density (BMD). The control group used a non-hormone-medicated intrauterine device (IUD). The BMD was measured using a dual energy X-ray absorptiometry instrument. Measurements included the lumbar spine (L(2)-L(4)), the proximal femur (femoral neck, Ward's triangle, trochanter) and distal radius. The period of treatment was 2 years and 44 women in the Implanon group and 29 in the IUD group provided data. Groups were comparable at baseline with respect to age, weight, body mass index, BMD and 17beta-oestradiol status. Changes from baseline in BMD in the Implanon group were not essentially different from those in the IUD group. There was no relationship between 17beta-oestradiol concentrations and changes in BMD in this study population. The results of the present study indicate that Implanon((R)) can safely be used in young women who have not yet achieved their peak bone mass.


Ring finger protein ZIN interacts with human immunodeficiency virus type 1 Vif.
Virion infectivity factor (Vif) protein of human immunodeficiency virus type 1 (HIV-1) is essential for the productive infection of primary human CD4 T lymphocytes and macrophages. Vif overcomes the HIV-inhibitory effects of cellular factor APOBEC3G, which has cytidine deaminase activity. We previously reported the isolation of a Vif-interacting ring finger protein, Triad 3, from a human leukocyte cDNA library, using the yeast two-hybrid system. The full-length cellular protein homologue of Triad 3 has been recently identified as the zinc finger protein inhibiting NF-kappaB (ZIN). Sequence analysis indicates that Triad 3 protein contains all four major ring-like motifs of ZIN. We report here that ZIN binds to purified Vif in vitro and that Triad 3/ZIN interacts with HIV-1 Vif in transfected human 293T cells, as demonstrated by coimmunoprecipitation. To test the biological relevance of this interaction, we produced infectious HIV-1 NL4.3 in the presence or absence of cotransfected ZIN. HIV-1 NL4.3 virus stocks produced in the presence of exogenously expressed ZIN were twofold less infectious in a single-cycle infectivity assay than virus produced in the absence of exogenous ZIN. It was further shown that cells infected with HIV NL4.3 virus stocks produced in the presence of exogenously expressed ZIN were impaired in viral DNA synthesis by twofold. The impairment in viral reverse transcription and the reduction in single-cycle viral infectivity were both shown to be dependent on the presence of Vif in the virus producer cells. The possible mechanisms by which ZIN interferes with the early events of HIV-1 replication are discussed.


[The current aspects of the diagnosis and procedure in gastroduodenal hemorrhages of ulcerous origin].
Basic problem in all discussions on bleeding gastroduodenal ulcers is the one pertaining to the surgical tactics and to the ascertainment of the indications for surgical intervention and the time for its performance. Adequate answer to this question comes from recognition of the following points: 1. Endoscopically established bleeding source and intensity; 2. Considerations on other endoscopic criteria, clinical manifestations of bleeding--hematemesis, melena or both, changes in the controlled hemodynamic and hematologic parameters, as well evaluation of the accompanying diseases of major and secondary importance on the part of the cardiovascular and respiratory system; 3. Site and time of application of electrocoagulation and periulcer sclerosification in patients considered adequate for them, complying with the indications and contraindications; 4. Adequately chosen operative method. For the period 1985-1990 a total of 81 patients with bleeding from gastroduodenal ulcers, uncontrollable by conservative treatment, have been operated; 37 of them died (overall lethality 13.96 per cent, operative lethality 45.67 per cent). The choice of surgery depended on the localization, nature and extent of the pathologic process, the type and anatomical position of the pathologic focus, correlation with tissues adjacent to the pathologic process, presence of adhesions, callosity, etc. The method of choice was gastric resection by Billroth I, which was preferred to Billroth II resection. Other methods being used were: excision and pyloroplasty, excision, pyloroplasty + vagotomy, suture + vagotomy--mainly for ulcers localized on the anterior duodenal wall, suture, suture + vagotomy, ligation of a. gastrica sin., etc.


Treatment satisfaction after 1 year high-power potassium-titanyl-phosphate photoselective vaporization of the prostate.
To investigate the factors that influence treatment satisfaction after high-power potassium-titanyl-phosphate (KTP) laser vaporization of the prostate, we compared the characteristics between patients who were satisfied and those who were not satisfied. In all, 97 patients aged between 53-82 years (median age 67 years) underwent high-power KTP laser vaporization of the prostate for lower urinary tract symptoms due to benign prostatic hyperplasia. At 12 months postoperatively, 60 patients were satisfied with the treatment, whereas 37 were dissatisfied. Although there were no differences in International Prostate Symptom Score (IPSS) values at baseline, the satisfied group scored better in total IPSS at 1, 3, 6, and 12 months postoperatively (P < 0.05). At baseline, the maximum flow rate (Qmax) was lower in the dissatisfied group and remained low throughout the follow-up period, with the exception of 1 month postoperatively (P < 0.05), compared with the satisfied group. There were no differences in other objective data between the two groups, including post-void residual and the number of voids based on the frequency-volume charts. In a multivariate model, a higher bladder contractility index was associated with a greater likelihood of treatment satisfaction 12 months after high-power KTP laser vaporization (odds ratio 1.024, 95% confidence interval 1.001-1.048, P < 0.05). Patients who were not satisfied following the surgery had a smaller improvement in subjective symptoms and Q(max). In addition, our findings suggest that the relative risk of treatment dissatisfaction following high-power KTP laser vaporization was increased in patients with weak detrusor contractility.


The outer membrane component of the multidrug efflux pump from Pseudomonas aeruginosa may be a gated channel.
OprM, the outer membrane component of the MexAB-OprM multidrug efflux pump of Pseudomonas aeruginosa, has been assumed to facilitate the export of antibiotics across the outer membrane of this organism. Here we purified to homogeneity the OprM protein, reconstituted it into liposome membranes, and tested its channel activity by using the liposome swelling assay. It was demonstrated that OprM is a channel-forming protein and exhibits the channel property that amino acids diffuse more efficiently than saccharides. However, antibiotics showed no significant diffusion through the OprM channel in the liposome membrane, suggesting that OprM functions as a gated channel. We reasoned that the protease treatment may cause the disturbance of the gate structure of OprM. Hence, we treated OprM reconstituted in the membranes with alpha-chymotrypsin and examined its solute permeability. The results demonstrated that the protease treatment caused the opening of an OprM channel through which antibiotics were able to diffuse. To elucidate which cleavage is intimately related to the opening, we constructed mutant OprM proteins where the amino acid at the cleavage site was replaced with another amino acid. By examining the channel activity of these mutant proteins, it was shown that the proteolysis at tyrosine 185 and tyrosine 196 of OprM caused the channel opening. Furthermore, these residues were shown to face into the periplasmic space and interact with other component(s). We considered the possible opening mechanism of the OprM channel based on the structure of TolC, a homologue of OprM.