Pharmacokinetic-pharmacodynamic study of apomorphine's effect on growth hormone secretion in healthy subjects.
Apomorphine (APO) stimulates growth hormone (GH) release via dopamine D2 receptors (DRD2). There is no specific study assessing the relationship between APO pharmacokinetic (PK) and the pharmacodynamic (PD) response e.g. GH release. The objective of the study is the PK-PD modelling of APO in healthy subjects. This is a randomized crossover study with s.c. administration of 5, 10, and 20 micro g/kg of APO in 18 healthy subjects. APO concentrations were modelled according to both a bi-compartmental model with zero-order absorption and a bi-compartmental model with first-order absorption. PK-PD relationship was modelled in accordance with the Emax Hill equation using plasma concentrations of APO calculated according to the bi-compartmental model with zero-order absorption. Modelled parameters were very similar to the experimental parameters. PK of APO was linear and there was no significant difference between the tested doses for AUC0--> infinity and Cmax (normalised to the dose 1 micro g/kg), t1/2alpha and t1/2beta. These parameters expressed as mean (CV%: SD/mean) were: 17.2 (26.9) ng/mL.min, 0.26 (33.3) ng/mL, 17.1 (54.2) and 45.2 (20.6) min, respectively (n = 53). An anticlockwise hysteresis loop (effect function of APO plasma concentration) appeared for each dose and each subject. The predicted and measured GH concentrations for all subjects and times were similar whatever the dose (P > 0.27). Emax values were 246 (121), 180 (107), 205 (139) ng/mL, respectively, and EC50 were 0.98 (48.1), 1.70 (62.3), 3.67 (65.2) ng/mL, respectively at dose 5, 10, and 20 micro g/kg (P < 10-4). APO and GH concentrations were predicted with good accuracy using bi-compartmental with zero-order absorption PK model and sigmoid Emax PD model, respectively.


Surgical treatment and anticoagulant therapy for liver injury due to cardiopulmonary resuscitation with lethal pulmonary embolization: A case report.
Cardiopulmonary resuscitation (CPR) can sometimes induce organ injury, however, such an occurrence is rare. We herein report a case of liver injury due to CPR with life-threatening pulmonary embolization (PE) that required the patient to undergo surgical hemostasis and antithrombotic therapy. A woman in her 70s fell off her bicycle. She suffered cardiopulmonary arrest and underwent CPR. She was diagnosed with PE and underwent catheter treatment and anticoagulant therapy; however, her blood pressure did not increase. Contrast-enhanced computed tomography revealed injury to the liver and inferior phrenic artery. Hemostasis could not be completely achieved by transcatheter arterial embolization alone. She was therefore transferred to our hospital and underwent damage control surgery (DCS). Definitive surgery (DS) performed 33 h after DCS showed right hepatic subcapsular hematoma and left hepatic subcapsular hematoma. We cut away the capsules and removed the hematomas. There were lacerations and oozing under the capsule in the left lobe. We sutured the laceration. At 72 h after undergoing DS, antithrombotic therapy was started. On day 19, the patient was discharged home by herself without any neurological damage. For a case of liver injury due to CPR with life-threatening PE, treatment with both hemostasis and antithrombotic therapy should be performed. Antithrombotic therapy was started appropriately in this case by accurately identifying the liver laceration and suturing it. Hemostasis following both DCS and DS with appropriate anticoagulant therapy was effective for the management of liver injury due to CPR with life-threatening PE.


Thrombolysis beyond the guidelines: two treatments in one subject within 90 hours based on a modified magnetic resonance imaging brain clock concept.
We report the first case of 2 intravenous thrombolysis treatments within 90 hours in a patient with early recurrent stroke. A 50-year-old man had improved significantly after intravenous thrombolysis for acute stroke. On the fourth day, he deteriorated dramatically because of recurrent stroke. Evidence of vessel reocclusion and profound perfusion/diffusion mismatch constituted the rationale for a second thrombolysis treatment, which resulted in vessel recanalization and significant neurologic improvement. The pathophysiological information obtained by multimodal magnetic resonance imaging may suit as a brain clock when repeat thrombolysis treatment is considered for early recurrent stroke.


No economic benefit of early knee reconstruction over optional delayed reconstruction for ACL tears: registry enriched randomised controlled trial data.
To analyse 5-year cost-effectiveness of early versus optional delayed acute anterior cruciate ligament (ACL) reconstruction. 121 young, active adults with acute ACL injury to a previously uninjured knee were randomised to early ACL reconstruction (n=62, within 10 weeks of injury) or optional delayed ACL reconstruction (n=59; 30 with ACL reconstruction within 6-55 months); all patients received similar structured rehabilitation. Real life data on health care utilisation and sick leave were obtained from regional and national registers. Costs and quality-adjusted life years (QALYs) were discounted at 3%. Full-analysis set (based on study randomisation) and as-treated analysis (according to actual treatment over 5 years) principles were applied. Mean cost of early ACL reconstruction was €4695 higher than optional delayed ACL reconstruction (p=0.19) and provided an additional 0.13 QALYs (p=0.11). Full-analysis set showed incremental net benefit of early versus optional delayed ACL reconstruction was not statistically significantly different from zero at any level. As-treated analysis showed that costs for rehabilitation alone were €13 650 less than early ACL reconstruction (p<0.001). Results were robust to sensitivity analyses. In young active adults with acute ACL injury, a strategy of early ACL reconstruction did not provide extra economic value over a strategy of optional delayed ACL reconstruction over a 5-year period. Results from this and previous reports of the KANON-trial imply that early identification of individuals who would benefit from either early ACL reconstruction or rehabilitation alone might reduce resource consumption and decrease risk of unnecessary overtreatment. ISRCTN84752559.


Prevalence and factors associated with neck injection among people who inject drugs in San Francisco, California.
Groin and neck injections are generally a last resort for people who inject drugs (PWID) who do not have easy access to functioning veins. These alternative injection practices can lead to an increased likelihood of adverse health outcomes. There is still much we do not know about groin and neck injections among PWID in the US, as the literature to-date comes from studies primarily focused on groin injections outside the US. We assessed prevalence, predictors, and associated behaviors of neck injection through a survey fielded in San Francisco, California, US. The sample comes from a longitudinal observational study that used targeted sampling to recruit PWID in San Francisco. The current study sample includes 239 PWID who completed their 12-month survey between June 2019 and June 2020. About a third of the sample reported injecting in their neck in the past 30 days, with the most common reason being lack of available veins. Age, past 6-month abscess / soft tissue infection, and past 30-day use of opioids mixed with cocaine were significantly associated with past 30-day neck injection in the final multivariate model. Past 30-day neck injection was also significantly associated with being injected by another person in the past 30 days. PWID at higher risk for vein deterioration were more likely to inject into their neck. Harm reduction strategies such as safer injection counseling, safe smoking supplies, use of "street doctors," and safe consumption sites may reduce instances of neck injection and/or associated health risks.


Exploitation of subabul stem lignin as a matrix in controlled release agrochemical nanoformulations: a case study with herbicide diuron.
The utilization of nanomaterials in the domain of agriculture is at an inception, especially in the development of controlled release agrochemical nanoformulations. The present study demonstrated the potential of subabul stem lignin as a matrix material in agrochemical formulations using nanotechnology. In this study, "nanoprecipitation" method was employed and "optimized" to fabricate a stable herbicide, "diuron nanoformulation" (DNF). "Optimized DNF" (ODNF) has 5.17 ± 0.49 % diuron loading efficiency (DLE) and 74.3 ± 4 % encapsulation efficiency (EE). The size of nanoparticles in ODNF was 166 ± 68 nm as revealed by FESEM/TEM studies. Physicochemical characterization of ODNF by UV, FT-IR, and DSC studies revealed the successful loading of diuron within the lignin matrix. The ODNF exhibited nonlinear biphasic release profile for diuron. Further, the bioefficacy of diuron released from ODNF was tested using canola (Brassica rapa). B. rapa seedlings grown in the soil supplemented with ODNF showed early signs of leaf chlorosis and mortality when compared with seedlings grown in the presence of commercial diuron formulation (CDF) or bulk diuron (BD), respectively. This study not only revealed the exploitation of subabul stem lignin as a "matrix" in the controlled release nanoformulation of diuron but also opened up new avenues for utilizing it as matrix for several other agrochemicals associated with the growth and development of the plant.


Cadmium Levels in Tissue and Plasma as a Risk Factor for Prostate Carcinoma: a Meta-Analysis.
Cadmium is a heavy metal that has been suggested to be a carcinogen by evidence. A number of published studies have investigated the association between cadmium levels and prostate cancer, but the results were inconsistent. Thus, we conducted a meta-analysis to get a precise estimate of this subject. After a careful searching and screening, a total of 11 publications containing 14 separated studies were included. Based on a random-effect model, the pooled data showed that cadmium levels of prostate tissues (standard mean difference (SMD) = 3.17, 95 % confidence interval (CI) = 0.60-5.74, P < 0.05) and plasma (SMD = 4.07, 95 % CI = 2.01-6.13, P < 0.05) were significantly higher in prostate cancer patients than those in the healthy controls. No difference of hair and nail cadmium levels between the prostate cancer cases and the controls was found. The data suggested that cadmium exposure might exert an influence on the tumorigenesis of prostate tissues. Future investigations with large sample sizes are needed to verify the results.


Persistent pulmonary hypertension of the newborn. Role of nitric oxide and endothelin in pathophysiology and treatment.
Persistent pulmonary hypertension of the newborn (PPHN) results in significant morbidity and mortality in otherwise normal term infants. Safe, effective therapies for PPHN will only be possible when they can be directed toward the specific defects producing this condition. In this review, the authors discuss three different categories of mediators that may play a role in the normal transition at birth and in the pathophysiology seen in PPHN: (1) lipid mediators, (2) the peptide endothelin, and (3) the oxidant radical, nitric oxide. The potential of using the last mediator, nitric oxide, as a treatment for PPHN is under intensive investigation and is discussed in the final section.


A new species of enkephalin precursor mRNA with a distinct 5'-untranslated region in haploid germ cells.
To elucidate the primary structure of preproenkephalin (A) mRNA expressed by haploid germ cells (round spermatids) in rat testis, we have screened a lambda gt11 cDNA library for preproenkephalin cDNA inserts. The largest cDNA insert contained a protein-coding sequence encoding 269 amino acid residues as well as 327 and 309 bases of the 5'- and 3'-untranslated regions, respectively. The protein-coding region plus 3'-untranslated region of the mRNA was over 99% homologous to that of brain preproenkephalin mRNA, whereas the 5'-untranslated region contained a distinct sequence including a partial sequence of intron A of the preproenkephalin gene [(1984) J. Biol. Chem. 259, 14301-14308; (1984) J. Biol. Chem. 259, 14309-14313]. Northern blot analysis using a 5'-end-specific probe showed that this type of preproenkephalin mRNA exists exclusively in the germ cells.


Insulin resistance at diagnosis in Japanese children with type 2 diabetes mellitus.
Insulin resistance at diagnosis was investigated in Japanese children with type 2 diabetes mellitus (T2DM). A total of 160 children with T2DM were divided into groups on the basis of percent overweight at time of diagnosis: group A (n = 28), <20%; group B (n = 55), 20-39%; group C (n = 37), 40-59%; group D (n = 40), ≥ 60%. Indicators of insulin resistance at diagnosis were compared among the four patient groups, and also between the children with T2DM and the 201 age-matched normal Japanese children. There were no significant differences in plasma glucose (PG) levels among the four patient groups. The mean concentration of fasting plasma immunoreactive insulin (IRI) was significantly higher in group D than in groups A and B (39.2 µU/mL vs 16.2 µU/mL and 24.1 µU/mL, P < 0.05, respectively). The mean homeostasis model assessment (HOMA-R) was significantly higher in group D than in all the other three groups (17.6 vs 7.8, 10.8 and 12.7, P < 0.05, respectively). The indicators HOMA-R and fasting IRI were significantly higher in each diabetes group, even in non-obese group A, than in normal children (P < 0.01, respectively). Japanese children with T2DM had insulin resistance at diagnosis regardless of percent overweight, and the degree of insulin resistance gradually increased with rise in percent overweight.


Long non-coding RNA and circular RNA and coding RNA profiling of plasma exosomes of osteosarcoma by RNA seq.
Osteosarcoma (OS) is a primary bone tumor with high malignancy and the mechanism of hematogenous metastasis in OS is still not clear. The plasma exosomes derived from osteosarcoma play a key role in the process of tumor metastasis. Here, we established RNA-seq dataset for lncRNAs, circRNAs and mRNAs in plasma exosomes from 10 OS patients and 5 healthy donors. A total of 329.52 Gb of clean data was obtained. Besides, 1754 lincRNAs, 7096 known and 1935 new circRNA was identified. Finally, gene expression profiles and differentially expressed genes (DEGs) were analyzed among these 15 samples. There were 331 DEGs of mRNA, 132 of lincRNA and 489 of circRNA was obtained, respectively. This data set provides a significant resource for relevant researchers to excavate potential dysregulated lncRNAs, circRNAs and mRNAs of plasma exosomes in OS versus normal conditions.


A meta-narrative review of recorded patient-pharmacist interactions: exploring biomedical or patient-centered communication?
Pharmacists worldwide require improved patient-centered communication skills as they transition from a dispensing role to enhanced involvement in patient care. Researchers have studied pharmacist communication through audio and video recordings of patient-pharmacist encounters. A meta-narrative review of research using these recordings will offer insight into the extent of biomedical vs. patient-centered communication in patient-pharmacist exchanges. This review aimed to characterize research on patient-pharmacists interactions using audio or video recordings and explore the 1) focus of research questions, 2) study design, 3) data analysis methods, 4) main findings and 5) presence of patient-centered vs. biomedical models of interaction. Drawing on the principles of meta-narrative systematic review, a literature search was performed to identify studies published in English. No publication date limits were implemented. Key search terms included: "audio recording", "video recording", "communication", "patient counseling", "patient interaction", "discourse analysis", "conversation analysis", "narrative analysis", and "content analysis". The search was conducted in five databases: Medline, Embase, International Pharmaceutical Abstracts (IPA), Web of Science, and Academic Search Complete. Forty-one articles met the inclusion criteria and represent 32 unique collections of patient-pharmacist recordings. The 23 quantitative studies focused on "what" was in the interaction, whereas the 5 qualitative studies characterized specialized pharmacy practice and 13 studies used conversational analysis to describe "how" patients and pharmacists interact. The majority of research described the content of recorded interactions in community pharmacies. Twenty-three studies presented evidence of a biomedical model, whereas 8 studies characterized a patient-centered focus. A developing body of research used recordings to describe the content of patient-pharmacist communication and explore the quality of the interactions, validation of coding tools, impact of an intervention, and patient-pharmacist power asymmetry. Study findings, particularly the identification of biomedical vs. patient-centered communication, were guided by the quantitative, qualitative, or conversational analysis research paradigm.


Association of three single nucleotide polymorphisms at the SIX1-SIX6 locus with primary open angle glaucoma in the Chinese population.
This study investigated the genetic association of three single nucleotide polymorphisms (SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma (POAG) in the Chinese population. A total of 866 subjects with POAG (685 high-tension glaucoma (HTG) and 181 normal-tension glaucoma (NTG)) and 266 control individuals were included. Significant genetic association was identified for rs10483727 in HTG (P=0.02; odds ratio (OR)=1.31), NTG (P=7.41×10(-6); OR=2.71), and POAG (i.e., HTG and NTG combined; P=0.001; OR=1.44). rs33912345 was also significantly associated with HTG (P=0.008; OR=1.36), NTG(P=2.72×10(-6); OR=2.27), and POAG (P=3.84×10(-4); OR=1.49). The rare SIX6 mutation, rs146737847, was not found in the subjects enrolled in this study. Stratification by patient age identified that both rs10483727 and rs33912345 were significantly associated with NTG in patients aged above 40 years (P=2.08×10(-5); OR=2.28), whereas in patients aged between 20-40 years, rs33912345 was significantly associated with NTG (P=0.017; OR=2.06). In HTG, the genetic associations for both rs10483727 and rs33912345 were significant in patients aged between 20-40 years (P=0.006; OR=1.56) but not in those aged above 40 years (P=0.118, OR=1.21 and P=0.042, OR=1.29, respectively). This study replicated the association of POAG with two SNPs at the SIX1-SIX6 locus and demonstrated that SNPs, rs10483727 and rs33912345, are significantly associated with POAG, especially with NTG in patients aged above 40 years.


The evolution of the mitochondrial disease diagnostic odyssey.
Mitochondrial diseases often require multiple years and clinicians to diagnose. We lack knowledge of the stages of this diagnostic odyssey, and factors that affect it. Our goals are to report the results of the 2018 Odyssey2 (OD2) survey of patients with a medical diagnosis of mitochondrial disease; and to propose steps to reduce the odyssey going forward, and procedures to evaluate them. Data are from the NIH-funded NAMDC-RDCRN-UMDF OD2 survey (N = 215). The main outcomes are Time from symptom Onset to mitochondrial disease Diagnosis (TOD) and Number of Doctors Seen during this diagnostic process (NDOCS). Expert recoding increased analyzable responses by 34% for final mitochondrial diagnosis and 39% for prior non-mitochondrial diagnosis. Only one of 122 patients who initially saw a primary care physician (PCP) received a mitochondrial diagnosis, compared to 26 of 86 (30%) who initially saw a specialist (p < 0.001). Mean TOD overall was 9.9 ± 13.0 years, and mean NDOCS 6.7 ± 5.2. Mitochondrial diagnosis brings extensive benefits through treatment changes and increased membership in and support of advocacy groups. Because TOD is long and NDOCS high, there is great potential for shortening the mitochondrial odyssey. Although prompt patient contact with primary mitochondrial disease specialists, or early implementation of appropriate tests, may shorten the diagnostic odyssey, specific proposals for improvement require testing and confirmation with adequately complete, unbiased data across all its stages, and appropriate methods. Electronic Health Record (EHRs) may help by accessing diagnostic codes early, but their reliability and diagnostic utility have not been established for this group of diseases.


[Calpain-2 and calcineurin protein expression in right atrial appendages from patients underwent valve replacement with or without atrial fibrillation].
To investigate the relationship between the protein expression of calpain-2 and calcineurin (CaN) and atrial fibrillation (AF) in patient with valvular heart disease (VHD). A total of 40 patients who underwent valve replacement surgery in our hospital from March 2013 to March 2014, right atrial appendages were excised during operation and patients were divided into sinus rhythm (SR) group (n = 17) and AF group (n = 23). The protein expression of calpain-2 and the α-isoform of CaN catalytic subunit (CnA) in the right atrial appendages were determined by Western blot. The protein levels of the full-length CnAa (60,000), the 45,000 fragment of CnAa without autoinhibitory domain, and calpain-2 were significantly upregulated in the AF group compared to the SR group (1.25 ± 0.51 vs. 0.76 ± 0.37, 1.08 ± 0.37 vs. 0.76 ± 0.25, and 0.82 ± 0.44 vs. 0.51 ± 0.19, respectively, all P < 0.05). Activated calpain-2-CaN signal pathway might be involved in the pathogenesis of AF.


APOE and dementia - resequencing and genotyping in 105,597 individuals.
The mechanism behind the strong association between the ɛ2/ɛ3/ɛ4 apolipoprotein E gene (APOE) polymorphism and Alzheimer's disease is not well-characterized. Because low plasma levels of apoE associate with risk of dementia, genetic variants altering apoE levels in general may also associate with dementia. The APOE gene was sequenced in 10,369 individuals, and nine amino acid-changing variants with frequencies ≥2/10,000 were further genotyped in 95,228 individuals. Plasma apoE levels were measured directly. Risk of all dementia and Alzheimer's disease (AD) increased with decreasing genetically determined apoE levels (P = 5 × 10-4 and P = 1 × 10-4 after APOE ɛ2/ɛ3/ɛ4 adjustment). Hazard ratios (95% confidence intervals) for all dementia and AD were 2.76 (1.39 to 5.47) and 4.92 (2.36 to 10.29) for the group with the genetically lowest apoE versus ɛ33. We found that genetically low apoE levels increase and genetically high levels decrease risk, beyond ɛ2/ɛ3/ɛ4. This underscores that dementia risk more likely relates to variants affecting levels of apoE.


New directions for the Morita-Baylis-Hillman reaction; homologous aldol adducts via epoxide opening.
Under trialkylphosphine catalyzed Morita-Baylis-Hillman reaction conditions, epoxides react with enones to give rise to homologous aldol adducts.


Effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its metabolite, N-methyl-4-phenylpyridinium ion, on dopaminergic nigrostriatal neurons in the mouse.
A single subcutaneous injection in the C57 black mouse of 40 mg/kg of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes a 90% depletion of striatal dopamine, as well as loss of 33% of neuronal cell bodies in the substantia nigra, zona compacta. By 4.5 months, there appears to be partial recovery of striatal dopaminergic function. After injection into mice, the MPTP metabolite, N-methyl-4-phenylpyridinium ion (MPP+) enters the striatum, and through some unknown mechanism is even more toxic than MPTP. However, repeated injections of maximally tolerated amounts of MPP+ do not damage dopaminergic nigrostriatal neurons.


The potency of bovine PPD tuberculins in guinea-pigs and in tuberculous cattle.
Potency differences between bovine purified protein derivative tuberculin preparations produced in two different centres and also between preparations produced within these centres, were detected in tuberculous cattle and correlated with potency differences in guinea-pigs. Although assays in groups of guinea-pigs sensitized with either killed Mycobacterium bovis or live BCG identified the weak batches and listed the tuberculins in the same order of potency as the cattle assays, there were nevertheless significant differences between potency estimates according to the mode of sensitization and the preparations compared. The implications for the standardization of tuberculin preparation in general are discussed.


The association between communication impairments and acquired alexithymia in chronic stroke patients.
Language dysfunction has recently been suggested to be one route to alexithymia, an impairment in recognizing and communicating one's own emotions. Neuropsychological evidence is needed to investigate the possibility that acquired language problems could underlie acquired alexithymia. This project examined data from a large group of chronic stroke patients (N = 118) to test whether self-reported or behavioral measures of language and communication problems were associated with alexithymia. We also examined the impact of hemisphere of damage on alexithymia. We found no differences in alexithymia levels for patients with observed language impairments on brief tests of picture naming, comprehension, and reading vs unimpaired patients. However, self-reported communication difficulties were found to be associated with higher scores of alexithymia, even after controlling for depression and anxiety. Patients with left- versus right-hemisphere damage did not differ in their alexithymia scores. We found partial support for the language hypothesis of alexithymia. We discuss potential reasons for the discrepant findings between the self-report and objective language measures and suggest that self-report measures may be more sensitive to milder, more pragmatic language impairments, as opposed to the severe structural language impairments measured by the cognitive screening tests.


Gender differences in the endotoxin-induced inflammatory and vascular responses: potential role of poly(ADP-ribose) polymerase activation.
Activation of poly(ADP-ribose) polymerase (PARP) is an important factor in the pathogenesis of various cardiovascular and inflammatory diseases. Here, we report that the gender-specific inflammatory response is preferentially down-regulated by PARP in male animals. Female mice produce less tumor necrosis factor-alpha and macrophage inflammatory protein-1alpha in response to systemic inflammation induced by endotoxin than male mice and are resistant to endotoxin-induced mortality. Pharmacological inhibition of PARP is effective in reducing inflammatory mediator production and mortality in male, but not in female, mice. Ovariectomy partially reverses the protection seen in female mice. Endotoxin-induced PARP activation in circulating leukocytes is reduced in male, but not female, animals by pharmacological PARP inhibition, as shown by flow cytometry. Pretreatment of male mice with 17-beta-estradiol prevents endotoxin-induced hepatic injury and reduces poly(ADP-ribosyl)ation in vivo. In male, but not female, animals, endotoxin induces an impairment of the endothelium-dependent relaxant responses, which is prevented by PARP inhibition. In vitro oxidant-induced PARP activation is reduced in cultured cells placed in female rat serum compared with male serum. Estrogen does not directly inhibit the enzymatic activity of PARP in vitro. However, PARP and estrogen receptor alpha form a complex, which binds to DNA in vitro, and the DNA binding of this complex is enhanced by estrogen. Thus, estrogen may anchor PARP to estrogen receptor alpha and to the DNA and prevent its recognition of DNA strand breaks and hence its activation. In conclusion, the gender difference in the inflammatory response shows preferential modulation by PARP in male animals.


Simultaneous use of Interphako interference contrast and polarization microscopy in the study of microorganisms.
Simultaneous application of polarization microscopy and Interphako interference contrast has been used to study the internal structure of algal cells. The interference contrast technique showed fine cell structures (important is the selection of interference colors according to the Mach-Zehnder interferometer setting). In a polarization microscope, the crossed polarization filters together with the first-order quartz compensator mounted turntable showed the maximum birefringence of the individual structures. Material containing green algae was collected in the villages Sýkořice and Zbečno, Protected Landscape Area (PLA) Křivoklátsko. The objects were studied in a Carl Zeiss Jena NfpK laboratory microscope equipped with an In 160 base body with an Interphako In contrast interference module including a Mach-Zehnder interferometer with variable phase contrast, a special condenser with interchangeable aperture plates, a turntable, a Meopta Praha polarizer, a LOMO Sankt Petersburg analyzer, and a quartz compensator with first-order red and the digital camera DSLR Nikon D 70. Green algae of three orders were studied: Siphonocladales, Zygnematales, and Desmidiales. Anisotropic structures were found in all studied representatives of the green algae of the phylum Chlorophyta. Especially their cell walls showed strong birefringence (in all representatives of these orders). On the other hand, a representative of the order Siphonocladales (the genus Cladophora, Cladophoraceae, Ulvophyceae) was rarely found to display weak birefringent granules of storage substances due to the setting of the Mach-Zehnder interferometer and the use of the first-order compensator (interference colors are intensified). In addition, a very weak birefringence of periphyton cells (microbial biofilm) was found. In the study of the second algae of the genus Spirogyra (Zygnemataceae, Zygnematales, Conjugatophyceae), a strongly birefringent connecting wall between algal cells was found in contrast to the weaker birefringence of the peripheral wall. It was the use of Interphako interference contrast together with polarization filters and a first-order quartz compensator that particularly emphasized the central part of the connecting wall. In the study of the twinned Pleurotaenium algae (Desmidiaceae, Desmidiales, Conjugatophyceae), a strongly birefringent wall was found along the periphery of the cell with a nucleus in the middle part (isthmus). In this narrowing in the center of the cell, a sharply delimited birefringent edge of the cell wall is visible, especially when using Interphako interference contrast along with crossed polarization filters and a first-order quartz compensator. In conclusion, Interphako interference contrast provides a high degree of image contrast in a microscope and, if suitably simultaneously complemented by polarization microscopy (including a first-order quartz compensator), it will allow us to infer some of the composition of the investigated structures. However, working with Interphako interference contrast is considerably more difficult (setting Mach-Zehnder interferometer) than using other contrast techniques (positive and negative phase contrast, color contrast, relief contrast, and dark field).


How does renewable energy technology innovation affect manufacturing carbon intensity in China?
Renewable energy technology innovation (RETI) is a crucial driver for promoting the manufacturing green transformation. However, few studies have explored the impact of RETI on manufacturing carbon intensity (MCI) from the perspective of spatial spillover and regional boundary. Based on the manufacturing panel data of 30 provinces in China from 2006 to 2020, this study examines the mechanism, spatial spillover effects, regional boundaries, and industry heterogeneity of RETI on MCI using the spatial Durbin model. The results show that (1) RETI significantly inhibits local and neighboring MCI. (2) The spatial spillover effect of RETI on MCI has a significant regional boundary, which is inhibitory in the range of 800 km and shows a significant "half-decay" characteristic at 400 km. However, in the range of 800 to 1400 km, RETI significantly promotes neighboring MCI. (3) The inhibitory effect of RETI on MCI has temporal and regional heterogeneity, which gradually increases over time, and the effect from high to low is central, west, and east. (4) RETI has a significant inhibitory effect on MCI of pollution-intensive, high-income, capital-intensive, and labor-intensive manufacturing in local and neighboring areas, but it has a more negligible effect on non-pollution-intensive, low-income, and technology-intensive MCI. The findings provide empirical evidence for formulating targeted and differentiated policy in manufacturing low-carbon development.


Effects of Cydonia oblonga Miller leaf and fruit flavonoids on blood lipids and anti-oxydant potential in hyperlipidemia rats.
To study the effects of Cydonia oblonga Miller (COM) total flavonoids (TF) from leaves and fruit on the blood lipid and antioxidant potentials using hyperlipidaemic rat models. Hyperlipidaemic rat models were created with high-lipid emulsion. Rats were distributed into normal controls, hyperlipidaemic models, and daily high (160mg/kg), medium (80mg/kg) and low (40mg/kg) TF from leaves and fruit and simvastatin (5mg/kg) groups. After four weeks, serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), alanine aminotransferase (ALT), aspartate aminotransferase (AST), as well as hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured. Compared with the hyperlipidaemic model group, TF significantly reduced serum TC, TG, LDL-C (P<0.01), ALT and AST (P<0.01 or P<0.05) and increased HDL-C (P<0.05 or P<0.01). TF also reduced MDA (P<0.01 or P<0.01). COM total flavonoids can effectively regulate the metabolism of lipids, and remove oxygen free radicals. This confirms its potential value in the prevention and treatment of hyperlipidaemia.


Enzymatically-responsive pro-angiogenic peptide-releasing poly(ethylene glycol) hydrogels promote vascularization in vivo.
Therapeutic angiogenesis holds great potential for a myriad of tissue engineering and regenerative medicine approaches. While a number of peptides have been identified with pro-angiogenic behaviors, therapeutic efficacy is limited by poor tissue localization and persistence. Therefore, poly(ethylene glycol) hydrogels providing sustained, enzymatically-responsive peptide release were exploited for peptide delivery. Two pro-angiogenic peptide drugs, SPARC113 and SPARC118, from the Secreted Protein Acidic and Rich in Cysteine, were incorporated into hydrogels as crosslinking peptides flanked by matrix metalloproteinase (MMP) degradable substrates. In vitro testing confirmed peptide drug bioactivity requires sustained delivery. Furthermore, peptides retain bioactivity with residual MMP substrates present after hydrogel release. Incorporation into hydrogels achieved enzymatically-responsive bulk degradation, with peptide release in close agreement with hydrogel mass loss and released peptides retaining bioactivity. Interestingly, SPARC113 and SPARC118-releasing hydrogels had significantly different degradation time constants in vitro (1.16 and 8.77×10(-2) h(-1), respectively), despite identical MMP degradable substrates. However, upon subcutaneous implantation, both SPARC113 and SPARC118 hydrogels exhibited similar degradation constants of ~1.45×10(-2) h(-1), and resulted in significant ~1.65-fold increases in angiogenesis in vivo compared to controls. Thus, these hydrogels represent a promising pro-angiogenic approach for applications such as tissue engineering and ischemic tissue disorders.


Effect of wheat-maize straw return on the fate of nitrate in groundwater in the Huaihe River Basin, China.
Straw return is becoming a routine practice in disposing of crop residues worldwide. However, the potential effect of such operation on the chemistry of local groundwater is not well documented. Here, shallow groundwater in an area where wheat-maize straw return is practiced was analyzed, and the seasonal changes in the nitrate concentration and the isotope compositions of NO3- and H2O were determined along two flow paths. Measured δD and δ18O in waters indicated that the groundwater was mainly recharged by atmospheric precipitation, while measured δ15N and δ18O in nitrate suggested that the sources for groundwater NO3- included urea fertilizer, soil nitrogen, and sewage/manure. Reduced NO3- concentrations coincided with an enrichment of organic matter in the groundwater of the straw return area, revealing an environmental condition that facilitates nitrate reduction, whereas increased δ15N-NO3- and δ18O-NO3- along the flow path suggested the occurrence of denitrification. Further analyses showed that, compared to the cases in the absence of straw return, as much as 80% and 90% of groundwater nitrate was removed in low and high water seasons in the straw return area, pointing to a potential positive effect of straw return to groundwater quality.


Perceptions of pharmacists about adverse effects of corticosteroid therapy: focus on osteoporosis.
To assess the perceptions of pharmacists regarding the adverse effects of corticosteroids, in particular corticosteroid-induced osteoporosis. Mailed survey of a random sample of pharmacists. Richmond, Virginia. 350 community and hospital pharmacists. Not applicable. Respondents' knowledge of adverse effects of corticosteroid therapy in men, premenopausal women, and postmenopausal women; the content of respondents' usual patient counseling for low- and high-dose therapy; and respondents' opinions of regimens for prevention of osteoporosis. Pharmacists associated gastritis, weight gain, and mood changes with corticosteroid use in a hypothetical 45-year-old man or 45-year-old premenopausal woman. For a hypothetical 65-year-old postmenopausal woman, pharmacists more frequently counseled about weight gain, osteoporosis, and gastritis. Patient counseling focused on these adverse effects for both low-dose (5 to 10 mg/day) and high-dose (> or = 30 mg/day) prednisone use. Osteoporosis was considered more likely in patients receiving high-dose corticosteroids on a long-term basis. Pharmacists responding to this survey frequently overlooked the association between low- and high-dose corticosteroid use and decreased bone density. Educational efforts are needed so that pharmacists can fulfill their potential for educating patients, monitoring corticosteroid therapy, and detecting drug-induced complications.


Antimicrobial activity and chemical profile of wood vinegar from eucalyptus (Eucalyptus urophylla x Eucalyptus grandis - clone I144) and bamboo (Bambusa vulgaris).
Microbial resistance to drugs is a public health problem; therefore, there is a search for alternatives to replace conventional products with natural agents. One of the potential antimicrobial agents is wood vinegar derived from the carbonization of lignocellulosic raw materials. The objectives of the present work were to evaluate the antibacterial and antifungal action of two kinds of wood vinegar (WV), one of Eucalyptus urograndis wood and another of Bambusa vulgaris biomass, and determine their chemical profile. The antimicrobial effect was assessed against Staphylococcus aureus, Pseudomonas aeruginosa, Salmonella enteritidis, Escherichia coli, Streptococcus agalactiae, and Candida albicans. The minimum inhibitory concentration and the minimum bactericidal and fungicidal concentrations were determined. Micrographs of the microorganisms before and after exposure to both kinds of wood vinegar were obtained by scanning electron microscopy. The chemical profile of the eucalyptus and bamboo vinegar was carried out by gas chromatography and mass spectrometry (GC/MS). Both types of WV presented significant antimicrobial activity, with the bamboo one having a higher efficiency. Both studied pyroligneous extracts seem promising for developing natural antimicrobials due to their efficiency against pathogens. GC/MS analyses demonstrated that the chemical profiles of both kinds of WV were similar but with some significant differences. The major component of the eucalyptus vinegar was furfural (17.2%), while the bamboo WV was phenol (15.3%). Several compounds in both WVs have proven antimicrobial activity, such as acetic acid, furfural, phenol, cresols, guaiacol, and xylenols. Together, they are the major in the chemical composition of the organic fraction of both WVs. Bamboo vinegar had a more expressive content of organic acids. Micrographs of microorganisms taken after exposure to both kinds of wood vinegar displayed several cell modifications. The potential of both types of wood vinegar as a basis for natural antimicrobial products seems feasible due to their proven effect on inhibiting the microorganisms' growth assessed in this experiment.


Modelling high-resolution electron microscopy based on core-loss spectroscopy.
There are a number of factors affecting the formation of images based on core-loss spectroscopy in high-resolution electron microscopy. We demonstrate unambiguously the need to use a full nonlocal description of the effective core-loss interaction for experimental results obtained from high angular resolution electron channelling electron spectroscopy. The implications of this model are investigated for atomic resolution scanning transmission electron microscopy. Simulations are used to demonstrate that core-loss spectroscopy images formed using fine probes proposed for future microscopes can result in images that do not correspond visually with the structure that has led to their formation. In this context, we also examine the effect of varying detector geometries. The importance of the contribution to core-loss spectroscopy images by dechannelled or diffusely scattered electrons is reiterated here.


IFN-γ gene loaded human umbilical mesenchymal stromal cells targeting therapy for Graft-versus-host disease.
Graft-versus-host disease (GVHD) is a frequent complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The application of mesenchymal stromal cells (MSCs) to treat GVHD patients refractory to initial steroid treatment has led to impressive results. In this study, we explored the potential of human umbilical mesenchymal stem cells (HUMSCs) transfected with the IFN-γ gene of human (h)/mice (m) (HUMSCs + Ad-h/mIFN-γ) carried by a recombinant adenoviral vector in the prevention and treatment of GVHD. We demonstrated that HUMSCs + Ad-h/mIFN-γ efficiently suppressed T lymphocyte proliferation and activation, induced G1 cell cycle arrest and apoptosis in vitro. To assess the in vivo efficacy of HUMSCs + Ad-h/mIFN-γ, Balb/c mice were induced to develop GVHD symptoms by tail vein injection of C57BL/6 splenocytes after irradiation. Weight, hair, survival, hemogram, and chimera condition of GVHD model mice were monitored before and after treatment, respectively. The results showed that HUMSCs + Ad-h/mIFN-γ reduced GVHD's incidence and severity on the model mice and provided a significant survival benefit. In conclusion, this study may provide validated evidence that the introduction of IFN-γ into HUMSCs would help ameliorate GVHD after allo-HSCT.


Changes of phasic pleural pressure in awake dogs during exercise: potential effects on cardiac output.
Eighty experiments were performed with nine awake dogs to study the changes of phasic-pleural pressure with exercise. The increased minute volume with exercise was obtained by more frequent pleural pressure swings and by a substantial extension of the pressure swings in both directions. The cyclic changes of stroke volume following the pressure swings support the hypothesis that alterations of pleural pressure affect the stroke volume and can act, if necessary, as a secondary pump for the circulation. Mean pleural pressure during exercise fell by 2.5 cm H2O from the rest value of 12.1 cm H2O. The absolute right atrial pressure during exercise (-2.69 mm Hg) was not different from that at rest (-2.39 mm Hg). However, the transmural right atrial pressure of 7.6 mm Hg during exercise was higher than the pressure of 6.2 mm Hg at rest because during exercise the right atrium was perfused by 38% higher blood flow than that at rest. The phasic pattern of right atrial pressure shows that there is good reason to assume that during inspiration the extrathoracic veins are collapsed at their entrance into the chest, but this collapse is removed during expiration. There is no reason to assume an effective, sustained collapse of extrathoracic veins. Rather we can visualize a rhythmical change of flow in extrathoracic veins from transient limitation to transient acceleration.


Assessment of peritoneojugular shunts by direct roentgenographic examination.
The silicone rubber tubing of the LeVeen peritoneojugular shunt can be safely punctured with a 23 gauge needle. Radiopaque contrast material can be injected through the needle to delineate the cause of any obstruction to the venous tubing.


Deferoxamine test and bone disease in dialysis patients with mild aluminum accumulation.
Aluminum bone disease is a frequent complication of dialysis patients. The deferoxamine (DFO) test has been advocated as a noninvasive procedure for the diagnosis of AI bone lesion. However most of these studies have been performed in symptomatic patients with significant AI bone disease. Whether this test may provide similar data at an earlier stage of AI toxicity is not known. The present study evaluates prospectively 28 patients with mild AI load. Patients studied ranged in age from 21 to 65 years; duration of dialysis was 5.6 +/- 3.2 years; deferoxamine, 40 mg/kg body weight, was infused at the end of dialysis. Serum AI was measured before DFO administration and before the next dialysis treatment. Bone biopsies were performed in all patients. Cortical bone AI was determined biochemically; trabecular and cortical bone AI were also determined histochemically. Mean basal serum AI (43.2 +/- 30.8 micrograms/L) and cortical bone AI (25.7 +/- 35.2 micrograms/g) were moderately increased. Basal serum AI correlated (r = 0.77) with the increment in serum AI after DFO infusion. After DFO, stainable trabecular and cortical bone AI correlated in a similar manner with both basal serum AI and increment in serum AI. Only biochemically determined cortical bone AI was not significantly related to basal serum AI. Nineteen of the 28 patients had evidence of osteitis fibrosa on bone biopsy. Stained AI surfaces but not trabecular AI were different in patients with low and patients with high bone formation rates. The bone findings, assessed as bone formation rates and resorption surfaces, did not correlate with biochemically or histochemically determined bone AI.(ABSTRACT TRUNCATED AT 250 WORDS)


Transient detection of early wallerian degeneration on diffusion-weighted MRI after an acute cerebrovascular accident.
We report three patients with a cerebrovascular accident studied serially by MRI, including diffusion-weighted imaging (DWI). In case 1, DWI 1 day after the onset of left frontoparietal cortical infarcts showed no abnormal signal in the left corticospinal tract. DWI 12 days after onset showed high signal in the corticospinal tract, interpreted as early wallerian degeneration. This had disappeared by 22 days after onset. In case 2, DWI obtained 7 days after the onset of a right internal capsule lacunar infarct showed high signal from the right corticospinal tract in the brainstem, which was less marked 15 days after onset. In case 3, MRI on postnatal day 7 showed a cerebral haemorrhage in the right corona radiata and high signal from the right corticospinal tract on DWI. The latter disappeared by day 23. DWI shows early wallerian degeneration; transient signal abnormalities within 2 weeks of stroke should not be mistaken for new ischaemic lesions.


Real-time tissue perfusion assessment using fluorescence imaging topography scanning system: A preclinical investigation.
We previously developed a real-time fluorescence imaging topography scanning (RFITS) system for intraoperative multimodal imaging, image-guided surgery, and dynamic surgical navigation. The RFITS can capture intraoperative fluorescence, color reflectance, and surface topography concurrently and offers accurate registration of multimodal images. The RFITS prototype is a promising system for multimodal image guidance and intuitive 3D visualization. In the current study, we investigated the capability of the RFITS system in intraoperative fluorescence vascular angiography for real-time assessment of tissue perfusion. We conducted ex vivo imaging of fluorescence perfusion in a soft casting life-sized human brain phantom. Indocyanine green (ICG) solutions diluted in dimethyl sulfoxide (DMSO) and human serum were injected into the brain phantom through the vessel simulating tube (2 ± 0.2 mm inner diameter) by an adjustable flow peristaltic pump. To demonstrate the translational potential of the system, an ICG/DMSO solution was perfused into blood vessels of freshly harvested porcine ears (n = 9, inner diameter from 0.56 to 1.27 mm). We subsequently performed in vivo imaging of fluorescence-perfused vascular structures in rodent models (n = 10). 5 mg/ml ICG solutions prepared in sterile water were injected via the lateral tail vein. All targets were imaged by the RFITS prototype at a working distance of 350-400 mm. 3D visualization of 10 µg/ml ICG-labeled continuous moving serum in the brain phantom was obtained at an average signal-to-background ratio (SBR) of 1.74 ± 0.03. The system was able to detect intravenously diffused fluorescence in porcine tissues with an average SBR of 2.23 ± 0.22. The RFITS prototype provided real-time monitoring of tissue perfusion in rats after intravenous (IV) administration of ICG. The maximum fluorescence intensity (average SBR = 1.94 ± 0.16, p < 0.001) was observed at Tpeak of ~30 seconds after the ICG signal was first detected (average SBR = 1.19 ± 0.13, p < 0.01). We have conducted preclinical studies to demonstrate the feasibility of applying the RFITS system in real-time fluorescence angiography and tissue perfusion assessment. Our system provides fluorescence/color composite images for intuitive visualization of tissue perfusion with 3D perception. The findings pave the way for future clinical translation.


Suicide nanoplasmids coding for ribosome-inactivating proteins.
Conventional eukaryotic expression plasmids contain a DNA backbone that is dispensable for the cellular expression of the transgene. In order to reduce the vector size, minicircle DNA technology was introduced. A drawback of the minicircle technology are considerable production costs. Nanoplasmids are a relatively new class of mini-DNA constructs that are of tremendous potential for pharmaceutical applications. In this study we have designed novel suicide nanoplasmid constructs coding for plant derived ribosome-inactivating proteins. The suicide-nanoplasmids were formulated with a targeted K16-lysine domain, analyzed for size, and characterized by electron microscopy. The anti-proliferative activity of the suicide-nanoplasmids was investigated in vitro by real time microscopy and the expression kinetic was determined using an enhanced green fluorescent protein nanoplasmid variant. In an aggressive in vivo neuroblastoma tumor model, treated mice showed a reduced tumor growth whereby the therapy was well tolerated.


Public health impact of the spread of Anopheles stephensi in the WHO Eastern Mediterranean Region countries in Horn of Africa and Yemen: need for integrated vector surveillance and control.
Anopheles stephensi is an efficient vector of both Plasmodium falciparum and Plasmodium vivax in South Asia and the Middle East. The spread of An. stephensi to countries within the Horn of Africa threatens progress in malaria control in this region as well as the rest of sub-Saharan Africa. The available malaria data and the timeline for the detection of An. stephensi was reviewed to analyse the role of An. stephensi in malaria transmission in Horn of Africa of the Eastern Mediterranean Region (EMR) in Djibouti, Somalia, Sudan and Yemen. Malaria incidence in Horn of Africa of EMR and Yemen, increased from 41.6 in 2015 to 61.5 cases per 1000 in 2020. The four countries from this region, Djibouti, Somalia, Sudan and Yemen had reported the detection of An. stephensi as of 2021. In Djibouti City, following its detection in 2012, the estimated incidence increased from 2.5 cases per 1000 in 2013 to 97.6 cases per 1000 in 2020. However, its contribution to malaria transmission in other major cities and in other countries, is unclear because of other factors, quality of the urban malaria data, human mobility, uncertainty about the actual arrival time of An. stephensi and poor entomological surveillance. While An. stephensi may explain a resurgence of malaria in Djibouti, further investigations are needed to understand its interpretation trends in urban malaria across the greater region. More investment for multisectoral approach and integrated surveillance and control should target all vectors particularly malaria and dengue vectors to guide interventions in urban areas.


Complications of percutaneous endoscopic gastrostomy in children: results of an Italian multicenter observational study.
Percutaneous endoscopic gastrostomy is the preferred way to achieve an artificial feeding route for patients requiring long-term enteral nutrition. Although the procedure is well-standardized, it carries early and late complications. To establish the mortality and morbidity of this technique in a large cohort of children. A multi-centre prospective clinical data collection from children undergoing percutaneous endoscopic gastrostomy tube implantation has been conducted from January 2004 to December 2007. Previous abdominal surgery was the only exclusion criterion. Follow-up visits were carried out at 1, 3, 6, 12, and 24 months after the procedure. 239 children (males, 55.2%; mean age 6.05±6.1years) were enrolled from nine tertiary Italian centres. Major complications occurred in 8 patients (3.3%). The cumulative incidence of complications was 47.7% at 24 months. The presence of thoraco-abdominal deformity was an independent predictor of complications at 12 months. No risk factors were identified in association to complications during the 1st tube replacement. In children undergoing percutaneous endoscopic gastrostomy placement minor complications are common, while severe morbidities are rare. Accurate follow up is essential to recognize every complication, in particular when risk factors such as thoraco-abdominal deformity exist.


Pharmacogenomics of GLP-1 receptor agonists: Focus on pharmacological profile.
Type 2 Diabetes mellitus (T2DM) is a multifactorial metabolic disorder also known as a silent killer disease. Macrovascular and microvascular complications associated with diabetes worsen the condition leading to higher comorbidity and mortality rate. Currently, available treatment strategies for diabetes include biguanides, sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, insulin and its analogs, DPP-4 (dipeptidyl-peptidase-4) inhibitors, SGLT-2 inhibitors, and Glucagon Like Peptide-1 receptor agonists (GLP-1RAs). Synthetic agonists of GLP-1 hormone, GLP-1RAs are an emerging class of anti-diabetic drugs which target the pathophysiology of diabetes through various mechanisms and at multiple sites. They promote insulin secretion from beta cells, and the proliferation of beta cells inhibits glucagon secretion, delays gastric emptying and induces satiety. However, treatment is reported to be associated with inter-individual variations and adverse drug reactions, which are also influenced by genetic variations. There have been a few pharmacogenetic studies have been carried out on this drug class. This review discusses all the available GLP-1RAs, their pharmacokinetics, pharmacodynamics and genetic variation affecting the inter-individual variation.


Role of a clinical pharmacist as part of a multidisciplinary care team in the treatment of HCV in patients living with HIV/HCV coinfection.
The objective of the study was to evaluate the role of a clinical pharmacist in hepatitis C virus (HCV) treatment of patients living with HIV/HCV coinfection. We conducted a descriptive study to quantify the functions of a clinical pharmacist in HCV treatment of patients living with HIV/HCV coinfection who were initiating HCV treatment at a publicly funded clinic between March 18, 2015 and September 15, 2016. The clinical pharmacist's role was categorized into eight categories: 1) HCV prior authorization (PA) completion; 2) HCV medication adherence counseling; 3) HCV drug-drug interaction (DDI) counseling and screening; 4) HCV medication counseling regarding common adverse events (AEs); 5) HCV counseling regarding HCV treatment outcomes and risk of reinfection; 6) ordering laboratory tests and interpretation of HCV laboratory values; 7) HIV medication AE assessment; and 8) other (including refilling medications and management of other comorbidities). One hundred and thirty-five patients initiated treatment during this timeframe: 77.0% were males, 56.3% non-cirrhotic, 77.0% HCV treatment-naïve, 45.9% HCV genotype 1a, and 83.0% initiated on ledipasvir/sofosbuvir. The clinical pharmacist completed 150 PAs, counseled on HCV medication adherence in 79.2% of patients, conducted HCV DDI counseling and screening in 54.2%, and monitored HCV medication AEs in 54.2%. The clinical pharmacist counseled patients on HCV treatment outcomes and risk of reinfection in 53.1%, ordered laboratory tests in 44.8%, and reported and interpreted laboratory values in 44.8%. The clinical pharmacist assessed HIV medication AEs in 54.2% of patients and participated in other activities in 42.7%. A clinical pharmacist's expertise as part of a multidisciplinary care team facilitates optimal treatment outcomes and provides critical support in the management of DAA therapy in individuals living with HIV/HCV coinfection.


[Smoking and alcohol cessation programs in patients with head and neck cancer].
Most head and neck cancers are associated with smoking and alcohol exposure. Smoking and alcohol cessation (ASC) is associated with improved quality of life, cancer therapy efficacy, decreased treatment-related and cardiovascular risks, and is expected to decrease the risk of second primary tumor. It is therefore a high priority in the plan of care. However, results of current ASC programs are disappointing and understanding the reasons of this is critical. We started a qualitative study in 6 academic centers including 3 university hospitals, one regional hospital and one comprehensive cancer center. We first interviewed surgeons and care givers involved in the management of head and neck cancers. Poor communication between stakeholders, absence of alignment of care goals between patients, surgeons and other caregivers, and low level of understanding by patients of the benefits of ASC were felt to represent frequent obstacles to successful outcome. More work is ongoing within the context of our IHNPACT umbrella protocol to identify hurdles associated with successful ASC.


Elevated frequencies of 6-thioguanine-resistant lymphocytes in multiple sclerosis patients treated with cyclophosphamide: a prospective study.
An autoradiographic assay for 6-thioguanine-resistant (TGr) lymphocytes was used to determine the frequency of in vivo derived variant T lymphocytes in peripheral blood from multiple sclerosis (MS) patients treated with monthly intravenous infusions of 750 mg/m2 of cyclophosphamide (CP). To analyze the time-course of response to CP, the MS patients were studied prospectively. Samples were obtained from the patients before the beginning of CP therapy, 4-5 times during the course of treatment, and, finally, 2 or 3 months after the completion of therapy. 2 weeks after the first CP infusion, the variant frequencies (Vfs) of the MS patients were significantly increased (p less than 0.05) above their pre-treatment values, but by 4 weeks following the first CP infusion the Vfs had fallen to normal or near-normal levels. After subsequent treatments, the frequencies of variant TGr cells were again higher than pre-treatment Vfs. However, within 7-13 weeks after the cessation of CP therapy, the Vfs of all subjects had returned to normal levels. The transient nature of the response indicates rapid in vivo selection against CP-induced TGr mutant cells. The mean pre-treatment Vf of the 4 MS patients who were cigarette smokers was 6.56 X 10(-6) which was significantly greater (p less than 0.05) than the mean Vf (1.52 X 10(-6) of the 4 MS patients who were non-smokers. The mean Vf from 8 assays of healthy non-smokers was 1.92 X 10(-6).


The investigation of the possible protective influence of selenium on antioxidant barrier in heart of rats exposed to lithium.
Selenium is an essential element possessing antioxidant properties and the treatment with it has displayed protective effects against toxicity of different substances occurring in the environment and food as well as against the side effects of some drugs. Lithium is used in medicine although numerous side effects can occur during therapy, including disturbances of the heart. For these reasons studies to find protective adjuvants have been performed. In the current study the possibility of selenium (as sodium selenite) application as a protective adjuvant in lithium treatment was studied. Male Wistar rats were treated: control - with saline; Li-group - with Li2CO3 (2.7 mg Li/kg b.w.); Se-group - with Na2SeO3 (0.5 mg Se/kg b.w.); Li+Se-group simultaneously with Li2CO3 and Na2SeO3 (2.7 mg Li/kg b.w. and 0.5 mg Se/kg b.w., respectively) by a stomach tube for a period of three weeks, once a day. In heart homogenate activities of antioxidant enzymes - catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), concentrations of low-molecular-weight antioxidants - ascorbic acid (AA) and reduced glutathione (GSH) as well as total antioxidant status (TAS) values were determined. GPx/SOD and CAT/SOD ratios were evaluated. In comparison with control selenium caused no significant changes of the studied parameters except for GPx, whereas lithium slightly disturbed TAS and markedly GPx, CAT and CAT/SOD ratio. In Li-treated rats co-administration of selenium displayed tendency towards restoring the impaired parameters. The results suggest that research on selenium application as an adjuvant in lithium therapy is worthy to be continued.


Urodynamic study and quality of life in patients with fibromyalgia and lower urinary tract symptoms.
The aim of this study was to evaluate clinical and urodynamic observations on women with fibromyalgia (FM) and lower urinary tract symptoms (LUTS). Fifty-one patients with FM and LUTS and 50 patients with LUTS without FM answered questions about urinary symptoms and also two questionnaires about quality of life measures: "Medical Outcomes Study 36-Item Short-Form Health Survey" and "King's Health Questionnaire". The urodynamic parameters evaluated were the following: maximum cystometric capacity, urine loss due to cough, Valsalva leak point pressure, and detrusor overactivity (DO). The groups were homogeneous concerning age, parity, body mass index, and genital prolapse. Symptoms such as increase of urinary frequency (p=0.007) and urge urinary incontinence (p=0.004) were statistically more common in the FM group. DO was the statistically most common urodynamic observation in patients with FM (p=0.02). Regarding the questionnaires about quality of life, the patients with fibromyalgia and LUTS had the worst results in all fields. In conclusion, patients with FM and LUTS have detrusor overactivity more often as well as an increase of urinary frequency, contributing to the quality of life worsening.


Nanospace theory for biomineralization.
The precipitation of inorganic crystals from body fluid requires (A) elimination of the macromolecules that inhibit for crystal formation, (B) sufficient supersaturation of the relevant ions, and (C) local restriction of molecular movement. All of these must be accomplished within a space of several nanometers width. Such a nanospace excludes most peptides and oligosaccharides (A). The relaxation time of the outer layer of hydration water (nano second order) on the nanospace wall is 1,000 times longer than that of free water (pico second order). This means that the structure temperature of vicinal water is low, thus the solubilities of calcium ions and phosphate ions are reduced (B,C). Stable ion clusters are formed easier in the nanospace than in the bulk water. The 5-6 nm space in which 3 nm thick hydroxyapatite crystallites can exist should be called critical space. The critical space should be formed according to the fibril diameter and disposition of the fibril or by deployment into the filaments, and by microtubular and lamellar structures.


Effects of dietary caffeine on topographic EEG after controlling for withdrawal and withdrawal reversal.
Despite several decades of research into the effects of caffeine on EEG, few consistent findings have emerged. Notwithstanding the likelihood that differences in methodology may explain some of the inconsistency, confidence in the published findings is undermined by the failure in previous studies to control for the effects of caffeine withdrawal and withdrawal reversal. Participants (n = 22) alternated weekly between ingesting placebo and caffeine (1.75 mg/kg) 3 times daily for 4 consecutive weeks. EEG activity was measured at 32 sites during eyes closed, eyes open, and performance of a vigilance task. Caffeine was found to have few and modest effects on EEG in the theta and alpha bandwidths, and no effects in the delta and beta bandwidths. Evidence was found of withdrawal, withdrawal reversal, and tolerance in relation to observed increases in theta power during task performance; withdrawal and withdrawal reversal in relation to increases in alpha power during all three behavioural conditions (eyes closed, eyes open, and task performance), and withdrawal-induced adverse effects in relation to aspects of subjective mood. The finding of similar increases in theta power following caffeine challenge and acute caffeine withdrawal casts doubt on whether caffeine may be viewed as having direct stimulant effects. Results could suggest that change in drug state, whether in the form of acute caffeine withdrawal or challenge, may be disruptive to electrophysiological activity in the brain.


Growth hormone signaling in vivo in human muscle and adipose tissue: impact of insulin, substrate background, and growth hormone receptor blockade.
GH induces insulin resistance in muscle and fat, and in vitro data indicate that this may involve cross-talk between the signaling pathways of the two hormones. Our objective was to investigate GH and insulin signaling in vivo in human muscle and fat tissue in response to GH, GH receptor blockade, and insulin stimulation. We conducted two randomized crossover studies. Sixteen healthy males participated. GH was administered as a bolus (n = 8) and constant infusion (n = 8). The bolus study included three arms: 1) control (saline), 2) GH (0.5 mg iv), and 3) GH blockade (pegvisomant 30 mg sc), each combined with a hyperinsulinemic glucose clamp. The infusion study included two arms: 1) GH infusion (45 ng/.kg.min, 5.5 h) and 2) saline infusion (5.5 h) combined with a hyperinsulinemic glucose clamp during the final 2.5 h. Muscle and fat biopsies were subjected to Western blotting for expression of Stat5/p-Stat5, Akt/p-Akt, and ERK1/2/p-ERK1/2 and to real-time RT-PCR for expression of SOCS1-3 and IGF-I mRNA. GH significantly reduced insulin sensitivity. The GH bolus as well as GH infusion induced phosphorylation of Stat5 in muscle and fat, and SOCS3 and IGF-I mRNA expression increased after GH infusion. Hyperinsulinemia induced Akt phosphorylation in both tissues, irrespective of GH status. In muscle, ERK1/2 phosphorylation was increased by insulin, but insulin per se did not induce phosphorylation of Stat5. GH exposure associated with insulin resistance acutely translates into GH receptor signaling in human muscle and fat without evidence of cross-talk with insulin signaling pathways. The molecular mechanisms subserving GH-induced insulin resistance in humans remain unclarified.


The Z-scheme--down hill all the way.
The Z-scheme is considered in the context of personal recollections of events during the time that it was conceived and an evaluation of its enduring importance.


mvmapper: Interactive spatial mapping of genetic structures.
Characterizing genetic structure across geographic space is a fundamental challenge in population genetics. Multivariate statistical analyses are powerful tools for summarizing genetic variability, but geographic information and accompanying metadata are not always easily integrated into these methods in a user-friendly fashion. Here, we present a deployable Python-based web-tool, mvmapper, for visualizing and exploring results of multivariate analyses in geographic space. This tool can be used to map results of virtually any multivariate analysis of georeferenced data, and routines for exporting results from a number of standard methods have been integrated in the R package adegenet, including principal components analysis (PCA), spatial PCA, discriminant analysis of principal components, principal coordinates analysis, nonmetric dimensional scaling and correspondence analysis. mvmapper's greatest strength is facilitating dynamic and interactive exploration of the statistical and geographic frameworks side by side, a task that is difficult and time-consuming with currently available tools. Source code and deployment instructions, as well as a link to a hosted instance of mvmapper, can be found at https://popphylotools.github.io/mvMapper/.


Incidence of endophthalmitis after 20-gauge vs 23-gauge vs 25-gauge pars plana vitrectomy.
To compare endophthalmitis rates after 20-gauge versus 23-gauge versus 25-gauge pars plana vitrectomy (PPV) in 2007-2008, and compare the rates with those of 2005-2006. Multicenter study including all patients who developed endophthalmitis following PPV performed by any of the authors during 2005-2008, and all patients who developed endophthalmitis following PPV at Penn State College of Medicine and Bascom Palmer Eye Institute during 2005-2008. The endophthalmitis rates after 20-gauge, 23-gauge and 25-gauge PPV during 2007-2008 were compared to those from 2005-2006. The endophthalmitis incidence during 2007-2008 was 1/4,403 (0.02%) for 20-gauge PPV, 1/3,362 (0.03%) for 23-gauge PPV, and 1/789 (0.13%) for 25-gauge PPV. There is no significant difference among these rates between any two of the three groups. Compared with the endophthalmitis rates among the same group of surgeons during 2005-2006, the 2007-2008 endophthalmitis rates following 20-gauge and 23-gauge PPV were stable, and the rate following 25-gauge PPV was marginally lower (p = 0.056; odds ratio = 0.15; 95% CI: (0.003, 1.03)). There was no significant difference in the 2007-2008 rates of endophthalmitis following 20-gauge versus 23-gauge versus 25-gauge PPV; among the same group of surgeons, the 2007-2008 rate of endophthalmitis following 25-gauge PPV was marginally lower than the 2005-2006 rate.


Programme costing of a physical activity programme in primary prevention: should the costs of health asset assessment and participatory programme development count?
This analysis aims to discuss the implications of the "health asset concept", introduced by the WHO, and the "investment for health model" requiring a "participatory approach" of cooperative programme development applied on a physical activity programme for socially disadvantaged women and to demonstrate the related costing issues as well as the relevant decision context. The costs of programme implementation amounted to €48,700. Adding the costs for developing the programme design of €48,800 results in total costs of €97,500; adding on top of that the costs of asset assessment running to €35,600 would total €133,100. These four different cost figures match four different types of potentially relevant decisions contexts. Depending on the decision context the total costs, and hence the incremental cost-effectiveness ratio of a health promotion intervention, could differ considerably. Therefore, a detailed cost assessment and the identification of the decision context are of crucial importance.


Role of Innate Immune Signaling in Non-Alcoholic Fatty Liver Disease.
Non-alcoholic fatty liver disease (NAFLD) has become the most epidemic liver disease worldwide owing to rapid changes in lifestyle over the past few decades. This chronic condition intertwines with low-grade inflammation and metabolic disequilibrium, and potentiates the onset and progression of devastating hepatic and extrahepatic complications. In addition to an integral role in promoting host defense, recent studies also implicate innate immune signaling in a multitude of processes that control the progression of NAFLD. The focus of this review is to highlight emerging evidence regarding the role of innate immunity in NAFLD and the integration of different pathways that affect both inflammation and metabolism across the spectrum of this liver morbidity.


Fetal dural sinus thrombosis: A systematic review.
Fetal dural sinus thrombosis (DST) is a rare condition. Although numerous case reports exist, the findings appear heterogenous and providing accurate patient counselling remains challenging. A systematic literature review was conducted in accordance with PRISMA guidance. Thirty-one studies including 78 patients were included in this review. No association with maternal or neonatal coagulopathy, infection or trauma was found. The average gestational age at diagnosis was 25 weeks (range 17-34 weeks). Approximately half of foetuses affected were female (48.7%); one quarter were male (25.6%) and one quarter had no sex stated (25.6%). Termination of pregnancy was chosen in 25.6% of cases (20/78). In continuing pregnancies,10.3% (6/58) experienced a perinatal death. Antenatally, the majority of lesions either decreased in size (38.5%) or completely resolved (32.7%). The neonatal or childhood outcome was normal in 88.0% of survivors (44/50). The average age at follow up was 16.4 months, ranging from birth to 6 years. This review found that 10% of DST cases experience in-utero or neonatal death. In survivors, the majority of cases reduce in size or completely resolve in pregnancy and 85% are reported to have a good outcome. However, further evidence is needed regarding long-term neurocognitive sequelae.


Pilot study of low-dose, divided maximum tolerated dose of CPT-11 in 21 consecutive patients with metastatic colorectal or gastric cancer.
We devised a new treatment regimen, delivering a frequent low dose of CPT-11, calculated by dividing the maximum tolerated dose (MTD) to reduce its toxicity without impairing its efficacy. CPI-11, 25 mg/m2, determined by dividing the MTD dose per month by 12, was given on days 1, 2, and 3 of every week, to 21 consecutive patients; 12 with metastatic colon cancer and 9 with metastatic gastric cancers. The total delivered dose of CPI-11 per patient was more than 1,000 mg in 17 (80.1%) of the 21 patients. Grade 3 marrow depression developed in 3 (14.3%) patients, and although nausea, vomiting, alopecia, and diarrhea developed in some patients, these side effects were all categorized as grade 2 or milder. The antitumor effect was evaluated in 18 patients with measurable lesions, who had received CPI-11 according to our regimen for at least 3 weeks. Of these 18 patients, 10, 7, and 1, respectively, had a found to have partial response, no change, or progression of disease, demonstrating a 55.6% efficacy rate [colon 6/10 (60.0%) and stomach 4/8 (50.0%)]. Moreover, time to progression (TTP) was greater than 90 days in 12 (75.0%) of these 18 patients. These results show that our low-dose, divided MTD of CPI-11 regimen is a promising method of reducing toxicity and strengthening the antitumor effect, justifying further large-scale comparative clinical studies to verify this potential.


Effect of seed source, light, and nitrogen levels on biomass and nutrient allocation pattern in seedlings of Pongamia pinnata.
Nitrogen (N) and light are critical determinants of plant growth and productivity. The present study attempts to quantify the underlying mechanisms and effects of light, N levels, and seed source on growth, biomass, nutrient allocations, and nutrient use efficiencies (NUEs) in seedlings of Pongamia pinnata. The differential and fixed hypothesis and isometric and allometric relationships were also examined. Six morphologically superior seed sources of P. pinnata from three contrasting agro-climatic conditions of India were evaluated with application of two levels of both N (low dose @ 5g plant-1 and 15 g plant-1) and light regimes (full light-100% and low light-50%) in mother nursery. Among the seed sources, the native Raipur seed source was found outstanding in growth, biomass, and nutrient use efficiency. N was more critical than light in promoting growth in seedlings of P. pinnata. High N and high light regimes increased shoot/root ratios. The components showed allometric growth and followed a differential allocation pattern. The exploitation of suitable genetic resources combined with managerial interventions is necessary for development of quality planting stock of P. pinnata. Nutrient use efficiencies, biomass production, and their allocation were important indicators and criteria for selection. The study suggests that Raipur and Jabalpur seed sources having high NUE should be grown along with adequate N application (15 g plant-1) and light conditions.


GLC determination of betahistine in serum.
A gas chromatographic method was developed for the determination of betahistine in serum in the range of 0.6-6.0 microgram/ml.


Rapid diagnosis of echovirus type 33 meningitis by specific IgM detection using an enzyme linked immunosorbent assay (ELISA).
During an outbreak of meningitis in France (in the Lyon area), from June to October 1982, serum and stool samples were collected from 227 patients. An enzyme-linked immunosorbent assay (ELISA) for titrating IgG and IgM antibodies anti-echovirus type 33 was developed and compared with the virus isolation technique, and with the titration of neutralizing antibodies. In 39 patients excreting echovirus 33 in faeces, the ELISA test allowed a positive serodiagnosis in 85% of the cases by detection of specific IgM (64% of the cases) and by seroconversion (21%). Compared with the neutralization (Nt) test, ELISA was found to be more sensitive. The antibody titres in ELISA were over 50 times higher and detected earlier than the neutralizing antibodies. This early immune response allowed a rapid diagnosis by specific IgM detection in the acute sera collected within 8 days after the appearance of the clinical symptoms in more than 50% of the 97 patients examined, whereas the Nt test allowed a positive serodiagnosis in only 32% of the patients. The use of a caesium chloride purified antigen insured the specificity of the reactions.


Capture of bacterial endotoxins using a supermacroporous monolithic matrix with immobilized polyethyleneimine, lysozyme or polymyxin B.
Bacterial endotoxins (BEs) are integrated part of Escherichia coli, a microorganism widely used for the production of recombinant proteins. BEs should be eliminated in the course of down stream processing of target protein produced by these bacteria. Supermacroporous monolith (continuous bed) columns, so called cryogel columns, with immobilized polyethyleneimine (PEI), polymyxin B (PMB) and lysozyme were employed for BEs capture. Due to the large interconnected pores it was possible to use cryogel columns at flow rates as high as 10 ml/min. The columns packed with Sepharose CL-4B with immobilized PEI, PMB and lysozyme were impossible to use at these high flow rates due to the collapse of the bed. The dynamic capacities of the cryogel columns were nearly independent of the flow rate. In the presence of EDTA, BEs were quantitatively captured from mixtures with a model protein, bovine serum albumin (BSA) at pH 7.2 with practically no protein losses. At pH 3.6 BEs were captured directly from non-clarified E. coli cell lysate resulting in more than 10(4) times BEs clearance.


Conformationally constrained diacylglycerol (DAG) analogs: 4-C-hydroxyethyl-5-O-acyl-2,3-dideoxy-D-glyceropentono-1,4-lactone analogs as protein kinase C (PKC) ligands.
The (R)-DAG-lactones (5 and 7E/Z) are conformationally constrained diacylglycerol (DAG) analogs with high potency as protein kinase C (PKC) ligands. Here, we have prepared and characterized their one-carbon lengthened analogs (6 and 8E/Z). The target compounds were synthesized from 1,2-O-isopropylidene D-xylose through a key intermediate, 4-C-hydroxyethyl-2,3-dideoxy-D-glyceropentono-1,4-lactone (13); they were evaluated as competitive ligands to displace bound [(3)H]phorbol 12,13-dibutyrate (PDBU) from a recombinant single isozyme (PKC-alpha). The binding affinities of the synthesized compounds were K(i) = 2.623 microM for 6, K(i) = 1.080 microM for 8Z and K(i) = 0.92 microM for 8E, which were ca. 27, 90, and 70 times less potent than the corresponding parent compounds (5, 7Z and 7E). Molecular modeling indicated that the reduced binding affinity of the representative 3-alkylidene lactone 8Z, as compared to 7Z, may be explained by its poor fit in the sn-1 binding mode as well as by its entropic loss due to the relatively flexible hydroxyethyl group.


Surveillance following orchidectomy for stage I seminoma of the testis.
From 1985 to 1988, 261 unselected patients entered a nationwide Danish study of surveillance only for testicular seminoma stage I. The median follow-up time after orchidectomy was 48 months, range 6-67 months. 49 patients relapsed (19%). Sites of relapse were paraaortic lymph nodes in 41 patients, pelvic lymph nodes in 5, inguinal lymph nodes in 2 and lung metastases in 1 patient. The median time to relapse was 14 months, range 2-37 months. The 4-year relapse-free survival was 80%. 37 of the relapsing patients (76%) had radiotherapy as relapse treatment. Of these patients, 4 (11%) had a second relapse and received chemotherapy. 1 died of disseminated seminoma. Of the relapsing patients, 12 (24%) had chemotherapy as relapse treatment because of bulky (11 patients) or disseminated disease (1 patient). None of these patients have had a second relapse. However, 2 patients died of infection due to chemotherapy-induced neutropenia. Thus, there have been three seminoma-related deaths (1.1%). The testicular tumour size had an independent prognostic significance. The 4-year relapse-free survivals were 94, 82 and 64% for tumours < 3, 3 to < 6 and > or = 6 cm, respectively. Patients with tumours > or = 6 cm will now be given prophylactic radiation treatment, whereas we will continue to use surveillance only after orchidectomy for patients with tumours < 6 cm.


Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials.
Anti-epidermal growth factor receptor (EGFR) agents [monoclonal antibodies (MoAbs), tyrosine kinase inhibitors (TKIs)] are targeted therapies used in advanced cancers. Arterial and venous thromboembolic events (ATEs and VTEs excluding catheter-related events) were not investigated with these agents, and the risk of these events is still unknown. We have carried out a meta-analysis in order to determine the incidence and the relative risk (RR) of VTEs and ATEs associated with these agents. Statistical analyses were conducted to calculate the summary incidence, RRs and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of the included studies. A total of 13 studies (7611 patients) was selected for this meta-analysis. The associated RRs of VTEs (11 studies comprising 7073 patients) and ATEs (5 studies consisting of 3030 patients) were 1.32 (95% CI 1.07-1.63; P equals 0.01) and 1.34 (95% CI 0.94-1.9; P equals 0.11) compared with control patients. The analysis of VTEs was also stratified by class of agents: MoAbs (RR 1.34; P equals 0.01) and oral TKIs (RR 1.16; P equals 0.65). Anti-EGFR agents are associated with a significant increase in the risk of VTEs. In particular, the risk is significant with cetuximab and panitumumab in settings where these drugs are currently approved.


Gas exchange after pulmonary fat embolism in dogs.
Gas exchange following moderately severe experimental pulmonary fat embolism was studied in nine dogs. A new method designed to describe the distribution of ventilation-perfusion ratios in the lung was applied before and after intravenous injection of homologous neutral fat. The dose of fat (0.75 ml/kg) was low enough to produce a small but significant decrease in arterial PO2 (mean change of 10 mm Hg) in the first 15 minutes after the embolism but high enough to result in the death of two of the four dogs that were allowed to survive the initial postembolism period. Pulmonary artery pressure and pulmonary vascular resistance both rose significantly within 5 minutes of the fat injection and remained elevated for the 2 hour experimental period. Immediately after the embolism there was an increase in the percentage of the total ventilation going to areas of the lung with ventilation-perfusion ratios between 10 and 100, which usually appeared as a discrete mode in the ventilation distribution. This mismatching of ventilation and perfusion partially resolved within 2 hours after the embolism, as indicated by the gradual disappearance of this population of gas exchanging units with relatively decreased blood flow. At no time within 2 hours after the embolism was there a significant increase in shunt or in ventilation to totally unperfused lung. The gas exchange pattern in the two dogs that subsequently died was indistinguishable from that of the other seven in the immediate postembolism period.


Increased statistical power with combined independent randomization tests used with multiple-baseline design.
Physicians often assess the effectiveness of treatments on a small number of patients. Multiple-baseline designs (MBDs), based on the Wampold-Worsham (WW) method of randomization and applied to four subjects, have relatively low power. Our objective was to propose another approach with greater power that does not suffer from the time requirements of the WW method applied to a greater number of subjects. The power of a design that involves the combination of two four-subject MBDs was estimated using computer simulation and compared with the four- and eight-subject designs. The effect of a delayed linear response to treatment on the power of the test was also investigated. Power was found to be adequate (>80%) for a standardized mean difference (SMD) greater than 0.8. The effect size associated with 80% power from combined tests was smaller than that of the single four-subject MBD (SMD=1.3) and comparable with the eight-subject MBD (SMD=0.6). A delayed linear response to the treatment resulted in important reductions in power (20-35%). By combining two four-subject MBD tests, an investigator can detect better effect sizes (SMD=0.8) and be able to complete a comparatively timelier and feasible study.


Measurement of optimal flow rate in gradient elution liquid chromatography.
Method development in gradient LC relies upon the selection of a solvent time program and a mobile phase flow rate. The flow rate, optimal for gradient separation cannot be inherently predicted by the isocratic value optimal for a given analyte, and rather should be identified independently to ensure the highest separation performance of gradient analysis. The optimal flow rate (Fopt) is defined herein as the solvent volumetric flow rate (F) maximizing the separation (Δs) of a predetermined peak-pair or the separation capacity (sc) of the entire LC analysis. The theoretical background and the experimental technique of measurement of Fopt in gradient elution analysis were considered and experimentally demonstrated. The technique of measuring Fopt is based on translatable changes of F where the product FtG (tG is the gradient time) was the same for all values of F. The Fopt was found as F corresponding to the maximum in Δs or in sc.


Sex-dependent performance differences in curvilinear aiming arm movements in octogenarians.
In an aging society, it is necessary to detect the cognitive decline of individuals at an early stage using simple measurement methods. This makes early health care possible for those affected. The aim of the study was to develop a classifier for cognitive state in older adults with and without mild cognitive impairment (MCI) based on kinematic parameters of linear and curvilinear aiming arm movements. In a group of 224 older adults over 80 years of age (cognitively healthy and MCI), the movement duration and intersegment intervals of linear and curvilinear arm movements of 20 cm were recorded. Movement duration was significantly longer in the curvilinear condition than in the straight movement, and MCI participants required significantly more time than cognitively healthy participants. Post-hoc analysis on the fluidity of movement in the curvilinear condition showed that MCI men had significantly longer inter-segmental intervals than non-MCI men. No difference was found in women. Based on the inter-segmental intervals, a simple classifier could be developed that correctly classified 63% of the men. In summary, aiming arm movements are only conditionally suitable as a classifier for cognitive states. For the construction of an ideal classifier, age-related degeneration of cortical and subcortical motor areas should be considered.


Occurrence of gastrin in gastric juice, in antral secretion, and in antral perfusates of cats.
Large amounts of gastrin are present in vagally induced gastric juice of cats. This gastrin is secreted directly into the gastric lumen from the antral mucosa, because in experiments in which the stomach was divided into one antral and one corporeal pouch, most of the gastrin appeared in the antrum, only small amounts appearing in the acid gastric juice. When the antrum was perfused with a slightly alkaline buffer solution, parallel recordings of the gastrin release into the antral lumen and into the gastric venous outflow revealed more gastrin to be secreted per minute into the gastric lumen than into the blood (2 to 23 times as much). Electrical vagal stimulations caused an increased release of gastrin both into the antral lumen and into the circulation.


An in vitro evaluation of the irrigating characteristics of ultrasonic and subsonic handpieces and irrigating needles and probes.
The objective of this in vitro study was to evaluate the efficacy of a variety of endodontic irrigating devices. This study utilized plastic blocks with artificial canals to simulate the clinical setting. The canals were instrumented, and red food dye was introduced into each canal. The blocks were placed in a jig to simulate maxillary and mandibular arch orientation. Irrigation was performed with: (a) B-D 22-gauge needle; (b) Monoject Endodontic Needle 23 and 27 gauge; (c) Max-i-Probe 25-, 28-, and 30-gauge probes; (d) Cavi-Endo ultrasonic handpiece; and (e) Micromega 1500 subsonic handpiece. A Sony Camcorder was used to record the effect of irrigation on the simulated canal contents. Tape review enabled the investigators to observe dye clearance effected by each modality. The Max-i-Probe probes were the most effective instrument used to clear dye from the simulated canals in both the mandibular and maxillary positions.


An open study comparing two regimens of gemeprost for the termination of pregnancy in the second trimester.
Two regimens of the prostaglandin E1 analogue, gemeprost, were compared in an open trial for termination of pregnancy between 12 and 18 weeks. Fifty women received 5 x 1 mg of gemeprost every 3 h and in another 50 cases, 4 x 1 mg of gemeprost was administered every 6 h. Although the median abortion interval was slightly shorter in the 3-hourly group (15.9 h vs. 16.9 h; p = 0.5), the cumulative abortion rates at 24 h were similar (88% vs. 82%; p less than 0.5). In women who aborted within the first 24 h, significantly fewer pessaries (p less than 0.01) were required to induce abortion in the 6-h treatment group (median 3, range 1-4) than the 3-h group (median 5, 2-5). Parous women in both treatment groups required fewer pessaries to induce abortion than did nulliparous women (not significant; p = 0.5). Significantly (p less than 0.01) fewer pessaries were required to induce abortion in the 6-h gemeprost group. The were no significant differences between the groups regarding incidences of diarrhea, vomiting, or the request for analgesia. These results suggest that in many women the number of pessaries used to induce mid-trimester abortion could be reduced by lengthening the interval between insertion of pessaries within the first 24 h, without loss of clinical efficacy.


Sugarcane vinasse as organo-mineral fertilizers feedstock: Opportunities and environmental risks.
Fertigation using sugarcane vinasse is expected in the sugar and alcohol industries; however, its indiscriminate practice can trigger soil salinization and contamination of water sources. This review article appraises the vinasse use as a precursor material in producing organo-mineral fertilizers. Vinasse use could be an alternative for the increased demand for organo-mineral fertilizers. In that case, the vinasse reuse would be maintained but through controlled practices and lower environmental impact. The state-of-art points to possible advantages associated with the vinasse conversion into organo-mineral fertilizers, such as ease of transport and handling, low variability in its composition, and lower risks of soil and water resources contamination. It has been summarized and critically discussed the past ten years (2011-2021, total number papers revised: 175) of research data about vinasse composition, along with the limitations to be overcome in the near future to enable the application of organo-mineral fertilizers. Possible nutrients supplementation beyond those already present in vinasse composition would depend on the crop requirement, and the impact on the soil biota and integrity should be better understood. The aspects discussed along the manuscript would be aligned with circular economy principles, converting a residue (vinasse) into a potential resource for agricultural activities, including sugar and alcohol industries. After all, although promising, obtaining organo-mineral fertilizers from vinasse must be empirically validated and its feasibility proven by comparative studies between fertigation and the use of organo-mineral fertilizers.


Inter-species Metabolic Interactions in an In-vitro Minimal Human Gut Microbiome of Core Bacteria.
Knowledge of the functional roles and interspecies interactions are crucial for improving our understanding of the human intestinal microbiome in health and disease. However, the complexity of the human intestinal microbiome and technical challenges in investigating it pose major challenges. In this proof-of-concept study, we rationally designed, assembled and experimentally tested a synthetic Diet-based Minimal Microbiome (Db-MM) consisting of ten core intestinal bacterial species that together are capable of efficiently converting dietary fibres into short chain fatty acids (SCFAs). Despite their genomic potential for metabolic competition, all ten bacteria coexisted during growth on a mixture of dietary fibres, including pectin, inulin, xylan, cellobiose and starch. By integrated analyses of metabolite production, community composition and metatranscriptomics-based gene expression data, we identified interspecies metabolic interactions leading to production of key SCFAs such as butyrate and propionate. While public goods, such as sugars liberated from colonic fibres, are harvested by non-degraders, some species thrive by cross-feeding on energetically challenging substrates, including the butyrogenic conversion of acetate and lactate. Using a reductionist approach in an in-vitro system combined with functional measurements, our study provides key insights into the complex interspecies metabolic interactions between core intestinal bacterial species.


Enamel matrix derivative promotes osteoclast cell formation by RANKL production in mouse marrow cultures.
Enamel matrix derivative (EMD) is used clinically to promote periodontal tissue regeneration, however, there are few reports regarding effects of EMD on bone metabolism. We evaluated the influence of EMD on osteoclast formation using in vitro bone marrow culture. Bioactive fractions were purified from EMD by reverse-phase HPLC on a C18 hydrophobic support, then mouse bone marrow cells were cultured with EMD or its purified fractions for 8 days. Following tartrate resistant acid phosphatase (TRAP) staining, TRAP-positive multinucleated cells were counted. The expression of receptor activator of NF-kappaB ligand (RANKL) in osteoblastic cells was detected using immunoblotting. EMD was dissolved in 0.1% (vol/vol) trifluoroacetic acid and applied to a C18 column for HPLC. Two major peaks were obtained of which the second (fraction numbers 21-25) was found to induce the formation of osteoclasts in mouse marrow cultures. Further, osteoprotegerin completely inhibited osteoclast formation in mouse marrow cultures with or without osteoblastic stromal cells, when being cultured with EMD or its purified fractions. In addition, Western blot analysis revealed the presence of RANKL in mouse osteoblastic cells stimulated with EMD or its purified fractions. Our results indicate that EMD induces the formation of osteoclasts through RANKL expressed by osteoblastic cells, and suggest that EMD may regulate both bone formation and bone resorption during periodontal tissue regeneration.


Respiration: The circuit for hypoxia-induced sighs.
Sighs are a response to hypoxia, altered lung volume, and emotional state. A recent study employing in vivo physiology, optogenetics, chemoablation, and genetic silencing shows the importance of gastrin releasing peptide-expressing neurons in mediating sighs.


Penicillins, cephalosporins, quinolones.
This article details the mechanisms of action, antimicrobial spectrum, pharmacokinetics, and adverse reactions of these three antibiotics.