Influence of different surface treatments on the short-term bond strength and durability between a zirconia post and a composite resin core material.
Reliable bonding between zirconia posts and composite resin core materials is difficult to achieve because of the smooth surface texture and lack of silica content of zirconia posts. The purpose of this study was to evaluate the effect of different surface treatments on the short-term bond strength and durability between a zirconia post and a composite resin core material. Eighty zirconia posts were divided into 4 groups (n=20). Specimens received 1 of 4 different surface treatments: group AIRB, airborne-particle abrasion; group TSC-SIL, tribochemical silica coating (CoJet system) and silanization (ESPE Sil); group AIRB-BSIL, airborne-particle abrasion and MDP-containing primer (Clearfil SE Bond Primer)/silane coupling agent (Clearfil Porcelain Bond Activator) mixture application; and group TSC-BSIL, tribochemical silica coating and MDP-containing primer/silane coupling agent mixture application. Average surface roughness (Ra) of zirconia posts produced by airborne-particle abrasion or silica coating was measured using an optical profilometer. Composite resin core foundations (Build-it FR) were formed using transparent acrylic resin tubes (12mm in length and 7mm in diameter). Each group was further divided into 2 subgroups of 10 specimens and stored in distilled water at 37 degrees C, either for 24 hours or for 150 days with 37,500 thermal cycles between 5 degrees C and 55 degrees C, with a dwell time of 30 seconds. Following water storage, the specimens were sectioned perpendicular to the bonded interface into 2-mm-thick post-and-core specimens under water cooling. Push-out tests were performed with a universal testing machine at a crosshead speed of 0.5mm/min. Debonded post surfaces were examined with SEM. Data were analyzed with 1- and 2-way ANOVA and Tukey multiple comparison tests (alpha=0.05). No significant differences were detected between the Ra values of airborne-particle-abraded and silica-coated specimens (P=.781). The short-term mean bond strengths for group TSC-BSIL (27.1 +/- 3.2 MPa) and TSC-SIL (25.2 +/- 2.4 MPa) were statistically higher (P<.001) than AIRB-BSIL (23.3 +/- 2.2 MPa). The relatively high bond strengths for groups TSC-BSIL and TSC-SIL decreased significantly after 150 days of water storage to 13.5 +/- 1.6 and 11.8 +/- 1.2 MPa, respectively (P<.001). Durable bonding was obtained only in group AIRB-BSIL (21.8 +/- 2.7 MPa), which was also the only group demonstrating predominantly cohesive failures in the core material after long-term water storage. Data suggest that the short-term high bond strength obtained with a silane coupling agent or MPD-containing primer/silane coupling agent mixture to silica-coated zirconia posts was decreased with water storage and thermal cycling, whereas a durable bond could be obtained when an MPD-containing primer/silane coupling agent mixture was applied to the airborne-particle-abraded post surface.


Sustainability assessment approaches based on water-energy Nexus: Fictions and nonfictions about non-conventional water resources.
In arid and semi-arid regions of the world, non-conventional water resources are considered as alternative water resources and a long-term rescue plan against severe water scarcity. To avoid negative impacts, some criteria and indices are required to justify the extent of this utilization. Production of non-conventional waters requires energy while consumption of energy implies various financial and environmental impacts. In this study, Relative Sustainability Probability has been estimated by "Sandoval-Solis" and "Multivariate Copula" approaches to shed light on fictions and nonfiction of non-conventional water resources. The proposed method has been implemented in the Kashan catchment in central Iran. Results indicate that the "Multivariate Copula" approach is generating the same results as the "Sandoval-Solis" approach but relatively much easier and much faster. Moreover, the proposed method could be inspiringly promoted to higher dimensions of Copula leading to more precise results in complex human-environment systems. Besides this, results are verifying non-conventional water fictions could not be considered as long term sustainable rescue attempts, particularly so in the case of seawater conveyance. Rethinking of sustainability definition should be considered in futuristic policy makings leading to a shift to untypical development scenarios, such as Halo-Engineering concept, insisting on lower water and energy consumption in arid and semi-arid regions.


Adductor canal block performed 20 hours after total knee arthroplasty to improve postoperative analgesia and functional recovery: a double-blind randomized controlled clinical trial.
The goal of postoperative pain protocols in total knee arthroplasty (TKA) is to get pain free patients throughout severe pain period without impairing walking ability. The aim of the study was to investigate if an adductor canal block performed 20 hours after TKA, in patients treated with systemic analgesia and intraoperative local infiltration anesthesia (LIA), improves postoperative pain and functional outcomes. A prospective randomized, double-blinded controlled study was conducted. One hundred eighty-three patients undergoing primary TKA were randomized to receive either a sham block or an adductor canal block with 20 mL of ropivacaine 0.5%. The primary outcome was resting and dynamic pain scores using the Numerical Pain Rating Scale (NPRS). Secondary outcomes included opioid rescue requirements, quadriceps and adductor muscle strength, patient ability for ambulation and complications. Two hours after the block, in adductor canal block group NPRS was significantly lower at rest (1 [0-2] vs. 3 [2-5], P<0.001) and with mobilization (5 [3-6] vs. 6 [5-8], P<0.001), and quadriceps strength was significantly higher (3.7 [2.7-6] vs. 3 (1.7-4.9), P=0.023). The differences were not maintained beyond 24 hours post-block. In the first 24 hours the percentage of patients with tramadol requirements was lower in the adductor canal block group (36 [38.3] vs. 52 [58.4], P=0.006). Other secondary outcomes were similar between groups. There were no patient falls. An adductor canal block done 20 hours after total knee arthroplasty reduces pain and opioid requirements without increasing the risk of falls. An optimal pain control, especially at movement was not achieved.


Maturation of the E. coli Glu2, Ile1, and Ala1B tRNAs utilizes a complex processing pathway.
Despite significant progress in understanding the diversity of tRNA processing pathways in Escherichia coli, the mechanism for the maturation of tRNAs encoded within the rRNA operons has not received much attention. Here, we show that the Glu2, Ile1, and Ala1B tRNAs, encoded by 10 genes located between the 16S and 23S rRNAs in the seven rRNA operons, are matured via a RNase E-independent processing pathway that utilizes at least six different enzymes. It has been shown that the Glu2 and Ile1-Ala1B pre-tRNAs released by initial RNase III cleavages of the 30S primary rRNA transcripts retain extended 5'-leader (35-139 nt) and 3'-trailer (166-185 nt) sequences. However, the 5' maturation of the tRNAs by RNase P is inhibited until the trailer sequences are shortened to 1-4 nucleotides, initially by a second RNase III cleavage at 31-42 nucleotides downstream of the CCA determinant followed by exonucleolytic trimming. The RNase III cleaved Glu2 and Ile1-Ala1B trailer fragments are degraded via PAP I- dependent exonucleolytic decay. Compared to the six previously characterized tRNA processing pathways, maturation of the Glu2, Ile1, and Ala1B tRNAs is considerably more complex and appears to be distinct from what occurs in Gram-positive bacteria.


Effect of a prior thyroid cancer on the survival of lung cancer patients: a retrospective study based on SEER database.
The effect of a history of thyroid cancer on the prognosis of lung cancer patients has not been fully investigated. Therefore, we aimed to evaluate this effect based on a large cohort. Data of 154844 lung cancer patients, of whom 406 had prior thyroid cancer, were collected from SEER database. Primary survival analysis was conducted between patients with and without prior thyroid cancer using Kaplan-Meier method. Secondary survival analysis was conducted to investigate the effects of the stage and histological subtype of the prior thyroid cancer on the survival of lung cancer patients. Propensity adjustment was used to reduce confounding effect. Compared to patients without prior malignancy, patients with prior thyroid cancer were predominantly female (72.4% vs. 48.7%, p < 0.001), had lower stage (proportion of localized tumor: 40.4% vs. 25.6%, p < 0.001), and larger proportion of surgery (52.2% vs. 29.4%, p < 0.001), and had better survival (5-year survival rate: 55.53% vs. 33.16%, p < 0.001). After propensity adjustment, the survival was similar between the groups (5-year survival rate: 55.53% vs. 51.78%, p = 0.24). The survival of patients with different stages (localized tumor vs. regional tumor: p = 0.88) or different histological subtypes (p = 0.46) of prior thyroid cancer were comparable. Survival of lung cancer patients with or without prior thyroid cancer was similar after propensity adjustment, and the stage or histological subtype of the prior thyroid cancer had no significant effect on the survival of lung cancer patients.


Effects of hind limb suspension on the development of dystrophic hamster muscle.
The effects of hind limb suspension on the development of dystrophic muscles was studied in five dystrophic hamsters (CHF 147, formally UMX 7.1) from age 20 days for 5 months. Their histochemical and contractile properties were compared to five aged-matched controls. Twitch and tetanic tensions (Po) were reduced in treated soleus by 22% and 32% and in plantaris by 29% and 39%, respectively; these reductions were proportional to their smaller cross-sectional areas. Twitch duration and half-relaxation times were not altered in experimental soleus muscle but the mean time to 50% of Po was 19 ms faster than the controls. Experimental soleus and plantaris had higher percentages of type II fibers, i.e., 63% and 97% compared with 37% and 93% in controls, respectively. A similar trend was seen in gastrocnemius and extensor digitorum longus muscles. Areas of both fiber types were reduced in all muscles, but only statistically significant differences in type I areas were seen in soleus and type II areas in the other three muscles. The percentages of fibers with centronuclei in whole cross sections, determined at different positions along the muscle lengths, were reduced by 30% in soleus and extensor digitorum longus. The areas of fiber necrosis were also reduced in experimental extensor digitorum longus and plantaris. These changes in nonweight-bearing muscles support the hypothesis that contractile activity can influence the development of dystrophic properties.


[The effect of biocides on the microflora of soils and their degradation. 4. The influence of substances inhibiting the straw decomposition on the nitrogen transformation (author's transl)].
1. Active ingredients retarding the carbon-transformation of straw (TCP, Thiuram, TBTO) also retard the nitrification. Their active period depends on the concentration and on the presence of organic matter. High doses of urea can inhibit the nitrification as well. 2. The activity of urease and the ammonification could not be influenced by adequate doses of the tested active ingredients. 3. The species of bacterium Azotobacter fixing the nitrogen from the air were inhibited by TCP, urea and D-chloramphenicol and promoted by Thiuram and WTZ II 277 after a short period of inhibition. 4. The fungi are very important in the biological nitrogen fixation after manuring straw and in prevention of nitrogen leaching in the autumn. 5. The sufficient concentration of the active ingredients to inhibit the nitrification are lower than the fungicidal concentrations. The soil bacteria could even not be restrained by doses of 5000 ppm. The bacilli were more retarded in presence of organic matters than in a not manured soil.


Atomic force microscopy observation and characterization of single virions and virus-like particles by nano-indentation.
Structure and function of viruses are intimately related, and one of the goals in virology is to elucidate the mechanisms behind this relation. A variety of research endeavours is focused on studying these mechanisms and a relatively new technique in this field is Atomic Force Microscopy (AFM). Using AFM virions and virus-like particles can be imaged and manipulated at the single particle level. Here we review recent AFM nano-indentations studies unveiling for instance the mechanics of capsid-genome interactions, morphological changes that drive viral maturation, capsid stabilizing factors and viral uncoating. We show that in an increasing amount of literature a clear link between mechanics and infectivity is observed, which not only provides us with new fundamental insights into virology, but also provides ways to improve virus-like particles for applications in nanomedicine and nanotechnology.


Protein catabolism during the postoperative course after renal transplantation.
Protein catabolic rate (PCR) was measured daily by computerized mass balance studies in 50 subjects during hospitalization after renal transplant. All subjects received 60 mg prednisone per day. PCR rose over the first 3 to 4 postoperative days and then stabilized at an accelerated level, which was sustained through the third posttransplant week. Rejection therapy with either 3 mg/kg/d prednisone or 15 mg/kg/d of methylprednisolone for 3 days further increased PCR, but there was no difference in PCR between these two regimens. Protein restriction did not decrease PCR and subjects offered a higher protein diet did not have further acceleration of PCR. We conclude that 60 mg/kg/d prednisone produces an obligatory acceleration of PCR that is further accentuated by higher steroid doses. The use of minimal maintenance doses of prednisone consistent with adequate immunosuppression seems wise. Protein balance may be improved if protein intake is increased to match individual rates of accelerated protein catabolism.


Association between hyperuricemia and acute kidney injury in critically ill patients with sepsis.
Sepsis-related AKI is related to short-term mortality and poor long-term prognoses, such as chronic renal insufficiency, late development of end-stage renal disease, and long-term mortality. In this study, we aimed to investigate the association of hyperuricemia with acute kidney injury (AKI) in patients with sepsis. The retrospective cohort study included 634 adult sepsis patients hospitalized in the intensive care unit (ICU) of the First Affiliated Hospital of Guangxi Medical University from March 2014 to June 2020 and the ICU of the Second Affiliated Hospital of Guangxi Medical University from January 2017 to June 2020. Based on the first serum uric acid level within 24 h of admission to the ICU, patients were divided into groups with or without hyperuricemia, and the incidence of AKI within seven days of ICU admission was compared between the two groups. The univariate analysis analyzed the effect of hyperuricemia on sepsis-related AKI, and the multivariable logistic regression model analysis was used. Among the 634 patients with sepsis, 163 (25.7%) developed hyperuricemia, and 324 (51.5%) developed AKI. The incidence of AKI in the groups with and without hyperuricemia was 76.7% and 42.3%, respectively, with statistically significant differences (2 = 57.469, P < 0.001). After adjusting for genders, comorbidities (coronary artery disease), organ failure assessment (SOFA) score on the day of admission, basal renal function, serum lactate, calcitonin, and mean arterial pressure, hyperuricemia was showed to be an independent risk factor for AKI in patients with sepsis (OR = 4.415, 95%CI 2.793 ~ 6.980, P < 0.001). For every 1 mg/dL increase in serum uric acid in patients with sepsis, the risk of AKI increased by 31.7% ( OR = 1.317, 95%CI 1.223 ~ 1.418, P < 0.001). AKI is a common complication in septic patients hospitalized in the ICU, and hyperuricemia is an independent risk factor for AKI in septic patients.


Monoterpene-Containing Substituted Coumarins as Inhibitors of Respiratory Syncytial Virus (RSV) Replication.
Respiratory syncytial virus (RSV) is a critical cause of infant mortality. However, there are no vaccines and adequate drugs for its treatment. We showed, for the first time, that O-linked coumarin-monoterpene conjugates are effective RSV inhibitors. The most potent compounds are active against both RSV serotypes, A and B. According to the results of the time-of-addition experiment, the conjugates act at the early stages of virus cycle. Based on molecular modelling data, RSV F protein may be considered as a possible target.


Skin color, aging, and plasma L-dopa levels.
Although plasma levels of L-dopa are derived substantially from catecholamine-synthesizing tissues, melanocytes--which produce L-dopa as part of the melanin synthetic cascade--also may be a source of circulating L-dopa. We compared plasma L-dopa levels in albino subjects and in Caucasian and Black normal volunteers and patients with essential hypertension. DOPA levels were similar among the subject groups. Among Caucasian normal volunteers, L-dopa levels were negatively correlated with subject age (r = -0.30, P less than 0.05), whereas norepinephrine levels tended to increase with subject age (r = 0.25, 0.05 less than P less than 0.10), so that the L-dopa:norepinephrine ratio was highly negatively correlated with subject age (r = -0.50, P less than 0.01). Skin pigmentation does not contribute importantly to plasma L-dopa levels in humans. In contrast with levels of norepinephrine, L-dopa levels appear to decrease during normal aging.


Assessing the impact of high blood pressure referrals on hypertension awareness and management, BMI, and blood pressure values in adult Samoans 2010-2019.
The Samoan population has experienced rapid increases in the prevalence of non-communicable diseases (NCDs) and NCD risk factors over the last 30 years. However, understanding how increased awareness and treatment of these conditions in reducing disease burden remains understudied. Using data from a longitudinal study (2010-2019) of cardiometabolic health among Samoan adults, we assess the impact of a referral for elevated blood pressure (BP) on changes in BP, physician's diagnoses of hypertension and medication use, body mass index (BMI), and other risk factors for elevated BP. Analyses compared adult Samoans (n = 328) who in 2010 either (1) received a referral for elevated BP (BP ≥ 140/90 mmHg) or (2) had measured BP indicative of pre-hypertension (BP ≥ 120/80 mmHg) but were not referred. Data were analysed using linear and logistic regression, paired T- and McNemar's tests, and Wilcoxon Rank Sum assessments. Referrals in 2010 significantly increased the odds of reporting a physician's diagnosis of hypertension (OR 2.16; 1.18, 3.95) and hypertension medication use (OR 3.52; 1.86, 6.73) in 2018; however, referrals, medication use, and diagnoses were not associated with BP values or reduced odds of having elevated BP. Despite the referral having positive effects on hypertension-related health care, our results demonstrate that other factors are influencing effective BP/hypertension control. We advocate for greater engagement of health researchers with local health sector actors to improve the probability that researcher-provided health referrals will result in long-term health improvements.


Production and enhanced biological activity of a novel GHRH analog, hGHRH with an N-terminal Pro-Pro extension.
Growth Hormone Releasing Hormone (GHRH) is one of the most important hormones in life. Because of its potential clinical importance, its short half-life, and its expensive chemical synthesis, an analog of hGHRH with a prolonged half-life and better activity has been studied for clinical application, especially for the treatment of muscle wasting, type II diabetes, or sleep disorders. The Pro-Pro-hGHRH(1-44) peptide has better activity. The fusion partner gene with 127 amino acid residues of the C-terminus from l-asparaginase was recombined with asp-pro-pro-hGHRH(1-44) gene synthesized by PCR method to form a fusion protein with the unique acid labile linker Asp-Pro. The recombinant protein was expressed to high levels in Escherichia coli BL21 (DE3). The Pro-Pro-hGHRH(1-44) peptide was purified to homogeneity by means of cell disruption, washing, ethanol precipitation, acid hydrolysis, and SP-Sephadex C-25, and Sephadex G-25 column chromatography. The fold of the purification was about 88 times and the yield was 1.1% of the total protein weight of the inclusion body. The peptide molecular mass of 5235.25 Da was determined by ESI mass spectroscopy. Its purity was determined by SDS-PAGE. In the study of the activity, we measured GH release of rat pituitary by using the antiserum kit against human GH. The peptide doses of 0.01, 0.1, 1.0, 7.72, and 20.9 microg/ml used, respectively, released the GH values of 0.1+/-0.1, 12.5+/-7.3, 16.6+/-5.8, 49.8+/-7.6, and 79.5+/-5.7 ng/ml whereas their blank controls, respectively, were 0.5+/-0.8, 4.1+/-2.6, 3.1+/-3.1, 4.7+/-1.8, and 1.2+/-0.3 ng/ml. The activity results of all dose groups except 0.01 microg/ml Pro-Pro-hGHRH(1-44) group and hGHRH(1-40) group showed that there were significant differences between GH released by the peptide and that by its blank control. With the increase of dosage, the differences were more significant. hGHRH(1-40) showed no measured GH release when the dose was up to 2 microg/ml. The activity results show that the Pro-Pro-hGHRH(1-44) peptide is a potential GH releasing analog.


Functional Annotation from Structural Homology.
With the nexus of super computing and the biotech revolution, it seems an era of predictive biology through systems biology may be at hand. Modern omics capabilities enable examination of the state of biological system in exquisite detail. The genome, transcriptome, proteome, and metabolome may all be largely knowable, at least for some model systems, providing a basis for modeling and simulation of molecular mechanisms, or pathways, that could capture a biological system's emergent properties. However, there are significant challenges remaining that impede the realization of this vision, perhaps the most significant being the missing functional annotation of genes and gene products. For even the most well-studied organisms as much as a third of called genes for a given genome are not annotated and more than half may be tenuous. Homology inferred from sequence similarity is the basis for much of genome annotation. Homology inferred from structural similarity could be a powerful complement to sequence-based annotation methods. Structural biology or structural informatics can be used to assign molecular function and may have increasing utility with the rapid growth of gene sequence databases and emerging methods for structure determination, like structure prediction based on coevolution. Here we describe tools and provide example cases using structural similarity at the level of quaternary structure, domain content, domain topology, and small 3D motifs to infer homology and posit function. Ultimately annotation by similarity, be it 3D structure homology or more classically primary sequence homology, must be founded by accurate annotation of one ortholog in the group-understanding every function encoded by a genome remains a major challenge to life science.


Intracellular sodium and calcium in the postischemic myocardium.
Intracellular sodium and calcium were measured in 30 isolated perfused rat hearts exposed to normothermic ischemic intervals varying from 0 to 40 minutes followed by 35 minutes of reperfusion. Accumulation of these elements was correlated with alterations in postischemic isovolumic contractile function. There were increases in calcium of 207%, 390%, and 681% of the non-ischemic control following reperfusion after respective ischemic intervals of 30, 35, and 40 minutes. These corresponded to decrements in peak developed pressure of 23.8% after 30 minutes, 68.6% after 35 minutes, and no recovery of function after 40 minutes of ischemia. Thirty-five and 40 minutes of ischemia produced 138% and 170% increases in intracellular sodium, respectively. These data show that there is a graded accumulation of intracellular sodium and calcium that correlates with the duration of ischemia and the degree of functional impairment in the postischemic heart. Measurement of intracellular sodium and calcium may, therefore, serve as an adjunct to other biochemical and functional factors used to quantitate postischemic and postcardioplegic damage in the development of new myoprotective regimens.


Historical data decrease complete blood count reflex blood smear review rates without missing patients with acute leukaemia.
The availability of historical data decreases the rate of blood smear review rates in outpatients, but we are unaware of studies done at referral centres. In the following study, we determined the effect of historical data on the rates of peripheral blood smears over a 3-month period and then the detection rate of patients with acute leukaemia. All results of complete blood counts (CBCs) tested on three ADVIA 120 analyzers at the regional Rabin Medical Centre, Beilinson Campus over a 3-month period were accessed on a computerised laboratory information system. Over a 3-month period, we determined the proportion of total CBC and patients with criteria for a manual differential count and the actual number of peripheral blood smears done. Finally, we determined the proportion of 100 consecutive patients with acute leukaemia detected using our criteria that included limiting reflex testing according to historical data. Over the 3-month period, there were 34,827 tests done in 12,785 patients. Without historical data, our smear rate would have been 24.5%, but with the availability of historical data, the blood smear review rate was 5.6%. The detection rate for cases of acute leukaemia was 100%. We conclude that the availability of previous test results significantly reduces the need for blood smear review without missing any patients with acute leukaemia.


Access to Structurally Diverse Quinoline-Fused Heterocycles via Rhodium(III)-Catalyzed C-C/C-N Coupling of Bifunctional Substrates.
Rhodium(III)-catalyzed C-H activation of heteroarenes and functionalization with bifunctional substrates such as anthranils allows facile construction of quinoline-fused heterocycles under redox-neutral conditions. The couplings feature broad substrate scope and provide step-economical access to two classes of quinoline-fused condensed heterocycles.


Thyroid disease mediated by molecular defects in cell surface and nuclear receptors.
The proposed mechanisms of RTH are not mutually exclusive. In fact, there is considerable experimental evidence that many if not all of these complex receptor interactions with elements of the transcriptional unit are involved in RTH. Several aspects of RTH remain unclear, in particular on a clinical level. We still do not completely understand the seeming paradox of a tight distribution of receptor mutations and wide variability in phenotypic presentation. The discovery that many of the RTH receptors have defects in corepressor interaction makes it tempting to speculate that the variability in RTH phenotype within kindreds is secondary to differences in corepressor expression. These issues may be better understood as research further proceeds into cofactors and their control of transcription. We also need better tools to determine thyroid status at a peripheral level. Basal metabolic rate, serum measurement of thyroid-responsive gene products, echocardiographic techniques, and other clinical measures have for the most part been unhelpful in determining thyroid status of specific organ systems. Consequently, therapeutic interventions for RTH are directed toward normalizing biochemical indices of thyroid homeostasis, without really knowing whether these efforts correct imbalances within crucial tissues. These studies, and the more widespread investigation of hormone receptor action in general, are moving at a breathtaking pace, and there is a keen interest in applying these principals to understanding the pathophysiologic mechanism of a variety of diseases.


[Malperfusion after Aortic Dissection - Management and Techniques].
Malperfusion is a common complication of aortic dissection and further increases this deadly disease's mortality. An effective treatment strategy requires a timely diagnosis based on the clinical findings and the available instruments, understanding the disease's pathomechanism, recognising the therapy options recommended by the guidelines, and the diagnostic and therapeutic innovations of the area of research. The final treatment decision should be patient- and case-specific. In this work, we have considered malperfusion after aortic dissection, not only as a complication of aortic dissection but as a separate disease and summarise important information that can contribute to efficient therapy decisions in everyday clinical practice.


Neural crest stem cell-specific deletion of the Pygopus2 gene modulates hair follicle development.
We show that neural crest stem cells affect mouse hair follicle development. During embryogenesis hair follicle induction is regulated by complex reciprocal and functionally redundant signals between epidermis and dermis, which remain to be fully understood. Canonical Wnt signalling is a hallmark of neural crest cells and also a prerequisite for hair follicle induction prior to hair placode formation in the epidermis. As neural crest stem cells invade the epidermis during early embryonic development we aimed at determining whether neural crest cells affect hair follicle development. To attenuate, but not silence, canonical Wnt signalling specifically in neural crest cells, we analyzed Wnt1-cre(+/-)::Pygo2(-/-) mice in which the β-catenin co-activator gene, Pygopus 2 (Pygo2), is deleted specifically in neural crest cells. Both, hair density and hair thickness were reduced in mutant mice. Furthermore, hair development was delayed and the relative ratio of hair types was affected. There was a decrease in zig-zag hairs and an increase in awl hairs. Mouse neural crest stem cells expressed ectodysplasin, an essential effector in the formation of zig-zag hair. Taken together, our data support the novel notion that neural crest cells are involved in the earliest stages of hair follicle development.


Effect of nickel chloride on body temperature and behavioral thermoregulation in the rat.
This study was designed to assess the effects of acute nickel chloride administration on behavioral and autonomic thermoregulation in the rat. In one experiment, male rats of the Fischer 344 strain were injected with nickel chloride (IP) at dosages of 0 to 24.0 mg/kg and placed in an environmental chamber maintained at an ambient temperature (Ta) of 10 or 20 degrees C. Colonic temperature was measured 60 min postinjection. Nickel chloride caused a dose-related decrease in colonic temperature, and the hypothermia was accentuated at the cooler Ta. In a second study, rats injected with 0, 6.0, 12.0, or 24.0 mg/kg nickel chloride were placed in a temperature gradient which allowed the rats to select their preferred thermal environment. Nickel chloride at dosages of 12.0 and 24.0 mg/kg caused a significant reduction in the selected Ta. At these dosages the rats were also significantly hypothermic at 60 min postinjection. In a third experiment, whole-body oxygen consumption (i.e., metabolic rate) was measured at Ta's of 10, 20, and 30 degrees C following a 12.0 mg/kg injection of nickel chloride. Nickel chloride caused an initial depression in metabolic rate and hypothermia at Ta's of 10 and 20 degrees C but not at 30 degrees C. In conclusion, (a) nickel chloride affects both behavioral and autonomic control of thermoregulation in the rat and appears to induce a regulated decrease in body temperature and (b) the behavioral thermoregulatory response of the rat is less sensitive to nickel chloride when compared to the mouse.


Effects of manipulation of water and nitrogen regime on the water relations of the desert shrub Larrea tridentata.
Water and nitrogen regimes of Larrea tridentata shrubs growing in the field were manipulated during an annual cycle. Patterns of leaf water status, leaf water relations characteristics, and stomatal behavior were followed concurrently. Large variations in leaf water status in both irrigated and nonirrigated individuals were observed. Predawn and midday leaf water potentials of nonirrigated shrubs were lowest except when measurements had been preceded by significant rainfall. Despite the large seasonal variation in leaf water status, reasonably constant, high levels of turgor were maintained. Pressure-volume curve analysis suggested that changes in the bulk leaf osmotic potential at full turgor were small and that nearly all of the turgor adjustment was due to tissue elastic adjustment. The increase in tissue elasticity with increasing water deficit manifested itself as a decrease in the relative water content at zero turgor and as a decrease in the tissue bulk elastic modulus. Because of large hydration-induced displacement in the osmotic potential and relative water content at zero turgor, it was necessary to use shoots in their natural state of hydration for pressure-volume curve determinations. Large diurnal and seasonal differences in maximum stomatal conductance were observed, but could not easily be attributed to variations in leaf water potential or leaf water relations characteristics such as the turgor loss point. The single factor which seemed to account for most of the diurnal and seasonal differences in maximum stomatal conductance between individual shrubs was an index of soil/root/ shoot hydraulic resistance. Daily maximum stomatal conductance was found to decrease with increasing soil/root/ shoot hydraulic resistance. This pattern was most consistent if the hydraulic resistance calculation was based on an estimate of total canopy transpiration rather than the more commonly used transpiration per unit leaf area. The reasons for this are discussed. It is suggested that while stomatal aperture necessarily represents a major physical resistance controlling transpiration, plant hydraulic resistance may represent the functional resistance through its effects on stomatal aperture.


The correlation between the development of sympathetic innervation and the development of medial hypertrophy in jejunal arteries in normotensive and spontaneously hypertensive rats.
The catecholaminergic innervation of jejunal arteries was examined during development in normotensive and hypertensive rats. It was determined that a hyperinnervation of jejunal vessels in the hypertensive rats is present from 2 weeks of age onwards, before significant elevation of blood pressure and medial hypertrophy of jejunal arteries occurs. It is concluded that this hyperinnervation may be causally related to the medial hypertrophy in arteries of hypertensive animals.


Microsurgical endoscopy-assisted anterior corpus callosotomy for drug-resistant epilepsy in an adult unresponsive to vagus nerve stimulation.
Because most of the corpus callosotomy (CC) series available in literature were published before the advent of vagus nerve stimulation (VNS), the efficacy of CC in patients with inadequate response to VNS remains unclear, especially in adult patients. We present the case of a 21-year-old female with medically refractory drop attacks that began at the age of 8 years, which resulted in the patient being progressively unresponsive to vagus nerve stimulation implanted at the age of 14 years. Corpus callosotomy was recommended to reduce the number of drop attacks. However, the patient had only mild cognitive impairments and no neurological deficits. For this reason, we were forced to plan a surgical approach able to maximize the disconnection for good seizure control while, at the same time, minimizing sequelae from disconnection syndromes and neurosurgical complications because in such cases of long-lasting epilepsy the gyri cinguli and the arteries can be tenaciously adherent and dislocated with all the normal anatomy altered. In this scenario, we opted for a microsurgical endoscopy-assisted anterior two-thirds corpus callosotomy. The endoscopic minimally invasive approach proved to be quite adequate in this technically demanding case and confirmed that CC may offer advantages, with good results, even in adult patients with drop attacks who have had inadequate response to VNS.


Fibroblast growth factor 23-Klotho and hypertension: experimental and clinical mechanisms.
Hypertension (HTN) and chronic kidney disease (CKD) are increasingly recognized in pediatric patients and represent risk factors for cardiovascular morbidity and mortality later in life. In CKD, enhanced tubular sodium reabsorption is a leading cause of HTN due to augmented extracellular fluid volume expansion. The renin-angiotensin-aldosterone system (RAAS) upregulates various tubular sodium cotransporters that are also targets of the hormone fibroblast growth factor 23 (FGF23) and its co-receptor Klotho. FGF23 inhibits the activation of 1,25-dihydroxyvitamin D that is a potent suppressor of renin biosynthesis. Here we review the complex interactions and disturbances of the FGF23-Klotho axis, vitamin D, and the RAAS relevant to blood pressure regulation and discuss the therapeutic strategies aimed at mitigating their pathophysiologic contributions to HTN.


A critical appraisal of continence in bladder exstrophy: Long-term outcomes of the complete primary repair.
Long-term continence outcomes for patients with bladder exstrophy are lacking in the literature. The complete primary repair of exstrophy (CPRE) is a widely adopted approach that seeks to normalize anatomy at the initial repair, thereby allowing early bladder filling and cycling. Previous reports of continence following CPRE, however, are limited by variable follow-up duration and continence definitions. To assess continence and factors associated with a positive outcome in a cohort of patients following CPRE with long-term follow-up. A retrospective chart review was conducted of all patients with primary bladder closure using CPRE at the present institution for classic bladder exstrophy from 1990 to 2010. Patients <6 years of age or with an incomplete continence assessment at last follow-up were excluded. Continence was defined as voiding volitionally with dry intervals of ≥3 h, which was consistent with other high-volume series in the literature. Twenty-nine of the 52 patients (56%) were eligible for inclusion. Twelve patients were continent at last follow-up, including seven boys and five girls. Mean follow-up for the entire cohort was 148 months. The Summary table displays comparisons between continent and incontinent patients. Of patients achieving continence, 42% did not require further continence operations, while 17% required only one additional continence operation. Long-term CPRE continence rates were lower than previously reported, but comparable to other series in the literature. Of those achieving continence, 59% will do so with zero or one additional operation. Sex and osteotomy status were not associated with continence outcomes, although age at follow-up was a predictor of continence, favoring older patients in the present series. The study was limited by lack of standardized, patient-reported continence outcomes and by the retrospective nature of the review. However, the data add to the literature of long-term continence outcomes and are important for counseling families both at initial repair and follow-up. Complete primary repair of exstrophy can achieve continence without additional operations in a subset of patients. Some patients, however, may not achieve continence until adolescence, underscoring the need for long-term urologic follow-up in patients with bladder exstrophy.


Psychological characteristics and responses to antihypertensive drug therapy.
The objective of this study was to explore the relationship between psychological characteristics and responses to antihypertensive drug therapy. Twenty-two hypertensive subjects underwent psychological evaluation and treatment with 1) a diuretic, hydrochlorothiazide (HCTZ); 2) an angiotensin-converting enzyme (ACE) inhibitor, quinapril; and 3) combined alpha + beta blockade (doxazosin + betaxolol). Anger-Out scores on the State-Trait Anger Expression Inventory were positively correlated with the HCTZ-induced fall in systolic blood pressure (p<0.01); Anger-In was negatively correlated with the quinapril-induced fall in systolic pressure (p<0.05). The target systolic blood pressure (130 mm Hg) was achieved with either HCTZ or quinapril in 79% of subjects without, vs. 25% of subjects with, childhood trauma (p=0.03). Responses to doxazosin + betaxolol were not correlated with psychological characteristics. The authors conclude that both inhibited anger expression and childhood trauma are associated with reduced response to a diuretic or ACE inhibitor. Combined alpha/beta blockade may be preferable to an ACE inhibitor or diuretic in treating selected hypertensive patients. Further studies should include examination of psychological factors in terms of the response to combined ACE inhibitor + diuretic therapy.


Olecranon fractures in children: treatment of a rare entity.
Olecranon fractures are a rare entity in children. The classification and treatment strategies are still discussed controversially. A retrospective chart review of all patients < 17 years admitted with an olecranon fracture at a Level I Trauma Center between 2005 and 2017 has been performed. 46 subjects were included. For classification of olecranon fractures in children the AO Pediatric Comprehensive Classification of Long Bone Fractures (AO-PCCF) was used. Fractures were classified along the fracture line, dislocation, joint involvement and affection of the apophysis. For statistical analysis, a comparison of two groups was performed using Student t test. One-way ANOVA and Tukey's multiple comparison test was used to identify differences between more than two groups. For all analysis p ≤ 0.05 was considered statistically significant. The mean age of the children was 8.5 years (2-16 years). Most children were treated with a conservative therapy (n = 29, 63.0%). 17 patients (36.9%) underwent osteosynthesis (plate or tension band wiring) of which three were initially treated with a conservative therapeutic approach. Children with operative treatment were significantly older compared to children treated conservatively. Interestingly, all patients with luxation were characterized by an oblique fracture line, one of them extraarticular, three intraarticular. Taken together, this study analyzed one of the largest selections of pediatric patients with olecranon fracture in regard to fracture type and treatment strategy. Based on the assumption that treatment strategies follow a fracture classification, a consistent classification method is needed which should take into account fracture morphology and localization, as considered by the AO-PCCF, and the dislocation as measured by Braque. Surgical treatment is needed in case of dislocation ≥ 5 mm, intra-articular fractures, instable fracture conditions caused by the fracture line, open fractures and the affection of the apophysis. Otherwise, the conservative treatment shows insufficient results in the elbow mobility. The reliable choice of treatments based on our classification was mirrored by the very low rate of conversion of treatment strategies. Level III-retrospective comparative study.


A flow cytometric method for determination of absolute counts of myeloid precursor dendritic cells in peripheral blood.
Circulating precursor dendritic cells (pDCs) constitute a rare population in peripheral blood. They have a typical immunophenotypic profile, yet, they cannot be identified by pDC-specific immunophenotypic markers and therefore, their accurate and absolute enumeration poses a challenge. Here, we report a method for the evaluation of absolute counts of myeloid pDC in minimally manipulated blood samples on a flow cytometer as a single platform. Three-color flow cytometry was done to identify myeloid pDC as CD33+ HLA-DR+ CD14/CD16(dim/negative) cells in commercially available TruCount trade mark tubes that contain a defined number of brightly fluorescent polystyrene beads. The normal range in peripheral blood of 41 healthy adults, as determined by this single-platform method, was 17.0+/-5.7 x 10(6)/l, or 0.64+/-0.23% of mononuclear cells (MNCs). In parallel experiments, we have compared our procedure with two published 'dual-platform' methods that derive the absolute pDC count from a relative number obtained by flow cytometry, and from absolute counts obtained from a haematological analyser. Regression analysis showed an excellent correlation between results obtained with our single-platform protocol and these double-platform procedures (R2 > or = 0.90). However, the values obtained by the single-platform method were significantly higher than those obtained by the dual-platform methods. The higher myeloid pDC numbers in this single-platform procedure are likely due to reduced cell loss in this 'lyse-no-wash' protocol compared with the other methods which include density gradient separation and centrifugation steps. The intra- and interassay variability were 4.4% (range, 2.04-8.96%) and 5.8% (range, 2.59-9.65%), respectively. Thus, the single-platform method described here allows accurate, rapid and simple measurement of circulating blood myeloid pDC and is suitable for routine enumeration of circulating myeloid pDC.


Distinct metabolism of N-glucosides of isopentenyladenine and trans-zeatin determines cytokinin metabolic spectrum in Arabidopsis.
The diversity of cytokinin (CK) metabolites suggests their interconversions are the predominant regulatory mechanism of CK action. Nevertheless, little is known about their directionality and kinetics in planta. CK metabolite levels were measured in 2-wk-old Arabidopsis thaliana plants at several time points up to 100 min following exogenous application of selected CKs. The data were then evaluated qualitatively and by mathematical modeling. Apart from elevated levels of trans-zeatin (tZ) metabolites upon application of N6 -(Δ2 -isopentenyl)adenine (iP), we observed no conversions between the individual CK-types - iP, tZ, dihydrozeatin (DHZ) and cis-zeatin (cZ). In particular, there was no sign of isomerization between tZ and cZ families. Also, no increase of DHZ-type CKs was observed after application of tZ, suggesting low baseline activity of zeatin reductase. Among N-glucosides, those of iP were not converted back to iP while tZ N-glucosides were cleaved to tZ bases, thus affecting the whole metabolic spectrum. We present the first large-scale study of short-term CK metabolism kinetics and show that tZ N7- and N9-glucosides are metabolized in vivo. We thus refute the generally accepted hypothesis that N-glucosylation irreversibly inactivates CKs. The subsequently constructed mathematical model provides estimates of the metabolic conversion rates.


Specialization of the entomopathogenic nematode Steinernema scapterisci with its mutualistic Xenorhabdus symbiont.
The level of specialization of the entomopathogenic nematode Steinernema scapterisci with its native Xenorhabdus symbiont was investigated by testing (1) the influence of non-native bacterial strains on nematode fitness within an insect-host (Galleria mellonella) and (2) specificity of the association between the nematode infective juveniles and non-native bacteria. All non-native Xenorhabdus spp. or Photorhabdus spp. strains tested were mutualistically associated with other entomopathogenic nematodes in nature. We showed that most of the Xenorhabdus spp. strains tested led to an insignificant difference of the nematode's fitness compared to the one obtained with the native bacterium. Conversely, Photorhabdus spp. strains almost entirely abolished nematode reproduction. The phylogenetic analysis of bacterial strains tested, showed that there was a negative correlation between S. scapterisci's reproduction rate with a bacterial strain and the genetic distance of this bacterial strain from the native one. We also showed that the native bacterium was the only one which was transmitted by S. scapterisci's infective juveniles. All these results, suggested a specialization between S. scapterisci and its native Xenorhabdus. As the same phenomenon was already demonstrated in the association between S. carpocapsae and X. nematophila, specialization between partners would not be an exception in entomopathogenic nematode-bacteria interactions. Nevertheless, S. scapterisci showed a dramatically higher compatibility with non-native Xenorhabdus spp. strains than did S. carpocapsae, suggesting differences in the co-evolutionary processes between nematodes and bacteria in these two model systems.


Dietary treatment for decreasing 141Ce body burden in immature rats.
The purpose of this work was to evaluate the effect of prolonged (immediate or delayed) administration of dietary additives to suckling rats on the absorption and retention of radioactive cerium in the body. The experiment was performed on 6-day-old suckling rats. According to dietary treatment the animals were divided into three groups. Each group was artificially fed over 8 h for 6 or 12 days on one of the diets: the first group of animals was fed milk, the second group was given ingredients of rat diet and the third received milk during the first 2 days of the experiment and the ingredients of rat diet afterwards. At the end of the artificial feeding period the pups returned to their mothers and suckled overnight. On the 1st day of the experiment the food was labelled with 141Ce. Whole body radioactivity was determined in a double crystal scintillation counter every 48 h over a 12-day period. Half of the animals from each group were killed 6 days after 141Ce administration and the other half after 12 days. At these intervals retention was determined in the gut, liver, kidneys and femur. The early and delayed administration of rat diet ingredients--fish meal, sunflower meal, alfalfa, cane molasses and premix--greatly reduced whole body retention. The early treatment was more efficacious than the delayed one. The reduction was mostly due to decreased gut retention but organ retentions were also lower. The results obtained indicate that by prolonged (immediate or delayed) administration of some dietary means the retention of radioactive cerium in sucklings can be significantly decreased.


Striatal astrocytic A2A-D2 receptor-receptor interactions and their role in neuropsychiatric disorders.
It is now generally accepted that astrocytes are active players in synaptic transmission, so that a neurocentric perspective of the integrative signal communication in the central nervous system is shifting towards a neuro-astrocentric perspective. Astrocytes respond to synaptic activity, release chemical signals (gliotransmitters) and express neurotransmitter receptors (G protein-coupled and ionotropic receptors), thus behaving as co-actors with neurons in signal communication in the central nervous system. The ability of G protein-coupled receptors to physically interact through heteromerization, forming heteromers and receptor mosaics with new distinct signal recognition and transduction pathways, has been intensively studied at neuronal plasma membrane, and has changed the view of the integrative signal communication in the central nervous system. One of the best-known examples of receptor-receptor interaction through heteromerization, with relevant consequences for both the physiological and the pharmacological points of view, is given by adenosine A2A and dopamine D2 receptors on the plasma membrane of striatal neurons. Here we review evidence that native A2A and D2 receptors can interact through heteromerization at the plasma membrane of astrocytes as well. Astrocytic A2A-D2 heteromers were found able to control the release of glutamate from the striatal astrocyte processes. A2A-D2 heteromers on striatal astrocytes and astrocyte processes are discussed as far as their potential relevance in the control of glutamatergic transmission in striatum is concerned, including potential roles in glutamatergic transmission dysregulation in pathological conditions including schizophrenia or the Parkinson's disease. This article is part of the Special Issue on "The receptor-receptor interaction as a new target for therapy".


Lack of pharmacokinetic interaction between oxcarbazepine and lamotrigine.
Epilepsy and bipolar disorder are commonly treated by combination drug therapy, such as lamotrigine and oxcarbazepine. To ensure the safety of this combination, information on pharmacokinetics and tolerability must be available. The objective of study was to evaluate the pharmacokinetics and tolerability of coadministered lamotrigine and oxcarbazepine in healthy subjects. This randomized, single-blind, parallel-group study comprised three cohorts: lamotrigine (200 mg daily) plus oxcarbazepine (600 mg twice daily), lamotrigine (200 mg daily) plus placebo, and oxcarbazepine (600 mg twice daily) plus placebo. Serial blood samples were collected at steady state to determine serum concentrations of lamotrigine and plasma concentrations of oxcarbazepine and its active metabolite 10-monohydroxy metabolite (MHD). Pharmacokinetic parameters were determined by noncompartmental methods. Tolerability was monitored through adverse event reports, clinical laboratory results, vital signs, and electrocardiograms. A total of 47 male volunteers received study drugs. At steady state, lamotrigine AUC((0-24)) and C(max) were not significantly affected by oxcarbazepine co-therapy, nor were MHD AUC((0-12)) and C(max) significantly affected by lamotrigine co-therapy. The most common adverse events, headache, dizziness, nausea, and somnolence, occurred more frequently during lamotrigine and oxcarbazepine combination therapy than during the monotherapy. No significant changes in clinical laboratory parameters, vital signs, or electrocardiograms were reported. In conclusion, the combination of lamotrigine and oxcarbazepine does not require dose adjustments based on pharmacokinetic data. However, it is important to recognize that the combination therapy was associated with more frequent adverse events.


Thermoregulation: an orphan receptor finds its way in the cold.
The hypometabolic state of torpor is a widely utilized and well-orchestrated response to food shortage. A new study shows that the melatonin-related orphan receptor GPR50 plays an important function in metabolic regulation for entry into torpor.


Role of calcium-binding protein regucalcin in regenerating rat liver.
Regucalcin is a novel calcium-binding protein which does not contain EF-hand motif as a Ca2+ -binding domain. The organization of the rat regucalcin gene consists of seven exons and six introns. Its mRNA is mainly present in liver but slightly in kidney with a size of 1.8 kb. Hepatic regucalcin mRNA expression is stimulated by various factors including calcium, calcitonin, insulin, and oestrogen in rats. The mRNA is also expressed in hepatoma cells (Morris hepatoma and HepG2). Regucalcin plays a role in the maintenance of cytosolic Ca2+ homeostasis in liver cells. Moreover, regucalcin has an inhibitory effect on Ca2+ /calmodulin-dependent enzyme activation, protein kinase C activation, and many Ca2+ -activated enzymes, indicating a role in the regulation of the Ca2+ -signalling system. Recently, regucalcin has been demonstrated to regulate nuclear function in liver cells. Regucalcin can inhibit Ca2+ -activated nuclear DNA fragmentation in rat isolated liver nuclei. Furthermore, the liver nuclear DNA and RNA syntheses are inhibited by regucalcin. Such an effect of regucalcin is also seen in the nuclei of regenerating rat liver. The regucalcin mRNA level is increased in regenerating liver. These findings suggest that regucalcin plays a regulatory role in the suppression for overexpression of proliferative cells.


Local causation.
The counterfactual and regularity theories are universal accounts of causation. I argue that these should be generalized to produce local accounts of causation. A hallmark of universal accounts of causation is the assumption that apparent variation in causation between locations must be explained by differences in background causal conditions, by features of the causal-nexus or causing-complex. The local account of causation presented here rejects this assumption, allowing for genuine variation in causation to be explained by differences in location. I argue that local accounts of causation are plausible, and have pragmatic, empirical and theoretical advantages over universal accounts. I then report on the use of presheaves as models of local causation. The use of presheaves as models of local variation has precedents in algebraic geometry, category theory and physics; they are here used as models of local causal variation. The paper presents this idea as stemming from an approach using presheaves as models of local truth. Finally, I argue that a proper balance between universal and local causation can be assuaged by moving from presheaves to fully-fledged sheaf models.


Hypertrophic cardiomyopathy: management issues in the new millennium.
Hypertrophic cardiomyopathy is an inherited cardiac disorder. Sudden cardiac death frequently occurs in otherwise healthy individuals, and accounts for nearly 35% of all sudden deaths within this age group. Although symptoms occur commonly, they often go unreported. Despite this, a degree of functional limitation is often seen on objective assessment. Management of hypertrophic cardiomyopathy is aimed at relieving symptoms, identifying and treating those individuals at increased risk of sudden death, and screening family members.


Indocyanine green fluorescence angiography for intraoperative assessment of blood flow: a feasibility study.
To introduce our preliminary experience with indocyanine green (ICG) fluorescence angiography for the assessment of lower leg bypasses. 1ml of 0.5% indocyanine green was intravenously injected in 9 patients with PAD who underwent paramalleolar artery bypass using saphenous vein grafts. A newly developed near-infrared camera system (PDE; Hamamatsu Photonics K.K. Hamamatsu, Japan) was used for this study. ICG fluorescence angiography was performed without any adverse events. Fluorescence images of ICG angiography could be viewed as real-time images of the angiography in eight patients, while one patient underwent graft revision with the absence of fluorescence in ICG angiography. ICG fluorescence angiography is clinically feasible and may help surgeons assess the quality of lower leg bypasses.


A review of GLP-1 receptor agonists in type 2 diabetes: A focus on the mechanism of action of once-weekly agents.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are one of the preferred approved treatment options for people with type 2 diabetes (T2D) and inadequate glycaemic control. The objective of this review is to provide a general clinical overview of the similarities and differences in the mechanisms of action (MoA) of the once-weekly GLP-1 RA class of medications, highlighting the role of pharmacists in providing optimal medication management, education and care for people with diabetes. This is a narrative review of the published literature regarding the MoA of the currently available once-weekly GLP-1 RAs in T2D. GLP-1 RAs have an established efficacy and safety profile. Their benefits derive from their blood glucose-lowering effects, which include pancreatic beta-cell-mediated glucose-dependent insulin secretion and suppressed glucagon release, and their ability to slow gastric emptying and promote satiety. GLP-1 RAs may also exert beneficial effects on multiple organ systems in which GLP-1 receptors are present, including the cardiovascular and renal systems. Differences between individual GLP-1 RAs with regard to their molecular size, structure and duration of action (short or longer acting) have led to differing pharmacodynamics and clinical effects such as degree of glycaemic control, weight loss abilities, cardiovascular effects and tolerability profiles. From the literature, this appears to be the first review of the evidence base supporting the MoA of once-weekly GLP-1 RAs in T2D aimed at pharmacists, with a particular emphasis on the expanding role of pharmacists in team-based diabetes management. As a class, GLP-1 RAs are an effective treatment option for people with T2D, shown to achieve multi-factorial clinical benefits. The results suggest that when selecting or advising about treatments, pharmacists should consider how the different once-weekly GLP-1 RAs and their MoA affect clinical outcomes in order to ensure optimal treatment for individuals.


Changes in mitochondrial redox state following an oral glucose load.
Changes in cytosol and mitochondrial redox state after an oral glucose load were studied in the liver of rats. The [NAD+]/[NADH] ratios increased 4-fold in the cytoplasm and 1.5-fold in the mitochondria 60 min after an oral glucose load, when serum IRI was maximally increased. It is suggested that an increase in mitochondrial redox state following an oral glucose load is due to an enhanced rate of removal of NADH by the respiratory chain, possibly due to an elevated level of insulin available to hepatocytes, and that an increase in cytosol redox state depends on an enhancement in mitochondrial oxidation of cytosol reducing equivalent.


Role of short courses on nailfold capillaroscopy in obtaining abilities for the identification of microvasculopathy in patients with Raynaud's phenomenon.
An early distinction between "normal" and "abnormal" capillaroscopic pattern during the first visit to a dermatologist has a crucial significance for a diagnostic management of Raynaud's phenomenon (RP). There exists a question about the level of expertise sufficient to evaluate the microcirculation. To evaluate the utility of short courses on NFC among dermatologists and medical students in obtaining sufficient abilities for the identification of microvasculopathy in patients with RP using videocapillaroscope and handheld dermoscope. Both groups participated in 1-h course on NFC. Before the course, participants were asked to classify 20 videocapillaroscopic and 10 dermoscopic capillaroscopic pictures into "normal" or "abnormal" pattern. Each picture was displayed on a separate slide MS PowerPoint for 10 s. The evaluation was repeated soon after the course. A total of 36 dermatologists and 49 medical students were enrolled. The rate of properly classified dermoscopic and videodermoscopic pictures increased after the course in both groups, but students improved the accuracy of classification on dermoscopic pictures to the greater extent than dermatologists. The rate of correctly recognized pictures with "abnormal" pattern was significantly greater than ones with "normal" pattern at the baseline and after the course, independently of imagining tool. Short courses on NFC may improve the classification of capillaroscopic images, even in medical staff with no previous experience in NFC. The recognition of capillaroscopic abnormalities seems to be easier than obtaining the confidence that evaluated picture has "normal pattern."


HelixFlex: bioinspired maneuverable instrument for skull base surgery.
Endoscopic endonasal surgery is currently regarded as the 'gold standard' for operating on pituitary gland tumors, and is becoming more and more accepted for treatment of other skull base lesions. However, endoscopic surgical treatment of most skull base pathologies, including certain pituitary tumors, is severely impaired by current instruments lack of maneuverability. Especially, gaining access to, and visibility of, difficult-to-reach anatomical corners without interference with surrounding neurovascular structures or other instruments, is a challenge. In this context there is the need for instruments that are able to provide a stable shaft position, while both the orientation and the position of the end-effector can be independently controlled. Current instruments that allow for this level of maneuverability are usually mechanically complex, and hence less suitable for mass production. This study therefore focuses on the development of a new actuation technique that allows for the required maneuverability while reducing the construction complexity. This actuation technique, referred to as multi-actuation, integrates multiple cable routings into a single steerable structure. Multi-actuation has been successfully integrated and tested in a handheld prototype instrument called HelixFlex. HelixFlex contains a 4 degrees of freedom maneuverable 5.8 mm (diameter) tip and shows promising results concerning its maneuverability and potential rigidity.


The release of Alzheimer's disease beta amyloid peptide is reduced by phorbol treatment.
Amyloid precursor protein (APP) is cleaved predominantly within the beta amyloid peptide (BAP) domain to release a non-amyloidogenic amino-terminal PN2 fragment. Treatment of cells with phorbol dibutyrate, an agent which activates protein kinase C, has been shown to increase the release of an amino-terminal fragment. A panel of mutant APP reporter constructs was expressed in which each of the potential phosphorylation sites located within the cytoplasmic domain of APP was replaced with alanine residues. Phorbol response patterns were unchanged for each of these mutants, suggesting that induced cleavage occurs independently of APP substrate phosphorylation. We find that phorbol (a) increases the release of a PN2 fragment that is consistent with the normal secretase activity, (b) decreases the release of a shorter amino-terminal APP fragment that is cleaved near the amino terminus of BAP, and (c) decreases the release of BAP which was identified based on electrophoretic mobility, epitope mapping, and radio-sequencing. These data demonstrate that pharmacological treatment can reduce the formation of BAP and suggests that protein kinase C activators could be developed as therapeutic agents to block BAP formation.


Heterogeneity of Flt3-expressing multipotent progenitors in mouse bone marrow.
Mechanisms of lymphoid and myeloid lineage choice by hemopoietic stem cells remain unclear. In this study we show that the multipotent progenitor (MPP) population, which is immediately downstream of hemopoietic stem cells, is heterogeneous and can be subdivided in terms of VCAM-1 expression. VCAM-1(+) MPPs were fully capable of differentiating into both lymphoid and myeloid lineages. In contrast, VCAM-1(-) MPPs gave rise to lymphocytes predominately in vivo. T and B cell development from VCAM-1(-) MPPs was 1 wk faster than that from VCAM-1(+) MPPs. Furthermore, VCAM-1(+) MPPs gave rise to common myeloid progenitors and VCAM-1(-) MPPs in vivo, indicating that VCAM-1(-) MPPs are progenies of VCAM-1(+) MPPs. VCAM-1(-) MPPs, in turn, developed into lymphoid lineage-restricted common lymphoid progenitors. These results establish a hierarchy of developmental relationship between MPP subsets and lymphoid and myeloid progenitors. In addition, VCAM-1(+) MPPs may represent the branching point between the lymphoid and myeloid lineages.


Enantiomeric resolution of drug compounds by liquid chromatography.
Novel techniques have recently emerged to separate chiral drug compounds into pure enantiomers. The mechanism, experimental difficulties, and applicability of these methods can very greatly, and the choices involved are not straightforward. The most significant new advances in the field of chiral separations have come from work done with liquid chromatographic systems and chiral stationary-phase columns. This review describes several commonly used approaches to chiral separation, dia-stereomeric derivatization, chiral mobile-phase additives, and three major types of chiral stationary phases. Although no single method can be judged superior for every drug application, it appears that chiral stationary phases have received the most attention recently and they are emphasized here.


WASP: allele-specific software for robust molecular quantitative trait locus discovery.
Allele-specific sequencing reads provide a powerful signal for identifying molecular quantitative trait loci (QTLs), but they are challenging to analyze and are prone to technical artifacts. Here we describe WASP, a suite of tools for unbiased allele-specific read mapping and discovery of molecular QTLs. Using simulated reads, RNA-seq reads and chromatin immunoprecipitation sequencing (ChIP-seq) reads, we demonstrate that WASP has a low error rate and is far more powerful than existing QTL-mapping approaches.


Nitrogen deposition and decreased precipitation does not change total nitrogen uptake in a temperate forest.
Decreased precipitation and increased anthropogenical by derived nitrogen (N) are important climate change factors that alter the availability of soil water and N which are crucial to root function and morphological traits. However, these factors are seldom explored in forests. To clarify how altered precipitation and N addition affect the uptake of organic and inorganic N by fine roots, a field hydroponic experiment using brief 15N exposures was conducted in a temperate forest in northern China. The root traits related to nutrient foraging (root morphology and mycorrhizal colonization) were measured simultaneously. Our results showed that all three tree species preferred ammonium (NH4+) over glycine and nitrate (NO3-), and NH4+ contributed 73% to the total N uptake from the soil. Uptake of glycine was higher than that of NO3-. Decreased precipitation, N addition, and their interaction increased NH4+ uptake rate compared with the control. Decreased precipitation decreased the glycine and NO3- uptake rate. Moreover, N addition, decreased precipitation and their interaction changed root morphological traits and significantly decreased mycorrhizal colonization. Although our treatments resulted in changes to the root traits and the forms of N uptake by plants, the total amount of N uptake did not change among all treatments. We conclude that although fine root traits of dominant tree species in temperate forests have high plasticity in response to climate change, nutrient balance in plants causes the total amount of N uptake to remain unchanged.


Competition between Intra and Intermolecular Pnicogen Bonds: Complexes between Naphthalene Derivatives and Neutral or Anionic Bases.
The PnF2 (Pn=P,As,Sb,Bi) on a naphthalene scaffold can engage in an internal pnicogen Pn⋅⋅⋅N bond (PnB) with an NH2 group placed close to it on the adjoining ring. An approaching neutral NH3 molecule can engage in a second PnB with the central Pn, which tends to weaken the intramolecular bond. The presence of the latter in turn weakens the intermolecular PnB with respect to that formed in its absence. Replacement of the external NH3 by a CN- anion causes a fundamental change in the bonding pattern, producing a fourth covalent bond with Pn, which rearranges into a trigonal bipyramidal motif. This addition disrupts the internal Pn⋅⋅⋅N pnicogen bond, recasting the PnF2 ⋅⋅⋅NH2 interaction into an NH⋅⋅⋅F H-bond.


Biomimetic affinity sensor for the ultrasensitive detection of neonicotinoids.
Multiple pesticides are often used in combination to protect crops from pests. This makes rapid on-site detection of pesticide contamination challenging. Herein, we describe a method for simultaneous detection of diverse neonicotinoid pesticides using a sensor that combines neonicotinoid-specific odorant-binding protein 2 (OBP2), which was cloned from an insect chemical sensing protein and modified gold nanoparticles with local surface plasmon resonance (LSPR)-based digital nanoplasmonometry (DiNM). When neonicotinoid pesticides bind to OBP2 on gold nanoparticles, the induced LSPR shift peak wavelength is too small to be measured using conventional LSPR immunoassays. DiNM records and compares the scattered image intensity in two adjacent wavelength bands, A and B, centered on the LSPR peak. It considers both the peak shift and the relative intensity change in these two bands, resulting in a significant LSPR signal enhancement. Then the spectral-image contrast was computed as the signal response. Using this approach, we obtained excellent limits of detection (LODs) of 1.4, 1.5, and 4.5 ppb for the neonicotinoids imidacloprid, acetamiprid, and dinotefuran, respectively. Blind tests demonstrated high positive and negative rates for teas, approximately 85 and 100%, respectively. Recombinant OBP2 produced in E. coli offers several advantages over antibodies, including high yield, time savings, and cost effectiveness. Moreover, this method is highly selective and sensitive to neonicotinoids, making it practical for field use.


Thermo-sensitive amylase-starch double-layer polymer nanoparticles with self-polishing and protein corona-free property for drug delivery applications.
Protein corona formation can lead to obstructive screening of targeting groups of nanoparticles (NPs). Also, the targeting groups are subjected to physiochemical interactions when exposed to solvents. Here, these two factors can influence NP targeting efficiency. Therefore, it is necessary to prepare a general method of preparing an anti-fouling NPs with protected targeting groups. Here, we designed α-amylase-starch double-layer coated poly (methyl methacrylate-co-acrylic acid) NPs (α-ams-SCMMA NPs), functionalized with aptamer targeting groups and doped with Tetrakis(para-hydraoxylphenyl) porphyrin (TPPOH) as a payload drug. Natural polysaccharide starch and enzyme α-amylase were applied here for thermo-sensitive activation of starch hydrolyzation in order to render the NPs' self-polishing from protein corona effects. During incubation with serum media, the protein corona was formed at the exterior shell of NPs, while the self-polishing process was activated to remove the "protein fouling" when the incubation temperature increased to 37 °C (body temperature). Mechanistically, the starch layer of α-ams-SCMMA NPs was readily hydrolysed by α-amylase, whereby the adsorbed protein corona could be efficiently eliminated and the targeting groups were then presented. With this unique self-polishing NP design, we believe our method can be applied for potential NP applications in cancer therepy due to excellent antifouling property and protected targeting groups.


Adverse reaction to metal debris in a patient with acetabular shell loosening 8 years after ceramic-on-metal total hip arthroplasty.
A 41-year-old woman presented 8 years after a left total hip arthroplasty. She complained of progressive groin pain for several months. Radiographs demonstrated a hard-on-hard bearing surface combination and radiolucent lines surrounding the acetabular shell. Laboratory analysis revealed a mild leukocytosis, a normal erythrocyte sedimentation rate, and a mildly elevated C-reactive protein. Serum cobalt and chromium levels were markedly elevated. Aspiration of the hip joint was negative for infection. Magnetic resonance imaging failed to demonstrate a pseudotumor. Revision total hip arthroplasty was performed, and a ceramic-on-metal bearing surface combination was explanted. Significant intraoperative findings included dark gray synovial fluid, metal transfer onto the ceramic femoral head, and a grossly loose acetabular shell pivoting about a single well-fixed screw. The explanted components otherwise appeared normal macroscopically. Histologic analysis of the capsular tissue demonstrated aseptic lymphocyte-dominated vasculitis-associated lesion and inclusion bodies consistent with third-body wear. Revision arthroplasty to a ceramic-on-polyethylene bearing surface combination was performed with a good clinical result and laboratory normalization at 9-month follow-up.


Comparative Effectiveness and Costs of Enoxaparin Monotherapy Versus Unfractionated Heparin Monotherapy in Treating Acute Coronary Syndrome.
Enoxaparin and unfractionated heparin (UFH) are guideline-recommended anticoagulants for patients with acute coronary syndrome (ACS), including unstable angina (UA) and myocardial infarction with (STEMI) or without ST-segment elevation (NSTEMI). Prior efficacy and safety evidence are mainly from clinical trials. Economic data are insufficient. This study examined the differences in utilization, effectiveness, safety, and costs in treating ACS between enoxaparin and UFH monotherapy using real-world data. Using data from 859 US hospitals, inpatients ≥ 18 years of age with a diagnosis of an initial episode of ACS between 2010 and 2016 were identified. Outcomes included 30-day risk of non-fatal myocardial infarction (MI), recurrent angina, in-hospital mortality, composite ischemic complication (having MI/recurrent angina/death), major bleeding, and costs. Multivariable regression was used to compare outcomes between enoxaparin and UFH monotherapy. Among 1,048,053 eligible patients (UA: 219,259; NSTEMI: 582,134; STEMI: 246,660), the prevalence of enoxaparin monotherapy was 12.0%, 13.9%, and 5.1%, and the prevalence of UFH monotherapy was 45.1%, 43.1% and 59.8%, for UA, NSTEMI, and STEMI patients, respectively. Enoxaparin was associated with a lower risk of ischemic complications and death among NSTEMI, but not in UA or STEMI patients, and with a lower risk of major bleeding in all patients. Cost savings per patient during index admission and 30-day follow-up for enoxaparin over UFH was $2972 for UA, $2475 for NSTEMI, and $3050 for STEMI. Enoxaparin was associated with a lower risk of ischemic complications (including death), lower costs, and better safety than UFH among NSTEMI patients. Improving upstream selection of anticoagulants in appropriate populations may help optimize clinical outcomes and costs.


Treatment of ADHD with amphetamine: short-term effects on family interaction.
This research seeks to study the impact on family function after 3 months of treatment with amphetamine. A total of 43 children, 6 to 11 years of age, with ADHD were treated with amphetamine for 3 months. Family function was studied before and after treatment by parent self-rating and independent observer ratings of videotaped parent-child interactions. The families with a child with ADHD were found to be more dysfunctional than control families. Families with children with severe ADHD behavior showed evidence of more family dysfunction compared to families with children with less severe ADHD behavior. After 3 months of treatment with amphetamine, the children's behavior and the mother's well-being and some aspects of parent-reported and observer-rated family functioning improved. This study gives support to the notion that some aspects of family dysfunction may be related to the child's ADHD behavior.


Pharmacokinetic factors as causes of variability in response to non-steroidal anti-inflammatory drugs.
Even the most widely used non-steroidal anti-inflammatory drugs (NSAID's) show considerable variations in their pharmacokinetic behaviour in volunteers and moreso in patients. An evaluation of the response-related pharmacokinetic parameters of the three presently most widely used NSAID's, namely diclofenac, indomethacin and piroxicam shows some obvious reasons: While the onset of absorption and the bioavailability of diclofenac varies considerably, we find relevant differences in the terminal plasma half-life of indomethacin and particularly piroxicam. Inter-patient variability in these parameters may contribute significantly to the observed variations in clinical response.


National dosimetric audit network finds discrepancies in AAA lung inhomogeneity corrections.
This work presents the Australian Clinical Dosimetry Service's (ACDS) findings of an investigation of systematic discrepancies between treatment planning system (TPS) calculated and measured audit doses. Specifically, a comparison between the Anisotropic Analytic Algorithm (AAA) and other common dose-calculation algorithms in regions downstream (≥2cm) from low-density material in anthropomorphic and slab phantom geometries is presented. Two measurement setups involving rectilinear slab-phantoms (ACDS Level II audit) and anthropomorphic geometries (ACDS Level III audit) were used in conjunction with ion chamber (planar 2D array and Farmer-type) measurements. Measured doses were compared to calculated doses for a variety of cases, with and without the presence of inhomogeneities and beam-modifiers in 71 audits. Results demonstrate a systematic AAA underdose with an average discrepancy of 2.9 ± 1.2% when the AAA algorithm is implemented in regions distal from lung-tissue interfaces, when lateral beams are used with anthropomorphic phantoms. This systemic discrepancy was found for all Level III audits of facilities using the AAA algorithm. This discrepancy is not seen when identical measurements are compared for other common dose-calculation algorithms (average discrepancy -0.4 ± 1.7%), including the Acuros XB algorithm also available with the Eclipse TPS. For slab phantom geometries (Level II audits), with similar measurement points downstream from inhomogeneities this discrepancy is also not seen.


Solitary vaginal metastasis from unsuspected renal cell carcinoma.
Four cases of solitary vaginal metastasis from previously unsuspected renal cell carcinoma are presented. Vaginal bleeding, the presenting symptom in each patient, led to the finding of the metastatic vaginal lesion and to the urological evaluation, which revealed the occult primary renal cell carcinoma. With surgical treatment 2 of the 4 patients have remained well for more than 5 years.


Children and adolescents coping with home isolation and social distancing during Covid-19 in Qatar: a cross sectional study with qualitative items.
Covid-19 related studies report psychological impacts during home isolation and social distancing. Despite that, children and adolescents were able to adopt coping strategies that assisted in lowering severe levels of psychological disorders. This study aims to report on the psychosocial implications of social distancing and isolation on children of different nationalities who reside in Qatar, and to reveal their coping ways. This is a cross sectional study with qualitative component at its end. The study is a part of a larger study that reported the results of a national screening for psychological disorders experienced by children and adolescents in Qatar. A bilingual online questionnaire included close-ended and one open-ended question to screen for psychological changes and identify coping strategies practiced by children and adolescents (7-18 years) during home-isolation and social distancing. The quantitative questionnaire had five main sections as follows: the sociodemographic characteristics, Spence Children's Anxiety Scale, Kutcher Adolescent Depression Scale, and Clinical Anger Scale). The last section screened for eight different coping strategies. The summative content analysis was used to analyze the open-ended question "What practices do you do at home that make you happy?". First, open coding was used (for identification), followed by the axial coding (for comparison), and lasted by sorting of coping strategies inductively. Six thousand six hundred and eight (6608) subjects participated between June 23 and July 18, 2020. The clinical outcomes of the study had varying prevalence and levels of severity, which ranged from mild to severe. Higher prevalence was noted for adjustment disorder 66.5% (n = 4396), and generalized anxiety 60% (n = 3858), in comparison to depression 40% (n = 2588). Additionally, participants reported using cognitive, spiritual, social, and physical coping strategies. Eight higher order themes were identified to reflect the coping strategies: playing with siblings or pets, gardening, cooking, practicing arts and crafts, and doing chores. Furthermore, Sociodemographic factors such as ethnicity, religion and family status played a considerable role in choosing the type of coping strategy. The uniqueness of the study is bringing the psychosocial implications of social distancing through the voices of children and adolescents, and coping strategies from their perspective. These results are of importance for educational and healthcare systems that are recommended to collaborate even in "normal" times to prepare these age categories for any future crises. The importance of daily lifestyle and family is highlighted as protectors, and crucial factors in emotional management.


Deoxyribose breakdown by the adriamycin semiquinone and H2O2: evidence for hydroxyl radical participation.
We report our finding that the reaction between the adriamycin semiquinone (produced by reduction of the drug by xanthine oxidase) and H2O2 in N2 causes deoxyribose degradation to a thiobarbituric acid-reactive chromogen. Deoxyribose breakdown was inhibited by scavengers of hydroxyl radicals, providing evidence for the participation of hydroxyl radicals. The reaction was detected in air, but was less efficient in air than in N2. Deoxyribose degradation did not require a metal catalyst, and was inhibited by superoxide dismutase in air, but not N2. A similar reaction with deoxyribose in DNA may be of major importance in the antitumour action of adriamycin.


Medical education and the role of computers--as seen through the eyes of a medical student.
The medical education system that currently exists depends more and more on the memory of the physician-in-training as the medical database expands. While the brain has been engineered to reason and conceptualize, its capacity to memorize is limited and remains unchanged as the growth of medical knowledge continues. While we are exploring the frontiers of modern medicine, we must also explore new methods of training. An educational system that is efficient and practical must be developed, and the computer should assume a vital role in replacing the memorization of seldom used, but clinically important information. This would enable students to focus on clinical applications, and advance the development of reasoning skills that are essential in medicine: MEDICAL EDUCATION AND COMPUTERS.


Candida guilliermondii-induced chorioretinitis in a patient with eating disorder.
Candidemia is a life-threatening fungal infection among patients undergoing long-term intravenous catheterization, hematopoietic stem cell transplantation, or immunosuppressive therapy, as well as patients with severe immunodeficiency or cancer. Endophthalmitis is a rare but severe form of ocular inflammation caused by infection of the intraocular cavity, which can lead to irreversible visual loss if not treated properly and promptly. The initial manifestation typically involves chorioretinitis, which requires early diagnosis and appropriate treatment. Candida guilliermondii is a non-Candida albicans yeast species; its frequency of detection in Japan has increased in recent years, and many drug-resistant and less-chorioretinitis-related strains are known. Here, we describe a 17-year-old girl with an eating disorder who exhibited chorioretinitis because of catheter-related bloodstream infection (CRBSI) caused by C. guilliermondii. The patient was hospitalized with severe weight loss, and she was presumed to develop candidemia because of immunosuppression during central parenteral nutrition therapy with a peripherally inserted central catheter. After onset of CRBSI, the catheter was immediately removed. Antifungal therapy was modified following fundus examination, fungal species confirmation, and drug sensitivity confirmation; thus, the patient recovered without long-term complications. To the best of our knowledge, this is the first report of C. guilliermondii-induced chorioretinitis in a patient with an eating disorder. Prolonged malnutrition and immunosuppression during nutritional therapy create a risk of candidemia in patients with eating disorders. After the onset of CRBSI, early administration and appropriate use of antifungal agents, with respect to specific ocular complications, are important for reduction of both mortality and ocular complications.


Prediction in rectal cancer.
The treatment of rectal cancer largely depends on disease stage at diagnosis, based on which patients can be classified as low, intermediate, or high risk. Prognostic and predictive markers, specific to each risk category, can be applied for optimal risk classification and subsequent treatment allocation. These markers are either histopathological, determined with imaging, or have a biomolecular background. This review provides an overview of the current status of treatment options and the use of prognostic and predictive markers in each risk category. An effort was made to identify those markers that are currently lacking in, but have the potential to improve, the clinical decision process by discussing the data from recent studies aimed at the development of new prognostic and predictive markers. At this moment, none of the markers studied has been proven to be of significant, independent value, justifying implementation in daily clinical practice. However, recent developments in imaging techniques and biomolecular research do show great potential.


[Subjective experiences in retirement adjustment : Qualitative results from Switzerland].
Previous research on retirement adjustment has been dominated by quantitative studies on the development of different indicators for adjustment success. In contrast, there is a lack of qualitative studies examining the subjective experiences of retirees in their adjustment process to the new life phase. The article deals with the subjective adjustment experiences of persons whose regular retirement was about 1 year ago. It focuses on experienced habituation requirements and subjectively relevant factors of life satisfaction. The findings are based on qualitative interview data from a more comprehensive mixed methods study conducted between 2019 and 2022 in the German-speaking part of Switzerland. In the course of the study, 25 semi-structured interviews were carried out and analyzed using qualitative content analysis. Entering the new life phase was predominately experienced positively, which was mainly associated with a gain in freedom and opportunities for regeneration; however, the time after retirement also entailed habituation requirements in different areas of life. Life satisfaction increased compared to the initial survey before retirement and was associated with various beneficial and critical factors, ranging from personal characteristics to social developments. Retirement itself is not necessarily a critical experience but can be accompanied by other critical events. A satisfactory life 1 year after retirement is linked to multiple factors. Among these, resources play an essential role.


Hypercapnia-induced vasodilation in the cerebral circulation is reduced in older adults with sleep-disordered breathing.
The prevalence of sleep-disordered breathing (SDB) is higher in older adults compared with younger individuals. The increased propensity for ventilatory control instability in older adults may contribute to the increased prevalence of central apneas. Reductions in the cerebral vascular response to CO2 may exacerbate ventilatory overshoots and undershoots during sleep. Thus, we hypothesized that hypercapnia-induced cerebral vasodilation (HCVD) will be reduced in older compared with younger adults. In 11 older and 10 younger adults with SDB, blood flow velocity in the middle cerebral artery (MCAV) was measured using Doppler transcranial ultrasonography during multiple steady-state hyperoxic hypercapnic breathing trials while awake, interspersed with room air breathing. Changes in ventilation, MCAV, and mean arterial pressure (MAP) via finger plethysmography during the trials were compared with baseline eupneic values. For each hyperoxic hypercapnic trial, the change (Δ) in MCAV for a corresponding change in end-tidal CO2 and the HCVD or the change in cerebral vascular conductance (MCAV divided by MAP) for a corresponding change in end-tidal CO2 was determined. The hypercapnic ventilatory response was similar between the age groups, as was ΔMCAV/Δ[Formula: see text]. However, compared with young, older adults had a significantly smaller HCVD (1.3 ± 0.7 vs. 2.1 ± 0.6 units/mmHg, P = 0.004). Multivariable analyses demonstrated that age and nadir oxygen saturation during nocturnal polysomnography were significant predictors of HCVD. Thus, our data indicate that older age and SDB-related hypoxia are associated with diminished HCVD. We hypothesize that this impairment in vascular function may contribute to breathing instability during sleep in these individuals.NEW & NOTEWORTHY This study demonstrates, for the first time, in individuals with sleep-disordered breathing (SDB) that aging is associated with decreased hypercapnia-induced cerebral vasodilation (HCVD). In addition to advanced age, the magnitude of nocturnal oxygen desaturation due to SDB is an equal independent predictor of HCVD.


"New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis.
De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPARalpha-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPARalpha target genes in FASKOL mice were corrected with a PPARalpha agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPARalpha agonist. These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of distinct physiological pools of PPARalpha in adult liver.


Contextual, organizational and ecological effects on the variations in hospital readmissions of rural Medicare beneficiaries in eight southeastern states.
The enactment of the Patient Protection and Affordable Care Act (ACA) has been expected to improve the coverage of health insurance, particularly as related to the coordination of seamless care and the continuity of elder care among Medicare beneficiaries. The analysis of longitudinal data (2007 through 2013) in rural areas offers a unique opportunity to examine trends and patterns of rural disparities in hospital readmissions within 30 days of discharge among Medicare beneficiaries served by rural health clinics (RHCs) in the eight southeastern states of the Department of Health & Human Services (DHHS) Region 4. The purpose of this study is twofold: first, to examine rural trends and patterns of hospital readmission rates by state and year (before and after the ACA enactment); and second, to investigate how contextual (county characteristic), organizational (clinic characteristic) and ecological (aggregate patient characteristic) factors may influence the variations in repeat hospitalizations. The unit of analysis is the RHC. We used administrative data compiled from multiple sources for the Centers of Medicare and Medicaid Services for a period of seven years. From 2007 to 2008, risk-adjusted readmission rates increased slightly among Medicare beneficiaries served by RHCs. However, the rate declined in 2009 through 2013. A generalized estimating equation of sixteen predictors was analyzed for the variability in risk-adjusted readmission rates. Nine predictors were statistically associated with the variability in risk-adjusted readmission rates of the RHCs pooled from 2007 through 2013 together. The declined rates were associated with by the ACA effect, Georgia, North Carolina, South Carolina, and the percentage of elderly population in a county where RHC is located. However, the increase of risk-adjusted rates was associated with the percentage of African Americans in a county, the percentage of dually eligible patients, the average age of patients, and the average clinical visits by African American patients. The sixteen predictors accounted for 21.52 % of the total variability in readmissions. This study contributes to the literature in health disparities research from the contextual, organizational and ecological perspectives in the analysis of longitudinal data. The synergism of multiple contextual, organizational and ecological factors, as shown in this study, should be considered in the design and implementation of intervention studies to address the problem of hospital readmissions through prevention and enhancement of disease management of rural Medicare beneficiaries.