Miracle-dz/UniFAR-FTUs huggingface dataset:
The Dual Amylin- and Calcitonin-Receptor Agonist KBP-042 Works as Adjunct to Metformin on Fasting Hyperglycemia and HbA1c in a Rat Model of Type 2 Diabetes

KBP-042 is a dual amylin and calcitonin receptor agonist that increases glucose tolerance and insulin action and reduces body weight in rat models of obesity and prediabetes. The objective of the present study was to 1) evaluate KBP-042 as a treatment of late-stage type 2 diabetes in a rat model and 2) assess the value of adding KBP-042 to the standard of care, metformin, to consider KBP-042 as a relevant drug for treating patients with type 2 diabetes. Two studies were included: an intervention study and a prevention study. In the intervention study, treatment with 5 µg/kg KBP-042 was initiated in 11-week-old Zucker diabetic fatty (ZDF) rats, in which glucose tolerance, fasting glycemia, and glycated hemoglobin were assessed after 4 weeks. In the prevention study, either metformin (400 mg/kg), KBP-042 (5 µg/kg), or a combination of both were administered to ZDF rats for a total of 9 weeks. Glycemia, glucose tolerance, and insulin tolerance were tested. Furthermore, fasting plasma insulin and glucagon levels were evaluated. Finally, pancreatic content of insulin was assessed as a surrogate marker of beta-cell mass. It was found that KBP-042 was efficient in lowering fasting plasma glucose as well as improving glucose tolerance, both as prevention and intervention of disease progression. Furthermore, KBP-042 was efficient in combination with metformin and had additional effects compared with either therapy alone. In conclusion, KBP-042 is a highly relevant therapeutic candidate against type 2 diabetes, effective both as an add-on therapy to metformin and as a stand-alone therapy.
An alternative agent for radial arterial graft spasm: Application of topical iloprost

Objective. This study is planned bringing about a new choice for the prophylaxis of RA spasm which is topical iloprost and compares its efficacy with papaverine and diltiazem. Design. Twenty eight CABG patients with RA grafts were categorized into four groups by taking into account the topical vasodilator (papaverine, diltiazem, iloprost and saline) that was utilized during harvesting. Arterial segments were separated into four rings and were than soaked with KCL, norepinephrine, phenylephrine and serotonin. Then, acetylcholine was given to induce relaxation and the preparations were put to rest for 10 minute. Results. The contraction response achieved by the vasoreactive agents was most effectively inhibited by papaverine. The effectiveness of the response obtained by iloprost was similar to that of papaverine and significantly stronger than that of diltiazem. Especially at high vasoreactive substance concentrations, diltiazem had a contraction close to that of the control while the protective effect was weaker than those of papaverine and iloprost. Conclusion. Iloprost can be recommended as a strong alternative to the topical agents used for preventing arterial graft spasm.
Bradykinin B2 Receptor–Dependent Enhancement of Enalapril-Evoked Hypotension in Ethanol-Fed Female Rats

Our previous studies showed that chronic ethanol feeding attenuates centrally (clonidine) evoked and potentiates peripherally (hydralazine) evoked hypotension in female rats. In this study, we investigated whether chronic ethanol (8 weeks, 5% wt/vol) alters hemodynamic responses elicited by angiotensin-converting enzyme (ACE) inhibition (enalapril) in telemetered female rats. Given the intimate interaction between ACE and bradykinin, studies were extended to investigate the role of bradykinin receptor (B2R) in ethanol-enalapril interaction. Compared with pair-fed controls, ethanol-fed female rats exhibited (1) higher renal expressions of ACE and B2R proteins and angiotensin II levels and (2) lower blood pressure. Pharmacological inhibition of ACE and B2R supports functional role for the higher levels of these 2 proteins in ethanol-fed rats because enalapril (10 mg/kg, intraperitoneally) caused significantly greater hypotensive response in ethanol-fed rats than in control rats. Further, blockade of B2R with bradyzide (2 mg/kg, intraperitoneally) abrogated the enhanced hypotensive effect of enalapril in ethanol-fed rats but had no effect on enalapril-evoked hypotension in control rats. Finally, enalapril enhancement of spontaneous baroreflex sensitivity (BRS) in control was absent in ethanol-fed rats. These findings demonstrate that chronic ethanol produces B2R-dependent enhancement of the hypotensive response elicited by enalapril and abrogates enalapril-evoked enhancement of spontaneous baroreflex response in female rats.
Interactions between liquid Sn-Bi based solders and contact metals for high temperature applications

Liquid solder interconnects are promising as an alternative approach to conventional high melting point solder interconnects for applications where the operating temperature is likely to exceed 125/spl deg/C. In order to ensure that a liquid solder interconnect remains in contact with the terminations on the component and the substrate, and that electrical contact between them remains unbroken, there must be some growth of an intermetallic compound (IMC) at the interfaces between the solder and the contact metallizations. However, given that IMC growth is generally much faster when the solder is liquid, the growing IMC must act as a strong diffusion barrier to suppress further IMC growth. This paper presents preliminary studies of liquid-phase Sn-Bi based solders that result in stable interfaces between the solders and three common contact metallizations, consisting of electroless Ni(P)/Au, of Cu and of Ti-W. Small quantities (1 or 2 %) of an additional element, including Cr, Si, Zn, Ag, Au, Al and Cu, have been alloyed with the eutectic Sn-Bi composition to find an effective inhibitor additive that can achieve a strong IMC diffusion barrier. IMCs and their growth rates, as well as the consumption rates of the three contact metallizations in contact with the molten solders, were investigated. Storage temperatures of 200/spl deg/ and 240/spl deg/ were used, with storage times ranging between two hours and one month. Results to date show that suitable additives can significantly reduce IMC growth rates for both the Ni(P)-Au and Cu contact metallizations, while no appreciable IMC growth is observed for Ti-W in contact with both the original and the various alloyed Sn-Bi based solders. Based on the current results, criteria to further assist the design of feasible molten liquid solder - contact metallization systems have been deduced.
The importance of morphological events and intercellular interactions in the regulation of prespore‐specific gene expression during sporulation in Bacillus subtilis

We have established a time course for the early morphological events of sporulation in Bacillus subtilis and related this to changes in gene expression, particularly those occurring in the prespore compartment. We have also systematically studied the effects of mutations in various regulatory (spo) genes on prespore‐specific gene expression. On the basis of these results, and those of other laboratories, at least four distinct temporal classes of prespore‐specific gene expression can now be distinguished. The first class begins within 15min of the formation of the spore septum, and requires the σ;F form of RNA polymerase. The second class, also directed by RNA polymerase containing σ;F, begins soon after the completion of prespore engulfment, and depends on an intercellular signal from the mother cell. This transcription results in synthesis of σ;G. However, σ;G activity, directing the third class of gene expression, appears only about 30min later and is dependent on the completion of prespore engulfment and on further interactions with the mother cell. The fourth class of gene expression has been described. The results demonstrate that the prespore programme of gene expression incorporates a series of control points modulated by information from the mother cell and on progress through the morphogenetic process.
Ambulatory blood pressure normality: results from the PAMELA study

Objective To determine ambulatory and home blood pressure means and distributions in relation to clinic blood pressure in a general population. Methods We obtained a random sample of 2400 subjects stratified by sex and 10 year age groups to be representative of residents aged 25–64 years of the city of Monza. Participation rate was 69% (1651 subjects). Blood pressure measurements consisted of clinic blood pressure (average of three measurements, sphygmomanometry), home blood pressure (average of morning and evening measurements, semiautomatic device) and ambulatory blood pressure (automatic readings at 20 min intervals, Space labs 90207). Clinic blood pressure was obtained both before and after home and ambulatory blood pressures. Data analysis did not include 213 subjects receiving antihypertensive drug treatment and was therefore limited to 1438 participants. Results: In the 1438 subjects, clinic, home and ambulatory blood pressure showed a normal-like distribution, with a taller peak and a narrower base for ambulatory than for home and clinic values. Clinic, home and ambulatory blood pressures were significantly related to each other (P always < 0.001). The means of the two clinic blood pressures obtained on consecutive days were superimposable (127.4 ± 17.0/82.3 ± 9.8 and 128.2 ± 16.5/81.9 ± 9.9 mmHg) and both were markedly higher than home and 24 h average blood pressures (8.2 mmHg), which were similar to one another. The differences between clinic and home or 24 h average blood pressure were similar in both sexes but increased with increasing age and clinic blood pressure values. The influence of clinic blood pressure values on the clinic-ambulatory or clinic–home blood pressure differences was more important than age. Although higher than the 24 h average value, daytime average blood pressure was also lower than clinic blood pressure. Night-time blood pressure was markedly lower than the daytime value in both sexes and at all ages. Conclusion Data from a large and unbiased sample of a general population show that home and 24 h or daytime average blood pressures are much lower than clinic blood pressure. The relatively close correlation between blood pressure values measured with the different methods used has allowed calculation of home and ambulatory blood pressure values corresponding to the accepted upper limit of normality of clinic blood pressure (140/90 mmHg). The upper limit of normality for the population was for both home and ambulatory blood pressures in the range 120–130 and 75–81 mmHg for systolic and diastolic values, respectively, with slight differences depending on sex and age. Taking 140/90 mmHg as the upper normal limit of the population is therefore an error that leads to individuals whose home or ambulatory blood pressures are high being considered as normotensive.
Intron Definition Is Required for Excision of the Minute Virus of Mice Small Intron and Definition of the Upstream Exon

ABSTRACT Alternative splicing of pre-mRNAs plays a critical role in maximizing the coding capacity of the small parvovirus genome. The small-intron region of minute virus of mice (MVM) pre-mRNAs undergoes an unusual pattern of overlapping alternative splicing—using two donors (D1 and D2) and two acceptors (A1 and A2) within a region of 120 nucleotides—that determines the steady-state ratios of the various viral mRNAs. In this report, we show that the determinants that govern excision of the small intron are complex and are also required for efficient definition of the upstream exon. For the MVM small intron in its natural context, the two donors appear to compete for the splicing machinery: the position of D1 favors its usage, while the primary sequence of D2 must be more like the consensus sequence than is D1 to be used efficiently. We have genetically defined the branch points that are used for generation of the major and minor spliced forms and show that recognition of components of the small-intron acceptors is likely to be the dominant determinant in alternative small-intron excision. We have also identified a G-rich intronic enhancer sequence within the small intron that is essential for splicing of the minor form (D2 to A2) but not the major form (D1 to A1) of MVM mRNAs and is required for efficient definition of the upstream NS2-specific exon. In its natural context, the small intron appears to be excised by a mechanism consistent with intron definition. When the MVM small intron is expanded, various parameters of its excision are altered, indicating that critical cis-acting signals are context dependent. Relative use of the donors and acceptors is altered, and the upstream NS2-specific exon is no longer efficiently defined. The fact that definition of the upstream NS2-specific exon can be achieved by the MVM small intron in its natural context, but not when it is expanded, suggests that the multiple determinants that govern definition and excision of the small intron are required, in concert, for upstream exon definition. Our data are consistent with a model in which alternative splicing of the MVM P4-generated pre-mRNAs is governed by a hybrid of intron- and exon-defining mechanisms.
Jejuna of patients with insulin‐dependent diabetes mellitus (IDDM) show signs of immune activation

The roles of enteric viruses and food antigens as possible triggers in human insulin‐dependent diabetes mellitus and the evidence that mucosal‐associated homing receptors are important in both human and experimental diabetes prompted us to undertake an immunohistochemical study of intestinal specimens from patients with IDDM. We studied jejunal morphology and immunohistochemistry in 26 patients with IDDM, 13 of whom had the HLA‐DQB1*0201 gene and therefore a higher risk of coeliac disease. The findings were compared with those in specimens from age‐matched controls. Villous structure and the density of the intraepithelial lymphocytes were normal in every biopsy specimen. The extent of positivity with anti‐DR and ‐DP antibodies in the villous epithelium was significantly greater in the specimens from patients than in those from controls (P = 0.0002 in both comparisons). The crypts were also more positive: for DR P = 0.0001, and for DP P = 0.002. The densities of T cells, CD4+, CD8+, and T cell receptor α/β+ and γ/δ+ cells in the epithelium and lamina propria were similar in patients and controls, but the patients had significantly more α4/β7 integrin+ cells in the lamina propria (P = 0.006). No difference was seen between HLA‐DQB1*0201‐positive and ‐negative patients. These findings reflect a stage of inflammation in the structurally normal intestines of patients with IDDM and suggest secretion of inflammatory Th1‐type cytokines in the intestine.
Inhibitor of Apoptosis Proteins Physically Interact with and Block Apoptosis Induced by Drosophila Proteins HID and GRIM

ABSTRACT Reaper (RPR), HID, and GRIM activate apoptosis in cells programmed to die during Drosophila development. We have previously shown that transient overexpression of RPR in the lepidopteran SF-21 cell line induces apoptosis and that members of the inhibitor of apoptosis (IAP) family of antiapoptotic proteins can inhibit RPR-induced apoptosis and physically interact with RPR through their BIR motifs (D. Vucic, W. J. Kaiser, A. J. Harvey, and L. K. Miller, Proc. Natl. Acad. Sci. USA 94:10183–10188, 1997). In this study, we found that transient overexpression of HID and GRIM also induced apoptosis in the SF-21 cell line. Baculovirus and Drosophila IAPs blocked HID- and GRIM-induced apoptosis and also physically interacted with them through the BIR motifs of the IAPs. The region of sequence similarity shared by RPR, HID, and GRIM, the N-terminal 14 amino acids of each protein, was required for the induction of apoptosis by HID and its binding to IAPs. When stably overexpressed by fusion to an unrelated, nonapoptotic polypeptide, the N-terminal 37 amino acids of HID and GRIM were sufficient to induce apoptosis and confer IAP binding activity. However, GRIM was more complex than HID since the C-terminal 124 amino acids of GRIM retained apoptosis-inducing and IAP binding activity, suggesting the presence of two independent apoptotic motifs within GRIM. Coexpression of IAPs with HID stabilized HID levels and resulted in the accumulation of HID in punctate perinuclear locations which coincided with IAP localization. The physical interaction of IAPs with RPR, HID, and GRIM provides a common molecular mechanism for IAP inhibition of theseDrosophila proapoptotic proteins.
Responses of periodontal ligament stem cells on various titanium surfaces.

OBJECTIVE Periodontal ligament has been reported to have adult stem cells (PDLSCs) which are responsible to regenerate the alveolar bone tissue after tooth is removed from its socket. Also PDLSCs may be the stem cells responsible for the osseointegration of titanium implants after installing the implant immediately in the fresh extracted socket. Here we tested cellular responses of PDLSCs on the various titanium surfaces to verify this notion. MATERIALS AND METHODS Titanium disc were prepared for the different surface textures; smooth machined, blasted with 75 and 125 μm Al(2) O(3) particles, and anodized. PDLSCs were cultured on these titanium discs and tested their proliferation and gene expressions of osteocalcin, osteopontin, type I collagen, and GAPDH. RESULTS Proliferation of PDLSCs was higher on the rough surface blasted with 75 μm Al(2) O(3) particles. Osteocalcin expression was increased on the Al(2) O(3) particle treated-surface regardless of its particle size. Type I collagen expression was generally decreased with time in 6 days culture. CONCLUSIONS In this experiment, it was shown that cultured PDLSCs proliferate in higher rate on the rough surface especially at the 75 μm Al(2) O(3) particle treated surface than other surfaces. Also, osteocalcin was highly expressed on the rough surfaces treated with 75 μm and 125 μm Al(2) O(3) particles.
Impairment of executive performance after transcranial magnetic modulation of the left dorsal frontal‐striatal circuit

The dorsal frontal‐striatal circuit is implicated in executive functions, such as planning. The Tower of London task, a planning task, in combination with off‐line low‐frequency repetitive transcranial magnetic stimulation (rTMS), was used to investigate whether interfering with dorsolateral prefrontal function would modulate executive performance, mimicking dorsal frontal‐striatal dysfunction as found in neuropsychiatric disorders. Eleven healthy controls (seven females; mean age 25.5 years) were entered in a cross‐over design: two single‐session treatments of low‐frequency (1 Hz) rTMS (vs. sham rTMS) for 20 min on the left dorsolateral prefrontal cortex (DLPFC). Directly following the off‐line rTMS treatment, the Tower of London task was performed during MRI measurements. The low‐frequency rTMS treatment impaired performance, but only when the subjects had not performed the task before: we found a TMS condition‐by‐order effect, such that real TMS treatment in the first session led to significantly more errors (P = 0.032), whereas this TMS effect was not present in subjects who received real TMS in the second session. At the neural level, rTMS resulted in decreased activation during the rTMS versus sham condition in prefrontal brain regions (i.e., premotor, dorsolateral prefrontal and anterior prefrontal cortices) and visuospatial brain regions (i.e., precuneus/cuneus and inferior parietal cortex). The results show that low‐frequency off‐line rTMS on the DLPFC resulted in decreased task‐related activations in the frontal and visuospatial regions during the performance of the Tower of London task, with a behavioral effect only when task experience is limited. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.
Assessment of the efficiency of pulmonary oxygenation. The choice of oxygenation index

Oxygen‐derived indices are often used as alternatives to determination of venous admixture (Qva/Qt) when a pulmonary arterial catheter is not in use, but the question of which more accurately indicates the efficiency of oxygenation is controversial. The theoretical relationships between six measures of oxygenation (Pao2, Sao2, P(A‐a)o2, Pao2/Fio2, P(A‐a)o2/Pao2, Pao2/Pao2) and venous admixture were analyzed with special reference to the influence of the concentration of inspired oxygen (Fio2). In addition, the predictability of Qva/Qt was evaluated on the basis of 100 authentic sets of arterial and mixed venous blood gas data. Of the above six indices, Pao2/Fio2 was most accurate (r = 0.88), but was far from independent of the Fio2 used. However, a direct Estimate of Venous Admixture (EVA) — based on arterial blood analysis and with C(a‐v)o2 assigned a value of 50 ml·l‐1 — predicted Qva/Qt still better (r = 0.95). It is concluded that when mixed venous blood gas data are lacking, EVA is the preferable measure of oxygenation.
Reliability and validity of the objective structured clinical examination in paediatrics

Summary. The assessment of clinical competence has traditionally been carried out through standard evaluations such as multiple choice question and bedside oral examinations. The attributes which constitute clinical competence are multidimensional, and we have modified the objective structured clinical examination (OSCE) to measure these various competencies. We have evaluated the validity and reliability of the OSCE in a paediatric clinical clerkship. We divided the examination into the four components of competence (clinical skills, problem‐solving, knowledge, and patient management) and evaluated the performance of 77 fourth‐year medical students. The skill and content domains of the OSCE were carefully defined, agreed upon, sampled and reproduced. This qualitative evaluation of the examination was both adequate and appropriate. We achieved both acceptable interstation and intertask reliability. When correlated with concurrent methods of evaluation we found the OSCE to be an accurate measure of paediatric knowledge and patient management skills. The OSCE did not correlate, however, with traditional measures of clinical skills including history‐taking and physical examination. Our OSCE, as outlined, offers an objective means of identifying weaknesses and strengths in specific areas of clinical competence and is therefore an important addition to the traditional tools of evaluation.