Molecular cloning of a new variant of human papillomavirus type 6 isolated from a Chinese woman and expression of its L1 gene in E. coli--molecular cloning & expression of HPV6 gene.
A human papillomavirus genome DNA of 7.9 kb from a Chinese woman with genital condyloma acuminata was cloned in BamHI site of pAT153. According to the results obtained from Southern blotting, restriction mapping as well as partial DNA sequencing, the isolated genome (HPV6BV) had obvious variance and was referred to as a new variant of HPV6 found in China the first time. HPV6BV L1 gene was successfully expressed in E. coli as a fusion protein with pUR288. The beta-galactosidase/L1 fusion protein reacted with both beta-galactosidase antiserum and HPV antibody using Western blot technique. The E. coli-produced fusion protein, possessing HPV antigenicity, may provide a reagent for clinical diagnosis and epidemiological survey.


Subunit composition of α5-containing nicotinic receptors in the rodent habenula.
Gene association studies in humans have linked the α5 subunit gene CHRNA5 to an increased risk for nicotine dependence. In the CNS, nicotinic acetylcholine receptors (nAChRs) that contain the α5 subunit are expressed at relatively high levels in the habenulo-interpeduncular system. Recent experimental evidence furthermore suggests that α5-containing receptors in the habenula play a key role in controlling the intake of nicotine in rodents. We have now analysed the subunit composition of hetero-oligomeric nAChRs in the habenula of postnatal day 18 (P18) C57Bl/6J control mice and of mice with deletions of the α5, the β2, or the β4 subunit genes. Receptors consisting of α3β4* clearly outnumbered α4β2*-containing receptors not only in P18 but also in adult mice. We found low levels of α5-containing receptors in both mice (6%) and rats (2.5% of overall nAChRs). Observations in β2 and β4 null mice indicate that although α5 requires the presence of the β4 subunit for assembling (but not of β2), α5 in wild-type mice assembles into receptors that also contain the subunits α3, β2, and β4.


Leptin and the hypothalamic-pituitary regulation of the gonadotropin-gonadal axis.
Leptin is an adipocyte-derived protein hormone which not only conveys a signal of the amount of energy stores to the central nervous system but also plays an important role in regulating neuroendocrine function. The importance of leptin in the reproductive system has been suggested by the reproductive dysfunction associated with leptin deficiency and resistance in both animal models and humans as well as the ability of leptin to accelerate the onset of reproductive function in normal mice. Transgenic mice overexpressing leptin also have accelerated puberty, and leptin administration reverses the fasting-induced suppression of sexual maturation in rodents, indicating that leptin may serve as the critical link between sufficient energy stores and proper functioning of the reproductive system. Normal women have a pulsatile release pattern of leptin that is significantly associated with the variations in luteinizing hormone (LH) and estradiol levels. In various animal models, leptin administration restores the LH pulsatility pattern which is suppressed during fasting, indicating a hypothalamic site of action since LH pulsatility is under the control of gonadotropin-releasing hormone (GnRH). In humans, leptin has been administered to a 9-year-old leptin-deficient girl, resulting in a gonadotropin secretory pattern consistent with early puberty. While in vitro experiments with hypothalamic explants and a GnRH-secreting neuronal cell line have shown that leptin can directly stimulate GnRH secretion, the lack of leptin receptors on GnRH neurons suggests that leptin may act through other hypothalamic neuropeptides. Several neuropeptides which act as downstream effectors of leptin have been investigated, and recent studies indicate that cocaine and amphetamine-regulated transcript may be such a mediator of leptin's effect on GnRH. Leptin receptors have also been identified in human pituitaries, and leptin may influence LH release from the pituitary. However, the current evidence is conflicting, and further studies are needed in order to clarify leptin's role at the level of the pituitary. Thus, accumulating evidence suggests that leptin can regulate gonadotropin levels, and its secretion may, in turn, be influenced by GnRH or gonadal steroids but appears to be independent of LH control.


RNase P: role of distinct protein cofactors in tRNA substrate recognition and RNA-based catalysis.
The Escherichia coli ribonuclease P (RNase P) has a protein component, termed C5, which acts as a cofactor for the catalytic M1 RNA subunit that processes the 5' leader sequence of precursor tRNA. Rpp29, a conserved protein subunit of human RNase P, can substitute for C5 protein in reconstitution assays of M1 RNA activity. To better understand the role of the former protein, we compare the mode of action of Rpp29 to that of the C5 protein in activation of M1 RNA. Enzyme kinetic analyses reveal that complexes of M1 RNA-Rpp29 and M1 RNA-C5 exhibit comparable binding affinities to precursor tRNA but different catalytic efficiencies. High concentrations of substrate impede the activity of the former complex. Rpp29 itself exhibits high affinity in substrate binding, which seems to reduce the catalytic efficiency of the reconstituted ribonucleoprotein. Rpp29 has a conserved C-terminal domain with an Sm-like fold that mediates interaction with M1 RNA and precursor tRNA and can activate M1 RNA. The results suggest that distinct protein folds in two unrelated protein cofactors can facilitate transition from RNA- to ribonucleoprotein-based catalysis by RNase P.


Shared IVF among female couples: clinical outcomes of the Reception of Oocytes from the Partner (ROPA) method.
What is the population undergoing the ROPA (Reception of Oocytes from Partner) method and what are the outcomes of the technique? Case series of all ROPA treatments carried out between 2011 and 2020 in 18 fertility clinics in Spain. Demographic characteristics, cycle features, laboratory and clinical outcomes, and the intentions regarding the disposition of surplus embryos were analysed. Donor patients were on average 3.5 years younger than recipients (P = 0.001). No significant differences were found in body mass index or anti-Müllerian hormone. In 13% of cases, fertility issues were found: poor ovarian reserve (6.8%); endometriosis (2.9%); and polycystic ovary syndrome (2.2%). Including cases of advanced age (38 years old or older), more than one-half of couples (53.6%) had some condition that could affect fertility. Mean number of mature oocytes per cycle was 10 (+/- 5.7), and fertilization rate was 74.5% (+/- 18.8). Mean number of viable embryos was 3.2 (+/- 1.5). Surplus embryos were cryopreserved in 50.4% of cycles. Outcomes after embryo transfers from ROPA, and subsequent frozen cycles were as follows: positive pregnancy test (61.0%), clinical pregnancy (54.1%) and miscarriage rate (16.1%). Other outcomes were live birth rate per embryo transfer (44.7%); multiple pregnancy rate (5.4%); per cumulative ROPA cycle (48.6%); and per couple (61.6%). The outcomes of the ROPA method are reassuring. About one-half of the ROPA cycles resulted in a live birth and one-quarter of the cycles had surplus embryos after achieving a live birth. Main neonatal outcomes were also reassuring.


A new database for food safety: EDID (Endocrine disrupting chemicals - Diet Interaction Database).
Diet is a significant source of exposure to endocrine disrupting chemicals (EDC); health risks cannot be excluded, in particular long-term effects in vulnerable Groups such as children. However, food safety assessment must also consider the effects of natural food components modulating the endocrine system. The scientific evidence on the complex interactions between EDC and food components is still limited. The new EDC-Diet Interactions Database (EDID) within the ISS EDC area (www.iss.it/inte/) aims to stimulate further research in the field of food toxicology: a database on international literature's studies, either on experimental systems and on animal population and humans, easy to consult and periodically updated. Examples of studies contained in EDID are provided concerning EDC with iodine, vitamins and phytoestrogens.


A motivational phone call improves participation to screening colonoscopy for those with a positive FIT in a national screening programme (NCT 03276091).
A large proportion of individuals with a positive faecal immunologic test (FIT) will never undergo the recommended colonoscopy despite a full sequence of reminders. This prospective study aimed to recruit refractory individuals by a motivational personalised phone call given by a screening physician. We evaluated the impact of a motivational phone call given by a physician of the screening organisation in order to convince patients with positive FIT to undergo a colonoscopy. 115 individuals with a positive FIT were targeted. After GP phone call, it was ascertained that 15 had had a colonoscopy, one died, one moved outside the region, and the GP refused the study phone call for 13. Finally, we attempted to call 85 individuals; 24 could not be reached, 5 colonoscopies had been performed, and thus 56 individuals were included. The main reason for colonoscopy refusal (33.9%) was wrong advice from the GP or the gastroenterologist. Among those included, 33.9% (19/56) underwent the colonoscopy within 22.7 months after FIT; 1 invasive cancer, 18 adenomas and 9 serrated sessile lesions were found. Motivational phone call performed by a physician from the screening organisation is effective to recruit a third of refractory individuals. Education for GPs and gastroenterologists is necessary to increase participation to colonoscopy and to avoid the performance of an inappropriate secondary FIT. NCT 03276091.


Learning by Observing, Pitching in, and Being in Relations in the Natural World.
This chapter describes a central tenet of Indigenous American social interaction, which emphasizes mutuality in collaboration and caring in Indigenous communities. This includes interactions with an agentive natural world, in which more-than-human beings act as participants in the lives of humans and vice versa. We argue that research on children's learning should take a broader view of interactional partners to include the natural world.


Beyond the Officially Sacred, Donor and Believer: Religion and Organ Transplantation.
Religious concerns might represent an important issue when donation for transplantation is discussed. Even if no religious tradition formally forbids organ donation and transplantation, members of the same religious group may have differing and often conflicting opinions in their own interpretation of how their religion encourages and/or supports organ donation and transplantation, as discussed in this article. It also should be considered that even if a religion refuses to define concrete rules about organ donation and transplantation, there are a great number of factors that may influence the decision-making process. Examples may include negative perceptions of the cutting and removal of organs or ignorance about the transplantation system, both of which would influence the decision-making process concerning transplantation. Knowledge of these facts may provide useful information, perhaps increasing transplant numbers.


Swimming training improves the vasodilator effect of angiotensin-(1-7) in the aorta of spontaneously hypertensive rat.
endothelial dysfunction plays a critical role in the pathogenesis of hypertension. It is well established that physical training has beneficial effects on the cardiovascular system. We recently reported that angiotensin-(1-7) [Ang-(1-7)] concentration and the Mas receptor expression is increased in the left ventricle of trained spontaneous hypertensive rats (SHR). The vascular effects of Ang-(1-7) in trained animals remain so far unknown. In the present study we investigated the effects of physical training on the vasodilator effect of Ang-(1-7) in the aorta of SHR. normotensive Wistar rats and SHR were subjected to an 8-wk period of 5% overload of body weight swimming training. Changes in isometric tension were recorded on myograph. Western blot was used to investigate Ang-(1-7) receptors expression. in aortas from normotensive rats Ang-(1-7) and ACh induced a concentration-dependent vasodilator effect, which was not modified by the physical training. Vessels from SHR had an impaired vasodilator response to Ang-(1-7) and ACh. The swimming training strongly potentiated the vasodilator effect induced by Ang-(1-7) in SHR, but did not modify the effect of ACh. Interestingly, Mas receptor protein expression was substantially increased by physical training in SHR. In trained SHR, the vasodilator effect of Ang-(1-7) was abrogated by removal of the endothelium and by the selective Ang-(1-7) receptor antagonists A-779 and d-Pro(7)-Ang-(1-7). l-NAME decreased Ang-(1-7) vasodilator response and indomethacin abolished the remaining dilatory response. physical training increased Mas receptors expression in SHR aortas, thereby improving the vasodilator effect of Ang-(1-7) through an endothelium-dependent mechanism involving nitric oxide and prostacyclin.


Extending the vascular examination by noninvasive means.
The Doppler and phleborheographic technics are highly accurate and convenient methods of diagnosing acute deep venous thrombosis, which cannot be detected reliably by clinical examination. Extent of occlusive disease can be more quantitatively estimated by the Doppler method in the peripheral arteries of the limbs and by oculoplethysmography and phonoangiography in the carotid arteries. Noninvasive methods permit screening of patients suspected of arterial or venous disease and provide physicians with an objective means of assessing therapeutic results.


[Colonic pseudo-obstruction (Ogilvie syndrome), associated with cesarean section. Report of 2 cases and review of the literature].
We inform of two cases of pseudoobstruction of the colon (Ogilvie's Syndrome) secondary to cesarean section. The clinical picture, the diagnostic method and alternatives of treatment are analyzed. The importance of the knowledge of the syndrome and prompt diagnosis is emphasized.


How accurate are computed tomographic scans in assessment of changes in tumor size?
The computed tomographic scan plays an integral part in the diagnosis and management of tumors; however, its potential has not yet been fully exploited. With a computer-assisted volume determination method, the reproducibility of derived volume calculations was assessed, and radiologists' standard interpretations of interval change on serial scans were compared with the investigators' calculations of tumor volume change. Interobserver reproducibility of tumor volume calculations of the mean of two repeated volume determinations was satisfactory (mean of 3 percent, median of 1 percent). There were 29 comparisons (47 scans of 19 patients with liver tumors) of computed tumor changes with the radiologists' computed tomographic reports of consecutive scans. In only 41 percent (12 of 29) of the cases did the radiologists' interpretations and the computer-assisted volume determinations agree. It is concluded that objective computer-assisted volume determination provides a potentially more sensitive assessment of tumor change and that such precise, specific, reproducible determination of tumor volume should further clinical research and improve patient care.


A comparison of the hallux valgus angle, range of motion, and patient satisfaction after use of dynamic and static orthoses.
Conservative treatment is recommended for mild and moderate hallux valgus. The treatment may include two different types of orthoses: a dynamic orthosis and a static orthosis. The aim of this study was to compare the hallux valgus angle, hallux valgus range of motion, and patient satisfaction after the use of a dynamic and a static orthosis for the treatment of hallux valgus. Twenty-four participants contributed to this cross-over study. Participants were randomly allocated to orthotic treatments at the start. The hallux valgus angle and range of motion were measured using a goniometer. Pain, signs and symptoms, function in activities of daily living (ADL), function in sport and recreation, and foot and ankle-related quality of life (QOL) were measured using the Foot and Ankle Outcome Score (FAOS) questionnaire. The participants then switched to using the other orthosis. A one-way repeated measure ANOVA was conducted to compare the measured variables in subjects at 4 conditions before and after of using each orthosis. There was a significant difference in the hallux valgus angle (p=0.001). The Bonferroni test indicated that both static and dynamic orthoses significantly decrease the angle of hallux valgus, respectively before static, after static (mean difference=-2.67, p=0.001) and before dynamic, after dynamic conditions (mean difference=-2.13, p=0.02). There was also a significant difference in subjects range of motion by using a dynamic orthosis in before dynamic, after dynamic conditions (mean difference=9.77, p=0.01). There was no significant difference in total FAOS score within the conditions (p=0.067). The use of both static and dynamic orthoses for 1 month can reduce the hallux valgus angle up to 2-3°. To achieve better results, it is suggested to wear orthoses for longer time. The dynamic orthosis also increases the passive range of motion of the first metatarsophalangeal joint and it seems to be effective during walking.


A randomised study of central versus peripheral intravenous nutrition in the perioperative period.
Out of 60 patients undergoing surgery for colo-rectal cancer, 30 were given total parenteral nutrition (TPN) via a peripheral venous catheter (PVC), and 30 via a central venous catheter (CVC). All Patients were treated for 10 days perioperatively. There were no complications of the treatment by CVC. The treatment had to be interrupted in 11 (= 37%) of those receiving TPN via PVC, 4 because of general inconvenience, 7 because of transient pain in the infusion arm without any sign of phlebitis. 63% suffered no complications. The study shows that, with most patients, it is possible to give TPN with an osmolality around 1100 mOsm/kg for up to 10 days via peripheral veins. For TPN of short duration, or where the duration of treatment is uncertain, it is recommended to give TPN initially via peripheral venous catheter, unless a central venous catheter is indicated for other reasons.


Tolerability and diagnostic usefulness of iohexol in urography. An open multicentre clinical trial.
The first experience with iohexol in urography in humans is reported. Injection of iohexol in a dose of 200 mg I/kg body weight into 34 patients with normal renal function was followed by only few and slight subjective adverse effects. A large number of laboratory tests revealed no toxic effects. High radiographic contrast was obtained.


Chemical characterisation of cheese associated fungi.
Recent work in our laboratory has demonstrated that the most common contaminating fungi on different types of cheese are;Penicillium commune, P. nalgiovense, P. solitum, P. discolor, P. roqueforti, P. crustosum, P. nordicum andAspergillus versicolor. On blue cheese a new speciesP. caseifulvum has been discovered as a surface contaminant. A large number of known and unknown metabolites have been described from the above mentioned cheese associated fungi from both synthetic media and real samples. Based on chemotaxonomy our laboratory has discovered thatP. roqueforti should be divided into three species:P. roqueforti (from cheese),P. carneum (from meat) andP. paneum (from bread). SimilarlyP. verrucosum should be divided intoP. verrucosum (from cereals) andP. nordicum (from cheese and meat products). Both species produce ochratoxins, however, only the former species produce citrinin.


A Unique Manifestation of Pupillary Fatigue in Autoimmune Autonomic Ganglionopathy.
To demonstrate a unique abnormality of the pupillary light reflex in patients with autoimmune autonomic ganglionopathy (AAG). Case series. Autonomic clinics at 2 university hospitals (University of Texas Southwestern Medical Center and Beth Israel Deaconess Medical Center). Seven patients with antibody-positive AAG. All patients with AAG underwent either monocular or binocular infrared pupillometry using a standard 2-second light stimulus at a defined intensity. Findings were compared with those from healthy control subjects and patients with other autonomic disorders. The light stimulus used in this study was selected to eliminate the normal phenomenon of pupil escape. The time to onset of redilation as well as other indices of pupillary constriction to light stimulus. Patients with AAG exhibited premature pupillary redilation (mean [SD], 1.02[0.20] seconds) compared with healthy control subjects (mean [SD], 2.24 [0.10] seconds) and other patients with autonomic disorders (mean [SD], 2.30 [0.12] seconds) (P.001). In healthy control subjects and patients with other autonomic disorders, pupillary redilation always followed the termination of the light stimulus; in patients with AAG, redilation consistently occurred during the light stimulus. In 1 patient, serial repetitive light stimulation further decreased the time to onset of redilation. Premature redilation of the pupil is a unique physiological feature seen only in patients with AAG. This phenomenon appears to be a manifestation of pupillary fatigue, a clinical correlate of defective synaptic transmission at the level of autonomic ganglia in antibody-positive AAG.


CCKB receptor activation protects CA1 neurons from ischemia-induced dysfunction in stroke-prone spontaneously hypertensive rats hippocampal slices.
We examined the effect of cholecystokinin octapeptide sulfated type (CCK-8S) on dysfunction of CA1 pyramidal neurons induced by in vitro ischemic insult in hippocampal slices of stroke-prone spontaneously hypertensive rats (SHRSP). CCK-8S shortened the time required for partial recovery from block of a population spike produced by ischemia. Furthermore, CCK-8S reduced ischemic insult-induced accumulation of K+ in extracellular space. Suppression of the K+ conductance by the CCKB receptor activation is suggested to contribute to neuroprotection by CCK-8S.


B7-H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression.
Aberrant tumor cell B7-H1 expression, a member of B7 family that can predominantly stimulate interleukin 10 (IL-10) products, contributed to the tumor immune evasion and tumor progression. This study was designed to investigate the expression of B7-H1 and IL-10 in normal pancreas tissues and pancreatic carcinoma samples, and to evaluate clinical significance of B7-H1 expression in pancreatic carcinoma. First, the B7-H1 and IL-10 expression in 40 pancreatic carcinoma samples and 8 healthy pancreas specimens using reverse transcription-PCR (RT-PCR) and western-blotting was detected. Localization of B7-H1 and IL-10 was confirmed by immunohistochemical (IHC) staining. Next, the association between B7-H1 expression and tumor differentiation and tumor stage was analyzed. Finally, the correlation between tumor-associated B7-H1 and IL-10 was evaluated. Pancreatic carcinoma samples demonstrated the up-regulated expression of B7-H1 and IL-10 at mRNA and protein level compared with normal pancreas tissues. IHC staining revealed that B7-H1 and IL-10 was almost localized in tumor cells. Analysis of relationship between B7-H1 and tumor clinicopathological characteristics showed that B7-H1 expression was significantly associated with poor tumor differentiation (P < 0.01) and advanced tumor stage (P < 0.01). Meanwhile, tumor-associated B7-H1 expression was also correlated with IL-10 products (P < 0.01, R (2) = 0.6985, mRNA level; P < 0.01, R (2) = 0.7236, protein level) in tumor cells. Our findings for the first time demonstrated up-regulated B7-H1 expression in human pancreatic carcinoma tissues, which might play a role in tumor progression and invasiveness. This expression seemed to be related to the ability of B7-H1 to promoting IL-10 secretion.


Structural and Functional Implications of Human Transforming Growth Factor β-Induced Protein, TGFBIp, in Corneal Dystrophies.
A major cause of visual impairment, corneal dystrophies result from accumulation of protein deposits in the cornea. One of the proteins involved is transforming growth factor β-induced protein (TGFBIp), an extracellular matrix component that interacts with integrins but also produces corneal deposits when mutated. Human TGFBIp is a multi-domain 683-residue protein, which contains one CROPT domain and four FAS1 domains. Its structure spans ∼120 Å and reveals that vicinal domains FAS1-1/FAS1-2 and FAS1-3/FAS1-4 tightly interact in an equivalent manner. The FAS1 domains are sandwiches of two orthogonal four-stranded β sheets decorated with two three-helix insertions. The N-terminal FAS1 dimer forms a compact moiety with the structurally novel CROPT domain, which is a five-stranded all-β cysteine-knot solely found in TGFBIp and periostin. The overall TGFBIp architecture discloses regions for integrin binding and that most dystrophic mutations cluster at both molecule ends, within domains FAS1-1 and FAS1-4.


Immunoreactive thyroglobulin in sera and saliva of patients with various thyroid disorders: role of autoantibodies.
The present study was designed to assess the transfer of thyroglobulin (Tg) and anti-Tg antibodies (TgAb) to saliva in subjects with positive TgAb in their sera. Group I consisted of normal euthyroid control subjects (n = 10). Group II were patients with various thyroid disorders and no TgAb in their sera (n = 6). Group III were patients with thyroid disorders and TgAb in their sera (n = 31). The mean serum Tg level (+/- SE) and mean TgAb level [mean % binding +/- SE (range)] were as follows: Group I, Tg: 22.0 ng/ml +/- 1.64 (n = 10); TgAb 1.91% +/- 0.34 (range 0.6% to 4%). Group II, Tg: 119.8 ng/ml +/- 28.0 (n = 6) TgAb 1.59% +/- 0.34 (0.64% to 2.7%). Group III Tg 167.9 ng/ml +/- 41.0 (n = 31) TgAb 23.2% +/- 3.87 (4.2% to 67.5%). The mean salivary Tg level (SaTg) and mean TgAb binding (% +/- SE range) in saliva were as follows: Group I SaTg 2.07 ng/ml +/- 0.39 (n = 10) SaTgAb 1.13% +/- 0.38 (0% to 3.1). Group II SaTg 3.41 ng/ml +/- 0.67 (n = 6), SaTgAb 0.55% +/- 0.29 (0-1.9%). Group III SaTg 5.22 ng/ml +/- 0.96 (n = 31), SaTgAb 3.1% +/- 1.58 (0 to 47.7%). Salivary TgAb were only present in 4 out of 31 cases of Group III. Mean serum Tg in group IV-A was 75.01 ng/ml +/- 52.1 (n = 11). Mean serum TgAb in group IV-A was 1.94% +/- 0.31 (n = 11).(ABSTRACT TRUNCATED AT 250 WORDS)


Postoperative gait analysis and hip muscle strength in patients with pelvic ring fracture.
The aims of present study were (1) to determine changes in kinematic and kinetic variables at 3 and 12 months after open reduction and internal fixation (ORIF) of pelvic ring fracture and (2) to determine the factor(s) associated with gait disorders that correlate with gait parameters measured at 12 months after surgery. Nineteen patients with pelvic ring fractures underwent ORIF and examined at 3 and 12 months postoperatively. The study also included a similar number of age-matched control subjects. Peak hip abduction angle, peak hip extension moment in the stance, peak hip abduction moment, and peak ankle plantarflexion moment at 3 months after ORIF were significantly lower than the respective control values. At 12 months, complete recovery was noted in peak hip abduction moment and peak ankle plantarflexion moment, whereas the recovery in peak hip abduction angle and peak hip extension moment in the stance was partial. The existence of neurological lesions and strength asymmetry of hip abductor and adductor at 3 months post-ORIF correlated with decreased peak hip abduction moment after ORIF. Our results highlighted characteristic gait patterns up to 12 months after ORIF for pelvic fracture, and these patterns correlated with neurological lesion and weakness of hip abductor and adductor muscles.


Coding-Complete Genome Sequences of G6P[14] Rotavirus Strain Detected in a Human Stool Specimen within the United States.
In this study, we report the detection of a G6P[14] rotavirus strain from a human stool sample within the United States. The full genotype constellation of the G6P[14] strain was identified as G6-P[14]-I2-R2-C2-M2-A11-N2-T6-E2-H3.


Antagonism of the renin-angiotensin system can counteract cardiac angiogenic vascular endothelial growth factor gene therapy and myocardial angiogenesis in the normal heart.
The aim of this study was to test the hypothesis that angiotensin converting enzyme inhibition or angiotensin II antagonism can counteract cardiac human vascular endothelial growth factor-A165 (phVEGF-A165) induced angiogenesis. Mice were given a single intramyocardial injection of phVEGF-A165. Either enalapril or candesartan was given subcutaneously for 10 consecutive days. Hearts were harvested and capillary count was performed by immunohistochemistry. With similar design, groups of mice were sacrificed after 24 h for the determination of tissue expression of phVEGF-A protein, mRNA expression of mouse VEGF-A, and VEGF receptors 1 and 2, after pEGFP-Luc transfection for luciferase expression. Increased myocardial capillary density (P < .02) induced by phVEGF-A165 was counteracted by both enalapril (P < .07) and candesartan (P < .02) and then did not differ from control values. We found that phVEGF-A165 induced myocardial hVEGF-A expression (110 +/- 15 pg/heart, P < .0001). Both enalapril and candesartan decreased (P < .01) expression of hVEGF-A to a level not different from control values. Although phVEGF-A165 upregulated (P < .0001) mVEGFR-2, addition of candesartan downregulated endogenous mVEGF-A (P < .0001) and mVEGFR-2 (P < .0001) below the level in normal myocardium. Enalapril or candesartan did not effect luciferase expression. Enalapril and candesartan both specifically inhibit phVEGF-A165 induced myocardial angiogenesis in the normal heart. The mechanism of inhibition is a combination of inhibition of cardiac hVEGF-A expression and of decreased endogenous expression of the mVEGF ligand and receptor system.


A test of reproducibility of blood pressure and heart rate variability using a controlled ambulatory procedure.
To determine whether the previously reported poor reproducibility of blood pressure variability measured by ambulatory blood pressure monitoring (ABPM) is due to the uncontrolled nature of physical and mental activity during the monitoring period. ABPM was performed on two separate days during which subjects performed identical activities, accompanied by the experimenter. Thus, activity and posture were controlled, both within and between subjects. Two measures of variability were used: SD and the root-mean-square of successive differences (RMSSD). Thirty-seven subjects participated. Each engaged in a series of activities, such as walking outdoors, editing and alphabetizing tasks, and eating lunch, while wearing an A & D 2420 ambulatory blood pressure monitor which took measurements at 5-min intervals. Measures of variability were computed within each session. Contrary to previous reports, reproducibility was moderately high for blood pressure, with significant correlations between SD and between RMSSD for systolic and diastolic blood pressure. Heart rate reproducibility was less good. Lack of standardization of activities from one occasion to another is a major reason for the poor reproducibility of blood pressure variability when measured using ABPM. Even when activities are standardized, however, the reproducibility of blood pressure variability is still only moderate and may limit the ability of researchers to detect associations between ABPM variability and other measures.


Development of a Pilates Teaching Framework from an international survey of teacher practice.
Pilates is used increasingly in a variety of clinical settings. However, there is lack of clarity in the literature as to what is meant by the term. Teachers incorporating apparatus based on the designs of Joseph Pilates (1883-1967) into their practice refer to themselves as Comprehensive Teachers, and this group divides itself further into Classical and Contemporary practice. The aim of this research was to explore the meanings of these terms with Comprehensive Teachers and to develop a framework that reflects current views and practice. Online international survey of Pilates Teachers through closed Facebook forums. Open questions were used to elicit views of the definition and practice of Pilates, and how standards should be set across the sector. Of 109 participants, 35% were based in the UK and 32% in the USA; 48% identified as Classical teachers, 32% as Contemporary, 5% as both and 15% as Matwork instructors. A thematic analysis of the qualitative data revealed agreement on the scope and content of Classical and Contemporary Comprehensive Pilates, however the discourse indicated there might be stereotyping about each other's practice. Classical teachers, for example, spoke of their own practice as authentic while Contemporary teachers used terms such as strict and inflexible for Classical practice. However, members of either group may incorporate both Classical and Contemporary approaches within their practice. We have designed a Pilates Teaching Framework to take into account the types of apparatus, the types of exercises and the order in which the exercises are executed. A framework that emphasises Pilates teaching rather than teacher practice is proposed for consistency and clarity when describing Pilates in professional and public contexts.


Coupling of folding and binding in the PTB domain of the signaling protein Shc.
The notion that certain proteins lack intrinsic globular structure under physiological conditions and that the attainment of fully folded structure only occurs upon the binding of target molecules has been recently gaining popularity. We report here the solution structure of the PTB domain of the signaling protein Shc in the free form. Comparison of this structure with that of the complex form, obtained previously with a phosphopeptide ligand, reveals that the Shc PTB domain is structurally disordered in the free form, particularly around the regions constituting the peptide binding pocket. The binding of the ligand appears to reorganize this pocket through local folding events triggering a conformational switch between the free and the complex forms.


Alterations on phosphodiesterase type 7 and 8 isozyme mRNA expression in Alzheimer's disease brains examined by in situ hybridization.
Phosphodiesterases (PDEs) play a central role in signal transduction by regulating intracellular levels of cyclic AMP (cAMP) and cGMP. It has been suggested that cAMP pathways could be upregulated in Alzheimer's disease. By in situ hybridization histochemistry we have determined the expression pattern of two newly described cAMP-specific phosphodiesterases families, PDE7 and PDE8, in several brain areas in control subjects. The hybridization levels of PDE8A mRNA were very low in all brain areas examined. High PDE7B and PDE8B mRNA signal intensities were found in the hippocampal formation. PDE7A was found to be present in both neuronal and non-neuronal cell populations. When the expression of these isozymes in control brains was compared with that in Alzheimer's disease brains staged according to Braak and Braak (Acta Neuropathol. (Berl.) 82 (1991), 239), we found that PDE8B was the only isozyme showing a significant increase, in cortical areas and parts of the hippocampal formation, at Braak stages III-VI. Our results show that the expression of specific cAMP PDE isoforms is selectively regulated in Alzheimer's disease and associated with the stages of the disease. The availability of animal models of Alzheimer's disease and of new pharmacological tools such as selective PDE inhibitors will allow study of the therapeutic potential of the control of cAMP levels in AD.


Is Alzheimer's disease an anterograde degeneration, originating in the brainstem, and disrupting metabolic and functional interactions between neurons and glial cells?
A novel hypothesis is suggested for the pathogenesis of Alzheimer's disease, i.e. that a degeneration of adrenergic neurons in locus coeruleus and/or of serotonergic neurons in the raphe nuclei leads to impairment in metabolic and functional interactions between neurons and astrocytes (in the cerebral cortex and hippocampus as well as in nucleus basalis magnocellularis), and that a resulting deficient supply of substrates and failing energy metabolism in both neurons and astrocytes causes neuronal cell death in these areas and thus interference with additional transmitter systems. The hypothesis is based on (1) the topographical distribution of ascending pathways from locus coeruleus and the raphe nuclei; (2) the peculiar termination of many of these fibres in varicosities, from which released transmitter molecules reach their targets by diffusion, rather than in genuine synapses, suggesting a partly non-neuronal target; (3) the effects of locus coeruleus lesions in experimental animals; (4) the emergence of new knowledge in cellular neurobiology, indicating profound metabolic and functional interactions between neurons and astrocytes; and (5) the effects of adrenergic and serotonergic agonists upon metabolism and function in rodent astrocytes and neurons. These compounds influence energy metabolism, membrane transport of potassium and production of growth factors in astrocytes, and glutamate release from glutamatergic neurons. They thus influence essential metabolic interactions between neurons and astrocytes, as well as neuronal-astrocytic interactions in potassium homeostasis at the cellular level. Obviously, neither the individual findings alone, nor their combination into a conceptual framework, prove the correctness of the hypothesis. However, they do provide a basis for further experimental work, using postmortem brain tissue from Alzheimer's patients and lesion studies in rodents, which can confirm or refute the hypothesis.


Two poles and a compass.
Rho GTPases control fundamental aspects of neutrophil chemotaxis: establishment of front and back and orientation toward the chemoattractant. Two reports in this issue show that activated Cdc42 at the leading edge helps orient the cell's axis in a signaling complex with G beta gamma, PAK1, and PIX alpha; while Rho, activated via G alpha 13, mediates formation of the uropod, which then interacts by mutual negative feedback with the front to reinforce polarization (Li et al., 2003 [this issue of Cell]; Xu et al., [this issue of Cell]).


Sth1, the ATPase subunit of the RSC chromatin remodeler has important roles in stress response and DNA damage repair in the pathogenic fungi Candida albicans.
Candida albicans, the most prevalent fungal pathogen, exists as a commensal in the human host. It is subjected to myriad physiological stress conditions in different host niches, which jeopardizes its fitness to survive and propagate as an established commensal. C. albicans has highly labile chromatin which gets remodeled in response to the stress conditions to facilitate the expression of several stress-responsive genes. Several epigenetic factors including histone variants, histone modifiers and chromatin remodelers that define the chromatin architecture play crucial roles in the regulation of the stress-responsive genes in this organism. Here we investigated the roles of the ATP-dependent chromatin remodeler RSC (Remodel the Structure of Chromatin) in several stress responses in C. albicans, by targeting the key ATPase component, Sth1, given its profound and similar roles exist in Saccharomyces cerevisiae. We have unraveled the crucial roles of the RSC complex (Sth1) in maintaining cell wall integrity and fighting against osmotic and oxidative stresses. We found that the mutant conditionally depleted of Sth1 was sensitive to the cell wall disrupting agents, and the mutant without exposure to any stressor accumulated higher chitin content in the cell wall as a defense mechanism to restore the cell wall integrity. Further, this was supported by the phosphorylation of MAPK1 protein Mkc1, which happens due to activation of the cell wall integrity pathway PKC1. We also observed the Sth1 mutant to be sensitive to oxidative and osmotic stresses in vitro, which are very important and imparted by the host defense mechanism. This suggests that the mutant could get attenuated and hence become less virulent than the wild-type when loss of function of Sth1 happens. We also found that Sth1 has a crucial role in maintaining genomic integrity as sth1 mutant cells accumulate extensive DNA damages and show the loss in cell viability. Overall this work suggests that Sth1 has an important role in fighting against some of the clinically relevant and physiologically important stresses. It also has a crucial role in fighting against stress to the genomic integrity and hence functions in DNA damage repair.


The Singapore 5-fluorouracil trial: intraocular pressure outcomes at 8 years.
To report the 8-year outcomes of Asian subjects who underwent trabeculectomy augmented by intraoperative 5-fluorouracil (5-FU) or placebo. Retrospective review of a randomized controlled trial. Subjects with primary open-angle or angle-closure glaucoma. Study subjects were prospectively followed up for 3 years. After the last subject recruited had completed 8 years of follow-up, the charts of all subjects were reviewed to capture data from the year 3 visit onward. Kaplan-Meier survival function with Cox regression was performed to identify risk factors associated with trabeculectomy failure at 8 years. The primary outcome was trabeculectomy failure defined as intraocular pressure (IOP) >21 or <6 mmHg on 2 consecutive occasions after the first 6 weeks after surgery, repeat glaucoma surgery, or loss of light perception. Further end points were defined at IOP levels >17 and >14 mmHg. Secondary outcomes included IOP at 8 years and number of glaucoma medications. Complete success was defined using IOP end points ≤ 21, ≤ 17, or ≤ 14 mmHg at 8 years without medications. Of the 243 enrolled subjects, 170 (70.0%) completed 8 years follow-up, 86 in the 5-FU and 84 in the placebo group. There was no significant difference in failure rates at 8 years for the failure definitions of IOP >21 mmHg (11.6% of the 5-FU group vs. 16.7% of the placebo group; P = 1.00), IOP >17 mmHg (23.3% of the 5-FU group vs. 31% of the placebo group; P = 0.78), and IOP >14 mmHg (46.5% of the 5-FU group vs. 58.3% of the placebo group; P = 0.37). Mean IOP at 8 years was 13.7 mmHg in the 5-FU versus 14.4 mmHg in the placebo group (P = 0.24). Mean number of medications was 0.65 drops in the 5-FU versus 0.93 drops in the placebo group (P = 0.06). Complete success with IOP ≤ 21 mmHg at 8 years was achieved in 48 subjects (55.8%) in the 5-FU and 33 subjects (39.3%) in the placebo group (P = 0.09). Absence of bleb microcysts at 1 year, preoperative IOP, and number of bleb needlings performed within the first year were significantly associated with failure. There was no significant difference in IOP between the 5-FU and the placebo group at 8 years. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Mondor's disease and aesthetic breast surgery: report of case secondary to mastopexy with augmentation.
Although the etiology of Mondor's disease remains obscure, trauma of some form is the most commonly cited cause. Surgical trauma has frequently been quoted, but references in the literature specifically implicating aesthetic breast surgery are scarce. In this article, we report a case of Mondor's disease secondary to mastopexy with concomitant augmentation mammaplasty.


Low-cost and resource-efficient monolithic photocatalyst with enhanced solar light utilization for the photocatalytic treatment of organic wastewater.
Developing low-cost, well-performing, and resource-efficient photocatalysts with enhanced solar light utilization can contribute to the practicability of photocatalytic techniques in organic wastewater treatment. This study fabricated and characterized a novel sunlight-driven BiOBr- and acetylene black (AB)-loaded monolithic photocatalyst. The fly ash-based geopolymer acts as photocatalyst support that can also provide adsorption sites and semiconductor metal oxide (Fe2O3). A conductive network in the geopolymer structure formed by AB can promote the separation of e--h+ pairs generated by active sites (BiOBr and Fe2O3). Moreover, the photothermal effect induced by AB can assist the photocatalytic reaction at the microinterface of the photocatalyst. This photocatalyst was suspended on the surface of an aqueous solution for sufficient contact with oxygen from the air and is thus beneficial for producing 1O2 and ·OH as the main active species. Within 30 min, it exhibited higher photothermal-photocatalytic activity with 96% removal efficiency of the target pollutant methylene blue (MB), which occurred at an initial concentration of 20 mg L-1. The demethylation and hydroxylation process induced by the active species constituted the primary degradation pathway for MB by Bi/AB/MFGP. Overall, this study provides a valuable reference for developing economical, effective, and practical photocatalysts and applying geopolymers in photocatalysis.


Cross-species infection of hepatitis E virus in a zoo-like location, including birds.
Hepatitis E virus (HEV) is a zoonotic pathogen of which several species of animals are considered to be reservoirs. Thirty-eight faecal samples, obtained from 22 species of animals including birds in a wildlife first-aid centre in Eastern China, were tested for HEV RNA. Our survey revealed that in total 28.9% (95% confidence interval 14.5-43.4) of the faecal samples from various mammals and birds were HEV RNA positive. Sequence and phylogenetic analyses of the 11 isolates demonstrated that all sequences clustered in genotype 4 with 96-100% identity to each other. In addition, serum samples from seven animal handlers have shown that five (71.4%) were seropositive. The findings imply that cross-species infection of HEV had probably occurred in this zoo-like location, and moreover, birds can be infected naturally with mammalian HEV.


Neuronal localization of specific angiotensin II binding sites in the rat inferior olivary nucleus.
Adult male Sprague-Dawley rats were treated with 3-acetylpyridine, a neurotoxin selective for the inferior olivary nucleus. Following treatment, the rats exhibited deficits in locomotor behavior indicative of destruction in the inferior olivary nucleus. The rats were sacrificed 3 weeks later, and the binding of 125I-sarcosine, isoleucine angiotensin II to brain homogenates and slide-mounted sections of brainstem was determined. Treatment with 3-acetylpyridine significantly decreased specific 125I-sarcosine, isoleucine angiotensin II binding in homogenates of posteroventral brainstem (containing the inferior olivary nucleus) by approximately 50%. Homogenates of dorsal brainstem and hypothalamus-thalamus-midbrain showed no significant changes in specific binding. Treatment with 3-acetylpyridine did not significantly alter the radioligand binding affinity which was determined in the hypothalamus-thalamus-midbrain. Autoradiographic analysis of 125I-sarcosine, isoleucine angiotensin II binding in the brainstem sections indicated that specific angiotensin II binding sites in the inferior olivary nucleus were virtually eliminated by the 3-acetylpyridine treatment. In addition, a comparatively small, but significant, decrease in specific 125I-sarcosine, isoleucine angiotensin II binding occurred in the solitary tract nucleus/dorsal vagal motor nucleus complex. These results indicate that specific angiotensin II binding sites in the inferior olivary nucleus occur exclusively on neuronal perikarya and/or dendrites.


A Clinical Study on Individualized Surgical Scheme of Hydrocephalus Complicated With Skull Defect.
This study intends to discuss the individualized selection of surgical scheme of hydrocephalus complicated with skull defect. A total of 141 patients with hydrocephalus complicated with skull defect in our hospital from January 2012 to December 2018 were the main subjects of this study. Among these 141 patients, 78 patients underwent shunt and skull repair surgery in our hospital. In the present study, according to the classification of bone window tension, and combined with factors that affect the operation, different surgical schemes were selected, namely, repair surgery in the first phase and shunt surgery in the second phase, or simultaneous surgery, or shunt surgery in the first phase and repair surgery in the second phase. The results of the present study show that an individualized surgical scheme can allow for the operation of hydrocephalus complicated with skull defect, without increasing the risk of complications, such as shunt infection, epidural hematoma, etc. The surgical scheme for hydrocephalus complicated with skull defect differs in clinic.


Combining automated peak tracking in SAR by NMR with structure-based backbone assignment from 15N-NOESY.
Chemical shift mapping is an important technique in NMR-based drug screening for identifying the atoms of a target protein that potentially bind to a drug molecule upon the molecule's introduction in increasing concentrations. The goal is to obtain a mapping of peaks with known residue assignment from the reference spectrum of the unbound protein to peaks with unknown assignment in the target spectrum of the bound protein. Although a series of perturbed spectra help to trace a path from reference peaks to target peaks, a one-to-one mapping generally is not possible, especially for large proteins, due to errors, such as noise peaks, missing peaks, missing but then reappearing, overlapped, and new peaks not associated with any peaks in the reference. Due to these difficulties, the mapping is typically done manually or semi-automatically, which is not efficient for high-throughput drug screening. We present PeakWalker, a novel peak walking algorithm for fast-exchange systems that models the errors explicitly and performs many-to-one mapping. On the proteins: hBclXL, UbcH5B, and histone H1, it achieves an average accuracy of over 95% with less than 1.5 residues predicted per target peak. Given these mappings as input, we present PeakAssigner, a novel combined structure-based backbone resonance and NOE assignment algorithm that uses just ¹⁵N-NOESY, while avoiding TOCSY experiments and ¹³C-labeling, to resolve the ambiguities for a one-to-one mapping. On the three proteins, it achieves an average accuracy of 94% or better. Our mathematical programming approach for modeling chemical shift mapping as a graph problem, while modeling the errors directly, is potentially a time- and cost-effective first step for high-throughput drug screening based on limited NMR data and homologous 3D structures.


Pharmacotherapy of autism spectrum disorders.
Although no pharmacological or behavioral therapy has currently proven effective for treating all core symptoms of autism, many dysfunctional behaviors may be treated pharmacologically. Drug treatments should always be part of a comprehensive management plan that includes behavioral and educational interventions, and should be focused on specific targets. Several classes of psychotropic medications have been used to decrease the wide range of "maladaptive" or "interfering" behaviors and associated medical problems that can interfere with relationships and physical health and hinder the implementation of various non-pharmacological interventions. Atypical neuroleptics have been shown to be useful in the treatment of behavioral symptoms in autism. Attention deficit and hyperactivity disorder medications may be effective for counteracting the additional features of hyperactivity and short attention span. Antiepileptic drugs and selective serotonin reuptake inhibitors have shown promising results, but there are no specific indications for them as of yet. With respect to potential drug targets, some clinical features are caused by a dysfunction in neurochemical signaling systems, and thus may improve with selective pharmacological interventions acting on specific abnormal neurobiological pathways. Recent animal studies can be useful models for understanding the common pathogenic pathways leading to autism spectrum disorders (ASDs), and have the potential to offer new biologically focused treatment options.


Pramipexole at a Low Dose Induces Beneficial Effect in the Harmaline-induced Model of Essential Tremor in Rats.
The aim of the study was to examine the effects of preferential agonists of dopamine D3 receptors: pramipexole and 7-OH-DPAT on the harmaline-induced tremor in rats (a model of essential tremor, ET). To study receptor mechanisms of these drugs, rats were pretreated with dopamine D3 receptor antagonists--SB-277011-A and SR-21502, an antagonist of presynaptic D2/D3 receptors--amisulpride, or a nonselective antagonist of D2-like receptors, haloperidol, at a postsynaptic dose. For tremor measurement, fully automated force plate actimeters were used and data were analyzed using fast Fourier transform. Harmaline (15 mg/kg ip)-triggered tremor was manifested by an increase in the power within 9-15 Hz band (AP2). Pramipexole administered at a low (0.1 mg/kg sc), but not higher doses (0.3 and 1 mg/kg sc), and 7-OH-DPAT (0.1, 0.3, and 1 mg/kg sc) reversed the harmaline-increased AP2. None of the examined dopamine antagonists: SB-277011-A (10 mg/kg ip), SR-21502 (15 mg/kg ip), haloperidol (0.5 mg/kg ip), or amisulpride (1 mg/kg ip) influenced the above effect of dopamine agonists. The present study indicates that pramipexole reduces the harmaline-induced tremor, which may suggest its beneficial effects in ET patients. However, mechanisms underlying its action are still unclear and need further examination.


Pathological and regulatory effects of anti-myelin antibodies in experimental allergic encephalomyelitis in mice.
Neurological deficit in experimental allergic encephalomyelitis (EAE) and multiple sclerosis (MS) is probably a consequence of synergy between T and B cell responses to CNS antigens. During the demyelinating phase of chronic relapsing EAE in ABH mice, anti-myelin oligodendrocyte glycoprotein (MOG) responses were increased compared to the inflammatory acute phase, but such levels did not correlate with the severity of clinical disease. The pathogenicity of antibodies (Ab) to MOG, myelin basic protein (MBP), proteolipid protein (PLP) and galactocerebroside (GalC) was investigated in vivo following injection at the onset of EAE. An IgG2a monoclonal Ab (mAb), clone Z12, directed to MOG augmented clinical disease and demyelination in ABH and C57BL/6 mice, but not MOG knock-out mice. No effect was observed with F(ab(2))' fragments of Z12 or with the anti-MOG IgG1 mAbs, clones Y10 or 8-18C5. Cobra venom factor partially reduced the augmenting effect of mAb Z12 suggesting a role for complement. The pathogenic effect of anti-myelin Abs was not restricted to MOG since an anti-GalC mAb exacerbated inflammation in the CNS while an MBP mAb (clone 22) reduced clinical disease. Taken together, these data provide further evidence that myelin-reactive Abs generated during autoimmune neurological disease may play an important role not only in the pathogenesis of disease but also the regulation of myelin-targeted autoimmune disease.


Paradigms in the structural biology of the mitogenic ternary complex FGF:FGFR:heparin.
The main achievements regarding the molecular interaction involving fibroblast growth factors (FGFs), canonical receptors (FGFRs) and the glycosaminoglycans (GAGs) heparan sulfate (HS)/heparin (Hp) are overviewed. Despite the recent works concerning the subject, conflicting paradigms in the structural biology of the resultant ternary complex FGF:FGFR:HS/Hp seem to persist up to these days. The principal dilemma, centered on the functional intermolecular complex of mitogenesis and angiogenesis, has been lasting for approximately a decade and a half since the publications of the two contradicting crystal structures, the asymmetric 2:2:1 versus the symmetric 2:2:2 complex model. When the principal results regarding this ternary complex are analyzed as a whole and through an impartial manner, conclusion heavily and reliably supports the existence and activity of both complex models. Selection of each complex is driven by multiple factors of different degrees of impact. Specificity in protein-binding motifs in ligands (although the minimal binding sequences are yet controversial), slight differences on the structure of the GAG-binding sites of FGF and of FGFR isoforms as well as on the possible ligand-induced conformational changes of FGFR are examples of these factors. Here, the structural biology of the mitogenic FGF:FGFR:HS/Hp ternary complex is revisited. Discussion is focused on the major attributes of this intermolecular complex including the existing conflicts about the righter biologically active model and information regarding ligand structure, conformation and minimal length required for binding to the growth factors and receptors. This review is very timely in light of the 100(th) anniversary of the discovery of Hp.


Azoxystrobin, a mitochondrial complex III Qo site inhibitor, exerts beneficial metabolic effects in vivo and in vitro.
Several anti-diabetes drugs exert beneficial effects against metabolic syndrome by inhibiting mitochondrial function. Although much progress has been made toward understanding the role of mitochondrial function inhibitors in treating metabolic diseases, the potential effects of these inhibitors on mitochondrial respiratory chain complex III remain unclear. We investigated the metabolic effects of azoxystrobin (AZOX), a Qo inhibitor of complex III, in a high-fat diet-fed mouse model with insulin resistance in order to elucidate the mechanism by which AZOX improves glucose and lipid metabolism at the metabolic cellular level. Acute administration of AZOX in mice increased the respiratory exchange ratio. Chronic treatment with AZOX reduced body weight and significantly improved glucose tolerance and insulin sensitivity in high-fat diet-fed mice. AZOX treatment resulted in decreased triacylglycerol accumulation and down-regulated the expression of genes involved in liver lipogenesis. AZOX increased glucose uptake in L6 myotubes and 3T3-L1 adipocytes and inhibited de novo lipogenesis in HepG2 cells. The findings indicate that AZOX-mediated alterations to lipid and glucose metabolism may depend on AMP-activated protein kinase (AMPK) signaling. AZOX, a Qo inhibitor of mitochondrial respiratory complex III, exerts whole-body beneficial effects on the regulation of glucose and lipid homeostasis in high-fat diet-fed mice. These findings provide evidence that a Qo inhibitor of mitochondrial respiratory complex III could represent a novel approach for the treatment of obesity.


The effect of the linker on the hydrolysis rate of drug-linked ester bonds.
Tailoring the length of a sulfide containing linker adjusts the hydrolysis of a drug-linked ester bond to values appropriate for once-a-week administrations. A model drug of paclitaxel was coupled using a hydrolyzable linker to a poly(ethylene glycol) macromonomer, via a conjugate addition reaction between a thiol and an acrylamide. The macromonomers were synthesized in three steps with an average overall yield of 70%. By changing the length of the linker from 3-sulfanylpropionyl to 4-sulfanylbutyryl, the half-life time of the release of the drug could be increased from 4.2+/-0.1 to 14.0+/-0.2 days. Drug-containing hydrogels were prepared by radical photopolymerization of these macromonomers with either the 3-sulfanylpropionyl or the 4-sulfanylbutyryl linker. The release of the drug from these hydrogels followed similar trends as the release of the drug from the soluble polymer-drug conjugates. The synthetic methodology employed does not involve the use of coupling reagents in the final conjugation between the drug and the polymer, excluding the presence of potential toxic residuals. The conjugation method is relatively simple and is applicable to nearly any hydroxyl-containing drugs.


Pleural effusion in Michigan caused by Coccidioides immitis after travel to an endemic area.
Primary coccidioidal disease is rarely diagnosed in the midwest in the nonimmunocompromised host. Since coast-to-coast travel is common today, many patients may become exposed to Coccidioides immitis while traveling in endemic areas. We present a case of acute coccidioidal pleural effusion in a Michigan woman who had recently visited northeastern Arizona. Her travel history was the single most important factor in the eventual diagnosis of coccidioidal pleural effusion.


Ultrasound-Guided PCNL - Why Are We Still Performing Exclusively Fluoroscopic Access?
While urologists are traditionally taught to perform percutaneous nephrolithotomy (PCNL) utilizing exclusively fluoroscopy, ultrasound has emerged as a safe alternative. This article showcases the major reasons why ultrasound-guided access should be considered the first-line approach for performing access for PCNL. There continues to be a need to further reduce radiation exposure in the management of kidney stone patients. This review showcases how performing ultrasound-guided PCNL has been associated with a shorter learning curve, increased patient safety, and the ability to perform x-ray free PCNL. Ultrasound-guided PCNL is not only an achievable skill for urologists to learn but provides multiple advantages over traditional fluoroscopic access. As every effort should be given to help reduce radiation exposure for kidney stone patients as well as performing surgeons and operating theater personnel, endourologists should strive to add this technique to their armamentarium.


NOS1AP in schizophrenia.
NOS1AP is an attractive candidate gene for schizophrenia susceptibility. Linkage and association studies from multiple samples drawn from different populations indicate that a schizophrenia susceptibility gene is located in the region of chromosome 1 containing NOS1AP. Increased NOS1AP expression is observed in postmortem samples from individuals with schizophrenia. NOS1AP binds to neuronal nitric oxide synthase and synapsin, other candidate genes for schizophrenia, and may disrupt signal transduction through the N-methyl d-aspartate receptor complex, leading to hypofunctioning of that system. In this review, I present the evidence supporting NOS1AP as a schizophrenia susceptibility gene, with a focus on explaining the strengths and weaknesses of the evidence obtained from each type of study that has been conducted.


Increased respiratory chemosensitivity induced by oral almitrine in healthy man.
Cardiorespiratory effects of 50 mg and 100 mg doses of almitrine and placebo given orally on separate test days to twelve healthy volunteers were assessed in a double-blind crossover study. The drug caused no significant changes in ventilation, mixed venous CO2 tension, metabolic rate, heart rate or blood pressure while they were resting and breathing room air. With progressive hypercapnia, however, the ventilatory response increased by 5% after the 50 mg dose (NS) and by 27% after the 100 mg dose (P less than 0.05). There were greater increases in the response to progressive hypoxia by 78% after 50 mg of almitrine (P less than 0.01) and by 120% after 100 mg (P less than 0.01), which was also significantly greater than the increase after the 50 mg dose (P less than 0.01). In contrast there were only minor and inconsistent changes in chemosensitivity after administering placebo. The findings are consistent with an agonist action of almitrine in the peripheral chemoreceptors and suggest that it may have clinical value in managing respiratory failure due to hypoventilation.


Pyrene-zipper array assembled via RNA duplex formation.
We describe a new strategy for multipyrene modification of RNA sequences to form unique structures of pyrene aromatic arrays, the "pyrene-zipper array", on duplex RNA that exhibits remarkably strong excimer fluorescence.


Evaluation of the biocompatibility of a coating material for an implantable bladder volume sensor.
As the applications for implantable medical devices have increased, the need for biocompatible packaging materials has become important. Recently, we reported an implantable sensor for real-time monitoring of the changes in bladder volume, which necessitated finding a safe coating material for use in bladder tissue. At present, materials like polyethylene glycol (PEG), polydimethylsiloxane (PDMS) and parylene-C are used in biomedical devices or as coating materials, owing to their excellent safety in various medical fields. However, few studies have assessed their safety in bladder tissue, therefore, we evaluated the biocompatibility of PEG, PDMS and parylene-C in the bladder. All three materials turned out to be safe in in vitro tests of live/dead staining and cell viability. In vivo tests with hematoxylin and eosin and immunofluorescence staining with MAC387 showed no persistent inflammation. Therefore, we consider that the three materials are biocompatible in bladder tissue. Despite this safety, however, PEG has biodegradable characteristics and thus is not suitable for use as packaging. We suggest that PDMS and parylene-C can be used as safe coating materials for the implantable bladder volume sensor reported previously.


Changes in Prolapse and Urinary Symptoms After Successful Fitting of a Ring Pessary With Support in Women With Advanced Pelvic Organ Prolapse: A Prospective Study.
To estimate the percentage of improvement in prolapse and urinary symptoms and adverse effects in women with advanced pelvic organ prolapse (POP) after 3 months of use of a ring pessary with support. In this prospective study, 109 consecutive women with advanced POP were fitted with a ring pessary with support; 73 (73/109, 67.0%) of the women had a successful 3-month pessary fitting trial. Prolapse symptoms, urinary symptoms, and urinary flow parameters were assessed at baseline and at 3 months. Adverse effects were assessed within 3 months. McNemar's test and paired-sample t tests were performed. Prolapse and urinary symptoms improved from baseline to 3 months, including bulging (90.4% to 23.3%; P <.001) and pressure (64.4% to 13.7%; P <.001). Voiding difficulty improved in 97.8% of the women (45/46; P <.001), splinting improved in 100% (19/19; P <.001), urge urinary incontinence improved in 76.9% (30/39; P <.001), and stress urinary incontinence improved in 58.1% (18/31; P = .025) after 3 months. After pessary treatment, the differences in maximum flow rate, mean flow rate, void volume, and postvoid residual at baseline and 3 months were statistically significant (P <.05). Vaginal discharge (32/73, 43.8%) was the most common adverse event. Vaginal ulcers developed in 7 (7/73, 9.6%) of the women. The ring pessary with support was successfully fitted in patients with advanced POP with a high success rate and few complications. The pessary could resolve more than half of the prolapse and urinary symptoms. Therefore, initial conservative treatment with a ring pessary with support in advanced POP is worthwhile.


Development and Validation Process of the Intensive Care Unit Omitted Nursing Care (ICU-ONC) Instrument Among French Canadian Nurses.
Background and Purpose: The purpose of this article is to document the development and validation process of an instrument adapted for French-speaking nurses and to measure the occurrence of omitted nursing care (ONC) in the ICU. Methods: An electronic Delphi panel, involving ICU nursing experts from the province of Quebec (Canada), was used to develop the intensive care unit omitted nursing care (ICU-ONC) instrument. For the validation process, an electronic cross-sectional survey was conducted. Results: A total of 564 nurses participated in the validation study. Exploratory factor analysis (EFA) performed on 478 complete observations supports the presence of a single-factor structure for the 22-item ICU-ONC instrument. Cronbach's α for the scale was 0.93, 95% CI (.92-.94), item-partial total correlations ranged from 0.49-0.68, and the mean/median interitem correlations were 0.38 and 0.37, respectively. Moderate negative correlations were found between the ICU-ONC instrument overall score and two related constructs: nurses' perception of the quality as well as the safety of care. Conclusions: Our current understanding of ONC in the ICU is based on the results drawn from the administration of generic instruments to ICU nurses. The novel 22-item ICU-ONC instrument can help better estimate the occurrence of the phenomena in the ICU.


Reactivity of hydroperoxide bound to a mononuclear non-heme iron site.
The first isolation and spectroscopic characterization of the mononuclear hydroperoxo-iron(III) complex [Fe(H(2)bppa)(OOH)](2+) (2) and the stoichiometric oxidation of substrates by the mononuclear iron-oxo intermediate generated by its decomposition have been described. The purple species 2 obtained from reaction of [Fe(H(2)bppa)(HCOO)](ClO(4))(2) with H(2)O(2) in acetone at -50 degrees C gave characteristic UV-vis (lambda(max) = 568 nm, epsilon = 1200 M(-1) cm(-1)), ESR (g = 7.54, 5.78, and 4.25, S = (5)/(2)), and ESI mass spectra (m/z 288.5 corresponding to the ion, [Fe(bppa)(OOH)](2+)), which revealed that 2 is a high-spin mononuclear iron(III) complex with a hydroperoxide in an end-on fashion. The resonance Raman spectrum of 2 in d(6)-acetone revealed two intense bands at 621 and 830 cm(-1), which shifted to 599 and 813 cm(-1), respectively, when reacted with (18)O-labeled H(2)O(2). Reactions of the isolated (bppa)Fe(III)-OOH (2) with various substrates (single turnover oxidations) exhibited that the iron-oxo intermediate generated by decomposition of 2 is a nucleophilic species formulated as [(H(2)bppa)Fe(III)-O*].


Whitening effects of adipose-derived stem cells: a preliminary in vivo study.
Many studies have reported various growth factors secreted from adipose-derived stem cells (ADSCs). In particular, regenerative effects in skin have received much attention in the clinical fields. The in vitro whitening effects of ADSCs have been reported. A previous study demonstrated that ADSCs secrete growth factors that inhibit both melanin synthesis and tyrosinase activity. This study aimed to investigate the in vivo whitening effect of ADSCs using mouse models. In the study, ADSCs were isolated from the adipose tissue of C57BL/6 mice and cultured. The ADSCs (1 × 10(6) cells in 30 μl of Hanks' balanced salt solution [HBSS]) then were injected intradermally in the dorsal area of the right ear, and 30 μl of HBSS was injected on the left ear as a control. After 7 days, both ears were irradiated with ultraviolet B (UVB) (150 mJ/cm(2)) three times at 2-day intervals. The sections of each ear were stained with hematoxylin-eosin, Fontana-Masson, and HMB-45 (a melanocytic cell-specific monoclonal antibody). The histologic parameters evaluated included inflammation (+/-), erosion (+/-), and melanin formation (graded on a scale of 1 to 3). No significant differences in inflammation or erosion were observed by hematoxylin and eosin staining (inflammation: p = 0.388; erosion: p = 0.355). However, significantly more melanin formation was observed in the control group than in the ADSC injection group by Fontana-Masson and HMB-45 staining (Fontana-Masson: p = 0.025; HMB-45: p = 0.015). The study findings suggest that ADSCs inhibit melanin formation induced by UV exposure. Potentially, ADSCs may be used as anti-aging agents, including skin whitening. Before human clinical studies can be conducted, further study is required to determine the mechanisms underlying the whitening effects of ADSCs and the safety of ADSC use. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


Delayed early antiretroviral treatment is associated with an HIV-specific long-term cellular response in HIV-1 vertically infected infants.
Antiviral T-cell immune responses appear to be crucial to control HIV replication. Infants treated before the third month of life with highly active antiretroviral treatment (HAART) did not develop a persistent HIV-specific immune response. We evaluated how delayed initiation of HAART after 3 months of age influences the development of HIV-1-specific T-cell responses during long-term follow-up in 9 HIV-1 vertically infected infants. These data suggest that a longer antigenic stimulation, due to a larger window for therapeutic intervention with HAART, is associated with the establishment of a persistent specific HIV immune response resulting in a long-term viral control of vertically infected infants.


Human Hepatic HepaRG Cells Maintain an Organotypic Phenotype with High Intrinsic CYP450 Activity/Metabolism and Significantly Outperform Standard HepG2/C3A Cells for Pharmaceutical and Therapeutic Applications.
Conventional in vitro human hepatic models for drug testing are based on the use of standard cell lines derived from hepatomas or primary human hepatocytes (PHHs). Limited availability, interdonor functional variability and early phenotypic alterations in PHHs restrict their use, whilst standard cell lines such as HepG2 lack a substantial and variable set of liver-specific functions such as CYP450 activity. Alternatives include the HepG2-derivative C3A cells selected as a more differentiated and metabolically active hepatic phenotype. Human HepaRG cells are an alternative organotypic co-culture model of hepatocytes and cholangiocytes reported to maintain in vivo-like liver-specific functions, including intact Phase I-III drug metabolism. In this study, we compared C3A and human HepaRG cells using phenotypic profiling, CYP450 activity and drug metabolism parameters to assess their value as hepatic models for pre-clinical drug testing or therapeutics. Compared with C3As, HepaRG co-cultures exhibit a more organotypic phenotype, including evidence of hepatic polarity with the strong expression of CYP3A4, the major isoform involved in the metabolism of over 60% of marketed drugs. Significantly greater CYP450 activity and expression of CYP1A2, CYP2E1 and CYP3A4 genes in HepaRG cells (comparable with that of human liver tissue) was demonstrated. Moreover, HepaRG cells also preferentially expressed the hepatic integrin α5 β1 - an important modulator of cell behaviour including growth and survival, differentiation and polarity. Drug metabolite profiling of phenacetin (CYP1A2) and testosterone (CYP3A4) using LC-MS/MS and HPLC, respectively, revealed that HepaRGs had more intact (Phase I-II) metabolism profile. Thus, HepaRG cells significantly outperform C3A cells for the potential pharmaceutical and therapeutic applications.


Brainstem hemorrhage presented as audiovestibular syndromes.
Brainstem hemorrhage usually presented with acute multiple neurologic dysfunction, and the prognosis was poor. Rarely, it can manifest with audiovestibular symptoms only. Here, we report a case of brainstem hemorrhage involving the right middle cerebellar peduncle and dorsal lateral pons presented with constant nonpulsatile tinnitus and rotatory vertigo. We believed that rotatory nystagmus should be regarded as a central sign until proven otherwise even if the neurologic signs are subtle.


Permanent Atrial Fibrillation is Restored And Sinus Rhythm Maintained Without Catheter Ablation After Atrial Septal Defect Closure: A Case Report.
Giant atrial septal defect (ASD) often is associated with atrial arrhythmia, such as atrial fibrillation (AF). The recovery rate of AF is very low. Moreover, it is difficult for the intervention of a giant atrial septal defect, and it also is more difficult to perform atrial septal puncture and left atrial appendage (LAA) closure after ASD occlusion. Here, we report a case of a giant ASD and permanent AF. We find that the AF is significantly improved after atrial septal defect (ASD) occlusion and left atrial appendage (LAA) occlusion, which is manifested by spontaneous restoration and maintenance of normal sinus rhythm.


Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor.
Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = -13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = -9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint = 15.6 μl/min/mg; T1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.


Adversity and persecutory ideation: A moderated mediational model.
Adversity has been identified as an important factor in models of psychopathology and can help in understanding persecutory ideation, although potential moderators and mediators for adult psychopathology have not been sufficiently examined. Experiential avoidance (EA) and Self-esteem (SE) are relevant factors to understand how adversity leads to persecutory ideation. This study hypothesized that adversity would be associated with persecutory ideation through heightened EA, and that this association would be strengthened in individuals with a discrepant high SE. Participants with persecutory ideation (n = 52), with depression (n = 35) and healthy controls (n = 51) were assessed with the Trauma History Screen, the Paranoia and Deservedness Scale, and the Beck Depression Inventory. A SE discrepancy index was calculated subtracting the normalized explicit SE score from the normalized implicit SE score (measured by a version of a Go/No-go association task). Our analysis revealed that adversity was associated with higher levels of paranoia and was mediated by EA. In addition, we found that the relationship between adversity and EA was moderated by SE discrepancy. Identification of moderating and mediating variables allows for increased understanding of persecutory ideation and the processes that should be targeted in the course of recovery.


Knowledge about asthma and COPD: associations with sick leave, health complaints, functional limitations, adaptation, and perceived control.
We sought to investigate associations between knowledge about the disease and sick leave, health complaints, functional limitations, adaptation and perceived control. Patients with asthma (n = 101) and COPD (n = 64) underwent lung function tests and completed questionnaires. In addition, all were asked the question: 'what is the diagnosis of your disease?', with the response categories: 'asthma' and 'COPD (chronic bronchitis or emphysema)'. Thirty-five percent of the asthma patients and 30% of the COPD patients did not know their correct diagnosis. Sick leave was not associated with knowledge about the disease in asthma and COPD. In asthma, much knowledge about management of the disease was associated with better adaptation (P = 0.01) and less perceived control over health by external factors (P = 0.02). Knowing the correct diagnosis was associated with less control over health by powerful others (P = 0.02). For COPD, more knowledge about management of the disease was associated with better adaptation (P = 0.02) and less control over health by internal factors (P = 0.01). Knowing the correct diagnosis was associated with less control over dyspnea at work (P = 0.01).


How to gauge investor behavior? A comparison of online investor sentiment measures.
Given the increasing interest in and the growing number of publicly available methods to estimate investor sentiment from social media platforms, researchers and practitioners alike are facing one crucial question - which is best to gauge investor sentiment? We compare the performance of daily investor sentiment measures estimated from Twitter and StockTwits short messages by publicly available dictionary and machine learning based methods for a large sample of stocks. To determine their relevance for financial applications, these investor sentiment measures are compared by their effects on the cross-section of stocks (i) within a Fama and MacBeth (J Polit Econ 81:607-636, 1973) regression framework applied to a measure of retail investors' order imbalances and (ii) by their ability to forecast abnormal returns in a model-free portfolio sorting exercise. Interestingly, we find that investor sentiment measures based on finance-specific dictionaries do not only have a greater impact on retail investors' order imbalances than measures based on machine learning approaches, but also perform very well compared to the latter in our asset pricing application.


Phototherapy-induced elevation of serum level of melanoma inhibitory activity.
Phototherapy is a frequently used treatment modality for a variety of dermatologic diseases. UV radiation has different effects on the skin, for example increased production and release of cytokines and other proteins, and is involved in the initiation and progression of skin cancer. Objective of this clinical trial was to investigate potential systemic effects of UV phototherapy on cytokine profiles in blood. In a prospective, mono-centric, one-armed study, the serum levels of the melanoma tumour marker "melanoma inhibitory activity" (MIA), Il-1α, Il-4, Il-6, Il-10, TNF-α and IFN-γ of 115 patients with different skin diseases were compared before and 24-48 hours as well as 2-4 weeks after the first phototherapy with PUVA (psoralen and ultraviolet A), UVA or UVB, or both. Data were analysed using linear mixed models. Estimated marginal means of MIA levels were 6.05 ng/mL (95%-CI: 5.37-6.72, range: 2.83-14.49) before the first treatment, which had significantly increased to 6.79 ng/mL 2-4 weeks after the first phototherapy (CI 95%: 6.12-7.47, range: 3.09-15.45; P = 0.0042). MIA levels 2-4 weeks after the first phototherapy were significantly higher than 24-48 hours after the first phototherapy (P = 0.0083). 2-4 weeks after the first treatment, TNF-α levels had decreased significantly (P = 0.033) more in patients with psoriasis who had responded well to phototherapy than in patients unresponsive to treatment. Serum levels of the other cytokines had not changed significantly. Short-term phototherapy significantly increased the serum levels of the melanoma tumour marker MIA. The potential clinical relevance of these findings (ie an increased risk of melanoma) is unclear and should be further investigated.


K-means clustering method for auditory evoked potentials selection.
Surface auditory evoked potentials are generally recorded using a headset of 32, 64 or 128 electrodes, but the quality of the responses is quite heterogeneous on the scalp surface. In some contexts, such as the analysis of auditory evoked potentials recorded in radio-frequency fields, the signal quality is essential, and it appears pertinent to consider only a limited number of electrodes. Therefore, before analysing signals influenced by radio-frequency fields, it is necessary to consider the preliminary step of selecting the channels where auditory activity is strong. This step is often realised by human visual selection and can take a considerable time. In this paper, a simple k-means clustering method is proposed, to select automatically the important channels, and the results are compared with traditional methods of selection. The method detected channels that showed a concordance rate of 86.5% with the visual selection (performed by five individuals) and gave the same final selection (only two extra electrodes in the automatic case). Moreover, the time needed for this automatic selection was 100 times less than that for the visual selection, and also human variability was avoided.


Schistosomiasis models with density dependence and age of infection in snail dynamics.
New models for schistosomiasis are developed. These models incorporate several realistic features including drug treatment for human hosts, an infection age in snail hosts, density-dependent birth rate of snails, distribution of schistosomes within human hosts, and disease-induced mortality in both human and snail hosts. The qualitative and quantitative mathematical properties of the models are studied, their biological consequences and some control strategies are discussed, and the results of the new models are compared with those of simpler models. It is shown that the new model may have a bifurcation at which the unique endemic equilibrium changes the stability and stable periodic solutions exist. This is quite different from the simpler models. Explicit thresholds of treatment rate are established above which the infection will be controlled under certain levels. Evaluations of cost-effectiveness are also discussed by analyzing the sensitivity of the mean number of parasites per person to changes of other parameters.


Anti-Outer membrane protein C antibodies in colorectal neoplasia.
Sporadic colorectal cancer (CRC) represents an enormous problem worldwide. Large intestinal microbiota play an important role in the colorectal carcinogenesis. The aim of the study was to investigate anti-Outer membrane protein C (anti-OmpC) antibodies, aimed at porin C, which is embedded in the outer membrane of gram-negative bacteria, in patients with colorectal adenoma (CRA), CRC and controls. The study included 22 patients with CRA (11 men, 11 women, aged 26-79, mean 65 ± 12), 11 patients with CRC (9 men, 2 women, aged 50-83, mean 66 ± 11) and 45 controls, blood donors (24 men, 21 women, aged 20-58, mean 38 ± 10). Serum anti-OmpC antibodies were investigated by means of ELISA. Values of 0-20 U/mL were considered to be negative; values >25 U/mL were assessed as positive. A total of 9/11 (82 %) patients with CRC had positive anti-OmpC antibodies. Anti-OmpC antibodies were negative or grey-zone in 37/45 (82 %) controls. Serum anti-OmpC were found to be significantly higher in patients with CRC (median 42.4, interquartile range (IQR) 22.2) compared to controls (median 18.3, IQR 12.4), p < 0.001. No statistically significant difference in anti-OmpC was found between controls (median 18.3, IQR 12.4) and CRA patients (median 17.7, IQR 16.5), p = 0.326. Anti-OmpC were significantly higher in patients with CRC (median 42.4, IQR 22.2) compared to patients with CRA (median 17.7, IQR 16.5), p = 0.011. Positivity of anti-OmpC antibodies was found in patients with CRC, which supports the contribution of gram-negative large intestinal microbiota to the pathogenesis of CRC.


Muscarinic agonists for senile dementia: past experience and future trends.
Clinical experience with muscarinic agonists in the symptomatic treatment of Alzheimer's disease includes studies of the effects of pilocarpine, arecoline, bethanechol, oxotremorine and RS 86. Although the results are somewhat conflicting, there is evidence that a subgroup of patients may respond with an improvement of cognitive and/or behavioural function. The existing agents tend to induce adverse effects due to the stimulation of peripheral muscarinic receptors. Furthermore they reduce (at least in vitro) acetylcholine release by an action on presynaptic receptors. Strategies to overcome these problems include the development of potent agonists with high blood-brain barrier penetration, the search for agents selective for muscarinic receptor subtypes (using cloned receptors as tools) and the identification of agents acting as presynaptic receptor antagonists, to increase acetylcholine release.


Role of prostaglandins in alveolar hypoxic vasoconstriction.
The role of prostaglandins as mediators of alveolar hypoxic vasoconstriction was investigated in dogs with the use of the prostaglandin synthesis inhibitors, aspirin and indomethacin. Alveolar hypoxia was induced by inserting double-lumened endotracheal tube into the carina and ventilating one lung with nigrogen while maintaining normal systemic oxygenation with 100% O(2) ventilation to the other lung. Relative perfusion to each lung was determined with 133Xenon and external counters. Infusions up to 25 mg/kg of indomethacin and up to 250 mg/kg of aspirin did not block the shift in perfusion from the alveolar hypoxic lung. In fact, the shift in perfusion from the alveolar hypoxic lung was slightly augmented by aspirin (P = 0.03). Thus, no positive role was demonstrated in the dog for prostaglandins in producing the vasoconstriction of alveolar hypoxia.


Underestimation of mutual interference of predators.
The usual method of estimating the mutual interference constant, m, assumes a linear (type I) functional response of predators. In the cases where the response is not linear, the application of the method introduces a bias in the estimation of the searching efficiencies. It is shown that, as a consequence, the value of m is underestimated. A new method is proposed, which allows for a type II functional response due to a handling time. A comparative analysis of 15 data sets from the literature shows that the proposed method gives values of m that are consistently higher than those estimated by the traditional method. The new method calculates the parameters with nonlinear regression and provides standard errors for the estimates. Therefore, the reliability of the searching efficiencies, the handling time and the constant m can be quantified. Very few of the interference constants are significantly different from m=1. This special value implies that the functional response is a function of the ratio of prey and predator densities. These empirical findings support the suggestion of Arditi and Ginzburg (1989) that the functional response might often be ratio-dependent, especially in complex and heterogeneous situations.


A functional intact SUMOylation machinery in Aspergillus flavus contributes to fungal and aflatoxin contamination of food.
SUMO adducts occur in Aspergillus flavus, and are implicated in fungal biology, while the underlying mechanism and the SUMOylation apparatus components in this saprophytic food spoilage mould, remain undefined. Herein, genes encoding SUMOylation cascade enzymes in A. flavus, including two heterodimeric SUMO E1 activating enzymes, a unique SUMO E2 conjugating enzyme, and one of SUMO E3 ligases, were identified and functionally analyzed. Global SUMO adducts immunoassay, multiple morphological comparison, aflatoxin attributes test, fungal infection and transcriptomic analyses collectively revealed that: E1 and E2 were essential for intracellular SUMOylation, and contributed to both stress response and fungal virulence-related events, including sporulation, colonization, aflatoxins biosynthesis; the primary E3 in this fungus, AfSizA, might serve as the molecular linkage of SUMOylation pathway to fungal virulence rather than SUMOylation-mediated stress adaptation. These findings demonstrated that SUMOylation machinery in A. flavus was functionally intact and contributed to multiple pathobiological processes, hence offering ideas and targets to control food contamination by this mycotoxigenic fungus.


Flow-volume curves in obstructive sleep apnea and snoring.
The diagnostic value of flow-volume curves for sleep apnea was studied in 32 patients with obstructive sleep apnea, 40 simple snorers, and 30 healthy nonsnorers. A sawtooth appearance of the flow-volume curve was seen in 22 of the sleep apnea patients (69%), 14 of the simple snorers (35%), and 10 of the nonsnorers (33%). The ratio of midexpiratory flow (FEF 50) to midinspiratory flow (FIF 50) was greater than 1 in 6 of the sleep apnea patients (19%), 3 of the simple snorers (8%), and 2 of the nonsnorers (7%). Thus, only the sawtooth sign was more frequently found in sleep apnea patients than in controls (p less than 0.01). Sleep apnea patients with a sawtooth appearance of the flow-volume curve had a higher apnea index (38.7 +/- 22 vs. 21.5 +/- 12.1; p less than 0.01) and lower nocturnal minimum oxygen saturation (68.1% +/- 16.8 vs. 81.3% +/- 9.97; p less than 0.01) than those without. In symptomatic snorers, sensitivity of the sawtooth sign for sleep apnea was 72% and specificity 61%, for a FEF50/FIF50 ratio above 1 sensitivity was 17% and specificity 83%. In asymptomatic patients, sensitivity of either sign was extremely poor (33%) and specificity was 67% for the sawtooth sign and 85% for FEF50/FIF50 greater than 1. We conclude that abnormal flow-volume curves are of limited value for predicting sleep apnea.


[Odontogenic cysts].
Odontogenic cysts form a group of diseases whose origin is linked to the persistence of epithelium resulting from the complex embryonic development of the teeth and jaws within the connective tissue. Inflammatory reactions of the surrounding area of the persisting odontogenic epithelium accompany epithelium proliferation, which leads to the development of a gradually expanding cavity that supersedes the surrounding structure. The correlation between activity of the inflammatory reaction and the development of the epithelial proliferation results in a relatively broad variation of histological features of the cyst wall. Since classification of cyst forms depends on their topographical features, clinical information on the classification of variations is urgently needed. For the classification of their clinical course of development and, in particular, in order to differentiate them from cystic odontogenic tumors of the jaw region, a histological examination of cyst wall tissue is necessary, all the more so since the development of a carcinoma deriving from the odontogenic epithelium has only been described in very few cases.


Uterine artery ligation for postabortal hemorrhage.
A case is presented that demonstrates that bilateral ligation of the ascending branches of the uterine artery to control uterine hemorrhage is as effective in the first trimester as it is in the last trimester.


Value of estimated pulse wave velocity to identify left ventricular hypertrophy prevalence: insights from a general population.
Aortic stiffness shares a similar profile of risk factors with left ventricular hypertrophy (LVH) and can also lead to LVH by itself. Published data have demonstrated the correlation between aortic stiffness and LVH. Recent data have revealed estimated pulse wave velocity (ePWV) to be a simple and cost-effective marker of the severity of aortic stiffness. Our analysis aimed to explore the association between ePWV and LVH prevalence, and to investigate the incremental value of ePWV for the identification of LVH prevalence. The present analysis based on a cross-sectional survey which included 11,597 participants from rural areas of southeastern China between Sep 2020 and Feb 2021. ePWV was formulated based on mean blood pressure and age according to a published algorithm. The prevalence of LVH was 14.56%. With the adjustment of age, sex, education, income and physical activity level, current drinking and smoking status, BMI, waist circumference, serum creatinine, total cholesterol, high density cholesterol, mean blood pressure, fasting plasma glucose, anti-hypertensive therapy, anti-diabetic therapy, lipid-lowering therapy, and cardiovascular disease history, every standard deviation increment of ePWV associated with a 2.993 times risk of LVH prevalence. When dividing ePWV into quartiles, the top quartile had a 4.520 times risk of LVH prevalence when compared with the bottom quartile. Furthermore, smooth spline analysis displayed that the association was linear in the whole range of ePWV (p for non-linearity = 0.073). Additionally, subgroup analysis revealed the association was robust to sex, obesity and diabetes, and younger people and hypertensive population were more vulnerable to the increase of ePWV than their corresponding counterparts. Finally, ROC analysis showed a significant advancement when introducing ePWV into established risk factors (0.787 vs. 0.810, p for comparison < 0.001), and reclassification analysis also confirmed significant improvement from ePWV to identify LVH prevalence (category-free net reclassification analysis = 0.421, p < 0.001; integrated discrimination index = 0.023, p < 0.001). Our analysis demonstrated a linear association between ePWV and LVH prevalence. Furthermore, our results suggest younger people and hypertensive population are more likely to have LVH prevalence with the increase of ePWV. More importantly, our findings implicate the incremental value of ePWV to optimize the identification of LVH prevalence in a general Chinese population.