[The role of calcium sensitive and vitamin D receptors in the pathogenesis of sporadic multiple parathyroid gland disease].
Sporadic multiple parathyroid gland disease is ¼ cases of primary hyperparathyroidism (PHPT). However, a single tactic for diagnosing and operating volume in patients with this variant of PHPT has not yet been developed. One of the possible directions in the search for pathogenetically substantiated methods of diagnosis and treatment is the study of the molecular genetic features of the disease and associated clinical and laboratory factors. To study the features of the expression of calcium sensitive (CaSR) and vitamin D (VDR) receptors on the surface of parathyroid cells in primary hyperparathyroidism with solitary and multiple lesions of the parathyroid glands, as well as its changes under the influence of a decrease in the filtration function of the kidneys. In a single center observational prospective study with retrospective data collection, there were patients who during 2019-2021. operated on for PHPT, secondary hyperparathyroidism (SHPT) and all cases of tertiary hyperparathyroidism (THPT) operated during 2014-2021. The expression of CaSR, VDR and its relationship with the main laboratory parameters, the clinical variant of hyperparathyroidism, and the morphological substrate were studied. The study included 69 patients: 19 with multiple and 25 with solitary PTG near PHPT, 15 with SHPT, 10 with THPT. A statistically significant decrease in the frequency of detection of normal expression of CaSR and VDR receptors occurs in any morphological variant of hyperparathyroidism and is observed in 93-60% of drugs. A decrease in the normal expression of CaSR in hyperplasia is detected statistically significantly less frequently than in adenoma (p≤0.01). The median expression intensity in adenoma was 2.5 (2:3), in hyperplasia 3.5 (3-4) (p≤0.01). The difference in the molecular mechanisms of the development of hyperparathyroidism with a predominance of a morphological substrate in the form of adenoma (PHPT with solitary adenoma) or hyperplasia (SHPT and PHPT with multiple PTG lesions) is realized in the frequency of maintaining normal CaSR expression in the PTG tissue. These mechanisms are implemented at the local level, their variability does not change under the influence of RRT. A common molecular genetic mechanism for the development of hyperparathyroidism with a predominance of a morphological substrate in the form of adenoma or hyperplasia has been found to reduce the frequency of maintaining normal VDR expression in PTG (up to 7-13%), p<0.01. This mechanism is implemented at the local level, its variability changes under the influence of RRT, reaching statistically significant differences in patients with THPT. The study demonstrates the features of changes in the expression of CaSR and VDR in PHPT with multiple lesions of the parathyroid glands. The relationship between the expression of these receptors and the clinical variant of hyperparathyroidism, the morphological substrate, the main laboratory parameters, and renal function was shown.


Bcl11b/Ctip2 controls the differentiation of vomeronasal sensory neurons in mice.
The transcription factor Bcl11b/Ctip2 plays critical roles in the development of several systems and organs, including the immune system, CNS, skin, and teeth. Here, we show that Bcl11b/Ctip2 is highly expressed in the developing vomeronasal system in mice and is required for its proper development. Bcl11b/Ctip2 is expressed in postmitotic vomeronasal sensory neurons (VSNs) in the vomeronasal epithelium (VNE) as well as projection neurons and GABAergic interneurons in the accessory olfactory bulb (AOB). In the absence of Bcl11b, these neurons are born in the correct number, but VSNs selectively die by apoptosis. The critical role of Bcl11b in vomeronasal system development is demonstrated by the abnormal phenotypes of Bcl11b-deficient mice: disorganization of layer formation of the AOB, impaired axonal projections of VSNs, a significant reduction in the expression of vomeronasal receptor genes, and defective mature differentiation of VSNs. VSNs can be classified into two major types of neurons, vomeronasal 1 receptor (V1r)/Gα(i2)-positive and vomeronasal 2 receptor (V2r)/Gα(o)-positive VSNs. We found that all Gα(i2)-positive cells coexpressed Gα(o) during embryogenesis. This coexpression is also observed in newly differentiated neurons in the adult VNE. Interestingly, loss of Bcl11b function resulted in an increased number of V1r/Gα(i2)-type VSNs and a decreased number of V2r/Gα(o)-type VSNs, suggesting that Bcl11b regulates the fate choice between these two VSN types. These results indicate that Bcl11b/Ctip2 is an essential regulator of the differentiation and dichotomy of VSNs.


Relation between methionine and inorganic sulphate in broiler rations.
In two experiments with 0-5 weeks old broiler chicks in battery-cages, it was examined whether the requirements for sulphur-containing amino acids in the ration could be reduced by addition of inorganic sulphate. The basal diet was a high energy practical-type broiler ration. The mineral mix included in this diet did not contain sulphates. The basal diet contained 0.73% methionine + cystine. By addition of synthetic methionine, experimental rations with 0.78, 0.82, 0.92 and 1.02% methionine + cystine, respectively, were obtained. The addition of methionine to the basal ration effected significant effects on weight gain (maximum 6-7% at 5 weeks of age) and on feed conversion (maximum 7-8% at 5 weeks of age). The addition of 0.1% Na2 SO4 (=0.068% inorganic sulphate) to the basal and the methionine supplemented diets resulted in an overall increase in weight gain at 5 weeks of age of 0.9% and a reduction in feed conversion of 1.2%; both effects were significant (P less than .05). However, the size of this effect proved to be independent on the contents of sulphur-containing amino acids in the ration. This indicates a small deficiency of the basal ration for inorganic sulphate.


Planktonic microbial profiling in water samples from a Brazilian Amazonian reservoir.
Our comprehension of the dynamics and diversity of freshwater planktonic bacterial communities is far from complete concerning the Brazilian Amazonian region. Therefore, reference studies are urgently needed. We mapped bacterial communities present in the planktonic communities of a freshwater artificial reservoir located in the western Amazonian basin. Two samples were obtained from rainy and dry seasons, the periods during which water quality and plankton diversity undergo the most significant changes. Hypervariable 16S rRNA and shotgun sequencing were performed to describe the first reference of a microbial community in an Amazonian lentic system. Microbial composition consisted mainly of Betaproteobacteria, Cyanobacteria, Alphaproteobacteria, and Actinobacteria in the dry period. The bacteria distribution in the rainy period was notably absent of Cyanobacteria. Microcystis was observed in the dry period in which the gene cluster for cyanotoxins was found. Iron acquisition gene group was higher in the sample from the rainy season. This work mapped the first inventory of the planktonic microbial community of a large water reservoir in the Amazon, providing a reference for future functional studies and determining other communities and how they interact.


Laser control of molecular rotation: Expanding the utility of an optical centrifuge.
Since its invention in 1999, the optical centrifuge has become a powerful tool for controlling molecular rotation and studying molecular dynamics and molecular properties at extreme levels of rotational excitation. This technique has been applied to a variety of molecular species, from simple linear molecules to symmetric and asymmetric tops, to molecular ions and chiral enantiomers. Properties of isolated ultrafast rotating molecules, the so-called molecular superrotors, have been investigated, as well as their collisions with one another and the interaction with external fields. The ability of an optical centrifuge to spin a particular molecule of interest depends on both the molecular structure and the parameters of the centrifuge laser pulse. An interplay between these two factors dictates the utility of an optical centrifuge in any specific application. Here, we discuss the strategy of assessing and adjusting the properties of the centrifuge to those of the molecular rotors and describe two practical examples of optical centrifuges with very different characteristics, implemented experimentally in our laboratory.


Regioselectivity of phase II metabolism of luteolin and quercetin by UDP-glucuronosyl transferases.
The regioselectivity of phase II conjugation of flavonoids is expected to be of importance for their biological activity. In the present study, the regioselectivity of phase II biotransformation of the model flavonoids luteolin and quercetin by UDP-glucuronosyltransferases was investigated. Identification of the metabolites formed in microsomal incubations with luteolin or quercetin was done using HPLC, LC-MS, and (1)H NMR. The results obtained demonstrate the major sites for glucuronidation to be the 7-, 3-, 3'-, or 4'-hydroxyl moiety. Using these unequivocal identifications, the regioselectivity of the glucuronidation of luteolin and quercetin by microsomal samples from different origin, i.e., rat and human intestine and liver, as well as by various individual human UDP-glucuronosyltransferase isoenzymes was characterized. The results obtained reveal that regioselectivity is dependent on the model flavonoid of interest, glucuronidation of luteolin and quercetin not following the same pattern, depending on the isoenzyme of UDP-glucuronosyltransferases (UGT) involved. Human UGT1A1, UGT1A8, and UGT1A9 were shown to be especially active in conjugation of both flavonoids, whereas UGT1A4 and UGT1A10 and the isoenzymes from the UGTB family, UGT2B7 and UGT2B15, were less efficient. Due to the different regioselectivity and activity displayed by the various UDP-glucuronosyltransferases, regioselectivity and rate of flavonoid conjugation varies with species and organ. Qualitative comparison of the regioselectivities of glucuronidation obtained with human intestine and liver microsomes to those obtained with human UGT isoenzymes indicates that, in human liver, especially UGT1A9 and, in intestine, UGT1A1 and UGT1A8 are involved in glucuronidation of quercetin and luteolin. Taking into account the fact that the anti-oxidant action as well as the pro-oxidant toxicity of these catechol-type flavonoids is especially related to their 3',4'-dihydroxyl moiety, it is of interest to note that the human intestine UGT's appear to be especially effective in conjugating this 3',4' catechol unit. This would imply that upon glucuronidation along the transport across the intestinal border, the flavonoids loose a significant part of these biological activities.


RNAi-Mediated Downregulation of Inositol Pentakisphosphate Kinase (IPK1) in Wheat Grains Decreases Phytic Acid Levels and Increases Fe and Zn Accumulation.
Enhancement of micronutrient bioavailability is crucial to address the malnutrition in the developing countries. Various approaches employed to address the micronutrient bioavailability are showing promising signs, especially in cereal crops. Phytic acid (PA) is considered as a major antinutrient due to its ability to chelate important micronutrients and thereby restricting their bioavailability. Therefore, manipulating PA biosynthesis pathway has largely been explored to overcome the pleiotropic effect in different crop species. Recently, we reported that functional wheat inositol pentakisphosphate kinase (TaIPK1) is involved in PA biosynthesis, however, the functional roles of the IPK1 gene in wheat remains elusive. In this study, RNAi-mediated gene silencing was performed for IPK1 transcripts in hexaploid wheat. Four non-segregating RNAi lines of wheat were selected for detailed study (S3-D-6-1; S6-K-3-3; S6-K-6-10 and S16-D-9-5). Homozygous transgenic RNAi lines at T4 seeds with a decreased transcript of TaIPK1 showed 28-56% reduction of the PA. Silencing of IPK1 also resulted in increased free phosphate in mature grains. Although, no phenotypic changes in the spike was observed but, lowering of grain PA resulted in the reduced number of seeds per spikelet. The lowering of grain PA was also accompanied by a significant increase in iron (Fe) and zinc (Zn) content, thereby enhancing their molar ratios (Zn:PA and Fe:PA). Overall, this work suggests that IPK1 is a promising candidate for employing genome editing tools to address the mineral accumulation in wheat grains.


A new cryptically dioecious species of bush tomato (Solanum) from the Northern Territory, Australia.
A new species of dioecious Solanum from the Australian "Dioicum Complex" of Solanum subgenus Leptostemonum is described. Solanum cowiei Martine sp. nov., is allied with other members of this problematic lineage, but differs in its slender leaves, limited armature and diminutive habit. The species was first segregated by botanists at the Northern Territory Herbarium as Solanum sp. Litchfield (I.D. Cowie 1428); and specimens representing this species have also been referred to by Symon as Solanum sp. Fitzmaurice River. Collections suggest that this is an endemic of the sub-arid tropical zone of the Northern Territory. SEM images support initial assumptions that the new species is cryptically dioecious via production of inaperturate pollen grains in morphologically hermaphrodite flowers.


Operative Time Predicts Long-Term Abdominal Morbidity and Complication Requiring Treatment after DIEP Flap Breast Reconstruction.
The relationship between skin-to-skin operative time and long-term complications, as well as complications requiring treatment, after deep inferior epigastric perforator (DIEP) flap breast reconstructions has not been thoroughly investigated. The study objective was to evaluate if operative time would independently prognosticate the type and number of treated complications, as well as long-term abdominal morbidity. Patients who underwent bilateral DIEP flaps from 2010 to 2021 by two senior surgeons with standardized surgical and postoperative protocols were retrospectively reviewed. Inclusion required at least 1 year of postoperative follow-up. Extensive multivariable regression analyses were utilized to adjust for potential confounders, including measures of intraoperative complexity. Three hundred thirty-five patients were entered into multivariable analyses. After risk adjustment, there was a significant increase in the risk of all treated complications per hour. Each hour of operation increased risk of complications requiring extended hospital stay for treatment by 25%, flap-site complications requiring readmission treatment by 24%, and flap-site complications requiring extended hospital stay for treatment by 26% (all p < 0.0001). Long-term abdominal morbidity (abdominal bulge) increased by 25% per hour of operative time (p < 0.0001). The number of complications requiring treatment, abdominal donor-site complications, and complications requiring extended hospital stay for treatment had statistically significant linear relationships with the duration of surgery (all p < 0.05). Operative time predicts long-term abdominal morbidity and complications requiring treatment, especially impacting the odds of developing abdominal bulges and complications requiring extended hospital stay for treatment or readmission treatment. This study emphasizes the importance of reducing operative time to improve DIEP flap breast reconstruction outcomes.


Age-related differences and complexity of ongoing activities in time- and event-based prospective memory.
Aging is presumed to disrupt self-initiated processing, and a time-based prospective memory task (i.e., action to be performed at a particular time) entails more self-initiated activities than an event-based prospective memory task (i.e., action to be performed to a critical event). Accordingly, older participants are predicted to be particularly bad in a time-based prospective memory task. However, the prediction is not always confirmed. Self-initiated activities entail central executive functioning. We therefore predicted the age deficit to emerge more clearly when the performance on the ongoing task also involved more central executive functioning. Time-based prospective memory among older adults collapsed when the complexity of the ongoing task increased. However, an age deficit was also obtained when the pacing of the event-based prospective memory task was high because of the general slowing of functioning by older adults.


Implicit memory for object locations depends on reactivation of encoding-related brain regions.
This study explored the correspondence between implicit memory and the reactivation of encoding-related brain regions. By using a classification method, we examined whether reactivation reflects only the similarities between study and test or voxels at the reactivated regions are diagnostic of facilitation in the implicit memory task. A simple detection task served as incidental encoding of object-location pairings. A subsequent visual search task served as the indirect (implicit) test of memory. Subjects did not know that their memory would be tested. Half of the subjects were unaware that some stimuli in the search task are the same as those that had appeared during the detection task. Another group of subjects was made aware of this relationship at the onset of the visual search task. Memory performance was superior for the study-test aware, compared to study-test unaware, subjects. Brain reactivation was calculated using a conjunction analysis implemented through overlaying the neural activity at encoding and testing. The conjunction analysis revealed that implicit memory in both groups of subjects was associated with reactivation of parietal and occipital brain regions. We were able to classify study-test aware and study-test unaware subjects based on the per-voxel reactivation values representing the neural dynamics between encoding and test. The classification results indicate that neural dynamics between encoding and test accounts for the differences in implicit memory. Overall, our study demonstrates that implicit memory performance requires and depends upon reactivation of encoding-related brain regions.


Digital health interventions for osteoporosis and post-fragility fracture care.
The growing burden from osteoporosis and fragility fractures highlights a need to improve osteoporosis management across healthcare systems. Sub-optimal management of osteoporosis is an area suitable for digital health interventions. While fracture liaison services (FLSs) are proven to greatly improve care for people with osteoporosis, such services might benefit from technologies that enhance automation. The term 'Digital Health' covers a variety of different tools including clinical decision support systems, electronic medical record tools, patient decision aids, patient apps, education tools, and novel artificial intelligence (AI) algorithms. Within the scope of this review are AI solutions that use algorithms within health system registries to target interventions. Clinician-targeted, patient-targeted, or system-targeted digital health interventions could be used to improve management and prevent fragility fractures. This review was commissioned by The Royal Osteoporosis Society and Bone Research Academy during the production of the 2020 Research Roadmap (https://theros.org.uk), with the intention of identifying gaps where targeted research funding could lead to improved patient health. We explore potential uses of digital technology in the general management of osteoporosis. Evidence suggests that digital technologies can support multidisciplinary teams to provide the best possible patient care based on current evidence and to support patients in self-management. However, robust randomised controlled studies are still needed to assess the effectiveness and cost-effectiveness of these technologies.


Role of soluble P-selectin and methylenetetrahydrofolate reductase gene polymorphisms (677C>T) in Egyptian patients with venous thromboembolism.
Venous thromboembolism (VTE) is a significant problem for surgical and medical hospitalized patients, leading to the possibility of serious illness and risk of death. The aim of the present study was to investigate soluble P-selectin levels and genetic polymorphisms in 5, 10-methylenetetrahydrofolate reductase (MTHFR 677C/T) and to evaluate its associations with VTE was the aim of work. The study involved 49 patients diagnosed as having VTE (as a patients group) as well as 24 apparently healthy volunteers (as controls group). All the participants included in the study were assessed for soluble serum P-selectin levels using the enzyme-linked immunosorbant assay technique. All the participants included in the study were genotyped for detection of MTHFR gene polymorphisms (677C > T) by restriction fragment length polymorphism. Concerning the results of soluble P-selectin, there were statistically significant differences between the two groups (P = 0.0210). Concerning the results of MTHFR gene polymorphisms, there were no statistically significant differences between the two groups regarding CT allele (P = 0.8790), but there were highly statistically significant differences between the two groups regarding CC, TT alleles as well as CC/CT and TT/CT alleles (P < 0.0001). According to our study, elevated soluble P-selectin levels as well as MTHFR gene polymorphisms are to be considered as independent risk factors for development of VTE, so it may be recommended to include P-selectin assay and detection of MTHFR gene polymorphisms when considering patients with thromboembolism even in the absence of any other predisposing factors.


Successful use of donepezil for the treatment of psychotic symptoms in patients with Parkinson's disease.
The risk of psychosis among patients with Parkinson's disease (PD) is high, and the management of these patients remains a substantial problem for physicians. Atypical antipsychotics, despite their advantages over conventional antipsychotics, can cause different side effects and deterioration of PD. Several reports have suggested that donepezil can be helpful in the treatment of psychotic conditions in patients with dementia with Lewy bodies and Alzheimer's disease. This report presents the results of preliminary study of six patients (four women, two men; age range, 60-75 years) with PD (range of duration, 3-7 years) and dementia complicated by psychosis. All patients were treated with antiparkinsonian therapy, and donepezil was added to their regular treatment. The severity of the psychotic symptoms was assessed using the Scale for the Assessment of Positive Symptoms, and extrapyramidal symptoms were assessed using the Simpson-Angus Scale. With the addition of donepezil (as much as 10 mg/day) to their constant antiparkinsonian treatment, five patients had clinically significant (more than 53%) improvement on the assessment scale, and one patient had minimal (24%) improvement after 6 weeks of the treatment. None of the patients had side effects or deterioration of parkinsonian symptoms. The results suggest that donepezil may ameliorate psychotic symptoms in patients with PD, but this will need to be tested further in controlled, double-blind trials.


Asymptomatic microembolism in patients with long-term ventricular assist support.
The incidence of clinically significant thromboembolic events is reported to be as high as 25% in patients with left ventricular assist devices (LVAD). Clinically detectable neurologic deficits resulting from thromboembolic events are reported to occur at a frequency of 0.0056% per patient-month with the Thermo Cardiosystems Heartmate 1000 (Woburn, MA) intraperitoneal LVAD (TCI). To date, the occurrence of asymptomatic cerebral microemboli in patients with this device has not been characterized. Transcranial doppler (TCD) monitorings were used for evaluation of the incidence of cerebral microembolism in 14 patients with the TCI LVAD. Studies were performed after LVAD support ranging from 7 to 305 days. Overall, 35 studies were obtained from the left middle cerebral artery for a duration of 30 minutes per study and the number of high intensity transient signals (HITS) were recorded. In one patient with a fatal stroke, an average of 0.86 HITS per study period (0.03/min) was observed. In 13 patients without any symptoms, an average of 0.46 HITS per study (0.016/min) was observed. Overall, no HITS were determined in 74% of the studies. Although the clinical significance or the nature of these microemboli is unknown, the data support that microembolism with the TCI LVAD is a rare event despite absence of anticoagulation. Long-term detailed neurocognitive testing and hematologic assessment is needed to establish the clinical relevance of these microemboli in patients with detected signals.


Meeting Disorders.
Although meetings are central to organizational work, considerable time devoted to meetings in Academic Health Centers appears to be unproductively spent. The primary purposes of this article are to delineate and describe Meeting Disorders, pathological processes resulting in these inefficient and ineffective scenarios, and Meeting Fatigue Disorder (MFD), a clinical syndrome. The paper also offers preliminary approaches to remedies. The authors integrate observations made during tens of thousands of hours in administrative meetings in academic medical settings with information in the literature regarding the nature, causes and potential interventions for dysfunctional groups and meetings. Meeting Disorders, resulting from distinct pathologies of leadership and organization, constitute prevalent subgroups of the bureaucrapathologies, pathological conditions caused by dysfunctional bureaucratic processes that generate excesses of wasted time, effort, and other resources. These disorders also generate frustration and demoralization among participants, contributing to professional burnout. Meeting Fatigue Disorder (MFD) is a subjective condition that develops in individuals who overdose on these experiences and may reflect one manifestation of burnout. Meeting disorders and Meeting Fatigue Disorder occur commonly in bureaucratic life. Resources and potential remedies are available to help ameliorate their more deleterious effects.


Multidetector computed tomography evaluation of origin, V2 segment variations and morphology of vertebral artery.
The current study aimed to determine the origin of vertebral artery (VA) on both sides and the levels of entry into respective foramen transversarium (FT), to evaluate possible effects of sex on the entry levels, and to investigate the frequency of VA dominance and VA hypoplasia based on the VA V2 segment. For this study, archived images of patients undergoing multidetector computed tomography (MDCT) examination of the chest and headneck for various reasons at Gaziantep University Medical Faculty Hospital were reviewed retrospectively. Three-dimensional reconstructions were performed for a total of 644 VA images from 322 patients using Horos software, and VA origin, the level of entry to FT and transverse diameters of both VA and FT were measured at the point of entry. It was found that, among males, the VA originated from the truncus brachiocephalicus on the right side in only 1 patient and from the aortic arch in 2 patients on the left side. Left VA emerging from the aortic arch was observed in 2 females. The right VA was found to enter the FT at C3 in 1 male, at C4 in 6 patients (5 males, 1 female), at C5 in 19 patients (3 males, 16 females), and at C6 in 300 patients (141 males, 159 females). The left artery entered the FT at C5 in 23 patients (9 males, 14 females) and at C6 in 298 patients (141 males, 157 females). Looking at the relationship between variations of VA origin and the levels of entry to the FT, it was observed that only one of the left VAs originating from the arcus aorta entered the FT at C6 and at C5 in all others. On the right side, there was only one VA originating from the truncus brachiocephalicus, which entered the FT at C3. Of the remaining 248 VAs originating from the subclavian artery, 5 VAs entered the FT at C4, 14 VAs at C5 and 229 VAs at C6. The measurements of VA diameters showed right VA hypoplasia in 14 patients and left VA hypoplasia in 17 patients. Also, the right VA dominance was found in 110 patients and the left VA dominance in 128 patients. A moderate, positive correlation was observed between VA and FT diameters in both sides. A regression analysis showed that a 1 mm change in the right VA diameter was associated with a 75% change in the FT diameter and a 1 mm change in the left VA diameter caused a 72% change in the FT diameter. An understanding of VA variations and FT morphometry is crucial for informed clinical practice. This will clearly affect the success rates of physicians in the diagnosis and treatment of pathologies involving cervical region. The presence of any VA variation in a patient should be investigated on computed tomography or magnetic resonance imaging images prior to surgery.


Clock drawing test in mild and moderate dementia of the Alzheimer's type: a comparative and correlation study.
(a) To compare two different clock drawing tests (CDTs) in mild and moderate dementia of the Alzheimer's type (DAT); (b) To examine presumed correlation between these CDTs and some demographic, cognitive and activities of daily living (ADL) variables in mild and moderate DAT. Cross-sectional study. Psychogeriatric outpatient clinic. 49 DAT patients, total; 26-mild, 23-moderate, mean age 77.8 and 80.6, respectively. Evaluations included the Mini-Mental State Examination (MMSE), the Cambridge Cognitive Examination (CAMCOG), the Instrumental Activities of Daily Living Scale (IADL), and a Basic Activities of Daily Living (BADL)-dressing subscale. Severity of dementia was determined with the Clinical Dementia Rating (CDR). Each clock was blindly scored by the same investigator, according to Shulman's and Freedman's methods. Mild and moderate DAT groups were similar in age, gender and education. Performance on Shulman's clock was similar between groups while moderate DAT subjects performed significantly worse on Freedman's clock compared to mild DAT patients. Both clocks correlated highly in mild and moderate DAT. CDT scores correlated significantly with age and education only in mild DAT. Neither clock correlated with ADLs in either stage of dementia severity. CDTs correlated with the MMSE score, and the CAMCOG score in mild DAT, and only with the CAMCOG score in moderate DAT. These correlations were still significant after controlling for age and education. Different aspects of cognition and dementia severity are reflected depending on how a clock drawing is scored. Some scoring systems may have greater sensitivity than others in monitoring progression of cognitive deterioration. Correlation between different CDTs and the variables studied (demographic, cognitive, ADLs), when present, is not ubiqitous and changes with the dementia severity.


Cardiovascular Phenotypes Profiling for L-Transposition of the Great Arteries and Prognosis Analysis.
Congenitally corrected transposition of the great arteries (ccTGA) is a rare and complex congenital heart disease with the characteristics of double discordance. Enormous co-existed anomalies are the culprit of prognosis evaluation and clinical decision. We aim at delineating a novel ccTGA clustering modality under human phenotype ontology (HPO) instruction and elucidating the relationship between phenotypes and prognosis in patients with ccTGA. A retrospective review of 270 patients diagnosed with ccTGA in Fuwai hospital from 2009 to 2020 and cross-sectional follow-up were performed. HPO-instructed clustering method was administered in ccTGA risk stratification. Kaplan-Meier survival, Landmark analysis, and cox regression analysis were used to investigate the difference of outcomes among clusters. The median follow-up time was 4.29 (2.07-7.37) years. A total of three distinct phenotypic clusters were obtained after HPO-instructed clustering with 21 in cluster 1, 136 in cluster 2, and 113 in cluster 3. Landmark analysis revealed significantly worse mid-term outcomes in all-cause mortality (p = 0.021) and composite endpoints (p = 0.004) of cluster 3 in comparison with cluster 1 and cluster 2. Multivariate analysis indicated that pulmonary arterial hypertension (PAH), atrioventricular septal defect (AVSD), and arrhythmia were risk factors for composite endpoints. Moreover, the surgical treatment was significantly different among the three groups (p < 0.001) and surgical strategies had different effects on the prognosis of the different phenotypic clusters. Human phenotype ontology-instructed clustering can be a potentially powerful tool for phenotypic risk stratification in patients with complex congenital heart diseases, which may improve prognosis prediction and clinical decision.


The treatment of fractures with a dynamic axial fixator.
The results obtained with a lightweight dynamic axial fixator in the treatment of fractures are reported. The apparatus comprises a single bar with articulating ends which clamp self-tapping screws and can be locked at an angle appropriate for axial alignment. A telescopic facility allows ready conversion from rigid to dynamic fixation once periosteal callus formation has commenced. Reduction and controlled distraction or compression are achieved by means of a detachable compressor unit. We treated 288 patients with fresh fractures and 50 with ununited fractures. The success rate for fresh fractures was 94%, with average healing times ranging from 3.4 to 6.5 months. In ununited fractures also, the success rate was 94% with average healing times ranging from 4.7 to 6.5 months. Complications were minimal. The device is versatile and can be applied in an average of 15 minutes. It permits ambulatory fracture care without sacrificing a sound anatomical result.


Deprotonation of a Seemingly Hydridic Diborane(6) To Build a B-B Bond.
Deprotonation of the doubly arylene-bridged diborane(6) derivative 1H2 with (Me3 Si)3 CLi or (Me3 Si)2 NK gives the B-B σ-bonded species M[1H] in essentially quantitative yields (THF, room temperature; M=Li, K, arylene=4,4'-di-tert-butyl-2,2'-biphenylylene). With nBuLi as the base, the yield of Li[1H] drops to 20 % and the 1,1-bis(9-borafluorenyl)butane Li[2H] is formed as a side product (30 %). In addition to the 1,1-butanediyl fragment, the two boron atoms of Li[2H] are linked by a μ-H bridge. In the closely related molecule Li[3H], the corresponding μ-H atom can be abstracted with (Me3 Si)3 CLi to afford the B-B-bonded conjugated base Li2 [3] (THF, 150 °C; 15 %). Li[1H] and Li[2H] were characterized by NMR spectroscopy and X-ray crystallography.


Initial Contact: The First Steps in Herpesvirus Entry.
The entry process of herpesviruses into host cells is complex and highly variable. It involves a sequence of well-orchestrated events that begin with virus attachment to glycan-containing proteinaceous structures on the cell surface. This initial contact tethers virus particles to the cell surface and results in a cascade of molecular interactions, including the tight interaction of viral envelope glycoproteins to specific cell receptors. These interactions trigger intracellular signaling and finally virus penetration after fusion of the viral envelope with cellular membranes. Based on the engaged cellular receptors and co-receptors, and the subsequent signaling cascades, the entry pathway will be decided on the spot. A number of viral glycoproteins and many cellular receptors and molecules have been identified as players in one or several of these events during virus entry. This chapter will review viral glycoproteins, cellular receptors and signaling cascades associated with the very first interactions of herpesviruses with their target cells.


RIM binding proteins (RBPs) couple Rab3-interacting molecules (RIMs) to voltage-gated Ca(2+) channels.
Ca(2+) influx through voltage-gated channels initiates the exocytotic fusion of synaptic vesicles to the plasma membrane. Here we show that RIM binding proteins (RBPs), which associate with Ca(2+) channels in hair cells, photoreceptors, and neurons, interact with alpha(1D) (L type) and alpha(1B) (N type) Ca(2+) channel subunits. RBPs contain three Src homology 3 domains that bind to proline-rich motifs in alpha(1) subunits and Rab3-interacting molecules (RIMs). Overexpression in PC12 cells of fusion proteins that suppress the interactions of RBPs with RIMs and alpha(1) augments the exocytosis triggered by depolarization. RBPs may regulate the strength of synaptic transmission by creating a functional link between the synaptic-vesicle tethering apparatus, which includes RIMs and Rab3, and the fusion machinery, which includes Ca(2+) channels and the SNARE complex.


3D prostate histology image reconstruction: Quantifying the impact of tissue deformation and histology section location.
Guidelines for localizing prostate cancer on imaging are ideally informed by registered post-prostatectomy histology. 3D histology reconstruction methods can support this by reintroducing 3D spatial information lost during histology processing. The need to register small, high-grade foci drives a need for high accuracy. Accurate 3D reconstruction method design is impacted by the answers to the following central questions of this work. (1) How does prostate tissue deform during histology processing? (2) What spatial misalignment of the tissue sections is induced by microtome cutting? (3) How does the choice of reconstruction model affect histology reconstruction accuracy? Histology, paraffin block face and magnetic resonance images were acquired for 18 whole mid-gland tissue slices from six prostates. 7-15 homologous landmarks were identified on each image. Tissue deformation due to histology processing was characterized using the target registration error (TRE) after landmark-based registration under four deformation models (rigid, similarity, affine and thin-plate-spline [TPS]). The misalignment of histology sections from the front faces of tissue slices was quantified using manually identified landmarks. The impact of reconstruction models on the TRE after landmark-based reconstruction was measured under eight reconstruction models comprising one of four deformation models with and without constraining histology images to the tissue slice front faces. Isotropic scaling improved the mean TRE by 0.8-1.0 mm (all results reported as 95% confidence intervals), while skew or TPS deformation improved the mean TRE by <0.1 mm. The mean misalignment was 1.1-1.9(°) (angle) and 0.9-1.3 mm (depth). Using isotropic scaling, the front face constraint raised the mean TRE by 0.6-0.8 mm. For sub-millimeter accuracy, 3D reconstruction models should not constrain histology images to the tissue slice front faces and should be flexible enough to model isotropic scaling.


[Structure of nocturnal sleep in sleep disorders among middle and late middle-aged patients].
This is a report on the electropolygraphical examination of nocturnal sleep and the study of emotional-personality changes in 53 patients with impaired sleep who were divided into two groups (24 middle-aged and 29 elderly patients). Day-time electropolygraphic examinations were carried out in 39 out of these patients in period of relaxed and alert wakefulness. The patients versus healthy controls showed a reduction in the total duration of sleep, a tendency toward a decrease in delta-sleep, rapid sleep and the number of completed cycles. The patients were further characterized by an increase in the time of falling asleep, the number of spontaneous awakenings and the time of wakefulness in the course of sleep. The elderly as compared with the middle-aged were characterized by a pronounced decrease in night sleep, the duration of Stage II and the number of completed cycles of nocturnal sleep. In the period of alert wakefulness, alpha-responsiveness in some modulated functional states was lower than in the control group.


Cortical porosis under plates. Reaction to unloading or to necrosis?
Cortical porosis under plates used for the fixation of fractures is often attributed to the interference of the plates with cortical perfusion, resulting in necrosis, which in turn induces remodeling. To our knowledge, no histomorphometric studies have been published that demonstrate the correlation between cortical necrosis and porosis. The objective of this study was to test the hypothesis that cortical necrosis is related to changes associated with porosis. Standard and railed plates were applied to intact femora in ten dogs. Histomorphometric studies done at eight and twenty-four weeks after insertion of the plate failed to show a significant positive correlation between necrosis and porosis irrespective of the type of plate used. Porosis was always greater in the inner cortical sector, where no increased necrosis was noted, than in the outer cortical sector, where necrosis was present.


LC-MS/MS sensitivity enhancement using 2D-SCX/RPLC and its application in the assessment of pharmacokinetics of clonidine in dried blood spots.
Dried blood spot (DBS) technology offers distinctive preclinical and clinical advantages primarily ascribed to microscale sampling (e.g., 40-80 µl per time point), and the nature of solid-state samples in filter papers. Logistic benefits in sample collection, storage and shipping also result. However, the effective DBS samples available for bioanalysis are finite, that is, in the order of approximately 1 µl equivalent of plasma (3-mm punch) from a DBS of approximately 15-20 µl whole blood samples. This represents 20- to 100-times fewer samples for bioanalysis compared with a typical plasma assay. It is critical to increase LC-MS/MS sensitivity to accommodate DBS bioanalysis. We developed a 2D strong cation exchange reversed-phase LC-MS/MS (2D-SCX/RPLC-MS/MS) for online enrichment, separation and detection of basic polar compounds, using clonidine hydrochloride as a model compound. Positively charged clonidine was retained and enriched in the first dimensional SCX column even in large volumes, eluted to a second dimensional RP column with ammonium acetate, de-salted with highly aqueous solvent and separated in an analytical RP column. Injection of 100 µl clonidine extract exhibited essentially the same peak shape as that from 1 µl and the response of clonidine increased quantitatively in the range of 1-100 µl. The method was successfully employed to analyze clonidine DBS samples from an in-house toxicology study, where clonidine hydrochloride was administered to cynomolgus monkeys to produce hypotensive effects. Of 55 DBS samples collected post-dose, a total of 52 samples were within the curve range of 0.1-50 ng/ml, where valid clonidine PK profiles were obtained. The PK parameters agreed well with the onset of hemodynamic changes measured with implanted miniature telemetry blood pressure transmitters. In comparison, only 21 samples were within the curve range of 2 to 1000 ng/ml from a HILIC-MS/MS method, which limited useful injection volume to 5 µl.


DNA sequence of a major human leukocyte interferon gene.
The gene for human leukocyte interferon alpha 2 (designated either LeIF A or HuIFN-alpha 2) has been isolated from a human genome library. The DNA sequence of this gene demonstrates that it lacks introns. The 3' noncoding sequences of the IFN-alpha 2 gene correspond to two types of IFN-alpha 2 cDNA clones we have isolated that have alternate sites of polyadenylylation. A comparison of seven human IFN-alpha sequences shows that they are homologous in the 5' flanking region and contain identical "TATA box" sequences. The recombinant lambda clone containing the IFN-alpha 2 gene also contains two copies of the "Alu family" repeat sequence.


gamma-Aminobutyric acid is a neuromodulator in sinus node of guinea pig heart.
A possible neurotransmitter role for gamma-aminobutyric acid (GABA) in the sinus node of guinea pig heart was examined. Among right atrium, left atrium, right ventricle, left ventricle, and sinus node, the highest amount of the endogenous GABA was found in the sinus node (1,240.6 +/- 120.8 nmol/g protein). The neuronal uptake of [3H]GABA was also the highest in the sinus node and kinetic analysis of the [3H]GABA uptake system in the sinus node showed one saturable component (Km = 17.3 microM, Vmax = 2.18 nmol.g protein-1.10 min-1). Autoradiography of [3H]GABA demonstrated heavy labeling of [3H]GABA in the nonmyelinated nerve fibers within the sinus node compared with findings in the atrial muscle. Electrical transmural stimulation evoked a Ca(2+)-dependent tetrodotoxin-sensitive release of [3H]GABA from the isolated sinus node preloaded with [3H]GABA in the presence of beta-alanine, thereby indicating that the [3H]GABA in the nerve is released from nerve terminals following electrical stimulation. These results provide evidence for the neuromodulator role of GABA in the sinus node of the guinea pig.


Cytologic diagnosis of rhinoscleroma.
The cytologic diagnosis of a case of rhinoscleroma was made on brushing specimens of a laryngeal lesion. The cytologic picture included aggregates of the characteristic Mikulicz cells, large, rounded histiocytes with an eccentric nucleus and vacuolar cytoplasm containing the short rods of Klebsiella rhinoscleromatis. Although the diagnosis of this chronic infectious disease involving the upper respiratory tract is routinely made by tissue biopsy and bacteriologic study of the lesions, the present report indicates that cytology has a definite place in its diagnosis.


Attenuation of inflammation by marine algae Turbinaria ornata in cotton pellet induced granuloma mediated by fucoidan like sulphated polysaccharide.
Turbinaria ornata, a commonly found marine brown algae along the Gulf of Mannar, Southeast coast of India was evaluated for its anti-inflammatory potential and the bioactive compound present in it was characterized. Cotton pellet induced granuloma model in rats was used to assess the anti-inflammatory potential of the aqueous extract of Turbinaria ornata (ATO) (30, 100 and 300mg/kg, p.o) which was compared with dexamethasone (0.1mg/kg, p.o) a standard anti-inflammatory agent. Granuloma weight, haematological parameters and plasma markers (LDH, GPT, and CRP) were estimated. Further, the levels of oxidative stress markers (SOD, GPx, GSH, LPO, and Nitrite) and inflammatory markers (Cathepsin D and MPO) in the hepatic tissue were measured. ATO decreased the granuloma weight dose dependently. ATO significantly reversed the levels of biochemical and inflammatory markers in comparison to the vehicle treated rats. The active constituent, fucoidan (sulphated polysaccharide) from the aqueous extract was fractionated and characterized using GCMS. The sulphated polysaccharide (TSP) from ATO confirms the presence of sulphates and sugars. The present findings suggest ATO to be a potent inhibitor of both proliferative and exudative phases of inflammation possibly mediated by the sulphated polysaccharides which might inhibit the action of COX-2 enzyme analogous to dexamethasone.


Molecular imaging of HER2 receptor: Targeting HER2 for imaging and therapy in nuclear medicine.
Targeting HER 2 for imaging and therapy in nuclear medicine has been used with a special emphasis on developing more powerful radiopharmaceuticals. Zirconium-89 plays an essential role in immune PET imaging so was used labeled with anti-HER2 antibody (Trastuzumab and Pertuzumab). Also there were attempts with other PET tracers as Cuprum-64 and Galium-68, as well as SPECT radiopharmaceuticals Indium-111 and Technetium- 99m. Regarding antibody pharmacokinetic that is not quite appropriate for imaging acquisition, several smaller molecules with shorter residence times have been developed. These molecules called nanobody, affibody, minibody do not compromize HER2 receptor affinity and specificity. Excess of Trastuzumab do not block the affinity of labeled affibodies. Silica nanoparticles have been conjugated to anti-HER2 antibodies to enable targeting of HER2 expressing cells with potential of drug delivery carry for antitumor agents and b(beta) or a(alfa) emitting radioisotopes commonly used for radionuclide therapy, as Iodine-131, Lutetium-177, Yttrium-90, Rhenium-188 and Thorium-277.


Leveraging dominant-negative histone H3 K-to-M mutations to study chromatin during differentiation and development.
Histone modifications are associated with regulation of gene expression that controls a vast array of biological processes. Often, these associations are drawn by correlating the genomic location of a particular histone modification with gene expression or phenotype; however, establishing a causal relationship between histone marks and biological processes remains challenging. Consequently, there is a strong need for experimental approaches to directly manipulate histone modifications. A class of mutations on the N-terminal tail of histone H3, lysine-to-methionine (K-to-M) mutations, was identified as dominant-negative inhibitors of histone methylation at their respective and specific residues. The dominant-negative nature of K-to-M mutants makes them a valuable tool for studying the function of specific methylation marks on histone H3. Here, we review recent applications of K-to-M mutations to understand the role of histone methylation during development and homeostasis. We highlight important advantages and limitations that require consideration when using K-to-M mutants, particularly in a developmental context.


Inhibiting signal transduction: recent advances in the development of receptor tyrosine kinase and Ras inhibitors.
Since aberrant cell signaling is implicated in the initiation, growth, and progression of cancer, proteins involved in signal transduction are rational therapeutic targets. Receptor tyrosine kinases (RTK) and Ras oncoprotein are examples of critical signaling proteins that mediate the processes of cellular growth and differentiation. Agents presently being evaluated as inhibitors of signal transduction include both natural and synthetic compounds, monoclonal antibodies, and antisense oligonucleotides. Preclinical studies of compounds which inhibit RTK and Ras have shown that these targets can be blocked, while side effects in animal models are minimal. Early clinical trials reveal that, in general, treatment with these compounds is both feasible and tolerable. However, many issues about STI remain unresolved including how to optimize schedule, how long to continue treatment, specific mechanisms of action, and how to optimize combinations of STI with standard therapeutic modalities. Addressing these issues may require a shift in the traditional paradigm of drug development, as conventional endpoints may not adequately capture the potential benefits from agents believed to act in a cytostatic vs. cytotoxic manner. This review will discuss the rationale and application of inhibiting signal transduction using inhibitors of RTK and Ras as prototypes of this class of agents.


Outbreak of infection by extended-spectrum beta-lactamase SHV-5-producing Serratia marcescens in a Mexican hospital.
Previous outbreaks caused by Serratia marcescens have been associated with contaminated medical equipment, intravenous fluids and inadequate hygiene. We carried out the molecular characterization of an outbreak produced by a cephalosporin-resistant S. marscescens that occurred in a Mexican hospital in August 1999. The lethality of this outbreak was 26%. Positive isolates were collected from 20 patients, one medical staff and three chlorhexidine disinfectant solutions. Results of PFGE, beta-lactamase patterns, sequencing of PCR amplifications, plasmid profiles, and mating experiments showed that the outbreak occurred by the dissemination of a S. marcescens SHV-5 producing strain. The adequate enforcement of procedures under the supervision of an infection control resulted in the abrupt end of the outbreak.


Examining mental health literacy and its correlates using the overclaiming technique.
The present study examined mental health literacy among the British general public using the overclaiming technique, where participants rate for familiarity a series of items, some of which are foils resembling real items. In total, 344 Britons rated for familiarity 30 mental health disorders, of which six were foils, and also completed measures of the Big Five personality factors, self-rated intelligence, self-reported knowledge of psychiatry, psychiatric skepticism, and their personal details. Using signal detection analysis, responses on the overclaiming measure were used to compute an accuracy index (accuracy in distinguishing real mental health disorders from foils) and a response bias (the tendency to response affirmatively to both real disorders and foils). Preliminary analysis showed that there were no significant sex differences on either the accuracy or response bias indices. Further analyses showed that greater accuracy was significantly predicted by higher self-rated intelligence, greater knowledge of psychiatry, and lower psychiatric skepticism. These results are discussed in terms of the benefits of using the overclaiming technique and signal detection analysis in the study of mental health literacy.


Identification of differentially expressed genes, associated functional terms pathways, and candidate diagnostic biomarkers in inflammatory bowel diseases by bioinformatics analysis.
Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory disorders caused by genetic influences, the immune system and environmental factors. However, the underlying pathogenesis of IBDs and the pivotal molecular interactions remain to be fully elucidated. The aim of the present study was to identify genetic signatures in patients with IBDs and elucidate the potential molecular mechanisms underlying IBD subtypes. The gene expression profiles of the GSE75214 datasets were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified in UC and CD patients compared with controls using the GEO2R tool. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses of DEGs were performed using DAVID. Furthermore, protein-protein interaction (PPI) networks of the DEGs were constructed using Cytoscape software. Subsequently, significant modules were selected and the hub genes were identified. In the GO and KEGG pathway analysis, the top enriched pathways in UC and CD included Staphylococcus aureus infection, rheumatoid arthritis, complement and coagulation cascades, PI3K/Akt signaling pathway and osteoclast differentiation. In addition, the GO terms in the category biological process significantly enriched by these genes were inflammatory response, immune response, leukocyte migration, cell adhesion, response to molecules of bacterial origin and extracellular matrix (ECM) organization. However, several other biological processes (GO terms) and pathways (e.g., 'chemotaxis', 'collagen catabolic process' and 'ECM-receptor interaction') exhibited significant differences between the two subtypes of IBD. The top 10 hub genes were identified from the PPI network using respective DEGs. Of note, the hub genes G protein subunit gamma 11 (GNG11), G protein subunit beta 4 (GNB4), Angiotensinogen (AGT), Phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) and C-C motif chemokine receptor 7 (CCR7) are disease-specific and may be used as biomarkers for differentiating UC from CD. Furthermore, module analysis further confirmed that common significant pathways involved in the pathogenesis of IBD subtypes were associated with chemokine-induced inflammation, innate immunity, adapted immunity and infectious microbes. In conclusion, the present study identified DEGs, key target genes, functional pathways and enrichment analysis of IBDs, enhancing the understanding of the pathogenesis of IBDs and also advancing the clarification of the underlying molecular mechanisms of UC and CD. Furthermore, these results may provide potential molecular targets and diagnostic biomarkers for UC and CD.


Synthesis and selection of de novo proteins that bind and impede cellular functions of an essential mycobacterial protein.
Recent advances in nonrational and part-rational approaches to de novo peptide/protein design have shown increasing potential for development of novel peptides and proteins of therapeutic use. We demonstrated earlier the usefulness of one such approach recently developed by us, called "codon shuffling," in creating stand-alone de novo protein libraries from which bioactive proteins could be isolated. Here, we report the synthesis and selection of codon-shuffled de novo proteins that bind to a selected Mycobacterium tuberculosis protein target, the histone-like protein HupB, believed to be essential for mycobacterial growth. Using a versatile bacterial two-hybrid system that entailed utilization of HupB and various codon-shuffled protein libraries as bait and prey, respectively, we were able to identify proteins that bound strongly to HupB. The observed interaction was also confirmed using an in vitro assay. One of the protein binders was expressed in Mycobacterium smegmatis and was shown to appreciably affect growth in the exponential phase, a period wherein HupB is selectively expressed. Furthermore, the transcription profile of hupB gene showed a significant reduction in the transcript quantity in mycobacterial strains expressing the protein binder. Electron microscopy of the affected mycobacteria elaborated on the extent of cell damage and hinted towards a cell division malfunction. It is our belief that a closer inspection of the obtained de novo proteins may bring about the generation of small-molecule analogs, peptidomimetics, or indeed the proteins themselves as realistic leads for drug candidates. Furthermore, our strategy is adaptable for large-scale targeting of the essential protein pool of Mycobacterium tuberculosis and other pathogens.


Effects of long-term treatment with 17 beta-estradiol and medroxyprogesterone acetate on water maze performance in middle aged female rats.
Although previous research has indicated that hormone replacement therapy benefits memory in menopausal women, several recent studies have shown either detrimental or no effects of treatment. These inconsistencies emphasize the need to evaluate the role of ovarian hormones in protecting against age-related cognitive decline in an animal model. The present study investigated the effects of long-term hormone treatment during aging on the Morris water maze. Female Long Evans hooded rats were ovariectomized at middle age (12-13 months) and were immediately placed in one of five groups: no replacement, chronic 17 beta-estradiol only, chronic 17 beta-estradiol and progesterone, chronic 17 beta-estradiol and medroxyprogesterone acetate (MPA), or cyclic 17 beta-estradiol only. 17 beta-estradiol was administered in the drinking water in either a chronic or cyclic (3 out of 4 days) fashion. Progesterone and MPA were administered via subcutaneous pellets. Following 6 months of hormone treatment, animals were tested on the Morris water maze. Animals performed four trials a day for 4 days and after the final day of testing a subset of animals completed a probe trial. Across 4 days of testing, rats receiving 17 beta-estradiol in combination with MPA performed significantly worse than all other groups receiving hormone replacement. In addition on the last day of testing, chronic 17 beta-estradiol administration was more beneficial than cyclic administration and no replacement. Thus compared to other hormone-treated groups, long-term 17 beta-estradiol treatment in combination with MPA results in impaired performance on the spatial Morris water maze.


Mechanistic Insights into Fast Charging and Discharging of the Sodium Metal Battery Anode: A Comparison with Lithium.
Na metal anode receives increasing attention as a low-cost alternative to Li metal anode for the application in high energy batteries. Despite extensive research efforts to improve the reversibility and cycle life of Na metal electrodes, their rate performance, i.e. electrochemical plating and stripping of Na metal at high current, is underexplored. Herein, we report that Na metal electrodes, unlike the more widely studied Li metal electrodes which survive high current density up to 20 mA/cm2, cannot be fast charged or discharged in common ether electrolyte. The fast charging, namely metal plating, is comprised by severe side reactions that decompose electrolyte into electrochemically inactive Na(I) solid species. The fast discharging, namely metal stripping, is disabled by local Na removal that deteriorates the electrical contact with the current collector. While the fast charging failure is permanent, the capacity loss from fast discharging can be recovered through a restructuring process at a low discharging current which rebuilds the electrical connection. We further reveal that the unsatisfactory rate performance of Na metal electrodes is associated with intrinsic physicochemical properties of Na. This study delineates the mechanistic origins of Na's limitation in fast plating and stripping, and demonstrates the necessity of improving the charging and discharging rate performance of Na metal electrodes.


Laquinimod attenuates inflammation by modulating macrophage functions in traumatic brain injury mouse model.
Traumatic brain injury (TBI) is a critical public health and socio-economic problem worldwide. A growing body of evidence supports the involvement of inflammatory events in TBI. It has been reported that resident microglia and infiltrating monocytes promote an inflammatory reaction that leads to neuronal death and eventually behavioral and cognitive impairment. Currently, there is no effective treatment for TBI and the development of new therapeutic strategies is a scientific goal of highest priority. Laquinimod, an orally administered neuroimmunomodulator initially developed for the treatment of multiple sclerosis, might be a promising neuroprotective therapy for TBI. Herein, we aim to investigate the hypothesis that laquinimod will reduce the central nervous system (CNS) damage caused by TBI. To test our hypothesis, Ccr2rfp/+ Cx3cr1 gfp/+ mice were submitted to a moderate TBI induced by fluid percussion. Sham controls were submitted only to craniotomy. Mice were treated daily by oral gavage with laquinimod (25 mg/kg) 7 days before and 3 days after TBI. The brains of mice treated or not treated with laquinimod were collected at 3 and 120 days post injury, and brain morphological changes, axonal injury, and neurogenesis were evaluated by microscopy analysis. We also isolated microglia from infiltrating monocytes, and the expression of immune gene mRNAs were analyzed by employing a quantitative NanoString nCounter technique. Laquinimod prevented ventricle enlargement caused by TBI in the long term. Immunohistochemical analyses revealed decreased axonal damage and restored neurogenesis in the laquinimod-treated TBI group at early stage (3 days post injury). Notably, laquinimod inhibited the monocytes infiltration to the brain. Hierarchial clustering demonstrated that the microglial gene expression from the TBI group treated with laquinimod resembles the sham group more than the TBI-water control group. Administration of laquinimod reduced lesion volume and axonal damage and restored neurogenesis after TBI. Laquinimod might be a potential therapy strategy to improve TBI long-term prognosis.


The breast cancer susceptibility-related polymorphisms at the TOX3/LOC643714 locus associated with lung cancer risk in a Han Chinese population.
It has been well established that besides environmental factors, genetic factors are also associated with lung cancer risk. However, to date, the prior identified genetic variants and loci only explain a small fraction of the familial risk of lung cancer. Hence it is vital to investigate the remaining missing heritability to understand the development and process of lung cancer. In the study, to test our hypothesis that the previously identified breast cancer risk-associated genetic polymorphisms at the TOX3/LOC643714 locus might contribute to lung cancer risk, 16 SNPs at the TOX3/LOC643714 locus were evaluated in a Han Chinese population based on a case-control study. Pearson's chi-square test or Fisher's exact test revealed that rs9933638, rs12443621, and rs3104746 were significantly associated with lung cancer risk (P < 0.001, P < 0.001, and P = 0.005, respectively). Logistic regression analyses displayed that lung cancer risk of individuals with rs9933638(GG+GA) were 1.89 times higher than that of rs9933638AA carriers (OR = 1.893, 95% CI = 1.308-2.741, P = 0.001). Similar findings were manifested for rs12443621 (OR = 1.824, 95% CI = 1.272-2.616, P = 0.001, rs12443621(GG+GA) carriers vs. rs12443621AA carriers) and rs3104746 (OR = 1.665, 95% CI = 1.243-2.230, P = 0.001, rs3104746TT carriers vs. rs3104746(TA+AA) carriers). The study discovered for the first time that three SNPs (rs9933638, rs12443621, and rs3104746) at the TOX3/LOC643714 locus contributed to lung cancer risk, providing new evidences that lung cancer and breast cancer are linked at the molecular and genetic level to a certain extent.


A life apart: the experience of women and the asylum practice of Charles Doherty at British Columbia's Provincial Hospital for the Insane, 1905-15.
Much of the study completed on psychiatry's treatment of women, has, understandably, focused on periods when the profession was particularly interested in female insanity. This article examines the asylum lives of women when their treatment was not of particular interest. During the 10-year period that Dr. Charles Edward Doherty was head of British Columbia's Provincial Hospital for the Insane, women were excluded from the reforms that characterized his tenure. Instead, women's experiences were shaped largely by the care of nurses and the atmosphere of the ward itself. On the ward, nurses and patients interacted to interpret asylum policy. In the absence of directed intervention, the informal psychiatry of ward life is clearly visible through the case files of patients, and is shown to be as shaped by patient resistance, compliance, and influence as it was by the dictates of the medical superintendent.


Anion channels in astrocytes: biophysics, pharmacology, and function.
The chloride/anion channels that have been so far identified in cultured astrocytes and those that have been confirmed in situ by a combination of mRNA identification, immunocytochemistry, and biophysical studies are reviewed. It is emphasized that we are just beginning to describe such channels and analyze their functions in astrocytes. The best-studied anion channels studied so far are those known as volume-regulated anion channels (VRACs). These, as for most channels, have been mainly studied in cultured astrocytes, but some correlative studies have been done in situ, because these channels have been emphasized as release routes for transmitters; namely, excitatory amino acids and ATP. They are activated by cell shape changes and cell swelling, and the release of amino acids and ATP and chloride currents, measured by whole cell clamping, by these processes has been well described, as is also their activation by low concentrations of extracellular ATP. However, the identity of these channels in astrocytes, as in all other cells, remains elusive. The potential involvement of VRACs in pathological states such as stroke, metastasis, and spreading depression is also discussed.


Proteomics in human cancer research.
Proteomics is now widely employed in the study of cancer. Many laboratories are applying the rapidly emerging technologies to elucidate the underlying mechanisms associated with cancer development, progression, and severity in addition to developing drugs and identifying patients who will benefit most from molecular targeted compounds. Various proteomic approaches are now available for protein separation and identification, and for characterization of the function and structure of candidate proteins. In spite of significant challenges that still exist, proteomics has rapidly expanded to include the discovery of novel biomarkers for early detection, diagnosis and prognostication (clinical application), and for the identification of novel drug targets (pharmaceutical application). To achieve these goals, several innovative technologies including 2-D-difference gel electrophoresis, SELDI, multidimensional protein identification technology, isotope-coded affinity tag, solid-state and suspension protein array technologies, X-ray crystallography, NMR spectroscopy, and computational methods such as comparative and de novo structure prediction and molecular dynamics simulation have evolved, and are being used in different combinations. This review provides an overview of the field of proteomics and discusses the key proteomic technologies available to researchers. It also describes some of the important challenges and highlights the current pharmaceutical and clinical applications of proteomics in human cancer research.


Musculoskeletal Pain and Injury in Indian Classical Dancers: A Systematic Review.
The majority of current research on dance injuries has been on ballet, leaving a void in recent data on musculoskeletal injuries in Indian classical [IC] dance. The prevalence of injuries among IC dancers remains unclear, stressing the importance of injury epidemiology research for improved diagnosis, treatment, prevention, and injury burden reduction. Through a thorough examination of published literature, this study sought to critically evaluate existing research on the epidemiology of musculoskeletal pain and injury in IC dancers. Using Google Scholar and PubMed, a systematic evaluation of the online literature published in English was carried out from inception up to December 31, 2021 following PRISMA guidelines. For studies estimating injury prevalence, the Joanna Briggs Institute Prevalence Critical Appraisal Tool and the Risk of Bias Tool (RoBT) were used to evaluate the studies' quality. Of 3,917 studies identified, 6 studies, all cross-sectional, of low quality, with a high risk of bias, and featuring young Bharatanatyam and Kathak dancers, were determined to be admissible. Because of the studies' heterogeneity, severe study limitations, and methodological variability, a meta-analysis could not be carried out. The evidence from the current review is severely constrained, lacking generalizability to IC dancers as a whole and Bharatanatyam in particular. Since injury epidemiology is essential to the whole injury-prevention puzzle, there is a need for standardization in future research, particularly with active and prospective injury surveillance, injury assessment, and injury reporting.


Renovascular Hypertension with Superimposed Aortic Arch Baroreceptor Failure: Case Report and Review of Literature.
Atherosclerotic renal artery diseases are among the most common causes of secondary hypertension. Baroreceptors, as carotid and aortic, are important regulatory mechanisms of blood pressure; their disruption can lead to labile blood pressure due to sympathetic overactivity: an entity called neurogenic hypertension. A disease such as aortic dissection can lead to a challenging combined etiology of secondary hypertension. It can affect both or one of the renal arteries leading to a renovascular pathology that can cause hypertension through RAAS activation. Also, surgical repair of the dissected aortic arch can disrupt baroreceptors leading to neurogenic hypertension. Case Report. We report a case of an 83-year-old female patient investigated for recurrent episodes of aphasia. She has a history of hypertension and coronary artery disease. Surgical history is significant for aortic valve replacement complicated by type A aortic dissection requiring surgical repair. Following surgery, the patient developed difficult-to-control and labile blood pressure. Workup included a CT angiogram of the abdominal aorta that showed an infrarenal dominant abdominal aortic aneurysm with juxtarenal aortic dissection; these findings were similar to previous findings. A diagnosis of aortic baroreceptor failure following aortic dissection repair was established, which lead to labile hypertension with superimposed renovascular pathology due to unilateral compromised renal artery blood flow following aortic dissection and thrombosis. This report highlights the importance of accurate diagnosis of secondary hypertension and its underlying mechanisms, as this has a huge impact on the choice of therapy to avoid undertreatment or overtreatment of hypertension.


Hsd3b2 associated in modulating steroid hormone synthesis pathway regulates the differentiation of chicken embryonic stem cells into spermatogonial stem cells.
Steroid hormones regulate differentiation of various types of cell during embryogenesis. Testosterone is one of the androgens that bind to receptors to regulate gene expression and promote spermatogenesis. Our results showed that testosterone, as a product of steroid hormones synthesis pathway, could facilitate the differentiation of embryonic stem cells (ESCs) into spermatogonial stem cells (SSCs). The analysis of the steroid hormones synthesis pathway demonstrated that 3beta-hydroxysteroid dehydrogenase2 (Hsd3b2) plays a major role in the synthesis of testosterone. In the absence of Hsd3b2, the expression of downstream genes such as Cyp1a1, Ugt1a1, and Hsd17b7 was not maintained. This reduction is probably due to the down-regulation of the steroid hormones synthesis pathway. Furthermore, qRT-PCR, immunofluorescence, and flow cytometry analysis confirmed that the steroid hormones synthesis pathway could facilitate the differentiation of ESCs. Altogether, these results lead to a model in which Hsd3b2 regulates ESCs differentiation via modulating the activity of steroid hormones synthesis pathway.


Indium- and Zinc-Mediated Acyloxyallylation of Protected and Unprotected Aldotetroses-Revealing a Pronounced Diastereodivergence and a Fundamental Difference in the Performance of the Mediating Metal.
The acyloxyallylation of unprotected aldoses was first demonstrated more than a decade ago as a potentially elegant two-carbon homologation of reducing sugars (upon ozonolysis); however, its application in real case syntheses remained scarce. Following up on such a successful showcase and to answer several pending questions about this attractive transformation, we engaged in an in depth methodological reinvestigation. The epimeric tetroses l-erythrose and d-threose in unprotected and protected form were successfully applied to the indium and also zinc-mediated acyloxyallylation, with the latter being a first for an unprotected sugar. The investigation largely benefited from the choice of these more exotic starting materials as it allowed unambiguous identification/quantification of the hexose-products which are available as authentic reference materials. The observed diastereoselectivities indicate a strong substrate control (stereochemistry at O2), and the influence of the reagent's structure on the selectivity was investigated in great detail. A strong facial diastereodivergence between related protected and unprotected structures was demonstrated and an unexpected, pronounced principle difference in performance between indium and zinc was revealed.


Functional analysis of carboxylesterase in human induced pluripotent stem cell-derived enterocytes.
Human carboxylesterase (CES) is a key esterase involved in the metabolism and biotransformation of drugs. Hydrolysis activity in the human small intestine is predominantly mediated by CES2A1 rather than CES1A. In drug development studies, Caco-2 cells are commonly used as a model to predict drug absorption in the human small intestine. However, the expression patterns of CES2A1 and CES1A in Caco-2 cells differ from those in the human small intestine. There are also species-specific differences in CES expression patterns between human and experimental animals. Furthermore, it is difficult to obtain primary human intestinal epithelial cells. Therefore, there is currently no system that can precisely predict features of drug absorption, such as CES-mediated metabolism, in the human intestine. To develop a novel system to evaluate intestinal pharmacokinetics, we analyzed CES expression and function in human induced pluripotent stem (iPS) cell-derived enterocytes. CES2A1 mRNA and protein levels in human iPS cell-derived enterocytes were comparable to Caco-2 cells, whereas CES1A levels were lower in human iPS cell-derived enterocytes compared with Caco-2 cells. p-nitrophenyl acetate hydrolysis in human iPS cell-derived enterocytes was significantly inhibited by the CES2A1-specific inhibitor telmisartan. Hydrolysis levels of the CES2A1-specific substrate aspirin were similar in human iPS cell-derived enterocytes and Caco-2 cells, whereas hydrolysis of the CES1A-specific substrate monoethylglycylxylidine was observed in Caco-2 cells but not in human iPS cell-derived enterocytes. These findings demonstrated that the expression and activity of CES isozymes in human iPS cell-derived enterocytes are more similar to the human small intestine compared with Caco-2 cells.


A method for measurement of nanogram quantities of 3-methylcholanthrene in stool samples.
The carcinogen 3-methylcholanthrene can be produced from deoxycholic acid and is postulated by some investigators to play a role in the pathogenesis of colon carcinoma. The small quantities of this compound which could be carcinogenic have been difficult to measure in feces because of many potentially interfering compounds. Using 3-[6-14C]methylcholanthrene as an internal standard, petroleum ether extraction, C-18 SepPak separation, preparative high performance liquid chromatography, and gas-liquid chromatography-mass spectrometry with selected ion monitoring, we developed an assay capable of detecting less than 35 ng of 3-methylcholanthrene per gram of stool. Application of this technique to stools of five patients with colon carcinoma and two normal controls revealed no detectable 3-methylcholanthrene in any stool sample. This negative result was confirmed by incubating radiolabeled cholic acid in fecal homogenates. Although greater than 90% of this radiolabeled bile acid was converted to deoxycholic acid, none of the radioactivity was found in the thin-layer chromatography fraction corresponding to 3-methylcholanthrene. These observations provide evidence against a role for 3-methylcholanthrene in pathogenesis of human colon carcinoma. Similar assays could be used for analysis of other carcinogens in stool samples.


Periodontal disease is associated with renal insufficiency in the Atherosclerosis Risk In Communities (ARIC) study.
Periodontitis, a chronic bacterial infection of the oral cavity, is a novel risk factor for atherosclerotic cardiovascular disease (CVD). Given the numerous shared risk factors for CVD and chronic kidney disease (CKD), we hypothesized that periodontitis also is associated with renal insufficiency in the Dental Atherosclerosis Risk in Communities study. We conducted a cross-sectional study of 5,537 middle-aged black and white men and women. Periodontitis was determined by using an independent clinically derived definition and categorized as healthy/gingivitis, initial, and severe. Renal insufficiency is defined as glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2 . Multivariable logistic regression models were used to estimate odds ratios and 95% confidence intervals for renal insufficiency using healthy/gingivitis as the referent group. A total of 2,276 individuals had initial periodontitis, and 947 individuals had severe periodontal disease. One hundred ten individuals (2%) had a GFR less than 60 mL/min/1.73 m2 . Compared with healthy/gingivitis, initial and severe periodontal disease were associated with a GFR less than 60 mL/min/1.73 m2 (odds ratio, 2.00; 95% confidence interval, 1.23 to 3.24) for initial periodontal disease and an odds ratio of 2.14 for severe disease (95% confidence interval, 1.19 to 3.85) after adjustment for important risk factors for CVD and CKD. Sensitivity analysis showed that initial and severe periodontitis were each associated with an elevated serum creatinine level (men, >1.4 mg/dL [>124 micromol/L]; women, >1.2 mg/dL [>106 micromol/L]; odds ratio, 3.21; 95% confidence interval, 1.32 to 7.76 and odds ratio, 5.39; 95% confidence interval, 2.08 to 13.99, respectively). This is the first study to show an association of periodontal disease with prevalent renal insufficiency. A prospective study is necessary to determine the exact nature of the observed relationship.


Prevalence of hepatitis C antibodies among hemodialysis patients in the Western province of saudi arabia.
We studied 408 patients on maintenance hemodialysis at four different centers in the Western province of Saudi Arabia to assess the prevalence of antibody against Hepatitis C Virus (HCV) and the possible risk factors. There were 212 males and 196 females with a mean age of 42.9 +/- 13.9 years (range 12 to 75 years). They were on dialysis for a period between 3 to 140 months with a mean of 52.2 + 38 months. Assay for anti-HCV was made by second generation ELISA. A total of 295 patients (72.3%) tested positive. The prevalence rates varied considerably among the four centers studied and were as follows: the center at Jeddah, 62.7%; two centers at Makkah, 87% and 79.7% respectively and one center at Taif, 80.9%. A total of 311 patients had received varying number of blood transfusions. Of these, 230 (74%) were anti-HCV positive as against 97 patients who were never transfused of whom 65 (67%) were positive. This difference did not reach statistical significance (P = 0.22). Similarly, we found no significant correlation between the anti-HCV prevalence rates and serum alanine transaminase levels (P = 0.93). Our study further confirms that there are routes other than blood transfusion involved in the transmission of the HCV and there is a need to determine these routes in order to prevent the spread of this virus.


Down-regulation of miR-124 target protein SCP-1 inhibits neuroglioma cell migration.
MicroRNAs (miRNAs) have been widely studied as a potential cancer agent, but its efficacy does not get improvement due to poor targeting. miRNAs have been reported to play multiple roles in the development of the tumor. miR-124 is expressed in various tumor. This study aimed to elucidate the expression of miR-124 in neuroglioma cells as well as its related mechanism. Expression of miR-124 in neuroglioma cells was assessed by Quantitative PCR (q-PCR). Astrocytes (RA cells) were used as control group. The relationship between miR-124 and SCP-1 was explored with bioinformatics tools. Luciferase reporter assay was performed to examine the expression of miR-124 target protein SCP-1. Gene interference technology was used to regulate expression of miR-124 and SCP-1 in neuroglioma cells, and q-PCR was performed to confirm gene interference effects. Migration of miR-124 and SCP-1 in neuroglioma cell was measured by wound healing assay and cell migration test. Compared with control group, the expressions of miR-124 (p=0.0015) and SCP-1 (p=0.0042) were higher in neuroglioma cells. Luciferase reporter assay proved that SCP-1 was the target of miR-124. Wound healing assay and migration test showed down-regulation of SCP-1 inhibited neuroglioma cell migration. Down-regulation of miR-124 didn't influence neuroglioma cell migration movement. miR-124 and SCP-1 in neuroglioma cell were highly expressed. MiR-124 impeded the progression of neuroglioma via down-regulating SCP-1.


The dilemma of menopause and hormone replacement--a challenge for women and health-care providers: knowledge of menopause and hormone therapy in Spanish menopausal women.
An important goal in menopause research is to develop knowledge and identify interventions that strive to promote, maintain and enhance well-being for women. To evaluate the knowledge of postmenopausal Spanish women about menopause and their knowledge of and trust in hormone replacement therapy (HRT) and to identify their sources of information and how those data are related to compliance with their prescription. A total of 270 symptomatic postmenopausal women were personally interviewed using a structured questionnaire, which was designed to collect information on their familiarity with medical menopause studies, the menopause and the effects of HRT, their knowledge of alternative therapies, and to identify their sources of information. The most well-known menopausal complaints were hot flushes, sweats, irregular menstruation, cessation of menstruation, irritability and mood changes. Following suggestions of other symptoms by the interviewer, other complaints such as vaginal dryness, insomnia and depression/anxiety were also mentioned. HRT and phytoestrogens were recognized as treatments for the climacteric by most of the women. A woman's decision to seek treatment was initiated in 77% of cases by the gynecologist, in 12% by the general practitioner, in 3% by friends/family and in 3% by books/magazines. The most frequent responses of women to the onset of menopausal symptoms were to talk with their partner (39%), to discuss it with their gynecologist (33%) or with their general practitioner (14%) and to talk with their friends/family or to read books/magazines (10%). Vasomotor symptoms are recognized as the main complaint during the climacteric and HRT and phytoestrogens as the main therapies. Gynecologists play an important role in assuring compliance with therapies related to the menopause.


Unilateral Maxillary Sinus Actinomycosis with a Closed Oroantral Fistula.
Actinomycosis is a bacterial infection due to Actinomyces israelii, a gram-positive, anaerobic organism that normally affects the cervicofacial region. However, facial injury or trauma (i.e., dental procedures) can allow this bacteria to inhabit other regions. There have been rare reports of actinomycosis of the paranasal sinuses. We present a case of a 50-year-old female who originally presented with a suspected oroantral fistula who subsequently was found to have actinomycosis involving her right maxillary sinus. Additionally, the dental extraction site revealed no connection with the maxillary sinus. We discuss the diagnostic approach and management of this patient as it relates to the limited existing literature.


Simultaneous 2D and 3D cell culture array for multicellular geometry, drug discovery and tumor microenvironment reconstruction.
Cell culture systems are indispensablein vitrotools for biomedical research. Although conventional two-dimensional (2D) cell cultures are still used for most biomedical and biological studies, the three-dimensional (3D) cell culture technology attracts increasing attention from researchers, especially in cancer and stem cell research. Due to the different spatial structures, cells in 2D and 3D cultures exhibit different biochemical and biophysical phenotypes. Therefore, a new platform with both 2D and 3D cell cultures is needed to bridge the gap between 2D and 3D cell-based assays. Here, a simultaneous 2D and 3D cell culture array system was constructed by microprinting technology, in which cancer cells exhibited heterozygous geometry structures with both 2D monolayers and 3D spheroids. Cells grown in 3D spheroids showed higher proliferation ability and stronger cell-cell adhesion. Spheroids derived from various types of cancer cell lines exhibited distinct morphologies through a geometrical confinement stimulated biomechanical transduction. Z-projected images of cancer cell aggregates were used to analyze 3D multicellular architecture features. Notably, by using a support vector machine classifier, we distinguished tumor cells from normal cells with an accuracy greater than 95%, according to the geometrical features of multicellular spheroids in phase contrast microscopy images. Cancer cells in multicellular spheroid arrays exhibited higher drug resistance of anticancer drug cisplatin than cells grown in 2D cultures. Finally, we developed a co-culture system composed of tumor spheroid arrays, fibroblast cells and photo-crosslinkable gelatin methacryloyl hydrogel to mimic tumor microenvironment which consisted of solid tumor massed, surrounding stromal cells and extracellular matrix. Together, our newly developed simultaneous 2D and 3D cell culture array has great potential in comprehensive evaluation of cellular events in both 2D and 3D, rapid production of spheroid arrays and multicellular geometry-based tumor cell detection.


Sources of cosmic dust in the Earth's atmosphere.
There are four known sources of dust in the inner solar system: Jupiter Family comets, asteroids, Halley Type comets, and Oort Cloud comets. Here we combine the mass, velocity, and radiant distributions of these cosmic dust populations from an astronomical model with a chemical ablation model to estimate the injection rates of Na and Fe into the Earth's upper atmosphere, as well as the flux of cosmic spherules to the surface. Comparing these parameters to lidar observations of the vertical Na and Fe fluxes above 87.5 km, and the measured cosmic spherule accretion rate at South Pole, shows that Jupiter Family Comets contribute (80 ± 17)% of the total input mass (43 ± 14 t d-1), in good accord with Cosmic Background Explorer and Planck observations of the zodiacal cloud.


The phylogenetic position of dicyemid mesozoans offers insights into spiralian evolution.
Obtaining phylogenomic data for enigmatic taxa is essential to achieve a better understanding of animal evolution. Dicyemids have long fascinated biologists because of their highly simplified body organization, but their life-cycles remain poorly known. Based on the discovery of the dicyemid DoxC gene, which encodes a spiralian peptide, it has been proposed that dicyemids are members of the Spiralia. Other studies have suggested that dicyemids may have closer affinities to mollusks and annelids. However, the phylogenetic position of dicyemids has remained a matter of debate, leading to an ambiguous picture of spiralian evolution. In the present study, newly sequenced transcriptomic data from Dicyema japonicum were complemented with published transcriptomic data or predicted gene models from 29 spiralian, ecdysozoan, and deuterostome species, generating a dataset (Dataset 1) for phylogenomic analyses, which contains 348 orthologs and 58,124 amino acids. In addition to this dataset, to eliminate systematic errors, two additional sub-datasets were created by removing compositionally heterogeneous or rapidly evolving sites and orthologs from Dataset 1, which may cause compositional heterogeneity and long-branch attraction artifacts. Maximum likelihood and Bayesian inference analyses both placed Dicyema japonicum (Dicyemida) in a clade with Intoshia linei (Orthonectida) with strong statistical support. Furthermore, maximum likelihood analyses placed the Dicyemida + Orthonectida clade within the Gastrotricha, while in Bayesian inference analyses, this clade is sister group to the clade of Gastrotricha + Platyhelminthes. Whichever the case, in all analyses, Dicyemida, Orthonectida, Gastrotricha, and Platyhelminthes constitute a monophyletic group that is a sister group to the clade of Mollusca + Annelida. Based on present phylogenomic analyses, dicyemids display close affinity to orthonectids, and they may share a common ancestor with gastrotrichs and platyhelminths, rather than with mollusks and annelids. Regarding spiralian phylogeny, the Gnathifera forms the sister group to the Rouphozoa and Lophotrochozoa, as has been suggested by previous studies; thus our analysis supports the traditional acoeloid-planuloid hypothesis of a nearly microscopic, non-coelomate common ancestor of spiralians.


Single dose oral pharmacokinetic profile rubraxanthone in mice.
Rubraxanthone is a main active constituent of kandis (Garcinia cowa Roxb), has showed many biological activity including antimicrobial, anti hypercholesterolemic, antiplatelet, antioxidant, cytotoxic, and anti-inflammatory properties. To the best of our knowledge, no reports on the pharmacokinetics (PK) of this rubraxanthone have been published. The PK of rubraxanthone in mice was examined after a single oral dose of 700 mg/kg rubraxanthone suspension in virgin coconut oil. Plasma samples were collected at different time points and further analyzed using validated chromatographic method. Pharmacokinetic parameters were calculated from observed plasma concentration-time profile. The maximum concentration of rubraxanthone in plasma was discovered in 1.5 h. The peak plasma concentration (Cmax) was 4.267 μg/mL, and the area under the curve (AUCt0-t ∞ ) was 560.99 μg h/L, with a 6.72-hour terminal half-life (T1/2). The volume of distribution (Vd/F) was 1200.19 mL/kg and 1123.88 mL/h/kg clearance (Cl/F).


Comparison of indigenous and exogenous microbial populations during slurry phase biodegradation of long-term hydrocarbon-contaminated soil.
In this study, a number of slurry-phase strategies were trialled over a 42 day period in order to determine the efficacy of bioremediation for long-term hydrocarbon-contaminated soil (145 g kg(-1) C(10)-C(40)). The addition of activated sludge and nutrients to slurries (bioaugmentation) resulted in enhanced hydrocarbon removal (51.6 ± 8.5 %) compared to treatments receiving only nutrients (enhanced natural attenuation [ENA]; 41.3 ± 6.4 %) or no amendments (natural attenuation; no significant hydrocarbon removal, P < 0.01). This data suggests that the microbial community in the activated sludge inoculum contributed to the enhanced removal of hydrocarbons in ENA slurries. Microbial diversity in slurries was monitored using DGGE with dominant bands excised and sequenced for identification. Applying the different bioremediation strategies resulted in the formation of four distinct community clusters associated with the activated sludge (inoculum), bioaugmentation strategy at day 0, bioaugmentation strategy at weeks 2-6 and slurries with autoclaved sludge and nutrient additions (bioaugmentation negative control). While hydrocarbon-degrading bacteria genera (e.g. Aquabacterium and Haliscomenobacter) were associated with the hydrocarbon-contaminated soil, bioaugmentation of soil slurries with activated sludge resulted in the introduction of bacteria associated with hydrocarbon degradation (Burkholderiales order and Klebsiella genera) which presumably contributed to the enhanced efficacy for this slurry strategy.


Relationship between serum cholesterol and the risk of acute myocardial infarction in a screened cohort in Okinawa, Japan.
Coronary heart disease (CHD) is rare in Japanese subjects and serum cholesterol levels are low. However, no data have been published relating the effect of serum cholesterol levels to the incidence of acute myocardial infarction (AMI) in Japan. Data from a large community-based mass screening registry are available for the geographically isolated island of Okinawa, Japan (1980 census, 1.11 million). A total of 38,053 participants (17,859 men and 20,194 women) whose serum cholesterol levels were determined in the 1983 mass screening were examined to determine whether they had experienced AMI. Every case of AMI that occurred during a 3-year period (1 April 1988 to March 1991) throughout Okinawa was recorded in a separate registry. The total number of cases of AMI was 1,021 (674 men and 347 women). Of these, 65 patients (41 men and 24 women) were identified by name, sex, birth date, and zip code in the mass screening registry. The cumulative incidence of AMI increased with the serum level of cholesterol: 42.1 (serum cholesterol < or = 167 mg/dl), 133.5 (serum cholesterol 168-191 mg/dl), 188.9 (serum cholesterol 192-217 mg/dl), and 323.0 (serum cholesterol > or = 218 mg/dl) per 100,000 screened subjects. Multiple logistic analysis was conducted to examine the effect of serum cholesterol on the risk of AMI with adjustment for other variables such as sex, age, systolic and diastolic blood pressure, and proteinuria. The adjusted odds ratio (95% confidence interval) of the observed serum levels of cholesterol was 1.66 (1.29-2.15) with a reference serum cholesterol level of < or = 167 mg/dl. The risk of AMI increased in proportion to the serum level of cholesterol. Serum cholesterol is an independent predictor of AMI in Okinawa, Japan.


Effectiveness of Early Measles, Mumps, and Rubella Vaccination Among 6-14-Month-Old Infants During an Epidemic in the Netherlands: An Observational Cohort Study.
Routinely, the first measles, mumps, and rubella (MMR) vaccine dose is given at 14 months of age in the Netherlands. However, during a measles epidemic in 2013-2014, MMR vaccination was also offered to 6-14-month-olds in municipalities with <90% MMR vaccination coverage. We studied the effectiveness of the early MMR vaccination schedule. Parents of all infants targeted for early MMR vaccination were asked to participate. When parent(s) suspected measles, their infant's saliva was tested for measles-specific antibodies. The vaccine effectiveness (VE) against laboratory-confirmed and self-reported measles was estimated using Cox regression, with VE calculated as 1 minus the hazard ratio. Three vaccinated and 10 unvaccinated laboratory-confirmed cases occurred over observation times of 106631 and 23769 days, respectively. The unadjusted VE against laboratory-confirmed measles was 94% (95% confidence interval [CI], 79%-98%). After adjustment for religion and sibling's vaccination status, the VE decreased to 71% (-72%-95%). For self-reported measles, the unadjusted and adjusted VE was 67% (40%-82%) and 43% (-12%-71%), respectively. Infants vaccinated between 6 and 14 months of age had a lower risk of measles than unvaccinated infants. However, part of the effect was caused by herd immunity, since vaccinated infants were more likely to be surrounded by other vaccinated individuals.