The clinical and cost burden of coronary calcification in a Medicare cohort: An economic model to address under-reporting and misclassification.
Coronary artery calcification (CAC) is a well-established risk factor for the occurrence of adverse ischemic events. However, the economic impact of the presence of CAC is unknown. Through an economic model analysis, we sought to estimate the incremental impact of CAC on medical care costs and patient mortality for de novo percutaneous coronary intervention (PCI) patients in the 2012 cohort of the Medicare elderly (≥65) population. This aggregate burden-of-illness study is incidence-based, focusing on cost and survival outcomes for an annual Medicare cohort based on the recently introduced ICD9 code for CAC. The cost analysis uses a one-year horizon, and the survival analysis considers lost life years and their economic value. For calendar year 2012, an estimated 200,945 index (de novo) PCI procedures were performed in this cohort. An estimated 16,000 Medicare beneficiaries (7.9%) were projected to have had severe CAC, generating an additional cost in the first year following their PCI of $3500, on average, or $56 million in total. In terms of mortality, the model projects that an additional 397 deaths would be attributable to severe CAC in 2012, resulting in 3770 lost life years, representing an estimated loss of about $377 million, when valuing lost life years at $100,000 each. These model-based CAC estimates, considering both moderate and severe CAC patients, suggest an annual burden of illness approaching $1.3 billion in this PCI cohort. The potential clinical and cost consequences of CAC warrant additional clinical and economic attention not only on PCI strategies for particular patients but also on reporting and coding to achieve better evidence-based decision-making.


Evolution of surgical trends in congenital heart disease: a population based study.
The aim of this study was to establish surgical trends in patients with congenital heart disease operated on between 1947 and 1997 in a population based study. All patients diagnosed as having congenital heart disease, born in Malta up to 1995 inclusive and operated for congenital heart disease up to 1997 inclusive were included. Analysis was carried out for lesions operated, age at surgery, operative centre and mortality rates, in the setting of a regional hospital providing congenital heart disease diagnostic and follow-up services for all Malta. Increasingly more operations for cardiac malformations are being carried out, with a progressively higher proportion of operations performed on complex conditions (P<0.001), at an ever younger age (P<0.001), and with a declining perioperative mortality (P<0.001). For the period 1990-1994, 4.2 operations for congenital heart disease/1000 live births were required. Factors which may increase or decrease this rate in future are discussed, along with costs of surgery. Surgery for congenital heart disease has become progressively more aggressive and safer since this method of treatment for these malformations was initiated, but this has occurred at a significant financial cost.


Persistent unexplained congenital clitoromegaly in females born extremely prematurely.
Unexplained clitoromegaly is a rare but well recognised feature in girls born premature. Although detected at birth, girls may re-present during childhood to paediatric urologists and gynaecologists who should be aware of this condition. The aim of the study was to describe the clinical findings and management of a series of girls presenting with persistent congenital clitoromegaly associated with prematurity. This was a retrospective notes review set in a tertiary referral centre for Paediatric and Adolescent Gynaecology (PAG). Eight girls with a mean age of 6 years were seen over an eight year period. In all cases a Disorder of Sex Development (DSD) had been previously excluded. The main symptoms were discomfort or concern about appearance. On examination five girls had excess skin over the clitoris and three had enlarged corporal tissue. Management included reassurance and simple measures to ease discomfort. In two cases the parents requested referral to a paediatric urologist to consider clitoral surgery. As survival rates for extreme prematurity improve, paediatric urologists and gynaecologists are likely to see more of these cases. Clinicians must be familiar with this condition to ensure children are managed appropriately.


Dissecting aneurysm of intracranial vertebral artery: case report and review of literature.
A spontaneous dissecting aneurysm of the intracranial portion of the dominant right vertebral artery presented as massive subarachnoid hemorrhage, excruciating headache, and respiratory arrest in a 57-year-old white man with a history of systemic hypertension. He died on the 3rd day. Postmortem examination revealed a dissecting hemorrhage extending for 2.1 cm along the artery; rupture of the intima, media, and adventitia could be demonstrated. The intramural accumulation of blood in the proximal segments appeared to be related to retrograde dissection within a media weakened by cystic degeneration. Accumulation of pools of mucoid ground substance was also demonstrated in other intracranial and extracranial arteries. Hemodynamic stresses due to arterial hypertension and physical exertion may have played a contributory role in the etiopathogenesis of this uncommon form of cerebrovascular accident. A comprehensive literature review permits a comparison of supratentorial and infratentorial dissecting aneurysms; vertebral and basilar artery dissections are presented in tabular form.


Pilot evaluation of a biopsychosocial integrated standardized patient examination in a family medicine clerkship.
A new biopsychosocial Integrated Standardized Patient Examination (ISPE) was implemented to assess communication skills for medical students participating in a family medicine clerkship. Mixed method, multi-level evaluation. Pilot ISPE scores were significantly higher than previous Objective Structured Clinical Examination (OSCE) (p < .01). Family Physician and Social/Behavioral Scientist rater scores were correlated (p < .001), and Cronbach's alpha statistics were acceptable (FM: alpha = .837; BH: alpha = .768). Preceptor scores on "relations with professionals" (beta = .694, p = .008) significantly predicted ISPE scores, but other clerkship assignment grades were inversely associated with ISPE. Qualitative focus group themes included lack of readiness, divergence in beliefs on scope of physician practice, and focus on grade. This pilot project describes the process and demonstrates the possibility of implementing a complex standardized patient case to assess students' management of complicated primary care patients with medical, psychological, and social issues.


The child with acute leg pain.
Diagnostic imaging is an essential component in the evaluation of a child with acute lower extremity pain or limp. Most, but not all, of the etiologies are traumatic. Frequently, the history and clinical examination are not specific. Radionuclide bone imaging is extremely rewarding in these circumstances. It represents the most useful examination used in evaluating the pathophysiology and full extent of the disorder. This article discusses the clinical presentation, pathophysiology, and characteristic imaging observations in the more common problems associated with hip and/or leg pain.


Angiotensin-Converting Enzyme 2 (ACE2) Is a Key Modulator of the Renin Angiotensin System in Health and Disease.
Angiotensin-converting enzyme 2 (ACE2) shares some homology with angiotensin-converting enzyme (ACE) but is not inhibited by ACE inhibitors. The main role of ACE2 is the degradation of Ang II resulting in the formation of angiotensin 1-7 (Ang 1-7) which opposes the actions of Ang II. Increased Ang II levels are thought to upregulate ACE2 activity, and in ACE2 deficient mice Ang II levels are approximately double that of wild-type mice, whilst Ang 1-7 levels are almost undetectable. Thus, ACE2 plays a crucial role in the RAS because it opposes the actions of Ang II. Consequently, it has a beneficial role in many diseases such as hypertension, diabetes, and cardiovascular disease where its expression is decreased. Not surprisingly, current therapeutic strategies for ACE2 involve augmenting its expression using ACE2 adenoviruses, recombinant ACE2 or compounds in these diseases thereby affording some organ protection.


Multi-modal liquid biopsy platform for cancer screening: screening both cancer-associated rare cells and cancer cell-derived vesicles on the fabric filters for a reliable liquid biopsy analysis.
Circulating tumor cells (CTCs) are receiving a great amount of scientific interest as a diagnostic biomarker for various types of cancer. Despite the recent progress in the development of highly sensitive CTC isolation devices, post-capture analysis of CTCs is still hindered by technical challenges associated with their rarity. Herein, we present a multi-modal CTC screening platform which is capable to analyze CTCs and CTC-derived extracellular vesicles (EVs), simultaneously from a single sample. Cytochalasin B (CB) treatment promotes cells to release large number of EVs from their surface, as demonstrated by CB-treated cells (5 µg/mL for 3 h) secreting 3.5-fold more EVs, compared to the non-treated cells. CB further generates 1.7-fold more EVs from the cells captured on our CTC filtration device (the fabric filter), compared to those from the cell culture flasks, owing to its multiple pore structure design which reduces the non-specific binding of EVs. Both CB-treated cancer cells and CB-induced EVs are found to overexpress tumor-associated markers, demonstrating a potential for the development of CTC dual-screening platform. Collectively, the results presented in this study reveal that our multi-modal cancer screening platform can synergistically improve the reliability and efficacy of the current CTC analysis systems.


Synthesis and in vitro evaluation of 7-dialkylaminomethylbenzo[g]quinoxaline-5,10-diones.
A series of benzo[g]quinoxaline-5,10-dione derivatives carrying a 7-dialkylaminomethyl substituent was synthesized and their in vitro cytotoxic activities were evaluated against four human cancer cell lines (HCT-15, SK-OV-3, MD-MB-468 and T-47D). The most active compound 9d showed cytotoxic activity comparable to that of doxorubicin against HCT-15 cancer cell line.


Changes in response waveform of retinal horizontal cells during dark and light adaptation.
Changes in response waveform of retinal horizontal cells during dark and light adaptation were examined in the tiger salamander retina. In addition to sensitivity changes, the response waveform of HC was altered during visual adaptation: following bleaching or in the presence of background illumination, a transient depolarizing overshoot was observed at the cessation of the test flash. In contrast to the hyperpolarizing light responses, the depolarizing off-overshoots do not follow the standard threshold recovery time course during dark adaptation, neither do they obey Weber's law for increment thresholds during light adaptation. Simultaneous intracellular recordings from photoreceptors and HC revealed that the off-overshoot responses in light-adapted HC are probably originated from a population of cells in the photoreceptor layer which are strongly coupled with the cones.


Effect of decreasing the dose rate of irradiation on the mouse lip mucosa. Comparison with fractionated irradiations.
The effect of continuous irradiation, delivered at five different dose rates (642, 76.8, 14.1, 2.9 and 1.5 Gy.h-1), has been investigated using the mouse lip mucosa. There was a striking dose rate effect (DRE) below 14.1 Gy.h-1 while above this dose rate the DRE was relatively small. No DRE was observed between irradiations delivered at 642 and 76.8 Gy.h-1. A comparison was made with the previously published results of high dose rate (84 Gy.h-1) fractionated irradiation (2, 4, 10 and 20 fractions). For both types of irradiation treatment an alpha/beta value of 7.4 Gy and a half-time for repair of 47 min was derived.


Intramuscular desmoplastic fibroblastoma: a case report of extreme rarities in extremities.
Soft tissue tumors are part of a wide and sometimes rare differential diagnostic landscape. Case description of these rare soft tissue masses helps the future differentiation and aids in preoperative multidisciplinary approach. Interpretation and staging, with the help of imaging, is key.


Developmental Remodelling of the Motor Cortex in Hemiparetic Children With Perinatal Stroke.
Perinatal stroke often leads to lifelong motor impairment. Two common subtypes differ in timing, location, and mechanism of injury: periventricular venous infarcts (PVI) are fetal white matter lesions while most arterial ischemic strokes (AIS) are cortical injuries acquired near term birth. Both alter motor system development and primary motor cortex (M1) plasticity, often with retained ipsilateral corticospinal fibers from the non-lesioned motor cortex (M1'). Task-based functional magnetic resonance imaging was used to define patterns of motor cortex activity during paretic and unaffected hand movement. Peak coordinates of M1, M1', and the supplementary motor area in the lesioned and intact hemispheres were compared to age-matched controls. Correlations between displacements and clinical motor function were explored. Forty-nine participants included 14 PVI (12.59 ± 3.7 years), 13 AIS (14.91 ± 3.9 years), and 22 controls (13.91 ± 3.4 years). AIS displayed the greatest M1 displacement from controls in the lesioned hemisphere while PVI locations approximated controls. Peak M1' activations were displaced from the canonical hand knob in both PVI and AIS. Extent of M1 and M1' displacement were correlated (r = 0.50, P = 0.025) but were not associated with motor function. Supplementary motor area activity elicited by paretic tapping was displaced in AIS compared to controls (P = 0.003). Motor network components may be displaced in both hemispheres after perinatal stroke, particularly in AIS and those with ipsilateral control of the affected limb. Modest correlations with clinical function may support that more complex models of developmental plasticity are needed to inform targets for individualized neuromodulatory therapies in children with perinatal stroke.


Assays of drug sensitivity for cells from human tumours: in vitro and in vivo tests on a xenografted tumour.
A human tumour which grows as a xenograft in immune-suppressed mice and forms colonies in vitro has been used to test the correlation between 2 methods of exposure of human tumour cells to chemotherapeutic agents. In vivo exposure to drugs was achieved by injection of tumour-bearing mice with each of 8 cytotoxic agents. For the in vitro exposure, cell suspensions were incubated for 1 h with the same series of drugs. The survival of tumour clonogenic cells was assayed in vitro after either treatment or dose-response curves were obtained. The 8 drugs were ranked according to their in vivo effect at doses equitoxic to mice, and according to their in vitro effect at concentrations designed to approximate to levels of drugs in human plasma. The ranks for in vivo and in vitro exposure correlated well.


Motor cortical excitability behavior in chronic spinal cord injury neuropathic pain individuals submitted to transcranial direct current stimulation-case reports.
Increased excitability of the motor cortex through transcranial direct current stimulation (tDCS) has been described as a non-pharmacological strategy for the treatment of Spinal Cord Injury neuropathic pain (SCINP). It is also believed that the ability to enhance motor cortex excitability (MCE) could be impaired within chronic SCINP individuals. The following case reports describe the MCE behavior in individuals with chronic SCINP submitted to electrical non-invasive neuromodulation. This article reports 11 cases with chronic SCINP in which each individual was submitted to a 5-day pre-post MCE analysis in order to evaluate its behavior after the anodal tDCS sessions. All cases maintained ongoing pharmacological treatment. Four individuals have shown negative variation of the MCE, two of which reported pain intensity reduction. Three other individuals had MCE-positive variation along 5 days, from which only one reported a VAS 0.5 pain reduction after the 5th day of observation. The other four individuals did not present significant variation of the MCE. The positive variation of MCE was significantly altered by adjunctive tDCS only in three individuals, though no clinically relevant reduction in pain intensity was reported among these participants. Key factors such as pain and injury duration, age, chronic medication use and underlying maladaptive neuroplasticity may influence responsiveness to brain stimulation within this population. These case reports try to add evidence for cautious recommendation of tDCS in chronic SCINP individuals and to the necessity of identifying groups of individuals that are most susceptible to neuromodulation.


Virgin coconut oil attenuates lipopolysaccharide-induced depression-like behaviors: Integrating network pharmacology analysis and molecular mechanism evaluation.
Depression is a mental disease that seriously affects the quality of life. Its pathophysiology is complex and includes neuroinflammation and apoptosis. Virgin coconut oil (VCO) is a natural food that has been found to have remarkable anti-inflammatory and antiapoptotic properties. We assessed the effects of VCO on depression and the related mechanisms by performing network pharmacology analysis and evaluating depressive-like behaviors in rat model and found that VCO-treatment alleviated the depressive-like behaviors, inhibited microglial and astrocytic activation and reduced neuronal loss in the hippocampus, possibly by decreasing neuronal apoptosis. In addition, network pharmacology analysis and western blotting showed that VCO might exert neuroprotective effects by activating Protein Kinase B (AKT)-related pathway. Taken together, our results revealed the previously unrecognized effects of VCO on depression, and further explored the underlying mechanism of depression.


New derivatives of hexahydroazepine, hexahydro(1,4,5)oxadiazepine and hexahydro(1,4,5)oxadiazocine with expected pharmacological activity.
New derivatives with the expected pharmacological activity of heterocyclic systems mentioned above having ether (1-6) and ester (7-10) groups were obtained.


Complete genus-level plastid phylogenomics of Alismataceae with revisited historical biogeography.
Alismataceae, an ancient lineage of monocots, has attracted attention due to its complex evolutionary history, ornamental value, and ecological role. However, the phylogenetic relationships and evolutionary history of the family have not been conclusively resolved. Here, we constructed the first complete genus-level plastid phylogeny of Alismataceae by using 78 genes and updated the historical biogeography based on the phylogenomic tree. Our results divide the Alismataceae into three major clades with robust support values; one clade comprises the former Limnocharitaceae, and the second clade includes the mainly temperate genera Alisma, Baldellia, Damasonium and Luronium, and the monotypic African genus Burnatia as a sister of the temperate genera. The remaining genera are either tropical or have some temperate species in addition to tropical ones, and they constitute the third major clade. Molecular dating and biogeographic analyses suggest that Alismataceae arose in Neotropical, West Palearctic, and Afrotropical regions during the Cretaceous, followed by the split into three main clades due to a combination of vicariance and dispersal events. Unlike earlier studies, we inferred that the mainly temperate clade likely originated from Afrotropical and West Palearctic regions during the Eocene. The most recent common ancestor of the other two clades lived in the Neotropical area during the Late Cretaceous. Long-distance dispersal and vicariance together seem to contribute to the transoceanic distribution of this family.


Isolated granulocytic sarcoma of the pancreas: a tricky diagnostic for primary pancreatic extramedullary acute myeloid leukemia.
We report two clinical cases of primary granulocytic sarcoma of the pancreas that were diagnosed on the surgical specimen. Atypical clinical and morphological presentations may have lead to pretherapeutic biopsies of the pancreatic mass in order to indicate primary chemotherapy. Literature review of this rare clinical presentation may help physicians to anticipate diagnostic and therapeutic strategies.


Optimising results from minimal access cranial suspension lifting (MACS-lift).
Between November 1999 and February 2005, 450 minimal access cranial suspension (MACS) lifts were performed. Starting with the idea of suspension for sagging soft tissues using permanent purse-string sutures, a new comprehensive approach to facial rejuvenation was developed in which the vertical vector appeared to be essential. The neck is corrected by extended submental liposuction and strong vertical traction on the lateral part of the platysma by means of a first vertical purse-string suture. The volume of the jowls and the cheeks is repositioned in a cranial direction with a second, slightly oblique purse-string suture. The descent of the midface is corrected by suspending the malar fat pad in a nearly vertical direction. In 23 cases (5.1%), the result in the neck was unsatisfactory, and additional work had to be done secondarily, or in later cases, primarily. The problem that appeared was unsatisfactory correction of platysmal bands (resolved with an additional anterior cervicoplasty) or vertical skin folds that appeared in the infralobular region (corrected with an additional posterior cervicoplasty). This article describes two ancillary procedures that, although not frequently necessary, can optimise the result of MACS lifting.


Usefulness of neutral red uptake method for investigation of the effects of recombinant hemopoietic growth factors on leukemic blasts proliferation.
By a colorimetric assay with dye (neutral red), the effects of recombinant human hemopoietic growth factors (rhG-CSF, rhGM-CSF, rhIL-3 and rhEPO) on the proliferation of leukemic blasts in vitro were investigated. Leukemic blasts were obtained from eight patients with acute myeloid leukemia (AML) (M1: two cases, M3: two cases, M4: four cases) and from four patients with acute lymphoid leukemia (ALL) (L2: four cases). It was shown that rhG-CSF, rhGM-CSF and rhIL-3 stimulated the blast proliferation in most cases of AML, although the degree and pattern of responses showed a striking variability in different patients. Moreover, rhGM-CSF and rhIL-3 also stimulated the leukemic blasts from some cases of ALL. No clear morphological modification providing evidence for terminal differentiation was observed when assessed by Wright stain. On the other hand, rhEPO did not have any stimulating effects on leukemic blasts in all cases. These results indicate the necessity of investigating the responses of leukemic blasts to hemopoietic growth factors in each patient prior to clinical use of such factors. For this assay, neutral red uptake method is useful because of its simplicity, rapidity, precision and convenience for handling a large volume of materials.


Preparation and characterization of spherical polymer packings from polybutadiene for size-exclusion chromatography.
Porous polymer spherical particles for column packings in nonaqueous size-exclusion chromatography (SEC) were prepared from 1,2-syndiotactic polybutadiene by suspension and evaporation method. The polymer microbeads obtained were crosslinked by radical reaction between 2-vinyl groups in polybutadiene with ultraviolet radiation, to render them insoluble. These microbeads have wider chromatographic separation width than polystyrene column packings. In addition, the polybutadiene microbeads did not show the excessive retention observed with commercial polystyrene columns for polycyclic aromatic compounds. Therefore, a close correlation between the elution volume and M, for polycyclic aromatic compounds was observed with polybutadiene microbeads columns.


Nucleotide -88 (C-T) promoter mutation is a common beta-thalassemia mutation in the Jat Sikhs of Punjab, India.
A study of beta-gene mutations in Jat Sikhs, a subcaste of Punjabis, revealed a very high prevalence (46%: 41/88) of the mild beta++ promoter region mutation -88 (C-T). Sixteen individuals presenting in homozygous form were clinically mild. Un-transfused patients had characteristic hematological findings: high Hb F (38.1-68.6%, mean 47.4%), high Hb A2 (5.7-9.8%, mean 6.88%), and the rest had adult hemoglobin. The 19 subjects with compound heterozygosity for -88 (C-T) and another beta-gene mutation presented both as thalassemia intermedia (four cases) and as thalassemia major (15 cases). One of the four patients with the milder phenotype had a second mild mutation, CAP+1 (beta++). In the other three cases with the milder phenotype, the second mutation was associated with the presence of the XmnI Ggamma polymorphism. Notably, the XmnI Ggamma was negative in all the -88 (C-T) alleles. None of the patients had associated alpha-thalassemia even in the thalassemia intermedia group. Haplotype analysis of the -88 (C-T) homozygous cases showed a single haplotype (+ - - - - + -) in all but two individuals. This haplotype is distinct from those described in the Africans with homozygous -88 (C-T), suggesting that the mutation in our population occurred independently.


Forwarding the Science of Sensory Features in Autism and Related Conditions.
This editorial accompanies the JADD Special Issue on Sensory Features in Autism and Related Conditions: Developmental Approaches, Mechanisms and Targeted Interventions. The editorial is a commentary on the state of the science in sensory features in autism and related conditions and provides a synopsis of the information contained in the special issue including provocative thoughts about moving the field forward in this area.


Simultaneous angiotensin receptor blockade and glucagon-like peptide-1 receptor activation ameliorate albuminuria in obese insulin-resistant rats.
Insulin resistance increases renal oxidant production by upregulating NADPH oxidase 4 (Nox4) expression contributing to oxidative damage and ultimately albuminuria. Inhibition of the renin-angiotensin system (RAS) and activation of glucagon-like peptide-1 (GLP-1) receptor signalling may reverse this effect. However, whether angiotensin receptor type 1 (AT1) blockade and GLP-1 receptor activation improve oxidative damage and albuminuria through different mechanisms is not known. Using insulin-resistant Otsuka Long-Evans Tokushima Fatty (OLETF) rats, we tested the hypothesis that simultaneous blockade of AT1 and activation of GLP-1r additively decrease oxidative damage and urinary albumin excretion (Ualb V) in the following groups: (a) untreated, lean LETO (n = 7), (b) untreated, obese OLETF (n = 9), (c) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d; n = 9), (d) OLETF + GLP-1 mimetic (EXE; 10 µg exenatide/kg/d; n = 7) and (e) OLETF + ARB +exenatide (Combo; n = 6). Mean kidney Nox4 protein expression and nitrotyrosine (NT) levels were 30% and 46% greater, respectively, in OLETF compared with LETO. Conversely, Nox4 protein expression and NT were reduced to LETO levels in ARB and EXE, and Combo reduced Nox4, NT and 4-hydroxy-2-nonenal levels by 21%, 27% and 27%, respectively. At baseline, Ualb V was nearly double in OLETF compared with LETO and increased to nearly 10-fold greater levels by the end of the study. Whereas ARB (45%) and EXE (55%) individually reduced Ualb V, the combination completely ameliorated the albuminuria. Collectively, these data suggest that AT1 blockade and GLP-1 receptor activation reduce renal oxidative damage similarly during insulin resistance, whereas targeting both signalling pathways provides added benefit in restoring and/or further ameliorating albuminuria in a model of diet-induced obesity.


Effects of the new Accreditation Council for Graduate Medical Education work hour rules on surgical interns: a prospective study in a community teaching hospital.
On July 1, 2011, the Accreditation Council for Graduate Medical Education (ACGME) eliminated 30-hour call in an attempt to improve resident wakefulness. We surveyed interns on the Newton Wellesley Hospital (NWH) surgery service before and after the transition from Q4 overnight call to a night float schedule. For 15 weeks, interns completed weekly surveys including the Epworth Sleepiness Scale (ESS). The service changed to a night float schedule after 3 weeks (ie, first to 3-4 and then to 6 nights in a row). The average ESS score rose from 9.8 ± 5.2 to 14.9 ± 3.1 and 14.4 ± 4.5 (P = .042) on the 3/4 and 6/1 schedules, respectively. Interns were more likely to be abnormally tired on either night float schedule (relative risk = 2.86; 95% confidence interval, 1.17-6.97, P = .029). The new ACGME work hours increased the ESS scores among interns at NWH and caused interns to be more tired than interns on the Q4 schedule. This is likely caused by the multiple nights of poor sleep without a post-call day to make up sleep.


Quantification of flavonol glycosides in Camellia sinensis by MRM mode of UPLC-QQQ-MS/MS.
Phenolic compounds are major components of tea flavour, in which catechins and flavonol glycosides play important roles in the astringent taste of tea infusion. However, the flavonol glycosides are difficult to quantify because of the large variety, as well as the inefficient seperation on chromatography. In this paper, a total of 15 flavonol glycosides in the tea plant (Camellia sinensis) were identified by the high performance liquid chromatography (HPLC) coupled to a time-of-flight mass spectrometer (TOF-MS), and a quantitative method was established based on multiple reaction monitoring (MRM) mode of ultra-high performance liquid chromatography (UPLC) coupled to a triple quadrupole mass spectrometer (QQQ-MS/MS). It provided the limit of detection and quantification to the order of picogram, which was more sensitive than the HPLC detection of the order of nanogram. The relative standard deviations of the intra- and inter-day variations in retention time and signal intensity (peak area) of six analytes were less than 0.26% and 4%, respectively. The flavonol glycosides of four tea cultivars were relatively quantified using the signal intensity (peak area) of product ion, in which six flavonol glycosides were quantified by the authentic standards. The results showed that the flavonol mono-, di- and tri-glycoside mostly accumulated in young leaves of the four tea cultivars. Notably, the myricetin 3-O-galactoside was the major component among the six flavonol glycosides detected.


Silencing of long noncoding RNA XIST attenuated Alzheimer's disease-related BACE1 alteration through miR-124.
Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder. However, its pathogenetic mechanism is still poorly understood. An increasing number of studies have evidenced the important role of long noncoding RNAs (lncRNAs) in AD. The aim of the current study was to investigate the effect and molecular mechanism of the lncRNA X-inactive specific transcript (XIST) in AD. Bilateral common carotid artery occlusion (2VO) was used to induce an AD model in mice. Hydrogen peroxide (H2 O2 ) was used to induce an AD model in N2a cells. The lncRNA XIST, miR-124, and BACE1 messenger RNA expression levels were detected by a real-time polymerase chain reaction. The BACE1 protein expression level was detected by western blot and immunofluorescence assay. The Aβ1-42 expression level was detected using an enzyme-linked immunosorbent assay kit. The expression level of lncRNA XIST was significantly upregulated in AD models, both in vivo and in vitro. Silencing of lncRNA XIST negatively regulated miR-124 and positively regulated BACE1 expression in N2a cells, which is attenuated by cotransfection of anti-miR-124 oligodeoxyribonucleotide (AMO-124). Silencing of lncRNA XIST reversed the effect of H2 O2 on miR-124, BACE1, and Aβ1-42 expression in N2a cells, which was reversed by cotransfection of AMO-124. Silencing of lncRNA XIST attenuated AD-related BACE1 alteration through miR-124. LncRNA XIST may be a new potential target for the treatment of AD.


Application of machine learning to predict transport modes from GPS, accelerometer, and heart rate data.
There has been an increased focus on active transport, but the measurement of active transport is still difficult and error-prone. Sensor data have been used to predict active transport. While heart rate data have very rarely been considered before, this study used random forests (RF) to predict transport modes using Global Positioning System (GPS), accelerometer, and heart rate data and paid attention to methodological issues related to the prediction strategy and post-processing. The RECORD MultiSensor study collected GPS, accelerometer, and heart rate data over seven days from 126 participants living in the Ile-de-France region. RF models were built to predict transport modes for every minute (ground truth information on modes is from a GPS-based mobility survey), splitting observations between a Training dataset and a Test dataset at the participant level instead at the minute level. Moreover, several window sizes were tested for the post-processing moving average of the predicted transport mode. The minute-level prediction rate of being on trips vs. at a visited location was 90%. Final prediction rates of transport modes ranged from 65% for public transport to 95% for biking. Using minute-level observations from the same participants in the Training and Test sets (as RF spontaneously does) upwardly biases prediction rates. The inclusion of heart rate data improved prediction rates only for biking. A 3 to 5-min bandwidth moving average was optimum for a posteriori homogenization. Heart rate only very slightly contributed to better predictions for specific transport modes. Moreover, our study shows that Training and Test sets must be carefully defined in RF models and that post-processing with carefully chosen moving average windows can improve predictions.


Sleeping over a sleep disorder - Awareness of obstructive sleep apnoea as a modifiable risk factor for hypertension and stroke: A survey among health care professionals and medical students.
Obstructive sleep apnoea (OSA) syndrome is an established and modifiable but under recognized risk factor for common disorders like stroke and hypertension. To assess awareness level of health care practitioners and medical students about OSA as a risk factor for stroke and hypertension. Questionnaire based survey with multiple response type and fill in the blanks type questions. The data was compiled and analyzed using SPSS version 19. 180 participants completed the survey questionnaire. Only 24 (13.3%) identified OSA as a reversible risk factor for ischemic stroke. 11 (6%) participants only could answer OSA as an identified risk factor for hypertension as per Seventh Joint National Committee report. This study reveals dismal level of awareness, among health professionals and medical students, about OSA being an established and modifiable risk factor for hypertension and ischemic stroke.


Evidence for an input to the molecular layer and the stratum granulosum of the dentate gyrus from the supramammillary region of the hypothalamus.
Injections of a mixture of tritiated amino acids were made into the posterior hypothalamus in a series of rats and cats. In every case in which the injection involved a significant proportion of the cells in the supramammillary region, labeled fibers could be followed to the dentate gyrus, the anterior hippocampal rudiment and the induseum griseum of both sides. In the dentate gyrus the hypothalamic afferents terminate in a narrow band in the outer half of the stratum gramulosum and the inner 20 micron or so, of the stratum moleculare, immediately deep to the zone of termination of the associational and commissural afferents. As judged by silver grain counts across the width of the zone of labeled terminals, the projection to the ipsilateral side is several times as heavy as that to the contralateral side, and although it involves the entire septo-temporal (=rostro-caudal) extent of the gyrus on both sides, the projection to the suprapyramidal (inner) blade of the dentate gyrus is approximately twice as heavy as that to the infrapyramidal (outer) blade.


Differential cholinergic modulation of synaptic encoding and gain control mechanisms in rat hippocampus.
Recent studies have highlighted a variety of cognitive effects caused by cholinolytic drug injections into different cortical structures. These findings were largely interpreted as evidence for location-specific cholinergic modulation of synaptic encoding mechanisms. Here, using evoked field responses in anaesthetized rat dorsal hippocampus we show that in addition to reinforcement of synaptic connections (long-term potentiation, LTP), endogenous acetylcholine also regulates firing gain of CA1 pyramidal neurons (EPSP-spike potentiation). Gain augmentation upon increase in cholinergic drive involves evoked synchronous firing at both apical and basal afferent projections, unlike enhancement of activity-induced LTP constrained to the basal afferent system. These data indicate that acetylcholine can act as an effective input and gain controller in the hippocampus. Modulation of synaptic plasticity would determine the relative dominance of afferent inputs while the facilitation of synchronous firing is likely to promote a more generalized spread of excitation and long range communication within the limbic cortex.


The construction of DNA molecules of figure-eight structure.
Using DNA molecules to construct a structural scaffold for nanotechnology is largely accepted. In this article, we report on two methods for constructing a figure-eight structure of DNA molecules having a relatively high yield that could be used further as a scaffold for nanotechnology applications. In the first method, two plasmids were constructed that, on digestion with a restriction endonuclease producing nicks in the corresponding sites and after heating, produced complementary single-stranded sequences, enabling the plasmids to hybridize to each other and forming a figure-eight structure. The formation of the figure-eight structure was analyzed by restriction analysis and gel electrophoresis as well as by atomic force microscopy. The second method makes use of the bacteriophage M13 that is obtained as either a single- or double-stranded circular DNA molecule. Two M13 molecules harboring complementary sequences were constructed and produced a figure-eight structure on hybridization. The methods described here could be used further for the construction of nanoelectronic devices.


A prospective analysis of cell-free fetal DNA concentration in maternal plasma as an indicator for adverse pregnancy outcome.
To evaluate whether cell-free fetal (cff) DNA in maternal plasma during the second trimester is a marker for developing pregnancy-associated complications. Two PCR techniques for the detection and quantitation of fetal DNA were compared. Plasma samples were prospectively collected from 84 pregnant women carrying male fetuses before amniocentesis (14-29 weeks). We later recorded 26 pregnancies with complicated outcomes, including five cases of fetal chromosomal abnormalities. For statistical analysis, two overlapping subgroups A and B were made. Each group was separately compared for total and fetal DNA with a corresponding group considered normal using Wilcoxon rank sum test. Male fetal DNA concentration in maternal plasma was quantified using real-time quantitative polymerase chain reaction (PCR) of SRY sequences. The samples were also analyzed by quantitative fluorescent PCR (QF-PCR) using highly polymorphic short tandem repeat DNA sequences (STRs), and the percentage of relative fetal allele concentration in maternal alleles was calculated and compared to the fetal/total DNA ratio obtained by real-time PCR. Quantities of total and fetal circulating DNA were significantly correlated (r(2) = 0.44, P < 0.0001) with a median total DNA concentration of 522 GE/mL (range 51-3047) and a median fetal DNA concentration of 8 GE/mL (range 0-879). Neither level was correlated with gestational age in pregnancies with normal (r(2) = -0.05; P = 0.66, and r(2) = 0.02; P = 0.88, respectively) and abnormal (r(2) = 0.45; P = 0.17, and r(2) = 0.11; P = 0.76, respectively) outcomes. Although both total and fetal DNA levels were always higher in women carrying pregnancies with chromosomal aberrations or having other pregnancy complications (P-values range from 0.028 to 0.267), these differences reached statistical significance only for total DNA levels between the group A and corresponding normal pregnancies (P = 0.028). The correlation between the fetal/total DNA ratio obtained by real-time PCR and the percentage of relative fetal allele concentration in maternal alleles obtained by QF-PCR was not found to be statistically significant (r(2) = 0.04; P = 0.76). Our results confirm the clinical value of fetal DNA measurement in maternal plasma during the second trimester as a supplement for the diagnosis of aneuploidies. Its use as a screening instrument for complications that develop later in pregnancy seems to be limited but needs further investigation. Although the QF-PCR assay has the advantage of being applicable to both female and male fetuses, this approach cannot be used for quantitation of cff DNA in maternal plasma samples.


Repair of 6-4 photoproducts in Saccharomyces cerevisiae.
We have developed a dot blot immunoassay for UV photoproducts which distinguishes 6-4 photoproducts from cyclobutane dimers. The assay uses a polyclonal antiserum that is specific for UV-irradiated DNA. Cyclobutane dimers are measured in DNA samples which have been treated with hot alkali to destroy 6-4 photoproducts. 6-4 Photoproducts are measured using blots that have been incubated in photoreactivating enzyme to eliminate cyclobutane dimers. A combination of the two treatments leaves no detectable antigenic lesions. Wild-type S. cerevisiae repairs 6-4 photoproducts, in the genome overall, more rapidly than cyclobutane dimers. The most sensitive alleles of rad1, rad2, rad3 and rad4 are completely unable to repair either kind of photoproduct. We conclude that 6-4 photoproducts are repaired by essentially the same mechanism as are cyclobutane dimers.


Diversity of DNA beta, a satellite molecule associated with some monopartite begomoviruses.
DNA beta molecules are symptom-modulating, single-stranded DNA satellites associated with monopartite begomoviruses (family Geminiviridae). Such molecules have thus far been shown to be associated with Ageratum yellow vein virus from Singapore and Cotton leaf curl Multan virus from Pakistan. Here, 26 additional DNA beta molecules, associated with diverse plant species obtained from different geographical locations, were cloned and sequenced. These molecules were shown to be widespread in the Old World, where monopartite begomoviruses are known to occur. Analysis of the sequences revealed a highly conserved organization for DNA beta molecules consisting of a single conserved open reading frame, an adenine-rich region, and a region of high sequence conservation [the satellite conserved region (SCR)]. The SCR contains a potential hairpin structure with the loop sequence TAA/GTATTAC; similar to the origins of replication of geminiviruses and nanoviruses. Two major groups of DNA beta satellites were resolved by phylogenetic analyses. One group originated from hosts within the Malvaceae and the second from a more diverse group of plants within the Solanaceae and Compositae. Within the two clusters, DNA beta molecules showed relatedness based both on host and geographic origin. These findings strongly support coadaptation of DNA beta molecules with their respective helper begomoviruses.


Doppler ultrasound examination of the anterior cerebral arteries of normal newborn infants: the effect of postnatal age.
Twenty-four normal term infants were examined by Doppler ultrasonography of the anterior cerebral arteries at least twice in the first 5 days of life. It was found by comparison with a duplex Doppler unit that the anterior cerebral arteries could be reliably insonated using a continuous wave Doppler ultrasound probe without the concomitant use of real time ultrasound sector scanning. It was shown that the pulsatility of the velocity waveform decreased and that diastolic frequency increased over the 5 days. The significance of, and possible mechanism for, this change is discussed.


The nature of the nitric oxide complexes of lipoxygenase.
The NO complex of lipoxygenase with EPR signals near g = 4.0 is an S = 3/2 system with D approximately 15 cm-1 similar to Fe2+-EDTA-NO. This may result from antiferromagnetic coupling of axial (D greater than E) high spin ferrous iron to NO. The other NO complex of lipoxygenase, with EPR signals below ge, may result from rhombic high spin ferrous iron coupled to NO with D greater than J. The quenching of both signals by a hydroperoxy derivative of linoleic acid probably represents replacement of NO by an oxygen ligand.


[Effect of sigetin treatment during reduced maternal-placental circulation in pregnant rabbits on the nucleic acid and total protein content of the organs of the progeny].
A study was made of the development of the progeny of rabbits (the whole body and individual organs) born to mothers with abnormal uteroplacental circulation (ligation of 40% of the preplacental vessels on the 18th day of pregnancy) treated with sigetin over the last trimester of pregnancy. Studies of the biochemical indicators (RNA, DNA, total protein in the brain and liver of sexually mature rabbit progeny) and physiological indicators (crude mass of the body, liver, brain and its parts) indicate that sigetin produces a therapeutic effect contributing to partial or complete compensation for the progeny underdevelopment because of mother's pathology.


Evaluating the Safety of Retroviral Vectors Based on Insertional Oncogene Activation and Blocked Differentiation in Cultured Thymocytes.
Insertional oncogenesis due to retroviral (RV) vector integration has caused recurrent leukemia in multiple gene therapy trials, predominantly due to vector integration effects at the LMO2 locus. While currently available preclinical safety models have been used for evaluating vector safety, none have predicted or reproduced the recurrent LMO2 integrations seen in previous X-linked severe combined immunodeficiency (X-SCID) and Wiskott-Aldrich clinical gene therapy trials. We now describe a new assay for assessing vector safety that recapitulates naturally occurring insertions into Lmo2 and other T-cell proto-oncogenes leading to a preleukemic developmental arrest in primary murine thymocytes cultured in vitro. This assay was used to compare the relative oncogenic potential of a variety of gamma-RV and lentiviral vectors and to assess the risk conferred by various transcriptional elements contained in these genomes. Gamma-RV vectors that contained full viral long-terminal repeats were most prone to causing double negative 2 (DN2) arrest and led to repeated cases of Lmo2 pathway activation, while lentiviral vectors containing these same elements were significantly less prone to activate proto-oncogenes or cause DN2 arrest. This work provides a new preclinical assay that is especially relevant for assessing safety in SCID disorders and provides a new tool for designing safer RV vectors.


Rainwater input reduces greenhouse gas emission and arsenic uptake in paddy rice systems.
This work aimed to test the hypothesis that rainwater-borne hydrogen peroxide (H2O2) can affect arsenic uptake by rice plants and emission of greenhouse gases in paddy rice systems. A mesocosm rice plant growth experiment, in conjunction with rainwater monitoring, was conducted to examine the effects of rainwater input on functional groups of soil microorganisms related to transformation of arsenic, carbon and nitrogen as well as various arsenic species in the soil and plant systems. The fluxes of methane (CH4), nitrous oxide (N2O) and carbon dioxide (CO2) were measured during selected rainfall events. The results showed that rainwater-borne H2O2 effectively reacted with Fe2+ present in paddy soil to trigger a Fenton-like reaction to produce •OH. Both H2O2 and •OH inhibited As(V)-reducing microbes but promoted As(III)-oxidizing microbes, leading to a net increase in arsenate-As that is less phytoavailable compared to arsenite-As. This impeded uptake of soil-borne As by the rice plant roots, and consequently reduced the accumulation of As in the rice grains. The input of H2O2 into the soil caused more inhibition to methanogens than to methane-oxidizing microbes, resulting in a reduction in CH4 flux. The microbes mediating the transformation of inorganic nitrogen were also under oxidative stresses upon exposure to the rainwater-derived H2O2. And the limited conversion of NO3- to NO played a crucial role in reducing N2O emission from the paddy soils. The results also indicated that the rainwater-borne H2O2 could significantly affect other biogeochemical processes that shape the wider ecosystems, which is worth further investigations.


Derivation and validation of a high sensitivity troponin-T HEART pathway.
The HEART Pathway is widely used for chest pain risk stratification but has yet to be optimized for high sensitivity troponin T (hs-cTnT) assays. We conducted a secondary analysis of STOP-CP, a prospective cohort study enrolling adult ED patients with symptoms suggestive of acute coronary syndrome at 8 sites in the United States (US). Patients had a 0- and 1-hour hs-cTnT measured and a HEAR score completed. A derivation set consisting of 729 randomly selected participants was used to derive a hs-cTnT HEART Pathway with rule-out, observation, and rule-in groups for 30-day cardiac death or myocardial infarction (MI). Optimal baseline and 1-hour troponin cutoffs were selected using generalized cross validation to achieve a negative predictive value (NPV) >99% for rule out and positive predictive value (PPV) >60% or maximum Youden index for rule-in. Optimal 0-1-hour delta values were derived using generalized cross validation to maximize the NPV for the rule-out group and PPV for the rule-in group. The hs-cTnT HEART Pathway performance was validated in the remaining cohort (n = 723). Among the 1452 patients, 30-day cardiac death or MI occurred in 12.7% (184/1452). Within the derivation cohort the optimal hs-cTnT HEART Pathway classified 36.5% (266/729) into the rule-out group, yielding a NPV of 99.2% (95% CI: 98.2-100) for 30-day cardiac death or MI. The rule-in group included 15.4% (112/729) with a PPV of 55.4% (95% CI: 46.2-64.6). In the validation cohort, the hs-cTnT HEART Pathway ruled-out 37.6% (272/723), of which 2 had 30-day cardiac death or MI, yielding a NPV of 99.3% (95% CI: 98.3-100). The rule-in group included 14.5% (105/723), yielding a PPV of 57.1% (95% CI: 47.7-66.6). A novel hs-cTnT HEART Pathway with serial 0- and 1-hour hs-cTnT measures has high NPV and moderate PPV for 30-day cardiac death or MI.


The focal cone electroretinogram.
The focal cone electroretinogram (ERG) in monkey retina has been examined with a 3 deg pulse of laser light (544 and 633 nm) centered on a 25 deg steady white rod saturating field. The stimuli were viewed simultaneously through a slit lamp and corneal contact lens. Cone ERGs were studied at different eccentricities from the fovea and compared with full-field corneal and intraretinal ERGs. The cone ERG is maximum at the fovea. There are two components to the on- (b-wave) and off- (d-wave) response, one slower, more long wavelength sensitive and more foveally oriented than the faster response. This makes the foveal cone ERG slower and more longer wavelength sensitive than the perifoveal ERG. This difference disappears at high rates (> 20 Hz) of stimulation. The foveal cone ERG is larger and slower than that of more peripheral retina. The slowness appears to be due to a subcomponent of the response which is especially prominent in the fovea and has a slightly greater long wavelength sensitivity than the more peripherally generated ERG. It may depend on a unique difference in L-M cone bipolar systems or in L-M cone interactions that are more prominent near the fovea.


Long-term survival of decentralized axons and incorporation of satellite cells in motor neurons of rock lobsters.
Previous electrophysiological experiments have shown that in the abdominal extensor muscles of rock lobsters, axons which were cut in surviving animals do not degenerate peripherally for several months, but conduct action potentials and release transmitter quanta on stimulation closely distal to the scar. Electron micrographs from the axon distal to the scar (in a reliably conducting region) show invasion of the axoplasmic space by nucleated cells, probably glia. After several months, the cell membranes of the invaders have vanished and apparently functional multiple nuclei remain. We suggest that decentralized axons may survive for months with the help of 'donated' nuclei.


The role of genetic testing in the prevention, diagnosis, and prognosis of sudden cardiac arrest in children.
Determining the pathogenesis of sudden cardiac arrest (SCA) in children is crucial for its management and prognosis. Our aim is to analyze the role of broad genetic testing in the prevention, diagnosis, and prognosis of SCA in Children. ECG, 12-lead holter, exercise testing, cardiac imaging, familial study, and genetic testing were used to study 29 families, in whom a child experienced SCA. After a thorough clinical and genetic evaluation a positive diagnosis was reached in 24/29 (83%) families. Inherited channelopathies (long QT syndrome and catecholaminergic polymorphic ventricular tachycardia) were the most prevalent 20/29 (69%) diagnosis, followed by cardiomyopathy 3/29 (10%). Broad genetic testing was positive in 17/24 (71%) cases. Using the Mann-Whitney test, we found that genetic testing (effect size = 0.625, p = 0.003), ECG (effect size = 0.61, p = 0.009), and exercise test (effect size = 0.63, p = 0.047) had the highest yield in reaching the final diagnosis. Genetic testing was the only positive test available for five (17%) families. Among 155 family members evaluated through cascade screening, 73 (47%) had a positive clinical evaluation and 64 (41%) carried a pathologic mutation. During 6 ± 4.8 years of follow-up, 58% of the survived children experienced an arrhythmic event. Of nine family members who had an ICD implant for primary prevention, four experienced appropriate ICD shock. The major causes of SCA among children are genetic etiology, and genetic testing has a high yield. Family screening has an additional role in both the diagnosis and preventing of SCA.


A Component Evaluation of a Randomised Control Community Intervention to Reduce Adolescent Alcohol Use in Australia.
Despite a decline in Australian adolescents reporting to have consumed alcohol, a high proportion of the adolescent population still consumes alcohol. Community-led prevention interventions that systematically and strategically implement evidence-based programs have been shown to be effective in producing population-behaviour change related to youth alcohol and drug use. This study evaluated the post-intervention effects of a multi-component community intervention in Australia. It comprised social marketing targeting adolescents and parents, and a community intervention to reduce underage alcohol sales. Structural equation modelling was used to examine direct and indirect effects of community intervention components on intention and consumption. Self-report surveys (N = 3377) and community sales data (27 communities) were analysed to evaluate the effect of the intervention components on intention and consumption before the age of 18. The intervention reduced alcohol sales to minors (OR = .82). Exposure to the social marketing was significantly associated with household no-alcohol rules (OR = 2.24) and parents not supplying alcohol (OR = .72). The intervention predicted intention not to consume alcohol before age 18; intention was associated with not consuming alcohol (OR = 5.70). Total indirect effects from the intervention through to intention were significant. However, parents setting a rule and not supplying alcohol were the only significant direct effects to intention. Parents setting a rule was directly associated with lower consumption. Overall, the intervention logic was supported by the data modelling. The study extends prior knowledge of community-based interventions to prevent adolescent alcohol use by identifying critical intervention components and effect mechanisms. ClinicalTrials.gov Identifier: ACTRN12612000384853.


The effect of co-actor group membership on the social inhibition of return effect.
Being part of a group is a crucial factor in human social interaction. In the current study we explored whether group membership affects reflexive automatic cognitive functioning, and specifically the social inhibition of return effect (SIOR; Welsh et al., 2005). SIOR is characterized by slower reaction times (RTs) to a location already searched by another agent. To examine whether group membership modulates SIOR, we recruited Muslim and Jewish students from the University of Haifa to perform a task with either an in-group member or an out-group member. Both IOR and SIOR were suggested to act as a foraging facilitator (Klein, 2000; Welsh et al., 2005). Accordingly, we predicted that the SIOR effect would be larger when performing the task with an in-group member than with an out-group member. The results confirmed our prediction by indicating that the co-actor's group membership modulated the SIOR effect. These findings are consistent with the notion that social factors play a critical role in producing the SIOR effect and provide a novel indication of the influence of social factors such as group membership on basic reflexive cognitive processes.


Acquired heat acclimation in rats subjected to physical exercise under environmental heat stress alleviates brain injury caused by exertional heat stroke.
Exertional heatstroke (EHS) is an emergency with a high mortality rate, characterized by central nervous system dysfunctions. This study aims to establish a Heat acclimation/acclimatization (HA) rat model in locomotion to recapitulate the physical state of human in severe environment of high temperature and humidity, and investigate the mechanism of organism protection in HA. (2) Methods: Wistar rats were exposed to 36 °C and ran 2 h/d for 21 days, acquired thermal tolerance test was conducted to assess the thermotolerance and exercise ability. Core temperature and consumption of water and food were observed. Expression of HSP70 and HSP90 of different tissues were determined by WB. Pathological structure of brain tissue was detected with HE staining. Proteomics was used to identify the differently expressed proteins in cerebral cortex of different groups. And key molecules were identified by RT-PCR and WB. (3) Results: HA rats displayed stronger thermotolerance and exercised ability on acquired thermal tolerance test. Brain water content of HA + EHS group reduced compared with EHS group. HE staining revealed slighter brain injuries of HA + EHS group than that of EHS. Proteomics focused on cell death-related pathways and key molecules Aquaporin 4 (AQP4) related to cell edema. Identification results showed HA increased AQP4, Bcl-xl, ratio of p-Akt/AKT and Bcl-xl/Bax, down-regulated Cleaved Caspase-3. (4) Conclusions: This HA model can ameliorate brain injury of EHS by reducing cerebral edema and cell apoptosis, offering experimental evidence for EHS prophylaxis.


Comprehensive tissue-specific proteome analysis of drought stress responses in Pennisetum glaucum (L.) R. Br. (Pearl millet).
Pearl millet is the fifth most important cereal crop worldwide and cultivated especially by small holder farmers in arid and semi-arid regions because of its drought and salt tolerance. The molecular mechanisms of drought stress tolerance in Pennisetum remain elusive. We have used a shotgun proteomics approach to investigate protein signatures from different tissues under drought and control conditions. Drought stressed plants showed significant changes in stomatal conductance and increased root growth compared to the control plants. Root, leaf and seed tissues were harvested and 2281 proteins were identified and quantified in total. Leaf tissue showed the largest number of significant changes (120), followed by roots (25) and seeds (10). Increased levels of root proteins involved in cell wall-, lipid-, secondary- and signaling metabolism and the concomitantly observed increased root length point to an impaired shoot-root communication under drought stress. The harvest index (HI) showed a significant reduction under drought stress. Proteins with a high correlation to the HI were identified using sparse partial least square (sPLS) analysis. Considering the importance of Pearl millet as a stress tolerant food crop, this study provides a first reference data set for future investigations of the underlying molecular mechanisms. Drought stress is the most limiting factor for plant growth and crop production worldwide. At the same time drought susceptible cereal crops are among the largest producers worldwide. In contrast, Pearl millet is a drought and salt tolerant cereal crop especially used in arid and semi-arid regions by small farmers. The multifactorial molecular mechanisms of this unique drought tolerance are not known. Here, we employ shotgun proteomics for a first characterization of the Pearl millet drought stress proteome. The experimental setup and the data set generated from this study reveal comprehensive physiological and proteomic responses of the drought stressed Pearl millet plants. Our study reveals statistically significant tissue-specific protein signatures during the adaptation to drought conditions. Thus, the work provides a first reference study of the drought stress proteome and related drought responsive proteins (DRP's) in Pearl millet.


Impact of the COVID-19 pandemic on cardiovascular mortality and catherization activity during the lockdown in central Germany: an observational study.
During the COVID-19 pandemic, hospital admissions for cardiac care have declined. However, effects on mortality are unclear. Thus, we sought to evaluate the impact of the lockdown period in central Germany on overall and cardiovascular deaths. Simultaneously we looked at catheterization activities in the same region. Data from 22 of 24 public health-authorities in central Germany were aggregated during the pandemic related lockdown period and compared to the same time period in 2019. Information on the total number of deaths and causes of death, including cardiovascular mortality, were collected. Additionally, we compared rates of hospitalization (n = 5178) for chronic coronary syndrome (CCS), acute coronary syndrome (ACS), and out of hospital cardiac arrest (OHCA) in 26 hospitals in this area. Data on 5,984 deaths occurring between March 23, 2020 and April 26, 2020 were evaluated. In comparison to the reference non-pandemic period in 2019 (deaths: n = 5832), there was a non-significant increase in all-cause mortality of 2.6% [incidence rate ratio (IRR) 1.03, 95% confidence interval (CI) 0.99-1.06; p = 0.16]. Cardiovascular and cardiac mortality increased significantly by 7.6% (IRR 1.08, 95%-CI 1.01-1.14; p = 0.02) and by 11.8% (IRR 1.12, 95%-CI 1.05-1.19; p < 0.001), respectively. During the same period, our data revealed a drop in cardiac catherization procedures. During the COVID-19-related lockdown a significant increase in cardiovascular mortality was observed in central Germany, whereas catherization activities were reduced. The mechanisms underlying both of these observations should be investigated further in order to better understand the effects of a pandemic-related lockdown and social-distancing restrictions on cardiovascular care and mortality.


Pyrimidine thioethers: A novel class of antidepressant agents, endowed with anxiolytic, performance enhancing and nootropic activity.
A series of new pyrimidine thioethers, recognized as the key intermediates in the synthesis of S-DABO antivirals, were prepared and evaluated both in vivo and in silico. The purpose of this evaluation was to find novel structural analogues of the known antihypoxic drug Isothiobarbamine endowed with improved pharmacological profile. The in vivo studies led to the identification of compounds 5c, 5e, and 5f endowed with antidepressant/anxiolytic, performance enhancing, and nootropic properties. Compounds 5c and 5f were further tested in mice affected by social depression and were able to increase motor and tentative search activity compared to control groups, along with higher interaction frequency and better results in a sucrose preference test. Overall, these data suggested a better psychoemotional state of the animals, treated with compounds 5c, and 5f. Moreover, 5c and 5f exhibited minimal acute toxicity, lower than Fluoxetine hydrochloride. Molecular modelling studies finally indicated the plausible biomolecular mechanism of action of compounds 5c, 5e, and 5f, which seem to bind GABA-A, melatonin, and sigma-1 receptors. Moreover, three-dimensional structure-activity relationships enabled to define a SAR model that will be of great utility for the design of further structurally optimized compounds of the above mentioned chemotype.


Comprehensive Index of Vocal Fatigue (CIVF): Development and Clinical Validation.
In this study, we sought to investigate whether auditory-perceptual and acoustic measures change after a passage-reading task and to develop a multidimensional index of performance fatigue in voice disorders. The clinical usefulness and cut-off scores of the newly developed index were also explored. A total of 150 patients (age = 35.65 ± 11.44 years) with voice disorders and 100 healthy controls (age = 35.04 ± 11.26 years) were enrolled in the study. Overall severity (OS) and acoustic measures of sentence samples were obtained before and after a passage-reading task and compared between the two positions. Acoustic features included cepstral peak prominence (CPP), σCPP, L/H spectral ratio (SR), and σSR. Using the changes (Δ) in those acoustic measures and the scores of the Vocal Fatigue Index (VFI), a predictive model of the ΔOS was established. The clinical cut-off point of the index was also identified. For the patient group, OS was higher, but CPP and σCPP were lower for the rear position (after reading the passage) compared to the front position (before reading the passage). A significant portion (adjusted R2 = 77.7%) of the ΔOS was predicted by ΔCPP, tiredness score of the VFI, ΔσCPP, ΔσSR, and ΔSR. The area under the curve of the newly developed index was .864 (sensitivity, 78.67%; specificity, 78.00%), and the index's criterion was >2.6489. The newly developed Comprehensive Index of Vocal Fatigue (CIVF) can quantify vocal fatigue in voice disorders, reflecting both acoustic and auditory perceptual changes after a passage-reading task. Further studies should explore the responsiveness of the CIVF and the impact of related factors on the CIVF in various voice disorders.


Spatial distribution of microplastics in a large watershed: a case study of the Ottawa River watershed.
River water was sampled at 105 locations in the Ottawa River watershed and analysed for microplastics. Sampling techniques were standardised and replicated at each sample location to give an indication of the spatial extent of microplastics at the watershed scale. Microplastic concentrations remained largely uniform, with no clear accumulation of microplastics towards the lower reaches of the watershed. An ANCOVA analysis determined that the only significant relationships to microplastic concentration were distance downstream on the main channel and tributaries and an increase of microplastic concentrations at boat launch locations. However, these relationships were not strong (R2 value of 0.15) and suggest a more complex interaction of microplastics in large watersheds. It is recommended that further research on microplastic pollution in rivers needs to also focus on temporal factors in addition to considering sinks as an important element in the distribution of microplastics at the watershed scale.


Public health and nuclear winter: addressing a catastrophic threat.
Despite the end of the Cold War, the world still has thousands of nuclear weapons and adversarial relations between the countries that possess them. A nuclear war could cause large and abrupt global environmental change known as nuclear winter, with potentially devastating public health consequences. A significant line of natural science research characterizes nuclear winter and its potential effect on global food security, but less has been done on the human impacts and policy implications. Therefore, this Viewpoint proposes an interdisciplinary research and policy agenda to understand and address the public health implications of nuclear winter. Public health research can apply existing tools developed for the study of other environmental and military issues. Public health policy institutions can help build preparedness and community resilience to nuclear winter. Given the extreme potential severity of nuclear winter, it should be treated as a major global public health challenge to be addressed by public health institutions and researchers.


Effects of chemical sympathectomy on hypertension and stroke in stroke-prone spontaneously hypertensive rats.
Neonates of male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with 6-hydroxydopamine (6-OHDA) on two different schedules. Peripheral sympathectomy, which was evaluated by the pressor response to exogenous noradrenaline (NA) or by the decrease in NA content of the spleen, was more evident in the NB-8 group (treated on 8th and 15th day after birth) than in the NB-1 group (treated at 6, 24 and 72 h after birth). The reduction of the NA content in the cerebral cortex was more prominent in the NB-1 group than in the NB-8 group. The blood pressure from 7 to 23 weeks of age was lower in the treated groups: NB-8 less than NB-1 less than control. Therefore, the reduction of blood pressure in the treated groups could be related to the severity of peripheral sympathectomy. The incidence of sroke was also lower in the treated groups: 38, 11 and 0% in the control NB-1 and NB-8 groups, respectively. Loading with 1% NaCl solution from 11 weeks of age enhanced the rise in blood pressure and increased the incidence of stroke in each group of rats: 100, 20 and 40% in the control. NB-1 and NB-8 groups, respectively. However, the onset of stroke after exhibiting a severe hypertension (greater than 200 mmHg) was delayed in the treated groups. It seems that the activated tone in the peripheral sympathetic nerve is likely to participate in the development of spontaneous hypertension. In addition to the high blood pressure level, the activated tone of sympathetic nerve innervating the cerebral vasculature may be partly involved in the development of stroke in the new strain of the SHR rats, SHRSP.


Immunological mechanisms and treatable traits of chronic rhinosinusitis in Asia: A narrative review.
To review the current literature on immunological mechanisms and treatable traits of chronic rhinosinusitis (CRS) in Asia. This is a narrative review of published data on the immunological mechanisms and treatable traits of CRS in Asia. Published English literature on CRS in Asian and Western countries was reviewed. Where available, the data extracted included epidemiology, immunology, bacterium, phenotype, endotype and treatment. CRS is a heterogeneous disease characterised by persistent locoregional mucosal inflammation of the paranasal sinuses. The inflammatory signatures of CRS vary across patients with distinct racial and ethnic backgrounds and geographic areas. Compared to CRS patients in Western countries, Asian CRS patients display less eosinophilic and Type 2 inflammation, which is associated with lower asthma and allergic rhinitis comorbidities. In contrast, Asian patients with CRS have more prominent non-eosinophilic inflammation than those in Western countries. In addition, Asian CRS patients may have different bacterial colonisation than patients in Western countries. Our review suggests that the distinct immunological mechanisms between Asian and Western CRS patients may influence the clinical phenotype, responses to treatment and outcomes. The treatable trait is a new strategy and therapeutic target identified by phenotype or endotype and has been proposed as a new paradigm for the management of diseases. Improved understanding of CRS phenotypic and endotypic heterogeneity and incorporation of treatable traits into clinical care pathways may facilitate more effective selections of therapeutic interventions, including surgery and biologics.


I drink alone: Mechanisms of risk for alcohol problems in solitary drinkers.
Although solitary drinking is less common than social drinking, it may be uniquely associated with heavy drinking and alcohol-related problems. There is also evidence that drinking contexts impact both expected and experienced alcohol effects. In particular, solitary drinking may be associated with an increased likelihood of drinking for negative reinforcement (e.g. to relieve stress). The current study examined how drinking context influences tension reduction expectancies and drinking motives, and the extent to which expectancies and motives mediate the link between solitary drinking and alcohol-related problems. We hypothesized that solitary drinking would be associated with greater tension reduction expectancies and coping motives which, in turn, would be associated with more alcohol related problems. Data were from 157 young adult moderate to heavy drinkers (21-30 years of age, 57% male) who completed baseline assessments in an alcohol administration study. A path model in Mplus tested the hypothesized mediated effects. Findings largely supported study hypotheses with significant indirect effects of solitary drinking (but not social drinking) on alcohol problems through stronger tension reduction expectancies and coping motives, though an indirect path through coping motives (but not expectancies) was also identified. Multi-group models by gender and race/ethnicity found that models operated similarly for men and women and for Non-Hispanic Caucasian and Racial/Ethnic Minority participants. The results provide important information about potential mechanisms through which solitary drinking may contribute to alcohol problems. These mechanisms represent potential targets of intervention (e.g. tension reduction expectancies, drinking to cope) for solitary drinkers.


Drug-fortified liposomes as carriers for sustained release of NSAIDs: The concept and its validation in the animal model for the treatment of arthritis.
Drug-fortified cationic liposomes of 6‑methoxy‑2‑naphthylacetic acid (6‑MNA) were prepared and characterized by various techniques. The residence time of drug-fortified liposomes in joint cavity was evaluated by intra-articular (IA) administration of the radio-labeled (99mTc) liposomal formulation in the inflamed joints in rats. The cationic liposomal formulation composed of 6‑MNA (3) as an active agent, its double salt (4) with the lipid 1,2‑distearoyl‑sn‑glycero‑3‑phosphoethanolamine (DSPE), and pharmaceutically acceptable excipients such as hydrogenated soyabean phospatidylcholine (HSPC) and 1,2‑dioleyloxy‑3‑trimethylammoniumpropane chloride (DOTAP) were developed using thin film hydration technique. The cryo-TEM analysis confirmed that the prepared optimized liposomal formulation (DFL-2) was a mixture of small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs). In addition, the TEM analysis confirmed that the prepared liposomes were of spherical in shape having liposome size in the range of 500-900 nm and zeta potential of about +30 mV. The developed cationic liposomes exhibited sustained release profile of payload of 6‑MNA for over >12 h and about five times higher retention in the inflamed animal joints after 24 h (by scintigraphy of the joints) as compared to the plain 6‑MNA solution when administered by IA route. The anti-inflammatory activity of prepared liposomal composition is evaluated by Freund's adjuvant induced arthritic model in rats. The liposomal formulation was well tolerated by all animals indicating good biocompatibility. Further, the cationic liposomal formulation treated group showed decreased erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level in comparison to the control and the standard groups in the in vivo study. The improved efficacy of the drug-fortified liposomal formulation was due to the coupled effect of longer retention and sustained release of the active drug 6‑MNA in the joints. From the obtained results it could be concluded that the combined effect of the cationic charge on the drug-fortified liposomes and the inherent affinity of the active agent towards the synovial joint tissues, coupled with slow release of the active drug due to double salt approach at the site of administration could potentially decrease the frequency of IA drug administration. Hence such a formulation could prove to be a therapeutic boon for the management of late stage arthritis.


Spinal cord stimulation and psychotropic medication use: Missing piece to the puzzle?
Psychotropic medications have modulatory effects on spinal cord stimulator (SCS) therapy and may play an important role in determining treatment success in chronic pain management. However, it remains unknown how SCS affects psychotropic use and whether the medications affect outcome. We performed a retrospective study to determine the prevalence of psychotropic medication (i.e. anxiolytic, antidepressant, and anticonvulsant) use among new SCS patients immediately before implantation and characterized the dosage changes at 1-year. We also sought to understand whether pre-operative medication status affects outcome, defined as device explantation due to treatment failure. In an analysis of 45 patients, 31%, 51% and 71% were actively taking anxiolytics, antidepressants, and anticonvulsants, respectively, before surgery. In the majority of cases, daily dosages remained the same for all three classes of medication at 1-year. Patients who were on two or more classes of medications pre-operatively had significantly lower explantation rate compared to those with one or none (12% vs. 43%, p = 0.041) and had 5.25 times less likelihood of explanation in the future (OR 5.25, 95%CI 1.18-23.2, p = 0.029). Our study suggest that peri-operative multimodality medical treatment may enhance the therapeutic efficacy and durability of SCS in carefully selected chronic pain patients.


Dose-dense chemotherapy for untreated poor-prognosis and relapsed germ-cell tumours: an 18-year experience with GAMEC chemotherapy.
To report a single-centre experience of the regimen GAMEC (granulocyte colony-stimulating factor, actinomycin-D, methotrexate with folinic acid rescue, etoposide and cisplatin) over 18 years in both untreated disease and relapse settings. This retrospective cohort study was based on 162 patients who received GAMEC dose-dense chemotherapy incorporating actinomycin and high dose methotrexate. Survival outcomes were compared. Risk categorization based on (1) the International Prognostic Factor Study Group (IPFSG) criteria and (2) two factors, lactate dehydrogenase (LDH) levels greater than the upper limit of normal and age ≥35 years, were also compared in terms of survival outcomes using Cox proportional hazard regression modelling. Seventy-five patients with poor-prognosis disease, according to International Germ Cell Cancer Collaborative Group classification, received GAMEC as initial therapy. With a median follow-up of 63 months, the median progression-free survival (PFS) was >14 months. The 2-year PFS rate was 61.5% (95% confidence interval [CI] 49.1-71.6), and the 3-year overall survival (OS) rate was 71.9%. Seventy-six patients received GAMEC as second-line therapy (following failure of bleomycin, etoposide and cisplatin or etoposide cisplatin). The median PFS was 7.5 months (95% CI 5.2-not evaluable), the 2-year PFS rate was 43.5% (95% CI 32.1-54.4) and the 3-year OS rate was 53.7% (95% CI 41.6-64.3). In the third-line setting (n = 11), the 2-year PFS was 18.2% (95% CI 2.8-44.2). Overall, the treatment-related death rate declined from 10.5% in the first 15 years to 2.6% in the last 5 years. GAMEC was an effective regimen in untreated poor-prognosis disease and on relapse following conventional cisplatin and etoposide-based chemotherapy. Risk categorization based on LDH/age is more sensitive than that based on the updated IPFSG criteria. It is possible to identify patients who are particularly likely to benefit from this treatment, which has the important advantages of short duration and absence of bleomycin, particularly in patients with central nervous system and mediastinal disease. Low-dose induction treatment is associated with safer delivery of treatment without compromising survival.


Applications of Resting-State Functional MR Imaging to Epilepsy.
We discuss the value of resting-state functional MR imaging (rsfMR imaging) as an emerging technique to address questions about memory and language that are central in surgery for temporal-lobe epilepsy, namely the identification and characterization of eloquent cortex to avoid surgical morbidity. The emergence of a robust set of data using rsfMR imaging has opened new avenues for exploring more direct relationships between neural networks and current cognitive function and prediction of postoperative change. These techniques are also being explored for their potential to characterize epilepsy subtypes, identify epileptic foci, and monitor treatment effects.


Antiaggressive effect of adjunctive clonazepam in schizophrenia associated with seizure disorder.
A case of schizophrenia associated with complex partial seizure disorder and postictal violence, both refractory to conventional treatment, is presented. Adjunctive treatment with clonazepam resulted in the cessation of the seizures and of persistent, violent hallucinations. The theoretical implications for possible mechanisms underlying at least some types of aggressive behavior are discussed.


Trimethyl 4,4',4''-(ethene-1,1,2-tri-yl)tribenzoate.
The title compound, C26H22O6, is formed as the major product from the reaction between syn-1,2-bis-(pinacolatoboron)-1,2-bis-(4-methyl-carb-oxy-phen-yl)ethene and excess methyl 4-iodo-benzoate in basic DMSO using a palladium catalyst at 80°C via Suzuki coupling followed by protodeboronation. Crystals were grown by slow evaporation of a hexa-nes solution at room temperature.


Analysis of the prognostic impact of tumor embolization before definitive radiotherapy for cervical carcinoma.
To assess whether embolization compromises the radiocurability of primary cervical cancer. Two hundred fifty-four patients with primary cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stages IB: 47; II: 91; IIIB: 102; IV: 14) were treated with external beam irradiation and Ir-192 high-dose-rate brachytherapy over a period of 15 years. Of these, 24 patients (9.4%) (FIGO stages IB: 1; II: 8; IIIB: 12; IV: 3) had had bilateral embolization of the internal iliac arteries before referral. The median age of the entire cohort was 66 years (range, 34-85 years). Tumor size was >5 cm and paraortic nodes were enlarged (> or =1 cm) on pretreatment CAT scan in 39.4% and 9.1% of patients, respectively. All patients with hemoglobin levels (hb-l) < or =11 g/dL (28.3%) received packed red cell transfusions (PRCT) before and/or during radiotherapy in an attempt to maintain levels >11 g/dL throughout treatment. Cross-table tests were used to compare the distribution of FIGO stage, tumor size, lymph node status, and pretreatment and treatment hb-l of embolized and nonembolized patients. The impact of embolization, along with the above-listed tumor characteristics, on disease-specific survival (DSS), pelvic control (PC), and distant metastases-free survival (MFS) was determined by univariate and multivariate analyses. Embolized patients presented at a statistically significant younger median age (55 vs. 67 years; p = 0.003), with larger tumors (66.7% vs. 36.5%; p = 0.007), and lower pretreatment hb-l (75% vs. 23.5%; p < 0.001) than nonembolized patients. There was no significant difference in stage distribution or lymph node status, and although embolized patients responded better to PRCT (50% vs. 29.6%), this difference was not statistically significant. Univariate analysis showed a trend toward decreased DSS (p = 0.09) and PC (p = 0.07) for embolized patients but no effect on MFS, whereas all other variables tested were significantly correlated with DSS, PC, and MFS (all p < 0.001). In the multivariate model, tumor embolization, FIGO stage, and pretreatment hb-l ceased to impact significantly on outcome. Tumor size remained the most powerful independent predictor for all endpoints tested, followed by treatment hb-l. Paraortic node status was significantly correlated with DSS and MFS. Although a trend toward poorer DSS and PC was observed in embolized patients, no impact on radiocurability could be demonstrated in multivariate analysis after controlling for the major tumor characteristics and treatment hb-l.


Glucose-free dialysis solutions: inductors of inflammation or preservers of peritoneal membrane?
Glucose and other bioincompatible factors of conventional peritoneal dialysis solutions may damage the peritoneal membrane. The aim of our study was to investigate whether replacement of glucose with icodextrin (ID) or amino acids (AA) affects inflammatory parameters or cancer antigen 125 (CA125). Either ID or AA was used, in random order, in one daily exchange during an 8-week period. After the first study period, the patients entered a washout period and then switched to the other study solution for an 8-week period. C-reactive protein (CRP) was measured in serum, and CA125, tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), and hyaluronan (HA) were measured in the overnight dwell dialysates at the beginning and end of the study periods. A university hospital. 22 patients with duration on peritoneal dialysis of 1.5 - 6.3 months. Levels of serum CRP and dialysate CA125, IL-6, HA, and sICAM-1 during use of ID and AA were compared to levels during use of glucose-only-based solutions. CRP increased significantly during use of ID. CA125 increased significantly during 8 weeks' use of AA, from 22.8 (5.4 - 89.0) to 42.9 (7.1 - 92.9) kU/L (p = 0.007). IL-6 increased during 8 weeks' use of AA, from 22.0 (9.0 - 108.0) to 36.5 (14.0 - 93.0) ng/L (p = 0.002) and ID, from 25.5 (8.0 - 82.0) to 40.0 (12.0 - 118.0) ng/L (p = 0.008). TNF-alpha also increased significantly during use of ID, but showed no significant changes during use of AA. The use of glucose-free solutions, especially AA, may lead to preservation of mesothelial cell mass and host defense. However, activation of systemic and peritoneal inflammation may appear during the use of ID and to a lesser extent during use of AA.


Change in metabolic parameters after switching from triple regimens with tenofovir alafenamide to dolutegravir-based dual therapy. Bi-lipid study.
The use of tenofovir alafenamide (TAF) has been associated with increased cholesterol and body weight. Real-life data on the metabolic effects of switching from a TAF-based triple regimen to a dolutegravir (DTG)-based two-drug regimen (2-DR) are scarce. A retrospective cohort study of patients who have switched from a triple TAF-based regimen to a 2-DR [DTG-lamivudine (DTG-3TC) or DTG- rilpivirine (DTG-RPV]) with at least 6 months of follow-up. The primary endpoint was the absolute change in lipid fractions at 6 months. Secondary outcomes were percentage changes in lipid fraction, effectiveness and safety at 6 and 12 months [intention to treat (ITT), missing = failures]. A total of 118 patients (87 on DTG-3TC, 31 on DTG-RPV) were included. Median age was 51 years (interquartile range: 43-59), 86% were male, CD4 T-cell count was 692 cells/μL, and 98% viral load (VL) < 50 copies/mL. At 6 months there was a decrease in total and low-density lipoprotein cholesterol of 10.7 mg/dL [95% confidence interval (CI): 2.2-19.1; p ≤ 0.001] and 8.3 mg/dL (95% CI: 0.74-15.9; p = 0.026), respectively. There was a reduction in cardiovascular risk from 4.5% at baseline to 4% at 12 months (p = 0.040). Virological effectiveness as determined by ITT analysis was 85.6% at 6 months and 66.1% at 12 months. Seven patients (5.9%) withdrew from the 2-DR and there was no virological failure. In real life, switching from a triple regimen with TAF to DTG-3TC or DTG-RPV dual therapy improves the lipid profile and is an effective and well-tolerated strategy.


Phototherapy for Cutaneous T-Cell Lymphoma.
Phototherapy with psoralen and ultraviolet A (PUVA) or narrowband-UVB (NBUVB) is frequently used for the patch and plaque stages of mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma. This article provides practical guidelines for the design and implementation of a phototherapy protocol for early stage MF, including an overview of treatment phases, response criteria, and considerations in the selection of a light source. Several evolving topics in phototherapy research are also discussed, including the relative efficacy of PUVA versus NBUVB, the role of maintenance therapy, risk of photocarcinogenicity, and combination therapies.


Predictors of success in hypertensives treated with biofeedback-assisted relaxation.
This paper describes differences in response in seventeen patients with essential hypertension who participated in a treatment program consisting of electromyograph biofeedback assisted relaxation training. Responders were found to have higher treatment values of urinary and plasma cortisol, Trait Anxiety and forehead muscle tension compared to treatment failures. Responders also sustained greater decreases in plasma, and urinary cortisol after treatment. These data are discussed in light of the ability to predict which hypertensive patients may be most benefitted by a relaxation based treatment.


Establishment of a high-sensitivity reporter system in mammalian cells for detecting juvenoids using juvenile hormone receptors of Daphnia pulex.
Environmental waters are polluted by various chemicals originating from human activities. Recently, the environmental risk of juvenile hormones (JHs) to aquatic microcrustaceans has been recognized by risk assessors and researchers. JH is a major arthropod hormone that regulates molting and reproduction and has analogs that have been used as insect growth regulators. JHs are known to disturb the sex determination system of Daphnia, which is a keystone animal in limnetic ecosystems and is not the target of extermination. To assess the risk of contaminant chemicals and to protect biodiversity, reliable methods for detecting such chemicals are essential. In this study, we attempted to establish a practical in vitro reporter assay system for detecting chemicals with JH activity. Using a newly constructed reporter vector (modified from the JH response element of Tribolium castaneum Krüppel homolog 1, which is a major JH responsive gene in insects), strong JH-dependent transcriptional activity (>40-fold activation) was found in Chinese hamster ovary cells that express JH receptors of Daphnia pulex. Dose-response analysis conducted on several JH and non-JH chemicals revealed that the established reporter assay system has strict specificity to JH chemicals, and the half maximum effective concentration (EC50 ) was between 10-7 and 10-9 m. These results suggest that the new system is a rapid and economical method for assessing the environmental risk of JH-active chemicals.


Atypical presentations of parathyroid gland pathology: A pictorial review.
Primary hyperparathyroidism is associated with significant morbidity and mortality. It is in this day and age, an eminently treatable condition which relies heavily on preoperative imaging to localise enlarged parathyroid glands. The imaging appearances of parathyroid gland enlargement are varied; this paper seeks to address some of its more unusual manifestations with an emphasis on its atypical enhancement patterns, mimics and associations. An enlarged glands may also present as an 'incidentaloma' in head and neck imaging performed for entirely different indications, or as part of sporadic or familial syndrome. Radiologists are in a good position to expedite the relevant investigations and curative treatment, and knowledge of the spectrum of imaging appearances is crucial.


Aluminofluoride activates hyperpolarization- and stretch-activated cationic channels in single smooth muscle cells.
Aluminofluoride (AF) has a variety of biological actions such as activation of GTP binding proteins and inhibition of phosphatases. In the present study, the effects of AF on hyper-polarization- and stretch-activated cationic channels (HA-SACs) were investigated in isolated gastric smooth muscle cells from the toad, Bufo marinus, using the patch-clamp technique. In cell-attached patches extracellular application of AF (20 mM KF plus 20 microM AlCl3) reversibly increased HA-SAC activity without changing its voltage sensitivity. The single channel current amplitude of HA-SACs was not affected during this procedure. The mechanism of AF-induced activation of HA-SACs remains unclear. However, this activation may play a role in contraction of smooth muscle induced by AF.


Value of High-Frequency Ultrasonography in the Qualitative and Semi-Quantitative Assessment of Immunoglobulin G4-Related Submandibular Sialadenitis.
To assess the value of high-frequency ultrasonography in the evaluation of immunoglobulin G4-related submandibular sialadenitis (IgG4-SS). Thirty-four submandibular glands in 17 patients with IgG4-SS were retrospectively enrolled, as well as 34 submandibular glands in 17 healthy control subjects. Qualitative ultrasonic features including submandibular gland size, border, echogenicity, and vascularity were reviewed. Two different scoring systems (0-16 and 0-48, respectively) were used for semi-quantitative analysis of imaging features. Comparison of both qualitative and semi-quantitative ultrasonic analysis were made between patients with IgG4-SS and healthy controls. Spearman correlation was used to explore relationships between variables. The submandibular glands with IgG4-SS presented with enlarged size, rough border, increased vascularity, and abnormal echogenicity (All P < .05). The most common echogenicity pattern for IgG-SS was diffuse hypoechoic foci pattern (44.1%), followed by superficial hypoechoic pattern (20.6%), tumor-like pattern (14.7%), and diffuse hypoechogenicity pattern (11.8%). Most IgG4-SS glands presented linear hyperechogenicity in parenchyma (91.2%). Based on both scoring system, scores of IgG4-SS were significantly higher than those of the controls (All P < .05). Association analysis of both scoring systems showed positive correlation of scores with vascularity in the gland parenchyma (All P < .05). The ultrasonic features of IgG4-SS comprise enlarged gland, rough border, increased vascularity, and abnormal echogenicity, which correlate with its pathological characteristics. The most common echogenicity pattern for IgG4-SS was diffuse hypoechoic foci pattern. Semi-quantitative analysis systems could be useful in the assessment of IgG4-SS. Ultrasound is a potential, valuable, and non-invasive tool for the diagnosis and evaluation of IgG4-SS.


Seroconversion rate after vaccination against COVID-19 in patients with cancer-a systematic review.
Coronavirus disease 2019 (COVID-19) has affected >210 million people worldwide. An optimal therapeutic approach for COVID-19 remains uncertain, to date. Since the history of cancer was linked to higher mortality rates due to COVID-19, the establishment of a safe and effective vaccine coverage is crucial in these patients. However, patients with cancer (PsC) were mostly excluded from vaccine candidates' clinical trials. This systematic review aims to investigate the current available evidence about the immunogenicity of COVID-19 vaccines in PsC. All prospective studies that evaluated the safety and efficacy of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were included, with immunogenicity after the first and the second dose as the primary endpoint, when available. Vaccination against COVID-19 for PsC seems overall safe and immunogenic after well-conducted vaccination schedules. Yet the seroconversion rate remains lower, lagged or both compared to the general population. Patients with hematologic malignancies, especially those receiving B-cell-depleting agents in the past 12 months, are the most at risk of poor seroconversion. A tailored approach to vaccination may be proposed to PsC, especially on the basis of the type of malignancy and of the specific oncologic treatments received.