Mental Health Conditions and Hyperthyroidism.
To evaluate the proportion of pediatric patients with concurrent diagnoses of hyperthyroidism and mental health conditions (MHCs) by using the Military Health System database. We hypothesized that the prevalence of mental health disorders would be higher in patients with hyperthyroidism compared with in the nonhyperthyroid population. The prevalence of hyperthyroidism and MHCs was calculated by using data extracted from the Military Health System Data Repository on military beneficiaries between 10 and 18 years old who were eligible to receive care for at least 1 month during fiscal years 2008 through 2016. Prevalence ratios were used to compare MHC diagnoses in those with versus without a diagnosis of hyperthyroidism. There were 1894 female patients and 585 male patients diagnosed with hyperthyroidism during the study period. Prevalence ratios for MHCs in those with versus without hyperthyroidism ranged from 1.7 (attention-deficit/hyperactivity disorder [ADHD]) to 4.9 (bipolar disorder). Strikingly, suicidality was nearly 5 times more likely in patients diagnosed with hyperthyroidism than in patients who were never diagnosed with hyperthyroidism. For each of the MHCs examined, with the exception of suicidality, the MHC diagnosis was more commonly made before the diagnosis of hyperthyroidism, with the highest proportion of patients being diagnosed with ADHD before receiving a diagnosis of hyperthyroidism (68.3%). There is a clear association between hyperthyroidism and each of the following MHCs: ADHD, adjustment disorder, anxiety, bipolar disorder, depression, and suicidality. This study highlights the need to consider this association when evaluating patients with overlapping symptoms and for effective mental health screening tools and resources for clinicians.


Prospective multicentre cross-sectional audit among older Australians accessing health and residential aged care services: protocol for a national advance care directive prevalence study.
Advance care planning (ACP), an ongoing communication and planning process, aims to clarify a person's values and preferences, so these guide decision-making if the person becomes unable to make his or her own decisions. Ideally, ACP results in completion of advance care directives (ACD), documents completed by competent people outlining their values, treatment preferences and/or appointment of a substitute decision-maker (SDM). ACDs are most effective at the point of care, where they can be used to inform treatment decisions. Australian governments fund initiatives and have developed policy to increase ACD completion rates. However, little is known about the prevalence of ACDs at the point of care in Australian health services, making ACP evaluation efforts difficult. This study aims to determine the prevalence of ACDs in records of older people in Australian hospitals, aged care facilities and general practices. This is a national multicentre cross-sectional prevalence study in selected aged care facilities, hospitals and general practices. Following a 2017 feasibility study, a new protocol incorporating key learnings was developed. Sites will be recruited via expression of interest process. Health records of people aged ≥65 years, admitted to or attending services on study day(s) will be audited by trained staff from sites. Site-level data will be collected during the expression of interest. The primary outcome is the presence of at least one ACD in the health record. Secondary outcomes include prevalence of other documented outcomes of ACP (by health practitioner(s)/family/SDM), assessment of ACD quality and content and concordance between the person's documented preferences and any medical treatment orders. Individuals and sites characteristics where ACDs are present will be explored. Protocol approval by Austin Health Human Research Ethics Committee, Melbourne, Australia (reference: HREC/18/Austin/109). Results will be disseminated via peer-reviewed journals and conferences. Participating sites and jurisdictions will receive individualised reports of findings.


Charge inversion of phospholipids by dimetal complexes for positive ion-mode electrospray ionization mass spectrometry analysis.
Phospholipids are vital constituents of living cells, as they are involved in signaling and membrane formation. Mass spectrometry analysis of many phospholipids is preferentially performed in the negative ion-mode because of their acidic nature. Here we have studied the potential of a digallium and dizinc complex to charge-invert a range of different types of phospholipids and measured their ion yield and fragmentation behavior in positive ion-mode tandem mass spectrometry. The dimetal complexes bind specifically the phosphate groups of phospholipids and add an excess of up to three positive charges per phosphate group. Three different phosphoinositide phosphates (mono-, di-, and triphosphorylated inositides), a phosphatidic acid, a phosphatidylcholine, a phosphatidylethanolamine, and a phosphatidylglycerol were investigated. The intensities obtained in positive ion-mode of phosphoinositide phosphates and phosphatidic acid bound to {LGa2}(5+) were between 2.5- and 116-fold higher than that of the unmodified lipids in the negative ion-mode. Native phosphoinositide ions yielded upon CID in the negative ion-mode predominantly product ions due to losses of H3PO4, PO3(-) and H2O. In comparison, CID spectra of {LGa2}(5+)-bound phosphoinositides generally resulted in fragment ions corresponding to loss of the full diglyceride chain as well as the remaining headgroup bound to {LGa2}(5+) as the most abundant peaks. A number of signature fragment ions of moderate abundance were observed that allowed for distinction between the three regioisomers of 1,2-di(9Z-octadecenoyl)-sn-glycero-3-[phosphoinositol-x,y-bisphosphate] (PI(3,4)P2, PI(3,5)P2, PI(4,5)P2).


Outcomes monitoring of health, behavior, and quality of life after nutrition intervention in adults with type 2 diabetes.
To examine changes in health and lifestyle indicators over 6 months in persons with type 2 diabetes mellitus receiving nutrition counseling from a registered dietitian, and to promote dietetics professionals' participation in outcomes monitoring and research. Prospective, noncontrolled descriptive study. Two hundred forty-four physician-referred adults with type 2 diabetes mellitus from 31 sites who received usual and customary nutrition counseling, and 83 registered dietitians. Glycemic control, coronary heart disease risk, self-management behaviors, and quality of life were measured at baseline, 3 months, and 6 months. Dietitians' perceptions of the study were also measured. Repeated-measures analysis of variance, paired t test, Wilcoxon signed rank test, sign test, Spearman correlation, and chi 2 analysis were conducted. Weight and glycemic control, coronary heart disease risk, and self-management behaviors improved significantly between baseline and 3 months and baseline and 6 months. Weight, body mass index, and glycosylated hemoglobin value also improved significantly between 3 months and 6 months. Increased time and/or number of sessions with the registered dietitian were associated with weight loss and reduced glycosylated hemoglobin, fasting plasma glucose, total cholesterol, and triglyceride levels. Self-perceived health status and missed workdays were significantly improved at 6 months. Difficulty obtaining current laboratory values, lack of time, and inability to reach subjects for follow-up presented the greatest obstacles for the dietitians. Positive outcomes were observed in adults receiving nutrition intervention for type 2 diabetes. Clinical improvements were greatest between baseline and 3 months, with stabilization between 3 months and 6 months, suggesting ongoing intervention is needed to support continued clinical progress. Dietitians found participation in this state affiliate-coordinated research project rewarding.


[Achievement of the elimination of tropical malaria in The Republic of Tajikistan].
To achieve the elimination of tropical malaria, Tajikistan divided its territory into districts in terms of the malariogenic potential (receptivity + vulnerability) and identified priority regions to be exposed, determined the population's fever background and the required personnel, equipment, and reagents for parasitological examinations, and compiled an inventory of malaria foci. The investigators tested a new (artesunate + sulfadoxine-pyrimethamine) treatment regimen in patients with tropical malaria and in parasite carriers and established active detection of malaria cases through homestead rounds and population examinations. The packages of antimalarial measures were improved, by annually evaluating their efficiency in accordance with the monitoring and estimation indicators.


Infectious and non-infectious complications in primary immunodeficiency disorders: an autopsy study from North India.
Primary immunodeficiency disorders (PID) include a wide spectrum of inherited disorders characterised by functional abnormalities of one or more components of the immune system. Recent updates from the genomic data have contributed significantly to its better understanding with identification of new entities. Diagnosis is always challenging due to their variable clinical presentation. With the evolution of molecular diagnosis, many of these children are being diagnosed early and offered appropriate therapy. However, in developing countries, early diagnosis is still not being made: as a result these patients succumb to their disease. Autopsy data on PID is notably lacking in the literature with histopathological evaluation of PID being limited to rare case reports. To analyse the clinical, immunologic (including mutational) and morphologic features at autopsy in 10 proven and suspected cases of primary immunodeficiency disorders diagnosed at our Institute over the past decade. Study includes a detailed clinico-pathological analysis of 10 proven and suspected cases of primary immunodeficiency disorders. A varied spectrum of infectious and non-infectious complications were identified in these cases of which fungal infections were found to be more frequent compared with viral or bacterial infections. Rare and novel morphological findings, like granulomatous involvement of the heart in a patient with chronic granulomatous disease, systemic amyloidosis in a teenage girl with X-linked agammaglobulinemia, are highlighted which is distinctly lacking in the literature. The present study is perhaps the first autopsy series on PID. Even in the molecular era, such analysis is still important, as correlation of pathological features with clinical symptoms provides clues for a timely diagnosis and appropriate therapeutic intervention.


Production of extracellular and total invertase by Candida utilis, Saccharomyces cerevisiae, and other yeasts.
Some strains of Candida utilis produce exceptionally large amounts of extracellular and total invertase. Strain Y-900 of C. utilis produces high yields whether the carbon source is sucrose, glucose, maltose, or xylose and still higher yields with lactic acid, glycerol, and ethyl alcohol. Approximately 20 to 30% of the total invertase of C. utilis is extracellular. Strains of Saccharomyces cerevisiae and Saccharomyces carlsbergensis are generally inferior to C. utilis in production of extracellular and total invertase, the difference being accentuated in shaken cultures. The industrial yeasts are generally superior in invertase production to the other yeasts included in the survey.


Gene flow and the genealogical history of Heliconius heurippa.
The neotropical butterfly Heliconius heurippa has a hybrid colour pattern, which also contributes to reproductive isolation, making it a likely example of hybrid speciation. Here we used phylogenetic and coalescent-based analyses of multilocus sequence data to investigate the origin of H. heurippa. We sequenced a mitochondrial region (CoI and CoII), a sex-linked locus (Tpi) and two autosomal loci (w and sd) from H. heurippa and the putative parental species, H. cydno and H. melpomene. These were analysed in combination with data from two previously sequenced autosomal loci, Dll and Inv. H. heurippa was monophyletic at mtDNA and Tpi, but showed a shared distribution of alleles derived from both parental lineages at all four autosomal loci. Estimates of genetic differentiation showed that H. heurippa is closer to H. cydno at mtDNA and three autosomal loci, intermediate at Tpi, and closer to H. melpomene at Dll. Using coalescent simulations with the Isolation-Migration model (IM), we attempted to establish the incidence of gene flow in the origin of H. heurippa. This analysis suggested that ongoing introgression is frequent between all three species and variable in extent between loci. Introgression, which is a necessary precursor of hybrid speciation, seems to have also blurred the coalescent history of these species. The origin of Heliconius heurippa may have been restricted to introgression of few colour pattern genes from H. melpomene into the H. cydno genome, with little evidence of genomic mosaicism.


Meaning and its measurement in psychosocial oncology.
Although 'meaning' is a construct that has been referred to for many years within psychological research, particularly in work to examine the ways in which individuals respond to crises or illness, it is only relatively recently that this has started to appear within the psychosocial oncology literature. Where the term has been used, there has been much variation in the way in which this has been operationalised and measured (a problem that has been evident within other areas of psychosocial oncology). This article will review some of the self-report measures that have been developed to assess levels of meaning, outlining their background and status regarding psychometric performance. This will be followed by some recommendations on measures that are particularly suited for use in further work. It is suggested that their application to examine conceptual issues of will be more productive if researchers aim to develop existing measures and not to create new measures. Use of those measures with better psychometric properties could in time facilitate larger data sets and allow for cross cultural comparisons of the impact of cancer on global and situational meaning. Specific recommendations are made for measures to be used in the assessment of global and situational meaning in cancer.


Addressing Competing Risks When Assessing the Impact of Health Services Interventions on Hospital Length of Stay.
Although hospital length of stay is generally modeled continuously, it is increasingly recommended that length of stay should be considered a time-to-event outcome (i.e., time to discharge). Additionally, in-hospital mortality is a competing risk that makes it impossible for a patient to be discharged alive. We estimated the effect of trauma center accreditation on risk of being discharged alive while considering in-hospital mortality as a competing risk. We also compared these results with those from the "naive" approach, with length of stay modeled continuously. Data include admissions to a level I trauma center in Quebec, Canada, between 2008 and 2017. We computed standardized risk of being discharged alive at specific days by combining inverse probability weighting and the Aalen-Johansen estimator of the cumulative incidence function. We estimated effect of accreditation using pre-post, interrupted time series (ITS) analyses, and the "naive" approach. Among 5,300 admissions, 12% died, and 83% were discharged alive within 60 days. Following accreditation, we observed increases in risk of discharge between the 7th day (4.5% [95% CI = 2.3, 6.6]) and 30th day since admission 3.8% (95% CI = 1.5, 6.2). We also observed a stable decrease in hospital mortality, -1.9% (95% CI = -3.6, -0.11) at the 14th day. Although pre-post and ITS produced similar results, we observed contradictory associations with the naive approach. Treating length of stay as time to discharge allows for estimation of risk of being discharged alive at specific days after admission while accounting for competing risk of death.


Use of human tissue to assess the oncogenic activity of melanoma-associated mutations.
Multiple genetic alterations occur in melanoma, a lethal skin malignancy of increasing incidence. These include mutations that activate Ras and two of its effector cascades, Raf and phosphoinositide 3-kinase (PI3K). Induction of Ras and Raf can be caused by active N-Ras and B-Raf mutants as well as by gene amplification. Activation of PI3K pathway components occurs by PTEN loss and by AKT3 amplification. Melanomas also commonly show impairment of the p16(INK4A)-CDK4-Rb and ARF-HDM2-p53 tumor suppressor pathways. CDKN2A mutations can produce p16(INK4A) and ARF protein loss. Rb bypass can also occur through activating CDK4 mutations as well as by CDK4 amplification. In addition to ARF deletion, p53 pathway disruption can result from dominant negative TP53 mutations. TERT amplification also occurs in melanoma. The extent to which these mutations can induce human melanocytic neoplasia is unknown. Here we characterize pathways sufficient to generate human melanocytic neoplasia and show that genetically altered human tissue facilitates functional analysis of mutations observed in human tumors.


Square wave voltammetry versus electrochemical impedance spectroscopy as a rapid detection technique at electrochemical immunosensors.
Square wave voltammetry (SWV) was compared to electrochemical impedance spectroscopy (EIS) in developing a label-free electrochemical immunosensor for the hormone estradiol. The immunosensor consists of a Au electrode anchored with a Au nanoparticle|thiolated Protein G-scaffold to facilitate immobilisation of an enhanced quantity of an almost uprightly aligned anti-estradiol capture antibody. Competitive immunoassays between an estradiol-bovine saline albumin complex and free estradiol in a sample were then promoted at the immunosensor. Next, SWV and EIS of [Fe(CN)(6)](3-/4-) were sequentially conducted at the immunosensor. SWV yielded familiar peak-shaped voltammograms with the peak currents readily employable in establishing calibration. A dynamic range up to approximately 1200 pg mL(-1) and a detection limit of 18 pg mL(-1) estradiol were achieved. In EIS, an electron transfer resistance estimated from the Nyquist plots was used in the calibration experiments. A comparable dynamic range up to approximately 1000 pg mL(-1) and a detection limit of 26 pg mL(-1) estradiol were obtained. However, a significantly 10 times longer analysis time and substantial effort were required to complete the EIS determinations relative to SWV. Moreover, a large amount of EIS data involving phase angle was collected but ignored because they would not contribute any useful information to quantitative determination. Overall, SWV was determined to be a more rapid, efficient, effective and low cost detection technique than EIS at label-free electrochemical immunosensors.


The influence of weather conditions on the activity of high-arctic arthropods inferred from long-term observations.
Climate change is particularly pronounced in the High Arctic and a better understanding of the repercussions on ecological processes like herbivory, predation and pollination is needed. Arthropods play an important role in the high-arctic ecosystem and this role is determined by their density and activity. However, density and activity may be sensitive to separate components of climate. Earlier emergence due to advanced timing of snowmelt following climate change may expose adult arthropods to unchanged temperatures but higher levels of radiation. The capture rate of arthropods in passive open traps like pitfall trap integrates density and activity and, therefore, serves as a proxy of the magnitude of such arthropod-related ecological processes. We used arthropod pitfall trapping data and weather data from 10 seasons in high-arctic Greenland to identify climatic effects on the activity pattern of nine arthropod taxa. We were able to statistically separate the variation in capture rates into a non-linear component of capture date (density) and a linear component of weather (activity). The non-linear proxy of density always accounted for more of the variation than the linear component of weather. After accounting for the seasonal phenological development, the most important weather variable influencing the capture rate of flying arthropods was temperature, while surface-dwelling species were principally influenced by solar radiation. Consistent with previous findings, air temperature best explained variation in the activity level of flying insects. An advancement of the phenology in this group due to earlier snowmelt will make individuals appear earlier in the season, but parallel temperature increases could mean that individuals are exposed to similar temperatures. Hence, the effect of climatic changes on the activity pattern in this group may be unchanged. In contrast, we found that solar radiation is a better proxy of activity levels than air temperature in surface-dwelling arthropods. An advancement of the phenology may expose surface-dwelling arthropods to higher levels of solar radiation, which suggest that their locomotory performance is enhanced and their contribution to ecological processes is increased.


Abnormal vitamin B(6) status is associated with severity of symptoms in patients with rheumatoid arthritis.
Patients with rheumatoid arthritis have low plasma vitamin B(6) levels and elevated plasma homocysteine responses to a methionine load. We examined whether these abnormalities are associated with clinical and biochemical indicators of disease status. We performed a cross-sectional study in 37 patients who met the American College of Rheumatology criteria for rheumatoid arthritis. Vitamin B(6) status was assessed by the plasma pyridoxal 5'-phosphate level and with the homocysteine response to a methionine load test. Clinical disease activity was assessed by joint counts, the Health Assessment Questionnaire disability score, and biochemical markers of the acute phase response. Plasma pyridoxal 5'-phosphate levels were inversely correlated with the erythrocyte sedimentation rate (r = -0.37, P = 0.02), C-reactive protein level (r = -0.52, P = 0.002), disability score (r = -0.37, P = 0.02), morning stiffness (r = -0.38, P = 0.02), and degree of pain (r = -0.33, P = 0.04). The increase in homocysteine levels after a methionine load correlated with the erythrocyte sedimentation rate (r = 0.39, P = 0.02), C-reactive protein level (r = 0.37, P = 0.03), disability score (r = 0.37, P = 0.04), degree of pain (r = 0.38, P = 0.02) and fatigue (r = 0.42, P = 0.01), number of painful joints (r = 0.43, P = 0.007), and number of swollen joints (r = 0.32, P = 0.05). Markers of vitamin B(6) status are associated with disease activity and severity, synovial burden, and pain in patients with rheumatoid arthritis, raising the possibility that impaired vitamin B(6) status in these patients is a result of inflammation.


Quantification of Hepatic UDP glucuronosyltransferase 1A splice variant expression and correlation of UDP glucuronosyltransferase 1A1 variant expression with glucuronidation activity.
The UDP glucuronosyltransferase (UGT) 1A gene cluster encodes nine UGT1A family members via splicing of individual first exons to common exons 2 through 5. Each of these nine UGT1As can also undergo alternative splicing at their 3' ends by using an alternate exon 5, resulting in 27 different UGT1A mRNA species with each UGT1A gene encoding three different combinations of 5A and 5B UGT1A exons. To examine the importance of UGT1A exon 5 splice variants on overall UGT1A activity, a nested quantitative polymerase chain reaction assay was developed to accurately assess the combined expression of exon 5 splice variants (termed v2/v3) versus the expression of wild-type (termed v1) for each specific UGT1A. v1 expression was 16-, 17-, 57- and 29-fold higher than that observed for the levels of v2/v3 for UGTs 1A1, 1A4, 1A6, and 1A9, respectively, in normal human liver specimens. In a series of 58 normal human liver specimens, the expression of both UGT1A1 v1 and v2/v3 mRNAs was positively correlated with raloxifene glucuronidation activity in corresponding microsomes prepared from the same specimens (p < 0.0001, r² = 0.720; p = 0.0002, r² = 0.241, respectively), with expression of both variants lower in individuals homozygous for the UGT1A1*28 allele (42% for v1, p = 0.041; 53% for v2/v3, p = 0.0075). The expression of UGT1A1 v2/v3 was 1.6-fold higher than v1 (p = 0.03) in HepG2 cells, and short interfering RNA knockdown of HepG2 v2/v3 increased raloxifene glucuronidation activity by 83%. Together, these data suggest that hepatic UGT1A v2/v3 mRNA species are minor form variants in human livers from most individuals.


Correlation between increased nitric oxide production and markers of endothelial activation in systemic sclerosis: findings with the soluble adhesion molecules E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1.
To determine the relationship between vascular function and the inflammatory response in systemic sclerosis (SSc), and to investigate whether production of endothelial-derived nitric oxide (NO) is disturbed in this disease. We measured plasma nitrate, urinary excretion of both nitrate and cGMP, and soluble adhesion molecules of endothelial origin in patients with SSc and in age- and sex-matched controls and compared these levels between groups. Additionally, we performed correlation analysis to determine how these variables were related to one another. Plasma nitrate and 24-hour-urinary excretion of nitrate in patients and controls were measured after a 72-hour nitrate-free-diet, using a gas chromatography/mass spectrometric method. Soluble adhesion molecules intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1 (sVCAM-1), and E-selectin and cytokines were measured by enzyme-linked immunosorbent assay. The expression of E-selectin was further investigated in skin biopsy specimens by immunoperoxidase staining, and the presence of inducible NO synthase by immunoblotting. Plasma nitrate and 24-hour-urinary-excretion of cGMP were significantly elevated in patients compared with controls, while 24-hour-urinary-excretion of nitrate tended to be elevated in SSc patients. Levels of sICAM-1, sVCAM-1, and sE-selectin were significantly elevated in the patients. Levels of plasma nitrate in the patients correlated significantly with levels of sVCAM-1 (P = 0.020) and sE-selectin (P = 0.018) and approached a significant correlation with sICAM-1 (P = 0.055), suggesting that activated endothelial cells may produce plasma nitrate. NO synthesis is elevated in SSc patients, and the activated endothelial cell is a likely site of its production.


Changes in the loads on an internal spinal fixator after iliac-crest autograft.
Spines are often stabilised posteriorly by internal fixation and anteriorly by a bone graft. The effect of an autologous bone graft from the iliac crest on implant loads is unknown. We used an internal spinal fixation device with telemetry to measure implant loads for several body positions and activities in nine patients before and after anterior interbody fusion. With the body upright, implant loads were often higher after than before fusion using a bone graft. Distraction of the bridged region led to high implant loads in patients with a fractured vertebra and to marked changes in load in those with degenerative instability. Leaving the lower of the bridged intervertebral discs intact led to only small changes in fixator load after anterior interbody fusion. A bone graft alone does not guarantee a reduction of implant loads.


The influence of structure and processing on the behavior of TiO2 protective layers for stabilization of n-Si/TiO2/Ni photoanodes for water oxidation.
Light absorbers with moderate band gaps (1-2 eV) are required for high-efficiency solar fuels devices, but most semiconducting photoanodes undergo photocorrosion or passivation in aqueous solution. Amorphous TiO2 deposited by atomic-layer deposition (ALD) onto various n-type semiconductors (Si, GaAs, GaP, and CdTe) and coated with thin films or islands of Ni produces efficient, stable photoanodes for water oxidation, with the TiO2 films protecting the underlying semiconductor from photocorrosion in pH = 14 KOH(aq). The links between the electronic properties of the TiO2 in these electrodes and the structure and energetic defect states of the material are not yet well-elucidated. We show herein that TiO2 films with a variety of crystal structures and midgap defect state distributions, deposited using both ALD and sputtering, form rectifying junctions with n-Si and are highly conductive toward photogenerated carriers in n-Si/TiO2/Ni photoanodes. Moreover, the photovoltage of these electrodes can be modified by annealing the TiO2 in reducing or oxidizing environments. All of the polycrystalline TiO2 films with compact grain boundaries investigated herein protected the n-Si photoanodes against photocorrosion in pH = 14 KOH(aq). Hence, in these devices, conduction through the TiO2 layer is neither specific to a particular amorphous or crystalline structure nor determined wholly by a particular extrinsic dopant impurity. The coupled structural and energetic properties of TiO2, and potentially other protective oxides, can therefore be controlled to yield optimized photoelectrode performance.


Identifying increased risk of post-infarct people with diabetes using multi-lag Tone-Entropy analysis.
Diabetes mellitus is associated with multi-organ system dysfunction. One of the key causative factors is the increased blood sugar level that leads to an increase in free radical activity and organ damage including the cardiovascular and nervous system. Heart rhythm is extrinsically modulated by the autonomic nervous system and cardiac autonomic neuropathy or dysautonomia has been shown to lead to sudden cardiac death in people with diabetes due to the decrease in heart rate variability (HRV). Current algorithms for determining HRV describe only beat-to-beat variation and therefore do not consider the ability of a heart beat to influence a train of succeeding beats. Therefore mortality risk analysis based on HRV has often not been able to discern the presence of an increased risk. This study used a novel innovation of the tone-entropy algorithm by incorporating increased lag intervals and found that both the sympatho-vagal balance and total activity changed at larger lag intervals. Tone-Entropy was found to be better risk identifier of cardiac mortality in people with diabetes at lags higher than one and best at lag seven.


Glandular distribution of immunoglobulins, J chain, secretory component, and HLA-DR in the human endometrium throughout the menstrual cycle.
Two-colour immunofluorescence was used to study components of the secretory immune system in the endometrium. Tissue sampling was performed in the follicular, ovulatory and luteal menstrual phase from women admitted for laparoscopic sterilization. The specimens were prepared for immunohistochemistry by a method that removes most extracellular immunoglobulin (Ig). The stroma contained only a few Ig-producing immunocytes, but was rich in HLA-DR positive cells. Most of the IgA- and IgM-producing immunocytes also expressed J chain, which is necessary for the generation of polymeric Ig (poly-Ig) with affinity for epithelial secretory component (SC or poly-Ig receptor). Throughout the menstrual cycle there was increasing accumulation of Ig within the endometrial glands, with preferential apical and intraluminal occurrence of IgA and IgM, usually along with J chain and SC. It is likely that some monomeric IgA (without J chain) and IgG enter the endometrial glands by passive diffusion from the stroma, but there is clearly an additional active external poly-Ig transport. Some of the glands stained for HLA-DR irrespective of the menstrual phase or degree of SC expression. Our findings suggest that active SC-mediated external transport of serum-derived (and to some extent locally produced) poly-Ig is enhanced in the luteal phase, and that SC and HLA class II molecules are differently regulated in the endometrial glands.


Simulation of acoustic wave propagation in dispersive media with relaxation losses by using FDTD method with PML absorbing boundary condition.
We present a method to incorporate the relaxation dominated attenuation into the finite-difference time-domain (FDTD) simulation of acoustic wave propagation in complex media. A dispersive perfectly matched layer (DPML) boundary condition, which is suitable for boundary matching to such a dispersive media whole space, is also proposed to truncate the FDTD simulation domain. The numerical simulation of a Ricker wavelet propagating in a dispersive medium, described by second-order Debye model, shows that the Ricker wavelet is attenuated in amplitude and expanded in time in its course of propagation, as required by Kramers-Kronig relations. The numerical results also are compared to exact solution showing that the dispersive FDTD method is accurate and that the DPML boundary condition effectively dampens reflective waves. The method presented here is applicable to the simulation of ultrasonic instrumentation for medical imaging and other nondestructive testing problems with frequency dependent, attenuating media.


Intracranial Atherosclerotic Disease: Current Concepts in Medical and Surgical Management.
This article reviews the current concepts in intracranial atherosclerotic disease (ICAD) as a common etiology of ischemic stroke; pathophysiologic mechanisms of ischemic stroke; diagnostic evaluation; and therapeutic modalities, including maximal medical therapy (MMT), percutaneous transluminal angioplasty and stenting (PTAS), and bypass surgery. Data from recent studies demonstrate that proper patient selection and timing of procedure and standardized PTAS techniques by experienced operators resulted in acceptably low periprocedural adverse events for patients who failed MMT. ICAD is a common cause of ischemic stroke. Complex pathology and high rates of recurrent and disabling ischemic strokes despite currently available treatments make ICAD the most challenging to treat of all ischemic stroke etiologies. Randomized trials previously showed that MMT, which involves the use of combinations of antiplatelet medications, targeted control of hypertension and serum low-density lipoprotein cholesterol, and adequate management of body weight through lifestyle modification, was superior to PTAS in decreasing rates of recurrent ischemic strokes from symptomatic ICAD. MMT performed better than expected, while periprocedural complications were significantly higher than expected in PTAS. Meanwhile, high rates of recurrent ischemic stroke despite MMT remain a great challenge. New clinical evidence continues to emerge on a safer application of PTAS, which is currently offered to a subset of patients who present with recurrent ischemic strokes despite MMT.


TAT peptide internalization: seeking the mechanism of entry.
During the last decade several peptides have been extensively studied for their ability to translocate across the plasma membrane. These peptides have been called "cell penetrating peptides" (CPP) or "protein transduction domains" (PTD). These peptides also promote the cellular uptake of various cargo molecules. Their mechanism of cellular entry appeared very intriguing since most publications in the field highlighted an energy-independent process. Indeed, cellular uptake of these peptides was still observed by fluorescence microscopy at low temperature or in the presence of several drugs known to inhibit active transport. In addition, internalization was reported to be much faster than known endocytic processes. However the involvement of a specific cellular component responsible for this uptake process appeared unlikely following intensive structure activity relationship studies using a wide panel of Tat analogues. Several reports about a possible artefactual redistribution of CPPs, and their associated cargos, during the cell fixation step commonly used for fluorescence microscopy have recently emerged in the literature. Moreover strong ionic interactions of CPPs with the cell surface also led to an overestimation of the recorded cell-associated fluorescent signal. It now seems well established that arginine-rich peptides are internalized by an energy dependent process involving endocytosis. Whatever the case, however, an increasing number of data indicate that the conjugation of non-permeant molecules to these CPPs allows their cellular uptake and leads to the expected biological responses, thus pointing to the interest of this delivery strategy. However, initial structure activity relationship studies of these CPPs will have to be reconsidered and the relative potency of each peptide (and their analogues) to vectorize the cargos to their most appropriate subcellular compartment will require careful re-evaluation.


Derivatives of 5,6-diphenylpyridazin-3-one: synthetic antimitotic agents which interact with plant and mammalian tubulin at a new drug-binding site.
A series of derivatives of 5,6-diphenylpyridazin-3-one (DPP) was examined for interactions with calf brain tubulin following the demonstration that many members of the class caused significant mitotic effects in intact animals, while others had activity against murine P388 leukemia. In L1210 cells several DPP derivatives caused a rise in the mitotic index which correlated well with the cytotoxicity of the drugs. Active DPP derivatives markedly stimulated tubulin-dependent guanosine triphosphate hydrolysis and inhibited tubulin polymerization or induced tubulin oligomer formation, depending on specific reaction conditions. These new agents, however, did not interfere with the binding to tubulin of radiolabeled colchicine, vinblastine, maytansine, or guanosine triphosphate. They thus appear to bind at a previously undescribed site on the tubulin molecule. Some DPP derivatives have significant herbicidal activity, causing mitotic disruption and a rise in the mitotic index in seedling root tissues. Although the DPP derivatives most toxic to plant tissues differ from those most active in inhibiting calf brain tubulin polymerization, virtually all active compounds bear a nitrile substituent at position 4 of the pyridazinone ring. Most active derivatives also bear substituents of varying structure at position 2 of this ring, but no clear structure-function pattern is apparent at this position. The phenyl rings in the most active herbicidal DPP derivatives either are unsubstituted or bear fluorine atoms. Derivatives with chlorine substituents have no detectable herbicidal activity. In contrast, interactions with calf brain tubulin are substantially enhanced if the phenyl rings bear chlorine substituents.


Occupational therapy entry-level education scholarship in Australia from 2000 to 2019: A systematic mapping review.
The number of occupational therapy degree programs in Australia has increased substantially over the last decade. During this time, Australian academics have produced a significant amount of scholarship focussed on entry-level education; however, the landscape of this scholarship has not been examined. The aim of this study was to review the literature on the scholarship of entry-level Australian occupational therapy education programs, specifically the topics explored and methods employed. An extensive search of nine databases produced 1,002 papers related to occupational therapy education. Two researchers screened each paper using inclusion and exclusion criteria. Seventy-six articles, published between 2000 and September 2019, were included. Data were extracted using a coding tool, and entered into NVivo, where data were analysed using queries and tallies of the characteristics of the articles. Sixty-eight articles were research and eight were other peer reviewed literature. Articles primarily focussed on student characteristics and perceptions. Quantitative research designs were predominant with surveys the most frequently used method. There were few articles that addressed the topic of teaching methods and approaches, and of these none addressed occupation-centred teaching. No articles addressed the learning environment. Four articles reported on an educational intervention that targeted participation, and attitudes/perceptions or knowledge/skills of students and/or academics. These findings inform understanding about what has been completed so far in the scholarship; and what topic focus and research designs could address gaps in existing knowledge. This review elucidated topics that have been well researched (student focus), as well as gaps in the scholarship (teaching methods and approaches including occupation-centred teaching, and the learning environment). It showed that quantitative designs were predominant, with qualitative approaches less frequently adopted. The results of this review could assist academics and researchers to focus their scholarship on topics that require further investigation and diversify research methods.


[Results of the use of a graft with a monocusp in radical correction of Fallot's tetrad].
The article deals with the results of complex study of the effect of pulmonary insufficiency on intracardiac hemodynamics and function of the heart in the immediate and late-term periods after radical correction of Fallot's tetralogy. Answers are also given to questions concerning the expediency of the use and functional adequacy of a xeno-pericardial monocusp in the closure mechanism of the pulmonary artery valve. The study showed that massive pulmonary regurgitation has a negative effect on the functional condition of the right ventricle in late-term postoperative periods. Convincing data were obtained which allow a graft with a monocusp of a bull's pericardium to be recommended for further clinical use to prevent insufficiency of the pulmonary artery valve after radical correction of Fallot's tetralogy.


Feasibility of using microbiology diagnostic tests of moderate or high complexity at the point - of - care in a delivery suite.
Point-of-care testing (POCT) is one of the fastest growing sectors of laboratory diagnostics. Most tests in routine use are haematology or biochemistry tests that are of low complexity. Microbiology POCT has been constrained by a lack of tests that are both accurate and of low complexity. We describe our experience of the practical issues around using more complex POCT for detection of Group B streptococci (GBS) in swabs from labouring women. We evaluated two tests for their feasibility in POCT: an optical immune assay (Biostar OIA Strep B, Inverness Medical, Princetown, NJ) and a PCR (IDI-Strep B, Cepheid, Sunnyvale, CA), which have been categorised as being of moderate and high complexity, respectively. A total of 12 unqualified midwifery assistants (MA) were trained to undertake testing on the delivery suite. A systematic approach to the introduction and management of POC testing was used. Modelling showed that the probability of test results being available within a clinically useful timescale was high. However, in the clinical setting, we found it impossible to maintain reliable availability of trained testers. Implementation of more complex POC testing is technically feasible, but it is expensive, and may be difficult to achieve in a busy delivery suite.


Derangement of Metabolic and Lysosomal Gene Profiles in Response to Dexamethasone Treatment in Sarcoidosis.
Glucocorticoids (GCs) play a central role in modulation of inflammation in various diseases, including respiratory diseases such as sarcoidosis. Surprisingly, the specific anti-inflammatory effects of GCs on different myeloid cells especially in macrophages remain poorly understood. Sarcoidosis is a systemic granulomatous disease of unknown etiology that occurs worldwide and is characterized by granuloma formation in different organs. Alveolar macrophages play a role in sarcoidosis granuloma formation and progressive lung disease. The goal of the present study is to identify the effect of GCs on transcriptomic profiles and the cellular pathways in sarcoidosis alveolar macrophages and their corresponding blood myeloid cells. We determined and compared the whole transcriptional signatures of alveolar macrophages from sarcoidosis patients and blood CD14+ monocytes of the same subjects in response to in vitro treatment with dexamethasone (DEX) via RNA-sequencing. In response to DEX, we identified 2,834 genes that were differentially expressed in AM. Predominant pathways affected were as following: metabolic pathway (FDR = 4.1 × 10-10), lysosome (FDR = 6.3 × 10-9), phagosome (FDR = 3.9 × 10-5). The DEX effect on AMs is associated with metabolic derangements involving glycolysis, oxidative phosphorylation and lipid metabolisms. In contrast, the top impacted pathways in response to DEX treatment in blood CD14+ monocytes were as following; cytokine-cytokine receptor interaction (FDR = 6 × 10-6) and transcriptional misregulation in cancer (FDR = 1 × 10-4). Pathways similarly affected in both cell types were genes involved in lysosomes, cytoskeleton and transcriptional misregulation in cancer. These data suggest that the different effects of DEX on AMs and peripheral blood monocytes are partly dictated by lineage specific transcriptional programs and their physiological functions.


Palm tocotrienol exerted better antioxidant activities in bone than alpha-tocopherol.
The aim of this study was to investigate the effects of vitamin E on the levels of lipid peroxidation and antioxidant enzymes in rat bones. Fifty-six normal male Sprague-Dawley rats, aged 3 months, were randomly divided into seven groups with eight rats in each group. The age-matched control group was given the vehicle olive oil, by oral gavage daily. Six of the treatment groups received either palm tocotrienol or pure alpha-tocopherol at the dose of 30, 60 or 100 mg/kg body weight, by oral gavage daily, 6 days a week for 4 months. Thiobarbituric acid-reactive substance (TBARS) that is an index to measure the level of lipid peroxidation and the antioxidant enzymes, glutathione peroxidase and superoxide dismutase levels were measured in the femur at the end of the study. Palm tocotrienol at the dose of 100 mg/kg body weight significantly reduced the TBARS level in the femur with a significant increase in glutathione peroxidase activity compared to the age-matched control group. These were not observed in the alpha-tocopherol groups. Palm tocotrienol was more effective than pure alpha-tocopherol acetate in suppressing lipid peroxidation in bone. Palm tocotrienol showed better protective effect against free radical damage in the femur compared to alpha-tocopherol. This study suggests that palm tocotrienol plays an important role in preventing imbalance in bone metabolism due to free radicals.


Randomized multicenter investigation of folate plus vitamin B12 supplementation in schizophrenia.
More effective treatments are needed for negative symptoms of schizophrenia, which are typically chronic, disabling, and costly. Negative symptoms have previously been associated with reduced blood folate levels, especially among patients with low-functioning variants in genes that regulate folate metabolism, suggesting the potential utility of folate supplementation. To determine whether folic acid plus vitamin B12 supplementation reduces negative symptoms of schizophrenia and whether functional variants in folate-related genes influence treatment response. Parallel-group, randomized, double-blind, placebo-controlled clinical trial of 16 weeks of treatment with 2 mg of folic acid and 400 μg of vitamin B12. Three community mental health centers affiliated with academic medical centers in the United States. Outpatients with chronic schizophrenia who were psychiatrically stable but displayed persistent symptoms despite antipsychotic treatment. Eligible patients were 18 to 68 years old, were treated with an antipsychotic agent for 6 months or more at a stable dose for 6 weeks or more, and scored 60 or more on the Positive and Negative Syndrome Scale. One hundred forty subjects were randomized to receive daily oral folic acid plus vitamin B12 or placebo. Change in negative symptoms (Scale for the Assessment of Negative Symptoms [SANS]), as well as positive and total symptoms (Positive and Negative Syndrome Scale). Folate plus vitamin B12 improved negative symptoms significantly compared with placebo (group difference, -0.33 change in SANS score per week; 95% CI, -0.62 to -0.05) when genotype was taken into account but not when genotype was excluded. An interaction of the 484C>T variant of FOLH1 (rs202676) with treatment was observed (P = .02), where only patients homozygous for the 484T allele demonstrated significantly greater benefit with active treatment (-0.59 change in SANS score per week; 95% CI, -0.99 to -0.18). In parallel, we observed an inverse relationship between red blood cell folate concentration at baseline and 484C allele load (P = .03), which persisted until 8 weeks of treatment. Change in positive and total symptoms did not differ between treatment groups. Folate plus vitamin B12 supplementation can improve negative symptoms of schizophrenia, but treatment response is influenced by genetic variation in folate absorption. These findings support a personalized medicine approach for the treatment of negative symptoms. clinicaltrials.gov Identifier: NCT00611806.


Integrated Multidimensional Maturity Assessments Predicting the High-risk Occurrence of Peak Angle Velocity During Puberty in Progressive Female Idiopathic Scoliosis.
A consecutive and prospective longitudinal study. To propose an integrated multidimensional maturity assessment that was designated as forming a reliable system precisely predicting the high-risk occurrence of peak angle velocity (PAV) in a group of progressive braced female idiopathic scoliosis (IS). Scoliosis deterioration is believed to keep pace with the evolution of skeletal maturity during puberty. There is, however, a paucity of data in the literature regarding which unidimensional or multidimensional maturity assessment was most informational, and could be employed to predict the likelihood of significant curve progression. In this prospective study, braced IS girls with open triradiate cartilage were recruited and followed up at 6-month regular intervals. At each visit, the following data were collected: chronologic age, stage of menses, standing height, Cobb angle of the main curve, spine length, status of triradiate cartilage, Risser sign, and digital skeletal age (DSA) scores. The height velocity (HV) and spine length velocity (SLV), as well as the angle velocity (AV) of each visit were calculated. Finally, those with main curve progression of ≥5 degrees during brace treatment and with a minimum of 2-year follow-up covering the closure of the triradiate cartilage were recruited in this analysis, and their PAV was defined as the peak of AV curves during the whole follow-up period in puberty. Logistic regression analysis was used to evaluate the contribution of each measurement to the risk of PAV onset. Thirty-six IS girls were finally recruited in the study, with an average age of 10.8 years at initial visit and 11.8 years at PAV. The average DSA score, spine length, standing height, and Cobb angle of main curve at PAV were 479.5, 326.7 mm, 150.8 cm, and 26.5 degrees, respectively. The average HV, AV, and SLV at PAV were 8.3 cm, 7.8 degrees, and 28.2 mm/y, respectively. The PAV occurred with Risser 0, 1, and 2 in 80.6%, 11.1%, and 8.3% of the IS girls and closed triradiate cartilages were found at PAV in all the girls. The logistic regression model revealed that the following variables contributed significantly to high-risk occurrence of PAV: chronologic age between 11 and 13 years [odds ratio (OR)=3.961; 95% confidence interval (CI), 1.023-15.342], Risser 0 (OR=14.261; 95% CI, 1.167-65.528), closed triradiate cartilage (OR=6.590; 95% CI, 1.612-26.943), DSA scores between 400 and 500 (OR=6.042; 95% CI, 1.282-28.482), HV>6 cm/y (OR=5.711; 95% CI, 1.105-29.526), Cobb angle of main curve >30 degrees (OR=5.492; 95% CI, 1.151-26.207) and SLV>20 mm/y (OR=5.973; 95% CI, 1.546-23.071). Integrated multidimensional maturity assessments, defined as chronologic age between 11 and 13 years, modified Risser 0, DSA scores between 400 and 500, HV>6 cm/y, and SLV>20 mm/y, combined with preexisting scoliotic curve >30 degrees, were prone to increase the risk of entering the rapid curve acceleration phase in progressive IS girls.


[Factors influencing noncompliance with medication regimens in the elderly].
Poor medication compliance is a major issue in the health care of older patients. To identify risk factors for medication noncompliance in the elderly, inpatients aged 65 years and older at Nagoya University Hospital and at Chubu National Hospital underwent a comprehensive geriatric assessment and tests for the assessment of medication compliance. The dependency of medication assistance by a caregiver is associated with low physical function activity, cognitive impairment, depression and communication inability. Medication noncompliance was not associated with the score of any component of comprehensive geriatric assessment. There was a good relationship between patient's knowledge of medications and the frequency of dosage interval, both of which were associated with the score of instrumental ADL, cognitive function and communication ability. The knowledge was also associated with the medication compliance at Nagoya University Hospital but not at Chubu National Hospital. These results may suggest that the elderly patient's understanding of a medication regimen is important but that other factors are also required to maintain their treatment regimen.


[How quickly do the effects of sector division appear? The initial results of the companion research of the Zurich sector division project].
Dividing the delivery system of larger psychiatric hospitals into defined smaller catchment areas called sectors, implies a contribution to quality assurance. Continuous monitoring and evaluation of a period before and after this reorganisation, which took place in 1994 for the central region of Zürich (Psychiatric University Hospital), allows perception of expected and possible unexpected changes. All newly registered patients were recorded within a time span divided into five periods of six month five each, the last one covering the first six months after sectorisation. This design permits to answer the question as to how fast the intended changes after sectorisation occur, and also to control side effects. Results show that sectorisation resulted in a marked increase of registrations from the defined catchment area of each sector, and that the investigated institutions achieve attainment of the aim to effect a special selection of psychiatric patients characterised by considerable psycho-social deficits. The two sectors display differences in respect of socio-demographic characteristics of newly registered patients.


Association of Facility Type With Procedural-Related Morbidities and Adverse Events Among Patients Undergoing Induced Abortions.
Multiple states have laws requiring abortion facilities to meet ambulatory surgery center (ASC) standards. There is limited evidence regarding abortion-related morbidities and adverse events following abortions performed at ASCs vs office-based settings. To compare abortion-related morbidities and adverse events at ASCs vs office-based settings. Retrospective cohort study of women with US private health insurance who underwent induced abortions in an ASC or office-based setting (January 1, 2011-December 31, 2014). Outcomes were abstracted from a large national private insurance claims database during the 6 weeks following the abortion (date of final follow-up, February 11, 2015). Facility type for abortion (ASCs vs office-based settings, including facilities such as abortion clinics, nonspecialized clinics, and physician offices). The primary outcome was any abortion-related morbidity or adverse event (such as retained products of conception, abortion-related infection, hemorrhage, and uterine perforation) within 6 weeks after an abortion. Two secondary outcomes, both subsets of the primary outcome, were major abortion-related morbidities and adverse events (such as hemorrhages treated with a transfusion, missed ectopic pregnancies treated with surgery, and abortion-related infections that resulted in an overnight hospital admission) and abortion-related infections. Among 49 287 women (mean age, 28 years [SD, 7.3]) who had 50 311 induced abortions, (23 891 [47%] first-trimester aspiration, 13 480 [27%] first-trimester medication, and 12 940 [26%] second trimester or later), 5660 abortions (11%) were performed in ASCs and 44 651 (89%) in office-based settings. Overall, 3.33% had an abortion-related morbidity or adverse event; 0.32% had a major abortion-related morbidity or adverse event; and 0.74% had an abortion-related infection. In adjusted analyses, there was no statistically significant difference between ASCs vs office-based settings, respectively, in the rates of abortion-related morbidities or adverse events (3.25% vs 3.33%, difference, -0.08%; [corrected] 95% CI, -0.58% to 0.43%; adjusted OR, 0.97; 95% CI, 0.81-1.17), major morbidities or adverse events (0.26% vs 0.33%; difference, -0.06%; 95% CI, -0.18% to 0.06%; adjusted OR, 0.78; 95% CI, 0.45-1.37), or infections (0.58% vs 0.77%; difference, -0.16%; 95% CI, -0.35% to 0.03%; adjusted OR, 0.75; 95% CI, 0.52-1.09). Among women with private health insurance who had an induced abortion, performance of the abortion in an ambulatory surgical center compared with an office-based setting was not associated with a significant difference in abortion-related morbidities and adverse events. These findings, in addition to individual patient and individual facility factors, may inform decisions about the type of facility in which induced abortions are performed.


[Volumetric brain findings in late depression. A study with quantified magnetic resonance tomography].
A number of observations including clinical manifestation, course, outcome, and family history, support the view that patients presenting with a major depression occurring first in late life should be treated as a nosological subgroup. In this study quantitative magnetic resonance imaging (MRI) was used to investigate volumes of different brain structures in 19 patients with late onset major depression (age of onset > 50) and 13 age matched controls. 3-D MRI sequences were acquired using a Siemens 1.5T scanner. Whole brain volume, CSF volume, volume of the frontal and temporal lobes and the volume of the amygdala-hippocampus complex were assessed using the software NMRWin. Compared to the controls, depressed patients showed a significantly lower whole brain volume and a significantly higher CSF volume, whereas volumes of the frontal and temporal lobes as well as the amygdala-hippocampus complex volumes were not significantly decreased. In addition, depressed patients exhibited a higher ventricle-brain ratio suggesting a higher degree of central atrophy compared to healthy individuals. Our results indicate that cerebral changes involving subcortical structures are of relevance in the pathogenesis of late-onset depression. Defining the aetiology of these lesions may be important for the development of preventive treatment of depression in the elderly.


Frequent loss of heterozygosity at chromosome 3p14.2-3p21 in human pancreatic islet cell tumours.
Pancreatic islet betacell tumours occur either sporadically or as part of inherited neoplastic syndromes, most commonly multiple endocrine neoplasia (MEN) type 1. Recently, a transgenic mouse model has been established in which the expression of the SV40 large T antigen was targeted to betacells by the rat insulin promoter, leading to the development of multiple pancreatic betacell tumours. In the advanced stages of tumour evolution, these tumours exhibited a high prevalence of loss of heterozygosity (LOH) on mouse chromosomes 9 and 16, at regions syntenic with regions 3q, 3p21, 6q12, 15q24 and 22q of the human genome. Loss of heterozygosity in human islet cell tumours was analysed in a PCR based approach at regions of the human genome syntenic with the mouse loci linked to pancreatic betacell tumours as well as the MEN1 gene on chromosome 11q13. These included 35 microsatellite markers in the human chromosomal regions 3q, 3p21, 6q12, 11q13, 15q24 and 22q. 21 patients diagnosed with insulinoma were analysed. Histologically, 16 tumours were benign, while 5 were malignant insulinomas. Thirteen of 21 (62%) tumours were found to have loss of genetic material on chromosome 3. The shortest region of overlap implicated a deletion at 3p14.2-3p21 region, corresponding to the marker D3S1295. We did not detect a substantial frequency of LOH in the other syntenic regions, except for the region of MEN 1 gene on 11q13 found to be deleted in 6 (29%) cases, including 3 of 4 tumours from MEN 1 families. Deletions of 3p14. 2-3p21 were observed in 8 of 15 (53%) benign tumours, and in 5 of 6 (83%) malignant neoplasms. These results indicate the high frequency of 3p14.2-3p21 deletions in human pancreatic betacell neoplasms. These finding suggest the presence of a tumour suppressor gene in this region, that may be important in the microevolution of these tumours towards malignancy.


COVID-19 breakthrough infections in type 1 diabetes mellitus: a cross-sectional study by the COVID-19 Vaccination in Autoimmune Diseases (COVAD) Group.
To investigate the frequency, profile, and severity of COVID-19 breakthrough infections (BI) in patients with type I diabetes mellitus (T1DM) compared to healthy controls (HC) after vaccination. The second COVID-19 Vaccination in Autoimmune Diseases (COVAD-2) survey is a multinational cross-sectional electronic survey which has collected data on patients suffering from various autoimmune diseases including T1DM. We performed a subgroup analysis on this cohort to investigate COVID-19 BI characteristics in patients with T1DM. Logistic regression with propensity score matching analysis was performed. A total of 9595 individuals were included in the analysis, with 100 patients having T1DM. Among the fully vaccinated cohort, 16 (16%) T1DM patients had one BI and 2 (2%) had two BIs. No morbidities or deaths were reported, except for one patient who required hospitalization with oxygen without admission to intensive care. The frequency, clinical features, and severity of BIs were not significantly different between T1DM patients and HCs after adjustment for confounding factors. Our study did not show any statistically significant differences in the frequency, symptoms, duration, or critical care requirements between T1DM and HCs after COVID-19 vaccination. Further research is needed to identify factors associated with inadequate vaccine response in patients with BIs, especially in patients with autoimmune diseases.


Risk of Venous Thromboembolism with Statins: Evidence Gathered via a Network Meta-analysis
Anticoagulants are the mainstay of treatment for venous thromboembolism (VTE). Studies have shown conflicting results regarding statins ability to reduce the incidence of VTE. To perform a network meta-analysis to determine which lipid-lowering agent was more efficacious in and had more evidence regarding reducing the VTE risk. Network meta-analysis of the randomized controlled trials (RCTs). RCTs that assessed the effectiveness and safety of statins or fibrates and compared them to a placebo or another statin were eligible for the study. The outcomes examined in the study were deep vein thrombosis, pulmonary embolism, and/or VTE. We conducted a comprehensive search of the Medline database from 1966 to February 2017, using specific search terms related to VTE and statins. Additionally, we screened, and cross-checked relevant systematic reviews and meta-analyses. We performed a network meta-analysis to compare the different lipid-lowering agents to each other and the placebo and their effectiveness. Twenty-seven RCTs were included in the network meta-analysis (n = 137,940). Pairwise meta-analysis revealed a statistically significant lower incidence of VTE with statins than with placebos (0.79% vs 0.99%, respectively; risk ratios: 0.87, 0.77-0.98; p = 0.022). Rosuvastatin had the most favorable effect in reducing VTE risk than the other statins, fenofibrate, and placebo. Fenofibrate was ranked the worst drug choice, because it increased risk of VTE when compared with the other statins. Rosuvastatin was the best choice for reducing the VTE risk when compared with the placebo (OR: 0.56, 0.42-0.75), atorvastatin (OR: 0.64, 0.44-0.95), pravastatin (OR: 0.50, 0.34-0.74), simvastatin (OR: 0.60, 0.42-0.86) and fenofibrate (OR: 0.37, 0.25-0.56). Compared with a placebo, rosuvastatin reduced the VTE risk by around 45% and fenofibrate increased the risk by 65%. Rosuvastatin is significantly reduces the risk of VTE when compared with a placebo, other statin subtypes, and fibrate. Furthermore, fenofibrate increased the VTE risk when compared with a placebo and statins.


A novel, cellulose synthesis inhibitory action of ancymidol impairs plant cell expansion.
The co-ordination of cell wall synthesis with plant cell expansion is an important topic of contemporary plant biology research. In studies of cell wall synthesis pathways, cellulose synthesis inhibitors are broadly used. It is demonstrated here that ancymidol, known as a plant growth retardant primarily affecting gibberellin biosynthesis, is also capable of inhibiting cellulose synthesis. Its ability to inhibit cellulose synthesis is not related to its anti-gibberellin action and possesses some unique features never previously observed when conventional cellulose synthesis inhibitors were used. It is suggested that ancymidol targets the cell wall synthesis pathway at a regulatory step where cell wall synthesis and cell expansion are coupled. The elucidation of the ancymidol target in plant cells could potentially contribute to our understanding of cell wall synthesis and cell expansion control.


No consistent association found between dental caries and body mass index in children.
Data sourcesPubMed, Embase, the Cochrane Library and reference lists of identified studies.Study selectionObservational studies comparing dental caries and body mass index (BMI) where BMI was clearly defined were considered.Data extraction and synthesisTwo reviewers independently abstracted data using standard forms with study quality being assessed using a modified version of the Agency for Healthcare Research and Quality (AHRQ) methodology checklist for cross-sectional studies. The weighted mean differences and corresponding 95% confidence intervals for dental caries between children with abnormal weight and those with normal weight were analysed.ResultsFourteen cross-sectional studies including 43,860 children (boys: 23,299; girls: 20,561) were included. Only two studies were considered to be of high quality, eight of medium quality and four of low quality. Four main patterns of associations between dental caries and BMI were found: five studies showed no association, five studies found a positive association, three an inverse association and one found a U-shaped pattern, which meant that the deft score was significantly higher in underweight children and there was a higher DMFT score in overweight and obese children.ConclusionsThis meta-analysis showed no differences in dental caries between underweight and normal weight children. Further studies are recommended using suitable sample sizes, to unify the criteria for BMI categorisation and the dental caries index, and investigate the confounding factors that might influence dental caries and BMI.


Diagnostic criteria for temporomandibular disorders (DC/TMD): interexaminer reliability of the Finnish version of Axis I clinical diagnoses.
Recently, updated diagnostic criteria for temporomandibular disorders (DC/TMD) were published to assess TMD in a standardised way in clinical and research settings. The DC/TMD protocol has been translated into Finnish using specific cultural equivalency procedures. To assess the interexaminer reliability using the Finnish translations of the DC/TMD-FIN Axis I clinical diagnostic assessment instruments. Reliability assessment data were collected during a 1-day DC/TMD Examiner Training Course at the University of Turku, Finland, in collaboration with the International DC/TMD Training and Calibration Center in Malmö University. Clinical TMD examinations according to the Finnish pre-final version of the DC/TMD Axis I assessment protocol were performed by four experienced TMD specialists on altogether 16 models. Kappa coefficient, overall percentage agreement (%A) as well as positive (PA) and negative (NA) agreements were used to define the reliability. Myofascial pain with referral, headache attributed to TMD and disc displacement (DD) without reduction without limited opening showed excellent kappa values (range 0·87-1·00). Fair-to-good reliability was observed for diagnoses of myalgia (k = 0·67), arthralgia (k = 0·71) and DD with reduction (k = 0·64). The PA was high for all pain-related diagnoses and DD without reduction without limited opening (medians ≥83%), and acceptable for DD with reduction (median 67%). The NA was high (medians ≥87%) for all DC/TMD diagnoses, except for myalgia which showed acceptable NA (median 75%). The %A was high for all assessed diagnoses (medians >85%). The findings of this study showed DC/TMD-FIN Axis I to demonstrate sufficiently high reliability for pain-related TMD diagnoses.


Commercially Available Insulin Products Demonstrate Stability Throughout the Cold Supply Chain Across the U.S.
A recent publication questioned the integrity of insulin purchased from U.S. retail pharmacies. We sought to independently validate the method used, isotope dilution solid-phase extraction (SPE) liquid chromatography mass spectrometry (LC-MS), and expand analysis to two U.S. Pharmacopeia (USP) methods (high-performance LC with ultraviolet detection and LC-MS). Each method was used to evaluate nine insulin formulations, purchased at four pharmacies, within five geographic locations in the U.S. All human and analog insulins measured by the USP methods (n = 174) contained the expected quantity of active insulin (100 ± 5 units/mL). When using isotope dilution SPE-LC-MS, units-per-milliliter values were well below product labeling due to unequal recovery of the internal standard compared with target insulin. Insulin purchased from U.S. pharmacies is consistent with product labeling.


Skill qualities as risk factors for contact injury in professional rugby league players.
We investigated the relationship between skill qualities and contact injury risk in professional rugby league players. Sixty-six professional rugby league players aged 23 ± 4 years (mean ± s) participated in this three-year prospective study. Players underwent assessments of tackling proficiency, dual-task draw-and-pass proficiency, reactive agility, pattern recall, and pattern prediction. The frailty model was applied to calculate the adjusted risk ratios of injury. When the players' age and playing position were adjusted in the frailty model, the risk ratios showed that reactive agility was a predictor for the risk of injury. Players with reactive agility decision times of >80 ms had a lower incidence (relative risk = 0.68, 95% CI 0.47-0.98, P = 0.04) of injuries than players with reactive agility decision times of ≤ 80 ms. Although there was no relationship between injury and the majority of skill qualities (P = 0.47-0.93), players with poor reactive agility performances (specifically longer decision times) had a lower risk of injury, suggesting that poor perceptual skill is protective against contact injuries in professional rugby league players. These players might inadvertently avoid the heavy collisions that result in injury, or at best result in partial contact that does not result in exposure to the full force of a tackle.


Multiple mechanisms of NADPH oxidase inhibition by type A and type B Francisella tularensis.
Ft is a facultative intracellular pathogen that infects many cell types, including neutrophils. In previous work, we demonstrated that the type B Ft strain LVS disrupts NADPH oxidase activity throughout human neutrophils, but how this is achieved is incompletely defined. Here, we used several type A and type B strains to demonstrate that Ft-mediated NADPH oxidase inhibition is more complex than appreciated previously. We confirm that phagosomes containing Ft opsonized with AS exclude flavocytochrome b(558) and extend previous results to show that soluble phox proteins were also affected, as indicated by diminished phosphorylation of p47(phox) and other PKC substrates. However, a different mechanism accounts for the ability of Ft to inhibit neutrophil activation by formyl peptides, Staphylococcus aureus, OpZ, and phorbol esters. In this case, enzyme targeting and assembly were normal, and impaired superoxide production was characterized by sustained membrane accumulation of dysfunctional NADPH oxidase complexes. A similar post-assembly inhibition mechanism also diminished the ability of anti-Ft IS to confer neutrophil activation and bacterial killing, consistent with the limited role for antibodies in host defense during tularemia. Studies of mutants that we generated in the type A Ft strain Schu S4 demonstrate that the regulatory factor fevR is essential for NADPH oxidase inhibition, whereas iglI and iglJ, candidate secretion system effectors, and the acid phosphatase acpA are not. As Ft uses multiple mechanisms to block neutrophil NADPH oxidase activity, our data strongly suggest that this is a central aspect of virulence.


Ponesimod for the treatment of relapsing multiple sclerosis.
Multiple Sclerosis (MS) is an immune-mediated, complex, chronic inflammatory, and neurodegenerative disease of the central nervous system. Among the several therapeutic options developed over the last decade for relapsing MS (RMS), fingolimod, a sphingosine 1-phosphate receptor (S1PR) modulator, was the first oral treatment. The adverse events associated with fingolimod have limited its use in certain populations, thus further stimulating the search for other S1PR modulators. The authors reviewed the English-published literature on ponesimod using the PubMed database. The search terms used were 'ponesimod' or 'ACT-128,800' and 'multiple sclerosis.' Available data on the pharmacological profile of ponesimod and the information on clinical efficacy and safety drawn from clinical trials in comparison with other S1PR modulators are presented and discussed. Published peer-reviewed data on long-term safety and efficacy are still lacking but have been collected and regulatory authorities expressed a favorable opinion to market access. At present, we believe that ponesimod has little chance of becoming a leading treatment for RMS due to the availability of many alternative options and the timing of market access. Given its favorable risk-benefit and convenience profile, however, ponesimod might become a leading option among S1P receptor modulators used for RMS.


Antipsychotic Medication Adherence and Healthcare Services Utilization in Two Cohorts of Patients with Serious Mental Illness.
To evaluate differences in patient characteristics and real-world outcomes in two distinct high-risk cohorts of patients with serious mental illness (SMI). Retrospective cross-sectional analysis using a national multi-payer claims database. Two SMI cohorts identified by a technical expert panel-patients recently discharged (RD) from an SMI-related hospitalization and early episode (EE) patients-were evaluated for antipsychotic medication adherence, healthcare utilization, and spending patterns. The analysis included 51,705 patients with bipolar disorder, major depressive disorder, and schizophrenia. More than half were over age 46 and >60% were female. Adherence to psychiatric medications was low (52.5% RD and 16.1% EE). More than half of RD and 100% of EE patients switched medications at least once annually, but 19% of RD patients switched ≥2 times compared to 14% of EE. The RD cohort (generally older and sicker) had higher psychiatric related utilization and higher annual costs (US$21,171 versus US$15,398). In both cohorts, women were more likely to have an emergency department (ED) and primary care provider (PCP) visit, but less likely to be hospitalized. Patients age <46 were less likely to have a PCP visit and more likely to have an ED visit, but younger patients age 18-24 were less likely to be hospitalized. Efforts to manage SMI are confounded by heterogeneity and low adherence to treatment. By better understanding which patients are at higher risk for specific adverse outcomes, clinicians can target interventions more appropriately to reduce the significant burden of SMI.


MOVE: weight management program across the Veterans Health Administration: patient- and facility-level predictors of utilization.
Health care systems initiating major behavioral health programs often face challenges with variable implementation and uneven patient engagement. One large health care system, Veterans Health Administration (VHA), recently initiated the MOVE!® Weight Management Program, but it is unclear if veterans most in need of MOVE!® services are accessing them. The purpose of this study was to examine patient and facility factors associated with MOVE!® utilization (defined as 1 or more visits) across all VHA facilities. Using national administrative data in a retrospective cohort study of eligible overweight (25 < = body mass index (BMI) < 30 and at least one obesity associated comorbidity) and obese (BMI > =30) VHA outpatients, we examined variation in and predictors of MOVE!® utilization in fiscal year (FY) 2010 using generalized linear mixed models. 4.39% (n = 90,230) of all eligible overweight and obese patients using VHA services utilized MOVE!® services at least once in FY 2010. Facility-level MOVE! Utilization rates ranged from 0.05% to 16%. Veterans were more likely to have at least one MOVE!® visit if they had a higher BMI, were female, unmarried, younger, a minority, or had a psychiatric or obesity-related comorbidity. Although substantial variation exists across VHA facilities in MOVE!® utilization rates, Veterans most in need of obesity management services were more likely to access MOVE!®, although at a low level. However, there may still be many Veterans who might benefit but are not accessing these services. More research is needed to examine the barriers and facilitators of MOVE!® utilization, particularly in facilities with unusually high and low reach.


Oral treatment with Berberine reduces peripheral nociception: Possible interaction with different nociceptive pathways activated by different allogeneic substances.
Berberine was identified in extracts of Berberis ruscifolia Lam., a plant used in traditional medicine as an analgesic. Its presence may be involved in the reported pharmacological activity of this species. However, there is still a lack of scientific research concerning its analgesic activity in the peripheral nervous system. To investigate Berb-induced antinociception in the formalin test and to evaluate several pathways related to its pharmacological antinociceptive effects in chemical models of nociception in mice. The antinociceptive activity of Berb was assessed by inducing the paw licking in mice with different allodynic agents. In the formalin test, the antiedematous and antithermal effect of Berb was evaluated simultaneously in the same experiment. Other nociceptive behavior produced by endogenous [prostaglandin E2 (PGE2), histamine (His), glutamate (Glu) or bradykinin (BK)] or exogenous [capsaicin (Caps) and cinnamaldehyde (Cin)] chemical stimuli, and activators as protein kinase A (PKA) and C (PKC), were also evaluated.The in vivo doses for p.o. were 3 and 30 mg/kg. Berb, at 30 mg/kg p.o., showed a significant inhibition of the nociceptive action in formalin in both phases being stronger at the inflammatory phase (59 ± 9%) and more active than Asp (positive control) considering the doses evaluated. Moreover, Berb inhibited the edema (34 ± 10%), but not the temperature in the formalin test. Regarding the different nociceptive signaling pathways evaluated, the most relevant data were that the administration of p.o. of Berb, at 30 mg/kg, caused significant inhibition of nociception induced by endogenous [His (72 ± 11%), PGE2 (78 ± 4%), and BK (51 ± 7%)], exogenous [Cap (68 ± 4%) and Cinn (57 ± 5%)] compounds, and activators of the PKA [(FSK (86 ± 3%)] and PKC [(PMA(86 ± 6%)] signaling pathway. Berb did not inhibit the nociceptive effect produced by Glu. The present study demonstrated, for the first time, the potential of Berb in several nociceptive tests, with the compound present in B. ruscifolia contributing to the analgesic effect reported for this species.


Relationship between quality of life and work ability among judicial employees.
As is known, occupational diseases hamper productivity by impairing not only the work ability, but also all the aspects related with the quality of life of employees. Maintenance of work ability is associated with the state of health needed to perform work activities, which when are properly done lead to satisfactory results for both organizations and workers. To investigate the relationship between quality of life and work ability among judicial employees. Cross-sectional observational study. The sample comprised 88 randomly selected judicial employees from both sexes. The study was conducted at the Court of Justice of Pernambuco, Recife, Brazil. Data collection was performed through questionnaires for sociodemographic variables, quality of life and Work Ability Index. Pearson's correlation was used for data analysis. 90.9% of participants had income equivalent to 5 or more times the minimum wage; 73.9% worked up to 6 hours per day; and 52.3% reported regular practice of physical activity. Correlation between work ability and quality of life was stronger for the participants with regular practice of physical activity (R=0.60; p<0.001) and shorter working time (R=0.61; p<0.001). On analysis per sex, work ability exhibited significant and moderate correlation with quality of life for both males (R=0.62; p<0.001) and females (R=0.40; p<0.010). Relative to the analyzed sample of judicial employees positive correlation was found between work ability and overall quality of life, as well as with quality of life physical health, social, psychological and environment domains.


Quantitative analysis of the time-dependent development of glucose-6-phosphatase-deficient foci in the livers of mice treated neonatally with diethylnitrosamine.
The development of glucose-6-phosphatase (G-6-Pase-)-deficient hyperbasophilic foci was analyzed at 4-week intervals in the livers of CD-1 and C57BL/6J x C3H/HeJ F1 (hereafter called B6C3F1) mice given a single i.p. injection of diethylnitrosamine (DEN) (0.1, 0.2, or 0.4 mumol/g body weight) within 24 hr after birth. Transections of G-6-Pase-deficient foci of hepatocytes were readily discernible in liver sections of DEN-treated mice of either sex at 8 weeks of age. The size and number of these foci per liver increased with time. The occurrence of G-6-Pase-deficient focus transections with diameters as large as 1 mm coincided with the gross appearance of 1-mm gray-white nodules in the livers of male B6C3F1 mice at 16 weeks of age and in females at 32 weeks of age. Transections of all grossly visible hepatic nodules from male and female mice were G-6-Pase deficient and hyperbasophilic; the great majority were diagnosed as mouse hepatomas type A. After a single neonatal dose of DEN, the number and rate of growth of the G-6-Pase-deficient foci and the incidence and rate of appearance of gross hepatomas were greater in the liver of male than in those of female mice. In contrast, the average numbers of G-6-Pase-deficient foci in the livers of male and androgenized female B6C3F1 mice at 36 weeks of age were approximately equal and about twice that observed for the livers of DEN-treated female controls. Quantitation of carcinogen-induced histochemically detectable foci and hepatomas as a function of time provides a useful tool for the analysis of initiation and promotion in the mouse liver.


[Enteroviral persistence in eye infections in monkeys (postuveitis syndrome)].
Follow-up (5.5 years) of monkeys with a history of acute enterovirus uveitis (AEU) after intraocular infection with ophthalmotropic ECHO 11 and ECHO 19 strains showed progressive changes in the infected eye; destruction of the iris, formation of films in the anterior chamber of the eye, deformation of the pupil, and signs of cataract and glaucoma. A short (1-30 days) stage of active reproduction of infective virus (up to 10(10) TCD50/g tissue in the first days postinfection) was followed by the second very long stage of limited specific multiplication of virus in ocular tissues. The virus was not detected during the second stage, but its components (virusspecific antigen and crystalloid accumulations of virions) were found in ophthalmic and conjunctival tissues; moreover, high levels of neutralizing antibodies were detected in the blood. The results indicate AEU transformed into a stubborn persistent infection of the eye in monkeys. The findings of this follow-up and published reports about many-year follow-up of children with AEU permit us to classify a post-uveitis disease as a special nosological form of a persistent enterovirus infection and denote it as enterovirus post-uveitis syndrome. The main signs of this syndrome are a history of AEU, progressive destructive changes in the anterior segment of the eye, presence of virus components in ocular tissues in remote periods after infection, and high antibody level in the blood.


Induction of immune responses in mice by vaccination with Liposome-entrapped DNA complexes encoding Toxoplasma gondii SAG1 and ROP1 genes.
To evaluate the immune responses induced by experimental DNA construct encoding Toxoplasma gondii (T. gondii) surface antigen1 (SAG1) and rhoptry protein 1 (ROP1) in mice as a hybrid gene. Truncated SAG1 and ROP1 DNA fragments were amplified using polymerase chain reaction (PCR) and inserted into pEGFP-N3 vector to construct recombinant plasmid pSAG1-ROP1. NIH3T3 mammalian cells were transiently transfected with the DNA construct. Female BALB/c mice were given three intramuscular injections of 10 micro g plasmid DNA entrapped in liposome. Four weeks after the final booster injection, blood samples were collected and subjected to enzyme-linked immuno sorbent assay (ELISA) to investigate humoral and cell-mediated immune responses. Reversal transcript-polymerase chain reaction (RT-PCR) was used to evaluate the transcription of inoculated DNA-liposome complex in the injected site. Dot-blot hybridization was employed in order to detect whether or not the injected DNA was incorporated into the genomic DNA of the immunized mice. Green fluorescence was observed in pSAG1-ROP1-transfected cells. Western blot analysis showed antibody recognition of the expressed SAG1-ROP1 was between 58 kDa and 75 kDa. No expression was observed in blank control plasmid-transfected cells. The sera of immunized mice exhibited antibodies to T. gondii tachyzoites and primarily interferon-gamma and interlukin-2. RT-PCR showed that the duration of transcribed inoculated liposome entrapped DNA in the injected muscular tissue was at least ten days post the first injection. Dot-blot hybridization revealed that the presence of foreign DNA in the splenocytes and peripheral blood leukocytes was transient and that no foreign DNA had inserted into the genomic DNA of mice immunized with pSAG1-ROP1. Immunization with a liposome-encapsulated DNA construct encoding the T. gondii SAG1 and ROP1 can induce humoral and cell-mediated immune responses.


Anorexigenic postprandial responses of PYY and GLP1 to slow ice cream consumption: preservation in obese adolescents, but not in obese adults.
Eating slowly increases the postprandial responses of some anorexigenic gut hormones in healthy lean subjects. As the rate of food intake is positively associated with obesity, the aim of the study was to determine whether eating the same meal at different rates evokes different postprandial anorexigenic responses in obese adolescent and adult subjects. Eighteen obese adolescents and adults were enrolled. A test meal was consumed on two different sessions by each subject, meal duration taking either 5 min (fast feeding) or 30 min (slow feeding). Circulating levels of glucagon-like peptide 1 (GLP1), peptide YY (PYY), glucose, insulin, and triglycerides were measured over 210 min. Visual analog scales were used to evaluate the subjective feelings of hunger and satiety. fast feeding did not stimulate GLP1 release in obese adolescent and adults, whereas slow feeding increased circulating levels of GLP1 only in obese adolescents. Plasma PYY concentrations increased both in obese adolescents and in adults, irrespective of the eating rate, but slow feeding was more effective in stimulating PYY release in obese adolescents than in adults. simultaneously, slow feeding evoked a higher satiety only in obese adolescents compared with fast feeding but not in obese adults. in obese adolescents, slow feeding decreased hunger (only at 210 min). irrespective of the eating rate, postprandial responses of insulin and triglycerides were higher in obese adults than in obese adolescents. Slow feeding leads to higher concentrations of anorexigenic gut peptides and favors satiety in obese adolescents, but this physiological control of food intake is lost in obese adults.


Prediction of papillary thyroid metastases to the central compartment: proposal of a model taking into consideration other thyroid conditions.
To construct risk prediction models for cervical lymph node metastasis (CLNM) of papillary thyroid carcinoma (PTC) under different thyroid disease backgrounds and to analyze and compare risk factors among different groups. This retrospective study included 518 patients with PTC that was pathologically confirmed post-operatively from January 2021 to November 2021. Demographic, ultrasound and pathological data were recorded. Univariate and multivariate logistic regression analyses were performed to identify factors associated with CLNM in the whole patient cohort and in patients grouped according to diagnoses of Hashimoto's thyroiditis (HT), nodular goiter (NG), and no background disease. Prediction models were constructed for each group, and their performances were compared. Analysis of the whole PTC patient cohort identified NG as independently associated with CLNM. The independent risk factors for patients with no background disease were the maximum thyroid nodule diameter and American College of Radiology Thyroid Imaging Reporting & Data System score; those for patients with HT were the maximum thyroid nodule diameter, ACR TI-RADS score, and multifocality; and those for patients with NG were the maximum thyroid nodule diameter, ACR TI-RADS score, multifocality and gender. Background thyroid disease impacts CLNM in PTC patients, and risk factors for CLNM vary among PTC patients with different background diseases. Ultrasound is useful for diagnosing background thyroid disease, which can inform treatment planning. Different prediction models are recommended for PTC cases with different thyroid diseases.


Tongue ischemia - an unusual presentation of Giant Cell Arteritis.
Unusual presentations of Giant Cell Arteritis (GCA) can sometimes delay the diagnosis and its prompt treatment. An 83-year-old male patient was admitted in the emergency department with a few hours evolution of tongue swelling, dysphagia and dysarthria. He also complained of a bitemporal headache with about 4 months of evolution and resistant to all treatment prescribed, including ergotamine, that he had started one week before. Upon examination, the patient presented a bilateral temporal pain and reduced mobility of the tongue which evolved to complete cyanosis. The blood tests revealed normocytic normochromic anaemia, an erythrocyte sedimentation rate of 62 mm/h, and C-reactive protein of 23,6 mg/dl. Cranial CT scan was normal and the cervical CT angiogram showed reduced vascularization of the left submandibular gland and of the base of the tongue. The cervical doppler ultrasound was compatible with arterial inflammation. Given the high suspicion of GCA, the patient was immediately put on a high dose of corticosteroid, resulting in a big improvement of the symptoms, which continued in the following weeks. In conclusion, the clinical suspicion of GCA is fundamental for an early diagnosis. The authors consider that ergotamine might have triggered tongue ischemia in this case.


Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees.
Melanocortin-4 receptor (MC4R) deficiency is the most frequent genetic cause of obesity. However, there is uncertainty regarding the degree of penetrance of this condition, and the putative impact of the environment on the development of obesity in MC4R mutation carriers is unknown. We determined the MC4R sequence in 2,257 obese individuals and 2,677 nonobese control subjects of European origin and established the likely functional impact of all variants detected. We then included relatives of probands carriers and studied 25 pedigrees, including 97 carriers and 94 noncarriers from three generations. Of the MC4R nonsynonymous mutations found in obese subjects, 68% resulted in a loss of function in vitro. They were found in 1.72% of obese versus 0.15% of nonobesed subjects (P = 6.9 x 10(-10)). Among the families, abnormal eating behavior was more frequent in both MC4R-deficient children and adults than in noncarriers. Although BMI was inversely associated with educational status in noncarrier adults, no such relationship was seen in MC4R mutation carriers. We observed a generational effect, with a penetrance of 40% in MC4R-deficient adults aged >52 years, 60% in 18- to 52-year-old adults, and 79% in children. The longitudinal study of adult carriers showed an increasing age-dependent penetrance (37% at 20 years versus 60% at >40 years). We have established a robust estimate of age-related penetrance for MC4R deficiency and demonstrated a generational effect on penetrance, which may relate to the development of an "obesogenic" environment. It remains to be seen whether appropriate manipulation of environmental factors may contribute to preventing the development of obesity even in those strongly genetically predisposed to it.


GRF treatment of late pregnant ewes alters maternal and fetal somatotropic axis activity.
To examine the effects of anabolic agents given during late gestation on the maternal and fetal somatotropic axes, we injected pregnant ewes twice daily with 0.15 mg somatocrinin (GRF)-(1-29) for 10 days beginning on day 130 of gestation. Maternal and fetal endocrine changes were compared with control animals using both in vivo and in vitro approaches. Treatment with GRF increased maternal plasma levels of growth hormone (GH) and insulin-like growth factor I (IGF-I;P less than 0.05) but not IGF-II. Under in vitro test conditions, maternal pituitary cells showed a greater maximal response (P less than 0.001) to GRF. In the fetuses of treated ewes, cord plasma GH levels were not significantly increased compared with controls. These animals had similar IGF-I but higher IGF-II (P less than 0.05) plasma levels. The maximal response of fetal pituitary cells to GRF was increased (P less than 0.001). GRF treatment had no influence on maternal and fetal pituitary cell responses to somatostatin under either basal or GRF-stimulated conditions. In addition, these treatments did not affect plasma levels of placental lactogen, glucose, or free fatty acids in the maternal and fetal sheep. These data are compatible with the hypothesis that treatment of pregnant ewes in the last days of gestation with GRF could support accelerated fetal growth.


cAMP-Dependent protein kinase (PKA) subunit mRNA levels in postmortem brain from patients with bipolar affective disorder (BD).
Earlier findings of elevated basal and stimulated PKA activities, and increased immunoreactive levels of PKA regulatory and catalytic subunits in discrete postmortem brain regions from bipolar disorder (BD) patients suggest that disturbances in PKA are involved in the pathophysiology of BD. PKA subunit mRNA levels were measured using SYBR Green real-time RT-PCR to determine if previously observed differences in immunoreactive levels of PKA RIIbeta and Calpha subunits were associated with corresponding changes in mRNA levels in temporal and frontal cortices from the same BD patients and matched controls. In distinct contrast to the higher immunolabeling levels of the PKA subunits previously reported in the BD brain, there were no significant differences in RIIbeta and Calpha subunit mRNA levels in the temporal and frontal cortices of BD patients compared with controls. These findings infer that the elevated PKA immunolabeling and activity found in the selected cerebral cortical regions of BD postmortem brain were due to a posttranscriptional mechanism, rather than changes in regulation of gene transcription and/or mRNA stability of the PKA subunits.


Stimulation of the non-specific resistance by Corynebacterium parvum and Bacillus calmette Guérin.
The effect of pretreatment of intravenously administered killed Corynebacterium parvum (CP) and living BCG was studied in various model systems. Both vaccines caused an increased resistance to Listeria monocytogenes, indicating macrophage activation. Only CP exerted a suppressive effect on T-cell-mediated immunological phenomena (skin allograft survival; antibody production to tetanus toxoid; expulsion of adult T. spiralis worms from intestine). Results of experiments with congenitally athymic (nu/nu) mice and their heterozygous thymus-bearing (+/nu) littermates indicated that CP can induce macrophage activation in the absence of functional T-cells, whereas BCG-induced stimulation is a T-cell-dependent phenomenon.