"Please see this man with a 69-year history of hypoglycaemia".
Mutations in the HNF4A gene are associated with hyperinsulinaemic hypoglycaemia in infants, frequently evolving into relative deficiency of insulin in adulthood ---as maturity onset diabetes of the young (MODY). A 69-year-old male with a strong family history of adult-onset diabetes was referred with lifelong hypoglycaemia, found to be due to a pathogenic HNF4A mutation. HbA1c levels were low, continuous glucose monitoring demonstrated frequent low glucose events in the early morning, and he was successfully treated with diazoxide. This case represents a new phenotype of a known mutation associated more commonly with MODY. The same mutation in one family led to profoundly different manifestations. Genetic causes of hyperinsulinaemic hypoglycaemia can present late in life and identifying such cases is important to allow the correct treatment to be established.


Cyclic AMP selectively uncouples mitogen-activated protein kinase cascades from activating signals.
Cells integrate signals to select the appropriate response from an array of possible outcomes. Signal integration causes the reorganization of signaling pathways by undescribed events. To analyze the molecular changes in signaling pathways that elicit different responses, we focused on the interaction between cyclic AMP (cAMP) and growth factors. We show that the activation of extracellular signal-regulated kinase 5 (ERK5), but not ERK1/2, by growth factors is disrupted by cAMP through cAMP-dependent protein kinase (PKA). Activation of MEKK2, a mitogen-activated protein (MAP) kinase kinase kinase upstream of ERK5 that is required for growth factor activation of ERK5, is also disrupted by PKA. Transcription of c-Jun is induced by ERK5, and like ERK5, c-Jun induction is also blocked by cAMP. Transcription from the serum response element, like activation of ERK1/2, is not blocked by cAMP. Collectively, these results support a model in which cAMP shapes the growth factor-induced cellular response through PKA-dependent uncoupling of selected MAP kinase cascades from activating signals.


Color Doppler sonography in the evaluation of erectile dysfunction.
Color Doppler sonography can be useful in the evaluation of erectile dysfunction, which can result from psychogenic, endocrinologic, neurogenic, pharmacologic, and vasogenic causes. It is used to determine the integrity of the vascular mechanism. After an intracavernosal injection of a vasodilatory agent, color Doppler sonography is performed to evaluate cavernosal arteries and dorsal vessels. Color flow imaging allows direct visualization of intrapenile anatomy, vascular variants, and disease. It is also helpful in demonstrating transitions in cavernosal and dorsal blood flow. Color Doppler sonography is combined with spectral interrogation of the cavernosal arteries and dorsal veins to help determine peak systolic and end-diastolic velocities. Cavernosal artery size and systolic velocities help diagnose arterial insufficiency. Recent work on cavernosal artery diastolic flow and dorsal vein flow has indicated that color Doppler sonography, when correlated with cavernosographic findings, may be helpful in diagnosing venous incompetence. Temporal variations in transitions in cavernosal artery and dorsal vein flow during various stages of erection are important in the accurate diagnosis of vasogenic impotence.


Escherichia coli sulfite reductase hemoprotein subunit. Prosthetic groups, catalytic parameters, and ligand complexes.
Escherichia coli NADPH-sulfite reductase can be dissociated into an oligomeric flavoprotein and a monomeric hemoprotein (HP) subunit in 4 M urea. HP catalyzes stoichiometric 6-electron reductions of SO32- (to S2-) and of NO2-, as well as 2-electron reduction of NH2OH, with reduced methyl viologen (MV+) as reductant. While Vmax values are highest with the nitrogenous substrates, Km for SO32- is 2 to 3 orders of magnitude less than the Km for NO2- or NH2OH. EPR spectroscopic and chemical analyses show that HP contains one siroheme and one Fe4S4 center per polypeptide. The heme is in the high spin Fe3+ state in HP as isolated. Near-quantitative reduction of the Fe4S4 center to a state yielding a g = 1.94 type of EPR spectrum by S2O42- and/or MV+ could be achieved if HP was converted to either the CN- or CO complex or treated with 80% dimethyl sulfoxide. HP binds one SO32- or CN- per peptide. Binding of these ligands, as well as CO, appears to be mutually exclusive and to involve the heme. The heme Fe3+/Fe2+ potential is shifted from -340 mV in the free HP to -155 mV in the HP-CN- complex. The potential of the Fe4S4 center is approximately 70 mV more negative in the CN- as opposed to the CO-ligated HP (-420 mV), a result which indicates the presence of heme-Fe4S4-ligand interaction in the HP complexes.


Crimean-Congo hemorrhagic fever in the Arab world: A systematic review.
Crimean-Congo hemorrhagic fever (CCHF) is an important tick-borne viral infection with a fatality rate of up to 50% during outbreaks. Crimean-Congo hemorrhagic fever virus (CCHFV) is sustained in the ecosystem in benign form through vertical and horizontal transmission cycles involving tick vectors, wildlife, and livestock. Hyalomma ticks are considered the major source of human infection. CCHF occurs most often among butchers, slaughterhouse workers, and farmworkers through infected tick bites or/and contact with blood and tissues of infected livestock. The nosocomial transmission can occur in auxiliary nurses and physicians through contact with the infected patients. The widespread distribution of CCHFV most probably occurred by ticks on migratory birds, or through international travel and trade of livestock and wildlife. During co-infections of ticks and vertebrates, reassortment among genome segments could play a significant role in generating diversity, and hence, a potential risk for the emergence of novel variants. In this systematic review, we aimed to determine the epidemiology, transmission, distribution, mortality, and clinical features of CCHF in 22 Arab countries, comprising the Arab world. Based on the analysis of 57 studies published from 1978 to 2021, we found 20 tick species that could be associated with CCHFV transmission. During the 43-year period, 321 cases of CCHF were reported from 9/22 Arab countries, Iraq, Kuwait, UAE, Saudi Arabia, Oman, Sudan, Egypt, Tunisia, and Mauritania. The mean case fatality rate was 29% during various outbreaks. Individuals working in abattoirs/slaughter houses, livestock farms, and healthcare were most at risk. Contact with blood or body secretions from infected animals and patients was the most common mode of transmission. A number of different animals, including cattle, goats, sheep, and camels were reported to be seropositive for CCHFV. The highest seroprevalence was observed in camels (29%), followed by cattle (21%), goats (15%), and sheep (14%). We discuss these results in the context of policy-making and potential preventative measures that can be implemented to reduce the burden of CCHF in the Arab world.


Long COVID and Chronic Conditions in the U.S. Workforce: Prevalence, Productivity Loss, and Disability.
This study examines how Long COVID, chronic conditions, and work outcomes affect the general workforce. It examines the prevalence of Long COVID and its associations with chronic conditions, and other sociodemographic characteristics using 2022 National Health Interview Survey data. Long COVID affected work attendance and disability risk, especially in those with mental health issues, angina, stroke, cancer, diabetes, chronic lung conditions, and musculoskeletal conditions. This study reveals the relationships between Long COVID, chronic conditions, and work outcomes.


Arbuscular mycorrhizal fungi differ in their ability to regulate the expression of phosphate transporters in maize (Zea mays L.).
Previous studies have found that some phosphate (Pi) starvation inducible transporter genes are downregulated and arbuscular mycorrhizal (AM) inducible Pi transporter genes are upregulated in maize roots associated with the fungus Glomus intraradices. However, little is known about the functional diversity of different AM fungal species in influencing the expression of Pi transporters in maize roots. Here, we studied the expression of two Pi transporter genes ZEAma:Pht1;3 (Pi starvation inducible) and ZEAma:Pht1;6 (AM inducible) in maize root colonized by different AM fungal inoculants. Non-mycorrhizal maize, maize colonized by Glomus deserticola (CA113), Glomus intraradices (IA506), Glomus mosseae (CA201), Gigaspora gigantea (MN922A) and the co-inoculation of all four species were established. The expression patterns of the two genes were quantified using real-time, reverse transcription polymerase chain reaction. The expression level of ZEAma:Pht1;6 was 26-135 times higher in AM plants than in non-mycorrhizal maize roots, whereas the expression level of ZEAma:Pht1;3 was five to 44 times lower in AM plants than in non-mycorrhizal plants. Expression of the two genes differed with inoculation treatment, and increasing the diversity of AM fungi in maize roots led to greater expression of ZEAma:Pht1;6 as well as Pi uptake in shoots. The expression of ZEAma:Pht1;6 was significantly positively correlated with AM colonization rate, concentration of AM biomarkers in maize roots, Pi uptake and dry weight of shoot, but negatively correlated with the expression of ZEAma:Pht1;3. Addition of Pi fertilizer at a low concentration significantly increased the expression of ZEAma:Pht1;6 but had no effect on the expression of ZEAma:Pht1;3.


Diagnosis and treatment of idiopathic thrombocytopenic purpura. American Society of Hematology ITP Practice Guideline Panel.
The American Society of Hematology established a panel to develop practice guidelines for the diagnosis and management of idiopathic thrombocytopenic purpura and to document the extent to which the recommendations are based on either scientific evidence or opinion. A comprehensive literature review found little high-quality scientific evidence to define the natural history of idiopathic thrombocytopenic purpura or to assess the efficacy of diagnostic tests and treatments for the disorder. Recommendations were therefore based on opinion, derived from a formal scoring procedure. In the panel's opinion, in most cases only a history, physical examination and complete blood cell count with examination of the peripheral blood smear are necessary in the routine work-up of patients with suspected idiopathic thrombocytopenic purpura. The panel suggests different treatment approaches in children and adults because of important differences in the behavior of the disease in the two patient groups. The panel recommends that idiopathic thrombocytopenic purpura accompanied by severe bleeding be treated with glucocorticoids, intravenous immunoglobulin and other measures, but that treatment and hospitalization are often unnecessary when patients have only mild to moderate thrombocytopenia or minimal bleeding. Idiopathic thrombocytopenic purpura in pregnant women and the risk of thrombocytopenia in their newborns pose specific problems for diagnosis and treatment.


The effect of CO2 pneumoperitoneum on serum prostate-specific antigen levels in patients undergoing laparoscopic cholecystectomy.
Recently, several studies have shown an elevation of serum prostate-specific antigen (PSA) levels after the events associated with presumed pelvic ischemia. Although it has been shown that CO2 pneumoperitoneum during laparoscopic surgery causes splanchnic ischemia, no study has investigated the PSA levels after this procedure. This study aimed to evaluate the effects of CO2 pneumoperitoneum on serum total PSA (tPSA) and free PSA (fPSA) levels in patients undergoing laparoscopic cholecystectomy. This study involved 30 men who underwent elective laparoscopic cholecystectomy. Serum tPSA and fPSA levels and f/tPSA ratios were determined the day before surgery (baseline), immediately before insufflation, after desufflation, and 24 hours and 7 days after surgery. Serum tPSA and fPSA values after desufflation and 24 hours after surgery were significantly higher than the values before insufflation and at baseline (P<0.01), whereas the f/tPSA ratio did not change (P>0.05). PSA levels decreased to baseline levels after 7 days. Our study showed that CO2 pneumoperitoneum during laparoscopic surgery can cause a rise in serum tPSA and fPSA levels. We think that CO2 pneumoperitoneum during laparoscopic surgery should be added to list of the events in which PSA measurements must be interpreted with caution.


A qualitative exploration of discharge destination as an outcome or a driver of acute stroke care.
Many patients with acute stroke do not receive recommended care in tertiary hospital settings. Allied health professionals have important roles within multidisciplinary stroke teams and influence the quality of care patients receive. Studies examining the role of allied health professionals in acute stroke management are scarce, and very little is known about the clinical decision making of these stroke clinicians. In this study we aimed to describe factors that influence the complex clinical decision making of these professionals as they prioritise acute stroke patients for recommended care. This qualitative study was part of a larger mixed methods study. The qualitative methodology applied was a constructivist grounded theory approach.Fifteen allied health professionals working with acute stroke patients at three metropolitan tertiary care hospitals in South Australia were purposively sampled.Semi-structured interviews were conducted face to face using a question guide, and digital recording. Interviews were transcribed and analysed by two researchers using rigorous grounded theory processes. Our analysis highlighted 'predicted discharge destination' as a powerful driver of care decisions and clinical prioritisation for this professional group. We found that complex clinical decision making to predict discharge destination required professionals to concurrently consider patient's pre-stroke status, the nature and severity of their stroke, the course of their recovery and multiple factors from within the healthcare system. The consequences of these decisions had potentially profound consequences for patients and sometimes led to professionals experiencing considerable uncertainty and stress. Our qualitative enquiry provided new insights into the way allied health professionals make important clinical decisions for patients with acute stroke. This is the first known study to demonstrate that the subjective prediction of discharge destination made early in an acute admission by allied health professionals, has a powerful influence over the care and rehabilitation provided, and the ultimate outcomes for stroke patients.


SENP1-mediated SUMOylation of SIRT1 affects glioma development through the NF-κB pathway.
Gliomas are the most common primary brain tumors in adults. Although they exist in different malignant stages, most gliomas are clinically challenging because of their infiltrative growth patterns and inherent relapse tendency with increased malignancy. Epigenetic alterations have been suggested to be an important factor for glioma genesis. Using mRNA probe hybridization, we identified SUMO-specific protease 1 (SENP1) as the most significantly upregulated SUMOylation regulator in glioma. Moreover, SENP1 was overexpressed in gliomas and predicted poor prognoses. Depletion of SENP1 reduced glioma cell activity, cycle arrest, and increased apoptotic activity. Mechanistically, SENP1 inhibited the protein expression of sirtuin 1 (SIRT1) through de-SUMOylation, and SIRT1 inhibited the activity of nuclear factor kappaB (NF-κB) by deacetylation. Rescue experiments revealed that downregulation of SIRT1 reversed the inhibitory effect of sh-SENP1 on glioma cell malignant phenotype, while downregulation of NF-κB reversed the activating effect of sh-SIRT1 on glioma cell malignant phenotype. Thus, SENP1-mediated de-SUMOylation of SIRT1 might be therapeutically important in gliomas.


Elevated breast cancer risk in irradiated BALB/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene.
Female BALB/c mice are unusually radiosensitive and more susceptible than C57BL/6 and other tested inbred mice to ionizing radiation (IR)-induced mammary tumors. This breast cancer susceptibility is correlated with elevated susceptibility for mammary cell transformation and genomic instability following irradiation. In this study, we report the identification of two BALB/c strain-specific polymorphisms in the coding region of Prkdc, the gene encoding the DNA-dependent protein kinase catalytic subunit, which is known to be involved in DNA double-stranded break repair and post-IR signal transduction. First, we identified an A --> G transition at base 11530 resulting in a Met --> Val conversion at codon 3844 (M3844V) in the phosphatidylinositol 3-kinase domain upstream of the scid mutation (Y4046X). Second, we identified a C --> T transition at base 6418 resulting in an Arg --> Cys conversion at codon 2140 (R2140C) downstream of the putative leucine zipper domain. This unique PrkdcBALB variant gene is shown to be associated with decreased DNA-dependent protein kinase catalytic subunit activity and with increased susceptibility to IR-induced genomic instability in primary mammary epithelial cells. The data provide the first evidence that naturally arising allelic variation in a mouse DNA damage response gene may associate with IR response and breast cancer risk.


Unified theory for light-induced halide segregation in mixed halide perovskites.
Mixed halide perovskites that are thermodynamically stable in the dark demix under illumination. This is problematic for their application in solar cells. We present a unified thermodynamic theory for this light-induced halide segregation that is based on a free energy lowering of photocarriers funnelling to a nucleated phase with different halide composition and lower band gap than the parent phase. We apply the theory to a sequence of mixed iodine-bromine perovskites. The spinodals separating metastable and unstable regions in the composition-temperature phase diagrams only slightly change under illumination, while light-induced binodals separating stable and metastable regions appear signalling the nucleation of a low-band gap iodine-rich phase. We find that the threshold photocarrier density for halide segregation is governed by the band gap difference of the parent and iodine-rich phase. Partial replacement of organic cations by cesium reduces this difference and therefore has a stabilizing effect.


Schistosoma-related molecules as a new strategy to combat type 1 diabetes through immune regulation.
The study of immune regulation mechanisms induced by parasites may help develop new treatment methods for inflammatory diseases including type 1 diabetes, which is related to type 1 immune responses. The negative correlation between schistosomiasis infection and type 1 diabetes has been confirmed, and the mechanism of Schistosoma-mediated prevention of type 1 diabetes may be related to the adaptive and innate immune systems. Schistosoma-related molecules affect immune cell composition and macrophage polarization and stimulate an increase in natural killer T cells. Furthermore, Schistosoma-related molecules can regulate the adaptive immune responses related to the prevention of type 1 diabetes and change the Th1/Th2 and Th17/Treg axis. Our previous review showed the role of regulatory T cells in the protective of type 1 diabetes mediated by Schistosoma. Here, we aim to review the other mechanisms of schistosomiasis infection and Schistosoma-related products in regulating the immune response associated with the treatment of type 1 diabetes.


Tailgut cyst accompanied with bony defect.
Retro-rectal cystic hamartoma (tailgut cyst), is an uncommon congenital developmental lesion, generally located in the retro-rectal space. Its diagnosis and approach is challenging because the retropelvic space is not familiar. We report a 51-year-old woman who presented with paresthesia and pain in perianal area. The magnetic resonance image showed high signal intensity on the T1-weighted image and iso to high signal intensity on the T2-weighted image of the retropelvic space and CT showed sacral bony defect. We chose the posterior approach for removal of the tailgut cyst. Histopathology exam of the retropelvic cyst revealed a multiloculated cyst containing abundant mucoid material lined by both squamous and glandular mucinous epithelium. The patient has recovered nicely with no recurrence. Tailgut cyst needs complete surgical excision for good prognosis. So, a preoperative high-resolution image and co-operation between neurosurgen and general surgeon would help to make safe and feasible diagnosis and surgical access.


Chimeric streptococcal plasmids and their use as molecular cloning vehicles in Streptococcus sanguis (Challis).
Chimeric plasmids, which were useful as cloning vehicles in a Streptococcus sanguis (Challis) host vector system, have been constructed. By using three different strategies of restriction endonuclease digestion and ligation, a deoxyribonucleic acid (DNA) fragment bearing an erythromycin resistance determinant was ligated in vitro to a phenotypially cryptic plasmid from Streptococcus ferus. Recombinant plasmids could be recovered after transformation of S. sanguis (Challis) with these preparations. Three useful chimeras were constructed. pVA680, 5.5 megadaltons in size, contained a single KpnI site into which passenger DNA may be spliced. pVA736, 5.0 megadaltons in size, contained single EcoRI, HindIII, and KpnI sites into which passenger DNA may be spliced. The EcoRI and KpnI sites of pVA736 may be used in combination with one another when ligating DNA into this plasmid. pVA738, 3.7 megadaltons in size, contained single HindIII and AvaI sites into which passenger DNA may be spliced. pVA680, pVA736, and pVA738 were stably maintained as multicopy plasmids in S. sanguis (Challis). None of them continued to replicate (amplify) in chloramphenicol-treated cells. By using pVA736 as a vector, we have cloned a chloramphenicol resistance determinant obtained from a large, conjugative streptococcal R plasmid. In addition, chromosomal DNA sequences from Streptococcus mutans have been inserted into pVA736 by using the KpnI-EcoRI site combination.


Phase 2 study of subcutaneous omacetaxine mepesuccinate for chronic-phase chronic myeloid leukemia patients resistant to or intolerant of tyrosine kinase inhibitors.
Omacetaxine mepesuccinate (omacetaxine) is a first-in-class cephalotaxine with a unique mode of action, independent of BCR-ABL, that has shown promising activity in patients with chronic myeloid leukemia (CML). This multicenter, noncomparative, open-label phase 2 study evaluated the efficacy and safety of subcutaneous omacetaxine in CML patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs); results in patients in chronic phase are reported here. Patients received subcutaneous omacetaxine 1.25 mg/m² twice daily days 1-14 every 28 days until hematologic response (up to a maximum of six cycles), then days 1-7 every 28 days as maintenance. Primary endpoints were rates of hematologic response lasting >8 weeks and major cytogenetic response (MCyR). Forty-six patients were enrolled: all had received imatinib, 83% had received dasatinib, and 57% nilotinib. A median 4.5 cycles of omacetaxine were administered (range, 1-36). Hematologic response was achieved or maintained in 31 patients (67%); median response duration was 7.0 months. Ten patients (22%) achieved MCyR, including 2 (4%) complete cytogenetic responses. Median progression-free survival was 7.0 months [95% confidence interval (CI), 5.9-8.9 months], and overall survival was 30.1 months (95% CI, 20.3 months-not reached). Grade 3/4 hematologic toxicity included thrombocytopenia (54%), neutropenia (48%), and anemia (33%). Nonhematologic adverse events were predominantly grade 1/2 and included diarrhea (44%), nausea (30%), fatigue (24%), pyrexia (20%), headache (20%), and asthenia (20%). Subcutaneous omacetaxine may offer clinical benefit to patients with chronic-phase CML with resistance or intolerance to multiple TKI therapies.


Visualizing and realizing caring in practice through guided reflection.
Guided reflection provides a challenging and supportive milieu for practitioners to learn through reflection towards achieving desirable work. This work inevitably demands confrontation with self and the conditions of practice that limit the achievement of desirable work. It also demands an understanding of what is desirable nursing. From an ideological position, desirable work is generally defined in terms of humanistic caring. The paper discusses how caring can be visualized and realized in practice through the experiences practitioners reflect on and share within guided reflection. This work is illustrated using using guided reflection dialogue.


Aspiration cytology of chromophobe cell carcinoma of the kidney.
Fine-needle aspiration biopsy findings in three cases of chromophobe cell carcinoma are described and correlated with histologic and ultrastructural observations. In addition, comparisons are made with three cases each of oncocytoma and granular cell carcinoma. The cells in aspiration smears from chromophobe cell carcinoma closely correlated with histologic pattern of three cell types which were not present in oncocytomas and granular cell carcinomas. These cells had prominent cell borders, and their cytoplasm was either opaque and granular (type I) or variably translucent and reticular (type II and III). Ultrastructurally, the translucent areas within the cytoplasm contained large numbers of microvesicles which were unique to chromophobe cell carcinoma and were not seen in other neoplasms. Fine-needle aspiration may be used to diagnose chromophobe cell carcinoma and distinguish it from other related renal neoplasms.


Adherence to a Mediterranean-like Diet as a Protective Factor Against COPD: A Nested Case-Control Study.
A diet rich in nutrients has been suggested to have protective effects against the development of chronic obstructive pulmonary disease (COPD). Since the traditional Mediterranean diet is high in nutrients, including antioxidants, vitamins, and minerals, it is of interest to study as a protective factor against COPD. Our aim was therefore to study its associations with development of COPD using population-based prospective data from the Västerbotten Intervention Programme (VIP) cohort. Data on diet from 370 individuals, who later visited the Department of Medicine at the University Hospital, Umeå, Sweden, with a diagnosis of COPD, were compared to 1432 controls. Adherence to a Mediterranean diet was assessed by a modified version of the Mediterranean diet score (MDS). Cases were diagnosed with COPD 11.1 years (mean) (standard deviation [SD] 4.5 years) after first stating their dietary habits in the VIP at a mean age of 55.5 years (SD 6.6 years). Higher MDS was associated with a higher level of education and not living alone. After adjustment for co-habiting and education level, individuals with an intermediate MDS and those with the highest MDS had a lower odds of developing COPD (odds ratio [OR] 0.73, 95% confidence interval [CI] 0.56-0.95; OR 0.56, 95% CI 0.37-0.86, respectively). These results remained also after adjustment for smoking intensity, i.e., numbers of cigarettes smoked per day (OR 0.73, 95% CI 0.53-0.99; OR 0.59, 95% CI 0.35-0.97), respectively). To conclude, adherence to a Mediterranean-like diet seems to be inversely associated with the development of COPD.


Effect of prostaglandin synthesis inhibitors on clonidine-induced diuresis in rats.
Clonidine is a centrally acting antihypertensive drug that also has marked renal effects. The role of renal prostaglandins in clonidine-induced diuresis was examined in anesthetized and conscious rats. Twelve surgically prepared rats were pretreated with either of two inhibitors of prostaglandin synthesis, indomethacin or meclofenamate (2 mg/kg), while thirteen rats served as controls. Clonidine (200 micrograms/kg/hr, i. v.) increased urine flow tenfold in both pretreated and nonpretreated controls whereas blood pressure and glomerular filtration rate were reduced by clonidine. Fractional excretions of sodium, potassium, total solute and water were enhanced similarly in these two groups of anesthetized rats. Experiments were also conducted in ten conscious rats pretreated with vehicle, indomethacin (2.0 and 7.5 mg/kg), or meclofenamate (2 mg/kg) prior to clonidine infusion. Marked diuresis occurred whether these rats were pretreated with vehicle or one of the nonsteroidal antiinflammatory drugs (NSAID). Thus, NSAID did not prevent the renal excretory response to clonidine in either anesthetized or conscious rats, suggesting that enhanced prostaglandin synthesis is not an essential component of the diuretic action of this drug in rats.


Overlapping and distinct neural correlates of imitating and opposing facial movements.
Previous studies have demonstrated that imitating a face can be relatively automatic and reflexive. In contrast, opposing facial expressions may require engaging flexible, cognitive control. However, few studies have examined the degree to which imitation and opposition of facial movements recruit overlapping and distinct neural regions. Furthermore, little work has examined whether opposition and imitation of facial movements differ between emotional and averted eye gaze facial expressions. This study utilized a novel task with 40 participants to compare passive viewing, imitation and opposition of emotional faces looking forward and neutral faces with averted eye gaze [(3: Look, Imitate, Oppose) x (2: Emotion, Averted Eye)]. Imitation and opposition of both types of facial movements elicited overlapping activation in frontal, premotor, superior temporal and anterior intraparietal regions. These regions are recruited during cognitive control, face processing and mirroring tasks. For both emotional and averted eye gaze photos, opposition engaged the superior frontal gyrus, superior temporal sulcus and the anterior intraparietal sulcus to a greater extent compared to imitation. Finally, stimulus type and instruction interacted, such that for the eye gaze condition only, greater activation was observed in the dorsal anterior cingulate (dACC) during opposition compared to imitation, while no significant dACC differences were observed for the emotional expression conditions, which instead showed significantly greater activation in the middle and frontal pole. Overall these results showed significant overlap between imitation and opposition, as well as increased activation of these regions to generate an opposing facial movement relative to imitating.


Political Hearts of Darkness: The Dark Triad as Predictors of Political Orientations and Interest in Politics.
This study investigated the relationships between the Dark Triad of personality (sub-clinical psychopathy, Machiavellianism, and narcissism) and four political variables: socio-religious conservatism, support for greater economic equality, overall liberal-conservative orientation, and interest in politics. A theoretical approach that focused on the influence of the Dark Triad in large groups was provided to interpret those relationships. Methodological issues found in previous research that related to the use of abbreviated scales to measure the dark traits and the use of unidimensional indicators of political orientations were addressed. A hierarchical regression analysis was conducted to determine whether any of the three dark traits could explain variance in the aforementioned political attributes over and above that accounted for by the Big Five, sex, age, and nationality, using the full personality scales and measures of political orientation that captured both social and economic liberalism-conservatism. Machiavellianism uniquely predicted lower levels of socio-religious conservatism, and both Machiavellianism and narcissism uniquely predicted lower levels of overall conservatism. There were important links between the Dark Triad and politics.


The Trauma Hemostasis and Oxygenation Research Network's Remote Damage Control Resuscitation Symposium.
This year, the Trauma Hemostasis and Oxygenation Research Network had its third annual conference from June 17 to 19 at the Solstrand Hotel, near Bergen, Norway. It was sponsored and organized by the Norwegian Naval Special Operation Commando together with the Norwegian Air Ambulance Foundation. The Trauma Hemostasis and Oxygenation Research Network is composed of more than 150 members from 16 countries who all have a common interest in the prevention and treatment of traumatic hemorrhagic shock. The network is multidisciplinary to include members from both the military and civilian medical community representing areas of surgery, critical care, emergency medicine, transfusion medicine, anesthesiology, hematology, and basic science.


Unexpected optical activity of cerium in Y2O3:Ce3+, Yb3+, Er3+ up and down-conversion system.
In this work we synthesized rare earth-doped yttria nanocrystals via the Pechini method. We used Ce(3+), Yb(3+) and Er(3+) as dopant ions and studied their behavior when they are simultaneously embedded in the yttrium oxide lattice. The tri-doped system exhibits both downshifting and up-converting properties, due to the presence of, respectively, cerium-erbium and ytterbium-erbium couples. Efforts were put into determination of the effects of the presence of increasing content of cerium. We synthesized a series of samples having the general formula (Y0.88-xCexYb0.1Er0.02)2O3, where x = 0.01, 0.02, 0.10, 0.20, and 0.40. The structural properties of the samples were analyzed by the X-ray powder diffraction (XRPD) technique and the morphological features were disclosed using transmission electron microscope (TEM) observations. Photoluminescence properties were tested by carrying out photoluminescence (PL) emission, photoluminescence excitation (PLE) and lifetime (LT) measurements.


Memantine for axonal loss of optic neuritis.
To determine the effect of memantine on axonal loss and visual function during the course of optic neuritis (ON). Sixty ON patients in a single-center, institutional setting were randomly assigned to the memantine or placebo groups. Patients with first attack of acute unilateral optic neuritis, with visual symptoms of 8 days' duration or less were enrolled in this trial. No patient had known multiple sclerosis, and none had taken immunomodulatory agent prior to or at the time of presentation. For all patients, the following characteristics were recorded and compared at initial presentation and 3 months afterward: visual acuity, retinal nerve fiber layer (RNFL) thickness, visual field parameters (mean deviation and pattern standard deviation), visual evoked potential, and contrast sensitivity. Fifty-four patients completed the 3-month follow up. There were no significant differences between the placebo and memantine groups for any of the characteristics at initial presentation. After 3 months, the only statistically significant difference between the two groups was in RNFL thickness. Memantine group subjects had higher thickness in nasal (P = 0.01), superior (P = 0.006), inferior (P = 0.01) quadrants and average (P = 0.01). However, temporal quadrant thickness was not different between two groups (P = 0.35). Memantine was effective in reduction of RNFL thinning, although this structural difference was not associated with improved visual function.


Ionization energies and cationic bond dissociation energies of RuB, RhB, OsB, IrB, and PtB.
Two-photon ionization thresholds of RuB, RhB, OsB, IrB, and PtB have been measured using resonant two-photon ionization spectroscopy in a jet-cooled molecular beam and have been used to derive the adiabatic ionization energies of these molecules. From the measured two-photon ionization thresholds, IE(RuB) = 7.879(9) eV, IE(RhB) = 8.234(10) eV, IE(OsB) = 7.955(9) eV, IE(IrB) = 8.301(15) eV, and IE(PtB) = 8.524(10) eV have been assigned. By employing a thermochemical cycle, cationic bond dissociation energies of these molecules have also been derived, giving D0(Ru+-B) = 4.297(9) eV, D0(Rh+-B) = 4.477(10) eV, D0(Os-B+) = 4.721(9) eV, D0(Ir-B+) = 4.925(18) eV, and D0(Pt-B+) = 5.009(10) eV. The electronic structures of the resulting cationic transition metal monoborides (MB+) have been elucidated using quantum chemical calculations. Periodic trends of the MB+ molecules and comparisons to their neutral counterparts are discussed. The possibility of quadruple chemical bonds in all of these cationic transition metal monoborides is also discussed.


TurnoveR: A Skyline External Tool for Analysis of Protein Turnover in Metabolic Labeling Studies.
In spite of its central role in biology and disease, protein turnover is a largely understudied aspect of most proteomic studies due to the complexity of computational workflows that analyze in vivo turnover rates. To address this need, we developed a new computational tool, TurnoveR, to accurately calculate protein turnover rates from mass spectrometric analysis of metabolic labeling experiments in Skyline, a free and open-source proteomics software platform. TurnoveR is a straightforward graphical interface that enables seamless integration of protein turnover analysis into a traditional proteomics workflow in Skyline, allowing users to take advantage of the advanced and flexible data visualization and curation features built into the software. The computational pipeline of TurnoveR performs critical steps to determine protein turnover rates, including isotopologue demultiplexing, precursor-pool correction, statistical analysis, and generation of data reports and visualizations. This workflow is compatible with many mass spectrometric platforms and recapitulates turnover rates and differential changes in turnover rates between treatment groups calculated in previous studies. We expect that the addition of TurnoveR to the widely used Skyline proteomics software will facilitate wider utilization of protein turnover analysis in highly relevant biological models, including aging, neurodegeneration, and skeletal muscle atrophy.


Regulation of cell cycle progression by forkhead transcription factor FOXO3 through its binding partner DNA replication factor Cdt1.
To ensure genome stability, DNA must be replicated once and only once during each cell cycle. Cdt1 is tightly regulated to make sure that cells do not rereplicate their DNA. Multiple regulatory mechanisms operate to ensure degradation of Cdt1 in S phase. However, little is known about the positive regulators of Cdt1 under physiological conditions. Here we identify FOXO3 as a binding partner of Cdt1. FOXO3 forms a protein complex with Cdt1, which in turn blocks its interaction with DDB1 and PCNA. Conversely, FOXO3 depletion facilitated the proteolysis of Cdt1 in unperturbed cells. Intriguingly, FOXO3 deficiency resulted in impaired S-phase entry and reduced cell proliferation. We provide data that FOXO3 knockdown mimics Cdt1 down-regulation and affects G1/S transitions. Our results demonstrate a unique role of FOXO3 in binding to Cdt1 and maintaining its level required for cell cycle progression.


Juvenile Idiopathic Arthritis: Diffusion-weighted MRI in the Assessment of Arthritis in the Knee.
Background Diffusion-weighted imaging (DWI) can depict the inflamed synovial membrane in arthritis. Purpose To study the diagnostic accuracy of DWI for the detection of arthritis compared with the clinical reference standard and to compare DWI to contrast material-enhanced MRI for the detection of synovial inflammation. Materials and Methods In this institutional review board-approved prospective study, 45 participants with juvenile idiopathic arthritis (JIA) or suspected of having JIA (seven boys, 38 girls; median age, 14 years [interquartile range, 12-16 years]) were included between December 2015 and December 2018. Study participants underwent pre- and postcontrast 3.0-T MRI of the knee with an additional DWI sequence. For the clinical reference standard, a multidisciplinary team determined the presence or absence of arthritis on the basis of clinical, laboratory, and imaging findings (excluding DWI). Two data sets were scored by two radiologists blinded to all clinical data; data set 1 contained pre- and postcontrast sequences (contrast-enhanced MRI), and data set 2 contained precontrast and DWI sequences (DWI). Diagnostic accuracy was determined by comparing the scores of the DWI data set to those of the clinical reference standard. Second, DWI was compared with contrast-enhanced MRI regarding detection of synovial inflammation. Results Sensitivity for detection of arthritis for DWI was 93% (13 of the 14 participants with arthritis were correctly classified with DWI; 95% confidence interval [CI]: 64%, 100%) and specificity was 81% (25 of 31 participants without arthritis were correctly classified with DWI; 95% CI: 62%, 92%). Scores for synovial inflammation at DWI and contrast-enhanced MRI agreed in 37 of 45 participants (82%), resulting in a sensitivity of 92% (12 of 13 participants; 95% CI: 62%, 100%) and specificity of 78% (25 of 32 participants; 95% CI: 60%, 90%) with DWI when contrast-enhanced MRI was considered the reference standard. Conclusion Diffusion-weighted imaging (DWI) was accurate in detecting arthritis in pediatric participants with juvenile idiopathic arthritis (JIA) or suspected of having JIA and showed agreement with contrast-enhanced MRI. The results indicate that DWI could replace contrast-enhanced MRI for imaging of synovial inflammation in this patient group. © RSNA, 2020 Online supplemental material is available for this article.


Central Role of Macrophages and Nucleic Acid Release in Myasthenia Gravis Thymus.
Myasthenia gravis (MG) is a neuromuscular disease mediated by antibodies against the acetylcholine receptor (AChR). The thymus plays a primary role in AChR-MG and is characterized by a type I interferon (IFN) signature linked to IFN-β. We investigated if AChR-MG was characterized by an IFN-I signature in the blood, and further investigated the chronic thymic IFN-I signature. Serum levels of IFN-β and IFN-α subtypes, and mRNA expression for IFN-I subtypes and IFN-stimulated genes in peripheral mononuclear blood cells (PBMCs) were analyzed. The contribution of endogenous nucleic acids in thymic expression of IFN-I subtypes was investigated in human thymic epithelial cell cultures and the mouse thymus. By immunohistochemistry, thymic CD68+ and CD163+ macrophages were analyzed in AChR-MG. To investigate the impact of a decrease in thymic macrophages, mice were treated with an anti-CSF1R antibody. No IFN-I signature was observed in the periphery emphasizing that the IFN-I signature is restricted to the MG thymus. Molecules mimicking endogenous dsDNA signalization (Poly(dA:dT) and 2'3'-cGAMP), or dexamethasone-induced necrotic thymocytes increased IFN-β and α-AChR expression by thymic epithelial cells, and in the mouse thymus. A significant decrease in thymic macrophages was demonstrated in AChR-MG. In mice, a decrease in thymic macrophages led to an increase of necrotic thymocytes associated with IFN-β and α-AChR expression. These results suggest that the decrease of thymic macrophages in AChR-MG impairs the elimination of apoptotic thymocytes favoring the release of endogenous nucleic acids from necrotic thymocytes. In this inflammatory context, thymic epithelial cells may overexpress IFN-β, which specifically induces α-AChR, resulting in self-sensitization and thymic changes leading to AChR-MG. ANN NEUROL 2023;93:643-654.


Investigation of Outbreak-Specific Nonsynonymous Mutations on Ebolavirus GP in the Context of Known Immune Reactivity.
The global response to the most recent EBOV outbreak has led to increased generation and availability of data, which can be globally analyzed to increase our understanding of immune responses to EBOV. We analyzed the published antibody epitope data to identify regions immunogenic for humans on the main GP antigenic target and determine sequence variance/nonsynonymous mutations between historical isolates and variants from the 2013-2016 outbreak. Approximately half of the GP sequence has been reported as targeted by antibody responses. Our results show an enrichment of nonsynonymous mutations (NSMs) within epitopic regions on GP (70%, p = 0.0133). Mapping NSMs to human epitope reactivity may be useful for future therapeutic and prophylaxis development as well as for our general understanding of immunity against EBOV.


Learning Deep Gradient Descent Optimization for Image Deconvolution.
As an integral component of blind image deblurring, non-blind deconvolution removes image blur with a given blur kernel, which is essential but difficult due to the ill-posed nature of the inverse problem. The predominant approach is based on optimization subject to regularization functions that are either manually designed or learned from examples. Existing learning-based methods have shown superior restoration quality but are not practical enough due to their restricted and static model design. They solely focus on learning a prior and require to know the noise level for deconvolution. We address the gap between the optimization- and learning-based approaches by learning a universal gradient descent optimizer. We propose a recurrent gradient descent network (RGDN) by systematically incorporating deep neural networks into a fully parameterized gradient descent scheme. A hyperparameter-free update unit shared across steps is used to generate the updates from the current estimates based on a convolutional neural network. By training on diverse examples, the RGDN learns an implicit image prior and a universal update rule through recursive supervision. The learned optimizer can be repeatedly used to improve the quality of diverse degenerated observations. The proposed method possesses strong interpretability and high generalization. Extensive experiments on synthetic benchmarks and challenging real-world images demonstrate that the proposed deep optimization method is effective and robust to produce favorable results as well as practical for real-world image deblurring applications.


Transcranial direct current stimulation for post-stroke dysphagia: a meta-analysis.
Strokes may cause some swallowing difficulty or associated dysphagia in 25-80% of patients. This phenomenon has been linked to increased morbidity and mortality. Therefore, the aim of this study was to evaluate the efficacy of transcranial direct current stimulation in patients with dysphagia in post-stroke patients. A systematic search in PubMed, Scopus, Web of Science and MEDLINE was conducted. The articles must have to evaluate an intervention that included transcranial direct current stimulation; the sample had to consist exclusively of patients with post-stroke dysphagia; and the experimental design consisted of randomized controlled trial. Difference in mean differences and their 95% confidence interval were calculated as the between-group difference in means divided by the pooled standard deviation. The I2 statistic was used to determine the degree of heterogeneity. Of the 9 investigations analyzed, all applied transcranial direct current stimulation in combination with conventional dysphagia therapy to the experimental group. All the studies analyzed identified improvements in swallowing function and meta-analysis confirmed their strong effect on reducing the risk of penetration and aspiration (Hedges's g = 0.55). The results showed that participants who received transcranial direct current stimulation significantly improved swallowing function. Transcranial direct current stimulation has positive effects in the treatment of poststroke dysphagia by improving swallowing function, oral and pharyngeal phase times and the risk of penetration and aspiration. Furthermore, its combination with conventional dysphagia therapy, balloon dilatation with catheter or training of the swallowing muscles ensures improvement of swallowing function. PROSPERO registration ID CRD42022314949.


An Amyloid Core Sequence in the Major Candida albicans Adhesin Als1p Mediates Cell-Cell Adhesion.
The human fungal commensal Candida albicans can become a serious opportunistic pathogen in immunocompromised hosts. The C. albicans cell adhesion protein Als1p is a highly expressed member of a large family of paralogous adhesins. Als1p can mediate binding to epithelial and endothelial cells, is upregulated in infections, and is important for biofilm formation. Als1p includes an amyloid-forming sequence at amino acids 325 to 331, identical to the sequence in the paralogs Als5p and Als3p. Therefore, we mutated Val326 to test whether this sequence is important for activity. Wild-type Als1p (Als1pWT) and Als1p with the V326N mutation (Als1pV326N) were expressed at similar levels in a Saccharomyces cerevisiae surface display model. Als1pV326N cells adhered to bovine serum albumin (BSA)-coated beads similarly to Als1pWT cells. However, cells displaying Als1pV326N showed visibly smaller aggregates and did not fluoresce in the presence of the amyloid-binding dye Thioflavin-T. A new analysis tool for single-molecule force spectroscopy-derived surface mapping showed that statistically significant force-dependent Als1p clustering occurred in Als1pWT cells but was absent in Als1pV326N cells. In single-cell force spectroscopy experiments, strong cell-cell adhesion was dependent on an intact amyloid core sequence on both interacting cells. Thus, the major adhesin Als1p interacts through amyloid-like β-aggregation to cluster adhesin molecules in cis on the cell surface as well as in trans to form cell-cell bonds.IMPORTANCE Microbial cell surface adhesins control essential processes such as adhesion, colonization, and biofilm formation. In the opportunistic fungal pathogen Candida albicans, the agglutinin-like sequence (ALS) gene family encodes eight cell surface glycoproteins that mediate adherence to biotic and abiotic surfaces and cell-cell aggregation. Als proteins are critical for commensalism and virulence. Their activities include attachment and invasion of endothelial and epithelial cells, morphogenesis, and formation of biofilms on host tissue and indwelling medical catheters. At the molecular level, Als5p-mediated cell-cell aggregation is dependent on the formation of amyloid-like nanodomains between Als5p-expressing cells. A single-site mutation to valine 326 abolishes cellular aggregation and amyloid formation. Our results show that the binding characteristics of Als1p follow a mechanistic model similar to Als5p, despite its differential expression and biological roles.


Ancient DNA analysis of human neolithic remains found in northeastern Siberia.
We successfully extracted DNA from a bone sample of a Neolithic skeleton (dated 3,600 +/- 60 years BP) excavated in northeastern Yakutia (east Siberia). Ancient DNA was analyzed by autosomal STRs (short tandem repeats) and by sequencing of the hypervariable region I (HV1) of the mitochondrial DNA (mtDNA) control region. The STR profile, the mitochondrial haplotype, and the haplogroup determined were compared with those of modern Eurasian and Native American populations. The results showed the affinity of this ancient skeleton with both east Siberian/Asian and Native American populations.


Leveraging ToF-SIMS imaging to investigate tenofovir disoproxil fumarate degradation at excipient interfaces in oral compressed tablets.
Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging has been used to study the hydrolysis of tenofovir disoproxil fumarate (TDF) to tenofovir monosoproxil (TM) within an oral compressed tablet. The ToF-SIMS images displayed a heterogenous distribution of the matrix components. Evaluation of the TM distribution revealed that it was primarily co-localized with areas of higher excipient concentration pointing toward excipient driven degradation. To support these observations, a compatibility study of TDF with each tablet component was performed via liquid chromatography. The ToF-SIMS imaging and compatibility study indicated that the excipient, Avicel® PH-102, was the primary driver of TM formation in the tablet. The hydrolysis degradation mechanism within the tablet is further rationalized through discussion of chemical and physical properties of the matrix components. The sum of this work demonstrates a new analytical workflow for probing and understanding matrix driven degradation in oral compressed tablets utilizing ToF-SIMS imaging.


A familial degenerative neuromuscular disease of Gelbvieh cattle.
A degenerative skeletal muscle disease with vascular, neurologic, and renal lesions and a probable familial distribution was identified in 4-20-month-old purebred Gelbvieh cattle. Thirteen affected animals were confirmed from 6 separate beef herds, with a mortality rate of 100%. Clinical signs in affected animals consisted of ataxia, weakness, and terminal recumbency. Gross and histologic muscle lesions were indicative of nutritional myopathy of ruminants, with a lack of myocardial lesions in most cases and only rare myocardial changes in a few animals. Acute to chronic lesions in most large skeletal muscle groups consisted of degeneration, necrosis, regeneration, fibrosis, and atrophy. Fibrinoid necrosis of arterioles was a common feature in multiple tissues. Lesions in the spinal cord white matter and peripheral nerves consisted of degeneration of the dorsal columns and axons, respectively. Changes in the kidneys consisted of chronic interstitial nephritis with fibrosis, hyaline droplet change and tubular epithelial vacuolar change and were most severe in the older calves. Intracytoplasmic myoglobin and iron were demonstrated within the hyaline droplets in degenerate renal cortical tubular epithelial cells. Vitamin E levels were deficient in most (6/7) of the animals tested. Investigation of the pedigree of affected animals revealed a common ancestry for all but 1 of the animals whose parentage could be traced. This investigation suggests that a hereditary metabolic defect, possibly involving antioxidant metabolism, could be responsible for this condition. Renal disease, possibly secondary to myoglobinuria, may be unique to this bovine condition.


CSN5 inhibition triggers inflammatory signaling and Rho/ROCK-dependent loss of endothelial integrity.
RhoGTPases regulate cytoskeletal dynamics, migration and cell-cell adhesion in endothelial cells. Besides regulation at the level of guanine nucleotide binding, they also undergo post-translational modifications, for example ubiquitination. RhoGTPases are ubiquitinated by Cullin RING ligases which are in turn regulated by neddylation. Previously we showed that inhibition of Cullin RING ligase activity by the neddylation inhibitor MLN4924 is detrimental for endothelial barrier function, due to accumulation of RhoB and the consequent induction of contractility. Here we analyzed the effect of pharmacological activation of Cullin RING ligases on endothelial barrier integrity in vitro and in vivo. CSN5i-3 induced endothelial barrier disruption and increased macromolecule leakage in vitro and in vivo. Mechanistically, CSN5i-3 strongly induced the expression and activation of RhoB and to lesser extent of RhoA in endothelial cells, which enhanced cell contraction. Elevated expression of RhoGTPases was a consequence of activation of the NF-κB pathway. In line with this notion, CSN5i-3 treatment decreased IκBα expression and increased NF-κB-mediated ICAM-1 expression and consequent adhesion of neutrophils to endothelial cells. This study shows that sustained neddylation of Cullin RING-ligases leads to activation the NF-κB pathway in endothelial cells, elevated expression of RhoGTPases, Rho/ROCK-dependent activation of MLC and disruption of the endothelial barrier.


Management of pancreatitis and pancreatic: fluid collections.
Acute pancreatitis is a constant management challenge, especially with peripancreatic collection that are one of the most common complications; after the first surgical attempts that had high mortality, there had to be a new approach based in decades of acquired knowledge in physiopathology added to the development of endoscopic intervention techniques and the evolution of endoscopic devices help to establish less invasive and conservative management. This review allows us to know the last advances in the management of acute pancreatitis, pancreatic pseudocyst and walled off necrosis, determined the right time for the management to become more invasive, even considering surgery at a final stage. It also reviews the different types of drainage of peripancreatic collections and the accessories currently in use.


Trauma Visits to a Pediatric Emergency Department During the COVID-19 Quarantine and "Stay at Home" Period.
Impact of social distancing on pediatric injuries is unknown. We retrospectively compared injury visits to a pediatric emergency department by individuals ≤21 years during "Stay at Home" (SHO) period to the same period in 2019 (non-SHO). Demographics, types, and outcomes of injuries were noted. Although, there was a 35.6% reduction in trauma-related emergency department visits during SHO period (1226 vs 1904), the proportion of injury visits increased (15.5% vs 8.1%, P < .001) and mean age was lower (5.8 yrs ±4.5 vs 8.4 yrs ± 5.2, P < .001). There were significant increases in visits related to child physical abuse (CPA), firearms, and dog bites. Further, significant increases in trauma alerts (P < .01), injury severity (P < .01), critical care admissions (P < .001), and deaths (P < .01) occurred during the SHO period. Although overall trauma-related visits decreased during SHO, the proportion of these visits and their severity increased. Trauma visits related to child physical abuse, dog bites, and firearms increased. Further studies are required to assess the long-term impact of pandemic on pediatric trauma epidemiology.


Neighborhood conditions and birth outcomes: Understanding the role of perceived and extrinsic measures of neighborhood quality.
Living in a disadvantaged neighborhood has been associated with adverse birth outcomes. Most prior studies have conceptualized neighborhoods using census boundaries and few have examined the role of neighborhood perceptions, which may better capture the neighborhood environment. In the present study, we examined associations between extrinsic and perceived neighborhood quality measures and adverse birth outcomes. Participants resided in the San Francisco Bay Area of California and were enrolled in Chemicals in Our Bodies, a prospective birth cohort (N = 817). The Index of Concentration at the Extremes (ICE) for income, Area Deprivation Index (ADI), and the Urban Displacement Project's measure of gentrification were included as census block group-level extrinsic neighborhood quality measures. Poor perceived neighborhood quality was assessed using an interview questionnaire. Linear regression models were utilized to examine associations between extrinsic and perceived neighborhood quality measures, and gestational age and birthweight for gestational age z-scores. Covariates in adjusted models were chosen via a directed acyclic graph (DAG) and included maternal age, education, and marital status. In adjusted models, having poor perceived neighborhood quality was associated with higher birthweight z-scores, relative to those who did not perceive their neighborhood as poor quality (β = 0.21, 95% confidence intervals = 0.01, 0.42). Relative to the least disadvantaged tertile, the upper tertile of the ADI was associated with a modest reduction in gestational age (β = -0.35, 95% confidence intervals = -0.67, -0.02). In the Chemicals in Our Bodies study population, extrinsic and perceived neighborhood quality measures were inconsistently associated with adverse birth outcomes.


GlycomicsDB - A Data Integration Platform for Glycans and their Strucutres.
Glycomics is a discipline of biology that deals with the structure and function of glycans (or carbohydrates). Analytical techniques such as mass spectrometry (MS) and nuclear magnetic resonance (NMR) are having a significant impact on the field of glycomics. However, effective progress in glycomics research requires collaboration between laboratories to share experimental data, structural information of glycans, and simulation results. Herein we report the development of a web-based data management system that can incorporate large volumes of data from disparate sources and organize them into a uniform format for users to store and access. This system enables participating laboratories to set up a shared data repository which members of interdisciplinary teams can access. The system is able to manage and share raw MS data and structural information of glycans.The database is available at http://www.glycomics.bcf.ku.edu.


The inaugural United States World Hospice and Palliative Care Day Celebration: A virtual coming together.
On October 10, 2020, the Memorial Sloan Kettering Cancer Center Supportive Care Service hosted their first-ever United States (US) World Hospice and Palliative Care Day (WHPCD) Celebration. The purpose of this article is to describe the US inaugural event in alignment with the broader goals of WHPCD and provide lessons learned in anticipation of the second annual conference to be held on October 5-6, 2021. Description of the inaugural event in the context of COVID-19 and WHPCD, co-planning conference team reflection, and attendee survey responses. The Worldwide Hospice Palliative Care Alliance initially launched WHPCD in 2005 as an annual unified day of action to celebrate and support hospice and palliative care around the world. The US-based innovative virtual conference featured 23 interprofessional hospice and palliative care specialists and patient and family caregiver speakers across nine diverse sessions addressing priorities at the intersection of COVID-19, social injustice, and the global burden of serious health-related suffering. Two primary aims guided the event: community building and wisdom sharing. Nearly 270 registrants from at least 16 countries and one dozen states across the US joined the free program focused on both personal and professional development. Unlike many other academic conferences and professional gatherings that were relegated to online forums due to pandemic-related restrictions, the US WHPCD Celebration was intentionally established to create a virtual coming together for collective reflection on the barriers and facilitators of palliative care delivery amid vast societal change. The goal to ensure a globally relevant and culturally inclusive agenda will continue to draw increased participation at an international level during future annual events. Finally, the transparent and respectful sharing of palliative care team experiences in the year preceding the conference established a safe environment for both individual expression and scholarly discussion.


Accuracy of electronic deposition of cells onto microscope slides using a cytometric positioning system.
The Cell Deposition System (CDS) analyzes and deposits biological cells to specific locations on microscope slides. This research will determine the accuracy of the CDS by comparing the stored computer data with the cells placement on the microscope slide. Two independent maps (Control 1 and Control 2) of cell placement for each slide were made, each map to provide a control for the other. The fluorescence data (cell sequence data) was compared to each of the control maps. For the slide, CT4, the error between maps was 13.6% mismatches, between Control 2 and the fluorescence data 32.1% mismatches. Comparing the maps 3/16 rows were perfectly matched; Whereas, comparing fluorescence data to maps 1/16 express perfect matches. Depositing cells in this manner is remarkable accurate. Nevertheless work remains to prevent the "disappearance" of cells, their adjacent positional invasion, and their clustering. This technique provides a superior preparative method for sample archival storage and for further automated multiparametric microscope assessment.


The Physiological Requirements of and Nutritional Recommendations for Equestrian Riders.
Equestrian sport is under-researched within the sport science literature, creating a possible knowledge vacuum for athletes and support personnel wishing to train and perform in an evidence-based manner. This review aims to synthesise available evidence from equitation, sport, and veterinary sciences to describe the pertinent rider physiology of equestrian disciplines. Estimates of energy expenditure and the contribution of underpinning energy systems to equestrian performance are used to provide nutrition and hydration recommendations for competition and training in equestrian disciplines. Relative energy deficiency and disordered eating are also considered. The practical challenges of the equestrian environment, including competitive, personal, and professional factors, injury and concussion, and female participation, are discussed to better highlight novelty within equestrian disciplines compared to more commonly studied sports. The evidence and recommendations are supported by example scenarios, and future research directions are outlined.


Film and digital periapical radiographs for the measurement of apical root shortening.
The aim of this study was to compare the accuracy and agreement of scanned film and digital periapical radiographs for the measurement of apical root shortening. Twenty-four film and digital [phosphor plate sensor (PPS)] periapical radiographs were taken using the long-cone paralleling technique for six extracted teeth before and after 1mm of apical root trimming. All teeth were mounted using a typodont and the radiographs were recorded using a film holder and polysiloxane occlusal index for each tooth to ensure standardization during the different radiographic exposures. The film radiographs were scanned and the tooth length measurements for the scanned film and digital (PPS) images were calculated using Image-J-Link 1.4 software (http://rebweb.nih.gov/ij/index.html) for the two groups. The accuracy and agreement among the tooth length measurements from each group and the true tooth length measurements were calculated using intra-class correlation (ICC) tests and Bland and Altman plots. A high level of agreement was found between the true tooth length measurements and the scanned film measurements (ICC=0.979, limit of agreement 0.579 to -0.565) and the digital (PPS) radiograph measurements (ICC= 0.979, limit of agreement 0.596 to -0.763). Moreover, a high level of agreement was found between the scanned film and digital (PPS) radiographs for the measurement of tooth length ICC=0.991, limit of agreement 0.411-0.231. Film and digital (PPS) periapical radiographs are accurate methods for measuring apical root shortening with a high level of agreement. Key words:Root shortening, measurement, periapical radiographs, film, digital.


A Host ER Fusogen Is Recruited by Turnip Mosaic Virus for Maturation of Viral Replication Vesicles.
Like other positive-strand RNA viruses, the Turnip mosaic virus (TuMV) infection leads to the formation of viral vesicles at the endoplasmic reticulum (ER). Once released from the ER, the viral vesicles mature intracellularly and then move intercellularly. While it is known that the membrane-associated viral protein 6K2 plays a role in the process, the contribution of host proteins has been poorly defined. In this article, we show that 6K2 interacts with RHD3, an ER fusogen required for efficient ER fusion. When RHD3 is mutated, a delay in the development of TuMV infection is observed. We found that the replication of TuMV and the cell-to-cell movement of its replication vesicles are impaired in rhd3 This defect can be tracked to a delayed maturation of the viral vesicles from the replication incompetent to the competent state. Furthermore, 6K2 can relocate RHD3 from the ER to viral vesicles. However, a Golgi-localized mutated 6K2GV is unable to interact and relocate RHD3 to viral vesicles. We conclude that the maturation of TuMV replication vesicles requires RHD3 for efficient viral replication and movement.


A New Infrared Heat Treatment on Hot Forging 7075 Aluminum Alloy: Microstructure and Mechanical Properties.
When hot forging 7075 aluminum alloy, as a military material durable enough for most of its applications, it needs to be heat-treated to ensure the target material property achieves the application requirements. However, the material properties change because of heat throughout usage. In this study, a new approach was devised to heat treat the alloy to prevent material property changes. The study further clarified the effect of rapid heat treatment on the high-temperature resistance of a hot forging 7075 aluminum alloy. Infrared (IR) heat treatment was used as a rapid heating technique to effectively replace the conventional resistance heat (RH) treatment method. Our experimental result showed that IR heat treatment resulted in better age hardening at the initial aging stage, where its tensile strength and elongation appeared like that of a resistance heat treatment. More so, based on hardness and tensile test results, the IR-heated treatment process inhibited the phase transformation of precipitations at a higher temperature, improving high-temperature softening resistance and enhancing the thermal stability of the hot forging 7075 aluminum alloy.


[Guided bone regeneration by using biodegradable co-polymer membranes in rabbits].
To repair long bone segmental defects using biodegradable poly epsilon-caprolactone (PCL) and polylactic acid(PLA) co-polymer membranes, and explore its role and mechanism in guided bone regeneration (GBR). Rabbit radial segmental defects (1.2 cm in length, retain the periosteum) were created in this study, 24 animals were divided into 2 groups. The membranes were used to enclose the defects in experimental group, and no treatment in control group. After 3, 6, and 12 weeks of operation, X-ray, gross and histological examinations were observed. The bone regeneration of experimental group was better than that of control group. Three weeks after operation, obvious external callus along the membrane were found in experimental group, and bony linking composed of external callus bridge were found in 6 weeks after operation. After 12 weeks of operation, callus bridge outside the membrane and bony reunion inside the membrane were achieved in experimental group. While in control group, typical nonunion was observed after 6 weeks of operation. Guided bone regeneration can be achieved by using biodegradable membrane. The defects are repaired by the means of outside membrane callus and relatively late inside membrane callus. The membrane can prevent the ingrowth of fibrous tissue into defect area, thus nonunion are avoid, and keep a high concentration of nutritive elements, also serve as a frame for osteocyte growth to enhance bone healing.


Clinical Implementation of In-House Developed MR-Based Patient-Specific 3D Models of Liver Anatomy.
Knowledge of patient-specific liver anatomy is key to patient safety during major hepatobiliary surgery. Three-dimensional (3D) models of patient-specific liver anatomy based on diagnostic MRI images can provide essential vascular and biliary anatomical insight during surgery. However, a method for generating these is not yet publicly available. This paper describes how these 3D models of the liver can be generated using open source software, and then subsequently integrated into a sterile surgical environment. The most common image quality aspects that degrade the quality of the 3D models as well possible ways of eliminating these are also discussed. Per patient, a single diagnostic multiphase MRI scan with hepatospecific contrast agent was used for automated segmentation of liver contour, arterial, portal, and venous anatomy, and the biliary tree. Subsequently, lesions were delineated manually. The resulting interactive 3D model could be accessed during surgery on a sterile covered tablet. Up to now, such models have been used in 335 surgical procedures. Their use simplified the surgical treatment of patients with a high number of liver metastases and contributed to the localization of vanished lesions in cases of a radiological complete response to neoadjuvant treatment. They facilitated perioperative verification of the relationship of tumors and the surrounding vascular and biliary anatomy, and eased decision-making before and during surgery.


[Characteristics of hemorheological processes in patients with chronic obstructive bronchitis combined with ischemic heart disease].
The study of 37 patients with chronic obstructive bronchitis combined with coronary heart disease during exacerbation of these diseases has revealed blood microcirculation disorders of its vascular, intra- and extravascular parts. It's also showed an increase in specific quantity of blood serum medium- and high-molecular surface-active substances, in mean corpuscular volume and sorptive activity of erythrocytes, nitrite/nitrate contents, and medium-molecular peptides. It has been revealed at the same time cytogenetic derangements of lymphocytes, low monocyte phagocytic activity. There were only 25.7% of the observed patients, who presented with some normal indices by the time of clinical remission of the diseases.


Malignant paraganglioma associated with succinate dehydrogenase subunit B in an 8-year-old child: the age of first screening?
Several studies have shown that patients with succinate dehydrogenase subunit B (SDHB) mutations have a very high risk for developing malignant paragangliomas. However, there is no consensus of what age screening for paragangliomas should start. We report a case of an 8-year-old white girl with a 3-year history of catecholamine excess-related complaints who was diagnosed with a malignant SDHB-associated mediastinal paraganglioma. The patient presented with intermittent sweating, headache, nausea, vomiting, fatigue and weight loss that had been present since she was 5 years of age. A large posterior mediastinal mass measuring 6.4 cm x 3.1 cm x 4.6 cm was discovered on computed tomography (CT) and magnetic resonance imaging (MRI). Laboratory data included an elevated level of urine normetanephrine of 45,400 microg/g creatinine (upper reference limit 718 microg/g) and elevated level of plasma normetanephrine of 62.4 nmol/l (upper reference limit <0.90 nmol/l). She was diagnosed with a thoracic paraganglioma and subsequently underwent surgical removal of the tumor and two lymph nodes. Histopathologic examination confirmed metastatic paraganglioma. Postoperatively, her blood pressure normalized and plasma normetanephrine levels remained normal. Our patient first presented with paraganglioma-associated signs and symptoms at the young age of 5 years. This case clearly illustrates the need for increased vigilance and screening for paragangliomas in families with SDHB at a younger age than previously thought.


Dual-Modality Immuno-PET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer Using an Anti-Prostate Stem Cell Antigen Cys-Diabody.
Pancreatic cancer has a high mortality rate due to late diagnosis and the tendency to invade surrounding tissues and metastasize at an early stage. A molecular imaging agent that enables both presurgery antigen-specific PET (immuno-PET) and intraoperative near-infrared fluorescence (NIRF) guidance might benefit diagnosis of pancreatic cancer, staging, and surgical resection, which remains the only curative treatment. Methods: We developed a dual-labeled probe based on A2 cys-diabody (A2cDb) targeting the cell-surface prostate stem cell antigen (PSCA), which is expressed in most pancreatic cancers. Maleimide-IRDye800CW was site-specifically conjugated to the C-terminal cys-tag (A2cDb-800) without impairing integrity or affinity (half-maximal binding, 4.3 nM). Direct radioiodination with 124I (124I-A2cDb-800) yielded a specific activity of 159 ± 48 MBq/mg with a radiochemical purity exceeding 99% and 65% ± 4.5% immunoreactivity (n = 3). In vivo specificity for PSCA-expressing tumor cells and biodistribution of the dual-modality tracer were evaluated in a prostate cancer xenograft model and compared with single-labeled 124I-A2cDb. Patient-derived pancreatic ductal adenocarcinoma xenografts (PDX-PDACs) were grown subcutaneously in NSG mice and screened for PSCA expression by immuno-PET. Small-animal PET/CT scans of PDX-PDAC-bearing mice were obtained using the dual-modality 124I-A2cDb-800 followed by postmortem NIRF imaging with the skin removed. Tumors and organs were analyzed ex vivo to compare the relative fluorescent signals without obstruction by other organs. Results: Specific uptake in PSCA-positive tumors and low nonspecific background activity resulted in high-contrast immuno-PET images. Concurrent with the PET studies, fluorescent signal was observed in the PSCA-positive tumors of mice injected with the dual-tracer 124I-A2cDb-800, with low background uptake or autofluorescence in the surrounding tissue. Ex vivo biodistribution confirmed comparable tumor uptake of both 124I-A2cDb-800 and 124I-A2cDb. Conclusion: Dual-modality imaging using the anti-PSCA cys-diabody resulted in high-contrast immuno-PET/NIRF images of PDX-PDACs, suggesting that this imaging agent might offer both noninvasive whole-body imaging to localize PSCA-positive pancreatic cancer and fluorescence image-guided identification of tumor margins during surgery.


Illuminated Focus: Vision Augmentation using Spatial Defocusing via Focal Sweep Eyeglasses and High-Speed Projector.
Aiming at realizing novel vision augmentation experiences, this paper proposes the IlluminatedFocus technique, which spatially defocuses real-world appearances regardless of the distance from the user's eyes to observed real objects. With the proposed technique, a part of a real object in an image appears blurred, while the fine details of the other part at the same distance remain visible. We apply Electrically Focus-Tunable Lenses (ETL) as eyeglasses and a synchronized high-speed projector as illumination for a real scene. We periodically modulate the focal lengths of the glasses (focal sweep) at more than 60 Hz so that a wearer cannot perceive the modulation. A part of the scene to appear focused is illuminated by the projector when it is in focus of the user's eyes, while another part to appear blurred is illuminated when it is out of the focus. As the basis of our spatial focus control, we build mathematical models to predict the range of distance from the ETL within which real objects become blurred on the retina of a user. Based on the blur range, we discuss a design guideline for effective illumination timing and focal sweep range. We also model the apparent size of a real scene altered by the focal length modulation. This leads to an undesirable visible seam between focused and blurred areas. We solve this unique problem by gradually blending the two areas. Finally, we demonstrate the feasibility of our proposal by implementing various vision augmentation applications.


Vasopressin generates a persistent voltage-dependent sodium current in a mammalian motoneuron.
During the period of life that precedes weaning, the facial nucleus of the newborn rat is rich in 3H-vasopressin binding sites, and exogenous arginine vasopressin (AVP) can excite facial motoneurons by interacting with V1 (vasopressor-type) receptors. We have investigated the mode of action of this peptide by carrying out single-electrode voltage-clamp recordings in coronal brainstem slices from the neonate. Facial motoneurons were identified by antidromic invasion following electrical stimulation of the genu of the facial nerve. When the membrane potential was held at or near its resting level, vasopressin generated an inward current whose magnitude was concentration related; the lowest peptide concentration still effective in eliciting this effect was 10 nM. The vasopressin-induced current, IAVP, was resistant to tetrodotoxin (TTX) and was insensitive to a reduction in extracellular calcium concentration. It was sustained, was inward at all potentials tested (-120 to -25 mV), and increased in magnitude during depolarization. IAVP was not generated by the blockade of a potassium current, because it did not reverse at hyperpolarized potentials, was not affected by a two-fold increase in the transmembrane potassium gradient, and was not modified by the potassium channel blockers tetraethylammonium bromide (TEA), 4-aminopyridin (4-AP), barium, cesium, quinine, glibenclamide, and apamin. Also, IAVP was not affected by changes in the transmembrane chloride gradient. In contrast, it could be reduced by partially substituting extracellular sodium with equimolar N-methyl-D-glucamine or Tris. Our results suggest that vasopressin increases the excitability of facial motoneurons by generating a persistent sodium-dependent membrane current that is voltage gated and TTX resistant.


Polycyclic aromatic hydrocarbons induce an inflammatory atherosclerotic plaque phenotype irrespective of their DNA binding properties.
Although it has been demonstrated that carcinogenic environmental polycyclic aromatic hydrocarbons (PAHs) cause progression of atherosclerosis, the underlying mechanism remains unclear. In the present study, we aimed to investigate whether DNA binding events are critically involved in the progression of PAH-mediated atherogenesis. Apolipoprotein E knockout mice were orally (24 wk, once/wk) exposed to 5 mg/kg benzo[a]pyrene (B[a]P), or its nonmutagenic, noncarcinogenic structural isoform benzo[e]pyrene (B[e]P). 32P-postlabeling of lung tissue confirmed the presence of promutagenic PAH-DNA adducts in B[a]P-exposed animals, whereas in B[e]P-exposed and vehicle control animals, these adducts were undetectable. Morphometrical analysis showed that both B[a]P and B[e]P caused an increase in plaque size, whereas location or number of plaques was unaffected. Immunohistochemistry revealed no differences in oxidative DNA damage (8-OHdG) or apoptosis in the plaques. Also plasma lipoprotein levels remained unchanged after PAH-exposure. However, T lymphocytes were increased > or =2-fold in the plaques of B[a]P- and B[e]P-exposed animals. Additionally, B[a]P and to a lesser extent B[e]P exposure resulted in increased TGFbeta protein levels in the plaques, that was mainly localized in the plaque macrophages. In vitro studies using the murine macrophage like RAW264.7 cells showed that inhibition of TGFbeta resulted in decreased tumor necrosis factor (TNF) alpha release, suggesting that enhanced TGFbeta expression in the plaque macrophages contributes to the proinflammatory effects in the vessel wall. In general, this inflammatory reaction in the plaques appeared to be a local response since peripheral blood cell composition (T cells, B cells, granulocytes, and macrophages) was not changed upon PAH exposure. In conclusion, we showed that both B[a]P and B[e]P cause progression of atherosclerosis, irrespective of their DNA binding properties. Moreover, our data revealed a possible novel mechanism of PAH-mediated atherogenesis, which likely involves a TGFbeta-mediated local inflammatory reaction in the vessel wall.


Bizarre behaviour, bizarre intruder and bizarre bowel obstruction.
An 82-year-old woman, with previous history of hiatal hernia, cholecystectomy and depression, has been admitted for worsening diffuse abdominal pain with constipation and vomiting for 4 days. She lived alone, without signs of dementia or cognitive impairment. The abdomen was distended and tender in middle quadrants. Abdominal x-ray revealed concentric distension of bowel loops. CT scan confirmed mechanical small bowel obstruction with a transition point in the right iliac fossa. At laparotomy, the obstruction was caused by an intraluminal mass. After enterotomy, a 5.5 cm large phytobezoar was extracted; immediately after, a small live insect jumped out from the vegetable mass crawling onto the surgical area. The specimen was sent for parasitology and identified as a crustacean isopod, terrestrial arthropod, classified in the phylum Arthropoda, subphylum Crustacea and order Isopoda. They usually live in humid, moist conditions, obtaining their nourishment from decomposing vegetable matter. They often colonise in greenhouse pot plants. No cases of parasitisation in vertebrate species have been reported to date.


Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung.
The mechanisms by which a primary tumor affects a selected distant organ before tumor cell arrival remain to be elucidated. This report shows that Gr-1+CD11b+ cells are significantly increased in lungs of mice bearing mammary adenocarcinomas before tumor cell arrival. In the premetastatic lungs, these immature myeloid cells significantly decrease IFN-gamma production and increase proinflammatory cytokines. In addition, they produce large quantities of matrix metalloproteinase 9 (MMP9) and promote vascular remodeling. Deletion of MMP9 normalizes aberrant vasculature in the premetastatic lung and diminishes lung metastasis. The production and activity of MMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. Our work reveals a novel protumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into an inflammatory and proliferative environment, diminishes immune protection, and promotes metastasis through aberrant vasculature formation. Thus, inhibition of Gr-1+CD11b+ cells could normalize the premetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis.


Primary nucleotide structure of predominant and alternate splice forms of equine insulin-like growth factor I and their gene expression patterns in tissues.
To isolate, clone, and determine primary nucleotide sequence of equine insulin-like growth factor I (IGF-I) and to examine IGF-I gene expression in tissues and cartilage from horses. Horses of various ages. Total RNA was isolated from tissues and purified. Complementary DNA (cDNA) was derived by reverse transcription and polymerase chain reaction (PCR) amplification and subcloned to plasmid vectors for sequencing and comparison with other species. Total RNA from various tissues was probed with radiolabeled cDNA or complimentary RNA constructs by use of northern blotting, tube hybridization, or PCR procedures to determine IGF-I expression patterns. Nucleotide sequence of equine IGF-I was 90% homologous to that of cows, 88% homologous to that of humans and sheep, and 77% homologous to that of rats. Amino acid sequence was identical to that of humans, cows, dogs, and pigs. A larger PCR product (IGF-IB) was consistent with alternate splicing with retention of IGF-I exon 4 sequence, similar to rats and mice. Northern blot analysis revealed multiple IGF-I transcripts; predominant sizes were 1.6 and 4.5 kb. The IGF-I message was commonly detected in liver, kidney, and cartilage from young foals and was diminished in cartilage from a 12-month-old horse. Nucleotide sequences of equine prepropeptides were different from those of other species, but the sequence coding the mature IGF-I peptide was more closely homologous. The larger IGF-IB form differed substantially in the carboxy-terminal. The biological action of the cleaved terminal was speculated to be autocrine feedback. Expression of IGF-I was apparent in many tissues, including cartilage, and was greater in immature horses.


Simian and feline immunodeficiency viruses: animal lentivirus models for evaluation of AIDS vaccines and antiviral agents.
Infection of captive macaques with simian immunodeficiency virus (SIV) and domestic cats with feline immunodeficiency virus (FIV), both discovered in the last five years, represent excellent animal models for infection of humans with the human immunodeficiency virus (HIV). Protection against challenge infection and protection against development of simian and feline acquired immunodeficiency syndrome has been achieved in each model by use of inactivated whole virus or virus-cell vaccines. A recombinant SIV envelope peptide vaccine has also proved efficacious. These vaccines have protected against 10-100 animal infectious doses of the homologous cell-free virus given systemically, and, in the simian model, apparently show cross protection against a heterologous strain of SIV. Protected animals appear free of any latent infection although late breakthroughs of infection in a few animals imply that not all vaccinated animals are completely protected. The mechanism of protection in the simian model apparently involves envelope antibody but the role of neutralizing antibody remains unclear. Questions remaining to be answered in both SIV and FIV models are: (1) the duration of immunity, (2) the extent of protection against heterologous strains and mucosal infection, (3) protection against infection with cell-associated virus and (4) the role, if any, of cellular immunity in vaccine protection. Initial attempts at post-infection immunotherapy with SIV vaccines have not yet been successful. The inactivated whole SIV and FIV vaccines offer a promising start and provide hope that a prophylactic AIDS vaccine will be developed. Use of these animal models for antiviral therapy is just now getting underway. Both models should prove especially useful for studies of prophylaxis and therapy, especially during the early stages of infection and for investigations on drug pharmacokinetics or toxicity that can not be done as well in HIV-infected humans. The animals will also be ideal for testing the pathogenicity of drug-induced mutant forms of SIV and FIV. For these purposes it will be necessary to create self-sustaining specific pathogen-free macaque and cat breeding colonies and provide increased housing facilities for infected animals. The future of AIDS research is crucially dependent on the long term availability of these animal models.


Prevalence of smoking among dentists in the Federal District of Brasília, Brazil.
To determine the prevalence of smoking among dentists in the Federal District of Brasília, Brazil. A descriptive, cross-sectional survey, involving 446 dentists residing in the Federal District, was conducted in the second semester of 2004. Data regarding the smoking habit were obtained using a World Health Organization questionnaire that was translated and validated for use in Brazil by the Brazilian National Cancer Institute. Individuals who had smoked a minimum of one cigarette per day for at least 6 months prior to the study outset were classified as regular smokers. The distribution of frequencies was analyzed using descriptive statistics (means and standard deviations), as well as calculation of prevalence rates. The different variables were compared using the chi-square test, and values of p < 0.05 were considered statistically significant. Of the dentists evaluated, 37% (42% of the males and 31.4% of the females) reported being smokers. The prevalence of smokers among dentists in the Federal District is above the national average for the adult population, which is approximately 32%. Although there was a predominance of males, the high number of female dentists who reported being smokers was a worrisome finding.


Positive tumour CD47 expression is an independent prognostic factor for recurrence in resected non-small cell lung cancer.
Immunotherapy is a promising advance in oncology. Limited information exists regarding the interrelationship between CD47 expression and tumour-associated macrophage-related immuno-microenvironment in patients with non-small cell lung cancer (NSCLC). These factors may predict novel immunotherapy efficacy. CD47 and PD-L1 expression was retrospectively assessed in 191 resected NSCLC specimens via immunohistochemistry. Forty-six patients with pulmonary infectious diseases were enrolled as the control group. The infiltration of macrophages (M2 and M1) and CD8+ T-lymphocytes was evaluated via dual-immunofluorescence staining. Targeted DNA sequencing was performed on NSCLC specimens. Survival analysis was performed using the Cox model. Using 2+/3+ as a CD47 positive (CD47pos) expression cut-off, the prevalence of CD47pos expression in NSCLC was 33.0% (63/191), significantly higher than in pulmonary infectious diseases. CD47pos expression was significantly higher in female, non-smoking and adenocarcinoma patients (p=0.020, p<0.001 and p<0.001, respectively). Furthermore, CD47pos expression was significantly correlated with epidermal growth factor receptor mutation (p<0.001). The expression of CD47 (H-score) in NSCLC was negatively correlated with tumour PD-L1 expression (p=0.0346) and tumour mutation burden (p=0.0107). CD47pos expression was independently correlated with poor disease-free survival in patients with resected NSCLC in multivariate Cox regression analysis (p=0.035). This study revealed the demographic, molecular and immuno-microenvironment characteristics of CD47 expression in NSCLC. We identified tumour CD47pos expression as an independent prognostic factor for recurrence in resected NSCLC. Our findings illustrate the potential of anti-CD47 treatment in NSCLC.


Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field.
Designing tight-binding ligands is a primary objective of small-molecule drug discovery. Over the past few decades, free-energy calculations have benefited from improved force fields and sampling algorithms, as well as the advent of low-cost parallel computing. However, it has proven to be challenging to reliably achieve the level of accuracy that would be needed to guide lead optimization (∼5× in binding affinity) for a wide range of ligands and protein targets. Not surprisingly, widespread commercial application of free-energy simulations has been limited due to the lack of large-scale validation coupled with the technical challenges traditionally associated with running these types of calculations. Here, we report an approach that achieves an unprecedented level of accuracy across a broad range of target classes and ligands, with retrospective results encompassing 200 ligands and a wide variety of chemical perturbations, many of which involve significant changes in ligand chemical structures. In addition, we have applied the method in prospective drug discovery projects and found a significant improvement in the quality of the compounds synthesized that have been predicted to be potent. Compounds predicted to be potent by this approach have a substantial reduction in false positives relative to compounds synthesized on the basis of other computational or medicinal chemistry approaches. Furthermore, the results are consistent with those obtained from our retrospective studies, demonstrating the robustness and broad range of applicability of this approach, which can be used to drive decisions in lead optimization.


Surgical Algorithmic Approach to Facilitate Primary Closure of the Anterolateral Thigh Flap Donor Site in Head and Neck Reconstruction.
Use of the anterolateral thigh (ALT) flap has gained popularity in head and neck reconstruction. However, donor sites that cannot achieve primary closure are reported to have poorer functional and aesthetic outcomes. Therefore, we propose an algorithm to facilitate primary closure of the donor site. Since May 2013, when an attempt at donor site direct closure failed, we have used a VY advancement flap or a propeller flap for primary closure of the donor site, using the remnant lateral thigh perforator or nearby medial thigh perforator. Otherwise, a skin graft was used. A total of 91 patients were enrolled in this algorithmic approach. We retrospectively reviewed patients with head and neck cancer who underwent cancer ablation and immediate ALT flap reconstruction since August 2010. The patients were then categorized into a "before" group and an "after" group according to the application time of the algorithm. Their demographics, intraoperative findings, and postoperative outcomes were analyzed. A total of 321 patients (309 men, 12 women) were enrolled, with 230 patients in the before group and 91 patients in the after group, with a mean age of 52.9 years. The mean size of the flap was 130 cm, with a mean width of 8.1 cm. No statistical difference existed between the groups. The donor site was directly closed in 82 patients (35.7%) in the before group. Using the perforator-based flap in 21 patients (23.1%), the donor site was closed primarily in 72 patients (79.1%) in the after group, contributing to a significantly higher donor site closure rate (P < 0.001). The average operative time was 348.7 minutes. The overall flap survival rate was 97.2%, donor-site complication rate was 6.9%, and hospitalization length was 23.5 days. None showed statistical differences between the groups. The proposed algorithm may considerably increase the primary closure rate of the ALT flap donor site.


Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34.
Tumor suppressor microRNAs (miRNA) provide a new opportunity to treat cancer. This approach, "miRNA replacement therapy," is based on the concept that the reintroduction of miRNAs depleted in cancer cells reactivates cellular pathways that drive a therapeutic response. Here, we describe the development of a therapeutic formulation using chemically synthesized miR-34a and a lipid-based delivery vehicle that blocks tumor growth in mouse models of non-small-cell lung cancer. This formulation is effective when administered locally or systemically. The antioncogenic effects are accompanied by an accumulation of miR-34a in the tumor tissue and downregulation of direct miR-34a targets. Intravenous delivery of formulated miR-34a does not induce an elevation of cytokines or liver and kidney enzymes in serum, suggesting that the formulation is well tolerated and does not induce an immune response. The data provide proof of concept for the systemic delivery of a synthetic tumor suppressor mimic, obviating obstacles associated with viral-based miRNA delivery and facilitating a rapid route for miRNA replacement therapy into the clinic.