Congenital fiber-type disproportion myopathy with type I fiber predominance and type II fiber smallness and atrophy--a sterological analysis.
Congenital myopathy with fiber-type disproportion is an established disorder, where type I fibers predominate with smallness of the same type. We report a family with three siblings (12-year-old boy, 9-year-old girl, and 6-year-old boy) with clinical features of congenital myopathy, where muscle biopsy in the eldest sib showed fiber-type disproportion. Type I fibers predominated with small and atrophic type II fibers which is unusual, especially when the child did not have any other clinical or biochemical abnormality to account for this type of variation. Further, a stereological analysis highlighted the differences with regards to number, size and even volume of the fiber types. A 3-dimensional concept is proposed for this morphological abnormality.


Evaluation study of a portable impedance biosensor for detection of avian influenza virus.
Current methods for detection of avian influenza virus (AIV) based on virus culture and RT-PCR are well established, but they are either time consuming or require specialized laboratory facilities and highly trained technicians. A simple, rapid, robust, and reliable test, suitable for use in the field or at the patient's bedside, is urgently needed. In this study, the performance of a newly developed portable impedance biosensor was evaluated by comparison with real-time reverse transcriptase PCR (rRT-PCR) and virus culture for detection of AIV in tracheal and cloacal swab samples collected from experimentally H5N2 AIV infected chickens. The impedance biosensor system was based on a combination of magnetic nanobeads, which were coated with AIV subtype-specific antibody for capture (separation and concentration) of a target virus, and a microfluidic chip with an interdigitated array microelectrode for transfer and detection of target virus, and impedance measurement of the bio-nanobeads and AI virus complexes in a buffer solution. A comparison of results obtained from 59 swab samples using virus culture, impedance biosensor and rRT-PCR methods showed that the impedance biosensor technique was comparable in sensitivity and specificity to rRT-PCR. Detection time for the impedance biosensor is less than 1h.


Expert or Esoteric? Philosophers Attribute Knowledge Differently Than All Other Academics.
Academics across widely ranging disciplines all pursue knowledge, but they do so using vastly different methods. Do these academics therefore also have different ideas about when someone possesses knowledge? Recent experimental findings suggest that intuitions about when individuals have knowledge may vary across groups; in particular, the concept of knowledge espoused by the discipline of philosophy may not align with the concept held by laypeople. Across two studies, we investigate the concept of knowledge held by academics across seven disciplines (N = 1,581) and compare these judgments to those of philosophers (N = 204) and laypeople (N = 336). We find that academics and laypeople share a similar concept of knowledge, while philosophers have a substantially different concept. These experiments show that (a) in contrast to philosophers, other academics and laypeople attribute knowledge to others in some "Gettier" situations; (b) academics and laypeople are much less likely to attribute knowledge when reminded of the possibility of error, but philosophers are not affected by this reminder; and (c) non-philosophy academics are overall more skeptical about knowledge than laypeople or philosophers. These findings suggest that academics across a wide range of disciplines share a similar concept of knowledge, and that this concept aligns closely with the intuitions held by laypeople, and differs considerably from the concept of knowledge described in the philosophical literature, as well as the epistemic intuitions of philosophers themselves.


Sexual harassment and abuse in sport: the role of the team doctor.
Sexual harassment and abuse occur in all sports and at all levels with an increased risk at the elite level. The physical and psychological consequences of sexual harassment and abuse are significant for the athlete, their team and for the health and integrity of sport in general. The sports medicine health professional has an integral role to play in the prevention of sexual harassment and abuse in sport. This paper provides sport healthcare professionals with a practical guide on prevention strategies and advice on the recognition and management of suspected abuse.


Inhibition of ribonucleic acid synthesis by nalidixic acid in Escherichia coli.
The effect of low concentrations of nalidixic acid on ribonucleic acid (RNA) synthesis in Escherichia coli was examined. It was observed that RNA synthesis in exponentially growing cells was not significantly affected, in harmony with previous studies. However, RNA synthesis was markedly depressed by nalidixic acid during starvation for an amino acid or during chloramphenicol treatment. This effect was not caused by increased killing or inhibition of nucleoside triphosphate synthesis by nalidixic acid. The pattern of radioactive uracil incorporation into transfer RNA or ribosomes was not changed by the drug. The sensitivity of RNA synthesis to nalidixic acid in the absence of protein production may be useful in probing the amino acid control of RNA synthesis.


Imaging mass spectrometry-based molecular histology differentiates microscopically identical and heterogeneous tumors.
Many tumors display significant cellular heterogeneity as well as molecular heterogeneity. Sensitive biomarkers that differentiate between diagnostically challenging tumors must contend with this heterogeneity. Mass spectrometry-based molecular histology of a patient series of heterogeneous, microscopically identical bone tumors highlighted the tumor cell types that could be characterized by a single profile and led to the identification of specific peptides that differentiate between the tumors.


A Stable Reverse Genetics System of Zika Virus Based on a Self-Splicing Group II Intron.
Zika virus (ZIKV) is a mosquito-borne flavivirus of the Flaviviridae family first isolated from a sentinel monkey in the Zika Forest, Uganda, in 1947. Since 2007, the virus has had a vast geographic expansion that extended to the Americas in 2015, leading to a series of large outbreaks. Although mainly transmitted by the bite of Aedes mosquitoes, human infection of ZIKV can also happen through unconventional routes such as sexual intercourse and, more importantly, vertical transmission. The genome of ZIKV is a single-stranded, positive-sense RNA molecule about 11 kb in length. The genome contains a single opening reading frame (ORF) flanked by highly structured 5' and 3' untranslated regions. To understand the mechanisms about ZIKV replication, transmission, and pathogenesis, reverse genetic tools are of great importance. In this chapter, a novel system is described for the generation and manipulation of a ZIKV infectious clone stabilized by a self-splicing group II intron, a mobile element with ribozyme activity. The intron can be spliced in vitro, and thus full-length vRNA can be prepared allowing virus genome manipulation required for further studies.


Psychopathology Related to Energy Drinks: A Psychosis Case Report.
Energy drinks (ED) are nonalcoholic beverages that have caffeine as their most common active substance. The rapid expansion of ED consumption has created concern in the scientific community as well as in the public opinion. We report a psychotic episode probably triggered by ED abuse in a young adult without previous psychotic disorders. We have reviewed the literature regarding the relationship between caffeine, energy drinks, and psychopathology. Few articles have been published about mental health effects of energy drinks and caffeine abuse. Nevertheless, this relationship has been suggested, specifically with anxiety disorders, manic episodes, suicide attempts, psychotic decompensation, and substance use disorder. ED consumption could represent a global public health problem because of the potential severe adverse effects in mental and physical health. To our knowledge, this article is probably the first case of psychosis related to ED abuse in an individual without previous psychotic disorders.


Electrophysiological evidence for the role of substance P in retinohypothalamic transmission in the rat.
The retinohypothalamic tract (RHT) is a neural pathway through which photic time cues are delivered directly to the mammalian circadian pacemaker in the suprachiasmatic nucleus (SCN). Although the excitatory amino acid glutamate is the primary neurotransmitter in the RHT, other substances such as substance P (SPq also have been suggested to play a role. The present study tested the hypothesis that SP participates in retinohypothalamic transmission and selectively modulates either N-methyl-D-aspartate (NMDA) or non-NMDA receptor-mediated neurotransmission. The SP antagonist L-703,606 depressed the excitatory postsynaptic current (EPSC) evoked by optic nerve stimulation in SCN neurons in rat hypothalamic slices. The SP antagonist also had a similar depressive effect on the NMDA and non-NMDA receptor-mediated components of the EPSC. These results suggest that SP is an excitatory neuromodulator contributing to the expression of both the NMDA and non-NMDA receptor-mediated components of retinohypothalamic transmission.


Upper airway imaging and function in obstructive sleep apnea in people with and without HIV.
Obstructive sleep apnea (OSA) is common in people living with HIV (PLWH), but the underlying mechanisms are unclear. With improved long-term survival among PLWH, aging and obesity are increasingly prevalent in this population. These are also strong risk factors for the development of obstructive sleep apnea. We used magnetic resonance imaging (MRI) to measure upper airway (UA) anatomy and tongue fat content in PLWH with OSA (PLWH+OSA, N=9) and in age-, sex-, and BMI-matched OSA controls (OSA, N=11). We also quantified change in UA dimension during tidal breathing (during wakefulness and natural sleep) at four anatomical levels from the hard palate to the epiglottis along with synchronous MRI-compatible electroencephalogram and nasal flow measurements. All participants underwent on a separate night a baseline polysomnogram to assess OSA severity and an additional overnight physiological sleep study to measure OSA traits. We found no difference between the PLWH+OSA and the OSA control group in UA volume (PLWH+OSA: 12.8 ml (10.1-17.0), OSA: 14.0 ml (13.3-17.9), median (IQR)) or tongue volume (PLWH+OSA: 140.2 ml (125.1-156.9), OSA: 132.4 ml (126.8-154.7)) and a smaller tongue fat content in PLWH+OSA (11.2% (10.2-12.4)) than in the OSA controls (14.8% (13.2-15.5), p=0.046). There was no difference in the dynamic behavior of the UA between the two groups. When pooled together, both static and dynamic imaging metrics could be correlated with measures of UA mechanical properties. Our data suggest similar underlying UA physiology in OSA in subjects with and without HIV.


Neutrophil-lymphocyte ratio findings and larynx carcinoma: a preliminary study in Turkey.
To identify the potential prognostic role of the neutrophil/lymphocyte (N/L) ratio in larynx carcinoma. Oncologic archive charts of patients with a larynx carcinoma diagnosis between the years 2010 and 2013 were retrospectively reviewed. The inclusion criterion was to be available with hemogram test prior to diagnostic procedure. Patients undergoing septorinoplasty comprised the control group. There were 65 cases in the study and 42 cases in control group meeting inclusion criteria. In general a non-significant increase in N/L ratio was observed with increasing tumor size and stage (p>0.05) in larynx carcinoma. The N/L ratio was found to be significantly higher in larynx carcinoma compared to control group (p=0.004). In conclusion, the N/L ratio was shown to be significantly increased in larynx carcinomas compared to control group. Further studies are needed to assess any prognostic role.


Families of nuclear receptors in vertebrate models: characteristic and comparative toxicological perspective.
Various synthetic chemicals are ligands for nuclear receptors (NRs) and can cause adverse effects in vertebrates mediated by NRs. While several model vertebrates, such as mouse, chicken, western clawed frog and zebrafish, are widely used in toxicity testing, few NRs have been well described for most of these classes. In this report, NRs in genomes of 12 vertebrates are characterized via bioinformatics approaches. Although numbers of NRs varied among species, with 40-42 genes in birds to 66-74 genes in teleost fishes, all NRs had clear homologs in human and could be categorized into seven subfamilies defined as NR0B-NR6A. Phylogenetic analysis revealed conservative evolutionary relationships for most NRs, which were consistent with traditional morphology-based systematics, except for some exceptions in Dolphin (Tursiops truncatus). Evolution of PXR and CAR exhibited unexpected multiple patterns and the existence of CAR possibly being traced back to ancient lobe-finned fishes and tetrapods (Sarcopterygii). Compared to the more conservative DBD of NRs, sequences of LBD were less conserved: Sequences of THRs, RARs and RXRs were ≥90% similar to those of the human, ERs, AR, GR, ERRs and PPARs were more variable with similarities of 60%-100% and PXR, CAR, DAX1 and SHP were least conserved among species.


Loss of DNA methylation disrupts syncytiotrophoblast development: Proposed consequences of aberrant germline gene activation.
DNA methylation is a repressive epigenetic modification that is essential for development and its disruption is widely implicated in disease. Yet, remarkably, ablation of DNA methylation in transgenic mouse models has limited impact on transcriptional states. Across multiple tissues and developmental contexts, the predominant transcriptional signature upon loss of DNA methylation is the de-repression of a subset of germline genes, normally expressed in gametogenesis. We recently reported loss of de novo DNA methyltransferase DNMT3B resulted in up-regulation of germline genes and impaired syncytiotrophoblast formation in the murine placenta. This defect led to embryonic lethality. We hypothesize that de-repression of germline genes in the Dnmt3b knockout underpins aspects of the placental phenotype by interfering with normal developmental processes. Specifically, we discuss molecular mechanisms by which aberrant expression of the piRNA pathway, meiotic proteins or germline transcriptional regulators may disrupt syncytiotrophoblast development.


A comparison of referral patterns to the pediatric endocrine clinic before and after FDA approval of growth hormone for idiopathic short stature.
Short stature is a common reason for referral to the pediatric endocrine clinic. In 2003, the US Food and Drug Administration (FDA) approved the use of growth hormone (GH) for the treatment of children with idiopathic short stature (ISS). To explore if this indication changed referrals for short stature (SS). A retrospective chart review of children seen for SS in the pediatric endocrine clinic between July 1998 and June 1999 (interval one, n=138) and July 2005-June 2006 (interval two, n=268) was performed. Variables collected included age, gender, height (h), and parental heights. Average height standard deviation score (HT-SDS) was -2.11 +/- 0.9 in interval one and -2.14 +/- 0.83 in interval two (p=ns). No differences in age, gender distribution, relationship between child and parental heights, the proportion of subjects started on GH for ISS or in the HT-SDS of those treated between the two intervals were identified. Nearly half of all children referred in each interval did not meet the technical criteria for short stature. No differences in referral patterns for SS in our area following FDA approval of GH for ISS were identified. Although referrals appear unchanged, additional investigation of GH prescribing patterns before and after this new indication is needed. Continued education of primary care physicians and the general public regarding the definition of SS and the eligibility for GH therapy should be pursued.


99mTc-HMPAO-labeled autologous versus heterologous leukocytes for imaging infection.
Radiolabeled autologous leukocytes are the gold standard for imaging infectious foci in patients. Good results have also been reported for radiolabeled heterologous leukocytes from noninfected donors. Until now, the 2 methods have not been directly compared. In this study, we compared the infection-imaging potential of 99mTc-hexamethylpropyleneamine oxime (HMPAO)-labeled autologous granulocytes with that of 99mTc-HMPAO-labeled granulocytes from either infected or noninfected donors in rabbits with Escherichia coli infection. The radiolabeled granulocyte preparations were studied in rabbits with an E. coli infection in the left calf muscle. The soft-tissue infections were scintigraphically visualized after injection of 18 MBq of either 99mTc-HMPAO purified autologous granulocytes or radiolabeled purified heterologous granulocytes from infected or noninfected donor rabbits. Gamma camera images were acquired at 2 min and at 1, 2, and 4 h after injection. After the last image, the rabbits were killed and uptake of the radiolabel in the dissected tissues was determined. The 99mTc-HMPAO autologous granulocytes and heterologous granulocytes from infected donors accurately revealed the infectious focus in the calf muscle at 2 h after injection. At 4 h after injection, a significantly better (P < 0.05) delineation of the infection was established with the 99mTc-HMPAO autologous granulocytes and 99mTc-HMPAO heterologous granulocytes from the infected rabbits than with the heterologous granulocytes from noninfected donors. With both cell preparations, the intensity of uptake in the infected calf muscle continuously increased until 4 h after injection. The 99mTc-HMPAO heterologous granulocytes from noninfected donors showed no significant increase in contrast after 2 h after injection. Absolute uptake in the infected calf muscle was much higher for 99mTc-HMPAO autologous granulocytes (7.81 +/- 1.21 percentage injected dose [%ID]) and 99mTc-HMPAO heterologous infected granulocytes (8.91 +/- 1.92 %ID) than for the radiolabeled heterologous noninfected granulocytes (2.32 +/- 0.75 %ID) (P < 0.04) at 4 h after injection. The ratio of infected muscle to noninfected contralateral muscle was significantly higher for 99mTc-HMPAO autologous granulocytes and 99mTc-HMPAO heterologous granulocytes from infected donors than for 99mTc-HMPAO heterologous granulocytes from noninfected donors (5.53 +/- 1.09, 3.86 +/- 0.75, and 1.86 +/- 0.31, respectively; P < 0.05). For nuclear medicine imaging of infection, purified granulocytes derived from infected rabbits are superior to purified granulocytes derived from noninfected donor rabbits. In addition, autologous granulocytes gave similar results to heterologous granulocytes from infected donor rabbits, suggesting the need for intrinsic cell activation for specific granulocyte migration.


Monitoring of low-level virus in natural waters.
The insoluble polyelectrolyte technique for concentrating virus is extended to extremely low virus levels. The effectiveness of this method employing a coliphage T2 model is a constant 20% over a range of virus levels from 10(3) to 10(-4) plaque-forming units/ml. The efficiency of the method is dependent upon pH control during the concentration phase. Although the study was initiated to develop a method for quantitating the effectiveness of water and wastewater treatment methods for the removal of viruses from waters at low concentrations, the potential of the technique for efficient monitoring of natural waters is apparent.


Quantum and classical dynamics in biochemical reactions.
The classic experiment of deVault and Chance touched off a long series of theoretical and experimental studies of the interplay between quantum and classical dynamics in photosynthetic electron transfer. More recently these issues have also been addressed in experiments on ligand binding reactions in heme proteins and through the study of kinetic isotope effects in enzymatic proton transfer. Theoretical effort has focused on a class of relatively simple models which display a surprisingly rich spectrum of dynamical behavior. Much less attention has been paid to a very important issue: Why are we allowed to use such simple models to describe such obviously complex molecules? Here we provide some tentative answers to this question, contrasting the cases of electron and proton transfer. We suggest that ideas based on simple models can inspire novel strategies for 'realistic' simulations, and that we can begin to think about the general problems of enzymatic catalysis in terms of dynamical pictures that previously have been applied only to the simpler case of electron transfer.


Virus infection speeds: theory versus experiment.
In order to explain the speed of Vesicular Stomatitis Virus (VSV) infections, we develop a simple model that improves previous approaches to the propagation of virus infections. For VSV infections, we find that the delay time elapsed between the adsorption of a viral particle into a cell and the release of its progeny has a very important effect. Moreover, this delay time makes the adsorption rate essentially irrelevant in order to predict VSV infection speeds. Numerical simulations are in agreement with the analytical results. Our model satisfactorily explains the experimentally measured speeds of VSV infections.


The head and neck muscles of the Philippine colugo (Dermoptera: Cynocephalus volans), with a comparison to tree-shrews, primates, and other mammals.
The colugos, or flying lemurs (Dermoptera), are arboreal gliding mammals that are commonly grouped with tree-shrews (Scandentia) and Primates in the superorder Euarchonta. However, little is known about the head and neck muscles of these gliding mammals. This raises difficulties for the discussion of not only the functional morphology and evolution of colugos, but also the origin, evolution, functional morphology, and phylogenetic relationships of the Euarchonta as a whole, and thus also of our own clade, the Primates. In this work, I describe the head and neck muscles of the colugo Cynocephalus volans, and compare these muscles with those of other mammals, either dissected by me or described in the literature. My observations and comparisons indicate that, with respect to the number of muscles, the plesiomorphic condition for euarchontans as well as for primates is more similar to that found in extant tree-shrews than in extant colugos. This is because various muscles that were probably plesiomorphically present in the euarchontan and primate clades, as, e.g., the stylohyoideus, mandibulo-auricularis, cleido-occipitalis, omohyoideus, and sternohyoideus, are not present as independent elements in extant colugos. These observations and comparisons also indicate that various laryngeal and facial muscles that are present in modern humans were absent in the last common ancestor of extant primates.


[Effect of root canal therapy combined pulp mummification in treatment of residual pulpitis after mummification in molars of the gerontal patients].
To evaluate the effect of root canal therapy combined with pulp mummification in treatment of residual pulpitis after mummification in molars of the gerontal patients. One hundred and twenty-two molars with residual pulpitis after mummification were obtained from 108 over 70 years patients. All molars were treated with root canal therapy combined with pulp mummification, and were evaluated after 1 month, 1 year and 2 years. The treatment of all molars was effective within 1 month. The treatment success rate at 1- and 2-year was 86.9% and 76.2%,respectively. Root canal therapy combined with pulp mummification is one of the effective methods to treat residual pulpitis after mummification in molars of the gerontal patients over 70 years.


Enantioselective hydrolysis of o-nitrostyrene oxide by whole cells of Aspergillus niger CGMCC 0496.
The asymmetric biohydrolysis is described of o-nitrostyrene oxide with high selectivity by whole cells of Aspergillus niger CGMCC 0496. Both the epoxide and diol could be obtained in a high state of optical purity (over 98%). Product inhibition was found when using a high ratio of substrate to cells.


Characterization of the reproduction of influenza A epidemic viruses in cell cultures.
Two influenza A epidemic viruses with different indices of virulence for humans have been compared with respect to their reproduction in human embryo kidney (HEK), human embryo lung (HEL), and chick embryo kidney (CEK) cell cultures. It has been shown that the highly virulent for humans A/Victoria/35/72 (H3N2) strain reproduced intensively in HEK and HEL cells irrespective of the inoculated dose (multiplicity of infection = 1 EID50 per cell and of 0.001 EID50 per cell, respectively). Efficient infection of a moderately virulent virus A/Bangkok/1/79 (H3N2) was registered in these cell cultures only after addition of trypsin to the maintenance medium. The viruses tested exhibited essentially no difference as to the intensity of their reproduction in CEK cell culture whose sensitivity remained unchanged after addition of trypsin to the maintenance medium.


The Impact of the COVID-19 Pandemic on the Psychological Well-Being of Caregivers of People with Dementia or Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.
The aim of this systematic review was to investigate the effects of the COVID-19 lockdown on the psychological well-being of caregivers of people with dementia or mild cognitive impairment (PwD/MCI). Electronic databases were searched from inception to August 2022 for observational studies investigating the COVID-19 lockdown and psychological well-being of caregivers of PwD/MCI. Summary estimates of standardized mean differences (SMD) in psychological well-being scores pre- versus during COVID-19 were calculated using a random-effects model. Fifteen studies including 1702 caregivers (65.7% female, mean age 60.40 ± 12.9 years) with PwD/MCI were evaluated. Five studies found no change in psychological well-being parameters, including depression, anxiety, distress, caregiver burden, and quality of life. Ten studies found a worsening in at least one parameter: depression (six studies, n = 1368; SMD = 0.40; 95%CI: 0.09-0.71; p = 0.01, I2 = 86.8%), anxiety (seven studies, n = 1569; SMD = 1.35; 95%CI: 0.05-2.65; I2 = 99.2%), caregiver distress (six studies, n = 1320, SMD = 3.190; 95%CI: 1.42-4.95; p < 0.0001; I2 = 99.4%), and caregiver burden (four studies, n = 852, SMD = 0.34; 95%CI: 0.13-0.56; p = 0.001; I2 = 54.1%) (p < 0.05). There was an increase in depression, anxiety, caregiver burden, and distress in caregivers of PwD/MCI during the lockdown in the COVID pandemic. This could have longer term consequences, and it is essential that caregivers' psychological well-being is assessed and supported, to benefit both themselves and those for whom they care.


Antibiotic Use in 2016 by Members of the American Association of Endodontists: Report of a National Survey.
This study surveyed the antibiotic prescribing practices of endodontists, and data were compared with previous surveys conducted in 1994 and 1999. A 17-question survey was sent via www.surveymonkey.com to 3000 active members of the American Association of Endodontists for responses about antibiotic prescribing practices and demographics. The data were analyzed using descriptive statistics, chi-square tests, and linear regression analyses. Six hundred eighty-six participants (22.86%) completed the survey. The most frequently prescribed antibiotics were amoxicillin (60.71%) followed by penicillin V (30.43%) and clindamycin for patients with allergies (95.4%). Respondents reported prescribing antibiotics for irreversible pulpitis with mild symptoms (1.75%), irreversible pulpitis with moderate symptoms (6.41%), necrotic pulp with symptomatic apical periodontitis (43.59%), chronic apical abscess without (10.50%) or with symptoms (29.74%), acute apical abscess (95.92%), avulsion (70.26%), endodontic surgery (41.69%), retreatment (silver point [23.76%] or gutta-percha [15.60%]), postoperative pain after instrumentation or obturation (12.39%), and perforation repair (5.98%). The type of practice (solo/group) and geographic region (Southeast) were significant predictors of increased antibiotic prescribing; 36.89% of respondents reported prescribing antibiotics that are not necessary, most commonly because of patient expectations. Since 1999, there has been a significant shift from prescribing penicillin V to amoxicillin as endodontists' first choice of antibiotic and a significant increase in the use of clindamycin for penicillin-allergic patients. Antibiotics continue to be prescribed in clinical situations for which they are typically not indicated, most commonly because of patient expectations. Regional differences in antibiotic prescribing practices by endodontists exist in the United States.


Calcium channels in Paramecium aurelia.
Reversal of swimming direction in paramecium is dependent on the calcium influx through the excitable-membrane calcium channels. Several mutants of Paramecium aurelia have been selected on the basis of their resistance to the paralyzing effect of barium. The mutants have reduced reversal behavior and are in the same three pawn genes as discovered by Kung (16, 17). Also, in barium solutions, the pawns live longer than the wild-type; however, pwB mutants are more resistant to barium toxicity than pwA mutants. These results suggest that the selection picked up mutants in the calcium channel. Electrophysiological studies demonstrate this point directly, showing defective calcium activation in all pawns, but also defective anomalous rectification in pwB mutants. A model is presented which accounts for the differences between pwA and pwB mutants. It ascribes the depolarization-sensitive "gate" function to the pwA gene product and the "pore" function to the pwB gene product. Additionally, the stability of the channel structure is demonstrated, channel half-life being from five to eight days.


Myoinositol improves sperm parameters and serum reproductive hormones in patients with idiopathic infertility: a prospective double-blind randomized placebo-controlled study.
Male infertility is a multifactorial disorder that affects a significant percentage of couples. Its etiology and pathogenesis remain elusive in about one-third of the cases; this is referred to as idiopathic infertility. Inositols mediate the sperm processes involved into oocyte fertilization, such as penetration of the ovum cumulus oophorus, binding with the zona pellucida and the acrosome reaction. The aim of this double-blind, randomized, placebo-controlled trial was to evaluate the efficacy and safety of myoinositol (the most abundant form of inositols present in nature) treatment in men with idiopathic infertility. To accomplish this, we evaluated the effects of myoinositol on sperm parameters and reproductive hormones at baseline and after 3 months of treatment in men with idiopathic infertility. No adverse reaction was observed. Myoinositol significantly increased the percentage of acrosome-reacted spermatozoa, sperm concentration, and total count and progressive motility compared to placebo. In addition, myoinositol rebalanced serum luteinizing hormone, follicle-stimulating hormone, and inhibin B concentrations. The clinical improvement of idiopathic infertile patients should encourage myoinositol use for the treatment of this disorder, even though its detailed mechanisms at the testicular level remain still unclear.


Perspectives on eating disorders and service provision: A qualitative study of healthcare professionals.
The study examined healthcare professionals' perspectives of eating disorder patients and services. Qualitative semi-structured interviews were conducted with 18 healthcare professionals resulting in two themes. First, the practical difficulties of meeting the complex service needs of people with eating disorders were illustrated. Second, staff recognised patient diversity and the consequent need for individualised interventions. Services are frustrated in meeting patient needs due to complex resource limitations, which do not amount only to lack of funding. Rather than eating disordered patients being viewed as 'difficult', as reported in previous qualitative research, they are only difficult in a context of limited resources.


Tacrolimus shows adequate efficacy in patients with antiphospholipid antibodies associated thrombocytopenia: a retrospective cohort study.
Thrombocytopenia is a common manifestation associated with the presence of antiphospholipid antibodies (aPL). The aim of this study is to investigate the efficacy and safety of tacrolimus treatment in aPL associated thrombocytopenia. This is a single-center retrospective study. Patients who had persistent positive aPL and thrombocytopenia that was treated with tacrolimus were included. A total of 49 patients [38 females (77.6%)] were enrolled from Nov 2013 to Apr 2022 with a median treatment duration of 22 months. Seventeen fulfilled classification criteria of antiphospholipid syndrome (APS), 18 systemic lupus erythematosus (SLE). The median age of study patients was 37 years (IQR 31, 48). Forty-three (87.8%) patients were on concomitant use of glucocorticoids, 6 on tacrolimus monotherapy. The overall response rate in this cohort was 85.7% (n = 42), including 49% of complete responses (n = 24). The median time to achieve a response was 3 months. Nine (18.4%) patients with overall response experienced a loss of response. The response rate during follow-up in patients with monotherapy was noninferior. Patients with positive antinuclear antibody (ANA) showed the tendency of maintaining response (p = 0.028). The 19 patients who were on medium and high dosage of glucocorticoids (> 15 mg prednisone/d) managed to taper glucocorticoids rapidly. Side effects were reported in 12.2% (n = 6) of the patients (elevated creatinine, general malaise, elevated liver enzyme). Tacrolimus has adequate efficacy, steroid-sparing effect and is well tolerated for aPL associated thrombocytopenia. Patients with positive ANA might benefit the most from tacrolimus treatment.


Hydrochlorothiazide-induced 131I excretion facilitated by salt and water.
Salt intake is restricted under clinical conditions for which thiazide diuretics are customarily used. Dietary iodide intake offsets any effect of thiazide on iodide loss. However, our correlation coefficients relating Na+ to Cl- to I- excretion indicate that as thiazide administration or sodium chloride intake increases renal Na+ and Cl- excretion, I- reabsorption by the nephron coordinately decreases. Increased sodium chloride and water intake by the dog doubled I-excretion rates. Hydrochlorothiazide increased the sodium chloride and water enhanced I-excretion rate as much as eight-fold. Without added NaCl, hydrochlorothiazide increased the excretion rate of 131I by three- to eightfold, acutely. Within five to seven days after 131I oral administration, hydrochlorothiazide (1 or 2 mg/kg twice daily) doubled the rate of 131I disappearance from plasma, reduced the fecal output of 131I, and increased its rate of renal excretion. When hydrochlorothiazide was administered, as much 131I was excreted in the first 24 hours as occurred in 48 hours when sodium chloride and water were given without hydrochlorothiazide. Thiazide administration in customary clinical dosage twice a day with substantial sodium chloride and water for the first two days after exposure to 131I, should therefore facilitate the safe excretion of 131I. This accelerated removal of 131I might be enhanced even more if thyroid uptake of 131I is blocked by administration of potassium iodide, as judged by the greater 131I recovery from thyroidectomized dogs.


Keratoconjunctivitis sicca, autoimmune diseases and adenovirus type 8 infection.
In epidemic keratoconjunctivitis caused by adenovirus type 8 (Ad8), 21 patients were followed between 1.5-18 months. Thirty-three percent of the patients developed classical corneal subepithelial opacities. In considering comorbidity possibly influencing the outcome of the disease it was found that: (1) two patients with keratoconjunctivitis sicca did not develop subepithelial opacities, (2) 6/9 patients showing little propensity for developing subepithelial opacities were found to have a variety of manifest diseases of autoimmune nature, and, (3) dense opacities developed in five subjectively healthy persons. These findings suggest that susceptibility to stromal keratitis in Ad8 infections might at least in part be determined by the condition of the host immune status.


Strategies and methods for aligning current and best medical practices. The role of information technologies.
Rapid change in American medicine requires that physicians adjust established behaviors and acquire new skills. In this article, we address three questions: What do we know about how to change physicians' practices? How can physicians take advantage of new and evolving information technologies that are likely to have an impact on the future practice of medicine? and What strategic educational interventions will best enable physicians to show competencies in information management and readiness to change practice? We outline four guiding principles for incorporating information systems tools into both medical education and practice, and we make eight recommendations for the development of a new medical school curriculum. This curriculum will produce a future medical practitioner who is capable of using information technologies to systematically measure practice performance, appropriateness, and effectiveness while updating knowledge efficiently.


Deiodinases and the Metabolic Code for Thyroid Hormone Action.
Deiodinases modify the biological activity of thyroid hormone (TH) molecules, ie, they may activate thyroxine (T4) to 3,5,3'-triiodothyronine (T3), or they may inactivate T3 to 3,3'-diiodo-L-thyronine (T2) or T4 to reverse triiodothyronine (rT3). Although evidence of deiodination of T4 to T3 has been available since the 1950s, objective evidence of TH metabolism was not established until the 1970s. The modern paradigm considers that the deiodinases not only play a role in the homeostasis of circulating T3, but they also provide dynamic control of TH signaling: cells that express the activating type 2 deiodinase (D2) have enhanced TH signaling due to intracellular build-up of T3; the opposite is seen in cells that express type 3 deiodinase (D3), the inactivating deiodinase. D2 and D3 are expressed in metabolically relevant tissues such as brown adipose tissue, skeletal muscle and liver, and their roles have been investigated using cell, animal, and human models. During development, D2 and D3 expression customize for each tissue/organ the timing and intensity of TH signaling. In adult cells, D2 is induced by cyclic adenosine monophosphate (cAMP), and its expression is invariably associated with enhanced T3 signaling, expression of PGC1 and accelerated energy expenditure. In contrast, D3 expression is induced by hypoxia-inducible factor 1α (HIF-1a), dampening T3 signaling and the metabolic rate. The coordinated expression of these enzymes adjusts TH signaling in a time- and tissue-specific fashion, affecting metabolic pathways in health and disease states.


Efficacy of two third-generation cephalosporins in prophylaxis for head and neck surgery.
Optimal antimicrobial prophylaxis during head and neck surgery is as yet unclear. The semisynthetic third-generation cephalosporin antibiotics would appear to have potential usefulness because of their broad antibacterial spectrum, favorable pharmacokinetic properties, and record of safety. Eighty patients were prospectively randomized into this placebo-controlled, double-blind study to receive either placebo, cefoperazone sodium, or cefotaxime sodium preoperatively and for 24 hours postoperatively. Infection rates were 78% for the placebo group and 10% for the group receiving the cephalosporin antibiotics. Infections were polymicrobial. Anaerobic bacteria constituted 42% of the pathogens isolated. Wound and serum antibiotic concentrations exceeded the minimal inhibitory concentration of the bacterial flora. This study establishes the necessity of antimicrobial prophylaxis for contaminated oncologic procedures of the head and neck. Our experience indicates that cefoperazone and cefotaxime are particularly useful.


Special Considerations and Assessment in Patients with Multiple Sclerosis.
Multiple sclerosis is a progressive autoimmune neurologic disorder that may affect any region of the central nervous system. Spasticity in patients with multiple sclerosis can be debilitating and detrimental to the function and quality of life of patients. Treatment options include oral medications, chemodenervation, physical therapy, and modalities. Cannabinoids in the form of a delta-9-tetrahydrocannabinol/cannabidiol oro-mucosal spray has been shown to be effective in addressing spasticity in multiple sclerosis. Successful treatment of spasticity will be integrated, multimodal, and individualized.


Flipped classroom improves Omani nursing students performance and satisfaction in anatomy and physiology.
Nursing students struggle with anatomy and physiology course because of the complicated terminology and the difficulty in handling large amounts of information. New, innovative instructional strategies must be integrated into nursing education to improve nursing students' performance in this challenging bioscience course. The aim of this study was to determine the impact of an innovative teaching strategy, the flipped classroom, on the performance and satisfaction of Omani nursing students in an anatomy and physiology course. A quasi-experimental design was used with two classes of 112 first-year nursing students at the College of Nursing, Sultan Qaboos University, Oman. Online videos and active-learning activities about the respiratory system were developed and implemented in an anatomy and physiology course with 53 first-semester nursing students. The control group consisted of a previous cohort of 59 students enrolled in the same course but taught with a traditional lecture approach. The impact of the flipped classroom strategy was measured by students' performance on the final examination and students' self-reported satisfaction. Wilcoxon signed-rank and Mann-Whitney U tests were used to compare students' academic performance. Our results showed that the performance of the flipped classroom group was better than that of the traditional lecture group. The mean scores of students instructed with the flipped classroom method on the respiratory system items in the final examination were significantly higher than those of the control group, U = 1089.00, z = - 2.789, p < .005. Moreover, the results of a survey showed that nursing students were satisfied with the flipped classroom method. Overall, 68 to 78% of students agreed or strongly agreed that the flipped classroom method improved their learning and increased their interest in the course. Compared with the didactic lecture format, flipped classroom strategy improved Omani nursing students' performance in and satisfaction with an anatomy and physiology course. These results show that the flipped classroom is an important teaching strategy in nursing education.


Cdc7-Dbf4 kinase overexpression in multiple cancers and tumor cell lines is correlated with p53 inactivation.
Cdc7 is a conserved serine/threonine kinase essential for the initiation of DNA replication, likely by activating the MCM DNA helicase at the G(1-) to S-phase transition. Cdc7 kinase activity requires association with its regulatory subunit Dbf4/activator of S-phase kinase. Cdc7-Dbf4 is also downstream of the conserved Ataxia telangectasia and RAD3-related kinase that responds to stalled replication forks or DNA damage. In this study, we found that Cdc7 protein was very low or undetectable in normal tissues and cell lines but had increased expression in approximately 50% of the 62 human tumor cell lines we examined. Most cell lines with increased Cdc7 protein levels also had increased Dbf4 abundance, and some tumor cell lines had extra copies of the DBF4 gene. A high expression of Cdc7 protein was also detected in primary breast, colon, and lung tumors but not in the matched normal tissues. We also found a high correlation between p53 loss and increased CDC7 and DBF4 expression in primary breast cancers (P = 3.6 x 10(-9) and 1.8 x 10(-10), respectively) and in the cancer cell lines we studied. Therefore, increased Cdc7-Dbf4 abundance may be a common occurrence in human malignancies.


Why is the Adachi procedure successful to avoid divergences in optical models?
Adachi proposed a procedure to avoid divergences in optical-constant models by slightly shifting photon energies to complex numbers on the real part of the complex dielectric function, ε1. The imaginary part, ε2, was ignored in that shift and, despite this, the shifted function would also provide ε2 (in addition to ε1) in the limit of real energies. The procedure has been successful to model many materials and material groups, even though it has been applied phenomenologically, i.e., it has not been demonstrated. This research presents a demonstration of the Adachi procedure. The demonstration is based on that ε2 is a piecewise function (i.e., it has more than one functionality), which results in a branch cut in the dielectric function at the real photon energies where ε2 is not null. The Adachi procedure is seen to be equivalent to a recent procedure developed to turn optical models into analytic by integrating the dielectric function with a Lorentzian function. Such equivalence is exemplified on models used by Adachi and on popular piecewise optical models: Tauc-Lorentz and Cody-Lorentz-Urbach models.


Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo.
Severe inflammation and astrocyte loss with profound demyelination in spinal cord and optic nerves are typical pathological features of neuromyelitis optica (NMO). A diagnostic hallmark of this disease is the presence of serum autoantibodies against the water channel aquaporin-4 (AQP-4) on astrocytes. We induced acute T-cell-mediated experimental autoimmune encephalomyelitis in Lewis rats and confronted the animals with an additional application of immunoglobulins from AQP-4 antibody-positive and -negative NMO patients, multiple sclerosis patients, and control subjects. The immunoglobulins from AQP-4 antibody-positive NMO patients are pathogenic. When they reach serum titers in experimental animals comparable with those seen in NMO patients, they augment clinical disease and induce lesions in the central nervous system that are similar in structure and distribution to those seen in NMO patients, consisting of AQP-4 and astrocyte loss, granulocytic infiltrates, T cells and activated macrophages/microglia cells, and an extensive immunoglobulin and complement deposition on astrocyte processes of the perivascular and superficial glia limitans. AQP-4 antibody containing NMO immunoglobulin injected into naïve rats, young rats with leaky blood-brain barrier, or after transfer of a nonencephalitogenic T-cell line did not induce disease or neuropathological alterations in the central nervous system. Absorption of NMO immunoglobulins with AQP-4-transfected cells, but not with mock-transfected control cells, reduced the AQP-4 antibody titers and was associated with a reduction of astrocyte pathology after transfer. Human anti-AQP-4 antibodies are not only important in the diagnosis of NMO but also augment disease and induce NMO-like lesions in animals with T-cell-mediated brain inflammation.


Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons.
The human genome contains vast genetic diversity as naturally occurring coding variants, yet the impact of these variants on protein function and physiology is poorly understood. RGS14 is a multifunctional signaling protein that suppresses synaptic plasticity in dendritic spines of hippocampal neurons. RGS14 also is a nucleocytoplasmic shuttling protein, suggesting that balanced nuclear import/export and dendritic spine localization are essential for RGS14 functions. We identified genetic variants L505R (LR) and R507Q (RQ) located within the nuclear export sequence (NES) of human RGS14. Here we report that RGS14 encoding LR or RQ profoundly impacts protein functions in hippocampal neurons. RGS14 membrane localization is regulated by binding Gαi-GDP, whereas RGS14 nuclear export is regulated by Exportin 1 (XPO1). Remarkably, LR and RQ variants disrupt RGS14 binding to Gαi1-GDP and XPO1, nucleocytoplasmic equilibrium, and capacity to inhibit long-term potentiation (LTP). Variant LR accumulates irreversibly in the nucleus, preventing RGS14 binding to Gαi1, localization to dendritic spines, and inhibitory actions on LTP induction, while variant RQ exhibits a mixed phenotype. When introduced into mice by CRISPR/Cas9, RGS14-LR protein expression was detected predominantly in the nuclei of neurons within hippocampus, central amygdala, piriform cortex, and striatum, brain regions associated with learning and synaptic plasticity. Whereas mice completely lacking RGS14 exhibit enhanced spatial learning, mice carrying variant LR exhibit normal spatial learning, suggesting that RGS14 may have distinct functions in the nucleus independent from those in dendrites and spines. These findings show that naturally occurring genetic variants can profoundly alter normal protein function, impacting physiology in unexpected ways.


Missense mutations in the gp91-phox gene encoding cytochrome b558 in patients with cytochrome b positive and negative X-linked chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a disorder of host defense due to genetic defects of the superoxide (O2-) generating NADPH oxidase in phagocytes. A membrane-bound cytochrome b558, a heterodimer consisting of gp91-phox and p22-phox, is a critical component of the oxidase. The X-linked form of the disease is due to defects in the gp91-phox gene. We report here biochemical and genetic analyses of patients with typical and atypical X-linked CGD. Immunoblots showed that neutrophils from one patient had small amounts of p22-phox and gp91-phox and a low level of O2- forming oxidase activity, in contrast to the complete absence of both subunits in two patients with typical CGD. Using polymerase chain reactions (PCR) on cDNA and genomic DNA, we found novel missense mutations of gp91-phox in the two typical patients and a point mutation in the variant CGD, a characteristic common to two other patients with similar variant CGD reported previously. Spectrophotometric analysis of the neutrophils from the variant patient provided evidence for the presence of heme of cytochrome b558. Recently, we reported another variant CGD with similar amounts of both subunits, but without oxidase activity or the heme spectrum. A predicted mutation at amino acid 101 in gp91-phox was also confirmed in this variant CGD by PCR of the genomic DNA. These results on four patients, including those with two variant CGD, are discussed with respect to the missense mutated sites and the heme binding ligands in gp91-phox.


Effects of certain resorcinol derivatives on the tyrosinase activity and the growth of melanoma cells.
Effects of certain resorcinol derivatives on tyrosinase activity, melanin formation and some other biological activities were studied in order to develop a new, potent depigmentor and/or antimelanoma drug. NKO-09, having isopentyl group in position 6 of resorcinal, exhibited a more potent effect than the compounds which have methyl (NKO-10), ethyl (NKO-11), hexyl (KOM-14), octyl (NKO-14), decyl (NKO-19), dodecyl (NKO-15) and tetradecyl (NKO-16) group in inhibiting the tyrosinase activities (both tyrosine hydroxylation and dopa oxidation). NKO-09 was more potent than hydroquinone in inhibiting the tyrosine hydroxylation; furthermore, NKO-09 inhibited the dopa oxidation different from hydroquinone. In the studies on melanin formation, protein synthesis and the growth of the melanoma cells, NKO-09 caused the most potent effect among the test compounds, except for the growth of the melanoma cells. KOM-14 was more potent than NKO-09 in the antimelanoma activity, and its effect was superior than that of 5-fluorouracil. From these findings, it is suggested that NKO-09 and KOM-14 can be used as an efficacious depigmentor and antimelanoma drug, respectively.


A contemporary insight of metabolomics approach for COVID-19: Potential for novel therapeutic and diagnostic targets.
The Coronavirus disease 2019 (COVID-19) pandemic is caused by rapidly spreading pathogenic virus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that affects vast majority of population worldwide. Although, around 80% of the cases had mild infection but still remaining 20% had developed respiratory failure and dysfunction of other organs that necessitate urgent oxygen therapy or specific interventions. Therefore, it is imperative to establish novel prognostic approaches to screen patients at high-risk of developing severe complications. The primary focus of current research for COVID-19 is to discover safe and efficacious vaccine for prevention and effective treatment for better management of the patients to overcome the pandemic. To achieve this goal, it is imperative to have better understanding of the molecular pathways involved in the pathophysiology and progression of severe COVID-19. The surge for reliable diagnostics and therapeutics targets for COVID-19 highlighted the great potential of high-throughput approach like metabolomics which may enable the development of personalized medicine.


Regulatory mechanism of Dictyostelium myosin light chain kinase A.
In this study, we examined the activation mechanism of Dictyostelium myosin light chain kinase A (MLCK-A) using constitutively active Ca2+/calmodulin-dependent protein kinase kinase as a surrogate MLCK-A kinase. MLCK-A was phosphorylated at Thr166 by constitutively active Ca2+/calmodulin-dependent protein kinase kinase, resulting in an approximately 140-fold increase in catalytic activity, using intact Dictyostelium myosin II. Recombinant Dictyostelium myosin II regulatory light chain and Kemptamide were also readily phosphorylated by activated MLCK-A. Mass spectrometry analysis revealed that MLCK-A expressed by Escherichia coli was autophosphorylated at Thr289 and that, subsequent to Thr166 phosphorylation, MLCK-A also underwent a slow rate of autophosphorylation at multiple Ser residues. Using site-directed mutagenesis, we show that autophosphorylation at Thr289 is required for efficient phosphorylation and activation by an upstream kinase. By performing enzyme kinetics analysis on a series of MLCK-A truncation mutants, we found that residues 283-288 function as an autoinhibitory domain and that autoinhibition is fully relieved by Thr166 phosphorylation. Simple removal of this region resulted in a significant increase in the kcat of MLCK-A; however, it did not generate maximum enzymatic activity. Together with the results of our kinetic analysis of the enzymes, these findings demonstrate that Thr166 phosphorylation of MLCK-A by an upstream kinase subsequent to autophosphorylation at Thr289 results in generation of maximum MLCK-A activity through both release of an autoinhibitory domain from its catalytic core and a further increase (15-19-fold) in the kcat of the enzyme.


Evaluation of myocardial triglyceride accumulation assessed on 1H-magnetic resonance spectroscopy in apparently healthy Japanese subjects.
Proton magnetic resonance spectroscopy ((1)H-MRS) enables the clinician to noninvasively assess the amount of ectopic fat in the liver, skeletal muscle and myocardium. Recent studies have reported that the myocardial triglyceride (TG) content is associated with aging, metabolic disorders and cardiac dysfunction. However, the clinical usefulness of myocardial TG measurements in Japanese subjects has not been fully investigated. The myocardial TG content was evaluated using (1)H-MRS in 37 apparently healthy Japanese subjects, and the left ventricular function was measured on cardiac magnetic resonance imaging (MRI). Blood pressure, body composition and biochemical markers were measured in a fasting state, and cardiopulmonary exercise testing (CPX) was performed to evaluate exercise capacity. The mean myocardial TG content was 0.85±0.40%. The myocardial TG content was significantly associated with the percent body fat (r=0.39), serum triglyceride level (r=0.40), estimated glomerular filtration rate (r=-0.37), anaerobic threshold (r=-0.36), maximal load of CPX (r=0.39), left ventricular end-diastolic volume (r=-0.41) and left ventricular end-systolic volume (LVESV) (r=-0.51) (all: p<0.05). In a multivariate analysis, the LVESV was found to be an independent factor of the myocardial TG content. (1)H-MRS may be useful for assessing the associations between the myocardial TG content and various clinical parameters, including those reflecting obesity, metabolic disorders, cardiac morphology and exercise capacity, noninvasively, even in Japanese subjects.


Radiomics: the bridge between medical imaging and personalized medicine.
Radiomics, the high-throughput mining of quantitative image features from standard-of-care medical imaging that enables data to be extracted and applied within clinical-decision support systems to improve diagnostic, prognostic, and predictive accuracy, is gaining importance in cancer research. Radiomic analysis exploits sophisticated image analysis tools and the rapid development and validation of medical imaging data that uses image-based signatures for precision diagnosis and treatment, providing a powerful tool in modern medicine. Herein, we describe the process of radiomics, its pitfalls, challenges, opportunities, and its capacity to improve clinical decision making, emphasizing the utility for patients with cancer. Currently, the field of radiomics lacks standardized evaluation of both the scientific integrity and the clinical relevance of the numerous published radiomics investigations resulting from the rapid growth of this area. Rigorous evaluation criteria and reporting guidelines need to be established in order for radiomics to mature as a discipline. Herein, we provide guidance for investigations to meet this urgent need in the field of radiomics.


TLR4 in skin cancer: From molecular mechanisms to clinical interventions.
The health and economic burden imposed by skin cancer is substantial, creating an urgent need for the development of improved molecular strategies for its prevention and treatment. Cutaneous exposure to solar ultraviolet (UV) radiation is a causative factor in skin carcinogenesis, and TLR4-dependent inflammatory dysregulation is an emerging key mechanism underlying detrimental effects of acute and chronic UV exposure. Direct and indirect TLR4 activation, upstream of inflammatory signaling, is elicited by a variety of stimuli, including pathogen-associated molecular patterns (such as lipopolysaccharide) and damage-associated molecular patterns (such as HMGB1) that are formed upon exposure to environmental stressors, such as solar UV. TLR4 involvement has now been implicated in major types of skin malignancies, including nonmelanoma skin cancer, melanoma and Merkel cell carcinoma. Targeted molecular interventions that positively or negatively modulate TLR4 signaling have shown promise in translational, preclinical, and clinical investigations that may benefit skin cancer patients in the near future.


Carbon dot-assisted luminescence of singlet oxygen: the generation dynamics but not the cumulative amount of singlet oxygen is responsible for the photodynamic therapy efficacy.
A novel carbon dot-based luminescence probe for singlet oxygen (1O2) with a conventional optical detector has been implemented through the specific formation of electronically excited carbonyls from the breakdown of unstable endoperoxide intermediates, and its application in the real-time in vivo monitoring of 1O2 in photodynamic therapy (PDT) is achieved. More attractively, the relationship between the dynamics details of photosensitizer-generated 1O2 and the PDT efficacy has been established through a modified multiple-target survival model, enabling a direct and easy estimate of the surviving fraction of tumor cells from the generation dynamics of 1O2. Both in vitro and in vivo therapy results revealed that the rapid generation dynamics of 1O2 rather than its cumulative amount is responsible for better treatment efficacy in PDT. Overall, the deeper insight into the important roles of the generation dynamics of 1O2 in the PDT efficacy is irreplaceably advantageous in substantially reduced risks from deleterious treatment-related side effects by screening advanced photosensitizers and determining the light exposure end point.


Selective Neuronal Mitochondrial Targeting in SARS-CoV-2 Infection Affects Cognitive Processes to Induce 'Brain Fog' and Results in Behavioral Changes that Favor Viral Survival.
Alterations in brain functioning, especially in regions associated with cognition, can result from infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and are predicted to result in various psychiatric diseases. Recent studies have shown that SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19) can directly or indirectly affect the central nervous system (CNS). Therefore, diseases associated with sequelae of COVID-19, or 'long COVID', also include serious long-term mental and cognitive changes, including the condition recently termed 'brain fog'. Hypoxia in the microenvironment of select brain areas may benefit the reproductive capacity of the virus. It is possible that in areas of cerebral hypoxia, neuronal cell energy metabolism may become compromised after integration of the viral genome, resulting in mitochondrial dysfunction. Because of their need for constant high metabolism, cerebral tissues require an immediate and constant supply of oxygen. In hypoxic conditions, neurons with the highest oxygen demand become dysfunctional. The resulting cognitive impairment benefits viral spread, as infected individuals exhibit behaviors that reduce protection against infection. The effects of compromised mitochondrial function may also be an evolutionary advantage for SARS-CoV-2 in terms of host interaction. A high viral load in patients with COVID-19 that involves the CNS results in the compromise of neurons with high-level energy metabolism. Therefore, we propose that selective neuronal mitochondrial targeting in SARS-CoV-2 infection affects cognitive processes to induce 'brain fog' and results in behavioral changes that favor viral propagation. Cognitive changes associated with COVID-19 will have increasing significance for patient diagnosis, prognosis, and long-term care.


Epidemiology of invasive meningococcal B disease in Australia, 1999-2015: priority populations for vaccination.
To describe trends in the age-specific incidence of serogroup B invasive meningococcal disease (IMD) in Australia, 1999-2015. Analysis in February 2017 of de-identified notification data from the Australian National Notifiable Diseases Surveillance System of all notifications of IMD in Australia with a recorded diagnosis date during 1999-2015.Major outcomes: IMD notification rates in Australia, 1999-2015, by age, serogroup, Indigenous status, and region. The incidence of meningococcal serogroup B (MenB) disease declined progressively from 1.52 cases per 100 000 population in 2001 to 0.47 per 100 000 in 2015. During 2006-2015, MenB accounted for 81% of IMD cases with a known serogroup; its highest incidence was among infants under 12 months of age (11.1 [95% CI, 9.81-12.2] per 100 000), children aged 1-4 years (2.82 [95% CI, 2.52-3.15] per 100 000), and adolescents aged 15-19 years (2.40 [95% CI, 2.16-2.67] per 100 000). Among the 473 infants under 2 years of age with MenB, 43% were under 7 months and 69% under 12 months of age. The incidence of meningococcal serogroup C (MenC) disease prior to the introduction of the MenC vaccine in 2003 was much lower in infants than for MenB (2.60 cases per 100 000), the rate peaking in people aged 15-19 years (3.32 per 100 000); the overall case fatality rate was also higher (MenC, 8%; MenB, 4%). The incidence of MenB disease was significantly higher among Indigenous than non-Indigenous Australians during 2006-2015 (incidence rate ratio [IRR], 3.8; 95% CI, 3.3-4.5). Based on disease incidence at its current low endemic levels, priority at risk age/population groups for MenB vaccination include all children between 2 months and 5 years of age, Indigenous children under 10 years of age, and all adolescents aged 15-19 years. Given marked variation in meningococcal disease trends over time, close scrutiny of current epidemiologic data is essential.


Effects of Anaerobic Culturing on Pathogenicity and Virulence-Related Gene Expression in Pneumococcal Pneumonia.
The pathogenicity of Streptococcus pneumoniae under anaerobic conditions remains largely unknown. We examined the pathogenicity of S. pneumoniae cultured under anaerobic conditions in a murine model of pneumococcal pneumonia. Mice were infected with S. pneumoniae grown under anaerobic or aerobic conditions. The pathogenic effects in vivo in the lower airway tract were then compared. The effect of anaerobic culture on lytA/ply transcript levels in vitro and in vivo were analyzed by quantitative real-time polymerase chain reaction. Mice inoculated with anaerobically cultured S. pneumoniae exhibited significantly lower survival rates and higher bacterial loads in the lungs and blood as compared to those infected with aerobically cultured S. pneumoniae. Aerobically cultured S. pneumoniae in the early log phase of growth was also able to induce severe pneumonia at levels equivalent to those of anaerobic S. pneumoniae. However, ply/gyrB transcript levels were significantly increased in the lungs of mice infected with anaerobically grown S. pneumoniae. In vitro, S. pneumoniae grown under anaerobic culture conditions demonstrated greater proliferation than S. pneumoniae grown under aerobic culture conditions, and bacterial concentrations were maintained for 24 hours without detectable upregulation of lytA messenger RNA. S. pneumoniae grown under anaerobic conditions had the potential to induce severe invasive bacteremic pneumococcal pneumonia in a manner different from that of S. pneumoniae grown under aerobic conditions.


[(NHC)CuX] complexes: synthesis, characterization and catalytic activities in reduction reactions and Click chemistry. On the advantage of using well-defined catalytic systems.
The preparation of three series of [(NHC)CuX] complexes (NHC = N-heterocyclic carbene, X = Cl, Br, or I) is reported. These syntheses are high yielding and only use readily available starting materials. The prepared complexes were spectroscopically and structurally characterized. Notably, two of them present a bridging NHC ligand between two copper centers in the solid state, an extremely rare coordination mode for these ligands. These complexes were then applied to two distinct organic reactions: the hydrosilylation of ketones and the 1,3-dipolar cycloaddition of azides and alkynes. In both transformations, outstanding catalytic systems were found for preparing the corresponding products in excellent yields and short reaction times. Most remarkably, the screening of well-defined systems in the hydrosilylation reaction allowed for the identification of a pre-catalyst previously overlooked since, originally, catalytic species were in situ generated. Under such conditions, major formation of [(NHC)(2)Cu](+) species, inactive in this reduction reaction, occurred instead of the expected copper hydride. These results highlight one of the most important advantages of employing well-defined complexes in catalysis: gaining an improved control of the nature of the catalytically relevant species in the reaction media.


Evaluation of Total Hip Arthroplasty Performed from a Lateral Approach as Optimal Treatment for Femoral Neck Fractures in Elderly, Active Patients.
The aim of the study was to evaluate total hip arthroplasty in terms of clinical and functional outcomes, rate of complications and hospitalization, as a treatment of choice for displaced femoral neck fractures. We retrospectively reviewed the data of 526 patients with THA operated on in our department between January 2017 and December 2021. Clinical examinations, functional outcome assessment and radiographic evaluation were performed during follow-up. Patients were evaluated at the following time points: postoperatively at 3 days, 6 weeks, 12 weeks and 1 year, and we recorded surgery related data, complications, Visual Analogue Scale pain score, Harris Hip Score, the Western Ontario McMaster Osteoarthritis Index, and range of motion. Low intraoperative blood loss, short surgical time, short hospitalization, early mobilization of the patient and a good range of motion testify that the modified direct lateral approach is a valuable procedure for the patients with THA. A VAS score evaluated at 3 days and 6 weeks indicated a very good overall postoperative experience. The HHS and Womac scores were evaluated at 6 weeks, 12 weeks and 1 year and showed excellent results. THA for active patients with a displaced fracture of the femoral neck is an excellent treatment option which provides lasting pain relief, a high level of function and very low rates of reoperation.


Adaptive object tracking based on an effective appearance filter.
We propose a similarity measure based on a Spatial-color Mixture of Gaussians (SMOG) appearance model for particle filters. This improves on the popular similarity measure based on color histograms because it considers not only the colors in a region but also the spatial layout of the colors. Hence, the SMOG-based similarity measure is more discriminative. To efficiently compute the parameters for SMOG, we propose a new technique, with which the computational time is greatly reduced. We also extend our method by integrating multiple cues to increase the reliability and robustness. Experiments show that our method can successfully track objects in many difficult situations.


Accurate spatiotemporal mapping of drug overdose deaths by machine learning of drug-related web-searches.
Persons who inject drugs (PWID) are at increased risk for overdose death (ODD), infections with HIV, hepatitis B (HBV) and hepatitis C virus (HCV), and noninfectious health conditions. Spatiotemporal identification of PWID communities is essential for developing efficient and cost-effective public health interventions for reducing morbidity and mortality associated with injection-drug use (IDU). Reported ODDs are a strong indicator of the extent of IDU in different geographic regions. However, ODD quantification can take time, with delays in ODD reporting occurring due to a range of factors including death investigation and drug testing. This delayed ODD reporting may affect efficient early interventions for infectious diseases. We present a novel model, Dynamic Overdose Vulnerability Estimator (DOVE), for assessment and spatiotemporal mapping of ODDs in different U.S. jurisdictions. Using Google® Web-search volumes (i.e., the fraction of all searches that include certain words), we identified a strong association between the reported ODD rates and drug-related search terms for 2004-2017. A machine learning model (Extremely Random Forest) was developed to produce yearly ODD estimates at state and county levels, as well as monthly estimates at state level. Regarding the total number of ODDs per year, DOVE's error was only 3.52% (Median Absolute Error, MAE) in the United States for 2005-2017. DOVE estimated 66,463 ODDs out of the reported 70,237 (94.48%) during 2017. For that year, the MAE of the individual ODD rates was 4.43%, 7.34%, and 12.75% among yearly estimates for states, yearly estimates for counties, and monthly estimates for states, respectively. These results indicate suitability of the DOVE ODD estimates for dynamic IDU assessment in most states, which may alert for possible increased morbidity and mortality associated with IDU. ODD estimates produced by DOVE offer an opportunity for a spatiotemporal ODD mapping. Timely identification of potential mortality trends among PWID might assist in developing efficient ODD prevention and HBV, HCV, and HIV infection elimination programs by targeting public health interventions to the most vulnerable PWID communities.


Effects of stress hormones on the production of volatile sulfur compounds by periodontopathogenic bacteria.
Little is known about the effects of stress hormones on the etiologic agents of halitosis. Thus, the aim of this study was to evaluate in vitro the effects of adrenaline (ADR), noradrenaline (NA) and cortisol (CORT) on bacteria that produce volatile sulfur compounds (VSC), the major gases responsible for bad breath. Cultures of Fusobacterium nucleatum (Fn), Porphyromonas endodontalis (Pe), Prevotella intermedia (Pi) and Porphyromonas gingivalis (Pg) were exposed to 50 µM ADR, NA and CORT or equivalent volumes of sterile water as controls for 12 and 24 h. Growth was evaluated based on absorbance at 660 nm. Portable gas chromatography was used to measure VSC concentrations. Kruskal-Wallis and the Dunn post-hoc test were used to compare the groups. For Fn, ADR, NA and CORT significantly reduced bacterial growth after 12 h and 24 h (p<0.05). All the substances tested increased hydrogen sulfide (H2S) production (p<0.05). For Pe, all the substances tested reduced bacterial development after 24 h (p<0.05), and NA significantly increased the H2S concentration after 12 h (p<0.05). In the Pg and Pi cultures, no effects on bacterial growth were observed (p>0.05). In the Pi cultures, ADR, NA and CORT increased H2S (p<0.05). Catecholamines and cortisol can interfere with growth and H2S production of sub-gingival species in vitro. This process appears to be complex and supports the association between stress and the production of VSC.


Loss of interferon antibodies during prolonged continuous interferon-alpha 2a therapy in hairy cell leukemia.
Although highly active in hairy cell leukemia (HCL), interferons (IFN) are not curative in this disease; current data indicate that prolonged IFN therapy will be necessary to control disease in the majority of patients. We previously observed acquired IFN resistance in association with neutralizing IFN-alpha 2a antibodies in small numbers of patients with HCL. This finding suggests that the requisite long-term therapy may be compromised if there is an increasing incidence over time of neutralizing antibodies. We performed a follow-up study of IFN antibodies in our patients receiving continuous IFN therapy. All 16 patients who were previously antibody negative remained so. Surprisingly, all nine patients who previously had non-neutralizing IFN antibodies became antibody negative after a median of 14.5 months. Moreover, 3 of 10 patients who had neutralizing antibodies became antibody negative and five had only non-neutralizing antibodies a median of 10 months from the time neutralizing antibody had first been detected. Only two patients had persisting neutralizing antibodies. Inhibition of neopterin synthesis, inhibition of generation of 2', 5' oligoadenylate synthetase activity, and inability to detect IFN in serum after subcutaneous injection of IFN-alpha 2a was observed only in the one patient tested with neutralizing IFN antibodies confirming that these antibodies have functional significance in vivo. We conclude that, although neutralizing IFN antibodies inhibit the effectiveness of IFN in vivo, these antibodies are produced only transiently during long-term therapy. The long-term effectiveness of this drug will not likely be affected in most patients by neutralizing antibody.


Immunotherapy of Dual-Function Vector with Both Immunostimulatory and B-Cell Lymphoma 2 (Bcl-2)-Silencing Effects on Gastric Carcinoma.
BACKGROUND Tumorigenesis is a kind of pathology marked by infinite proliferation and restrained apoptosis compared with normal cells. The abnormal expression of some proto-oncogenes and apoptosis inhibition are essential for tumor growth, which has been confirmed by molecular biologic and immunologic studies. The hypofunction of the host immune system also drives the development and metastasis of malignant tumors. Bcl-2, which has a critical role in regulating apoptosis, is overexpressed in several cancers. MATERIAL AND METHODS In this study, we constructed a dual-function small hairpin RNA (shRNA) vector containing an Bcl-2-silencing shRNA and a TLR7-stimulating ssRNA and examined it effect on tumor cell growth and proliferation. RESULTS Stimulation with this bi-functional vector in vitro promoted significant apoptosis of MFC cells by regulating the expression of apoptosis-related proteins and induced secretion of type I IFNs. Most importantly, this bi-functional vector more effectively inhibited subcutaneous MFC cell growth than did single shRNA and ssRNA treatment in vivo. Natural killer (NK) and CD4+ T cells were required for effective tumor suppression, and TLR7 was shown to play a helper role in the activation of NK cells and CD4+ T cells, possibly by regulating the expression of receptors or secretion of cytokines. CONCLUSIONS This bi-functional vector that contained ssRNA and shRNA may represent a promising approach for tumor therapy.


Garlic consumption and cancer prevention: meta-analyses of colorectal and stomach cancers.
Animal and in vitro studies have provided evidence of an anticarcinogenic effect of active ingredients in garlic. The objective was to conduct meta-analyses of the epidemiologic literature on the association between garlic consumption and risk of stomach, colon, head and neck, lung, breast, and prostate cancers. Meta-analyses were conducted for all cancers mutually and separately for colorectal and stomach cancers in relation to consumption of exclusively raw garlic, cooked garlic, or both (RC garlic). Eighteen studies reported a relative risk estimate for RC garlic consumption and cancer risk. In the meta-analyses of colorectal and stomach cancer, the reference categories ranged from no consumption to consumption of 3.5 g/wk, whereas the highest categories ranged from any consumption to >28.8 g/wk. The average difference between the highest and lowest categories was 16 g/wk. The random-effects relative risk (RR) estimate of colorectal cancer and RC garlic consumption, excluding garlic supplements, was 0.69 (95% CI: 0.55, 0.89). For stomach cancer, the random-effects RR estimate was 0.53 (95% CI: 0.31, 0.92). The heterogeneity among studies for the latter outcome (P: = 0.0002) indicates the questionableness of the generalizability of this summary estimate. An indication of publication bias for all cancers combined is evident from a funnel plot of RC garlic consumption and cancer risk and from the results of the Begg and Mazumdar test (P: = 0.049). High intake of RC garlic may be associated with a protective effect against stomach and colorectal cancers. Heterogeneity of effect estimates, differences in dose estimation, publication bias, and possible alternative hypotheses (eg, confounding by total vegetable consumption) preclude sole reliance on summary effect estimates.


Moyamoya in a child treated with interferon for recurrent osteosarcoma.
Moyamoya is a cerebral vasculopathy of unknown etiology rarely described as a late effect after the treatment of childhood cancer. We describe a 12-year-old female who developed moyamoya after the completion of systemic chemotherapy, surgery, and adjuvant interferon alpha for osteosarcoma with pulmonary metastases. Given the importance of characterizing late effects after the treatment of childhood cancer, the potential role of interferon alpha in the development of moyamoya is discussed.


Is there an optimal surgery time after endoscopic resection in early gastric cancer?
The patients with early gastric cancer who have undergone incomplete endoscopic resection (ER) generally need additional surgery because of the possibility of lymph node metastasis. The aim of study was to evaluate the optimal time interval from ER to additive surgery by evaluating the effect of time interval on the surgical and oncological outcomes. We analyzed 154 patients who underwent additive gastrectomy after incomplete ER at Severance and Gangnam Severance Hospitals. The time interval point, at which operative time and estimated intraoperative blood loss (EBL) of the earlier operation group and the later operation group showed the greatest disparities, was evaluated. The patients were divided into 2 groups according to the time interval point, as the earlier operation group (group A) and the later operation group (group B). We retrospectively evaluated the clinicopathological characteristics and surgical and oncological outcomes. The greatest difference between operative time and EBL was in the groups who underwent operation before and after 29 days. Of the 154 patients, 78 were in group A (≤29 days) and 76 in group B (>29 days). There were no differences in the clinicopathological characteristics and oncological outcomes except for tumor size. The operative time and EBL were significantly longer and more in group A compared with group B. The time interval between ER and additive surgery is associated with surgical outcomes. Additive surgery at about 1 month after ER may be optimal for better surgical outcomes without affecting the oncological outcomes.


Biofortified Maize Improves Selenium Status of Women and Children in a Rural Community in Malawi: Results of the Addressing Hidden Hunger With Agronomy Randomized Controlled Trial.
Background: Selenium deficiency is widespread in the Malawi population. The selenium concentration in maize, the staple food crop of Malawi, can be increased by applying selenium-enriched fertilizers. It is unknown whether this strategy, called agronomic biofortification, is effective at alleviating selenium deficiency. Objectives: The aim of the Addressing Hidden Hunger with Agronomy (AHHA) trial was to determine whether consumption of maize flour, agronomically-biofortified with selenium, affected the serum selenium concentrations of women, and children in a rural community setting. Design: An individually-randomized, double-blind placebo-controlled trial was conducted in rural Malawi. Participants were randomly allocated in a 1:1 ratio to receive either intervention maize flour biofortified with selenium through application of selenium fertilizer, or control maize flour not biofortified with selenium. Participant households received enough flour to meet the typical consumption of all household members (330 g capita -1 day-1) for a period of 8 weeks. Baseline and endline serum selenium concentration (the primary outcome) was measured by inductively coupled plasma mass spectrometry (ICP-MS). Results: One woman of reproductive age (WRA) and one school-aged child (SAC) from each of 180 households were recruited and households were randomized to each group. The baseline demographic and socioeconomic status of participants were well-balanced between arms. No serious adverse events were reported. In the intervention arm, mean (standard deviation) serum selenium concentration increased over the intervention period from 57.6 (17.0) μg L-1 (n = 88) to 107.9 (16.4) μg L-1 (n = 88) among WRA and from 46.4 (14.8) μg L-1 (n = 86) to 97.1 (16.0) μg L-1 (n = 88) among SAC. There was no evidence of change in serum selenium concentration in the control groups. Conclusion: Consumption of maize flour biofortified through application of selenium-enriched fertilizer increased selenium status in this community providing strong proof of principle that agronomic biofortification could be an effective approach to address selenium deficiency in Malawi and similar settings. Clinical Trial Registration: http://www.isrctn.com/ISRCTN85899451, identifier: ISRCTN85899451.


[Chronic juvenile kidney insufficiency. Results of a Swiss questionnaire].
From 1972 to 1974 a collaborative prospective study was undertaken to determine the incidence, causes and clinical course of chronic renal failure (CRF) in pediatric patients (age 1/2-16 years) in Switzerland. In addition, information concerning the occurrence of terminal CRF observed between 1967 and 1971 was obtained. CRF is defined as persistently elevated serum creatinine greater than 2 mg/100 ml. The small size of Switzerland (population 6.27 million) and the availability of specialized medical care favoured relative completeness of data. a) Non-terminal CRF. - Prevalence was 4.5 per million total population = 18.5 per million children (1/2-16 years old) (n = 28 at 31. 12. 1974). Causes: renal disease was acquired in 14% and congenital in 86% (hereditary nephropathies excluding polycystic kidneys 4%, polycystic kidneys 14%, hypoplasia 14%, urinary tract abnormalities 54%). Progression of CRF: mean time interval in which serum creatinine doubled was, in the group of acquired renal diseases, 8.3 months (n = 6); in hereditary nephropathies 14.3 months (n = 4); in the group of polycystic kidneys and hypoplasia 41.2 months (n = 6), and in patients with urinary tract abnormalities 35.8 months (n = 15). Body height was reduced in all groups as compared with normal children: 1.0 SDS (standard deviation scores) in acquired renal diseases (n = 9), 5.1 SDS in cystinosis (n = 2), 0.4 SDS in polycystic kidneys (n = 4), 1.6 SDS in hypoplasia (n = 5), and 2.3 SDS in urinary tract abnormalities (n = 16). b) Terminal CRF. - Mean yearly incidence (1967-1974, n = 68) was 1.36 per million total population = 5.6 per million children (1/2-16 years). Causes: In contrast to the situation in non-terminal CRF, acquired diseases were observed in 56% of all patients. Hereditary nephropathies were found in 12%, polycystic kidneys in 1.5%, hypoplasia in 4.5%, and urinary tract abnormalities in 26%. Between 1970 and 1972 , 7 of 21 patients, and during 1973/1974 13 of 16 pediatric patients, were treated by intermittent hemodialysis and renal transplantation. On 31. 12. 1974, 18 of these 20 treated patients were alive, and of these 14 had a functioning graft.


A Bayesian state-space model using age-at-harvest data for estimating the population of black bears (Ursus americanus) in Wisconsin.
Population estimation is essential for the conservation and management of fish and wildlife, but accurate estimates are often difficult or expensive to obtain for cryptic species across large geographical scales. Accurate statistical models with manageable financial costs and field efforts are needed for hunted populations and using age-at-harvest data may be the most practical foundation for these models. Several rigorous statistical approaches that use age-at-harvest and other data to accurately estimate populations have recently been developed, but these are often dependent on (a) accurate prior knowledge about demographic parameters of the population, (b) auxiliary data, and (c) initial population size. We developed a two-stage state-space Bayesian model for a black bear (Ursus americanus) population with age-at-harvest data, but little demographic data and no auxiliary data available, to create a statewide population estimate and test the sensitivity of the model to bias in the prior distributions of parameters and initial population size. The posterior abundance estimate from our model was similar to an independent capture-recapture estimate from tetracycline sampling and the population trend was similar to the catch-per-unit-effort for the state. Our model was also robust to bias in the prior distributions for all parameters, including initial population size, except for reporting rate. Our state-space model created a precise estimate of the black bear population in Wisconsin based on age-at-harvest data and potentially improves on previous models by using little demographic data, no auxiliary data, and not being sensitive to initial population size.


The prevention, diagnosis, referral and management of melanoma of the skin: concise guidelines.
Melanoma of the skin is an increasingly common tumour, which often has a slow early growth rate during which curable lesions may be detected and removed. Physicians therefore have the potential to reduce mortality and this guideline is intended to promote early diagnosis of melanoma. The majority of melanomas occur in white-skinned people. The most common risk factors are pale sun-sensitive skin and the presence of increased numbers of melanocytic naevi (moles). Melanoma is more common in women than men; the mean age of onset is 50 years; and a fifth of cases occur in young adults. In the UK population the most common sites are on the lower leg in women, and on the back in men. The predictors of melanoma are progressive change in the shape, size and colour of moles. This guideline provides a series of photographs of moles, melanomas and other skin lesions, which may resemble melanomas.


Exposing catalytic versatility of GTPases: taking reaction detours in mutants of hGBP1 enzyme without additional energetic cost.
The catalytic power of enzymes is usually ascribed to a few catalytically competent residues as revealed by site-directed mutagenesis studies in conjunction with biochemical, thermodynamic and structural analyses. Surprisingly, the mutations of such pivotal residues in a GTPase that can hydrolyse GTP even to GMP, namely hGBP1, have been reported to result only in marginal changes of the catalytic rate compared to the wild type. Our large-scale ab initio quantum-mechanical/molecular-mechanical (QM/MM) metadynamics simulations disclose that the replacement of catalytically competent residues by the inert amino acid alanine, S73A and E99A, opens a plethora of molecularly different reaction pathways featuring very similar energy barriers and thus rates. These hitherto unknown reaction channels are established by mechanistically involving far-distant residues using "floating" water molecules, which connect them via hydrogen-bonding bridges to the nucleophilic water molecule, thus allowing for efficient long-distance proton transfer via the Grotthuss mechanism. Given the generic nature of the disclosed detour mechanisms that provide the molecular underpinning of catalytic versatility and thus mutational robustness of hGBP1, it is expected that the same concept is operational for GTPases in a broad sense.


Replacement of Lys by Glu in a transmembrane segment strongly impairs the function of the uracil permease from Saccharomyces cerevisiae.
The co-transport of uracil and protons through the plasma membrane of the yeast Saccharomyces cerevisiae is mediated by a specific permease encoded by the FUR4 gene. The uracil permease is a multi-spanning membrane protein that follows the secretory pathway to the plasma membrane. Recent experimental data led to the proposal of a two-dimensional model of its topology. A spontaneous mutant corresponding to the substitution of Lys-272 by glutamic acid was obtained. The influence of this mutation was studied by comparing the wild-type and mutant permeases produced in a strain carrying a chromosomal deletion of the FUR4 gene. The mutant permease is correctly targeted to the plasma membrane and its stability is similar to that of the wild-type permease. The uptake parameters for the mutant permease were impaired and showed an approximately 65-fold increase of apparent K(m) and a decrease in apparent Vmax. Equilibrium binding measurements with enriched plasma membrane preparations showed an approximately 70-fold increase in apparent Kd in the mutant, whereas its Bmax. was similar to that of the wild type. Lys-272 is fully conserved in the uracil permease family and is predicted to lie in the fourth transmembrane segment of the protein. It seems to be essential for both efficient uracil binding and translocation.


Min-max operators in texture analysis.
A signature is generated for a given picture by operating on it with different masks. The operations are gray level generalizations of ``shrink'' and ``expand'' for binary pictures using Serra's morphological methods [10]. The signature is a set of numbers, each corresponding to an application of an operator at a certain scale and direction, and can be used to analyze the discriminate textures. It is shown that this family of signatures includes as special cases several currently used texture descriptors.


Corticosteroid Is Associated with Both Hip Fracture and Fracture-Unrelated Arthropathy.
We aimed to investigate whether and how corticosteroid use was associated with serious hip arthropathy. This population-based cohort study analyzed the Taiwan National Health Insurance Research Database and screened the one-million random sample from the entire population for eligibility. The steroid cohort consisted of 21,995 individuals who had used systemic corticosteroid for a minimum of 6 months between January 1, 1997 and December 31, 2006. They were matched 1:1 in propensity score on the index calendar date with controls who never used steroid. All participants were followed up until occurrence of serious hip arthropathy that required arthroplasty, withdrawal from the national health insurance, or the end of 2011. Surgical indication was classified as fracture-related and -unrelated. The cumulative incidence of hip arthroplasty was estimated by the Kaplan Meier method. The association with steroid exposure was explored by the Cox proportional hazard model. Cumulative incidences of hip arthroplasty after 12 years of follow-up were 2.96% (95% confidence interval [CI], 2.73-3.2%) and 1.34% (95% CI, 1.2-1.51%) in the steroid users and non-users, respectively (P<0.0001). The difference was evident in fracture-related arthroplasty with 1.89% (95% CI, 1.71-2.09%) versus 1.10% (95% CI, 0.97-1.25%), but more pronounced in fracture-unrelated surgery, 1.09% (95% CI, 0.95-1.24%) versus 0.24% (95% CI, 0.19-0.32%). Multivariate-adjusted Cox regression analysis confirmed steroid use was independently associated with both fracture-related (adjusted hazard ratio [HR], 1.65; 95% CI, 1.43-1.91) and unrelated arthroplasty (adjusted HR, 4.21; 95% CI, 3.2-5.53). Moreover, the risk for fracture-unrelated arthropathy rose with steroid dosage, as the adjusted HR increased from 3.30 (95% CI, 2.44-4.46) in the low-dose subgroup, 4.54 (95% CI, 3.05-6.77) in intermediate-dose users, to 6.54 (95% CI, 4.74-9.02) in the high-dose counterpart (Ptrend<0.0001). Corticosteroid use is associated with long-term risk of hip arthroplasty, particularly for fracture-unrelated arthropathy.


Results of national registration of familial adenomatous polyposis.
The Danish Polyposis Register was established in 1971 with the aim of improving the poor prognosis of familial adenomatous polyposis (FAP), and in 1975 the register became national. The aim of the present study was to evaluate the prevalence of colorectal cancer and survival rate in FAP patients before and after the establishment of the Danish Polyposis Register. The Danish Polyposis Register was established by collecting information on probands and construction of their pedigrees. Family members at risk were offered prophylactic endoscopic and molecular genetic examination, and affected individuals were treated by colectomy. At the end of 2001, the Danish Polyposis Register included 434 patients from 165 families. The incidence rate was 1.90x10(-6) and the prevalence rate 4.65x10(-5). Colorectal cancer on the basis of FAP constituted 0.07% of all colorectal cancers in the 1990s. Colorectal cancer was diagnosed in 170/252 probands (67%) and in 5/182 call-up patients (3%) (p<0.001). The cumulative crude survival was 94% in call-up patients compared with 44% in probands (p<0.0001). A comparison of two periods, 1900-1975 and 1976-2001, demonstrated a decreased prevalence of colorectal cancer from 60% to 27% (p<0.0001), and an increased use of colectomy from 52% to 93% (p<0.00001). The cumulative crude survival in FAP showed substantial improvement with time (p<0.00001). Since the establishment of the Danish Polyposis Register, the prevalence of colorectal cancer has decreased considerably and the prognosis has improved substantially. The work of the Danish Polyposis Register is probably the main cause of this improvement.


GD3 expression by cultured human tumor cells of neuroectodermal origin.
Seven monoclonal antibodies (mAbs) reactive with ganglioside II3(NeuAc)2-LacCer (GD3) were generated; four of these mAbs (DMAb-21, DMAb-22, DMAb-23, and DMAb-24) by immunizing mice with GD3 adsorbed to Salmonella minnesota and the remaining three (DMAb-7, DMAb-8, and DMAb-17) with melanoma line SK-MEL 28, which contains 1.4 nmol sialic acid of GD3 per mg protein. The specificities of the mAbs were defined by high-performance thin-layer chromatography (HPTLC) immunostain and solid-phase radioimmunoassay (SP-RIA) with a panel of purified gangliosides. DMAb-7 and DMAb-8 reacted with GD3, IV3(NeuAc)2nLcOse4Cer(3',8'-LD1), and very weakly with IV3(NeuAc)2II3NeuAcGgOse4Cer (GT1a), but not with II3NeuAc-LacCer (GM3), II3NeuAcGgOse3Cer(GM2), II3NeuAcGgOse4Cer (GM1), II3NeuAc, IV3NeuAcGgOse4Cer (GD1a), II3(NeuAc)2GgOse3(GD2), II3(NeuAc)2GgOse4Cer (GD1b), IV3NeuAcII3(NeuAc)2, GgOse4Cer(GT1b), suggesting the binding epitope to be a terminal tetrasaccharide NeuAc alpha 2-8NeuAc alpha 2-3Gal beta 1-4(Glc or GlcNAc). DMAb-7 and DMAb-8 were used to investigate the expression of GD3 on cultured human tumor cells of neuroectodermal origin. Thirteen of 19 gliomas, 3 of 5 medulloblastomas, 5 of 5 neuroblastomas, 2 of 2 melanomas, and 1 of 3 teratomas were shown to react with DMAb-8 and/or DMAb-7 by cell surface-RIA (CS-RIA) and immunofluorescence (IF) assays. HPTLC and densitometric analysis confirmed these results, as positive immunostains in the GD3 region were obtained with oligoganglioside fractions from 9 glioma, 1 medulloblastoma, 2 neuroblastoma, 1 melanoma, and 1 teratoma cell line. Glioma cell line U-105 MG and medulloblastoma cell line Daoy contain GD3 as shown by HPTLC immunostain analysis of extracts, although GD3 was undetectable on the cell surface as determined by CS-RIA and IF.(ABSTRACT TRUNCATED AT 250 WORDS)