Glucose-induced early changes in cytoplasmic calcium of pancreatic beta-cells studied with time-sharing dual-wavelength fluorometry.
The cytoplasmic calcium concentration (Ca2+i) was measured in suspensions of fura-2-loaded mouse pancreatic beta-cells by recording the 340:380 nm fluorescence excitation ratio. Exposure to 20 mM glucose resulted in an initial reduction and later increase of Ca2+i irrespective of preincubation in medium containing 0.5 or 1.28 mM Ca2+ and 0 or 3 mM glucose. When elevating the Ca2+ concentration to 5 or 10 mM only 5 min before raising glucose to 20 mM, the sugar-induced reduction of Ca2+i became more pronounced like the subsequent increase. However, when the Ca2+ concentration was increased from 1.28 to 10 mM 2 min after stimulation with glucose, there was a sudden pronounced Ca2+i transient, which was followed by a decrease and a slower secondary rise. After preincubation in 20 mM glucose the glucose-induced initial reduction of Ca2+i was only seen in a Ca2+-deficient medium. Reintroduction of the sugar in the presence of extracellular Ca2+ resulted in an immediate rise of Ca2+i, the rapidity of which depended on the transmembrane Ca2+ gradient. The results emphasize the role of a saturable beta-cell pool of Ca2+ in glucose-induced reduction of Ca2+i and indicate that the first phase of insulin release depends on an influx of extracellular Ca2+.


Spinal cord metabolism of the 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine-treated monkey.
Nine monkeys (Macaca fascicularis) were used in this study. Four monkeys were rendered parkinsonian by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 0.5 mg/kg intravenously. Three animals were injected once daily for 4 days, and one animal once weekly for 4 weeks. Five animals were used as controls. All MPTP-treated animals demonstrated the same clinical features which included akinesia, bradykinesia, a flexed posture of the trunk and all extremities, decreased initiation of the threat response, decreased vocalization and difficulty in swallowing. An increase in rigidity and reflexes was noted in all extremities. Tremor was present in all animals. Determination of the local spinal metabolic rate of glucose (LSMRg) utilization revealed an increase (P less than 0.05) in LSMRg in Rexed layer I in all cord segments and in Rexed layer II in both cervical and lumbar segments. Rexed layer X demonstrated a significant (P less than 0.05) increase in LSMRg at the cervical cord. The LSMRg in the animal that received weekly injections was similar to the daily injected animals.


Characterization of a bystander effect induced by the endocrine-disrupting chemical 6-propyl-2-thiouracil in zebrafish embryos.
This study was conducted to evaluate possible bystander effects induced by the model chemical 6-propyl-2-thiouracil (PTU) on melanin synthesis. Zebrafish (Danio rerio) embryos were treated with PTU by either microinjection exposure, via waterborne exposure or indirectly through bystander exposure. Melanin content, related mRNA and protein expression were examined at the end of exposure (36 h post-fertilization). Direct exposure to PTU decreased the melanin content, up-regulated mRNA expressions of oculocutaneous albinism type 2 (OCA2), tyrosinase (TYR), dopachrometautomerase (DCT), tyrosinase-related protein 1 (TYRP1) and silver (SILV), and increased the protein expressions of TYR and SILV. Bystander exposure also up-regulated mRNA and protein expressions of TYR and SILV but increased melanin contents. Correlation analysis demonstrated that mRNA expressions of OCA2, TYR, DCT, TYRP1, SILV and protein expressions of TYR and SILV in bystander exposure groups were positively correlated with corresponding expressions in microinjection exposure groups. The results might have environmental implications and highlight the need to consider the bystander effects when assessing potential risks of endocrine-disrupting chemicals.


Sleep cystometries in children with nocturnal enuresis.
A combined analysis was done of sleep and bladder filling during sleep. Cystometry did not specifically affect sleep, since most of the cystometry studies in cases of enuresis did not lead to sleep stage changes on electroencephalography. Bladder instability was not accompanied by lighter sleep. Increasing patient age did not appear to have any influence on sleep or bladder behavior. We conclude that it is possible to provoke enuresis at any sleep stage and that sleep is unaffected by bladder filling in enuretic patients.


Hardcore smoking after comprehensive smoke-free legislation and health warnings on cigarette packets in Hong Kong.
To examine if there were changes in the proportion of hardcore smokers and factors associated with hardcore smoking before and after implementation of smoke-free legislation, and warning labels on cigarette packets in Hong Kong in January 2007. Repeated cross-sectional surveys of the general population in Hong Kong. Data from all daily smokers aged ≥ 15 years in the population-based Thematic Household Surveys from 2005 (n = 3740) and 2008 (n = 2958) were used to estimate the prevalence of hardcore smokers before and after implementation of smoke-free legislation. A logistic regression model was used to identify the factors associated with hardcore smoking, and to examine if there were any changes in their associations with the likelihood of hardcore smoking after implementation of smoke-free legislation. The proportion of hardcore smokers among current daily smokers increased significantly from 22.5% [95% confidence interval (CI) 21.1-23.8%] in 2005 to 28.3% (95% CI 26.7-29.9%) in 2008. Change in the strength of the association of hardcore smoking with three factors was observed. The strength of the association between hardcore smoking and 'necessity in social functions' [odds ratio (OR) 0.54, 95% CI 0.31-0.95) and 'necessity for killing time' (OR 0.56, 95% CI 0.36-0.89) decreased, while the association between hardcore smoking and 'necessity as refreshment' increased (OR 3.02, 95% CI 1.43-6.39) after implementation of smoke-free legislation and warning labels on cigarette packets. 'Smoking had become a habit' was the factor associated most strongly with hardcore smoking (OR 4.88, 95% CI 4.02-5.93). The proportion of hardcore smokers remained stable in Hong Kong from 2005 to 2008. While the implementation of the two tobacco control measures may have provided an environment to reduce social smoking in hardcore smokers, addiction appeared to be the most important factor associated with hardcore smoking. More effective and tailor-made cessation services that target this group of smokers are needed.


Clinical analysis of extranodal non-Hodgkin's lymphoma in the sinonasal tract.
We investigated the clinical analysis of non-Hodgkin's lymphoma (NHL) of the sinonasal tract, including the survival rate and treatment outcome. Fifty patients who had previously received a diagnosis of extranodal NHL of the sinonasal cavity from May 1992 to April 2001 were included. We reviewed the patients' clinical characteristics and the survival rates, retrospectively. Of 50 patients, 49 were classified as having extranodal NK/T cell lymphoma and only one patient as having diffuse large B cell (DLBC) lymphoma according to the new WHO classification. Even though higher mortality rates were observed in patients receiving chemotherapy alone than in those receiving chemotherapy and radiation therapy in the advanced stage, the combination treatment of chemotherapy and radiation therapy failed to demonstrate a significantly higher survival rate.


Superiority of a Representative MRI Flow Waveform over Doppler Ultrasound for Aortic Wave Reflection Assessment in Children and Adolescents With/Without a History of Heart Disease.
Wave separation analysis (WSA) reveals the impact of forward- and backward-running waves on the arterial pressure pulse, but the calculations require a flow waveform. This study investigated (1) the variability of the ascending aortic flow waveform in children and adolescents with/without a childhood heart disease history (CHD); (2) the accuracy of WSA obtained with a representative flow waveform (RepFlow), compared with the triangulation method and published ultrasound-derived adult representative flow; (3) the impact of limitations in Doppler ultrasound on WSA; and (4) generalizability of results to adults with a history of CHD. Phase contrast MRI was performed in youth without (n = 45, Group 1, 10-19 years) and with CHD (n = 79, Group 2, 7-18 years), and adults with CHD history (n = 29, Group 3, 19-59 years). Segmented aortic cross-sectional area was used as a surrogate for the central pressure waveform in WSA. A subject-specific virtual Doppler ultrasound was performed on MRI data by extracting velocities from a sample volume. Time/amplitude-normalized ascending aortic flow waveforms were highly consistent amongst all groups. WSA with RepFlow therefore yielded errors < 10% in all groups for reflected wave magnitude and return time. Absolute errors were typically 1.5-3 times greater with other methods, including subject-specific (best-case/virtual) Doppler ultrasound, for which velocity profile skewing introduced waveform errors. Our data suggest that RepFlow is the optimal approach for pressure-only WSA in children and adolescents with/without CHD, as well as adults with CHD history, and may even be more accurate than subject-specific Doppler ultrasound in the ascending aorta.


L-Phenylalanine preloading reduces the (10)B(n, α)(7)Li dose to the normal brain by inhibiting the uptake of boronophenylalanine in boron neutron capture therapy for brain tumours.
Boron neutron capture therapy (BNCT) is a cellular-level particle radiation therapy that combines the selective delivery of boron compounds to tumour tissue with neutron irradiation. Previously, high doses of one of the boron compounds used for BNCT, L-BPA, were found to reduce the boron-derived irradiation dose to the central nervous system. However, injection with a high dose of L-BPA is not feasible in clinical settings. We aimed to find an alternative method to improve the therapeutic efficacy of this therapy. We examined the effects of oral preloading with various analogues of L-BPA in a xenograft tumour model and found that high-dose L-phenylalanine reduced the accumulation of L-BPA in the normal brain relative to tumour tissue. As a result, the maximum irradiation dose in the normal brain was 19.2% lower in the L-phenylalanine group relative to the control group. This study provides a simple strategy to improve the therapeutic efficacy of conventional boron compounds for BNCT for brain tumours and the possibility to widen the indication of BNCT to various kinds of other tumours.


Aggregation and partitioning of amyloid peptide fragments in the presence of a lipid bilayer: A coarse grained molecular dynamics study.
Amyloidogenicity and toxicity of amyloid peptides have been linked to the peptide aggregation and interactions with lipid bilayers. In this work we used the coarse grained MARTINI model to study the aggregation and partitioning of amyloid peptide fragments Aβ(1-28) and Aβ(25-35) in the presence of a dipalmitoylphosphatidylcholine bilayer. We explored the peptide aggregation starting from three initial spatial arrangements where free monomers were placed in solution outside the membrane, at the membrane-solution interface, or in the membrane. We found that Aβ(1-28) and Aβ(25-35) interact with the bilayer quite differently. The Aβ(1-28) fragments show strong peptide-peptide and peptide-lipid interactions leading to irreversible aggregation where the aggregates stay confined to their initial spatial location. The Aβ(25-35) fragments show weaker peptide-peptide and peptide-lipid interaction leading to reversible aggregation and accumulation at the membrane-solution interface irrespective of their initial spatial arrangement. Those findings can be explained in terms of the shape of the potential of mean force for the single-peptide translocation across the membrane.


Tablet PC-based competency evaluation for nursing students in three Asian countries: Cross-sectional comparative study.
This study evaluated a practical competency evaluation for nursing students in three Asian countries using tablet PC-based tests. The need to evaluate practical competencies in a non-face-to-face manner continues to pose challenges in nursing education. This study presents descriptive comparative research on a tablet PC-based evaluation of practical competencies in three countries. tablet PC-based clinical practice competency evaluation was conducted among nursing college students in Korea, Vietnam and Mongolia. In total, 124 students answered 65 questions for practical competency evaluation and items on its usefulness. Students from Korea had the highest score of nursing competencies (41.6 points; n = 59, SD 6.02), followed by those from Vietnam (26.3 points; n = 30, SD 4.97) and Mongolia (18.4 points; n = 35, SD 5.36). Scores for usability showed an inverse relationship with competency scores. Questions incorporating video showed the lowest proportion of low-discrimination items. This research recognized that using video which provides contextual elements can increase item discrimination. These findings suggest that incorporating video into evaluation items in tablet-PC-based tests is useful for international comparison.


An oscillating/pulsating electric toothbrush versus a high-frequency electric toothbrush in the treatment of gingivitis.
The objective of this study was to compare the effect of an oscillating/pulsating power toothbrush (Oral-B ProfessionalCare 7000; PC 7000) and a high-frequency power toothbrush (Philips Sonicare Elite; SE) on the reversal of experimental gingivitis. The study had a randomised, examiner-blind, split-mouth design. After dental prophylaxis, subjects refrained from brushing mandibular teeth for 21 days to allow development of gingivitis. During a 4-week treatment phase, the right or left side of the mouth was brushed with either the PC 7000 or the SE toothbrush as randomly allocated. Plaque and gingivitis were assessed at baseline (Day 0), after 21 days of no oral hygiene, and after 1, 2 and 4 weeks of brushing twice daily. Gingival abrasion was assessed at Day 0 and after 1, 2 and 4 weeks of product use. Of 38 enrolled subjects, 35 provided evaluable data. The experimentally induced gingivitis (EIG) phase resulted in higher bleeding and plaque scores as compared to Day 0. During the treatment phase, plaque and bleeding scores were significantly lower with the PC 7000 than the SE toothbrush. After 4 weeks of use, the mean plaque scores changed from 2.78 (Day 21 of EIG phase) to 0.70 for the PC 7000 and from 2.67 (Day 21) to 0.88 for the SE. The mean bleeding scores changed from 1.86 (Day 21) to 1.24 for the PC 7000 and from 1.88 (Day 21) to 1.42 for the SE. No major differences were found between brushes with regard to gingival abrasion. The oscillating/pulsating power toothbrush (Oral-B ProfessionalCare 7000) was more effective than the high-frequency power toothbrush (Philips Sonicare Elite) at plaque removal and improvement of gingival condition, with no greater potential for causing gingival abrasion.


Short-term and long-term plasticity at corticostriatal synapses: implications for learning and memory.
The striatum is the major division of the basal ganglia, representing the input station of the circuit and arguably the principal site within the basal ganglia where information processing occurs. Striatal activity is critically involved in motor control and learning. Many parts of the striatum are involved in reward processing and in various forms of learning and memory, such as reward-association learning. Moreover, the striatum appears to be a brain center for habit formation and is likely to be involved in advanced stages of addiction. The critical role played by the striatum in learning and cognitive processes is thought to be based on changes in neuronal activity when specific behavioral tasks are being learned. Accordingly, excitatory corticostriatal synapses onto both striatal projecting spiny neurons and interneurons are able to undergo the main forms of synaptic plasticity, including long-term potentiation, long-term depression, short-term forms of intrinsic plasticity and spike timing-dependent plasticity. These specific forms of neuroplasticity allow the short-term and long-term selection and differential amplification of cortical neural signals modulating the processes of motor and behavioral selection within the basal ganglia neural circuit.


Comparative clinical pharmacology and pharmacokinetic interactions of aromatase inhibitors.
The clinical development of aromatase inhibitors (AIs) has been closely guided by clinical pharmacological investigations. During the early phases of development studies were focused on dose-related pharmacological effectiveness and specificity. More recently attention has been given to the metabolic changes which AIs elicit, with particular regard to their potential use in early breast cancer and the prophylactic setting. Pharmacological effectiveness has been studied with plasma oestrogen assays but primary oestrogens (E1 and E2) are not helpful in comparing the third generation inhibitors: anastrozole, letrozole, exemestane. All three of these compounds suppress whole body aromatisation by >96%. Most recently, we have established that significantly greater inhibition is achieved by letrozole than anastrozole at their clinically used dosages. This more complete inhibition is paralleled by significantly greater suppression of E1S.A broad panel of endocrine investigations has indicated that these compounds have essentially complete specificity at their clinical dosages. A minor androgenic effect of exemestane is revealed by a significant suppression of sex hormone binding globulin (SHBG). Lipid and bone biomarker data are being collected in many current studies. A pharmacokinetic interaction has been established between letrozole and tamoxifen, whereby reduced circulating levels of letrozole are found with combined application. Neither anastrozole nor letrozole have any effect on plasma concentrations of tamoxifen when given in combination with it.


Factors affecting completion of laparoscopic myomectomy.
This study aimed to elucidate the factors affecting completion of laparoscopic myomectomy without unintended surgery. The medical records of 143 patients who underwent laparoscopic myomectomy desiring to retain their uterus were retrospectively reviewed. Unintended surgery was defined as the need for conversion to other surgical methods including laparotomy or laparoscopic hysterectomy at any time during the procedures. All variables associated with completion of laparoscopic myomectomy in the univariate analysis were selected at the threshold ofp < 0.25 and then tested in a multiple-logistic regression model. The rate of unintended surgery was 13.3%. Univariate analysis revealed that age, previous abdomino-pelvic surgery, current medical disease, transfusion, > five myomas, myoma size > 8.2 cm, posterior wall location of myoma, intramural type of myoma, and the presence of adenomyosis were statistically significant risk factors for unintended surgery. Multivariate logistic regression analysis demonstrated that completion of laparoscopic myomectomy was significantly influenced by a history of previous abdomino-pelvic surgery (odds ratio; 6.46, 95% CI, 0.03-0.41; p value 0.04). The risk of unintended surgery during laparoscopic myomectomy is associated with a history of previous abdomino-pelvic surgery.


Plagiarism: A silent epidemic in scientific writing - Reasons, recognition and remedies.
Plagiarism is one of the most serious forms of scientific misconduct prevalent today and is an important reason for significant proportion of rejection of manuscripts and retraction of published articles. It is time for the medical fraternity to unanimously adopt a 'zero tolerance' policy towards this menace. While responsibility for ensuring a plagiarism-free manuscript primarily lies with the authors, editors cannot absolve themselves of their accountability. The only way to write a plagiarism-free manuscript for an author is to write an article in his/her own words, literally and figuratively. This article discusses various types of plagiarism, reasons for increasingly reported instances of plagiarism, pros and cons of use of plagiarism detection tools for detecting plagiarism and role of authors and editors in preventing/avoiding plagiarism in a submitted manuscript. Regular usage of professional plagiarism detection tools for similarity checks with critical interpretation by the editorial team at the pre-review stage will certainly help in reducing the menace of plagiarism in submitted manuscripts.


Recent Advanced in the Treatment of Advanced SCC Tumors.
Squamous cell carcinoma (SCC) is the second most frequent form of skin cancer after basal cell carcinoma. While most SCC can be treated by surgery or radiotherapy, some progress into an advanced form and are no longer suitable for these treatments. Guidelines and staging systems have help to define these advanced SCC (aSCC), for which prognosis was very poor until recently. Platin-based chemotherapy was traditionally used, but few prospective trials and no treatment regimen was recommended. Furthermore, toxicity in elderly patients limited its use. The development of immunotherapy has improved the prognosis of these difficult-to-treat aSCC. In this review, we define high risk and aSCC and explored current treatment strategies for these tumors.


Risk factors for sleep disturbance in patients with cervical myelopathy and its clinical significance: a cross-sectional study.
Sleep disturbance is highly prevalent in patients with spinal cord injury and is one of the most important clinical issues affecting their quality of life. However, it has not been properly measured or treated in patients with cervical myelopathy (CM), although most typical or atypical symptoms of CM are known to be risk factors for sleep disturbance. In addition, previous studies identified that the presence of sleep disturbance is unintentionally missed under the current evaluation process for degenerative spinal disease without direct investigation using validated tools for sleep. Therefore, studies about sleep disturbances in patients with CM are essential. The purpose of this study was to investigate the prevalence of sleep disturbance in patients with CM using validated tools and to understand its mechanism by identifying high-risk patients. Cross-sectional study. Consecutive patients diagnosed with CM. Pittsburgh sleep quality index. This study was performed on patients diagnosed with CM. Sleep disturbance was determined using the Pittsburgh sleep quality index. Variables associated with sleep disturbance including demographics, lifestyle, medical history, and radiologic parameters were investigated. Independent risk factors related to sleep disturbance were identified using multivariate logistic regression analysis. A total of 203 patients with CM were included in our study. Among them, 126 patients (62.1%) were men, and the mean age was 63.0 years. Despite male predominance, sleep disturbance was identified in 71.4% of patients (145 of 203). Multivariate analysis identified a worse depression scale score, a lower modified Japanese Orthopedic Association score, chronic shoulder joint pain, smaller spinal cord area, and decreased cervical range of motion as independent risk factors for sleep disturbance. In patients with CM, sleep disturbance was associated with a more severe type of myelopathy. Further studies including polysomnography and measurement of melatonin will be helpful to identify the mechanisms of the sleep disturbance in patients with CM and to improve their quality of life and clinical outcomes.


Chelation therapy for patients with elevated body lead burden and progressive renal insufficiency. A randomized, controlled trial.
Nephropathy is known to occur in persons exposed to high levels of lead, but the question of whether long-term exposure to low levels of environmental lead is associated with impaired renal function remains controversial. To examine whether chelation therapy slows the progression of renal insufficiency in patients with mildly elevated body lead burden. Randomized, controlled trial. Academic medical center in Taiwan. 32 patients with chronic renal insufficiency (serum creatinine level > 132.6 micromol/L [1.5 mg/dL] and < 353.8 micromol/L [4.0 mg/dL]), mildly elevated body lead burden (> 0.72 micromol [150 microg] of lead per 72-hour urine collection and < 2.90 micromol [600 microg] of lead per 72-hour urine collection [EDTA mobilization tests]), and no history of heavy lead exposure. The treatment group received 2 months of chelation therapy; the control group received no therapy. The reciprocal of serum creatinine (1/Cr) was used as an index of progressive renal insufficiency. Rates of progression of renal insufficiency were similar in the treatment group and the control group during a 12-month baseline observation period (1/Cr, 0.000054 L/micromol per month compared with 0.000046 L/micromol per month; P > 0.2). After the 2-month treatment period, improvement in renal function was greater in the treatment group than in the control group. In the 12 months after the treatment period, renal insufficiency progressed more slowly in the treatment group than in the control group (1/Cr, 0.000033 +/- 0.00038 L/micromol per month compared with 0.000045 +/- 0.000038 L/micromol per month; P = 0.0030). Chelation therapy seems to slow the progression of renal insufficiency in patients with mildly elevated body lead burden. This implies that long-term exposure to low levels of environmental lead may be associated with impaired renal function in patients with chronic renal disease.


Enzymes of glucose and fatty acid metabolism in early and term human placenta.
The activity of enzymes involved in glycolysis, gluconeogenesis, and lipoenesis in early and term human placenta was determined. A high activity of pyruvate kinase was found, indicating high glycolytic potential. The activity of this enzyme tended to decrease with gestation. The presence of phosphoenolpyruvate carboxylase activity was detected, suggesting the possibility of gluconeogenesis in the placenta. Very low activity of enzymes involved in fatty acid synthesis was found, whereas the activity of the pentose shunt pathway enzymes, glucose-6-phosphogluconate dehydrogenases, was relatively high. This suggested a role of this pathway in the synthesis of lipids other than fatty acids in the placenta. The activities of enzymes in the human placenta and their changes during gestation where compared to previous observations on enzymes in rat placenta.


The hunter becomes the hunted: when cleptobiotic insects are captured by their target ants.
Here we show that trying to rob prey (cleptobiosis) from a highly specialized predatory ant species is risky. To capture prey, Allomerus decemarticulatus workers build gallery-shaped traps on the stems of their associated myrmecophyte, Hirtella physophora. We wondered whether the frequent presence of immobilized prey on the trap attracted flying cleptoparasites. Nine social wasp species nest in the H. physophora foliage; of the six species studied, only Angiopolybia pallens rob prey from Allomerus colonies. For those H. physophora not sheltering wasps, we noted cleptobiosis by stingless bees (Trigona), social wasps (A. pallens and five Agelaia species), assassin bugs (Reduviidae), and flies. A relationship between the size of the robbers and their rate of capture by ambushing Allomerus workers was established for social wasps; small wasps were easily captured, while the largest never were. Reduviids, which are slow to extract their rostrum from prey, were always captured, while Trigona and flies often escaped. The balance sheet for the ants was positive vis-à-vis the reduviids and four out of the six social wasp species. For the latter, wasps began by cutting up parts of the prey's abdomen and were captured (or abandoned the prey) before the entire abdomen was retrieved so that the total weight of the captured wasps exceeded that of the prey abdomens. For A. pallens, we show that the number of individuals captured during attempts at cleptobiosis increases with the size of the Allomerus' prey.


Spatial and temporal dispersion patterns of pollinators and their relationship to the flowering strategy of Yucca whipplei (Agavaceae).
A field investigation of the mutualistic interaction between a monocarpic perennial plant, Yucca whipplei, and its host-specific pollinator and seed predator, Tegeticula maculata (Lepidoptera: Prodoxidae), was conducted to determine how the resource utilization pattern and population dynamics of the pollinator have influenced the evolution of the flowering and fruiting pattern of the plant. Although the temporal pattern of emergence of pollinators results in a relatively close tracking of flower abundance within a season, the ratio of pollinators to open flowers does vary significantly within a season, as well as between seasons. At any point in time during the flowering season, the population of adult yucca moths is distributed evenly among the available flowers, so that the number of pollinators on an inflorescence is directly proportional to the number of open flowers available. The relative isolation of individual flowering plants appears to have little effect on the distribution of pollinators among inflorescences. The number of fruits initiated on a plant is directly proportional to the number of flowers produced, and is also partially determined by the time of flowering. Yucca whipplei always produces many more flowers than fruits. Most flowers are not fertilized, and the plants also generally abort and abscise immature fruits after flowering. Fruit production of at least some plants, however, appeared limited by pollination. It is also expected that in some years the relative abundance of pollinators will be low enough that most plants will be pollinator-limited. It is suggested that the pattern of flowering and fruiting of this species has evolved in response to the unpredictability of pollinator availability, both within and between seasons. Resource uncertainty and selection acting on the male component of fitness may also be involved.


Of origins and pedigrees: lineage tracing of dendritic cells.
Understanding the ontogeny of distinct hematopoietic cell types remains a challenge. In this issue, Schraml et al. contribute to unraveling the complexity of a central component of the mononuclear phagocyte system by using a new in vivo approach to trace the progeny of common dendritic cell precursors.


Expression of mineralocorticoid and glucocorticoid receptor mRNA in the human hippocampus.
The genomic effects of corticosteroids in the brain are mediated through two receptors with a high affinity for cortisol: the glucocorticoid and mineralocorticoid receptor (GR/MR). We used competitive reverse transcription-polymerase chain reaction to quantify the amount of MR and GR mRNA in hippocampal tissue obtained from patients with temporal lobe epilepsy. MR and GR mRNA were expressed at approximately the same levels as in tissues known for high glucocorticoid/mineralocorticoid sensitivity, i.e. liver or kidney. MR mRNA concentrations were significantly higher in the hippocampus of women (0.24+/-0.04 aU, arbitrary units; mean+/-SEM) than in men (0.14+/-0.01 aU, P<0.006) or children (0.09+/-0.02, P<0. 007). No such differences were observed for GR mRNA expression.


The tissue distribution of Ia- and IgM-positive cells in adult and newborn miniature pigs.
Distribution of Ia- and IgM-positive cells was compared in tissues of adult and newborn miniature pigs, using indirect immunoperoxidase and immunofluorescent techniques with monoclonal antibodies. The different distribution patterns were found mainly in adult jejunum and kidney. Both IgM- and Ia-staining were ascertained in the lamina propria between the Lieberkühn crypts and in the lymphoid follicles of the jejunum. Moreover, IgM-positive cells were demonstrated in the crypts while Ia-reaction was seen in the lamina propria of the villi. In the kidney, IgM-staining was limited to the glomeruli. On the contrary, a distinct Ia-reaction was found mainly in intertubular structures. Small differences in IgM- and Ia-positive cell distribution were also noted in the mesenteric lymph nodes and in the spleen. Developmental changes of the adult distribution patterns (chiefly that of IgM-positive cells) were found in all tissues studied at 2 days of age.


Drosophila melanogaster U1 and U2 small nuclear RNA genes contain common flanking sequences.
The flanking sequences of three U2 genes (or pseudogenes) and one U1 gene of Drosophila melanogaster have been determined. Comparison of the sequences reveals a remarkable homology between position -30 and -65 upstream from the structural genes, starting with a TATA box-like sequence. The 3' flanking regions are also conserved in all genes and contain a canonical A-A-T-A-A-A polyadenylation signal.


Double-negative regulatory T cells induce allotolerance when expanded after allogeneic haematopoietic stem cell transplantation.
Double-negative (DN) regulatory T cells (Tregs) are specialized T lymphocytes involved in the down-modulation of immune responses, resulting in allotolerance after allogeneic haematopoietic stem cell transplantation (HSCT). Most of the properties of DN Tregs were identified in murine models, including the unique ability to suppress alloreactive syngeneic effector T cells in an antigen-specific manner via Fas/Fas-ligand interactions. We investigated the behaviour of DN Tregs following human allogeneic HSCT with regard to occurrence of graft-versus-host disease (GvHD) and restoration of T-cell receptor repertoire in a cohort of 40 patients. The frequency of DN Tregs and CD4/CD8 TCR repertoire was measured serially and at the time of diagnosis of GvHD by flow cytometry. Analysis demonstrated a positive correlation between degree of alloreactivity, as measured by grade of GvHD, and the number of variable beta chain (Vbeta) family expansions in both T-cell populations. We also found that a deficiency of DN Tregs was associated with an increased number of Vbeta family expansions, and most importantly, with the occurrence of GvHD. All individuals who demonstrated more than 1% DN Tregs did not develop GvHD, providing evidence that DN Tregs participate in peripheral tolerance to prevent GvHD when expanded after allogeneic HSCT.


Alirocumab: First Global Approval.
Alirocumab (Praluent®) is a fully human monoclonal antibody developed by Regeneron Pharmaceuticals and Sanofi that has been approved in the US as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolaemia (HeFH) or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. It specifically binds proprotein convertase subtilisin/kexin type 9 (PCSK9)-a down regulator of liver low-density lipoprotein (LDL)-receptors-thereby increasing the ability of the liver to bind LDL-cholesterol (LDL-C) and reducing levels of LDL-C in blood. It has been shown to reduce LDL-C levels in patients with hypercholesterolaemia, including HeFH, both as monotherapy and in conjunction with statin therapy. This article summarizes the milestones in the development of alirocumab leading to this first approval.


Organ preservation in rectal cancer patients following complete clinical response to neoadjuvant chemoradiotherapy: Long-term results in three patients.
Rectal cancer patients following complete clinical response to neoadjuvant chemoradiotherapy (CRT) can be followed up without surgery. Those patients in particular who needed abdominoperineal resection before CRT choose the follow-up protocol, should they be given the necessary information. The purpose of this study was to demonstrate the long-term follow-up results of patients following neoadjuvant CRT without surgery.


Release of O-sulfate groups under mild acid hydrolysis conditions used for estimation of N-sulfate content.
The treatment of chondroitin sulfate isolated from cultured B16 mouse melanoma cells with 0.04 M HCl at 100 degrees C for 90 min released up to 45% of O-sulfate residues as free inorganic sulfate. In addition to the release of inorganic sulfate, extensive degradation of this polysaccharide as well as of cartilage chondroitin sulfate, pig rib cartilage proteoglycan, heparin and hyaluronic acid was also evident under these conditions. The above hydrolysis conditions are used for characterizing 35S-labeled heparan sulfates synthesized by cultured cells and to calculate ratio of N- and O-sulfates in these molecules. Our results suggest that caution is necessary in interpreting the results of mild acid hydrolysis of glycosaminoglycans.


Diverting ileostomy during primary debulking surgery for ovarian cancer: Associated factors and postoperative outcomes.
To examine the use, as well as postoperative and long-term oncologic outcomes of diverting loop ileostomy (DI) during primary debulking surgery (PDS) for ovarian cancer. Patients with stage II-IV ovarian, fallopian tube, or primary peritoneal carcinoma who underwent colon resection during PDS from 1/2005-1/2014 were identified. Demographic and clinical data were analyzed. Of 331 patients, 320 (97%) had stage III/IV disease and 278 (84%) had disease of high-grade serous histology. Forty-four (13%) underwent a DI. There were no significant differences in age, comorbidity index, smoking status, serum albumin, or attending surgeon between the DI and non-DI groups. Operative time (OR=1.21; 95% CI, 1.03-1.42; p=0.02) and length of rectosigmoid resection (OR=1.04; 95% CI, 1.01-1.08; p=0.02) were predictors of DI on multivariable analysis. The overall anastomotic leak rate was 6%. A comparison of groups (DI vs non-DI) showed no significant differences in major complications (30% vs 23%; p=0.41), anastomotic leak rate (5% vs 7%; p=0.60), hospital length of stay (10 vs 9days; p=0.25), readmission rate (23% vs 17%; p=0.33), or interval to postoperative chemotherapy (41 vs 40days; p=0.20), respectively. Ileostomy reversal was successful in 89% of patients. Median follow-up was 52.6months. There were no differences in median progression-free (17.9 vs 18.6months; p=0.88) and overall survival (48.7 vs 63.8months; p=0.25) between the groups. In patients undergoing PDS, those with longer operative time and greater length of rectosigmoid resection more commonly underwent DI. DI does not appear to compromise postoperative outcomes or long-term survival.


Molecular docking and pharmacophoric modelling of 1,5-disubstituted tetrazoles as inhibitors of two proteins present in cancer, the ABL and the mutated T315I kinase.
A docking study of a set of several 1,5-disubstituted tetrazoles compounds has been performed to predict the poses of some potential inhibitors of the Abelson tyrosine-protein kinase and the mutated Abelson tyrosine-protein kinase T315I. The study was conducted through Lamarckian genetic algorithms in Autodock4 package. Bayesian calculations were performed; specificity and sensitivity values as well as positive predicted values, and negative predicted values were calculated using a set of 99 known experimentally active ligands and 385 decoys for the Abelson tyrosine-protein kinase from the Directory of Useful Decoys database. Root mean square deviation values were calculated though the X-ray crystallographic data of the bioactive pose of imatinib as reference, and the pose obtained with the above methods. The obtained results show the importance of the protein interactions with the halogens present in some of these 1,5-disubstituted tetrazoles ligands, as well as the presence of some hydrophobic fragments, obtained via the pharmacophoric model, concluding that the eight novels 1,5-disubstituted tetrazoles compounds herein identified, could be effective inhibitors of Abelson tyrosine-protein kinase, using a docking calculations.


The new cell theoryThe Master Builder Alfonso Martinez Arias Basic Books, 2023, 352 pp.
A developmental biologist urges a return to cell-centric models of life.


Pharmaceutical policies used by private health insurance companies in Saudi Arabia.
Currently, the Council of Cooperative Health Insurance (CCHI) is the body responsible for regulating health insurance in the KSA. While the cooperative health insurance schedule (i.e., model policy for health insurance) is available on the CCHI web site, policies related to pharmaceuticals are ambiguous. The primary objective of this study was to assess the impact of health insurance policies provided by health insurance companies in KSA on access to medication and its use. This study was descriptive in design and used a survey, which was conducted through face-to-face interviews with the medical managers of health insurance companies. The survey took place between March and June, 2011. All 25 insurance companies accredited by CCHI were eligible to be included in the study. Out of these 25 companies, three were excluded from this survey as no response was received. All the 16 companies responded "Yes" that they had a prior authorization policy; however, their reasons varied. Eight (50%) of the companies were concerned about the duration of treatment. While 10 (62.5%) did not offer additional coverage over the CCHI model policy, the other 6 (37.5%) reported that they could reconcile certain conditions. The survey also demonstrated that 10 insurance companies allowed refilling of medication but with certain limitations. Six out of the 10 permitted refilling within a maximum time of three months, whereas the other four companies did not have any time-based limits for refilling. The other six companies did not allow refilling without prescription. Although this paper was primarily descriptive, the findings revealed a substantial scope for improvement in terms of pharmaceutical policy standards and regulation in the health insurance companies in KSA. Additionally, the study highlighted such areas to augment the overall quality use of medication, over-prescribing and irrational use of medication. Further research, thus, is definitely needed.


Relative quantitation of proteins fractionated by the ProteomeLab PF 2D system using isobaric tags for relative and absolute quantitation (iTRAQ).
We describe an optimised protocol for application of isobaric tags for relative and absolute quantitation (iTRAQ) and tandem mass spectrometry to obtain relative quantitative data from peptides derived from tryptic digestions of proteins fractionated by using the 2D liquid-phase ProteomeLab PF 2D technique. This methodology is suitable for the quantitation of proteins from a pool of co-eluting proteins which are often difficult to identify for the purpose of candidate protein selection for biologically relevant qualitative/quantitative changes under experimental conditions or in disease states. iTRAQ quantitation also facilitates the possibility of result to result comparison using other methodologies such as UV protein quantitation via the ProteomeLab PF 2D technique. The optimised protocol outlined here allows relative quantitation by MALDI-TOF/TOF mass spectrometry with high sensitivity and without the need to perform 2D HPLC separation of labelled peptides. The overall outcome is the simplification in the data complexity and the ease of use of the labelling protocol.


Trichoderma as a biological control agent: mechanisms of action, benefits for crops and development of formulations.
Currently, the food and economic losses generated by the attack of phytopathogens on the agricultural sector constitute a severe problem. Conventional crop protection techniques based on the application of synthetic pesticides to combat these undesirable microorganisms have also begun to represent an inconvenience since the excessive use of these substances is associated with contamination problems and severe damage to the health of farmers, consumers, and communities surrounding the fields, as well as the generation of resistance by the phytopathogens to be combated. Using biocontrol agents such as Trichoderma to mitigate the attack of phytopathogens represents an alternative to synthetic pesticides, safe for health and the environment. This work explains the mechanisms of action through which Trichoderma exerts biological control, some of the beneficial aspects that it confers to the development of crops through its symbiotic interaction with plants, and the bioremedial effects that it presents in fields contaminated by synthetic pesticides. Also, detail the production of spore-based biopesticides through fermentation processes and formulation development.


Pre-ovulatory changes in cyclic AMP and prostaglandin concentrations in follicular fluid of gilts.
The concentrations of cyclic adenosine 3', 5'-monophosphate (cyclic AMP) and prostaglandins E and F (PGE and PGF) were determined in follicular fluid collected from follicles of prepubertal gilts at various times after treatment with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) to induced ovulation. The concentrations of cyclic AMP, PGE and PGF in the follicular fluid after PMSG treatment but prior to hCG injection were about 1 pmol/ml, 1 ng/ml and 0.2 ng/ml, respectively. After hCG administration, the follicular fluid levels of cyclic AMP increased markedly, reaching a peak (400-fold increase) about 4 h after injection and then declined gradually to pre-hCG levels. A second rise (2.5- to 5-fold increase) occurred about 30 h after hCG with the levels being sustained up to the expected time of ovulation. In contrast, the levels of PGE and PGF remained relatively constant until 28-30 h after hCG treatment. Thereafter, the concentrations of both prostaglandins began to rise with the increases becoming more pronounced and reaching maximal values as the expected time of ovulation approached. These data provide further evidence for a physiological role of follicular prostaglandins in the process of ovulation but do not support an obligatory role for prostaglandins in the acute gonadotropin stimulation of cyclic AMP formation.


An enhanced antibacterial nanoflowers AgPW@PDA@Nisin constructed from polyoxometalate and nisin.
A new composite, AgPW@PDA@Nisin, with shell-core structure was successfully synthesized by a polydopamine (PDA) surfaced conjugated nisin (an antibacterial 34 amino acid polycyclic peptide) as shell and polyoxometalates (Ag3PW12O40 = AgPW) as core. The composite was characterized by the zeta potential, scanning electron microscopy (SEM), transmission electron microscope (TEM), X-ray diffraction analysis (XRD), fourier transform infrared (FT-IR). The AgPW@PDA@Nisin showed flower hierarchical structure and potential antibacterial activity against S. aureus ATCC29213. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of it were 4 and 32 μg/mL. AgPW@PDA@Nisin nanoflowers-induced bacterial death bears the characteristic of cell morphology, membrane integrity and permeability changing, nucleotide leakage. It indicated that the AgPW@PDA@Nisin interfere with the cell membrane, resulting in antibacterial activity against S. aureus. The cytotoxicity of the nanoflowers was low on HDF-a (human dermal fibroblasts) cells. A new class of hybrid inorganic-organic nanoflowers based on polyoxometalates and nisin with enhanced antibacterial properties can be developed for food preservation.


Interference with endogenous EZH2 reverses the chemotherapy drug resistance in cervical cancer cells partly by up-regulating Dicer expression.
Cervical cancer is one of the most common female malignancies in the world, and chemotherapeutic drug resistance is a major obstacle to cancer therapy. Enhancer of zeste homolog 2 (EZH2) is an enzymatic subunit of polycomb repressive complex 2 (PRC2) and catalyzes the repressive histone H3 lysine 27 trimethylation (H3K27me3). However, the role of EZH2 on the chemotherapy drug resistance in cervical cancers remains unclear. In the present study, the cervical carcinoma specimens and paired normal tissue specimens were obtained and the expression of EZH2 was detected by western blotting. The results showed that high levels of EZH2 were detected in cervical carcinoma tissues, compared with paired control tissues (**p < 0.01). Next, three pairs of shRNA specific to EZH2 were designed and used to interfere with endogenous EZH2 expression. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays following treatment with various concentrations of cisplatin in HeLa and HeLa/DDP cells. The MTT assay results showed that knockdown of EZH2 in HeLa/DDP cells caused a 2.29- or 1.83-fold decrease in the cisplatin IC50 values (for shRNA1-EZH2, 34.88 vs. 15.21 μg/mL; p < 0.01; for shRNA3-EZH2, 34.88 vs. 19.09 μg/mL; p < 0.01). The EZH2 activity was also suppressed by 3-deazaneplanocin A (DZNep), EZH2 inhibitor, and the results demonstrated that, meanwhile, DZNep potently inhibited cell viability of HeLa/DDP cells, partly by suppression the levels of EZH2 and H3K27me3, but not H3K27me2, which was detected by western blotting analysis. Moreover, cell migration assay results showed that knockdown of EZH2 decreased cell metastasis of cervical cancer cells. Furthermore, cell cycle was detected by fluorescence-activated cell sorting (FACS) assay and the results demonstrated that interference with EZH2 expression increased the percentage of cells at G0/G1 phase and the HeLa/DDP cells were blocked at G0/G1 phase. Interestingly, western blotting results revealed that higher expression of EZH2 was related with lower level of Dicer in HeLa/DDP cells. Finally, in vivo tumorigenicity experiments results demonstrated that interference with endogenous EZH2 by shRNA specific to EZH2 or inhibition EZH2 by DZNep could significantly increase antitumor effects in nude mice. Thus, inhibiting the levels of endogenous EZH2 effectively reversed the cisplatin resistance and increased the cisplatin sensitivity in cisplatin-resistant HeLa/DDP cells. EZH2 might be a potential target for treating chemotherapeutic drug-resistant cervical cancers.


Soot Morphology and Nanostructure in Complex Flame Flow Patterns via Secondary Particle Surface Growth.
While the majority of studies explore soot formation in relatively simple, one-dimensional flames, most real-world flames consist of complex flows defined by large-scale turbulent eddies, recirculating flow patterns, and buoyancy effects. The effects of complex flow on soot physicochemical properties are poorly understood. This work employs an inverted gravity flame reactor (IGFR) to compare differences in soot growth between a one-dimensional laminar diffusion flame and a recirculating flame. Computational fluid dynamics (CFD) and experimental observations show particle oscillations between (i) a rich region with a high concentration of surface growth species, and (ii) a high-temperature oxidation region. Transmission electron microscopy (TEM) shows a significant difference in final primary particle diameter, where the one-dimensional flame produces primary particles 10 to 25 nm in diameter and the recirculating flame produces primary particles 25 to 75 nm in diameter. Additionally, larger primary particles from the recirculating flame contain both single and multiple cores. We propose that due to the spheroidal shape of the large primary particles, the secondary surface growth is primarily a result of polyaromatic hydrocarbon (PAH) condensation during re-entrainment of mature soot into the fuel-rich region followed by subsequent liquid layer carbonization in the high-temperature environment of the flame front. The recirculating flow patterns in the IGFR and repeated particle growth/oxidation cycle can serve as a model for soot formation in the large-scale flames with complex flow patterns, such as forest fires, coal fire plants, and other sources.


A case of acquired laryngomalacia in an infant, with endoscopy before and after establishing the diagnosis for the first time.
A 12-week-old infant girl born at 27 weeks gestation, with multiple comorbidities, was referred to the paediatric otolaryngology team due to stridor and feeding difficulties. Initial airway endoscopy was performed, showing no abnormal findings. The infant underwent frequent hospitalisations for recurrent cyanotic spells. Despite initial laryngoscopy and bronchoscopy not showing abnormalities, a repeat endoscopy demonstrated laryngomalacia, significant enough to require a supraglottoplasty. This is the first report to confirm, with video evidence, that some cases of laryngomalacia are acquired rather than congenital, even in infancy.


Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach.
Endoxifen is one of the most important metabolites of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX ) is observed under tamoxifen standard dosing and patients with breast cancer who do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at a 26% higher recurrence risk compared with patients with endoxifen concentrations exceeding this value. In this investigation, 10 clinical tamoxifen studies were pooled (1,388 patients) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modeling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared with postmenopausal patients, premenopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared with elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for premenopausal patients, this subpopulation may benefit most from individualized tamoxifen dosing.


Associations between school lunch consumption and urinary phthalate metabolite concentrations in US children and adolescents: Results from NHANES 2003-2014.
Diet is a major route of phthalate exposure in humans due to use in food packaging materials. School lunches may be an important contributor to phthalate exposure in children and adolescents in the US because of the large amount of packaging necessary for mass-produced foods. We used 2003-2014 National Health and Nutrition Examination Survey data to study the association between school lunch consumption and urinary phthalate metabolite concentrations in children (ages 6-11 years, N = 2196) and adolescents (ages 12-19 years, N = 2314). After adjustment for other covariates, children who Always consumed school lunch had significantly elevated urinary concentrations of the following phthalate metabolites compared to levels in children who Never ate school lunch: sum of di(2‑ethylhexyl) phthalate metabolites, (28% higher, 95% confidence interval, CI: 10, 49%); mono‑(carboxy‑octyl) phthalate (MCOP; 43% higher, 95% CI: 17, 76%) and mono‑n‑butyl phthalate (18% higher, 95% CI: 3.5, 34%). We did not find statistically significant associations in adolescents, but the trend for MCOP concentrations was similar to that of children. In sensitivity analyses, associations between 24-hour recall of cafeteria food and urinary phthalate metabolites were not statistically significant, which could indicate that associations observed with Always consuming school lunch are due to residual confounding. Our findings show that children who Always eat school lunch had higher levels of exposure to some phthalates, but the source of differences in exposure need to be evaluated in additional studies.


Recurrent Urinary Tract Infections in Females and the Overlap with Overactive Bladder.
There are an estimated 33 million men and women with overactive bladder (OAB) in the USA. Despite the prevalence of OAB, it remains a frequently misdiagnosed condition. OAB has shared symptomatology with other common urologic conditions, namely recurrent urinary tract infections (UTIs). Here, we will review key distinguishing features of OAB that aid in establishing an accurate diagnosis and recent advances in OAB management. Recent studies have shown that among women presenting with lower urinary tract symptoms, the majority were diagnosed with UTIs and treated without performing a urine culture as routine care. The authors found that when urine cultures were obtained, less than half of women had a positive urine culture, suggesting that empiric treatment of UTIs without cultures commonly led to a misdiagnosis of UTI. The symptoms of OAB have overlap with other common conditions, most notably UTI, BPH, and bladder cancer/carcinoma in situ. Despite the shared symptomatology of OAB and UTI, the timing of symptom onset is usually very different between the two. UTI symptoms are generally acute, whereas those of OAB are generally chronic. OAB and UTI share the common features of urgency, frequency, and nocturia. However, dysuria and hematuria are not features of OAB, while they are frequently seen in UTI. Of note, urgency, frequency, and nocturia are rarely seen in bladder cancer/carcinoma in situ; when these symptoms do occur, it is generally in the setting of microhematuria. One study of patients with carcinoma in situ found that 41% had macroscopic hematuria and 44% had microscopic hematuria at presentation. In patients with lower urinary tract symptoms, it is important to perform a urinalysis (UA) to evaluate for microhematuria to rule out the possibility of malignancy. First-line treatment of OAB (outside the setting of UTI) involves behavioral modification, including bladder training, fluid management, and pelvic floor exercises. Numerous studies have supported behavioral modification strategies as the most efficacious initial step in treatment. Although routinely given for recurrent UTIs and vaginal atrophy in postmenopausal women, several review articles have shown that vaginal estrogen is an effective treatment of lower urinary tract symptoms. The importance of distinguishing OAB from other conditions presenting with similar symptoms is key in preventing misdiagnosis, treatment delays, and antibiotic overuse. Here, we have reviewed key parameters distinguishing OAB from UTI, the most commonly misdiagnosed condition among those presenting with lower urinary tract symptoms (LUTS). Given that UTI is the most commonly misdiagnosed condition among women with OAB, we recommend relying on urine cultures and the constellation of acute-onset dysuria, frequency, and urgency as more important diagnostic factors in distinguishing these conditions.


Rhodium(III)-Catalyzed Allylic C(sp(3))-H Activation of Alkenyl Sulfonamides: Unexpected Formation of Azabicycles.
Unsaturated N-sulfonamides undergo a Rh(III)-catalyzed allylic C(sp(3))-H activation followed by insertion with an exogenous internal alkyne. The reaction generates [3.3.0], [4.3.0], and [5.3.0] azabicyclic structures with excellent diastereoselectivity. Deuterium labeling experiments implicate a 1,3-Rh shift as a key step in the mechanism.


Congener-specific distribution of polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls in animal feed.
Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and polychlorinated biphenyls (PCBs) were extracted by accelerated solvent extraction from animal feed samples and analysed by high-resolution gas chromatography/high-resolution mass spectrometry (HRGC/HRMS). In all of the feed samples analysed, the concentrations of PCDD/Fs and PCBs were below the existing tolerance limit of 5 pg I-TEQ g(-1) and 200 ng g(-1) fat, respectively. The mean concentrations of the total PCDDs, total PCDFs and total PCBs were 1.73-11.50 pg g(-1), 0.23-11.91 pg g(-1) and 60.00-234.40 pg g(-1) feed, respectively. Investigation of the correlations among the concentrations of PCDDs, PCDFs and PCBs showed that samples containing increased amounts of PCDFs also contained higher concentrations of PCDDs, with an average ratio of PCDF:PCDD of about 1.23:1 (r(2)=0.72, p<0.05). The correlation between the concentrations of PCDD/Fs and PCBs was positive but not significant.


Profiling of Protein N-Termini and Their Modifications in Complex Samples.
Protein N termini are a unique window to the functional state of the proteome, revealing translation initiation sites, co-translation truncation and modification, posttranslational maturation, and further proteolytic processing into different proteoforms with distinct functions. As a direct readout of proteolytic activity, protein N termini further reveal proteolytic regulation of diverse biological processes and provide a route to determine specific substrates and hence the physiological functions for any protease of interest. Here, we describe our current protocol of the successful Terminal Amine Isotope Labeling of Substrates (TAILS) technique, which enriches protein N-terminal peptides from complex proteome samples by negative selection. Genome-encoded N termini, protease-generated neo-N termini, and endogenously modified N termini are all enriched simultaneously. Subsequent mass spectrometric analysis therefore profiles all protein N termini and their modifications present in a complex sample in a single experiment. We further provide a detailed protocol for the TAILS-compatible proteome preparation from plant material and discuss specific considerations for N terminome data analysis and annotation.


Scrotoshisis, bilateral extra-corporeal testicular ectopia and testicular torsion.
Although anomalies of testicular descent are common, scrotoschisis and extracorporeal testicular ectopia is rare with only 3 reported cases in literature. This is a report of a neonate presenting with scrotoschisis and bilateral extracorporeal testicular ectopia. The right testis underwent torsion before presentation, resulting in gangrene of that testis, requiring orchidectomy. The scrotum was explored and the viable left testis placed in the scrotum and fixed in that position. The left testis has remained normal at 9 months of follow up. The possible embryology and management of this curious anomaly is discussed.


Trans fat intake during pregnancy or lactation increases anxiety-like behavior and alters proinflammatory cytokines and glucocorticoid receptor levels in the hippocampus of adult offspring.
Changes in dietary habits, including the increased consumption of processed foods, rich in trans fatty acids (TFA), have profound effects on offspring health in later life. Thus, this study aimed to assess the influence of maternal trans fat intake during pregnancy or lactation on anxiety behavior, as well as markers of inflammation, oxidative stress, and expression of glucocorticoid receptors (GR) of adult male offspring. Female Wistar rats were supplemented daily with soybean oil/fish oil (SO/FO) or hydrogenated vegetable fat (HVF) by oral gavage (3.0 g/kg body weight) during pregnancy or lactation. After weaning, male offspring received only standard diet. On the postnatal day 60, anxiety-like symptoms were assessed, the plasma was collected for the quantification of cytokines levels and the hippocampus removed for biochemical and molecular analysis. Our findings have evidenced that offspring from HVF-supplemented dams during pregnancy or lactation showed significantly greater levels of anxiety behavior. HVF supplementation increased plasma levels of proinflammatory cytokines and these levels were higher in the lactation period. In contrast, HVF supplementation decreased plasma levels of IL-10 in relation to SO/FO in both periods. Biochemical evaluations showed higher reactive species generation, protein carbonyl levels and catalase activity in offspring from HVF-supplemented dams during lactation. In addition, offspring from HVF-supplemented dams showed decreased GR expression in both supplemented periods. Together, these data indicate that consumption of TFA in different periods of development may increase anxiety-like behavior at least in part via alterations in proinflammatory and anti-inflammatory cytokine levels and GR expression in limbic brain regions.


Early-life exposure to hardship increased risk tolerance and entrepreneurship in adulthood with gender differences.
Many entrepreneurs credit their success to early hardship. Here, we exploit geographical differences in the intensity of China's Great Famine to investigate the effect of hardship during formative years on individual personality and engagement in business entrepreneurship. To exclude factors that might confound the relation between famine intensity and entrepreneurship, we model famine intensity by random weather shocks. We find robust evidence that individuals who experienced more hardship were subsequently more likely to become entrepreneurs (defined broadly as self-employed or business owners). Importantly, the increase in entrepreneurship was at least partly due to conditioning rather than selection. Regarding the behavioral mechanism, hardship was associated with greater risk tolerance among men and women but increased business ownership only among men. The gender differences were possibly due to the intricate relationship between a Chinese social norm—men focus more on market work, while women focus more on domestic work—and interspousal risk pooling associated with occupational choices. Scientifically, these findings contribute to a long-standing debate on whether entrepreneurship is due to nature or nurture, particularly how hardship conditions people to be entrepreneurial. The findings also highlight the importance of gender differences in shaping the effect of early-life experience on life cycle outcomes.


Unintentional Continuation of Medications Intended for Acute Illness After Hospital Discharge: A Population-Based Cohort Study.
Patients are vulnerable to medication-related errors during transitions in care. Patients discharged from acute care hospitals may be at an elevated risk for the unintentional continuation of medications prescribed to prevent or treat complications that are associated with acute illness but are no longer indicated. We sought to evaluate rates of (primary objective) and risk factors for (secondary objective) potentially unintentional medication continuation following hospitalization. A population-based cohort study of more than one million patients 66 years of age or older who were hospitalized in Ontario, Canada, between 2003 and 2011 and followed for 1 year (2004 to 2012). We created distinct cohorts by identifying seniors not previously receiving four classes of medications typically used to treat or prevent complications of acute illness: (1) antipsychotic medications, (2) gastric acid suppressants (histamine-2 blockers and proton pump inhibitors), (3) benzodiazepines, and (4) inhaled bronchodilators and steroids. After excluding documented indications, we followed patients to ascertain whether these medications were continued after hospital discharge, and assessed risk factors for their continuation using generalized estimating equations. The primary outcome was the new dispensation of any of the selected medications within 7 days of hospital discharge. Prescription without documented indication occurred across all medication classes, from 12,209 patients (1.4 %) for antipsychotic medications to 34,140 patients (6.1 %) for gastric acid suppressants. Risk factors for unintentional continuation varied across medication groups, but rates were consistently higher for older patients, those with multiple comorbidities, and emergency hospitalizations. The largest absolute risk factor across all medications was a hospitalization > 7 days [OR 2.03 (95 % CI 1.94-2.11) for respiratory inhalers, 6.35 (95 % CI 5.91-6.82) for antipsychotic medications]. These medications were often continued at 1 year of follow-up, and accounted for a total additional medication cost of over CAD$18 million for the study population. Discharged patients are at risk of being prescribed and dispensed medications that are typically intended to prevent or treat complications of acute illness, despite having no documented indication for chronic use.


Repeatability of renal arterial spin labelling MRI in healthy subjects.
Arterial spin labelling (ASL) can be used to measure renal perfusion non-invasively. The aim of this study was to determine the repeatability of this technique in healthy kidneys to vindicate its use in clinic. Two groups of healthy volunteers were imaged two different days to assess intra- and inter-session repeatability. Oblique-coronal data volumes were acquired on a 1.5 T scanner with a dedicated abdominal 32-channel body phased array coil. ASL was performed using a multi-TI FAIR labelling scheme and 3D GRASE imaging module. Background suppression and respiratory triggering were used. T(1) maps of the kidney were acquired using the same sequence with background suppression disabled. For the group with multiple intra-session ASL measurements, the average cortical perfusion was 197 mL min(-1)100 g(-1) and average cortical T(1) was 1265 ms. For both perfusion and T(1) the variation shown by the within-subject standard deviation (SDws) (14.6 mL min(-1)100 g(-1) and 33.4 ms) and coefficient of variation (CVws) (7.52 and 2.69%, respectively) was small for all the analyses carried out. Bland-Altman plots were also used to visualise the variation between the same parameters collected from the different scanning sessions in both groups, and demonstrated good reproducibility. We have shown that in healthy volunteers, ASL parameters are repeatable over a short and long period. This supports the overall aim of using ASL in the clinic to assess longitudinal renal perfusion changes in patients.


Long-term Surveillance of Patients with Complete Response Following Chemotherapy for Metastatic Nonseminomatous Germ Cell Tumor.
There is controversy regarding the management of patients with normal markers and residual masses (≤1 cm) after chemotherapy for nonseminomatous germ cell tumors (NSGCTs). To determine long-term outcomes of a surveillance strategy in such patients. A retrospective review of our multidisciplinary testicular cancer database was performed. All patients who underwent primary chemotherapy for metastatic NSGCTs were identified between 1981 and 2016. A complete response (CR) was defined as normalization of serum tumor markers and a ≤1 cm residual mass in the largest axial dimension following chemotherapy. All such patients were surveilled. Outcome variables of interest were time to death, time to cancer-specific survival, and time to relapse. Overall survival and relapse-free survival were calculated using the Kaplan-Meier method, and the cumulative incidence of cause-specific survival rates was calculated using competing risk analysis. The impact of risk group and chemotherapy regimen on relapse-free survival was assessed using log-rank test. During the study period, 1429 metastatic germ cell tumor patients were treated with primary chemotherapy. CR was achieved in 191 (18.5%) NSGCT patients. The median age at diagnosis was 27.4 yr, with a median follow-up of 81.1 mo. The majority had American Joint Committee on Cancer stage II at diagnosis (I: 23.8%; II: 49.2%; III: 27%) and International Germ Cell Cancer Collaborative Group good-risk disease (good: 78%; intermediate: 17.8%; poor: 4.2%). Of the 191 patients with a CR, 175 (91.6%) never relapsed and remain disease free. Sixteen (8.4%) patients relapsed after a median of 11.3 mo (range 1-332 mo), with over half (nine patients; 4.7%) relapsing in the retroperitoneum only and salvaged successfully with postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) alone. Of these nine patients, only two (1%) had viable disease in the PC-RPLND specimen. The remaining seven patients had relapses outside the retroperitoneum and received salvage chemotherapy ± postchemotherapy resection. Overall, nine (4.7%) patients have died, but only four (2.1%) from testis cancer. Our data, the largest series to date, confirm that surveillance is safe and effective for men who achieve a CR following chemotherapy for metastatic NSGCTs. Surveillance is a safe strategy for patients who achieve a complete response following chemotherapy for metastatic testis cancer.


Ayurvedic management in limb girdle muscular dystrophy - A case report.
Limb girdle muscular dystrophy (LGMD) is a type of Muscular dystrophy (MD), heterogeneous devastating complex genetic disorders causing progressive weakness and degeneration of muscles. LGMD is hereditary autosomal diseases characterized by weak and wasteful limb girdle muscles. The available management of LGMD in biomedicine is unsatisfactory. Here we present a case of LGMD managed with combinations of Ayurvedic oral medicines and Panchakarma procedures. The Ayurvedic diagnosis of the condition was considered as Mansagata Vata (∼neuromuscular diseases), a type of Vatavyadhi (∼neuromusculo skeleton disorders). The patient was treated with Shalishashtika Pinda Swedana and Mustadi Yapana Basti for the duration of 16 days along with following Ayurvedic oral medicines: Yograj Guggulu 500 mg with 40 ml Dashamoola Kwatha, Ekangaveera Rasa 125 mg with honey, a combination of Ashwagandha Churna -2g, Satavari Churna - 2g, and Sankha Bhasma 500 mg with milk, Narsinha Churna- 3g and Ashwagandhavleha- 5g with milk. All medicines were given twice a day. Patient's condition was assessed for symptoms of pain, walking distance, power and reflexes of both upper and lower limb and psedohypertrophy of both calf muscles. Serum Creatine Phoshphokinase (S.CPK) level and electromyography (EMG) were also measured. There was symptomatic improvement in the patient's condition and reduction in S.CPK level. The study suggests that LGMD can be satisfactorily managed with Ayurvedic oral medicines and Panchakarma therapy.


The presence of human papillomavirus (HPV) in placenta and/or cord blood might result in Th2 polarization.
The purpose of this study was to evaluate if an early exposure to human papillomavirus (HPV) during the prenatal period or infancy could result in HPV16-specific T helper (Th) responses resembling those of adults with HPV-induced lesions. We tested HPV16-specific cell-mediated immunity (CMI) in children born with HPV-positive umbilical cord blood and/or placenta or having persistent oral HPV infection and in constantly oral HPV-negative controls. Peripheral blood mononuclear cells from 33 children from the Finnish HPV Family Study cohort (mean age 14.7 years) were stimulated with peptide pools covering the amino acid sequence of the HPV16 E2, E6, and E7 proteins. Lymphocyte proliferation, secretion of cytokines (IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-10, IL-17A), and the frequency of Foxp3+ regulatory T-cells were determined in relation to the HPV DNA status during a 14-year follow-up. 73.6% of cases and 85.7% of controls responded against HPV16 E2, while reactivity against E6 was found in 10.5 and 35.7%, respectively. The proliferative response against E6 and E7 was more frequent in controls than in cases (p = 0.047). No HPV16-specific CMI response or antibodies were detected in two children with persistent oral HPV16. The profiles of induced cytokines indicated higher levels of IL-5, IL-10, and IL-17A in children with HPV DNA in placenta and/or cord blood than in other children. HPV16-specific CMI is common in HPV DNA-negative children. The cytokine profile in children infected with HPV16 during early life suggests that the viral dose and/or specific environment created by the placenta may have significant impact on the type of HPV-specific immunity.


Seasonal occurrence, removal, mass loading and environmental risk assessment of 55 pharmaceuticals and personal care products in a municipal wastewater treatment plant in Central Greece.
A comprehensive study, which contains the seasonal occurrence, removal, mass loading and environmental risk assessment of 55 multi-class pharmaceuticals and personal care products (PPCPs), took place in the wastewater treatment plant (WWTP) of Volos, Greece. A one year monitoring study was performed and the samples were collected from the influent and the effluent of the WWTP. Solid phase extraction was used for the pre-concentration of the samples followed by an LC-DAD-ESI/MS analysis. Positive samples were further confirmed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The maximum concentrations of the PPCPs varied between 21 ng/L and 15,320 ng/L in the influents and between 18 ng/L and 9965 ng/L in the effluents. The most commonly detected PPCPs were the diuretic furosemide, the beta-blockers atenolol and metoprolol, the analgesics paracetamol, nimesulide, salicylic acid and diclofenac and the psychomotor stimulant caffeine. The removal efficiencies ranged between negative and high removal rates, demonstrating that the WWTP is not able to efficiently remove the complex mixture of PPCPs. The estimated mass loads ranged between 5.1 and 3513 mg/day/1000 inhabitants for WWTP influent and between 4.1 to 2141 mg/day/1000 inhabitants for WWTP effluent. Finally, environmental risk assessment has been regarded a necessary part of the general research. According to the results produced from the calculation of the risk quotient on three trophic levels, the anti-inflammatory drug diclofenac and the antibiotics, trimethoprim and ciprofloxacin, identified to be of high potential environmental risk for acute toxicity, while diclofenac also for chronic toxicity.


[Chemotherapy with curative intent before (neoadjuvant) or after (adjuvant) surgery for colorectal cancer liver metastases].
The 5-year risk of progression after complete resection of liver metastases is of 50% to 75%. Trials which have evaluated adjuvant systemic chemotherapy using 5FU--folinic acid, sometimes in association with intra-arterial chemotherapy, are not powerful and did not demonstrate a clear survival benefit. It is strongly recommended to participate to clinical trials. An adjuvant chemotherapy with the LV5FU2 regimen during 6 months is a reasonable option if the patient has not been included in a trial (professional agreement). A preoperative chemotherapy is not recommended if liver metastases are considered as right away resectable but it should be discussed if resectability is uncertain and/or in case of pejorative factors (professional agreement). If metastases resection has been facilitated or made possible by pre-operative chemotherapy, post-operative resumption of this chemotherapy should also been discussed (professional agreement).


Bernese periacetabular osteotomy for hip dysplasia in young adults.
Hip dysplasia is one of the most common disorders of the hip, presenting in the first three years of life. Literature has shown that an association exists between developmental dysplasia of the hip and the development of secondary hip osteoarthritis in early adulthood. Treatment options are directed toward relieving symptoms and delaying or preventing the onset of arthritis in the affected hip. Total hip arthroplasty is a surgical option, but has been associated with a high rate of failure in younger, physically active patients. This article discusses the Bernese periacetabular osteotomy procedure as a treatment modality, which restores coverage of the femoral head with the acetabulum. Changing the anatomy allows the surgeon to increase the surface area of the femoral head that bears the patient's weight. Increasing the weight-bearing surface may prevent further damage to the hip's cartilage and delay the onset of osteoarthritis.


OxLDL upregulates CXCR2 expression in monocytes via scavenger receptors and activation of p38 mitogen-activated protein kinase.
Chemokine receptor CXCR2 has been implied to play a substantial role in pathogenesis of atherosclerosis, but the underlying molecular mechanisms remain to be clarified. In the present study, we examined the modulating effect of oxLDL on expression of CXCR2 and its functional effect in monocytes. OxLDL (20-microg protein/ml), but not LDL (80-microg protein/ml), upregulated the surface expression of the CXC chemokine receptor CXCR2 (measured by flow cytometry) in both human freshly peripheral blood monocytes and human monocytic U937 cells. OxLDL, but not LDL, increased CXCR2 mRNA determined by RT-PCR in both cells. Treatment of oxLDL (40-microg protein/ml) enhanced chemotaxis of U937 cells to IL-8 and their adhesion to an endothelial cell line, ECV304 (both P<0.05 vs. control). Pretreatment of monocytes with scavenger receptor inhibitors, polyinosinic acid (100 microg/ml) and dextran sulfate (50 microg/ml) attenuated CXCR2 expression, but pertussis toxin or cholera toxin had no effect. OxLDL induced the activation of p38MAPK in monocytes, and this effect of oxLDL was blocked by the scanvenger receptor inhibitors. Furthermore, p38 MAPK inhibitors SB203580 or SK&F86002 markedly reduced oxLDL-induced CXCR2 expression. This observation demonstrated that oxLDL upregulates CXCR2 expression in monocytes and promotes the chemotaxis and adhesion of monocytes. The effect of oxLDL is mediated through scavenger receptor and p38 MAPK activation.


Immersed boundary-finite element model of fluid-structure interaction in the aortic root.
It has long been recognized that aortic root elasticity helps to ensure efficient aortic valve closure, but our understanding of the functional importance of the elasticity and geometry of the aortic root continues to e-volve as increasingly detailed in vivo imaging data become available. Herein, we describe a fluid-structure interaction model of the aortic root, including the aortic valve leaflets, the sinsuses of Valsalva, the aortic annulus, and the sinotubular junction, that employs a version of Peskin's immersed boundary (IB) method with a finite element (FE) description of the structural elasticity. As in earlier work, we use a fiber-based model of the valve leaflets, but this study extends earlier IB models of the aortic root by employing an incompressible hyperelastic model of the mechanics of the sinuses and ascending aorta using a constitutive law fit to experimental data from human aortic root tissue. In vivo pressure loading is accounted for by a backward displacement method that determines the unloaded configurations of the root model. Our model yields realistic cardiac output at physiological pressures, with low transvalvular pressure differences during forward flow, minimal regurgitation during valve closure, and realistic pressure loads when the valve is closed during diastole. Further, results from high-resolution computations indicate that although the detailed leaflet and root kinematics show some grid sensitivity, our IB model of the aortic root nonetheless produces essentially grid-converged flow rates and pressures at practical grid spacings for the high-Reynolds number flows of the aortic root. These results thereby clarify minimum grid resolutions required by such models when used as stand-alone models of the aortic valve as well as when used to provide models of the outflow valves in models of left ventricular fluid dynamics.


Heme oxygenase is expressed in human pulmonary artery smooth muscle where carbon monoxide has an anti-proliferative role.
Heme oxygenase is the rate-limiting enzyme in the catabolism of heme to carbon monoxide, bilirubin and free iron. Many cell types express heme oxygenase-2 constitutively while heme oxygenase-1 is induced at sites of inflammation and oxidative stress. In systemic blood vessels, carbon monoxide may have an important homeostatic role where, like its better-studied counterpart nitric oxide, it is emerging as a vasodilator and an inhibitor of proliferation. However, much less is known regarding the role of heme oxygenase and carbon monoxide in the pulmonary circulation where vascular responses are very different. Here, using primary cultures of human pulmonary artery smooth muscle cells, we present novel data showing that this cell type expresses heme oxygenase-2 constitutively and, in the presence of oxidants, can induce heme oxygenase-1. We also show that the carbon monoxide-releasing molecule, tricarbonyldichlororuthenium (II) dimer, potently and profoundly inhibits proliferation of human pulmonary artery smooth muscle cells. Pulmonary hypertension is a disease characterised by abnormal vascular smooth muscle cell growth and remodelling of the pulmonary vasculature. Our observations support the growing evidence that the heme oxygenase/carbon monoxide system may play a role in the pathology of pulmonary hypertension.


State containment measures, living arrangements, and mental health of U.S. older adults during the COVID-19 pandemic.
Early in the coronavirus pandemic, U.S. states implemented several different types of containment measures to slow the disease's spread. Early evidence indicates containment measures were associated with changes in individuals' mental health. This study explores the associations between U.S. state containment measures and older adults' mental health and importantly, whether the associations vary by living arrangement and gender. The study analyzed national sample of adults aged 50 or older from 12 waves (April-July 2020) of the U.S. Household Pulse Survey (N = 394,934). State fixed-effects models linked four state containment measures (stay-at-home order, restaurant closure, bar closure, and movie theater closure) to levels of depression and anxiety across different types of living arrangements, net of controls. Men and women were analyzed separately. Stay-at-home order and restaurant and bar closure, but not movie theater closure, were associated with higher levels of depression and anxiety in older adults. Living arrangements moderated the associations for women but not men. For women, compared to living alone, living with a spouse or intergenerational family was associated with higher levels of anxiety and depression during stay-at-home order and restaurant closure. The associations between containment measures and mental health vary by type of living arrangement and were gendered, likely because household situations create different demands and supports that men and woman experience differently. Although containment measures are necessary to protect public health, paying attention to these underlying dynamics can inform policymakers' efforts to implement policies that balance harms and benefits for older adults.


Delaying surgery for clinical T1b-T2bN0M0 renal cell carcinoma: Oncologic implications in the COVID-19 era and beyond.
During COVID-19, many operating rooms were reserved exclusively for emergent cases. As a result, many elective surgeries for renal cell carcinoma (RCC) were deferred, with an unknown impact on outcomes. Since surveillance is commonplace for small renal masses, we focused on larger, organ-confined RCCs. Our primary endpoint was pT3a upstaging and our secondary endpoint was overall survival. We retrospectively abstracted cT1b-T2bN0M0 RCC patients from the National Cancer Database, stratifying them by clinical stage and time from diagnosis to surgery. We selected only those patients who underwent surgery. Patients were grouped by having surgery within 1 month, 1-3 months, or >3 months after diagnosis. Logistic regression models measured pT3a upstaging risk. Kaplan Meier curves and Cox proportional hazards models assessed overall survival. A total of 29,746 patients underwent partial or radical nephrectomy. Delaying surgery >3 months after diagnosis did not confer pT3a upstaging risk among cT1b (OR = 0.90; 95% CI: 0.77-1.05, P = 0.170), cT2a (OR = 0.90; 95% CI: 0.69-1.19, P = 0.454), or cT2b (OR = 0.96; 95% CI: 0.62-1.51, P = 0.873). In all clinical stage strata, nonclear cell RCCs were significantly less likely to be upstaged (P <0.001). A sensitivity analysis, performed for delays of <1, 1-3, 3-6, and >6 months, also showed no increase in upstaging risk. Delaying surgery up to, and even beyond, 3 months does not significantly increase risk of tumor progression in clinically localized RCC. However, if deciding to delay surgery due to COVID-19, tumor histology, growth kinetics, patient comorbidities, and hospital capacity/resources, should be considered.


Vaccine development reconsidered.
This paper briefly reviews work on vaccine development since the early 1950s with special emphasis on identification of immunogens and their presentation to the host so as to elicit an immune response. This is illustrated primarily by a discussion of the development of a candidate meningococcal B vaccine based on a capsular carbohydrate outer membrane protein complex. Work on malaria and living Salmonella typhi vaccine is also discussed.


Postoperative lateral ligamentous laxity diminishes with time after TKA in the varus knee.
For successful TKA, good soft tissue balance is one of the most important factors; however, it is unknown whether the coronal balance immediately after surgery is maintained with time. We hypothesized, if neutral mechanical alignment was achieved at the time of TKA, some degree of lateral ligamentous laxity could be accepted and the laxity would diminish with time. To confirm this hypothesis, we posed two scientific questions: (1) Does the coronal ligament balance measured immediately after TKA change with time? (2) Does the degree of preoperative varus alignment correlate with the lateral or medial ligamentous laxity observed after TKA? We measured coronal lateral or medial ligamentous laxity in 71 knees with varus deformities immediately after surgery and at 3, 6, and 12 months thereafter. The mean mechanical axis was 15.9 degrees varus preoperatively and 0.4 degrees varus postoperatively. The mean medial ligamentous laxity was relatively constant postoperatively from immediately after surgery to 12 months. However, the mean lateral ligamentous laxity was as much as 8.6 degrees immediately after surgery and decreased to 5.1 degrees at 3 months. The lateral ligamentous laxity immediately after surgery correlated with the preoperative varus mechanical axis. Our data show residual lateral ligamentous laxity observed in preoperative varus deformity may be corrected spontaneously after TKA.


Novel chiral stationary phases for optical resolution by ligand-exchange high-performance liquid chromatography.
Novel chiral stationary phases, (1R,2S)- and diastereomeric (1S,2S)-2-carboxymethylamino-1,2-diphenylethanol, were prepared from (1R,2S)- and (1S,2S)-2-amino-1,2-diphenylethanol, respectively, and were bound to silica gel pretreated with 3-glycidoxypropyltrimethoxysilane. The chiral stationary phases were found to be very effective for the optical resolution of amino acids, amino acid derivatives and hydroxy acids by ligand-exchange high-performance liquid chromatography.


Strain-specific Antimicrobial Activity of Lactoferrin-based Food Supplements.
The iron-binding glycoprotein lactoferrin is well known for its wide range of antibacterial effects. However, the aim of this study was to show that its antibacterial activity is not generally applicable to a bacterial species as a whole. In disk diffusion assays performed with 112 isolates from 13 bacterial species (including the foodborne pathogens Bacillus cereus and Staphylococcus aureus), a lactoferrin-based food supplement showed no inhibition of growth on 24%, moderate inhibition on 31%, and strong inhibition on 45% of all tested isolates. Minimal inhibitory concentrations against B. cereus and Bacillus thuringiensis strain-specifically ranged from 0.31 mg/mL to no impairment at all. Further 11 commercially available lactoferrin-based food supplements and purified bovine lactoferrin showed strain- as well as product-specific growth inhibition. In comparison to bovine lactoferrin, human lactoferrin showed no inhibitory effects. In summary, purified lactoferrin and lactoferrin-based food supplements inhibit bacterial growth in a dose-, strain-, and product-dependent manner. Thus, a general antimicrobial effect of lactoferrin against a specific bacterial species cannot be assumed.


Dietary Effects on Monocyte Phenotypes in Subjects With Hypertriglyceridemia and Metabolic Syndrome.
In patients with hypertriglyceridemia, a short-term low-saturated fat vs high-saturated fat diet induced lower plasma lipids and improved monocyte phenotypes. These findings highlight the role of diet fat content and composition for monocyte phenotypes and possibly cardiovascular disease risk in these patients. (Effects of Dietary Interventions on Monocytes in Metabolic Syndrome; NCT03591588).


Heteromorphic algal life histories: The seasonal pattern and response to herbivory of the brown crust, Ralfsia californica.
Little is known about the natural history of crustose phases of heteromorphic algae. A qualitative model describing their life history strategies has hypothesized that the morphologies and seasonal occurrences of the two phases evolved largely in response to variable grazing pressure. Crustose phases are predicted to occur when grazing is intense, and erect phases when grazing is reduced. The brown algal crust Ralfsia calfornica, which is the non-obligatory alternate phase of Scytosiphon lomentaria and/or Petalonia fascia, was studied on San Juan Island, Washington, USA. Both phases inhabit pools in the midto upper-intertidal zone, with the crust reaching maximum abundance between 1.8 and 2.3 m. The crust undergoes radical and predictable seasonal fluctuations in abundance, with a maximum in March-April and minimum in August. The erect phases are winter annuals, with maxima in January-April. Thus the crustose and erect phases show high temporal overlap. Colonization studies on new substrata showed that: 1) the crust is ephemeral, with a lifespan of 7-12 months, 2) it reproduces throughout the year and its propagules rapidly colonize new substrata at almost any time, while 3) erect phases appear only during the winter. Manipulations of limpets indicated that they do not directly graze the crust and are not responsible for its seasonal fluctuations in abundance; however, they are crucial to its persistence because they remove potential competitors. The crust fits poorly into models relating morphology to successional status in that it is ephemeral and opportunistic yet is grazer-resistant and grazer-dependent. Furthermore, both the crust and its erect phases are most abundant in the winter, when grazing appears to be least intense. Thus this heteromorphic complex exhibits interesting characteristics not predicted by current models.


A longitudinal study of onset of drinking among high-school students.
During the course of the school year 30% of high-school abstainers started using distilled spirits. The influence of intra- and interpersonal characteristics on beginning to drink is assessed.


Training and Assessment in Pediatric Endoscopy.
A key aspect of pediatric gastroenterology practice is the ability to perform endoscopy procedures safely, effectively, and efficiently. Similar to adult endoscopy, performance of pediatric endoscopy requires the acquisition of related technical, cognitive, and integrative competencies to effectively diagnose and manage gastrointestinal disorders in children. However, the distinctive requirements of pediatric patients and their families and the differential spectrum of disease highlight the need for a pediatric-specific training curriculum and assessment framework to ensure endoscopic procedures are performed safely and successfully in children. This review outlines the current state of evidence as it pertains to pediatric endoscopy training and assessment.


Design of a naphthalimide-based probe for acrolein detection in foods and cells.
Acrolein is a highly toxic agent that can be generated exogenously and endogenously. Therefore, a highly specific and sensitive probe for acrolein with potential applications in acrolein detection must be developed. In this research, a novel fluorescent probe named "probe for acrolein detection" (Pr-ACR) was designed and synthesized based on a naphthalimide fluorophore skeleton, and a thiol group (-SH) was introduced into its structure for acrolein recognition. The -SH traps acrolein via Michael addition and the resultant interaction product of the probe inhibits the photoinduced electron transfer process and produce a strong fluorescence at 510 nm. The probe showed high sensitivity and specificity for acrolein. HPLC-MS/MS analysis verified that it can be used to quantify acrolein in foods, such as soda crackers, red wine, and baijiu, with a fluorescence spectrophotometer. After methyl esterification, the methyl esterified probe (mPr-ACR) successfully visualised acrolein in Hela cells under a laser scanning confocal microscope. This finding proved that Pr-ACR and mPr-ACR are potential tools for the detection and visualisation of acrolein from different sources.


Pain control in tonic immobility (TI) and other immobility models.
This chapter deals with the mechanisms modulating pain during TI and other immobility responses in different animal species. In mammals the presence of high voltage slow waves in the electroencephalogram during TI suggests the activation of the thalamic gate, a mechanism blocking all sensory information, including pain. In rabbits TI transiently suppresses all the behavioral responses to persistent nociceptive stimulation by the activation of an opioid mechanism outlasting TI offset by 1h. On the other hand, in rodents, also not injuring nociceptive stimuli applied during TI elicit a delayed opioid analgesia that develops within 45min. Moreover, both opioid and non-opioid mechanisms of analgesia have been observed. TI strongly reduces inflammatory responses by activating the vagal-neocortical-sympathetic axis, a feedback control of neuro-immune mechanisms. Several models of noxious and non-noxious restraint and of post-restraint immobility resembling TI have been proposed. Moreover in lizards, hyperalgesia occurs during and after TI.


Correction: Incidence and contributing factors of glucose intolerance in Saudi postpartum women: Sub-group analysis from RAHMA study.
[This corrects the article DOI: 10.1371/journal.pone.0210024.].