Can microprocessor knees reduce the disparity in trips and falls risks between above and below knee prosthesis users?
While all lower limb prosthesis walkers have a high risk of tripping and/or falling, above knee prosthesis users are reported to fall more frequently. Recognising this, engineers designed microprocessor knees (MPK) to help mitigate these risks, but to what extent these devices reduce this disparity between above and below knee users is unclear. A service review was carried out in a prosthetic limb centre regarding the frequency of trips and falls in the previous four weeks. Data from unilateral, community ambulators were extracted. Ordered logistic regressions were applied to investigate whether MPKs mitigated the increased risk of trips and falls for prosthetic knee users, compared to below knee prosthesis users. Socio-demographics (sex, age), prosthesis (prosthesis type, years of use), health (comorbidities, vision, contralateral limb status, medication), and physical function (use of additional walking aids, activity level) were included as covariates. Of the 315 participants in the analysis, 57.5% reported tripping and 20.3% reported falling. Non-microprocessor prosthetic knee (non-MPK) users were shown to trip significantly more than below knee prosthesis users (OR = 1.96, 95% CI = 1.17-3.28). Other covariates showing a significant association included contralateral limb injuries (OR = 1.91, 95% CI = 1.15-3.18) and using an additional walking aid (OR = 1.99, 95% CI = 1.13-3.50). Non-MPK users were also shown to fall significantly more than below knee prosthesis users (OR = 3.34, 95% CI = 1.73-6.45), with no other covariates showing a significant association. MPK users did not show an increased frequency of trips (OR = 0.74, 95% CI = 0.33-1.64) or falls (OR = 0.34, 95% CI = 0.18-2.62), compared to below knee prosthesis users. Of those who tripped at least once in the previous four weeks, those using a non-MPK (OR = 2.73, 95% CI = 1.30-5.74) presented an increased frequency of falling. These findings provide evidence to suggest that the use of MPKs reduces the difference in falls risk between above knee and below knee prosthesis users, providing justification for their provision.


Dynamic Changes of Inhibitory Killer-Immunoglobulin-Like Receptors on NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation: An Initial Study.
Killer-immunoglobulin-like receptors (KIRs) are critical natural killer (NK) cell regulators. The expression of KIRs is a dynamic process influenced by many factors. Their ligands-HLA(Human Leukocyte Antigen) class I molecules-are expressed on all nucleated cells that keep NK cells under control. In hematopoietic stem cell transplantation (HSCT), NK cells play an essential role in relapse protection. In the presented pilot study, we characterized the dynamic expression of inhibitory KIRS (iKIRs), which protect cells against untoward lysis, in donors and patients during the first three months after HSCT using flow cytometry. The expression of all iKIRs was highly variable and sometimes correlated with patients' clinical presentation and therapy regiment. Cyclophosphamide (Cy) in the graft-versus-host disease (GvHD) prevention protocol downregulated KIR2DL1 to just 25% of the original donor value, and the FEAM (Fludarabine + Etoposid + Ara-C + Melphalan) conditioning protocol reduced KIR2DL3. In lymphoid neoplasms, there was a slightly increased KIR2DL3 expression compared to myeloid malignancies. Additionally, we showed that the ex vivo activation of NK cells did not alter the level of iKIRs. Our study shows the influence of pre- and post-transplantation protocols on iKIR expression on the surface of NK cells and the importance of monitoring their cell surface.


Cryotherapy compared with trichloroacetic acid in treating genital warts.
In an observer blind comparative study, 130 men with penile warts were randomly allocated to treatment with either cryotherapy or trichloroacetic acid (TCAA). There was no significant difference in response to treatment, side effects, or recurrence rates between the two treatments. Warts resolved in 81% of patients treated with TCAA compared with 88% of those treated with cryotherapy. Early recurrence occurred in 36% of patients treated with TCAA and in 39% of those treated with cryotherapy.


Can we explain demography through culture?
"An attempt has been made here to understand how far the culture of a community can be held responsible in the determination of its demographic aspects of life....[The authors] analyse the cultural norms and values, beliefs and superstitions, taboos and other related factors in relation to fertility. Various situations arising out of these features have been examined in the background of different religious faiths through the categorical analysis of different [Indian] census data."


[The experience of uncertainty of fathers and mothers in the process of the announcement of cerebral palsy of their children].
This qualitative research shows differences and similarities between mother and father's experience of incertitude in the process of the announcement of the cerebral palsy and the adaptation strategies used. Interviews have been conducted with 17 parents (10 mothers and 7 fathers). Results of the research reveals three main triggering factors of incertitude: incertitude in regards with the survival of the child, the unpredictability of the evolution of the child and the ambiguity of the information regarding the cerebral palsy Triggering factors of the incertitude are the same for both parents but their reactions towards the these factors and their way of coping with the situation vary.


New Genes in the Drosophila Y Chromosome: Lessons from D. willistoni.
Y chromosomes play important roles in sex determination and male fertility. In several groups (e.g., mammals) there is strong evidence that they evolved through gene loss from a common X-Y ancestor, but in Drosophila the acquisition of new genes plays a major role. This conclusion came mostly from studies in two species. Here we report the identification of the 22 Y-linked genes in D. willistoni. They all fit the previously observed pattern of autosomal or X-linked testis-specific genes that duplicated to the Y. The ratio of gene gains to gene losses is ~25 in D. willistoni, confirming the prominent role of gene gains in the evolution of Drosophila Y chromosomes. We also found four large segmental duplications (ranging from 62 kb to 303 kb) from autosomal regions to the Y, containing ~58 genes. All but four of these duplicated genes became pseudogenes in the Y or disappeared. In the GK20609 gene the Y-linked copy remained functional, whereas its original autosomal copy degenerated, demonstrating how autosomal genes are transferred to the Y chromosome. Since the segmental duplication that carried GK20609 contained six other testis-specific genes, it seems that chance plays a significant role in the acquisition of new genes by the Drosophila Y chromosome.


High-Resolution 3D Bioprinting of Photo-Cross-linkable Recombinant Collagen to Serve Tissue Engineering Applications.
Various biopolymers, including gelatin, have already been applied to serve a plethora of tissue engineering purposes. However, substantial concerns have arisen related to the safety and the reproducibility of these materials due to their animal origin and the risk associated with pathogen transmission as well as batch-to-batch variations. Therefore, researchers have been focusing their attention toward recombinant materials that can be produced in a laboratory with full reproducibility and can be designed according to specific needs (e.g., by introducing additional RGD sequences). In the present study, a recombinant protein based on collagen type I (RCPhC1) was functionalized with photo-cross-linkable methacrylamide (RCPhC1-MA), norbornene (RCPhC1-NB), or thiol (RCPhC1-SH) functionalities to enable high-resolution 3D printing via two-photon polymerization (2PP). The results indicated a clear difference in 2PP processing capabilities between the chain-growth-polymerized RCPhC1-MA and the step-growth-polymerized RCPhC1-NB/SH. More specifically, reduced swelling-related deformations resulting in a superior CAD-CAM mimicry were obtained for the RCPhC1-NB/SH hydrogels. In addition, RCPhC1-NB/SH allowed the processing of the material in the presence of adipose tissue-derived stem cells that survived the encapsulation process and also were able to proliferate when embedded in the printed structures. As a consequence, it is the first time that successful HD bioprinting with cell encapsulation is reported for recombinant hydrogel bioinks. Therefore, these results can be a stepping stone toward various tissue engineering applications.


Polyadenylation precedes splicing in vitro.
Vertebrate premessenger RNAs are usually spliced and polyadenylated. In vivo analysis of the relative kinetics of the two reactions is difficult. We have used in vitro processing systems to investigate the order of splicing and polyadenylation of chimeric precursor RNAs containing a single intron and a poly(A) site. Polyadenylated, but not spliced, intermediate RNA appeared first and reached a low steady-state level early during incubation, properties consistent with its being a reaction intermediate in the production of doubly-processed spliced and polyadenylated product RNA. The kinetics of polyadenylation suggested that polyadenylated RNA was the only intermediate in the production of doubly-processed RNA. Spliced, but not polyadenylated, RNA also appeared. This species, however, continued to accumulate during reaction, and could not be chased into product spliced and polyadenylated RNA. These data support a preferred order of reaction for 3' terminal introns and exons in which polyadenylation precedes splicing.


Hereditary hemorrhagic telangiectasia treated with low dose intravenous bevacizumab.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder that leads to mucocutaneous telangiectasias, epistaxis, and gastrointestinal bleeding. Depending on the severity and manifestation of the disease, various therapeutic modalities have been used, from local bleeding control to surgery or concomitant drug therapy. Several articles under review have presented guidelines for treatment of HHT with bevacizumab as a direct anti-angiogenesis strategy. Still, neither the exact optimal dose nor the minimum effective dose of intravenous bevacizumab in patients with severe HHT has been reported. A 55-year-old man presented with long-standing epistaxis, recent melena, dizziness, and a three-generation family history of chronic epistaxis, anemia, and regular blood transfusions. Treatment with argon plasma coagulation (APC) for the gastrointestinal bleeding failed to raise hemoglobin levels, we considered using the bevacizumab. We report a patient with severe HHT, who was treated with low-dose bevacizumab (2 mg/kg) and improved substantially.


P300 energy loss in aging and Alzheimer's disease.
The amplitude of the event-related potential P300 component is sensitive to aging and Alzheimer's disease (AD). Using a standard 20-electrode configuration, the P300 was measured during an "oddball" task in 14 young normal individuals (YN: 21-41 years), 11 elderly normal individuals (EN: 61-80 years), and 23 probable AD patients (AD: 63-93 years; NINCDS-ADRDA criteria). P300 latencies and amplitudes were measured at PZ. Additionally, algorithmic calculations were made from spline plots across the 11 central electrodes for P300 peak voltage latency and total field energy. The measured versus calculated latencies were in general agreement. Furthermore, the measured P300 voltage amplitude was closely related to the calculated total field energy. P300 voltage latency was significantly prolonged in the elderly, but not more so in AD patients (average latency [ms ± SD]; YN, 315 ± 21; EN, 364 ± 48 and AD, 361 ± 56). P300 amplitude showed the expected pattern of change from young to elderly to AD (average voltage [uV ± SD]; YN, 13 ± 5.1; EN, 8.3 ± 2.8; and AD, 4.9 ± 3.3). Summing the squares of each wave (an indication of power: P = V2 R) showed the expected change with age more strongly than the P300 amplitude (average ± SD; YN, 44,397 ± 32,386; EN, 9,996 ± 7,018; and AD, 3,347 ± 2,971). Mini-Mental State Exam scores showed no relationship to P300 latency and minimal relationship to amplitude. Results suggest that the P300 is not obliterated in early AD, but is barely discernable in late AD. The approaches to calculating the P300 described here are potentially useful for measuring specific neural systems affected by aging and AD.


Mechanical and metabolic interplay in the brain metastatic microenvironment.
In this Perspective, we provide our insights and opinions about the contribution-and potential co-regulation-of mechanics and metabolism in incurable breast cancer brain metastasis. Altered metabolic activity can affect cancer metastasis as high glucose supply and demand in the brain microenvironment favors aerobic glycolysis. Similarly, the altered mechanical properties of disseminating cancer cells facilitate migration to and metastatic seeding of the brain, where local metabolites support their progression. Cancer cells in the brain and the brain tumor microenvironment often possess opposing mechanical and metabolic properties compared to extracranial cancer cells and their microenvironment, which inhibit the ease of extravasation and metastasis of these cells outside the central nervous system. We posit that the brain provides a metabolic microenvironment that mechanically reinforces the cellular structure of cancer cells and supports their metastatic growth while restricting their spread from the brain to external organs.


Serum lipids and other risk factors for diabetic retinopathy in Chinese type 2 diabetic patients.
To investigate the association of serum lipids and other risk factors with diabetic retinopathy (DR) in Chinese type 2 diabetic patients. Five hundred and twenty-three type 2 diabetic patients underwent ophthalmic examination by experienced retinal specialists to assess their DR. Serum lipids, including triglycerides, total cholesterol, high density lipoprotein cholesterol (HDLC), and low density lipoprotein cholesterol (LDLC), were measured using Roche automated clinical chemistry analyzers. The concentration of very low density lipoprotein cholesterol (VLDLC) was calculated based on total cholesterol, HDLC and LDLC. Hyperlipidemia was defined as a total cholesterol concentration of 6.2 mmol/L or higher or the use of lipid-lowering medications. The association of risk factors with any DR or proliferative diabetic retinopathy (PDR) was assessed using the odds ratio (OR) and its 95% confidence interval (CI), calculated from logistic regression models. In multivariate logistic regression models, hyperlipidemia (OR=2.39, 95% CI: 1.02-5.66), higher VLDLC (OR=1.59, 95% CI: 1.14-2.23), and higher triglyceride (OR=1.18, 95% CI: 1.03-1.37) were associated with increased risk of DR. A longer diabetic duration was associated with increased risk of DR (P<0.0001) and PDR (P=0.002) in a dose-response manner. Higher systolic blood pressure (P=0.02) and higher serum creatinine (P=0.01) were independently associated with increased risk of DR, and female gender was associated with increased risk of PDR (P=0.03). Among Chinese type 2 diabetic patients, hyperlipidemia, higher VLDLC, and higher triglyceride were independently associated with increased risk of DR, suggesting control of serum lipids may decrease the risk of DR.


Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data.
The severity of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly heterogeneous. Studies have reported that males and some ethnic groups are at increased risk of death from COVID-19, which implies that individual risk of death might be influenced by host genetic factors. In this project, we consider the mortality as the trait of interest and perform a genome-wide association study (GWAS) of data for 1778 infected cases (445 deaths, 25.03%) distributed by the UK Biobank. Traditional GWAS fails to identify any genome-wide significant genetic variants from this dataset. To enhance the power of GWAS and account for possible multi-loci interactions, we adopt the concept of super variant for the detection of genetic factors. A discovery-validation procedure is used for verifying the potential associations. We find 8 super variants that are consistently identified across multiple replications as susceptibility loci for COVID-19 mortality. The identified risk factors on chromosomes 2, 6, 7, 8, 10, 16, and 17 contain genetic variants and genes related to cilia dysfunctions (DNAH7 and CLUAP1), cardiovascular diseases (DES and SPEG), thromboembolic disease (STXBP5), mitochondrial dysfunctions (TOMM7), and innate immune system (WSB1). It is noteworthy that DNAH7 has been reported recently as the most downregulated gene after infecting human bronchial epithelial cells with SARS-CoV-2. Eight genetic variants are identified to significantly increase the risk of COVID-19 mortality among the patients with white British ancestry. These findings may provide timely clues and potential directions for better understanding the molecular pathogenesis of COVID-19 and the genetic basis of heterogeneous susceptibility, with potential impact on new therapeutic options.


Poor specificity of low growth hormone and cortisol levels during fasting hypoglycemia for the diagnoses of growth hormone deficiency and adrenal insufficiency.
Fasting tests are used to identify the cause of hypoglycemia in children. The purposes of this study were to (1) determine whether growth hormone and cortisol levels obtained at the time of hypoglycemia in such tests can identify children with growth hormone and/or cortisol deficiency and (2) identify potential clinical factors that influence growth hormone and cortisol responses to hypoglycemia. The design consisted of chart review of all diagnostic fasting tests conducted over a 3-year period (n = 151). A normal growth hormone level was defined as >/=7.5 ng/mL, and a normal cortisol level was defined as >/=18 mug/dL. During the fasting tests, 84 children (median age: 1.3 years [2 days to 14.3 years]), became hypoglycemic, with blood glucose </=50 mg/dL. Diagnoses included normal, ketotic hypoglycemia, hyperinsulinism, fatty acid-oxidation defects, glycogen-storage disease, and late dumping hypoglycemia. A total of 70% had growth hormone and cortisol levels less than the "normal" thresholds regardless of diagnosis. Of various factors (age, diagnosis, fast duration, duration blood glucose level of <60 mg/dL, and blood glucose nadir), only age was positively associated with cortisol, and none were consistently related to growth hormone. A singe low growth hormone or cortisol value at the time of fasting hypoglycemia has poor specificity for the respective diagnoses of growth hormone deficiency and adrenal insufficiency.


Diminishing the risk of nonrelapse mortality in hematopoietic stem cell transplantation: Prediction of exposure to the cyclophosphamide metabolite carboxyethylphosphoramide mustard.
Our objectives were (1) to develop a population pharmacokinetic model for cyclophosphamide, 4-hydroxycyclophosphamide, and carboxyethylphosphoramide mustard (a reporter for nonrelapse mortality) in hematopoietic stem cell transplantation patients and (2) to validate a Bayesian approach to dosing. In this study 147 patients received intravenous infusions of 60 mg. kg -1. d -1 cyclophosphamide for 2 days, followed by 12 to 14.4 Gy total body irradiation. A population model was developed to fit concentration-time data of cyclophosphamide and metabolites. Bayesian prediction of the area under the curve (AUC) was validated by dividing the data set into an index set (98 patients) and validation set (49 patients). Parameters from the index data set were used as priors. Cyclophosphamide elimination was best described by noninducible and inducible routes producing 4-hydroxycyclophosphamide. Induction was described by a zero-order maximum fold of induction-type increase in enzyme level. The prediction of the AUC of carboxyethylphosphoramide mustard was clinically accurate and precise (mean prediction error = -3.5% and root mean squared prediction error = 12.2%) with data limited to 5 to 6 points obtained in the first 16 hours. However, the AUC of 4-hydroxycyclophosphamide was overestimated (mean prediction error = 16.9%-23.6%). Several alternative models did not improve the result. The integrated mechanism-based model describes the pharmacokinetics of cyclophosphamide and carboxyethylphosphoramide mustard. Accurate modeling of 4-hydroxycyclophosphamide is limited by its chemical instability. Exposure to carboxyethylphosphoramide mustard could be accurately and precisely predicted with minimal data obtained over a 16-hour period after the first dose, offering the potential of pharmacokinetically guided dosing to reduce the nonrelapse mortality rate.


Hydrogen sulfide exposure increases desiccation tolerance in Drosophila melanogaster.
Hydrogen sulfide (H(2)S) has been shown to effect physiological alterations in several animals, frequently leading to an improvement in survival in otherwise lethal conditions. In the present paper, a volatility bioassay system was developed to evaluate the survivorship of Drosophila melanogaster adults exposed to H(2)S gas that emanated from a K(2)S donor. Using this bioassay system, we found that H(2)S exposure significantly increased the survival of flies under arid and food-free conditions, but not under humid and food-free conditions. This suggests that H(2)S plays a role in desiccation tolerance but not in nutritional stress alleviation. To further confirm the suggestion, the mRNA levels of two desiccation tolerance-related genes Frost and Desat2, and a starvation-related gene Smp-30, from the control and treated flies were measured by quantitative real-time PCR. These genes were up-regulated within 2h when the flies transferred to the arid and food-free bioassay system. Addition of H(2)S further increased Frost and Desat2 mRNA levels, in contrast to Smp-30. Thus, our molecular results were consistent with our bioassay findings. Because of the molecular and genetic tools available for Drosophila, the fly will be a useful system for determining how H(2)S regulates various physiological alterations.


Consensus recommendations on the use of botulinum toxin type a in facial aesthetics.
The use of botulinum toxin type A for facial enhancement is the most common cosmetic procedure currently undertaken in the United States. Overall clinical and study experience with botulinum toxin type A treatment for facial enhancement has confirmed that it is effective and safe in both the short and long term. Nevertheless, consistent guidelines representing the consensus of experts for aesthetic treatments of areas other than glabellar lines have not been published. Therefore, a panel of experts on the aesthetic uses of Botox Cosmetic (botulinum toxin type A; Allergan, Inc., Irvine, Calif.) was convened to develop consensus guidelines. This publication comprises the recommendations of this panel and provides guidelines on general issues, such as the importance of the aesthetic evaluation and individualization of treatment, reconstitution and handling of the botulinum toxin type A, procedural considerations, dosing and injection-site variables, and patient selection and counseling. In addition, specific considerations and recommendations are provided by treatment area, including glabellar lines, horizontal forehead lines, "crow's feet," "bunny lines" (downward radiating lines on the sides of nose), the perioral area, the dimpled chin, and platysmal bands. The review of each area encompasses the relevant anatomy, specifics on injection locations and techniques, starting doses (total and per injection point), the influence of other variables, such as gender, and assessment and retreatment issues. Factors unique to each area are presented, and the discussion of each treatment area concludes with a review of key elements that can increase the likelihood of a successful outcome. Summary tables are provided throughout.


Refractory pain, existential suffering, and palliative care: releasing an unbearable lightness of being.
Since the beginning of the hospice movement in 1967, "total pain management" has been the declared goal of hospice care. Palliating the whole person's physical, psychosocial, and spiritual states or conditions is central to managing the pain that induces suffering. At the end-stage of life, an inextricable component of the ethics of adjusted care requires recognition of a fundamental right to avoid cruel and unusual suffering from terminal illness. This Article urges wider consideration and use of terminal sedation, or sedation until death, as an efficacious palliative treatment and as a reasonable medical procedure in order to safeguard the "right" to a dignified death. Once the state establishes a human right to avoid refractory pain of whatever nature in end-stage illness, a coordinate responsibility must be assumed by health care providers to make medical judgments consistent with preserving the best interests of a patient's quality of life by alleviating suffering. The principle of medical futility is the preferred construct for implementing this professional responsibility. Rather than continue to be mired in the vexatious quagmire of the doctrine of double effect--all in an effort to "test" whether end-stage decisions by health care providers are licit or illicit--a relatively simple test of proportionality, or cost-benefit analysis, is proffered. Imbedded, necessarily, in this equation is the humane virtue of compassion, charity, mercy or agape. Assertions of state interest in safeguarding public morality by restricting intimate associational freedoms to accelerate death in a terminal illness are suspicious, if, indeed, not invalid. No terminally ill individual suffering from either intractable somatic or non-somatic pain, or both, should be forced to continue living.


Impact of clinical status and salivary conditions on xerostomia and oral health-related quality of life of adolescents with type 1 diabetes mellitus.
To investigate the influence of clinical status and salivary conditions on the presence of xerostomia on adolescents with and without type 1 diabetes mellitus (DM1), and further to investigate the influence of clinical status, salivary conditions and xerostomia on oral health-related quality of life (OHQoL) of those with DM1. A cross-sectional study was performed on 102 adolescents, 51 with DM1 and 51 nondiabetics. Xerostomia was detected by asking a question about the sensation of having 'dry mouth', and Oral Health Impact Profile-14 was used to measure the impact of xerostomia on OHQoL. The clinical status was assessed by using decayed, missing or filled and Community Periodontal indices, and by evaluating oral manifestations; and the following salivary conditions were evaluated: stimulated salivary flow, pH, buffer capacity, total protein, amylase, urea, calcium, and glucose salivary concentrations. Multiple logistic regression analysis was used to evaluate the influence of clinical status and salivary conditions on xerostomia and the impact of xerostomia on the OHQoL of adolescents with DM1. Clinical status and salivary conditions was shown to have no influence on the presence of xerostomia. Bivariate (P = 0.00) and logistic regression (P = 0.01) analysis showed a significant association between DM1 and xerostomia. Logistic regression analysis showed association between xerostomia (P = 0.00) and OHQoL, and caries experience (P = 0.03) and OHQoL. DM1 showed to be predictive of a high prevalence of xerostomia in adolescents. Caries experience and xerostomia showed to have a negative impact on the OHQoL of adolescents with DM1.


Practice patterns of underrepresented minority nurse practitioners in New York state, 2000.
Using data collected from a sample of 1,319 nurse practitioners (NPs) in New York state in 2000, differences in practice patterns by race and ethnicity were identified. NPs from underrepresented minority (URM) groups were more likely than non-URM NPs to work in hospitals, community health centers, and schools but less likely to work in physician offices and NP practices. URM NPs were also more likely to report a specialty certification in women's health. Several different measures of primary care provision were examined, with URM NPs substantially more likely to meet all four measures of primary care practice than non-URM NPs. Finally, URM NPs were more likely than non-URM NPs to practice in federally designated health profession shortage areas.


[Examination of percutaneous microwave coagulation and radiofrequency ablation therapy for metastatic liver cancer].
Percutaneous microwave coagulation therapy (PMCT) and radio frequency ablation therapy (RFA) as treatments for metastatic liver cancer were examined. PMCT or RFA was administered for 18 metastatic liver cancer lesions (primary lesion: 11 colon rectal cancer, one esophagus cancer, one thyroid cancer, one pancreatic cancer, one pheochromocytoma) in 16 patients from July 1999 to March 2002. RFA was performed 1 time for 12 minutes in principle, using a Cool-tip RF system from Radionics. Patients had a mean age of 58.8 years and the mean diameter of the neoplasms was about 22 mm. Critical complications were not seen. The rate of partial recurrence was 35.3% as of March, 2002, in an average observation period of 7.3 months. On the other hand, with the medical treatment for the hepatocellular carcinoma provided during this period, the rate of partial recurrence was 14.8%. The treatment of metastatic liver cancer by PMCT and RFA is associated with a high rate of a recurrence as compared with hepatocellular carcinoma, and needs to be examined to discover ways of adaptation and improvement of the technology.


Thoracic Nerve Root Schwannoma Filling the Spinal Canal Almost Entirely Without any Neurological Deficits.
Spinal tumours may be classified in three groups: 1) extradural, 2) intradural extramedullary and 3) intramedullary spinal cord tumours. Intradural extramedullary tumours arise from the leptomeninges or nerve roots and include schwannomas. A schwannoma is usually a firm grey-whitish tumour growing near a nerve trunk or ramus. It can be separated from the nerve without damaging neural tissue. Schwannomas are usually solitary tumours. We present the case of a 37-year-old male who underwent surgery for a tumour in the upper thoracic segment of the spinal canal. Although the tumour filled the spinal canal almost entirely, the patient did not manifest any neurological deficits. During the surgery, the tumour was removed completely. A histological examination confirmed a benign schwannoma lesion (WHO G1). The question whether doctors are keen to order more diagnostic investigations (including both laboratory and imaging studies) than are necessary is often asked in clinical practice. The cost factor is also important. Not every patient with back pain is referred for an MRI study in the absence of characteristic neurological signs. The case of our patient, however, speaks in favour of early referral for such diagnostic modalities. Appropriate imaging studies, even in patients presenting with no neurological deficits, may help detect pathologies than can lead to severe disability. A spinal canal tumour filling the spinal canal almost entirely and displacing the spinal cord could cause spinal cord damage at any time with all the dire consequences such as paraplegia and loss of the ability to walk.


Implant failure with spontaneous rapid exfoliation: case reports.
The predictability and success of endosseous dental implants has secured their place as a standard treatment modality. Nevertheless, a small number of implants will fail regardless of operator experience or clinically recognizable cause. This article presents two cases of early failure of two-stage dental implants manifesting in a spontaneous and rapid exfoliation. Two healthy adult male patients received single-tooth, machined titanium implant fixtures during uncomplicated stage-one surgical procedures. After an uneventful early postoperative healing phase, both patients returned during the 4 to 6 week time period with failing implants. Clinical examination in both cases revealed the exfoliation of a fixture from the edentulous area with varying signs of soft tissue reaction in each instance. Radiographs revealed osteotomy sites along with the coronally migrating fixtures, with one of the exfoliated implants accompanied by apparent perifixtural radiolucency. In both cases, the implant fixtures were removed digitally without anesthesia. Subsequent medical follow-up was noncontributory, and ultimate healing was uneventful in both cases. Two separate attempts in the mandibular right second premolar region of one patient ended in similar failures despite the successful osseointegration of an identical fixture on the contralateral side. Few cases of early exfoliation of dental implants have been reported in the literature. Although the exact etiology of the early fixture loss in these two patients is unclear, the description of these cases can add to the published knowledge of dental implant failures and potentially lead to the uncovering and prevention of their causative mechanisms.


A review of the efficacy of tooth bleaching.
Current tooth lightening systems use hydrogen peroxide or carbamide peroxide which releases hydrogen peroxide as the bleaching agent. In vitro and in vivo studies, mostly comparing different bleaching systems, have demonstrated the efficacy of vital and non-vital tooth bleaching. Bleaching treatments are affected by a number of factors including the actual cause of tooth discoloration. All in-surgery bleaching agents are chemically activated and, whilst better results are possible with lights, these are not essential. Shade change can be evaluated subjectively and may be observed after only a few nights with Night Guard Vital Bleaching (NGVB). Objective methods of shade evaluation are used in most randomized controlled trials. There are a number of methods used to bleach teeth but NGVB using 10% carbamide peroxide in trays produces the optimal result with the least side-effects. The'inside/outside' bleaching technique using 10% carbamide peroxide is the most effective and safest method of bleaching non-vital teeth. Although more than 90% success has been reported, regression of the colour change is a common problem in vital and non-vital tooth bleaching and retreatment is necessary in many cases, usually after 1-3 years. The overwhelming evidence indicates that tooth bleaching is effective if supervised by a dentist. The clinician should be able to inform patients that both vital and non-vital tray bleaching using 10% carbamide peroxide can produce excellent results when supervised. However, shade regression is likely in 1-3 years.


Dalitz analysis of D0-->K(0)(S)pi(+)pi(-).
In e(+)e(-) collisions using the CLEO detector, we have studied the decay of the D0 to the final state K(0)(S)pi(+)pi(-) with the initial flavor of the D0 tagged by the decay D(*+)-->D0pi(+). We use the Dalitz technique to measure the resonant substructure in this final state and clearly observe ten different contributions by fitting for their amplitudes and relative phases. We observe a K(*)(892)(+)pi(-) component which arises from doubly Cabibbo suppressed decays or D0-D0; mixing.


Clinical profiles predictive of outcome in pontine hemorrhage.
We reviewed predictive factors of poor outcome in pontine hemorrhage in 38 patients admitted to the neurological-neurosurgical intensive care unit. Twenty-one patients died within days of admission (55%). Nine patients were severely or moderately disabled and dependent on others for daily care (24%). Eight patients made a good recovery (21%). Death was significantly more common in patients with a history of hypertension, coma on admission, absent motor response, absent corneal reflex or oculocephalic responses. However, clinical and CT features observed only in patients who died were hyperthermia (core temperature > 39 degrees C), tachycardia (> 110 beat/min), CT evidence of extension into the midbrain and thalamus, and acute hydrocephalus on admission. Good recovery only occurred in patients who were alert on admission and had small unilateral pontine hemorrhages. These clinical profiles should be useful in determining the level of care and future resuscitative efforts.


Bayesian statistical modeling of disinfection byproduct (DBP) bromine incorporation in the ICR database.
Statistical models are developed for bromine incorporation in the trihalomethane (THM), trihaloacetic acids (THAA), dihaloacetic acid (DHAA), and dihaloacetonitrile (DHAN) subclasses of disinfection byproducts (DBPs) using distribution system samples from plants applying only free chlorine as a primary or residual disinfectant in the Information Collection Rule (ICR) database. The objective of this study is to characterize the effect of water quality conditions before, during, and post-treatment on distribution system bromine incorporation into DBP mixtures. Bayesian Markov Chain Monte Carlo (MCMC) methods are used to model individual DBP concentrations and estimate the coefficients of the linear models used to predict the bromine incorporation fraction for distribution system DBP mixtures in each of the four priority DBP classes. The bromine incorporation models achieve good agreement with the data. The most important predictors of bromine incorporation fraction across DBP classes are alkalinity, specific UV absorption (SUVA), and the bromide to total organic carbon ratio (Br:TOC) at the first point of chlorine addition. Free chlorine residual in the distribution system, distribution system residence time, distribution system pH, turbidity, and temperature only slightly influence bromine incorporation. The bromide to applied chlorine (Br:Cl) ratio is not a significant predictor of the bromine incorporation fraction (BIF) in any of the four classes studied. These results indicate that removal of natural organic matter and the location of chlorine addition are important treatment decisions that have substantial implications for bromine incorporation into disinfection byproduct in drinking waters.


A cerium oxide-based nanomedicine for pH-triggered chemodynamic/chemo combination therapy.
Chemodynamic therapy (CDT) is a kind of novel cancer treatment with minimal side effects. As the therapeutic efficacy of a single CDT is usually not satisfactory, combining other therapeutic modalities with CDT is commonly used to improve the therapeutic efficacy. However, such kinds of combination therapeutic systems may suffer from the issue of side effects. Herein, we report a pH-triggered chemodynamic/chemo combination therapeutic nanomedicine based on CeO2-MnO2 nanorods (CMNRs). Such a nanomedicine (DOX@PCMNR-RGD) is prepared by coating RGD-conjugated charge-reversal polymers onto the surface of CeO2-MnO2 nanoparticles, followed by loading doxorubicin (DOX) onto it. Under mild acidic conditions, the surface charge of nanomedicine may change from negative to positive because of the charge-reversal polymer, making it easy to be internalized into cells. In addition, the tumor overexpressed hydrogen peroxide (H2O2) can be selectively catalyzed into highly toxic hydroxyl radicals (˙OH) under acidic conditions by DOX@PCMNR-RGD, showing CDT activity. Meanwhile, the acidic condition can trigger the release of DOX, showing chemotherapeutic activity. Thus, our study provides a pH-triggered chemodynamic/chemo combination therapeutic nanoplatform with minimal side effects.


Upstreaming palliative care for patients with heart failure.
Upstreaming palliative care, practicing and advocating for palliative care earlier in the heart failure (HF) trajectory, is an idea whose time has come. In this article, we explore the meaning of palliative care for HF and then discuss its relationships with both chronic care and end-of-life care. A case study is used to envision the practical implementation of palliative care into existing systems of care. We conclude by discussing the clinician's role in implementing palliative care earlier for individuals with HF by practice and advocacy.


Late nail lesions rejection in a stable bilateral forearm allograft at 60 months posttransplantation.
We present a case of late nail lesions rejection in a stable and compliant bilateral forearm allograft at 60 months posttransplantation, confirming that rejection features in vascularized composite tissue allotransplantation are more heterogeneous with multiple clinical implications, despite apparently appropriate immunosuppressive treatment. Our observations may help to better characterize and to fully understand the onset and dynamics of skin rejection after human hand allotransplantation; nevertheless, further investigations are required, and careful monitoring of the grafts by direct inspection is advisable in all patients to start rapidly appropriate and effective treatment.


First tracking of the oceanic spawning migrations of Australasian short-finned eels (Anguilla australis).
Anguillid eel populations have declined dramatically over the last 50 years in many regions of the world, and numerous species are now under threat. A critical life-history phase is migration from freshwater to distant oceans, culminating in a single life-time spawning event. For many anguillids, especially those in the southern hemisphere, mystery still shrouds their oceanic spawning migrations. We investigated the oceanic spawning migrations of the Australasian short-finned eel (Anguilla australis) using pop-up satellite archival tags. Eels were collected from river estuaries (38° S, 142° E) in south-eastern temperate Australia. In 2019, 16 eels were tracked for up to about 5 months, ~ 2620 km from release, and as far north as the tropical Coral Sea (22° S, 155° E) off the north-east coast of Australia. Eels from southern Australia appeared to access deep water off the Australian coast via two main routes: (i) directly east via Bass Strait, or (ii) south-east around Tasmania, which is the shortest route to deep water. Tagged eels exhibited strong diel vertical migrations, alternating between the warm euphotic zone (~ 100-300 m, 15-20 °C) at night and the mesopelagic zone (~ 700-900 m, 6-8 °C) during the day. Marine predators, probably lamnid sharks, tuna, or marine mammals, ended many eel migrations (at least ~ 30%), largely before the eels had left the Australian continental shelf. The long and risky marine migrations of Australasian eels highlight the need for better information on the processes contributing to eel mortality throughout the life cycle, including the impacts of future changes to oceanic currents, predator abundance and direct anthropogenic disturbances.


Control of the proportion of inner cells by asymmetric divisions and the ensuing resilience of cloned rabbit embryos.
Mammalian embryo cloning by nuclear transfer has a low success rate. This is hypothesized to correlate with a high variability of early developmental steps that segregate outer cells, which are fated to extra-embryonic tissues, from inner cells, which give rise to the embryo proper. Exploring the cell lineage of wild-type embryos and clones, imaged in toto until hatching, highlights the respective contributions of cell proliferation, death and asymmetric divisions to phenotypic variability. Preferential cell death of inner cells in clones, probably pertaining to the epigenetic plasticity of the transferred nucleus, is identified as a major difference with effects on the proportion of inner cell. In wild type and clones, similar patterns of outer cell asymmetric divisions are shown to be essential to the robust proportion of inner cells observed in wild type. Asymmetric inner cell division, which is not described in mice, is identified as a regulator of the proportion of inner cells and likely gives rise to resilient clones.


Validity and Reliability of the Persian Version of Baecke Habitual Physical Activity Questionnaire in Healthy Subjects.
Baecke Habitual Physical Activity Questionnaire (BHPAQ) has widely been employed in clinical and laboratorial studies as a tool for measuring subjects' physical activities. But, the reliability and validity of this questionnaire have not been investigated among Persian speakers. Therefore, the aim of the current study was examining the reliability and validity of the Persian version of the BHPAQ in healthy Persian adults. After following the process of forward-backward translation, 32 subjects were invited to fill out the Persian version of the questionnaire in two independent sessions (3 - 7 days after the first session) in order to determine the reliability index. Also, the validity of the questionnaire was assessed through concurrent validity by 126 subjects (66 males and 60 females) answering both the Baecke and the International Physical Activity Questionnaire (IPAQ). An acceptable level of intraclass correlation coefficient (ICC of work score = 0.95, sport score = 0.93, and leisure score = 0.77) was achieved for the Persian Baecke questionnaire. Correlations between Persian Baecke and IPAQ with and without the score for sitting position were found to be 0.19 and 0.36, respectively. The Persian version of the BHPAQ is a reliable and valid instrument that can be used to measure the level of habitual functional activities in Persian-speaking subjects.


Temporary bypass for superior vena cava reconstruction with Anthron bypass tubeTM.
Total superior vena cava (SVC) clamping for SVC replacement or repair can be used in thoracic surgery. A bypass technique is an option to avoid hemodynamic instability and cerebral venous hypertension and hypoperfusion. The present report describes a venous bypass technique using Anthron bypass tubeTM for total SVC clamping. Indications for this procedure include the need for a temporary bypass between the brachiocephalic vein and atrium for complete tumor resection. This procedure allows the surgeons sufficient time to complete replacement of SVC or partial resection of SVC without adverse effects. Further, it is a relatively simple procedure requiring minimal time.


The Improving Global Health Programme - leadership development in the NHS through overseas placement.
The Improving Global Health (IGH) programme develops leadership capacity within the National Health Service (NHS) in a novel way. NHS employees collaboratively run quality improvement projects within organisations in low-income and middle-income countries with whom long-standing healthcare partnerships have been built. Leadership behaviours are developed through theoretical and experiential learning, alongside induction and mentorship. The health systems of overseas partners are strengthened through projects that align with local priorities. This article develops solutions to two main problems: how reciprocal global health programmes can be designed and how global health programmes based in leadership can attract women and black and minority ethnic groups into leadership. The outcomes of both sides of the IGH programme are described here. The overseas perspective is described using the reflections of two current partners, highlighting improvements in the local healthcare system and demonstrating growth in local team members. The UK perspective is evaluated using two surveys sent to different groups of returned IGH participants. Leadership, global health and quality improvement skills improve, having a significant and long-lasting impact on career trajectory. The IGH programme is attracting women and black and minority ethnic groups into leadership. Through collaboration and reciprocity, the IGH programme is developing a new cadre of NHS leader that is diverse and inclusive. The use of long-standing healthcare partnerships ensures that learning is shared and growth is mutual, creating development within the overseas and UK partner alike.


Nausea threshold in apparently healthy individuals who drink fluids containing graded concentrations of copper.
Ingestion of drinking water with a high copper content may induce acute gastrointestinal effects, mainly nausea and vomiting, rarely diarrhea and abdominal pain. The objectives of this study were to define nausea threshold in apparently healthy adult volunteers who received graded concentrations of copper and to explore how individual thresholds were modified by delivering copper in an orange-flavored drink. Sixty-one healthy subjects received 200 mL of a copper-containing solution in purified water, at concentrations 0, 2, 4, 6, 8, 10, and 12 mg/L, as copper sulfate, in random order. Nausea threshold concentration for first response was established and then this threshold was confirmed. Subsequently, following the same design, subjects received the same copper concentrations (up to 12 mg/L), delivered in an orange-flavored drink, starting at the confirmed threshold concentration found in water. Mild nausea shortly after ingestion of copper-containing water was the most frequent finding (33/61 subjects), starting at 4 mg/L; vomiting was observed in 7 individuals, starting at 6 mg/L. The NOEL for copper in purified water was 2 and 4 mg/L for nausea and vomiting, respectively. When copper was provided as an orange-flavored drink, 11 subjects (18%) reported nausea, starting at 8 mg Cu/L, and no subjects vomited up to 12 mg Cu/L. It is concluded that after consumption of copper in purified water, the NOEL is 2 mg Cu/L and the LOAEL 4 mg Cu/L for nausea, while tolerable intake is between 2 and 4 mg Cu/L in water depending on whether apparent or confirmed nausea is used as the criterion to define critical effects.


Diet choice in weight-restored patients with eating disorders; progressive autonomy process by nutritional education.
Human eating behaviour is regulated by multiple factors. Anorexia nervosa patients show a restrictive eating pattern while bulimia nervosa patients present bingeing-purging episodes. Although treatments are specially successful in the normalization of body composition, maladaptive eating behaviours tend to persist being a risk factor for relapse and recurrence. The aim of this work was to assess the quality of the nutritional choice of eating disorders patients after a year of nutritional education and to assess improvements in choice capacity. Thirty-one outpatients of an eating disorders unit planned a menu after body composition normalization and repeated this plan each three months during a one-year programme of nutritional education. Patients improved the time spent on the assignment (p < 0.01), Body Mass Index (p < 0.01), their body fat mass (p < 0.01) and the content of energy (p < 0.05), carbohydrates (p < 0.01) and polyunsaturated fatty acids (p < 0.05) in their chosen menus. No differences were found on proteins, total fat or fat profile, vitamins or minerals. 12.9% and 3.2% of the patients chose their menu according to the recommendations of caloric and lipid profile, respectively, after a year of nutritional education. Although patients improved energy and carbohydrates content of the menus they tended to reduce caloric and fat food choices, which could lead to relapse and recurrence. Specific nutritional education programmes along with the mandatory psychological and psychiatric treatment may be effective. One year of nutritional education combined with psychological and psychiatric treatment improved those factors usually involved in relapse and recurrence, thus contributing to a proper outcome.


Inhibition of protein palmitoylation, raft localization, and T cell signaling by 2-bromopalmitate and polyunsaturated fatty acids.
The ability of the Src family kinases Fyn and Lck to participate in signaling through the T cell receptor is critically dependent on their dual fatty acylation with myristate and palmitate. Here we identify a palmitate analog, 2-bromopalmitate, that effectively blocks Fyn fatty acylation in general and palmitoylation in particular. Treatment of COS-1 cells with 2-bromopalmitate blocked myristoylation and palmitoylation of Fyn and inhibited membrane binding and localization of Fyn to detergent-resistant membranes (DRMs). In Jurkat T cells, 2-bromopalmitate blocked localization of the endogenous palmitoylated proteins Fyn, Lck, and LAT to DRMs. This resulted in impaired signaling through the T cell receptor as evidenced by reductions in tyrosine phosphorylation, calcium release, and activation of mitogen-activated protein kinase. We also examined the ability of long chain polyunsaturated fatty acids (PUFAs) to inhibit protein fatty acylation. PUFAs have been reported to inhibit T cell signaling by excluding Src family kinases from DRMs. Here we show that the PUFAs arachidonic acid and eicosapentaenoic acid inhibit Fyn palmitoylation and consequently block Fyn localization to DRMs. We propose that inhibition of protein palmitoylation represents a novel mechanism by which PUFAs exert their immunosuppressive effects.


Serum bone gamma carboxyglutamic acid-containing protein in primary hyperparathyroidism and in malignant hypercalcemia. Comparison with bone histomorphometry.
Serum bone gamma-carboxyglutamic acid-containing (Gla) protein (sBGP), a sensitive and specific marker of bone turnover, was measured in 25 patients with primary hyperparathyroidism and in 24 patients with bone metastases with or without hypercalcemia. Despite similar levels of hypercalcemia, sBGP was increased in primary hyperparathyroidism (14.2 +/- 9.6 ng/ml, P less than 0.001), was decreased in malignant hypercalcemia (3.1 +/- 2.8 ng/ml, P less than 0.001), and was normal in patients with bone metastases without hypercalcemia (6.6 +/- 2.7 ng/ml). In primary hyperparathyroidism, sBGP was correlated with serum immuno-reactive parathyroid hormone (r = 0.90), calcium (r = 0.73), and with the adenoma weight (r = 0.79). After parathyroidectomy, sBGP slowly returned to normal values within 2-6 mo, suggesting that sBGP reflects increased bone turnover rather than a direct effect of parathyroid hormone on BGP synthesis at the cell level. An iliac crest biopsy was performed in 11 patients with primary hyperparathyroidism and in 9 cancer patients in a noninvaded area. sBGP was significantly correlated with all parameters reflecting bone formation but not with bone resorption. Patients with bone metastases were analyzed according to the presence or the absence of hypercalcemia. In contrast to normocalcemic patients who had normal sBGP, hypercalcemic patients had decreased sBGP (P less than 0.001) and a lower bone formation at the cellular level (P less than 0.05). Thus, biochemical and histological data suggest that an unknown humoral factor might be responsible for this uncoupling between increased resorption and decreased formation. This uncoupling, rather than local release of calcium by the metastatic process, might be responsible for hypercalcemia in patients with bone metastases.


Medical informatics in the medical curriculum--when?
Undergraduate teaching of medical informatics (MI) at the Medical School University of Zagreb has been changing its position in the medical curriculum. Nowadays, this subject is positioned in the second year of the medical curriculum. The aim of this paper is to find out what the students of the second year (S2Y) and of the sixth year (S6Y) think about the position of MI in the medical curriculum. The results of students' opinions have shown that MI should be positioned: in the last two years (63% of S2Y, 36% of S6Y), in the middle (11% of S2Y, 21% of S6Y), and at the beginning of the medical curriculum (26% of S2Y, 43% of S6Y). However, analysing this question according to previous experience of the students of both groups, it can be concluded that: the S6Y with more previous experience shift the subject towards the end of the medical curriculum, and the S2Y with more previous experience shift the subject towards the beginning of the medical curriculum. According to our long-term experience and students' opinion, the most relevant MI subjects, any kind of medical application, should necessarily come at the end of the medical curriculum.


Evaluation and Comparison of Citalopram and Venlafaxine for Management of Hot Flashes in Women with Breast Cancer.
Breast cancer is the most common cancer in women worldwide. Premature menopause and hot flashes are the main complications of breast cancer treatments. About 40 to 50 percent of breast cancer women who undergo chemotherapy are experiencing premature menopause symptoms, including hot flashes. Some endocrine therapies such as tamoxifen and aromatase inhibitors are associated with induction or aggravating hot flashes. Hot flashes are often debilitating and significantly impair daily functions. Therefore many therapeutic options have been studied so far for the management of this adverse effect. However, there are still some clinical challenges in managing hot flashes in patients with breast cancer. We aimed to evaluate and compare the efficacy of venlafaxine and citalopram on hot flashes in breast cancer women receiving tamoxifen. We conducted a double-blind, placebo-controlled trial in forty-one, 35 to 65 years old female patients. The study lasted for four weeks, and the follow-up was for two months. Venlafaxine and citalopram treatments started with doses of 37.5 mg or 10 mg, respectively. Venlafaxine and citalopram dosages were increased in the second week to 75 and 20 mg, respectively. The study was conducted during the year 2017. The results indicated that the total efficacy was significantly different in groups receiving citalopram, venlafaxine, and placebo. Total efficacy in the placebo group, venlafaxine, and citalopram was 14.3, 53.8, and 64.3%, respectively (p=0.02). During the second week, the efficacy in groups receiving citalopram, venlafaxine, and placebo was 57.1, 53.8, and 14.3%, respectively (p=0.04). Generally, both citalopram and venlafaxine were well tolerated. The associated adverse effects were mild to moderate in both groups. Although citalopram was associated with more adverse effects, including constipation, it was more effective in reducing the frequency of hot flashes when compared to venlafaxine or placebo.


Qualitative assessment of von Willebrand factor (vWF) in cirrhotics following repeated doses of desmopressin acetate.
Qualitative abnormalities in von Willebrand Factor (vWF) in patients with cirrhosis have been little studied with contrasting results. We used crossed immunoelectrophoresis (2-DIE) and multimeric analysis of vWF in eight patients with stable hepatic cirrhosis to evaluate abnormalities in vWF before and 1 h following intravenous administration of three doses of desmopressin acetate (0.3 micrograms/kg) given at baseline, 4 and 24 h. We thought that qualitative abnormalities might be more easily detected following desmopressin as this is known to release vWF from storage sites. There was an increased electrophoretic mobility on 2-DIE in all patients with no change following desmopressin. The multimeric analysis did not show an increase in lower molecular weight multimers, but showed a statistically significant increase in higher molecular weight multimers following desmopressin (P less than 0.02). These results suggest that the vWF of cirrhotics has an abnormal charge (not altered by release following desmopressin) which would explain the increased electrophoretic mobility on 2-DIE with a normal pattern of lower molecular weight multimers using multimeric analysis.


Dosing of renal replacement therapy in acute kidney injury: lessons learned from clinical trials.
Prescribing dialysis to manage acute kidney injury (AKI) is common and recently has become a controversial area for physicians. The concept of dialysis "dose" initially was developed for end-stage renal disease and has been extended to AKI in the last decade. Urea kinetic modeling has been the mainstay of dose quantification in end-stage renal disease. Extrapolation of these techniques to critically ill patients with AKI is difficult because of a non-steady state leading to a variable increase in urea generation rate, alterations in total-body water and its compartmental distribution, and changing renal excretory capacity. Additional challenges are imposed when dose is considered for different modalities of dialysis that vary in operational characteristics (diffusion, convection, and adsorption), duration (intermittent and continuous), and frequency. The purpose of this article is to review the concept of dialysis dose, perform a critical assessment of the most important clinical trials of dialysis dose in AKI, summarize clinical evidence from these trials, and define key research issues that should be addressed in the future.


Histopathologic features of genetically determined ovarian cancer.
Inheritance of germline mutations of BRCA1 or BRCA2 genes account for approximately 10% of ovarian carcinomas, but the characterization of these genetically determined cancers is incomplete. The objective of our study was to characterize the histologic features of ovarian carcinomas associated with germline mutations of BRCA1 and BRCA2. Thirty-two ovarian carcinomas associated with germline BRCA1 or BRCA2 mutations and 40 ovarian carcinomas from patients screened as negative for germline mutations were obtained from three centers. A gynecologic pathologist, blinded to mutation status, reviewed each case, with documentation of the histologic type, Gynecologic Oncology Group (GOG) grade, architectural and nuclear grade, Silverberg grade, and mitotic activity. All BRCA1 and BRCA2 mutation-associated cases were invasive serous carcinomas, and of these 50% were GOG grade 3, 41% had an architectural grade of 3 (predominant solid architecture), 84% a nuclear grade of 3, 72% a mitotic score of 3 (>25 mitoses per 10 HPF), and 75% a Silverberg grade of 3. The differences in histologic type (p = 0.001) and Silverberg grade (p = 0.002) between these tumors and the control group were statistically significant and remained so when comparisons between BRCA carriers and noncarriers were restricted to carcinomas of serous histology alone. Ovarian carcinomas associated with germline mutations of BRCA1/BRCA2 are, in this study, invasive serous carcinomas, with a statistically significant higher histologic grade than ovarian carcinomas without BRCA mutations when using the recently proposed Silverberg grading system.


Genetic erosion and population resilience in Daphnia longispina O.F. Müller under simulated predation and metal pressures.
This study investigated the effects of nonselective predation (culling) and metal toxicity on the genetic diversity of laboratory populations of the cladoceran Daphnia longispina. Populations, comprising five clones differing in their sensitivity to lethal concentrations of a metal-rich mine drainage effluent, were subjected to all possible combinations of three levels (absent, weak, and strong) of each stressor. Observed population densities were compared to those expected from a life history experiment, and clone frequencies were determined by allozyme profiling. Culling did not affect population density, although clonal diversity was higher than the control. Populations stressed by mine drainage recovered to their initial densities within 12 days, though the most sensitive genotypes disappeared under both weak and strong metal stress levels. Because the surviving resistant clones were shown to be the most sensitive ones to other chemicals (Cd and H+), it is suggested that successive inputs of partially lethal concentrations of different chemicals can lead to the disappearance of the population, even if the time between inputs is large enough to allow density recovery. These results suggest that changes in abundance are not enough to evaluate ecological effects of chemicals on the environment and information on co-tolerance and multiple tolerance within populations is highly valuable to prevent their extinction. Moreover, populations exposed to low levels of both stressors showed clonal diversity levels identical to controls, highlighting the importance of low level effects of nonselective stressors in the maintenance of high clonal diversity levels in Daphnia populations, and thus further supporting the intermediate disturbance hypothesis.


Unexpected Ground-Glass Opacities on Abdominopelvic CT of a Patient With a Negative SARS-CoV-2 Antigen Test Result and No Respiratory Symptoms Upon Admission.
One of the biggest challenges during the coronavirus disease 2019 (COVID-19) pandemic continues to be the detection of asymptomatic and presymptomatic persons infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Persons infected with SARS-CoV-2 who do not have symptoms of COVID-19 may transmit the virus to others and may have subclinical lung abnormalities. Some hospitals use SARS-CoV-2 antigen tests for pre-admission screening testing because they are relatively inexpensive, have a rapid turnaround time, and can be performed at the point of care; however, antigen tests are generally less sensitive than nucleic acid amplification tests with reverse transcription polymerase chain reaction (RT-PCR) assay. Moreover, as the local COVID-19 prevalence increases, the negative predictive value of antigen tests may decrease, meaning that the probability of having false-negative results may increase. We present a case of a patient who, prior to admission for a surgical procedure, had a negative antigen test result for SARS-CoV-2, had no respiratory symptoms, and had no suspected or known exposure to SARS-CoV-2; however, she tested positive for SARS-CoV-2 RNA after admission. The only factor that led the healthcare team to suspect SARS-CoV-2 infection was an unexpected finding of bilateral ground-glass opacities on an abdominopelvic computed tomography (CT), which was performed to assess the extent of a perianal abscess the patient presented. This case highlights the importance of using highly sensitive SARS-CoV-2 tests for pre-admission screening testing in the hospital setting.


Nanocarbons for Catalytic Desulfurization.
Nanocarbon catalysts are green and sustainable alternatives to metal-based catalysts for numerous catalytic transformations. The application of nanocarbons for environmental catalysis is an emerging research discipline and has undergone rapid development in recent years. In this focus review, we provide a critical analysis of state-of-the-art nanocarbon catalysts for three different catalytic desulfurization processes. In particular, we focus on the advantages and limitations as well as the reaction mechanisms of the nanocarbon catalysts at the molecular level.


Pneumococcal Conjugate Vaccine and Pneumonia Prevention in Children with Congenital Heart Disease.
A successful strategy to prevent Streptococcus pneumoniae infections is the administration of pneumococcal conjugate vaccines (PCVs). To analyze the effectiveness of the 7- and 13-valent PCV for the prevention of all-cause pneumonia. A retrospective cohort of children younger than 5 years of age, with congenital heart disease (CHD) and different vaccination schedules, was analyzed. History of vaccination was confirmed with verifiable records. The outcome measure was all-cause pneumonia or bronchopneumonia. Protocol was approved by the Institutional Review Board. For comparisons, we used inferential statistics with Chi-square and Fisher's exact test; a p ≤ 0.5 was considered statistically significant. Relative and absolute risks reduction and number needed to treat were also calculated. A total of 348 patients were included: 196 with two or more doses of PCV (considered the vaccinated group), and 152 in the unvaccinated group. There was a statistically significant difference for pneumonia events (p < 0.001) between the vaccinated (26/196) and unvaccinated (51/152) groups. The relative risk reduction was 60.5%, and the absolute risk reduction, 20.3%. There were no differences between patients who received two, three or four doses. The number needed to vaccinate to prevent one event of pneumonia was 5 children. At least two doses of PCV in children with CHD reduced the risk of all-cause pneumonia.


Structure of Lisch nodules in neurofibromatosis type 1.
Postmortem examination of the eyes of a patient with neurofibromatosis Type I was performed by light and electronmicroscopy. Lisch nodules were examined and found to consist of a condensation of spindle cells on the anterior iris surface. When nodules were pigmented an underlying stromal naevus was present. Lisch nodules are confirmed as being of melanocytic origin.


A multi-omic analysis of the dorsal striatum in an animal model of divergent genetic risk for alcohol use disorder.
The development of selectively bred high and low alcohol-preferring mice (HAP and LAP, respectively) has allowed for an assessment of the polygenetic risk for pathological alcohol consumption and phenotypes associated with alcohol use disorder (AUD). Accumulating evidence indicates that the dorsal striatum (DS) is a central node in the neurocircuitry underlying addictive processes. Therefore, knowledge of differential gene, protein, and phosphorylated protein expression in the DS of HAP and LAP mice may foster new insights into how aberrant DS functioning may contribute to AUD-related phenotypes. To begin to elucidate these basal differences, a complementary and integrated analysis of DS tissue from alcohol-naïve male and female HAP and LAP mice was performed using RNA sequencing, quantitative proteomics, and phosphoproteomics. These datasets were subjected to a thorough analysis of gene ontology, pathway enrichment, and hub gene assessment. Analyses identified 2,108, 390, and 521 significant differentially expressed genes, proteins, and phosphopeptides, respectively between the two lines. Network analyses revealed an enrichment in the differential expression of genes, proteins, and phosphorylated proteins connected to cellular organization, cytoskeletal protein binding, and pathways involved in synaptic transmission and functioning. These findings suggest that the selective breeding to generate HAP and LAP mice may lead to a rearrangement of synaptic architecture which could alter DS neurotransmission and plasticity differentially between mouse lines. These rich datasets will serve as an excellent resource to inform future studies on how inherited differences in gene, protein, and phosphorylated protein expression contribute to AUD-related phenotypes.


Long term sequelae of sex steroid treatment in the management of constitutionally tall stature.
To evaluate possible long term side effects of high doses of sex steroids in the management of constitutionally tall stature, with special attention to hypothalamic-gonadal function. Sixty four tall adult men and 180 tall adult women, who received supraphysiological doses of sex hormones during puberty, were interviewed in a standardised way at a mean follow up period of 10 years after cessation of treatment. Sixty one untreated tall adult men and 94 untreated tall adult women served as controls. The majority of the subjects were satisfied with their decision regarding hormone treatment. Seventy seven per cent of the women and 78% of the men reported one or more side effects during treatment. Most side effects were mild. In women, only 3% stopped treatment because of an adverse event; in men, the reported side effects never stopped treatment. The frequency of reported side effects in women was higher during treatment with high doses of oestrogens than during oral contraceptive use, indicating a dose dependent relationship. Amenorrhoea of longer than six months after cessation of therapy was found in 5%. Menstrual cycle characteristics of previously treated women were comparable with controls. Malignancy was not reported. Information about a total of 127 pregnancies was obtained and revealed no distinct differences in details and outcome between previously treated women and men, and controls. At a mean follow up of 10 years there is no evidence that pharmacological doses of sex hormones have a long term effect on reproductive function. However, this period is still too short to draw definite conclusions.


Results of the National Breast Cancer Screening Program in Croatia (2006-2016).
To assess the uptake of the Croatian National Breast Cancer Screening Program from 2006 to 2016. The Croatian National Breast Cancer Screening Program, a biennial program targeting women aged 50-69, started in October 2006. From 2006 to 2016, four cycles were completed. One cycle lasted two years, with the exception of the first cycle, which lasted three years. To determine the number of detected cancers in each cycle, the screening program data were merged with the data of the Croatian National Cancer Registry. Our results were compared with the reference values from the European guidelines for quality assurance in breast cancer screening and diagnosis. Around 150 000 mammography exams were performed every year. The response rates for cycle 1, cycle 2, cycle 3, and cycle 4 were 63%, 57%, 60%, and 59%, respectively. Further assessment rate was 6.5%. Breast cancer was identified in 5583 women, with 4.8 cancers detected per 1000 mammography exams. The National Breast Cancer Screening Program in Croatia reached a substantial proportion of the target group. Yet, additional efforts are needed to reach at least 70% of the target population.


Critical role of Brg1 member of the SWI/SNF chromatin remodeling complex during neurogenesis and neural crest induction in zebrafish.
Brg1 is a member of the SWI/SNF chromatin-remodeling complex, and in some organisms Brg1 has been shown to interact with beta-catenin and positively control the TCF/LEF transcription factor that is located downstream of the Wnt signal transduction pathway. During development, TCF/LEF activity is critical during neurogenesis and head induction. In zebrafish, Brg1-deficient embryos exhibit retinal cell differentiation and eye defects; however, the role of Brg1 in neurogenesis and neural crest cell induction remains elusive. We used zebrafish deficient in Brg1 (yng) or Brg1 specific-morpholino oligonucleotide-mediated knockdown to analyze the embryonic requirements of Brg1. Our results indicate that reduction in Brg1 expression leads to the expansion of the forebrain-specific transcription factor, six3, and marked reduction in expression of the mid/hind-brain boundary and hind-brain genes, engrailed2 and krox20, respectively. At 12 hpf, the expression of neural crest specifiers are severely affected in Brg1-morpholino-injected embryos. These results suggest that Brg1 is involved in neural crest induction, which is critical for the development of neurons, glia, pigment cells, and craniofacial structures. Brg1 is a maternal factor, and brg1-deficient embryos bearing the yng mutation derived from heterozygote intercrosses exhibit lesser effects on neural crest-specific gene expression, but show defects in neurogenesis and neural crest cell differentiation. This is exhibited by the aberrant brain patterning, a reduction in the sensory neurons, and craniofacial defects. These results further elucidate the critical role for Brg1 in neurogenesis, neural crest induction, and differentiation.


Genetic variability of hepatitis C virus in South Egypt and its possible clinical implication.
Egypt is one of the countries with very high rates of hepatitis C virus (HCV) related morbidity and mortality. However, little is known about geographical and clinical differences in genetic variability of HCV in Egypt. Using direct sequencing and phylogenetic analysis of partial core/E1 and NS5B regions of the HCV genome, HCV genotype/subtype was determined in 129 HCV-infected patients residing in three governates in south Egypt: Assuit, Sohag, and Qena. According to clinical stage of infection, patients were categorized into four groups: asymptomatic carriers, n = 16; chronic hepatitis C patients, n = 36; liver cirrhosis, n = 54; and hepatocellular carcinoma (HCC), n = 23. Genotype 4a was detected in 80.6%, whereas 1g, 4l, 4n, 4o, 4f, and 4m were identified in 7.7%, 4.7%, 3.9%, 1.6%, 0.8%, and 0.8% of cases, respectively. The prevalence of 4a differed regionally; from 88.5% (in Sohag) to 64% (in Assuit, P = 0.002). Genotypes 4l and 4n had a higher prevalence in Assuit (12.8%, 10.3%) than Sohag (0%, 0%; P < or = 0.011). Difference in clinical features of determined genotypes/subtypes was observed; more carriers of non-4a variants (4l and 4n, 4f, or 4m) had chronic hepatitis compared to carriers of 4a (53.3% vs. 23.1%, P = 0.025), while more patients with 4a had liver cirrhosis (45.2% vs. 13.3%, P = 0.023). Two HCV-4o strains were isolated in this study, both from patients with HCC. In conclusion, geographical diversity of HCV was revealed in this study in southern Egypt. A further case-control study is required to confirm the trends of differential pathogenicity of HCV subtypes, indicated by this study.


Prospects and applications of enucleation in solid pseudopapillary neoplasms of the pancreas.
Solid pseudopapillary neoplasms (SPNs) of the pancreas are rare, low-grade, malignant neoplasms that are mostly seen in young women in the second and third decades of life and are quite uncommon in children. Standard resection for benign and borderline neoplasms of the pancreas is associated with a substantial risk of postoperative morbidity and long-term functional impairment, whereas enucleation leads to less morbidity and preserves healthy parenchyma as well as exocrine and endocrine function. Enucleation of SPNs has been increasingly reported to be feasible and safe for preserving the normal physiological function of the pancreas, especially in teenagers and children. This review summarizes findings published in recent years on the enucleation of SPNs as well as potential future developments and directions. Enucleation has undoubtedly come to stay as an alternative surgical procedure for SPNs. However, many questions remain unresolved, and future directions toward the best surgical indication, the prevention and intervention of complications, especially pancreatic fistula, intraoperative resection margin safety assessment, and long-term oncology prognosis remain to be evaluated and should be explored in future clinical trials.


[Use of thymodepressin for treating autoimmune cytopenia].
To study influence of thymodepressin on the course of autoimmune cytopenia. Thymodepressin is a new synthetic hemoregulatory dipeptide (gamma-D-Glu-D-Trp). It was used for the treatment of 22 patients with autoimmune cytopenia. Hemoglobin levels were elevated in autoimmune hemolytic anemia and platelet levels were high in idiopathic thrombocytopenic purpura. A thymodepressin course resulted in a fall of total lymphocyte count and activated CD3+CD69+ lymphocytes. The above results, safety, absence of toxicity and allergenicity, parenteral and intranasal useability open perspectives for further studies of therapeutic action of thymodepressin as an immunodepressant in autoimmune processes.


Lipase ligands in Nelumbo nucifera leaves and study of their binding mechanism.
Lotus (Nelumbo nucifera) leaves have been widely used in weight-loss foods to prevent obesity in China. In this work, a facile procedure based on ligand fishing was developed to isolate and identify lipase inhibitors present in lotus leaves. Highly stable and active lipase-Fe3O4 superparamagnetic nanoparticle conjugates (LMNPs) were prepared and used as baits. Two flavonoids in lotus leaf extract were found to bind to the baits and were identified as quercetin-3-O-β-d-arabinopyranosyl-(1→2)- β-d-galactopyranoside (1) and quercetin-3-O-β-d-glucuronide (4) based on electrospray ionization-mass spectrometric analyses. Their 50% inhibitory concentrations on lipase (IC50) were 52.9 ± 3.2 and 17.1 ± 1.5 μg/mL, respectively. In addition, they were found to significantly quench the fluorescence of lipase, suggesting their strong affinities with this enzyme, which was further evidenced by molecular docking. Ligand fishing based on LMNPs shows great power for fast screening and identification of lipase inhibitors present in edible and medicinal plants.


Enantio- and stereospecific syntheses of 15(R)-Me-PGD2, a potent and selective DP2-receptor agonist.
The first total synthesis of 15(R)-Me-PGD2 3 is reported. The synthesis is based on the enantioselective and stereospecific syntheses of synthon 17 and its attachment to the five-membered ring by a olefin cross metathesis reaction. This approach permits the introduction of a side chain with a predetermined stereogenic center into the prostanoid ring, resulting in the synthesis of 15R-methyl prostaglandin D2 and allows rapid access to other prostanoids.


Nail Psoriasis Treatment: Insights into Current Progress and Future Trends.
Nail psoriasis is a chronic condition which causes pain and functional impairment; thus, it restricts the activities of daily living and worsens the quality of life. Different chemotherapeutic options are available for treating nail psoriasis such as systemic, intralesional, and topical therapies. However, current chemotherapy suffers from several limitations and to overcome them, new advancements are being made worldwide. Various reports have been published on current progress in the treatment of nail psoriasis such as clinical efficacy studies of novel antipsoriatic agents and novel formulation strategies for current chemotherapy. There are several novel nail formulations for the treatment of nail disorders, particularly onychomycosis, such as vesicular colloidal structure (liposomes, niosomes, transfersomes, ethosomes, etc.) and nonvesicular colloidal structures (nano-emulgel, nanocapsules, thermosensitive gel, etc.) These formulations can also prove beneficial for the treatment of nail psoriasis, and will be heavily explored in the near future. This review provides a brief introduction to the disease, its pathogenesis, and its treatment modalities. The review also throws light onto progress and future perspectives in nail psoriasis treatment.


Quota sampling in internet research: practical issues.
Quota sampling has been suggested as a potentially good method for Internet-based research and has been used by several researchers working with Internet samples. However, very little is known about the issues or concerns in using a quota sampling method in Internet research. The purpose of this article was to present the practical issues using quota sampling in an Internet-based study. During the Internet study, the research team recorded all recruitment issues that arose and made written notes indicating the possible reasons for the problems. In addition, biweekly team discussions were conducted for which written records were kept. Overall, quota sampling was effective in ensuring that an adequate number of midlife women were recruited from the targeted ethnic groups. However, during the study process, we encountered the following practical issues using quota sampling: (1) difficulty reaching out to women in lower socioeconomic classes, (2) difficulty ensuring authenticity of participants' identities, (3) participants giving inconsistent answers for the screening questions versus the Internet survey questions, (4) potential problems with a question on socioeconomic status, (5) resentment toward the research project and/or researchers because of rejection, and (6) a longer time and more expense than anticipated.


Convenient and clean synthesis of imines from primary benzylamines.
The current syntheses of imines from benzylamines are often performed in organic solvents or under harsh reaction conditions. Clean oxidation of primary benzylamines to imines has been successfully achieved using H(2)O(2) in water at room temperature catalyzed by V(2)O(5). Among the 10 imine products, 5 of them precipitated from the reaction and led pure products after simple filtration. No organic solvents are needed in the whole process. The yields are good to quantitative. This represents an efficient and green procedure of the synthesis of imines. A similar green oxidation of benzylamines to aromatic aldehydes is also reported. A benzylic anion-involved mechanism is proposed based on the experiments.


Construction of multifunctional cuboctahedra via coordination-driven self-assembly.
We present a general strategy for the synthesis of stable, multifunctional cuboctahedral complexes in which coordination-driven self-assembly allows for precise control over positioning of either ferrocene or crown ether functionalities. The appropriate stoichiometric combination of functionalized 120 degree diplatinum acceptor units with tritopic donor units afforded supramolecular cuboctahedra with covalently linked functional groups. The compounds are characterized by multinuclear NMR spectroscopy, electrospray ionization mass spectrometry, and electrochemistry.


Moxibustion for treating pain: a systematic review.
The objective of this study was to assess the evidence for or against the effectiveness of moxibustion as a treatment option for pain. Fourteen electronic databases were searched. Randomized clinical trials (RCTs) testing moxibustion in human patients with pain of any type were considered. Trials using direct or indirect moxibustion were included. Studies comparing moxibustion with other treatments of unproven effectiveness, studies testing moxibustion together with other treatments of unproven efficacy and trials where pain was not a central symptom of the condition were all excluded. The selection of studies, data extraction, and validation were performed independently by two reviewers. Four RCTs met all the inclusion criteria. Others were of poor methodological quality. Two RCTs suggested significant pain reductions for indirect moxibustion in osteoarthritis as compared with drug therapy (n = 200, RR, 1.11; 95% CI of 1.02 to 1.21, p = 0.02, heterogeneity: chi2 = 1.03, p = 0.31, I2 = 3%). The other two RCTs suggested positive effects of indirect or direct moxibustion on pain in scleroma or herpes zoster compared to drug therapy, respectively. We conclude that few RCTs are available that test the effectiveness of moxibustion in the management of pain, and most of the existing trials have a high risk of bias. Therefore, more rigorous studies are required before the effectiveness of moxibustion for the treatment of pain can be determined.


Development and initial validation of the localized scleroderma skin damage index and physician global assessment of disease damage: a proof-of-concept study.
To develop and assess the psychometric properties of the Localized Scleroderma (LS) Skin Damage Index (LoSDI) and Physician Global Assessment of disease Damage (PGA-D). Damage was defined as irreversible/persistent changes (>6 months) due to previous active disease/complications of therapy. Eight rheumatologists assessed the importance of 17 variables in formulating the PGA-D/LoSDI. LS patients were evaluated by two rheumatologists using both tools to assess their psychometric properties. LoSDI was calculated by summing three scores for cutaneous features of damage [dermal atrophy (DAT), subcutaneous atrophy (SAT) and dyspigmentation (DP)] measured at 18 anatomic sites. Patient GA of disease severity (PtGA-S), Children's Dermatology Life Quality Index (CDLQI) and PGA-D were recorded at the time of each examination. Thirty LS patients (112 lesions) and nine patient-visit pairs (18 lesions) were included for inter- and intra-rater reliability study. LoSDI and its domains DAT, SAT, DP and PGA-D demonstrated excellent inter- and intra-rater reliability (reliability coefficients 0.86-0.99 and 0.74-0.96, respectively). LoSDI correlated moderately with PGA-D and poorly with PtGA-S and CDLQI. PGA-D correlated moderately with PtGA-S, but poorly with CDLQI. To complete the LS Cutaneous Assessment Tool (LoSCAT), we developed and evaluated the psychometric properties of the LoSDI and PGA-D in addition to the LS Skin Severity Index (LoSSI). These instruments will facilitate evaluation of LS patients for individual patient management and clinical trials. LoSDI and PGA-D demonstrated excellent reliability and high validity. LoSCAT provides an improved understanding of LS natural history. Further study in a larger group of patients is needed to confirm these preliminary findings.


The molecular basis of Celmer's rules: the stereochemistry of the condensation step in chain extension on the erythromycin polyketide synthase.
Modular polyketide synthases (PKSs), for example, the 6-deoxyerythronolide B synthase (DEBS) responsible for synthesis of the aglycone core of the macrolide antibiotic erythromycin, generate an impressive diversity of asymmetric centers in their polyketide products. However, as noted by Celmer, macrolides have the same absolute configuration at all comparable stereocenters. Understanding how the stereochemistry of chain extension in controlled is therefore crucial to determining the common mechanism of action of these enzymes. We aimed to elucidate the molecular basis of Celmer's rules through in vitro studies with DEBS 1-TE, a bimodular derivative of DEBS from Saccharopolyspora erythraea, which uses (2S)-methylmalonyl-coenzyme. A to produce both D- and L-methyl centers in its triketide lactone product. We show here that condensation of (2S)-methylmalonyl-CoA in module 2 proceeds with decarboxylative inversion without cleavage of the C-H bond adjacent to the methyl group; in contrast, in module 1 the chain extension process involves loss of the hydrogen attached to C-2 of the methylmalonyl-CoA precursor. The production of the D-methyl center in module 2 without loss of hydrogen from the asymmetric center of the (2S)-methylmalonyl-CoA establishes that condensation takes place with inversion of configuration as in fatty acid biosynthesis. The loss of the key hydrogen from the (2S)-methylmalonyl-CoA to produce the L-methyl center generated in module 1 implies that an additional obligatory epimerization step takes place in that module. The nature and timing of the epimerization remain to be established.


fleN, a gene that regulates flagellar number in Pseudomonas aeruginosa.
The single polar flagellum of Pseudomonas aeruginosa plays an important role in the pathogenesis of infection by this organism. However, regulation of the assembly of this organelle has not been delineated. In analyzing the sequence available at the Pseudomonas genome database, an open reading frame (ORF), flanked by flagellar genes flhF and fliA, that coded for a protein (280 amino acids) with an ATP-binding motif at its N terminus was found. The ORF was inactivated by inserting a gentamicin cassette in P. aeruginosa PAK and PAO1. The resulting mutants were nonmotile on motility agar plates, but under a light microscope they exhibited random movement and tumbling behavior. Electron microscopic studies of the wild-type and mutant strains revealed that the mutants were multiflagellate, with three to six polar flagella per bacterium as rather than one as in the wild type, indicating that this ORF was involved in regulating the number of flagella and chemotactic motility in P. aeruginosa. The ORF was named fleN. An intact copy of fleN on a plasmid complemented the mutant by restoring motility and monoflagellate status. The beta-galactosidase activities of eight flagellar operon or gene promoters in the wild-type and fleN mutant strains revealed a direct correlation between six promoters that were upregulated in the fleN mutant (fliLMNOPQ, flgBCDE, fliEFG, fliDS orf126, fleSR, and fliC) and positive regulation by FleQ, an NtrC-like transcriptional regulator for flagellar genes. Based on these results, we propose a model where FleN influences FleQ activity (directly or indirectly) in regulating flagellar number in P. aeruginosa.


Inhalation of ozone induces DNA strand breaks and inflammation in mice.
Ozone (O3) is a well-known oxidant pollutant present in photochemical smog. Although ozone is suspected to be a respiratory carcinogen it is not regulated as a carcinogen in most countries. The genotoxic and inflammatory effects of ozone were investigated in female mice exposed to ozone for 90 min. The tail moment in bronchoalveolar lavage (BAL) cells from BALB/c mice was determined by the comet assay as a measure of DNA strand breaks. Within the first 200 min after exposure, the BAL cells from the mice exposed to 1 or 2 ppm ozone had 1.6- and 2.6-fold greater tail moments than unexposed mice. After 200 min there was no effect. It could be ruled out that the effect during the first 200 min was due to major infiltration of lymphocytes or neutrophils. Unexpectedly, ozone had no effect on the content of 8-oxo-deoxyguanosine (8-oxo-dG) in nuclear DNA or on oxidised amino acids in the lung tissue. The mRNA level of the repair enzyme ERCC1 was not increased in the lung tissue. Inflammation was measured by the cytokine mRNA level in lung homogenates. An up to 150-fold induction of interleukin-6 (IL-6) mRNA was detected in the animals exposed to 2 ppm ozone compared to the air-exposed control mice. Also at 1 ppm ozone, the IL-6 mRNA was induced. The large induction of IL-6 mRNA in the lung took place after DNA strand breaks were induced in BAL. This does not support the notion that inflammatory reactions are the cause of DNA damage. To determine whether these exposures were mutagenic, Muta Mice were exposed to 2 ppm ozone, 90 min per day for 5 days. No treatment-related mutations could be detected in the cII transgene. These results indicate that a short episode of ozone exposure at five times the threshold limit value (TLV) in US induces lung inflammatory mediators and DNA damage in the cells in the lumen of the lung. This was not reflected by an induction of mutations in the lung of Muta Mice.


A Secondary Processing Site in the Precursor of the Small Subunit of Ribulose Bisphosphate Carboxylase of Chlamydomonas reinhardtii y-1.
When the precursor of ribulose bisphosphate carboxylase of Chlamydomonas reinhardtii y-1 is bound to antibodies and treated with the soluble cell fraction, it is cleaved to the mature form (M(r) 16,500) via an intermediate of M(r) 18,500. Although this intermediate has only been observed in vitro, it may be produced during processing of the precursor in vivo.


Point mutation bias in SARS-CoV-2 variants results in increased ability to stimulate inflammatory responses.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces severe pneumonia and is the cause of a worldwide pandemic. Coronaviruses, including SARS-CoV-2, have RNA proofreading enzymes in their genomes, resulting in fewer gene mutations than other RNA viruses. Nevertheless, variants of SARS-CoV-2 exist and may induce different symptoms; however, the factors and the impacts of these mutations are not well understood. We found that there is a bias to the mutations occurring in SARS-CoV-2 variants, with disproportionate mutation to uracil (U). These point mutations to U are mainly derived from cytosine (C), which is consistent with the substrate specificity of host RNA editing enzymes, APOBECs. We also found the point mutations which are consistent with other RNA editing enzymes, ADARs. For the C-to-U mutations, the context of the upstream uracil and downstream guanine from mutated position was found to be most prevalent. Further, the degree of increase of U in SARS-CoV-2 variants correlates with enhanced production of cytokines, such as TNF-α and IL-6, in cell lines when compared with stimulation by the ssRNA sequence of the isolated virus in Wuhan. Therefore, RNA editing is a factor for mutation bias in SARS-CoV-2 variants, which affects host inflammatory cytokines production.


HPLC Determination of Enantiomeric Purity for 1-Styrene-3-Hexyl Propynol.
A rapid and sensitive high performance liquid chromatography method was developed and validated for the determination of enantiomeric purity of 1-styrene-3-hexyl propynol. Baseline separation with resolution greater than 2.0 was achieved within 17 min on a CHIRALCEL OD-H (25 cm × 0.46 cm; particle size 5 μm) column using n-hexane:isopropanol (95:5 v/v) as mobile phase at a flow rate of 1 mL·min-1 and 25°C as column temperature. The analytes were detected by UV absorbance at 210 nm. The effects of column, composition of mobile phase, temperature and flow rate on the chromatography were investigated. The method was extensively validated and proved to be robust. The recoveries were in the range of 99.6-102.6% with relative standard \deviation <0.32%. The limit of detection and limit of quantitation for (S)-1-styrene-3-hexyl propynol were 0.0041 and 0.22 μg·mL-1, and for (R)-1-styrene-3-hexyl propynol were 0.0036 and 0.19 μg·mL-1, respectively. This method was proved to be accurate, stable, rapid and sensitive for the determination of enantiomeric purity of 1-styrene-3-hexyl propynol and its homologs.


Risk-based inspection applied to two-post above-ground automotive lifts.
The safe use of two-post above-ground automotive lifts (2PAG lifts) has received particular attention in the province of Québec (Canada) following the death of a young mechanic. The inspection and preventive maintenance of this equipment is a problem highlighted in accident investigation reports and by representatives of the sector. Therefore, the work presented in this article aimed at proposing a complete and detailed inspection grid for 2PAG lifts by establishing an exhaustive list of verification criteria, baseline states and the inspection frequency for each criterion according to their criticality. The grid was built from standards, existing grids, manufacturers' manuals, interviews and tests. The inspection frequency for each criterion was established using a decision-making algorithm, notably using the concepts of progressive and sudden failures as well as redundancy. Twenty-three of the 74 inspection criteria established in the grid require routine monitoring.