Automated robotic harvesting of protein crystals-addressing a critical bottleneck or instrumentation overkill?
One of the critical steps in high throughput crystallography that so far has evaded automation is the actual harvesting of the delicate crystals from the mother liquor in which they are growing. The late-stage operation of harvesting is presently a most risky and loss-intensive procedure, compounded by its tight integration with the critical steps of cryo-protection and cryo-quenching. Recent advances in micromanipulation robotics and micro-fabrication have made it possible to seriously consider automation of protein crystal harvesting. Based on the experience gained during the development of an operator-assisted (and now operator-assisting) universal micromanipulation robot (UMR) prototype, we discuss the challenges ahead for the design of a fully autonomous, integrated system capable of the reliable harvesting of protein microcrystals. Experience from participation in NIH structural genomics projects and feedback from bottleneck workshops indicates that genuine demand exists in the high throughput community as well as in pharmaceutical production pipelines, justifying the effort and resources to develop autonomous harvesting robotics.


BAP1 Missense Mutations in Cancer: Friend or Foe?
BRCA-associated protein-1 (BAP1) is mutated in several cancers and a few therapies targeting BAP1 loss-of-function mutations have been proposed, some of them being already tested in clinical trials. However, most of the missense mutations have not been functionally characterized, although such information is essential for successful patient stratification.


Comparison of hypothalamic mRNA levels in mice euthanized by CO₂ inhalation and focused-beam microwave irradiation.
Focused-beam microwave irradiation (FBMI) is a relatively new method for euthanasia of small mammals and is available to most researchers. Compared with CO₂ inhalation, this method of euthanasia has the advantage of preserving fast-degrading metabolites. But differences in brain RNA quantity and quality, gene expression and histology in mice euthanized by CO₂ inhalation versus FBMI have not been investigated. Here the authors report that a smaller quantity of RNA was isolated from brains of mice euthanized by FBMI compared with those of mice euthanized by CO₂ inhalation. They also found relative differences in the levels of the expression of some genes. These studies suggest that either method can be used for histological analysis or RNA isolation, but the authors caution against combining the techniques within a single study on gene expression.


Plasminogen receptors on rat colon carcinoma cells.
Cells from rat carcinoma cell lines PROb (giving progressive tumours) and REGb (giving regressive tumours) have cell surface receptors which bind specifically rat plasminogen and plasmin. Affinity for Pg was found to be higher in PROb (Kd = 10(-7) M) than in REGb cells (Kd = 5.10(-7) M) but with a concomitant decrease in the number of binding sites, 0.9 x 10(6)/cell (range from 0.6 to 1.2 x 10(6)) in PROb vs 3.6 x 10(6)/cell (range 1.2 to 6 x 10(6)) in REGb cells. The number and the affinity of binding sites varied in an opposite way in PROb and REGb cells. The difference in affinity parameters was unrelated to the degree of invasiveness of tumour cells in syngenetic rats. Bound plasmin retained its enzymatic activity, which indicates that its binding does not involve the catalytic active site. In cell solubilisates plasminogen receptor appeared as one major band situated in the area of 50-60 kDa.


Results of transurethral resection plus adjuvant intravesical chemotherapy for superficial bladder cancer.
We analyzed the results of conservative therapy for superficial bladder cancer to determine the risk factors for recurrence and progression. Between May 1984 and February 1997, 111 patients with primary superficial bladder cancer were treated by a transurethral resection with or without intravesical instillation of chemotherapy, or for patients with concomitant carcinoma in situ (CIS), bacillus Calmette-Guérin. We examined the relationship between tumor stage, grade, incidence of concomitant CIS and recurrence-free survival according to pathologic findings and the drugs instilled. The incidence of concomitant CIS in pT1, grade 3 tumors was significantly higher than that in pTa, grade 1 tumors (42% vs. 3%, P= 0.006). The 5-year recurrence-free survival rate of all patients was 73%. There was no significant difference in recurrence-free survival and pathologic stage, tumor grade, presence of concomitant CIS, or drugs used for instillation. However, the recurrence-free survival in patients with > or = 5 tumors was significantly lower than in patients with less than 5 tumors. Of the 111 patients, only 3 patients demonstrated disease progression and underwent a radical cystectomy, while 1 patient with a pT1b, grade 3 tumor developed a tumor in the ureter. No patient died of bladder cancer. Our results indicate that the prognosis of superficial bladder cancer patients with a high-stage, high-grade (pT1, grade 3) tumor is favorable when treated by a transurethral resection and intravesical instillation. Bacillus Calmette-Guérin therapy is useful to prevent the recurrence of tumors with concomitant CIS.


Effects of reduced follicle-stimulating hormone dosage before human chorionic gonadotropin trigger on in vitro fertilization outcomes.
To determine whether a reduced dose of follicle-stimulating hormone (FSH) before human chorionic gonadotropin (hCG) trigger during ovarian stimulation can affect in vitro fertilization (IVF) outcomes. This study included 347 patients with a normal ovarian response who received a reduced dose of FSH before hCG trigger for 2-3 days (Group A) and 671 patients who did not receive a reduced dose (Group B) from a university-affiliated IVF center between January 2021 and December 2022. The primary endpoint was estrogen (E2) and progesterone (P) levels on the day of hCG trigger, fresh embryo transfer cycles, laboratory outcomes, and clinical outcomes between the two groups. On the day of hCG trigger, Group A had significantly lower E2 and P levels than those in Group B (3454.95 ± 1708.14 pg/mL versus 3798.70 ± 1774.26 pg/mL, p = 0.003; and 1.23 ± 0.53 ng/mL versus 1.37 ± 0.59 ng/mL, p < 0.001, respectively). The proportion of patients with P levels ≥ 1.5 ng/mL was 22.48% in Group A compared to 34.58% in Group B (p < 0.001), while the proportion of patients with E2 ≥ 5000 pg/mL was 15.27% in Group A compared to 25.93% in Group B (p < 0.001). The fresh embryo-transfer cycle rate in Group A was higher than that in group B (54.47% and 32.64%, respectively; p < 0.001). Despite the reduction in FSH dosage, there were no significant differences between groups regarding the number of oocytes retrieved, total number of mature oocytes, normal fertilization rate, cleavage rate, Day 3 top-quality rate, implantation rate, pregnancy rate per cycle, and early pregnancy loss rate. While a reduced dose of FSH prior to hCG trigger during ovarian stimulation did not significantly affect IVF outcomes, it was associated with lower E2 and P levels, resulting in fewer cycles with E2 ≥ 5000 pg/mL and P ≥ 1.5 ng/mL on the day of the hCG trigger.


Long term comparison between single stage Baerveldt and Ahmed glaucoma implants in pediatric glaucoma.
To compare the long term intraocular pressure control in pediatric glaucoma patients who underwent single stage Baerveldt glaucoma valve and Ahmed glaucoma valve S2 implantation. A retrospective study was conducted to analyze the data of patients with single stage Baerveldt glaucoma valve and Ahmed valve implantation at Children Hospital Los Angeles. Medical records of patients were reviewed retrospectively and divided into two groups. All cases received single stage valve implantation in which the tube was inserted primarily into the anterior chamber. In cases with Baerveldt implants, the silicone tube was ligated near its plate location with a single absorbable suture. Group 1 included patients with Baerveldt glaucoma implant model BG 101-350, while group 2 included patients with Ahmed valve implant model S-2. Patients' data collected ranged over the period from 2001 to 2008. The minimum follow up period was 6 month; maximum follow up period was 8 years. All patients were below 18 years of age. Success was considered if last postoperative IOP was between 8 and 24 mm Hg (with or without medications), no additional glaucoma surgery after valve implantation, and absence of visually significant complications. Group 1 included 20 cases and group 2 included 11 cases. Long term success rate based on criterion defined was 80% for group 1 (Baerveldt) with average IOP postoperatively on last follow-up of 19.6 mm Hg. In group 2 (Ahmed), average postoperative pressure was 24 mm Hg with 6 out of 11 considered successful based on criterion giving 54.5% success rate. In the long term, single stage Baerveldt implantation appears to control pressure well in pediatric glaucoma.


Defining optimal thickness for maximal self-fieldJcin YBCO/CeO2multilayers grown on buffered metal.
The effect of multilayering YBa2Cu3O6+x(YBCO) thin films with sequentially deposited CeO2layers between YBCO layers grown on buffered metallic template is investigated to optimize the self-field critical current densityJc(0). We have obtained that the improvement inJc(0)clearly depends on the YBCO layer thickness and temperature, where at high temperatureJc(0)can be increased even 50% when compared with the single layer YBCO films. Based on our experimental results and theoretical approach to the growth mechanism during multilayer deposition, we have defined a critical thickness for the YBCO layer, where the maximal self-fieldJc(0)is strongly related to the competing issues between the uniform and nonuniform strain relaxation and the formation of dislocations and other defects during the film growth. Our results can be directly utilized in the future coated conductor technology, when maximizing the overall in-fieldJc(B)by combining both the optimal crystalline quality and flux pinning properties typically in bilayer film structures.


Plant stress hormones suppress the proliferation and induce apoptosis in human cancer cells.
Cellular stressors induce various outcomes including inhibition of cell proliferation and cell death. Sodium salicylate (SA), a plant stress hormone, can suppress the proliferation or cause apoptosis in certain mammalian cancer cells. Plant stress hormones are activators of cellular responses, including cell death, to diverse stress situations in plants. Thus, we hypothesized that plant stress hormones share the ability to adversely affect cancer cells. We found that the plant stress hormone SA suppressed proliferation of lymphoblastic leukemia, prostate, breast and melanoma human cancer cells. Jasmonic acid (JA), a plant stress hormone belonging to the Jasmonate family, induced death in lymphoblastic leukemia cells and caused suppression of cell proliferation in the other human cancer cells mentioned above. Another member of the Jasmonate family, methyl jasmonate (MJ), induced death in each of the cell lines. Plant stress hormones did not affect normal human lymphocytes, in contrast to their strong effect on lymphoblastic leukemia cells. JA and MJ caused apoptotic death, as determined by characteristic nuclear morphology, flow cytometric DNA profile and elevation of caspase-3 activity. Finally, mice bearing EL-4 lymphoma and treated with MJ, survived for significantly (P = 0.00953) longer periods of time than untreated mice. These findings suggest that plant stress hormones may potentially be a novel class of anti-cancer drugs.


Quantitative analysis of corneal microstructure in keratoconus utilising in vivo confocal microscopy.
To establish and quantify the in vivo confocal microscopic features of moderate to advanced keratoconus. Nineteen keratoconus subjects were catergorised using Orbscan-derived corneal apex power and pachymetry as exhibiting moderate (n=7) and advanced (n=12) keratoconus. Control subjects included 23 noncontact lens wearers (Group A) and 15 contact lens wearers (Group B). All subjects underwent Confoscan slit scanning in vivo confocal microscopy. Compared with Group A (4912+/-434 cells/mm(2)), basal epithelial density was significantly lower in both moderate (4592+/-414 cells/mm(2), P<0.05) and advanced keratoconus (4530+/-596 cells/mm(2), P=0.01). In comparison to Group A (761+/-118 cells/mm(2)), anterior stroma keratocyte density was significantly greater in both moderate keratoconus (883+/-111 cells/mm(2), P=0.001) and advanced keratoconus (952+/-122 cells/mm(2), P<0.001). Compared to Group A (504+/-80 cells/mm(2)) posterior stroma keratocyte density was also significantly greater in advanced keratoconus (599+/-97 cells/mm(2), P<0.001) and posterior stromal keratocyte density appeared to increase with increasing severity of keratoconus (P<0.05). However, comparing control Groups A and B, contact lens wear per se, was associated with significantly reduced (P=0.000) keratocyte density in the anterior stroma (609+/-66 cells/mm(2)) and demonstrated a trend (P=0.056) in the posterior stroma (470+/-63 cells/mm(2)). Keratoconic corneas (429+/-72 microm) were significantly thinner than control Groups A (508+/-77 mm) and B (495+/-80 microm). The presence of keratoconus did not affect the endothelial cell density (P=0.54). In vivo confocal microscopy can provide insight into the microstructural changes that occur in keratoconus.


Diastereoselective synthesis of the endo- and exo-spirotetronate subunits of the quartromicins. The first enantioselective Diels-Alder reaction of an acyclic (Z)-1,3-diene.
[reaction: see text]. Diastereoselective syntheses of the endo- and exo-spirotetronates 1 and 2, corresponding to the galacto and agalacto fragments of quartromicins A3 and D3, are described. The key step of these syntheses are highly enantio- and diastereoselective Lewis acid catalyzed Diels-Alder reactions of the 1,1,3,4-tetrasubstituted diene 3.


Predictors of pregnancy and live-birth in couples with unexplained infertility after ovarian stimulation-intrauterine insemination.
To identify baseline characteristics of couples that are likely to predict conception, clinical pregnancy, and live birth after up to four cycles of ovarian stimulation with IUI in couples with unexplained infertility. Secondary analyses of data from a prospective, randomized, multicenter clinical trial investigating pregnancy, live birth, and multiple pregnancy rates after ovarian stimulation-IUI with clomiphene citrate, letrozole, or gonadotropins. Outpatient clinical units. Nine-hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial. As part of the clinical trial, treatment was randomized equally to one of three arms and continued for up to four cycles or until pregnancy was achieved. Conception, clinical pregnancy, and live-birth rates. In a multivariable logistic regression analysis, after adjustment for other covariates, age, waist circumference, income level, duration of infertility, and a history of prior pregnancy loss were significantly associated with at least one pregnancy outcome. Other baseline demographic and lifestyle characteristics including smoking, alcohol use, and serum levels of antimüllerian hormone were not significantly associated with pregnancy outcomes. While age and duration of infertility were significant predictors of all pregnancy outcomes, many other baseline characteristics were not. The identification of level of income as a significant predictor of outcomes independent of race and education may reflect differences in the underlying etiologies of unexplained infertility or could reveal disparities in access to fertility and/or obstetrical care. NCT01044862.


The long-term effects of childhood adiposity on depression and anxiety in adulthood: A systematic review.
This review aimed to evaluate the association between childhood adiposity and depression and anxiety risk in adulthood. MEDLINE, PsychInfo, Embase, CINAHL, and Scopus were searched on June 6, 2022, to identify studies that investigated the association between childhood weight status (age ≤18 years) and outcomes of depression and/or anxiety in adulthood (age ≥19 years). Study quality was assessed using the Newcastle-Ottawa Scale and results were narratively synthesized. Sixteen studies were eligible for inclusion, with heterogeneity in methods and follow-up durations complicating comparisons. Six out of eight studies found a statistically significant association between childhood adiposity and increased likelihood of depression in adulthood, particularly in females. However, overall evidence was of moderate quality and study limitations prevented causal conclusions. In contrast, limited evidence and mixed findings were reported for the associations between childhood adiposity and depressive symptom severity or anxiety outcomes in adulthood. Evidence suggests that childhood adiposity is associated with greater vulnerability to depression in adulthood, particularly in females. However, further research is warranted to address the limitations discussed. Future research should also explore how changes in weight status from childhood to adulthood might differentially influence the likelihood of depression.


The hepatitis B virus X gene product transactivates the HIV-LTR in vivo.
It has previously been shown that the hepatitis B virus (HBV) X gene product, HBx, transactivates homologous and heterologous transcriptional regulatory sequences of viruses, including the human immunodeficiency virus type 1 (HIV1) long terminal repeat (LTR), and various cellular genes in vitro. To evaluate the transactivating function of HBx in vivo, we generated transgenic mice carrying the X open reading frame under the control of the human antithrombin III (ATIII) gene regulatory sequences. These mice express the 16 Kd HBx protein in the liver, as demonstrated by immunoprecipitation studies. Crossbreeding of HBx mice with transgenics carrying either the chloramphenicol acetyl transferase (CAT) bacterial or the lacZ reporter gene driven by the HIV1-LTR allowed us to demonstrate, for the first time, the in vivo transactivating function of HBx protein.


What is the clinical impact of positive cultures at the time of primary total shoulder arthroplasty?
Cultures taken at the time of primary shoulder arthroplasty are commonly positive for Cutibacterium acnes. Despite our limited understanding of the clinical implication of deep tissue inoculation from dermal colonization, significant efforts have been made to decolonize the shoulder prior to surgery. The purpose of this study is to determine differences in clinical outcomes based on culture positivity at the time of primary shoulder arthroplasty. A series of 134 patients who underwent primary anatomic or reverse total shoulder arthroplasty and had intraoperative cultures obtained via a standard protocol were included. In each case, 5 tissue samples were collected and processed in a single laboratory for culture on aerobic and anaerobic media for 13 days. Minimum 2-year functional outcomes scores (American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form [ASES] and Single Assessment Numeric Evaluation [SANE]) and reoperation data were analyzed. Forty-two (31.3%) patients had positive cultures (30 C acnes and 21 with at least 2 positive cultures) at the time of surgery. There was no statistically significant difference in postoperative functional outcome scores (ASES: 82.5 vs. 81.9; P = .89, SANE: 79.5 vs. 82.1; P = .54) between culture-positive and culture-negative cohorts. There were no cases of infection. Two patients (4.8%; 2/42) with positive cultures required reoperation compared with 4 patients (5.6%; 4/71) without positive cultures. The apparent colonization by nonvirulent organisms in patients undergoing primary shoulder arthroplasty does not appear to have a clinically significant effect on functional outcomes or need for repeat surgery in the short term.


Suicidal ideation and its relationship with mental health reported by different informants among children aged 6-12.
Suicidal ideation in children has received less attention than in adolescents. This study aimed to explore the self-reported prevalence of suicidal ideation among children aged 6-12 and to identify the relationship between self-reported suicidal ideation and children's mental health reported by different informants in Chinese setting. The study sample was 1479 children aged 6-12 from three elementary schools in Tianjin. Children completed the Dominic Interactive to report their mental health and suicidal ideation. Parents and teachers completed the Socio-Demographic Questionnaire and the Strengths and Difficulties Questionnaire (SDQ). The prevalence of suicidal thoughts and death thoughts was 18.05 % and 16.90 %, respectively. Parent reported emotional symptoms, ADHD, and externalized problems were associated with death thoughts, and ADHD was associated with suicidal thoughts. For teacher's reports, emotional symptoms, and impact were associated with death thoughts, and ADHD, peer problems, internalized problems, and internalized and externalized comorbidity were associated with suicidal thoughts. All of the children's self-reported mental health problems were associated with suicidal thoughts and death thoughts. Causality cannot be inferred in a cross-sectional study. Suicidal ideation is not uncommon in Chinese children. The relationships between mental health problems and suicidal ideation varied in different informants. Suicide prevention in young children should be enhanced, and screening for suicidal ideation is recommended at the onset of different informants who reported specific mental health problems.


A new test for detecting ongoing selection.
Much effort has been made to search for signatures of past natural selection in DNA sequences. However, currently acting selection is rarely detected in natural populations because of its rarity, low detection power of available methods, or both. Here, we develop a new test to detect viability selection over a single generation. In this test, one specific type of chromosomes is chosen as a reference, while all other chromosomes are designated as "focal". The test compares measures of variation between two groups of "focal" chromosomes: those found in reference/focal heterozygous individuals and those found in focal/focal homozygous individuals. In the absence of selection, we do not expect differences between these two groups as long as mating is random. On the other hand, currently acting selection can cause differences in some measures of variation. We applied this test to typing data for In(2L)t inversion polymorphism in a Drosophila melanogaster population, using "standard" (non-inverted) chromosomes as the focal class. Although the frequencies of In(2L)t and standard chromosomes did not deviate from the Hardy-Weinberg equilibrium, we found differences in allele frequency and the number of haplotypes between the two groups of standard chromosomes. This new test, in conjunction with the Hardy-Weinberg test, may shed light on how often strong selection is operating in extant populations.


An analysis by chemical class of Salmonella mutagenicity tests as predictors of animal carcinogenicity.
For a number of years, investigators have recognized that humans potentially are exposed to large numbers of genotoxicants. Many efforts have attempted to validate various short-term bioassays for use as rapid, inexpensive screens for genotoxicants--especially carcinogens. In this analysis, we examine Salmonella mutagenicity as an indicator of potential carcinogenicity by comparing published (and when possible, evaluated) Salmonella results with the evaluated Gene-Tox animal carcinogen data base. The Salmonella bioassay does especially well in those cases where the level of evidence for carcinogenicity is the strongest. Analysis shows that except for specific classes of compounds, the plate-incorporation protocol and the preincubation protocol are equally efficient at detecting mutagens. This paper also demonstrates how validation values (sensitivity, specificity, etc.) vary with chemical class. Overall, this analysis demonstrates that when used and interpreted in a meaningful chemical class context, the Salmonella bioassay remains extremely useful in identifying potential animal carcinogens.


[Peripheral Ischemia in Diabetic Retinopathy and Retinal Vein Occlusion: New Insights with Ultra-Wide-Angle Fundus Imaging and Wide-Angle Fluorescein Angiography].
In several diseases such as diabetic retinopathy and retinal vein occlusion, relevant pathophysiological changes take place in the retinal periphery. These changes may determine the prognosis and outcomes of therapy. Recent ultra-wide-angle camera systems promise improved and simplified visualisation of the outer periphery of the retina. This could potentially lead to novel clinical applications of these methods, with potential impact on therapy decisions. Literature and database research on ultra-wide imaging for diabetic retinopathy and retinal vein occlusion. With ultra-wide-angle angiography, it is possible to visualise up to 3.2-fold more retinal surface than conventional 7SF images (7SF: 7 standard field). Initial studies imply that diabetic changes can be found outside of the boundaries of the 7SF images. Patients with central vein occlusion have more extended and severe macular oedema and poorer visual acuity if ischemia of the periphery is more pronounced (measured by the ischemic index [ISI]). The amount of ischemia influences the size of the macular oedema, its resolution under therapy and the number of anti-VEGF injections needed to treat it. Ultra-wide-angle camera systems allow visualisation of the peripheral retina outside the boundaries of standard methods. Initial studies have detected potentially relevant changes in the outer periphery, which would have been missed by 7SF. Nevertheless, there have been no systematic studies on the relevance of these changes with regards to prognosis and therapeutic decisions.


The possibility of inventing new technologies in the detection of cancer by applying elements of the canine olfactory apparatus.
In order to find better tools in the diagnosis of cancer in an earlier and more precise manner, researchers have explored the use of volatile organic compound (VOCs) as a way to detect this disease. Interestingly, the canine olfactory apparatus was observed to detect cancer in two anecdotal reports. After the description of these events, researchers began to study this phenomenon in a structured way in order to assess the ability of canines in detecting cancer-related VOCs. Due to the fact that some of these studies have shown that the canine olfactory apparatus is highly proficient in the detection of cancer-related VOCs, in this article we assess the possibility of constructing a bioelectronic-nose, based on canine olfactory receptors (ORs), for the purpose of diagnosing cancer in a more sensitive, specific, and cost effective manner than what is available nowadays. Furthermore, in order to prove the feasibility and the need of the proposed apparatus, we searched for the following type of articles: all of the studies that have examined, to our knowledge, the ability of dogs in detecting cancer; articles that assess the dog olfactory receptor (OR) gene repertoire, since a central part of the proposed bioelectronic nose is being able to recognize the odorant that emanates from the cancerous lesion, and for that purpose is necessary to express the canine ORs in heterologous cells; examples of articles that depict different devices that have been built for the purpose of detecting cancer-related VOCs, so as to assess if the construction of the proposed apparatus is needed; and articles that describe examples of already constructed bioelectronic noses, in order to demonstrate the existence of a technical precedent and thus the plausibility of the proposed device.


Sleep and hypnotic drugs.
In recent years the effectiveness of hypnotic drugs has had to be assessed in terms of a greatly increased knowledge of the physiology and pathology of sleep. The normal pattern of sleep and wakefulness involves a cyclic alternation between three rather than two basically dissimilar states of the brain and body - alert wakefulness, rapid-eye-movement (REM) sleep and non-rapid-eye-movement (NREM) sleep. The pattern of this alternation in individual people results from the interaction of many influences - biological (including genetic, early developmental and later degenerative influences), psychological, social and environmental factors, various physical and psychiatric disorders, and most drugs which affect the central nervous system. The quality of sleep is not related in any simple or constant manner either to its duration or to the proprotions of time spent in each stage of sleep. Among the disorders of sleep, insomnia is a far more common problem of medical management than are enuresis, narcolepsy, somnambulism or nightmares. With a few exceptions, most hypnotic drugs now in widespread use cease to be effective in treating insomnia after the first few nights. However, the ineffective treatment is often continued because insomnia will be even worse during the initial period of drug withdrawal. These factors and the toxicity of hypnotic drugs when taken in overdose make the long-term treatment of insomnia more difficult than was previously supposed. Barbiturates should no longer be prescribed. Some of the non-barbiturates, such as glutethimide and methaqualone, have no advantage over the barbiturates. The benzodiazepine hypnotics, nitrazepam and flurazepam, are less toxic in overdose and are relatively effective in treating insomnia. Chloral hydrate and its derivates are useful alternative drugs for short-term use. Measures to improve sleep without drugs deserve greater emphasis than they have had in the past.


Recovery of injured cingulum in a patient with brain injury: diffusion tensor tractography study.
Little is known about neural recovery of an injured cingulum following brain injury. We report on a patient with brain injury who showed apparent neural recovery of an injured cingulum on follow up diffusion tensor tractography (DTT). A 53-year-old female patient had suffered hypoxic ischemic brain injury for a period of approximately nine hours following spontaneous subarachnoid hemorrhage and intraventricular hemorrhage, and underwent coiling of a left ruptured aneurysm of the posterior communicating artery. She showed severe cognitive impairment, so that she could not be evaluated on the Mini-Mental State Examination, however, her cognition showed improvement to 21 at five months after onset and 24 at 14 months after onset on the Mini-Mental State Examination. On seven-day DTT for the fornix in the patient, we observed a discontinuation in the left crus and thinning of the right crus. However, on 14-month DTT, the thinned right fornical crus had disappeared. Regarding the cingulum, on seven-day DTTs, discontinuations of both cingulums anterior to the genu of the corpus callosum were observed. However, on 14-month follow up DTT, the right cingulum was elongated to the right basal forebrain and no change in the discontinuation of the left cingulum was observed. These changes observed on DTT in both cingulums appeared to indicate recovery of the injured cingulum in this patient. The results of this study may suggest a mechanism for recovery of injured cingulum following brain injury.


The impact of new systemic therapies on survival and time on hormonal treatment in hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: A population-based study in British Columbia from 2003 to 2013.
The purpose of this study was to determine whether new systemic therapy regimens have resulted in improved survival and increased time on first- and second-line hormonal treatment for patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) over time. Patients diagnosed with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative MBC were identified across 3 time cohorts (2003-2005, 2007-2009, and 2011-2013). Data were prospectively collected. Cases with previous, synchronous, or subsequent contralateral breast cancer were excluded. The types of first- and second-line therapies, the times on first- and second-line hormonal treatment, and the median survival times were compared across the cohorts. Within the time period analyzed, 9 new adjuvant systemic therapies (with or without neoadjuvant therapy) and 2 metastatic systemic therapies were approved at BC Cancer for the treatment of HR-positive, HER2-negative MBC. In the 3 time cohorts, 3953 patients diagnosed with MBC were identified. Among the 2432 patients (62%) who had HR-positive/HER2-negative disease, 2197 (90%) received at least 1 line of systemic therapy after the diagnosis of MBC, and 80% of these patients (1752 of 2197) received first- and/or second-line hormonal treatment. The median duration on hormonal treatment was 9.0 months for the first line and 6.1 months for the second line. The durations were similar across the time cohorts (range for the first line, 8.9-9.0 months; range for the second line, 6.0-6.1 months). The median survival for the entire study population was 2.0 years (95% confidence interval, 1.8-2.1 years), and there was no significant difference between the cohorts (range, 1.9-2.0 years). Even though more adjuvant and metastatic systemic therapies have been approved since 2003, population-level gains in survival and the time on hormonal treatment for patients with HR-positive, HER2-negative MBC have not been made over the course of a decade.


Basolateral membrane conductance in A6 cells: effect of high sodium transport rate.
Conductance of apical and basolateral membranes in short-circuited cultured renal distal cells (A6) was determined using microelectrodes. Epithelia were pre-incubated with 0.1 mumol/l dexamethasone in the presence of 4 mumol/l amiloride to prevent increase in apical Na+ entry. Omission of amiloride increased the Isc from 5.7 to 27.6 microA/cm2 due to the rise in apical membrane conductance from 21 to 595 microS/cm2. Apical fractional resistance decreased from 0.89 to 0.40 and cells depolarized from -52 to -4 mV. Basolateral membrane conductance, which was 320 microS/cm2 at partially inhibited transport, was not significantly altered during the first 2 min following establishment of high transport activity; it started to increase thereafter reaching a more than threefold higher value of 1324 microS/cm2 within 12 min. The gain cannot be explained by increase in partial K+ conductance. Disappearance of the conductance after reduction of basolateral Cl- or in the presence of the Cl- channel blocker 5-nitro-2-(3-phenylpropylamino)benzoate indicates a Cl- conductance, which appears to be activated by depolarization.


Optimal acupuncture protocol improving symptoms of typical dry eye syndrome: meta-analysis and systematic review.
Previous meta-analyses have shown a superiority of acupuncture over artificial tear for treating typical dry eye syndrome (DES). However, given that the acupuncture protocols were quite diverse in the randomized controlled trials (RCTs) included in the meta-analyses, it is necessary to establish the acupuncture guidelines. Thus, the optimal acupuncture protocol involved in improvements of tear-film breakup time (BUT) or Schirmer tear test (STT) was examined by meta-analyses for RCTs in patients with typical DES. Eight databases until Jun 2018 were searched for 21 RCTs (n = 1542 eyes) comparing effectiveness of acupuncture versus artificial tear control. Indirect comparison of Bucher analysis was used to find specific acupoints (SAPs) improving BUT or STT by comparing the outcomes between subgroups of the RCTs including and excluding certain SAPs. Meta-analysis was examined for the outcomes in subgroups of the RCTs based on the number of SAPs, and network meta-analysis was for multiple pairwise comparisons across the protocols using the SAPs to yield relative effects. The Bucher analyses identified nine SAPs with positive effects on BUT or STT, and the positive relations of two SAPs involved in improvements of both BUT and STT suggested potential combinations of three ('KI3-LI4-SP6' or 'KI3-GB14-ST2') or four SAPs ('KI3-BL1-EX-HN7-SP6'). Subgroup meta-analyses showed the SAP-depending improvements of BUT or STT in the subgroups including more than three SAPs, compared with the artificial tear control. Meta-regression and network meta-analyses revealed significant correlations between the number of SAPs and the improvements of BUT and STT, and demonstrated that acupuncture using four SAPs for 21-30 days, particularly at two-three times per week, can be optimal for improving the symptoms of typical DES. These results provide useful information for guiding acupuncture in clinical trials for DES.


Following the legacy of professors Barbara Starfield and Leiyu Shi in Brazil as health policy: the National Health Survey (PNS), led by the Brazilian National Institute of Geography and Statistics (IBGE) and the Primary Care Assessment Tool (PCAT).
We present to the scientific community the pioneering of Brazilian National Institute of Geography and Statistics (IBGE, the Brazilian Census Bureau) in partnership with the Ministry of Health, the largest fieldwork ever conducted in a single country in the world, using the PCAT in a national household sample survey, visiting more than 100,000 households and 40% of the country's municipalities. In Brazil, PCAT is being consolidated as an instrument to support public policy for the evaluation of primary health care. We believe that it represents a virtuous example of dialogue between scientific community and health management, following the legacy of Professors Barbara Starfield and Leiyu Shi.


Effects of genetic sex and genomic background on epistasis in rainbow trout (Oncorhynchus mykiss).
Epistasis among quantitative trait loci (QTL) for survival (upper thermal tolerance, UTT) and morphological (fork length, FL and condition factor, K) traits was detected in purestrain and interstrain rainbow trout (Oncorhynchus mykiss) families. One sex-linked (OmyFGT19TUF) and three autosomal (Omy325UoG, Ssa14DU and Ssa20.19NUIG; linkage groups B, D and S, respectively) microsatellite loci linked to UTT QTL in this species were used. Within half sib families, significant effects of full sib family on epistasis involving Omy325UoG and OmyFGT19TUF were detected at a rate significantly higher than expected for UTT (p < 0.001*) and FL (p < 0.01*), using results significant at comparisonwise significance thresholds derived from permutational analysis. Measured across half sib families, the phenotype of female genotypic classes was more divergent from the family trait mean than that of males where epistasis involved the sex-linked locus OmyFGT19TUF (p = 0.0176*), and also for means over all families (p = 0.0355*). Female genotypic classes were also more divergent (p = 0.0011 **) from the full sib trait mean where three-way interaction between OmyFGT19TUF, one of the autosomal loci and full sib family was significant, and marginally more divergent for trait means of genotypic classes across all full sib families (p = 0.0856+). There was no evidence that these effects were more pronounced in hybrid F1 families than purestrains.


Resonance Raman evidence for an unusually strong exogenous ligand-metal bond in a monomeric nitrosyl manganese hemoglobin.
Resonance Raman spectroscopy has been employed to determine the vibrational modes of monomeric nitrosyl manganese Chironomus thummi thummi hemoglobin (CTT IV). This insect hemoglobin has no distal histidine. By applying various isotope-labeled nitric oxides (14N16O, 15N16O, 14N18O), we have identified the Mn11-NO stretching model at 628 cm-1, the Mn11-N-O bending mode at 574 cm-1 and the N-O stretching mode at 1735 cm-1. The results suggest a strong Mn11-NO bond and a weak N-O bond. The vinyl group substitution does not influence the nu (Mn11-NO), delta (Mn11-N-O) and nu (N-O) vibrations. The Mn11-NO stretching frequency is insensitive to distal histidine interactions with NO, whereas the N-O stretching frequency is sensitive. Nitric oxide also binds to Met manganese CTT IV to form an Mn111. NO complex which undergoes a slow but complete autoreduction resulting in the Mn11.NO species. In manganese meso-IX CTT IV, the Mn111. NO Mn11. NO conversion alters the intensities of the porphyrin ring modes at 342, 360, 1587 and 1598 cm-1, but shifts the frequencies at 1504 and 1633 cm-1 (in Mn111.NO) to 1497 and 1630 cm-1 (in Mn11. NO), respectively. The unshifted marker line at 1378 cm-1 reflects the fact that the pi electron densities of the porphyrin ring are the same in the two complexes.


Glibenclamide treatment modulates the expression and localization of myosin-IIB in diabetic rat brain.
Myosin-IIB is a non-muscle isoform in the brain with increased expression in the brains of diabetic rats. Chronic hyperglycemia caused by diabetes can impair learning and memory. Oral hypoglycemic agents such as glibenclamide have been used to control hyperglycemia. We report changes in the expression and distribution of myosin-IIB in the frontal cortex and hippocampus of diabetic rats treated with glibenclamide. The brains were removed after 43 days of treatment with glibenclamide (6 mg/kg bw orally), homogenized and analyzed by Western blotting, qRT-PCR and immunohistochemistry. Myosin-IIB expression increased in the brains of diabetic rats. However, protein expression returned to control levels when treated with glibenclamide. In addition, the expression of MYH10 gene encoding non-muscle myosin heavy chain-B decreased in diabetic rats treated with glibenclamide. Moreover, we found weak myosin-IIB labeling in the hippocampus and frontal cortex of rats treated with glibenclamide. Therefore, the expression of myosin-IIB is affected by diabetes mellitus and may be modulated by glibenclamide treatment in rats. Structural changes in the hippocampus and prefrontal cortex are reversible, and glibenclamide treatment may reduce the patho-physiological changes in the brain. Our findings can contribute to the understanding of the regulation of myosins in the brains of diabetic rats.


Multicenter Prospective Analysis of Stroke Patients Taking Oral Anticoagulants: The PASTA Registry - Study Design and Characteristics.
The management of atrial fibrillation and deep venous thrombosis has evolved with the development of direct oral anticoagulants (DOAC), and oral anticoagulant (OAC) might influence the development or clinical course in both ischemic and hemorrhagic stroke. However, detailed data on the differences between the effects of the prior prescription of warfarin and DOAC on the clinical characteristics, neuroradiologic findings, and outcome of stroke are limited. The prospective analysis of stroke patients taking anticoagulants (PASTA) registry study is an observational, multicenter, prospective registry of stroke (ischemic stroke, transient ischemic attack, and intracerebral hemorrhage) patients receiving OAC in Japan. This study is designed to collect data on clinical background characteristics, drug adherence, drug dosage, neurological severity at admission and discharge, infarct or hematoma size, acute therapy including recanalization therapy or reverse drug therapy, and timing of OAC re-initiation. Patient enrollment started in April 2016 and the target patient number is 1000 patients. The PASTA prospective registry should identify the status of stroke patients taking OAC in the current clinical practice in Japan.


Experimental Design for Distributed Parameter Vector Systems.
We formulate an optimal design problem for the selection of best states to observe and optimal sampling times and locations for parameter estimation or inverse problems involving complex nonlinear nonlinear partial differential systems. An iterative algorithm for implementation of the resulting methodology is proposed.


Optical coherence tomography imaging of the anterior chamber angle.
Primary angle closure glaucoma is a common cause of visual loss worldwide. Gonioscopy and other current methods of assessment of the anatomy of the anterior segment relevant to the diagnosis of this disease, such as ultrasound biomicroscopy, have significant limitations. Anterior segment optical coherence tomography, with its rapid, noncontact, and high-resolution image acquisition, seems to be a promising tool for the evaluation of the anterior chamber angle configuration, including changes induced by illumination and laser peripheral iridotomy. It has the potential for use as a rapid screening tool for detection of occludable angles. Ongoing clinical studies should help to evaluate its efficacy in this regard.


[Electron microscopic study of the surface of nonirradiated and UV-irradiated human blood lymphocytes].
The action of the short-wave ultraviolet radiation (UV, 254 nm) upon the outer perimembrane layers (OPML) of the human blood lymphocytes was studied with the aid of electron microscopy. The alcian blue and ruthenium red dye was used for the contrasting of the OPML. The UV-exposure of cells in shown to lead to the diminution of the dye-adsorbing cell surface as well as to the change of the nature of the observed OPML structures. The problem of the connection between the structural changes of the cell surface with modification of antigen properties of immunocompetent cells is discussed.


Genotyping of Enterocytozoon bieneusi in AIDS patients from the north west of England.
In this study Enterocytozoon bieneusi -positive faeces samples from AIDS patients in the north west of England were investigated by polymerase chain reaction (PCR) and DNA sequencing for potential zoonotic origins. The ITS and flanking regions of the rDNA was amplified by PCR and product sequenced. Sequences were compared with those held on GenBank to ascribe known genotypes. Of 13 E. bieneusi -positive samples tested, all gave a 508 bp amplification product by PCR. The samples yielded the following: genotypes B (n=11; so far only been found in humans), D (n=1; has been reported from humans and a laboratory macaque) and K (n=1; previously identified only from a cat). A possible zoonotic link with cats has been demonstrated for one human case. The origin of the majority of cases in the north west of England is unknown and may indicate that genotype B is solely a human pathogen.


Dynamic magnetic resonance imaging of carbogen challenge on awake rabbit brain at 1.5T.
Anesthesia may alter the cellular components contributing to the magnetic resonance imaging (MRI) signal intensities. Developing awake animal models to evaluate cerebral function has grown in importance. To investigate a noninvasive strategy for dynamic MRI (dMRI) of awake rabbits during carbogen challenge. A nonmetallic assistive device with a self-adhering wrap secure procedure was developed for the head fixation of awake rabbits. Multi-shot gradient echo echo-planar imaging sequence was applied for the dMRI on a 1.5 T clinical MRI scanner with a quadrature head coil. The carbogen challenge pattern was applied in a sequence of air - carbogen - air - carbogen - air. Twelve scans were performed for each block of carbogen challenge. T2-weighted fast-spin echo and T1-weighted gradient echo sequences were performed before and after dMRI to evaluate the head position shifts. The whole dMRI scan time was about 30 minutes. The position shift of 8 rabbits in the x-and y-direction was less than 3%. The average MRI signal intensities (SI) from the 8 rabbits during carbogen challenge was fitted well using exponential growth and decay functions. The average MRI SI increase due to carbogen inhaling was 1.51%. The proposed strategy for head dMRI on an awake rabbit during carbogen challenge is feasible.


Curcumin inhibits UVB-induced matrix metalloproteinase-1/3 expression by suppressing the MAPK-p38/JNK pathways in human dermal fibroblasts.
Curcumin (diferuloylmethane) is a polyphenol derived from turmeric (Curcuma longa), which is commonly used as a spice. Recent studies have shown that curcumin has a wide range of pharmacological activities, including anticarcinogenic, antioxidant, anti-inflammatory and antiangiogenic activities. However, the antiphotoageing effects of curcumin have yet to be characterized. In this study, we investigated the inhibitory effects of curcumin on matrix metalloproteinase (MMP)-1 and MMP-3 expression in human dermal fibroblast cells. Western blot analysis revealed that curcumin inhibited ultraviolet (UV) B-induced MMP-1 and MMP-3 expression. Furthermore, curcumin significantly blocked UVB-induced reactive oxygen species generation in fibroblasts. Curcumin treatment significantly blocked the UVB-induced activation of nuclear factor (NF)-κB and activator protein (AP)-1. Additionally, curcumin strongly repressed the UVB-induced phosphorylation of p38 and c-Jun N-terminal kinase. Curcumin prevented UVB-induced MMP expression through mitogen-activated protein kinase/NF-κB inhibition and AP-1 activation. In conclusion, curcumin may be useful for preventing and treating skin photoageing.


A rev/beta-galactosidase fusion protein binds in vitro transcripts spanning the rev-responsive element of human immunodeficiency virus type 1 (HIV-1).
The rev protein of human immunodeficiency virus type 1 (HIV-1), a phosphoprotein of 20 kDa apparent molecular mass, is essential to target the mRNA for virion polypeptides into the cytoplasm. This effect is mediated by a specific RNA stretch (rev-responsive element = RRE) localized within a 3'-terminal segment of the mRNA encoding virion proteins. We present evidence that rev expressed as a beta-galactosidase fusion protein in E. coli forms a complex with in vitro transcripts containing the RRE; it can be precipitated by monoclonal antibodies with rev or beta-galactosidase specificity. In addition, specific binding of rev protein to RNA could be demonstrated by Northwestern blotting.


Hot flashes are associated with psychological symptoms of anxiety and depression in peri- and post- but not premenopausal women.
To explore the relationship between anxiety, depression, vasomotor symptoms, and menopausal status among middle-aged women. A population-based study involving a rural Taiwanese population. Participants received a structured questionnaire, which included the hospital anxiety and depression scale (HADS), gynecological history and a checklist of menopausal symptoms in the most recent 2 weeks. A total of 1273 women with no history of surgical menopause and hormonal therapy history participated. The mean anxiety, depression, and total HADS scores were 4.3 +/- 3.3, 3.3 +/- 2.8 and 7.6 +/- 5.3, respectively, and did not differ according to menopausal status. A total of 10.5% participants reported hot flashes within the previous 2 weeks. After controlling for educational status and insomnia, anxiety (6.0 +/- 3.8 versus 4.1 +/- 3.1) and depression scores (4.0 +/- 3.3 versus 3.2 +/- 2.7) were significantly higher (p < 0.001) compared with those without hot flashes. These differences were attributed to peri- and postmenopausal subjects. Hot flashes in peri- and postmenopausal women were associated with anxious and depressive symptoms in East Asian population with low prevalence of vasomotor symptoms.


Relationships between intelligence and concept identification in adulthood as a function of stage of learning.
Three groups (n = 54) of participants aged 17-26, 39-51 and 59-76 were asked to solve two types of concept problems to investigate the intellectual correlates of concept identification as a function of stage of learning in adulthood. Predictions derived from the Gf-Gc theory of Horn and Cattell were partially supported in each age group. Differential ability-performance relations as a function of stage of learning were considerably less potent in the elderly versus the young and middle aged. Comparisons both within and between age groups suggested that a dynamic picture of interactions among organismic and task-related variables is preferable, reflecting structural changes in such relationships with practice and cohort membership.


Successful treatment of persistent and severe SARS-CoV-2 infection in a high-risk chronic lymphocytic leukemia patient using Ronapreve™ antibodies.
Patients with lymphoproliferative diseases are at an increased risk of an incomplete immune response following vaccination or SARS-CoV-2 infection and might develop persistent viral infection and severe COVID-19 disease. We present a case of successful treatment of persistent and mechanical-ventilation-requiring SARS-CoV-2 infection in a del17+ CLL patient using exogenous antibodies.


Developmental changes in the(45)Ca (2+) uptake byTrichoderma viride mycelium.
The rate of the(45)Ca(2+) uptake by the submergedTrichoderma viride mycelium increased with the age of the culture from 6 h until a maximum which was reached at about 30 h, and then decreased until the uptake was virtually zero. The decrease in the rate of the(45)Ca(2+) uptake was accompanied by an increase of mycelial mass. The uptake rate could not be reactivated upon substituting the medium for a fresh one, without or with dilution of the mycelium. The results suggest that the rate of(45)Ca(2+) uptake reflects the biological age of the submerged culture. The surface-cultivated mycelium took up(45)Ca(2+) proportionally with time. The autoradiography of colonies showed that(45)Ca(2+) was distributed homogeneously throughout the mycelium during vegetative growth while conidiation was accompanied by a massive accumulation of(45)Ca(2+) in conidia.


Computed tomography of a symptomatic infarcted thoracic lipoma.
Intrathoracic lipomas are often asymptomatic and incidentally discovered on routine chest radiographs. An infarcted, pedunculated thoracic lipoma causing chest pain is described. The possibility of liposarcoma was suggested by an inhomogeneous computed tomography appearance and an attenuation value that was greater than that of normal subcutaneous fat.


Renal cell carcinoma following bariatric surgery.
Obesity, hypertension, smoking, and amphetamine diet pills increase the risk for renal cell carcinoma (RCC). Obesity causes a four-fold increase. We report our 11-year experience with RCC after bariatric operations. 5 patients with RCC were identified out of 2,287 bariatric surgical patients since 1993 on retrospective chart review. 4 of the 5 patients were females. At time of their bariatric operation, patients were age 29-52 (43.4) years, weighed 109-158 (129.8) kg, and BMI was 43-60 (49.4). All tumors were incidentally discovered 8-66 (27.4) months postoperatively when the patients weighed 54-94 (71.4) kg, with BMI 21-34 (26.6). Preoperative renal ultrasound obtained within 3 months of the bariatric operation was normal in 4; the other did not have a preoperative study. The latter patient had a vertical banded gastroplasty 12 years before and the RCC was discovered 5 1/2 years later during work-up for a revision. 3 had a distal gastric bypass and 1 underwent adjustable gastric banding. 4 of the patients had a radical nephrectomy and 1 underwent a partial nephrectomy. Tumors were 2.0-8.7 (4.4) cm in size, and all were clear-cell RCC without vascular or extrarenal involvement. None has had recurrence at 3-67 (30.8) months follow-up. 1 patient died from a stroke 18 months later. Reversal of obesity following bariatric surgery does not eliminate risk for RCC. Preoperative and annual postoperative ultrasonography may be useful in identifying early stage RCC. Lesions that are not pure cysts must be evaluated with CT scans or MRI. Nephrectomy may be curative.


[Depression and environmental, cultural and psychosocial variables in aging: "the delusions and sweet sadness of the elderly"].
The need to distinguish, in the elderly, a condition that is strictly and exclusively psychological characterised by an attitude of "sweet sadness" from a frankly pathological situation typical of the clinical picture of depression is underlined.


Photo-assisted transformation of furosemide: Exploring transformation pathways, structure database and suspect and non-target workflows for comprehensive screening of unknown transformation products in wastewaters and landfill leachates.
In recent years, transformation products-(TPs) of pharmaceuticals in the environment have received considerable attention. In this context, here, a customized overview of transformation of Furosemide-(FRS) in aqueous matrices treated by photo-oxidation is provided as a proof of concept. Hence, the primary goal of the study was to display an integrated strategy by combining the target (parent-molecule) and suspect screening-(SS) approaches (TPs) in order to build an in-house High-Resolution mass spectrometry (HRMS) database able to provide reference information (chromatographic/spectral) for environmental investigations in complex matrices (wastewaters/landfill leachates). Data analysis was performed by optimizing a SS workflow. Additional confirmation for the proposed structural elucidation was provided by correlating retention time to the proposed structure employing three prediction models. This approach was applied for the tentative identification of 35 TPs of FRS, 28 of which are reported herein for the first time. Finally, SS and non-target analysis (NTA) have been successfully applied for retrospective screening of FRS and its TPs in real samples. The findings demonstrated that SS allows the proper identification of TPs of FRS in complex matrices proving its outstanding importance compared to NTA. In total, six TPs were identified by SS with potential ecotoxicological implications for two of them according to in silico risk assessment.


Lifetime Burden of Psychological Symptoms, Disorders, and Suicide Due to Cancer in Childhood, Adolescent, and Young Adult Years: A Systematic Review and Meta-analysis.
A cancer diagnosis and treatment may result in highly traumatic periods with lasting psychological consequences for children, adolescent, and young adult patients with cancer (CYACs). Early identification and management may prevent long-term psychological morbidity and suicide. To analyze risk, severity, and risk factors for depression, anxiety, psychotic disorders, and suicide in CYACs and noncancer comparators. Literature search of PubMed, MEDLINE, Embase, PsycINFO, CINAHL, and PubMed Central from January 1, 2000, to November 18, 2022. Full-length articles in peer-reviewed journals that measured and reported risk and/or severity of depression, anxiety, psychotic disorders, and suicide mortality in CYACs and a noncancer comparator group. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed with prospective PROSPERO registration. Risk ratios (RRs) were used for dichotomous outcomes, and standardized mean differences (SMDs) were used for continuous outcomes. SMDs were defined as follows: 0.2, small; 0.5, medium; and 0.8, large. Sources of heterogeneity and risk factors were investigated using sensitivity, subgroup, and meta-regression analyses. From 7319 records, 52 studies were included. Meta-analyses revealed that CYACs were at increased lifetime risk of severe symptoms or a disorder of depression (RR, 1.57; 95% CI, 1.29-1.92), anxiety (RR, 1.29; 95% CI, 1.14-1.47), and psychotic disorders (RR, 1.56; 95% CI, 1.36-1.80) relative to both matched controls and their siblings. Overall suicide mortality was not significantly elevated (RR, 1.63; 95% CI, 0.78-3.40). The mean severity of depression was found to be elevated in CYACs receiving treatment (SMD, 0.44; 95% CI, 0.13-0.74) and long-term survivors (SMD, 0.18; 95% CI, 0.02-0.33). The mean severity of anxiety was found to be elevated only during treatment (SMD, 0.16; 95% CI, 0.03-0.20). Findings of this systematic review and meta-analysis suggest that CYACs may experience lasting psychological burden long into survivorship. Timely identification, preventive efforts, and psycho-oncological intervention for psychological comorbidity are recommended.


In vitro stability of the inhibition of serum converting enzyme by fosinopril.
With captopril, it has been shown that an erroneous measurement of serum angiotensin converting enzyme (ACE) can be induced by the dissociation of the inhibitor-ACE complex during long-term storage. We have studied the possible dissociation of the fosinopril-ACE complex during the storage of serum samples from healthy male volunteers given a single dose of fosinopril. Serum samples were collected from 5 volunteers, 5 min before, then 4 and 24 h after a unique oral dose of 10 mg fosinopril. ACE activity was measured by a colorimetric and a fluorimetric assay during the hour following the sampling (day 0) and after 21 or 61 days of storage at -20 or -196 degrees C. The degree of ACE inhibition measured in vitro in fresh serum samples differed according to the technique used. Fosinopril has a long-lasting effect with 80% inhibition 24 hours after drug administration. Storage at -20 and -196 degrees C induced a significant decrease in the degree of inhibition measured with the colorimetric method. With the fluorimetric method, a decrease in ACE inhibition was only observed after storage at -20 degrees C but not at -196 degrees C.


Characterization of cardiac mechanics and incident atrial fibrillation in participants of the Cardiovascular Health Study.
Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear. In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF. Of 4341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over a median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (heart rate [HR], 1.80; 95% CI, 1.31-2.45; P < 0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain. Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that LA mechanical dysfunction precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF. This research was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, and N01HC85086 and grants KL2TR001424, R01HL107577, U01HL080295, and U01HL130114 from the NIH's National Center for Advancing Translational Sciences, and National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.


Inactivation of Hepatovirus A in wastewater by 254 nm ultraviolet-C irradiation.
Hepatovirus A is known as a waterborne and foodborne virus that can be transmitted from one person to another through contaminated water and raw food. Therefore, it is necessary to survey the circulation of this type of enteric virus in the wastewater to prevent prospective outbreaks. Wastewater samples collected from WWTP El Menzeh I and Charguia I have been the subject for physicochemical, bacteriological (MPN) and virological analyses. Hepatovirus A (HAV) detection was carried out using the standard reverse transcription-polymerase chain reaction (RT-PCR). Hepatovirus A was detected respectively in 62% (63/102) and 66% (92/140) of the collected wastewater samples at El Menzeh I and Charguia I WWTPs. The treated effluent by natural oxidizing lagoon procedure was characterized by a poor physical-chemical and virological qualities but with excellent bacteriological quality. Consequently, this effluent is not suitable to be recycled and reused in agriculture or even dismissed in the environment. The treated sewage by activated sludge and rotating biodisk procedures turned out to be of a very good physical-chemical quality but with a poor bacteriological and virological quality. After tertiary UV-C254 nm irradiation, the faecal indicator bacteria concentration was mostly reduced and removed. These findings confirmed the need for improvement and upgrade of the treatment processes used in these two studied sewage purification plants and the necessity of implementation and establishment of a proper national virological standard to control the circulation rates of enteric viruses in Tunisian municipal wastewater.


Hypoxia Enhances Proliferation of Human Adipose-Derived Stem Cells via HIF-1ɑ Activation.
Adipose tissue-derived stem cells (ASCs) have been recently isolated from human subcutaneous adipose tissue. ASCs may be useful in regenerative medicine as an alternative to bone marrow-derived stem cells. Changes in the oxygen concentration influence physiological activities, such as stem cell proliferation. However, the effects of the oxygen concentration on ASCs remain unclear. In the present study, the effects of hypoxia on ASC proliferation were examined. Normal human adipose tissue was collected from the lower abdomen, and ASCs were prepared with collagenase treatment. The ASCs were cultured in hypoxic (1%) or normoxic (20%) conditions. Cell proliferation was investigated in the presence or absence of inhibitors of various potentially important kinases. Hypoxia inducible factor (HIF)-1α expression and MAP kinase phosphorylation in the hypoxic culture were determined with western blotting. In addition, the mRNA expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2 in hypoxic or normoxic conditions were determined with real-time RT-PCR. The effects of these growth factors on ASC proliferation were investigated. Chromatin immunoprecipitation (ChIP) of the HIF-1α-binding hypoxia responsive element in FGF-2 was performed. HIF-1α was knocked down by siRNA, and FGF-2 expression was investigated. ASC proliferation was significantly enhanced in the hypoxic culture and was inhibited by ERK and Akt inhibitors. Hypoxia for 5-15 minutes stimulated the phosphorylation of ERK1/2 among MAP kinases and induced HIF-1α expression. The levels of VEGF and FGF-2 mRNA and protein in the ASCs were significantly enhanced in hypoxia, and FGF-2 increased ASC proliferation. The ChIP assay revealed an 8-fold increase in the binding of HIF-1α to FGF-2 in hypoxia. HIF-1α knockdown by siRNA partially inhibited the FGF-2 expression of ASCs induced by hypoxia. ASC proliferation was enhanced by hypoxia. HIF-1α activation, FGF-2 production, and the ERK1/2 and Akt pathway were involved in this regulatory mechanism.


Differences in saccharin preference and genetic alterations of the Tas1r3 gene among senescence-accelerated mouse strains and their parental AKR/J strain.
The senescence-accelerated mouse (SAM) is used as an animal model of senescence acceleration and age-associated disorders. SAM is derived from unexpected crosses between the AKR/J and unknown mouse strains. There are nine senescence-prone (SAMP) strains and three senescence-resistant (SAMR) strains. Although SAMP strains exhibit strain-specific and age-related pathological changes, the genes responsible for the pathologic changes in SAMP strains have not been comprehensively identified. In the present study, we evaluated sweet taste perception using the two-bottle test. We compared genotypes of the taste related gene, Tas1r3, using SAM strains and the parental AKR/J strain. The two-bottle test revealed that SAMR1 (R1), SAMP6 (P6), SAMP8 (P8), and SAMP10 (P10) mice were saccharin-preferring strains, whereas AKR/J did not prefer saccharin. All genotypes of the R1, P6, P8, and P10 strains at the polymorphic sites in Tas1r3, which is known to influence saccharin preference, were identical to those of C57BL6/J, a well-known saccharin-preferring strain, and were completely different from those of the parental AKR/J strain. These genetic alterations in SAM strains appear to arise from an unknown strain that is thought to have been crossed with AKR/J initially.


Trisomy 5 mosaicism in amniotic fluid with normal outcome.
A case of prenatally diagnosed true mosaicism for trisomy 5 with a clinically normal outcome is presented. Trisomy 5 was detected in 23% of cells obtained by amniocentesis, but it was not detected from cells obtained by fetal blood sampling. While in this case the finding at amniocentesis did not reflect the status of the fetus, care must be exercised in reaching this conclusion in all cases.


The surface of human menisci and its aging alterations during age. A combined scanning and transmission electron microscopic examination (SEM, TEM).
Eight macroscopically normal menisci of different ages were obtained at autopsy to study their surface structure. The investigation was carried out using transmission and scanning electron microscopic (TEM, SEM) examinations. The combined methods have not been used before. An understanding of physiologic alterations during age has to be furnished for further research of pathological alterations. The surface relief shows clear differences in different age groups. The meniscus surface of the newborn is built of randomly arranged, equally sized folds and cell formations. The TEM-examination reveals a loose net work of collagen fibrils which is not covered by a membrane-like structure on the joint cavity surface. With age the linear folds become wider extending from the anterior to the posterior segment. They are most prominent in the inner zone; in the middle and outer zone they are flattened at areas of interdigitation. These folds are most likely preparation artefacts rather than closely packed fiber bundles or pathologic osteoarthritic alteration of the surface. This is supported by the TEM examination showing a loose 3-dimensional fiber net work. Early degenerative alterations of the meniscus surface are characterized by a slit-like destruction of this superficial fiber net.


The oxidation of p-phenylenediamine, an ingredient used for permanent hair dyeing purposes, leads to the formation of hydroxyl radicals: Oxidative stress and DNA damage in human immortalized keratinocytes.
The hair-dyeing ingredient, p-phenylenediamine (PPD), was previously reported to be mutagenic, possibly by inducing oxidative stress. However, the exact mechanism of PPD in inducing oxidative stress upon skin exposure during hair-dyeing in human keratinocytes remains unknown. The aim of our studies was therefore to investigate the toxicity of PPD and its by-products in human immortalized keratinocytes (HaCaT) after auto-oxidation and after reaction with hydrogen peroxide (H2O2). We found that the PPD half maximal effective cytotoxic concentration (EC50) to HaCaT is 39.37 and 35.63 μg/mL after 24 and 48 h, respectively, without addition of H2O2 to induce oxidation. When PPD (10 or 100 μg/mL) is combined with 10.5 μg/mL of H2O2, intracellular ROS production by HaCaT after 1 h was significantly increased and enhanced levels of DNA damage were observed after 4 h of exposure. After 24 h incubations, 20 μg/mL of PPD increased the level of DNA oxidation in HaCaT. Also, we found that the in vitro reaction between PPD and H2O2, even below the maximum allowance by cosmetic industries, released hydroxyl radicals which can damage DNA. Taken together, we conclude that PPD alone and when combined with H2O2 increases the formation of reactive oxygen species in human keratinocytes, leading to oxidative stress and subsequent DNA damage. These alterations suggest that the mechanism by which PPD exposure, alone or combined with H2O2, damages keratinocytes by the formation of the high reactive HO∙ radicals.


Variability in the growth hormone response to growth hormone-releasing hormone alone or combined with pyridostigmine in type 1 diabetic patients.
In man the GH response to GHRH is variable within and between subjects. Pyridostigmine (PD), an acetylcholinesterase inhibitor, has been shown to reduce the variability of the GH response to GHRH in normal subjects. The aim of this study was to assess the existence of either inter- or intraindividual variability in the GH response to GHRH in type 1 diabetic patients. Moreover, we investigated the effect of PD on such variability in the same patients. Seven (4 females-3 males) nonobese type 1 diabetic patients underwent two experiments performed in consecutive days according to a single-blind protocol: 1) 120 mg oral PD 60 min before iv injection of human (h) GHRH-(1-29) NH2, 100 micrograms in 2 ml of sterile water; 2) oral placebo 60 min before iv injection of 100 micrograms hGHRH. The two experiments were then repeated, following the same procedure, one and two weeks after the start of the study. The GH peaks after GHRH were variable within different subjects but also in the same subject on different occasions. However, the mean GH peak levels after GHRH in the three tests were not significantly different (14.2 +/- 3.5, 15.3 +/- 3, 16.5 +/- 6.4 micrograms/L, respectively), the coefficient of variation for each test was 65%, 51.8%, 102.4%, respectively (mean 73.1 +/- 15.1%). The GH response to GHRH was always significantly enhanced by PD administration: the mean GH peak levels in the three tests were 31.9 +/- 7.1, 44.8 +/- 10.4, 49.9 +/- 13.1 micrograms/L, respectively, without significant differences between tests.(ABSTRACT TRUNCATED AT 250 WORDS)


Experimental and theoretical rationalization for the base pairing abilities of inosine, guanosine, adenosine, and their corresponding 8-oxo-7,8-dihydropurine, and 8-bromopurine analogues within A-form duplexes of RNA.
Inosine is an important RNA modification, furthermore RNA oxidation has gained interest due, in part, to its potential role in the development/progression of disease as well as on its impact on RNA structure and function. In this report we established the base pairing abilities of purine nucleobases G, I, A, as well as their corresponding, 8-oxo-7,8-dihydropurine (common products of oxidation at the C8-position of purines), and 8-bromopurine (as probes to explore conformational changes), derivatives, namely 8-oxoG, 8-oxoI, 8-oxoA, 8-BrG, and 8-BrI. Dodecamers of RNA were obtained using standard phosphoramidite chemistry via solid-phase synthesis, and used as models to establish the impact that each of these nucleobases have on the thermal stability of duplexes, when base pairing to canonical and noncanonical nucleobases. Thermal stabilities were obtained from thermal denaturation transition (Tm ) measurements, via circular dichroism (CD). The results were then rationalized using models of base pairs between two monomers, via density functional theory (DFT), that allowed us to better understand potential contributions from H-bonding patterns arising from distinct conformations. Overall, some of the important results indicate that: (a) an anti-I:syn-A base pair provides thermal stability, due to the absence of the exocyclic amine; (b) 8-oxoG base pairs like U, and does not induce destabilization within the duplex when compared to the pyrimidine ring; (c) a U:G wobble-pair is only stabilized by G; and (d) 8-oxoA displays an inherited base pairing promiscuity in this sequence context. Gaining a better understanding of how this oxidatively generated lesions potentially base pair with other nucleobases will be useful to predict various biological outcomes, as well as in the design of biomaterials and/or nucleotide derivatives with biological potential.


Genetic and biochemical analyses of the tec operon suggest a route for evolution of chlorobenzene degradation genes.
The TecA broad-spectrum chlorobenzene dioxygenase of Burkholderia sp. strain PS12 catalyzes the first step in the mineralization of 1,2,4, 5-tetrachlorobenzene. The catabolic genes were localized on a small plasmid that belongs to the IncPbeta incompatibility group. PCR analysis of the genetic environment of the tec genes indicated high similarity to the transposon-organized catabolic tcb chlorobenzene degradation genes of Pseudomonas sp. strain P51. Sequence analysis of the regions flanking the tecA genes revealed an upstream open reading frame (ORF) with high similarity to the todF 2-hydroxy-6-oxo-2,4-heptadienoate hydrolase gene of Pseudomonas putida F1 and a discontinuous downstream ORF showing high similarity to the todE catechol 2,3-dioxygenase gene of strain F1. Both homologues in strain P51 exist only as deletion remnants. We suggest that different genetic events thus led to inactivation of the perturbing meta-cleavage enzymes in strains P51 and PS12 during the evolution of efficient chlorobenzene degradation pathways. Biochemical characterization of TodF-like protein TlpF and a genetically refunctionalized TodE-like protein, TlpE, produced in Escherichia coli provided data consistent with the proposed relationships.


Effect of human recombinant erythropoietin on human marrow megakaryocyte colony formation in vitro.
The effect of human recombinant erythropoietin (EP) on the growth of human marrow megakaryocyte colony forming units (CFU-M) in vitro was investigated by the use of a plasma clot assay. EP as a single stimulating factor or as an additional factor to optimal concentration of leucocyte conditioned medium (PHA-LCM) had no effect on the number of CFU-M derived colonies. However, addition of EP (0.5-1 U/ml) to cultures with suboptimal concentrations of PHA-LCM increased megakaryocytic colony formation by 50-90% but had no effect on the number of granulocytic-monocytic colonies (CFU-GM). Exposure of marrow cells to EP for 24-48 h in liquid suspension cultures, followed by removal of the hormone and assaying the cells for CFU-M in plasma clots, resulted in a 50-100% increase of megakaryocyte colony formation in vitro. The augmenting effect of EP on CFU-M growth in vitro was abolished when EP was added to the medium after the third day of culture. The presence of factors in human serum and in PHA-LCM was an absolute requirement for the hormone to exert its potentiating effect on human CFU-M growth in vitro. Recombinant EP potentiates the growth of human marrow CFU-M and this effect seems to be exerted during the early stages of CFU-M development in vitro.


Fate and transport of monoterpenes through soils. Part II: calculation of the effect of soil temperature, water saturation and organic carbon content.
This theoretical study was performed to investigate the influence of soil temperature, soil water content and soil organic carbon fraction on the mobility of monoterpenes (C10HnOn') applied as pesticides to a top soil layer. This mobility was expressed as the amount volatilized and leached from the contaminated soil layer after a certain amount of time. For this, (slightly modified) published analytical solutions to a one dimensional, homogeneous medium, diffusion/advection/biodegradation mass balance equation were used. The required input-parameters were determined in a preceding study. Because the monoterpenes studied differ widely in the values for their physico-chemical properties, the relative importance of the various determinants also differed widely. Increasing soil water saturation reduced monoterpene vaporization and leaching losses although a modest increase was usually observed at high soil water contents. Organic matter served as the major retention domain, reducing volatilization and leaching losses. Increasing temperature resulted in higher volatilization and leaching losses. Monoterpene mobility was influenced by vertical water flow. Volatilization losses could be reduced by adding a clean soil layer on top of the contaminated soil. Detailed insight into the specific behaviour of different monoterpenes was obtained by discussing intermediate calculation results; the transport retardation factors and effective soil diffusion coefficients. One insight was that the air-water interface compartment is probably not an important partitioning domain for monoterpenes in most circumstances. The results further indicated that biodegradation is an important process for monoterpenes in soil.


"I'm in this world for a reason": Resilience and recovery among American Indian and Alaska Native two-spirit women.
American Indian and Alaska Native sexual minority (two-spirit) women are vulnerable to substance misuse and mental health challenges due to multiple minority oppressed status and exposure to stress and trauma. Yet, these women find pathways toward healing and wellness. We conducted a qualitative data analysis of interviews derived from a national health study and gained an understanding of 11 two-spirit women's resilience and recovery patterns. Emergent from the data, a braided resiliency framework was developed which elucidates multilayered abilities, processes, and resources involved in their resiliency. We recommend that resilience-promoting strategies be incorporated into substance misuse and mental health interventions.


Recombinant goldfish growth hormones (gfGH-I and -II) expressed in Escherichia coli have similar biological activities.
Complementary DNA regions coding for two different mature goldfish growth hormones (gfGH-I and gfGH-II) with four and five cysteine residues were cloned into the bacterial expression vector, pRSETA. The recombinant gfGH-I (five cysteines) and -II (four cysteines) were produced in Escherichia coli as the fusion proteins carrying N-terminal 6XHis tag, which facilitates purification by using metal chelating affinity chromatography under denaturing condition with urea. The recombinant hormones were further refolded by gradually removing the urea. Native gfGH was also purified from goldfish pituitary glands and served as a positive control in the present study. The native and recombinant hormones were tested in goldfish hepatic radioreceptor assay and in vitro Spi 2.1 promoter activation assay. Our results showed that the two recombinant gfGHs are biologically active, and they have similar biological activities despite their having different cysteine contents.


The crystal structure of an inactive dimer of PDZ-binding kinase.
The overexpression of PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) has been associated with hematologic tumors, breast cancer and various other cancers. However, the three-dimensional structure of PBK has not been solved. In this study, we determined the crystal structure of human PBK, which has two phospho-mimicking mutations T9E and T198E. The structural data indicated that PBK may assemble into an inactive dimer in alkaline conditions. Analytical size-exclusion chromatography and analytical ultracentrifugation confirmed that PBK exists in a conformational transition between dimers and monomers at different pH conditions. Co-IP and kinase assays suggested that the active state of PBK is a monomer and does not form a dimer even under alkaline conditions. These results showed that the conformational transition of PBK is important for its kinase activity regulation. Collectively, our observations may provide a novel starting point for structure-based functional studies.


Mn(II) and Cu(II) complexes of a bidentate Schiff's base ligand: spectral, thermal, molecular modelling and mycological studies.
Complexes of manganese(II) and copper(II) of general composition M(L)2X2 have been synthesized [L=2-acetyl thiophene thiosemicarbazone and X=Cl(-) and NO3(-)]. The elemental analysis, molar conductance measurements, magnetic susceptibility measurements, mass, IR, UV, NMR and EPR spectral studies of the compounds led to the conclusion that the ligand acts as a bidentate manner. The Schiff's base ligand forms hexacoordinated complexes having octahedral geometry for Mn(II) and tetragonal geometry for Cu(II) complexes. The thermal studies suggested that the complexes are more stable as compared to ligand. In molecular modelling the geometries of Schiff's base and metal complexes were fully optimized with respect to the energy using the 6-31g(d,p) basis set. The mycological studies of the compounds were examined against the plant pathogenic fungi i.e. Rhizoctonia bataticola, Macrophomina phaseolina, Fusarium odum.


The uterine pathological features associated with sentinel lymph node metastasis in endometrial carcinomas.
In recent years, sentinel lymph node excision and ultrastaging have been performed in endometrial carcinomas to obtain information about lymph node status, avoiding unnecessary complete pelvic and paraaortic lymphadenectomy. The purpose of this retrospective study was to provide a comprehensive evaluation of the pathological features of endometrial carcinomas and their significance in association with sentinel lymph node involvement. Patients with endometrial carcinomas, preceded by sentinel lymph node mapping, were classified into Group-I and Group-II with negative and positive involvement, respectively. The pathological features, associated with sentinel lymph node involvement, were statistically analyzed, including determination of test performance parameters. Among 70 patients who had undergone hysterectomy and sentinel lymph node excision, 61 had carcinoma and 9 had atypical hyperplasia. There were 50 patients in Group-I and 10 in Group-II. In Group-II, the significant pathological features were: 1) lower uterine segment involvement (100%), 2) an average tumor size of ≥5 CM, 3) lymphovascular invasion (50%), 4) cervical stromal invasion (40%), and 5) depth of myometrial invasion of ≥50% (50%). The incidences of these pathological features were significantly less in Group-I. Statistical analyses singled out "lower uterine segment involvement" as the most important feature. We have identified five pathological features which are associated with sentinel lymph node involvement. Since lower uterine segment involvement has occurred in all cases of the Group-II cohort, we recommend FIGO and other organizations that determine staging rules should consider whether tumors that involve the lower uterine segment should be staged as higher than "1a", if the findings in this small series are confirmed by other studies. The results of this study may guide pathologists and oncologists in the diagnostic and therapeutic approaches to management of endometrial carcinomas.


[Nebivolol in treatment of multiple cerebral aneurysms].
We examined the effect of nebivolol on blood pressure control after subarachnoidal hemorrhage in three patients with multiple aneurysms. Endovascular intervention was applied to treat the bleeding aneurysms of all patients, and the silent aneurysms were followed-up. In all patients nebivolol was used as long-term anti-hypertensive medication. With nebivolol treatment the blood pressure in our patients was maintained in the normal range with no unexpected shoot-ups. The size of the silent aneurysms did not increase and the endovascularly treated aneurysms demonstrated acceptable morphology on follow-up catheter-angiography. After endovascular treatment of the bleeding aneurysm, strict blood pressure control is essential in those with multiple aneurysms to prevent the rupture of silent aneurysms. Antihypertensive medications with a 24-hour effect are preferable. Nebivolol seemed to be an appropriate medication for this purpose in all of our patients.


Successful remediation of soils with mixed contamination of chromium and lindane: Integration of biological and physico-chemical strategies.
Soils contaminated by organic and inorganic pollutants like Cr(VI) and lindane, is currently a main environmental challenge. Biological strategies, such as biostimulation, bioaugmentation, phytoremediation and vermiremediation, and nanoremediation with nanoscale zero-valent iron (nZVI) are promising approaches for polluted soil health recovery. The combination of different remediation strategies might be key to address this problem. For this reason, a greenhouse experiment was performed using soil without or with an organic amendment. Both soils were contaminated with lindane (15 mg kg-1) and Cr(VI) (100 or 300 mg kg-1). After one month of aging, the following treatments were applied: (i) combination of bioaugmentation (actinobacteria), phytoremediation (Brassica napus), and vermiremediation (Eisenia fetida), or (ii) nanoremediation with nZVI, or (iii) combination of biological treatments and nanoremediation. After 60 days, the wellness of plants and earthworms was assessed, also, soil health was evaluated through physico-chemical parameters and biological indicators. Cr(VI) was more toxic and decreased soil health, however, it was reduced to Cr(III) by the amendment and nZVI and, to a lesser extent, by the biological treatment. Lindane was more effectively degraded through bioremediation. In non-polluted soils, nZVI had strong deleterious effects on soil biota when combined with the organic matter, but this effect was reverted in soils with a high concentration of Cr(VI). Therefore, under our experimental conditions bioremediation might be the best for soils with a moderate concentration of Cr(VI) and organic matter. The application of nZVI in soils with a high content of organic matter should be avoided except for soils with very high concentrations of Cr(VI). According to our study, among the treatments tested, the combination of an organic amendment, biological treatment, and nZVI was shown to be the strategy of choice in soils with high concentrations of Cr(VI) and lindane, while for moderate levels of chromium, the organic amendment plus biological treatment is the most profitable treatment.


Age-related susceptibility of naive and memory CD4 T cells to apoptosis induced by IL-2 deprivation or PHA addition.
The increased age-associated incidence of infectious and cancer diseases has been related to the alteration of immune functioning found in the elderly (immunosenescence). The reduction of naive T cells, which determine an impaired ability to mount immune responses to new antigens, represents a hallmark of the aging process. The aim of this study was to evaluate the susceptibility to apoptosis of purified naive and memory CD4(+) T cells from peripheral blood of healthy people ranging in age from 20 to 98 years. Two mechanisms of T cell elimination by apoptosis have been evaluated: cytokine deprivation and activation-induced cell death. After Interleukin-2 deprivation, the percentage of naive and memory CD4(+) apoptotic cells significantly increased with donor age concomitantly with a reduction of Bcl-2 expression and an increase of intracellular content of reactive oxygen species. After phytohemagglutinin addition, the percentage of apoptotic cells, the expression of CD95, and the intracellular reactive oxygen species, were not significantly correlated with age both in naive and memory CD4(+) T cells. Our data demonstrate the existence of functional alterations of naive and memory T cell populations during ageing. These alterations are mainly related to the mechanism of the apoptotic event rather than to the type of cell population involved (naive or memory). The alterations of naive and memory T cells may have implications in the age-related susceptibility to diseases.


Cultured interstitial cells from human heart valves express both specific skeletal muscle and non-muscle markers.
Cardiac valve interstitial cells are a phenotypically diverse and dynamic population, comprising myofibroblasts, fibroblasts and smooth muscle cells. To understand how these contribute to valve function and to optimize the choice of cells for seeding tissue-engineered valves, we are fingerprinting interstitial cells from all four human heart valves for useful phenotypic markers. We have begun by selecting markers indicated as of interest from previous work on myofibroblast-like cell lines. We show that interstitial cells express a variety of skeletal muscle contractile proteins and the skeletal muscle transcription factor myogenin, but not the related factors MyoD, myf-5 and MRF4, suggesting partial activation of the muscle programme in these cells. Expression of non-muscle isoforms of creatine kinase (CK-B) and AMP deaminase (AMPD2 and AMPD3) was found in contrast to muscle-restricted isoforms. Non-muscle isoforms of alpha- and beta-tropomyosins were detected specifically in contrast to skeletal muscle-specific isoforms. Several members of the Frizzled (FZD) family of Wnt receptors were also detected. In addition, intact cusps of all four valves from pig were capable of contacting to non-receptor and receptor-mediated stimulation in vitro. We conclude that interstitial cells from human heart valves express various sarcomeric proteins, and suggest that these cells have contractile potential due to a unique pattern of expression of both muscle-specific and non-muscle isoforms of metabolic and structural proteins. This may be under the control of myogenin, activated through specific Wnt/FZD signaling. Identifying such molecular markers could prove useful for engineering allogenic non-valve cell sources for seeding the synthetic valve.


Reproductive effort in two subtidal populations of the limpet, Patelloida mufria.
The reproductive cycle and reproductive effort (RE) of 2 populations of the acmaeid limpet Patelloida mufria were investigated in a subtidal region of N.S.W., Australia. These two populations had vastly different densities, rates of growth and mortality. Nonetheless, their patterns of spawning were remarkably similar with 5 spawning periods during the year of monitoring, and their values for RE were very similar; individuals from each population spawned about 35% of their somatic weight each 6 months. This does not, therefore, conform with theories that the RE of populations should be correlated with their rates of mortality. The results for P. mufria were compared with those of 4 populations of Cellana tramoserica and 2 of P. alticostata which had been studied previously at this location. There was still no general correlation between RE and mortality, but by only using certain combinations of these 8 populations (i.e. only one from each species at a time), positive or negative correlations could be obtained. This illustrated the need to ensure that intraspecific variability is accounted for in any analysis of life-history strategies. Finally, it was concluded that instead of the absolute vale of RE being important, the amount of flexibility in this and other traits may represent the real difference in strategies amongst species.


Synthesis, characterization and adsorption behavior of cotton fiber based Schiff base.
Structural modification of Cotton (Cot) fiber was carried out using ε-caprolactone (CL) as a monomer and oxydianiline (ODA) as a Schiff base forming agent in the presence of V2O5 catalyst in dimethylsulfoxide medium for 24h under air atmosphere (0.10MPa) at 80°C. The obtained products were analyzed for the characteristics and also for its adsorption of hexavalent chromium (Cr(VI)) and rhodamine 6G (R6G) dye molecules. The 1H NMR spectrum confirms the Schiff base formation at 8.7ppm. The adsorption study confirms the Pseudo second order kinetics with Langmuir adsorption model. The structurally modified Cot fiber based Schiff base exhibited the highest adsorption behavior through chemical interaction forces. The thermodynamic parameters were determined and confirmed the endothermic adsorption process.


The pups' endometrium morphology is affected by maternal malnutrition during suckling.
This study aims to determine the effects of maternal protein and energy malnutrition during lactation on the endometrial structures of the offspring at puberty. At parturition, dams were randomly assigned to the following groups: control group (C), with free access to a standard laboratory diet containing 23% protein; protein-restricted (PR) group, with free access to an isoenergy and protein-restricted diet containing 8% protein; and energy-restricted (ER) group, receiving standard laboratory diet in restricted quantities. After weaning, all female pups had free access to standard laboratory diet. At puberty, the animals were sacrificed with pentobarbital and only females on the diestrum stage were used for the analyses. The stereological method used for quantifying the uterine endometrium was the M42 test system. When compared to C group, both PR and ER groups presented a significant reduction in the length density of the glands (PR=53%, ER=35.7%, p<0.001), in the volumetric density of the epithelium (PR=49%, ER=38%, p<0.001) and lumen (PR=42.7%, p<0.001; ER=23.8%, p<0.001) and in the surface density of the inner (PR=22%, ER=13.8%, p<0.001) and outer (PR=55.4%, p<0.01; ER=40.6%, p<0.001) glands. The volumetric density of the stroma was significantly higher in both PR (114%, p<0.001) and ER (117%, p<0.001) groups. In all parameters studied, there was no significant difference between PR and ER groups. Our results show that the protein and energy restriction during lactation leads to an atrophy of the uterine endometrial glands of the offspring at puberty.