Genotoxicity testing of three monohaloacetic acids in TK6 cells using the cytokinesis-block micronucleus assay.
Chemical disinfection of water generates harmful chemical compounds, known as disinfection by-products (DBPs). One class of DBPs is constituted by haloacetic acids (HAAs), the second major group in prevalence (after trihalomethanes) detected in finished drinking water. In this article, we report the results obtained in the evaluation of the chromosome damage induced by three monohaloacetic acids, namely iodoacetic acid (IAA), bromoacetic acid (BAA) and chloroacetic acid (CAA). To evaluate the induction of chromosome damage, we used the cytokinesis-block micronucleus test that measures the ability of genotoxic agents to induce both clastogenic and/or aneugenic effects. No previous data exist on the effects of these compounds on human chromosomes. We tested five doses of each HAA, in addition to the negative and positive controls. The highest dose tested for each HAA was that immediately lower than the dose producing total cytotoxicity. Our results show that none of the three HAAs tested was able to increase significantly the frequency of micronucleus in binucleated TK6 cells, the rank order in decreasing cytotoxicity was IAA > BAA >> CAA.


A double blind, randomized, placebo-controlled phase II study to assess the safety and efficacy of orally administered SP-303 for the symptomatic treatment of diarrhea in patients with AIDS.
The aim of this study was to investigate the safety and effectiveness of orally administered SP-303 in patients with AIDS and diarrhea. This is a multicenter, phase II, randomized, double blind, placebo-controlled study. HIV-positive subjects with a history of a CD4 count <200 or an AIDS-defining illness were admitted to an inpatient study unit and screened for diarrhea defined as at least three abnormal (i.e., soft or watery) stools and >200 g of abnormal stool weight over a 24-h period. Subjects discontinued all antidiarrheal agents >24 h before enrollment. Stool samples were studied for routine pathogens. Subjects received 500 mg p.o. of SP-303 or placebo every 6 h for 96 h (4 days). Stool frequency and weights were recorded. Subjects were monitored for symptoms and side effects and were seen 1 wk later in follow-up. A total of 26 subjects received SP-303, and 25 received placebo. There were no significant demographic differences between treatment arms. A total of 41 subjects (80%) were receiving antiretroviral therapy and 39 subjects (77%) were receiving at least one protease inhibitor. Stool studies revealed no pathogens in 48 of 51 patients (94%). There were no serious adverse events or laboratory abnormalities. The SP-303 treatment group demonstrated a mean reduction from baseline stool weight of 451 g/24 h versus 150 g/24 h with placebo on day 4 of treatment (p = 0.14), and a mean reduction in abnormal stool frequency of three abnormal stools in 24 h versus two in 24 h in the placebo group (p = 0.30). Daily measures analysis over 4 days of treatment demonstrated that SP-303 subjects had a significant reduction in stool weight (p = 0.008) and abnormal stool frequency (p = 0.04) when compared to placebo-treated subjects. SP-303 is safe and well tolerated. These results suggest that SP-303 may be effective in reducing stool weight and frequency in patients with AIDS and diarrhea.


Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer.
Pembrolizumab is a programmed death receptor-1 masking antibody approved for metastatic non-small cell lung cancer. This Phase 2 study (NCT02818920) of neoadjuvant pembrolizumab in non-small cell lung cancer had a primary end point of safety and secondary end points of efficacy and correlative science. Patients with untreated clinical stage IB to IIIA non-small cell lung cancer were enrolled. Two cycles of pembrolizumab (200 mg) were administered before surgery. Standard adjuvant chemotherapy and radiation were encouraged but not required. Four cycles of adjuvant pembrolizumab were provided. Of 35 patients enrolled, 30 received neoadjuvant pembrolizumab and 25 underwent lung resection. Only 1 patient had a delay before surgery attributed to pembrolizumab; this was due to thyroiditis. All patients underwent anatomic resection and mediastinal lymph node dissection; the majority (18/25%, 72%) of patients underwent lobectomy. Of the 25 patients, 23 had an initial minimally invasive approach (92%); 5 of these were converted to thoracotomy (21.7%). R0 resection was achieved in 22 patients (88%), and major pathologic response was observed in 7 of 25 patients (28%). The most common postoperative adverse event was atrial fibrillation, affecting 6 of 25 patients (24%). Median chest tube duration and length of stay were 3 and 4 days, respectively. One patient required readmission to the hospital within 30 days. There was no mortality within 90 days of surgery. In this study, pembrolizumab was safe and well tolerated in the neoadjuvant setting, and its use was not associated with excess surgical morbidity or mortality. Minimally invasive approaches are feasible in this patient population, but may be more challenging than in cases without neoadjuvant immunotherapy. Pathologic response was higher than typically observed with standard neoadjuvant chemotherapy.


Sexuality in persons with lower extremity amputations.
There is a paucity of information regarding sexual functioning in persons with lower extremity amputations. The purpose of this study was to describe sexual and psychological functioning and health status in persons with lower extremity amputation. Self-report surveys assessed sexual functioning (Derogatis Inventory), depression (Beck Depression Inventory, anxiety (State-Trait Anxiety Inventory), and health status (Health Status Questionnaire) in a convenience sample of 30 men with lower extremity amputations. Mean age of the participants was 57 years (range 32-79). Mean duration since amputation was 23 months (range 3-634 months). Twenty one subjects (70%) had trans-tibial and seven subjects (23%) had trans-femoral amputations. A majority of subjects were experiencing problems in several domains of sexual functioning. Fifty three percent (n = 16) of the subjects were engaged in sexual intercourse or oral sex at least once a month. Twenty seven percent (n = 8) were masturbating at least once a month. Nineteen subjects (63%) reported orgasmic problems and 67% were experiencing erectile difficulties. Despite these problems, interest in sex was high in over 90% of the subjects. There was no evidence of increased prevalence of depression or anxiety in these subjects when compared to other outpatient adult populations. Sexual problems were common in the subjects studied. Despite these problems, interest in sex remained high. Few investigations have been directed toward identifying the psychological and social factors that may contribute to these problems and more research with a larger population is needed in this area.


Role of Kruppel-like factors in leukocyte development, function, and disease.
The Krüppel-like transcription factor (KLF) family participates in diverse aspects of cellular growth, development, differentiation, and activation. Recently, several groups have identified new connections between the function of these factors and leukocyte responses in health and disease. Gene targeting of individual KLFs in mice has uncovered novel and unexpected physiologic roles among myeloid and lymphocyte cell lineage maturation, particularly in the bone marrow niche and blood. In addition, several KLF family members are downstream targets of stimuli and signaling pathways critical to T-cell trafficking, T regulatory cell differentiation or suppressor function, monocyte/macrophage activation or renewal, and B memory cell maturation or activation. Indeed, KLFs have been implicated in subtypes of leukemia, lymphoma, autoimmunity, and in acute and chronic inflammatory disease states, such as atherosclerosis, diabetes, and airway inflammation, raising the possibility that KLFs and their upstream signals are of therapeutic interest. This review focuses on the relevant literature of Krüppel-like factors in leukocyte biology and their implications in clinical settings.


Antibodies to oxidized low-density lipoproteins and angiographically assessed coronary artery disease in white patients.
Low-density lipoprotein (LDL) can be oxidatively modified by reactive oxygen species, thus generating oxLDL. The latter induce formation of specific antibodies (oxLDLAb), which are detectable in patients with atherosclerosis, in which they might play a pathogenic or a protective role. Thus, we aimed to investigate the association of antibodies with oxidized LDLs (oxLDL) (oxLDLAbs) with coronary artery disease (CAD) and acute coronary syndromes. In a cross-sectional study of 529 consecutive patients undergoing quantitative coronary angiography for suspected CAD, we measured the titer of IgG oxLDLAbs by ELISA. With regression analysis techniques, we also investigated the determinants of oxLDLAb titer and the association of oxLDLAbs with CAD severity. We found no significant differences of oxLDLAb titer between groups of patients without and with different CAD severity. The oxLDLAb titer was 18.6 enzyme units (EU) (11.5 to 25.7 EU/mL) (mean, 95% CI) in patients without CAD; 16.8 EU (9.6 to 24.2 EU) in patients with stenosis <50%; and 19.9 EU (15 to 24.8 EU), 17.2 (13.8 to 20.6 EU), and 14.7 EU (12.1 to 17.3 EU) in those with in 1-, 2-, or 3-vessel > or =50% stenosis, respectively. Similarly, no differences of oxLDLAb titer between patients without and with acute coronary syndrome were found. The oxLDLAb titer correlated weakly with aging and with serum total, LDL, and HDL cholesterol and plasma homocysteine levels; however, only age and HDL cholesterol remained significant predictors of the oxLDLAb titer at a stepwise regression analysis. The results of this study, which was adequately powered from the statistical standpoint, provided no evidence for an association of IgG oxLDLAb titer with angiographically assessed CAD in whites.


Downregulation of ZNF278 arrests the cell cycle and decreases the proliferation of colorectal cancer cells via inhibition of the ERK/MAPK pathway.
Zinc finger protein 278 is a zinc finger transcription factor encoded on the 22q12.2 chromosome. Previous studies revealed that ZNF278 expression was significantly upregulated in colorectal cancer (CRC) tissue compared to adjacent non-tumor tissue. However, the expression and specific roles of ZNF278 in CRC remain unknown. ZNF278 expression was knocked down using specific siRNAs, which was confirmed by western blotting, and the effects of ZNF278 siRNAs on CRC cell proliferation were investigated. In addition, the effects of ZNF278 overexpression were confirmed by western blotting and cell proliferation assay. Correlations between ZNF278 and the ERK/MAPK pathway were also detected by western blotting. We found that ZNF278 knockdown significantly induced cell cycle arrest, resulting in cyclin D1/E1 downregulation and p21 upregulation. Moreover, we demonstrated that downregulation of ZNF278 decreased the proliferation of CRC cells via inhibition of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway for the first time. In conclusion, ZNF278 played a prominent role in the pathogenesis of CRC, and promoted CRC cell proliferation via the ERK/MAPK pathway, suggesting that it may act as a potential target in the diagnosis or treatment of CRC.


Let's Talk About Sex: A Survey of Patients' Preferences When Addressing Sexual Health Concerns in a Family Medicine Residency Program Office.
Comprehensive medical care should embody the biopsychosocial care model and encompass all aspects of health. Sexual health topics may be overlooked or avoided because of patient and provider discomfort. Our purpose was to better understand patients' preferences about discussing sexual concerns in primary care. We hypothesized that most individuals have sexual concerns, but many barriers prevent them from seeking care. We surveyed patients at a family medicine residency program office. The survey explored whether patients had experienced sexual concerns, preferences for addressing concerns in the office, and barriers and facilitators to addressing concerns. Results were analyzed using counts and proportions. Pearson correlations, Pearson χ2 analyses, and independent samples t-tests were used to explore demographic differences in responses. Most participants indicated that physicians should ask all patients about having sexual concerns and that physicians should initiate these conversations. Younger participants were more likely to have this preference. Participants identified embarrassment as the most common barrier to sexual health conversations. Participants indicated it was easier to discuss sexual concerns with physicians of the same gender and/or a physician they had seen before. The majority of patients prefer active inquiry about sexual health concerns from primary care physicians. However, because a large minority prefer not to be asked about sexual health, physicians should inquire sensitively, particularly with older patients. Continuity of patient-physician relationship and allowing patients to choose their provider based on gender may also help facilitate these discussions.


Evaluation of wheat gluten in milk replacers and calf starters.
Two trials were conducted to evaluate wheat gluten as an ingredient in calf feeds. In one trial, Holstein bull calves (n = 120) were assigned for 6 wk to one of five milk replacers, which contained different percentages of CP and different percentages of protein furnished from soluble wheat gluten. Within a given protein percentage, BW gains of calves were not affected by the percentage of protein that was supplied as wheat gluten. Calves fed milk replacer containing 18% CP with 33% wheat gluten gained as much as calves fed replacers containing 20% CP. In another trial, newborn Holstein calves (n = 62) were used. Protein supplements of the calf starters used until 7 wk of age were either soybean meal or spray-dried wheat gluten and soybean meal. No significant differences were observed between the two treatments. Also, no significant carry-over effect occurred when all calves received a common diet from 7 to 10 wk of age.


The Common Attributes of Successful Care Manager Programs for High-Need, High-Cost Persons: A Cross-Case Analysis.
Many programs use care managers to improve care coordination for high-need, high-cost patient populations. However, little is known about how programs integrate care managers into care delivery or the attributes shared by successful programs. We used a case study approach to examine the common attributes of 10 programs for high-need, high-cost individuals utilizing a longitudinal care manager that had achieved success in reducing cost, improving quality, or increasing patient satisfaction. Through interviews with program leaders and document review, we identified 10 common attributes of successful care manager programs, offering insights for providers aiming to better serve the high-need, high-cost population.


Critical role of Ca2+ ions in the reaction mechanism of Euphorbia characias peroxidase.
A cationic peroxidase was isolated and characterized from the latex of the perennial Mediterranean plant Euphorbia characias. The purified enzyme contained one heme prosthetic group identified as ferric iron-protoporphyrin IX. In addition, the purified peroxidase contained 1 mol of endogenous calcium per mol of enzyme; removal of this calcium ion resulted in almost complete loss of the enzyme activity. However, when excess Ca(2+) was added to the native enzyme the catalytic efficiency was enhanced by 3 orders of magnitude. The mechanism of activation was studied using a wide range of spectroscopic and analytic techniques. Analysis of the steady state by stopped-flow measurements suggests that the main effect of calcium ions is to favor the oxidation of the ferric enzyme by hydrogen peroxide to form compound I, whereas the other steps of the catalytic cycle seem to be affected to a lesser extent. UV/vis absorption spectra and CD measurements show that the heme iron is pentacoordinated high-spin in native enzyme and remains so after the binding of Ca(2+). Only minor changes in the secondary or tertiary structure of the protein could be detected by fluorescence or CD measurements in the presence of Ca(2+) ions, except for a significant perturbation of the Fe(3+) inner sphere geometry, as detected by EPR measurements. We propose that Ca(2+) binding to a low affinity site induces a reorientation of the distal histidine changing the almost inactive form of Euphorbia peroxidase to a high activity form. This is the first example of a peroxidase that responds as an on/off switch to variations in the external Ca(2+) level.


Clinical diagnostic value of free body of reduced iron protoporphyrin in uterus epithelial cells on cervical carcinoma and precancerous lesion.
Cervical cancer is a common malignant tumor in women with increased incidence and younger onset age. As a curable tumor, timely diagnosis and early intervention are critical. Based on the golden standard of cervical tissues pathology examination, we investigated the value of free body of reduced iron protoporphyrin (FH) in uterus epithelial cells for the diagnosis of cervical cancer and precancerous lesions, aiming to provide novel methods for early screening of cervical cancer. A total of 574 women who were screened for cervical cancer according to golden standard of pathology as the reference, were recruited for the analysis of authenticity, reliability, and predictive values of FH. The diagnostic value of FH on cervical carcinoma and precancerous lesion diagnosis was further analyzed. 340 individuals had normal cervical or benign lesion by pathology examination, while 155 people had precancerous lesion, among which 79 cases presented early infiltration and infiltrative cancer. In FH screening, 361 and 213 people had negative and positive results, respectively. No significant differences in the results were observed between the two methods in screening cancer and precancerous lesion (p>0.05). FH showed 93.55% sensitivity and 81.94% specificity in diagnosing precancerous lesion, while the sensitivity and specificity for cervical cancer diagnosis were 93.53% and 81.01%, respectively. FH assay was demonstrated to have advantages of high diagnostic value for cervical cancer and precancerous lesion, and might be used for early screening.


Ezrin Expression is Increased During Disease Progression in a Tauopathy Mouse Model and Alzheimer's Disease.
The lack of diagnostic tools and disease-modifying treatments against Alzheimer's disease (AD) and related disorders, collectively known as tauopathies, has led to a socioeconomic burden of epidemic proportion. Proteomics approaches can be used to identify novel proteome changes that could help us understand the pathogenesis of tau-related pathological hallmarks and/or cellular stress responses associated with tauopathy. These studies, however, need to be conducted taking into consideration brain region specificity and stage of neurodegeneration in order to provide insights about the pathological role of the identified proteins. We used a tauopathy mouse model (JNPL3) that expresses human tau bearing a P301L mutation and develops motor impairment, the severity of which correlates with the increased accumulation of pathological tau. Tissue was dissected from asymptomatic and severely motor impaired JNPL3 mice as well as non-transgenic littermate controls and subjected to two-dimensional gel electrophoresis. Differentially abundant protein spots were identified by tandem mass spectrometry. Postmortem mild cognitive impairment (MCI), AD and normal aging controls were used to validate the pathological significance of the identified protein. Ezrin was identified as a protein that is upregulated in tau-mediated neurodegeneration. We demonstrate that Ezrin protein abundance increased in JNPL3 mice preceded motor impairment and was sustained in severely motor impaired mice. Ezrin expression was also increased in the temporal cortex of MCI and AD patients. The results demonstrate that increased Ezrin protein abundance changes are associated with the early stages of neurodegeneration in tauopathy models and human disease. Understanding the role of Ezrin in tauopathies such as AD may provide new insights for targeting tau-mediated neurodegeneration.


Coronary disease is not associated with robust alterations in inflammatory gene expression in human epicardial fat.
Epicardial adipose tissue (EAT) is the visceral fat depot of the heart. Inflammation of EAT is thought to contribute to coronary artery disease (CAD). Therefore, we hypothesized that the EAT of patients with CAD would have increased inflammatory gene expression compared with controls without CAD. Cardiac surgery patients with (n = 13) or without CAD (n = 13) were consented, and samples of EAT and subcutaneous adipose tissue (SAT) were obtained. Transcriptomic analysis was performed using Affymetrix Human Gene 1.0 ST arrays. Differential expression was defined as a 1.5-fold change (ANOVA P < 0.05). Six hundred ninety-three genes were differentially expressed between SAT and EAT in controls and 805 in cases. Expression of 326 genes was different between EAT of cases and controls; expression of 14 genes was increased in cases, while 312 were increased in controls. Quantitative reverse transcription PCR confirmed that there was no difference in expression of CCL2, CCR2, TNF-α, IL-6, IL-8, and PAI1 between groups. Immunohistochemistry showed more macrophages in EAT than SAT, but there was no difference in their number or activation state between groups. In contrast to prior studies, we did not find increased inflammatory gene expression in the EAT of patients with CAD. We conclude that the specific adipose tissue depot, rather than CAD status, is responsible for the majority of differential gene expression.


Diallyl trisulfide inhibits 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung cancer via modulating gut microbiota and the PPARγ/NF-κB pathway.
Smoking is the primary risk factor for developing lung cancer. Chemoprevention could be a promising strategy to reduce the incidence and mortality rates of lung cancer. Recently, we reported that A/J mice exposed to tobacco smoke carcinogens displayed the reshaping of gut microbiota. Additionally, garlic oil was found to effectively inhibit the carcinogenic effects of tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in lung tumorigenesis. Diallyl trisulfide (DATS), which is the predominant compound in garlic oil, exhibits various biological activities. To further explore the chemopreventive action and potential mechanism of DATS on lung tumorigenesis, we established a lung adenocarcinoma model in A/J mice stimulated by NNK. Subsequently, we employed multi-omics combined molecular biology technologies to clarify the mechanism. The results indicated that DATS significantly decreased the number of lung tumors in NNK induced A/J mice. Interestingly, we discovered that DATS could modulate gut microbiota, particularly increasing the abundance of F. rodentium, which has inhibitory effects on tumor growth. Mechanistically, DATS could activate the PPARγ pathway, leading to the negative regulation of the NF-κB signaling pathway and subsequent suppression of NF-κB-mediated inflammatory factors. Collectively, these findings provide support for DATS as a potential novel chemopreventive agent for tobacco carcinogen-induced lung cancer.


[Rehabilitation of patients with chronic obstructive lung disease].
Pulmonary rehabilitation is well established and is increasingly prescribed as part of the treatment for chronic obstructive pulmonary disease (COPD). Relevant scientific literature and our own clinical experience is presented. The essential elements of rehabilitation include a multidisciplinary approach; focus on the individual patient; and emphasis on emotional, social, and physical health aspects. The selected patients have COPD symptoms; are fully aware of their physical limitations and motivated to take an active part in the treatment. Pulmonary rehabilitation is also beneficial for patients with other chronic lung diseases A systematic programme includes a detailed clinical examination of the patient, teaching, training in mucus mobilization and breathing techniques, exercise training and psychosocial support. Evidence-based effects of rehabilitation include symptom relief, increased exercise performance, improved quality of life and reduced use of health services. Pulmonary rehabilitation is also necessary before and after lung transplants and in connection with volume reducing surgery for emphysema.


Suicides in the military: the post-modern combat veteran and the Hemingway effect.
Suicides in the military have increased over the last ten years. Much effort has been focused on suicide prevention and treatment, as well as understanding the reasons for the sharp increase in military suicides. Despite this effort, the definitive causes of military suicides remain elusive. Further, highly effective suicide prevention and treatment approaches have not yet been developed. The purpose of this article is to present a short review of the current state of suicide prevention interventions within the context of the military. The root causes of suicidal behavior and the role of combat in the military are each discussed. Interpersonal-psychological theory of suicide and the military transition theory are introduced as guiding frameworks for understanding suicides and suicidal behavior amongst active military personnel and military veterans. The article concludes with a set of recommendations for moving forward in understanding and addressing suicides in the military.


TSC1 sets the rate of ribosome export and protein synthesis through nucleophosmin translation.
Nucleophosmin (B23) is a nucleolar phosphoprotein that has been implicated in numerous cellular processes. In particular, nucleophosmin interacts with nucleolar components of newly synthesized ribosomes to promote ribosome nuclear export. Nucleophosmin is a classic mitogen-induced protein, with changes in its expression correlating with growth factor stimulation. In this study, we examined the underlying mechanism of nucleophosmin induction and showed that hyperproliferative signals emanating from oncogenic H-Ras(V12) cause tremendous increases in nucleophosmin protein expression. Nucleophosmin protein accumulation was dependent on mammalian target of rapamycin (mTOR) activation, as rapamycin completely prevented nucleophosmin induction. Consistent with this finding, genetic ablation of Tsc1, a major upstream inhibitor of mTOR, resulted in nucleophosmin protein induction through increased translation of existing nucleophosmin mRNAs. Increases in nucleophosmin protein accumulation were suppressed by reintroduction of TSC1. Induction of nucleophosmin through Tsc1 loss resulted in a greater pool of actively translating ribosomes in the cytoplasm, higher overall rates of protein synthesis, and increased cell proliferation, all of which were dependent on efficient nucleophosmin nuclear export. Nucleophosmin protein accumulation in the absence of Tsc1 promoted the nuclear export of maturing ribosome subunits, providing a mechanistic link between TSC1/mTOR signaling, nucleophosmin-mediated nuclear export of ribosome subunits, protein synthesis levels, and cell growth.


The homotetrameric phosphoseryl-tRNA synthetase from Methanosarcina mazei exhibits half-of-the-sites activity.
Synthesis of cysteinyl-tRNA(Cys) in methanogenic archaea proceeds by a two-step pathway in which tRNA(Cys) is first aminoacylated with phosphoserine by phosphoseryl-tRNA synthetase (SepRS). Characterization of SepRS from the mesophile Methanosarcina mazei by gel filtration and nondenaturing mass spectrometry shows that the native enzyme exists as an alpha4 tetramer when expressed at high levels in Escherichia coli. However, active site titrations monitored by ATP/PP(i) burst kinetics, together with analysis of tRNA binding stoichiometry by fluorescence spectroscopy, show that the tetrameric enzyme binds two tRNAs and that only two of the four chemically equivalent subunits catalyze formation of phosphoseryl adenylate. Therefore, the phenomenon of half-of-the-sites activity, previously described for synthesis of 1 mol of tyrosyl adenylate by the dimeric class I tyrosyl-tRNA synthetase, operates as well in this homotetrameric class II tRNA synthetase. Analysis of cognate and noncognate reactions by ATP/PP(i) and aminoacylation kinetics strongly suggests that SepRS is able to discriminate against the noncognate amino acids glutamate, serine, and phosphothreonine without the need for a separate hydrolytic editing site. tRNA(Cys) binding to SepRS also enhances the capacity of the enzyme to discriminate among amino acids, indicating the existence of functional connectivity between the tRNA and amino acid binding sites of the enzyme.


[Forensic medical implications of histomorphological changes in the bone and cartilage tissues under effect of radiation].
The objective of the present work was to study roentgenological, microscopic, and histomorphological changes in the bone and cartilage tissues under effect of different doses of gamma-ray radiation from Gammatron-2 (GUT Co 400) and betatron bremsstrahlung radiation (25 MeV). The total radiation dose varied from 9.6 Gy to 120 Gy per unit area during 5-8 weeks. The study included 210 patients at the age from 7 to 82 years (97 men and 113 women). Histomorphological studies were carried out using samples of bone and cartilage tissues taken from different body regions immediately after irradiation and throughout the follow-up period of up to 4 years 6 months. Control samples were the unexposed bone and cartilage tissues from the same subjects (n = 14). The tissues were stained either with eosin and hematoxylin or by Van Gieson's and Mallory's methods. Gomori's nonspecific staining was used to detect acid and alkaline phosphatase activities. Moreover, argyrophilic substance was identified in the cartilaginous tissue. Best's carmine was used for glycogen staining and Weigert's stain for elastic fibers. Metachromasia was revealed by toluidine blue staining and fat by the sudan III staining technique. In addition, the ultrastructure of cartilaginous tissue was investigated. Taken together, these methods made it possible to identify the signs of radiation-induced damage to the bone and cartilage tissues in conjunction with complications that are likely to develop at different periods after irradiation including such ones as spontaneous fractures, deforming arthrosis and radiation-induced tumours.


Prevalence and characteristics of glaucoma among Korean adults.
The purpose of this study was to investigate the prevalence and characteristics of glaucoma in the population of the rural Korean town, Sangju. Residents of Sangju aged greater than 50 years old were included in this study. Participants completed an interview examining their medical and ophthalmic history Information was collected on the participants' uncorrected and best corrected vision scores, slit lamp examination results, angle width measurements using the Van Herick technique, gonioscopy if the angle width was less than 1 / 4 angle, intraocular pressure (IOP) assessed with the Goldmann applanation tonometry, optic disc examination results, and a visual field test results using frequency-doubling perimetry in cases in which glaucoma was suspected. Glaucoma was diagnosed according to the criteria described by the International Society for Geographic and Epidemiological Ophthalmology. 1,118 residents aged greater than 50 years were examined initially from a population of 2,984 people. Of these, 671 subjects (60%) participated in this study. The prevalence of glaucoma was determined to be 3.4% (95% confidence interval [CI], 2.1-4.8). Open-angle glaucoma with low IOP was determined to be the most common form with a prevalence rate as high as 2.5% (95% CI, 1.8-3.7). Additionally, primary angle closure glaucoma was determined to have a prevalence rate of 0.3% (95% CI, 0.1-0.9). Open-angle glaucoma with low IOP accounted for 94.4% of the open-angle glaucoma cases. The prevalence of glaucoma among the population of rural Sangju was 3.4%, and open-angle glaucoma with low IOP was the most common form accounting for 94.4% of the total number of cases.


Identification and functional prediction of long non-coding RNAs related to oxidative stress in the jejunum of piglets.
Oxidative stress (OS) is a pathological process arising from the excessive production of free radicals in the body. It has the potential to alter animal gene expression and cause damage to the jejunum. However, there have been few reports of changes in the expression of long noncoding RNAs (lncRNAs) in the jejunum in piglets under oxidative stress. The purpose of this research was to examine how lncRNAs in piglet jejunum change under oxidative stress. The abdominal cavities of piglets were injected with diquat (DQ) to produce oxidative stress. Raw reads were downloaded from the SRA database. RNA-seq was utilized to study the expression of lncRNAs in piglets under oxidative stress. Additionally, six randomly selected lncRNAs were verified using quantitative real-time polymerase chain reaction (qRT‒PCR) to examine the mechanism of oxidative damage. A total of 79 lncRNAs were differentially expressed (DE) in the treatment group compared to the negative control (NC) group. The target genes of DE lncRNAs were enriched in Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Chemical carcinogenesis-reactive oxygen species, the Foxo signaling pathway, colorectal cancer, and the AMPK signaling pathway were all linked to oxidative stress. Our results demonstrated that DQ-induced oxidative stress causes differential expression of lncRNAs, laying the groundwork for future research into the processes involved in the jejunum's response to oxidative stress.


A mouse T cell product that preferentially enhances IgA production. II. Physicochemical characterization.
Certain subsets of helper T cells, following stimulation with concanavalin A, secrete factors that specifically enhance the production of IgG1, IgE, and IgA by lipopolysaccharide-stimulated B cells. In the previous report, we describe a factor from the helper T cell line MB2-1 which enhances IgA production. IgA-enhancing factor has been purified from serum-free supernatants of this cell line. The purified lymphokine is a family of microheterogeneous polypeptides presumably modified post-translationally. IgA-enhancing factor has a native m.w. of 45,000 to 60,000 with subunits of between 24,000 and 28,000 under reducing conditions. Upon Edman degradation, a single amino-terminal sequence is detected which is identical to that of the lymphokine interleukin 5. IgA-enhancing factor activity is thus mediated by the same polypeptide that has been characterized as type II B cell growth factor, T cell-replacing factor, and eosinophil-differentiation factor.


[Suspension of geriatric admissions in France in 2023: a national PUGG survey of the French Society of Geriatrics and Gerontology].
France is experiencing exceptionally high closures of hospital geriatric beds, which increases the difficulties of access to geriatric care for the oldest and most frail French citizens. The French Society of Geriatrics and Gerontology (SFGG) conducted a national survey in January 2023 among French geriatricians and gerontologists with the aim of drawing up an inventory of the closure of hospital geriatric beds in France and the reasons for these closures. The online survey was carried out among the 1,600 members of the SFGG between January 8 and 22, 2023. The results showed that 34.7% of geriatric units were affected by bed closures in January 2023, with 25.7% of beds closed on average. All levels of hospital geriatric sectors were affected by bed closures, but rehabilitation units were the most affected ones. The most frequent reason for bed closures was the lack of nurses, then the lack of physicians, and finally the lack of nursing aids. Reopening dates were not defined in more than 90% of cases. Resolving this crisis will imply recognizing and revaluing geriatric caregivers, both financially and in terms of more appropriate caregiver/patient ratios. These measures are necessary to avoid the bankruptcy of hospitals and to preserve decent, respectful and dignified care for our seniors.


How to Build a Bacterial Cell: MreB as the Foreman of E. coli Construction.
Cell shape matters across the kingdoms of life, and cells have the remarkable capacity to define and maintain specific shapes and sizes. But how are the shapes of micron-sized cells determined from the coordinated activities of nanometer-sized proteins? Here, we review general principles that have surfaced through the study of rod-shaped bacterial growth. Imaging approaches have revealed that polymers of the actin homolog MreB play a central role. MreB both senses and changes cell shape, thereby generating a self-organizing feedback system for shape maintenance. At the molecular level, structural and computational studies indicate that MreB filaments exhibit tunable mechanical properties that explain their preference for certain geometries and orientations along the cylindrical cell body. We illustrate the regulatory landscape of rod-shape formation and the connectivity between cell shape, cell growth, and other aspects of cell physiology. These discoveries provide a framework for future investigations into the architecture and construction of microbes.


Biomimetic versus sintered macroporous calcium phosphate scaffolds enhanced bone regeneration and human mesenchymal stromal cell engraftment in calvarial defects.
In contrast to sintered calcium phosphates (CaPs) commonly employed as scaffolds to deliver mesenchymal stromal cells (MSCs) targeting bone repair, low temperature setting conditions of calcium deficient hydroxyapatite (CDHA) yield biomimetic topology with high specific surface area. In this study, the healing capacity of CDHA administering MSCs to bone defects is evaluated for the first time and compared with sintered beta-tricalcium phosphate (β-TCP) constructs sharing the same interconnected macroporosity. Xeno-free expanded human bone marrow MSCs attached to the surface of the hydrophobic β-TCP constructs, while infiltrating the pores of the hydrophilic CDHA. Implantation of MSCs on CaPs for 8 weeks in calvaria defects of nude mice exhibited complete healing, with bone formation aligned along the periphery of β-TCP, and conversely distributed within the pores of CDHA. Human monocyte-osteoclast differentiation was inhibited in vitro by direct culture on CDHA compared to β-TCP biomaterials and indirectly by administration of MSC-conditioned media generated on CDHA, while MSCs increased osteoclastogenesis in both CaPs in vivo. MSC engraftment was significantly higher in CDHA constructs, and also correlated positively with bone in-growth in scaffolds. These findings demonstrate that biomimetic CDHA are favorable carriers for MSC therapies and should be explored further towards clinical bone regeneration strategies. STATEMENT OF SIGNIFICANCE: Delivery of mesenchymal stromal cells (MSCs) on calcium phosphate (CaP) biomaterials enhances reconstruction of bone defects. Traditional CaPs are produced at high temperature, but calcium deficient hydroxyapatite (CDHA) prepared at room temperature yields a surface structure more similar to native bone mineral. The objective of this study was to compare the capacity of biomimetic CDHA scaffolds with sintered β-TCP scaffolds for bone repair mediated by MSCs for the first time. In vitro, greater cell infiltration occurred in CDHA scaffolds and following 8 weeks in vivo, MSC engraftment was higher in CDHA compared to β-TCP, as was bone in-growth. These findings demonstrate the impact of material features such as surface structure, and highlight that CDHA should be explored towards clinical bone regeneration strategies.


Normalized effect size (NES): a novel feature selection model for Urdu fake news classification.
Social media has become an essential source of news for everyday users. However, the rise of fake news on social media has made it more difficult for users to trust the information on these platforms. Most research studies focus on fake news detection in the English language, and only a limited number of studies deal with fake news in resource-poor languages such as Urdu. This article proposes a globally weighted term selection approach named normalized effect size (NES) to select highly discriminative features for Urdu fake news classification. The proposed model is based on the traditional inverse document frequency (TF-IDF) weighting measure. TF-IDF transforms the textual data into a weighted term-document matrix and is usually prone to the curse of dimensionality. Our novel statistical model filters the most discriminative terms to reduce the data's dimensionality and improve classification accuracy. We compare the proposed approach with the seven well-known feature selection and ranking techniques, namely normalized difference measure (NDM), bi-normal separation (BNS), odds ratio (OR), GINI, distinguished feature selector (DFS), information gain (IG), and Chi square (Chi). Our ensemble-based approach achieves high performance on two benchmark datasets, BET and UFN, achieving an accuracy of 88% and 90%, respectively.


Prognosis Predictions by Families, Physicians, and Nurses of Patients with Severe Acute Brain Injury: Agreement and Accuracy.
Effective shared decision-making relies on some degree of alignment between families and the medical team regarding a patient's likelihood of recovery. Patients with severe acute brain injury (SABI) are often unable to participate in decisions, and therefore family members make decisions on their behalf. The goal of this study was to evaluate agreement between prognostic predictions by families, physicians, and nurses of patients with SABI regarding their likelihood of regaining independence and to measure each group's prediction accuracy. This observational cohort study, conducted from 01/2018 to 07/2020, was based in the neuroscience and medical/cardiac intensive care units of a single center. Patient eligibility included a diagnosis of SABI-specifically stroke, traumatic brain injury, or hypoxic ischemic encephalopathy-and a Glasgow Coma Scale ≤ 12 after hospital day 2. At enrollment, families, physicians, and nurses were asked separately to predict a patient's likelihood of recovering to independence within 6 months on a 0-100 scale, regardless of whether a formal family meeting had occurred. True outcome was based on modified Rankin Scale assessment through a family report or medical chart review. Prognostic agreement was measured by (1) intraclass correlation coefficient; (2) mean group prediction comparisons using paired Student's t-tests; and (3) prevalence of concordance, defined as an absolute difference of less than 20 percentage points between predictions. Accuracy for each group was measured by calculating the area under a receiver operating characteristic curve (C statistic) and compared by using DeLong's test. Data were collected from 222 patients and families, 45 physicians, and 103 nurses. Complete data on agreement and accuracy were available for 187 and 177 patients, respectively. The intraclass correlation coefficient, in which 1 indicates perfect correlation and 0 indicates no correlation, was 0.49 for physician-family pairs, 0.40 for family-nurse pairs, and 0.66 for physician-nurse pairs. The difference in mean predictions between families and physicians was 23.5 percentage points (p < 0.001), 25.4 between families and nurses (p < 0.001), and 1.9 between physicians and nurses (p = 0.38). Prevalence of concordance was 39.6% for family-physician pairs, 30.0% for family-nurse pairs, and 56.2% for physician-nurse pairs. The C statistic for prediction accuracy was 0.65 for families, 0.82 for physicians, and 0.76 for nurses. The p values for differences in C statistics were < 0.05 for family-physician and family-nurse groups and 0.18 for physician-nurse groups. For patients with SABI, agreement in predictions between families, physicians, and nurses regarding likelihood of recovery is poor. Accuracy appears higher for physicians and nurses compared with families, with no significant difference between physicians and nurses.


Single-cell transcriptional logic of cell-fate specification and axon guidance in early-born retinal neurons.
Retinal ganglion cells (RGCs), cone photoreceptors (cones), horizontal cells and amacrine cells are the first classes of neurons produced in the retina. However, an important question is how this diversity of cell states is transcriptionally produced. Here, we profiled 6067 single retinal cells to provide a comprehensive transcriptomic atlas showing the diversity of the early developing mouse retina. RNA velocities unveiled the dynamics of cell cycle coordination of early retinogenesis and define the transcriptional sequences at work during the hierarchical production of early cell-fate specification. We show that RGC maturation follows six waves of gene expression, with older-generated RGCs transcribing increasing amounts of guidance cues for young peripheral RGC axons that express the matching receptors. Spatial transcriptionally deduced features in subpopulations of RGCs allowed us to define novel molecular markers that are spatially restricted. Finally, the isolation of such a spatially restricted population, ipsilateral RGCs, allowed us to identify their molecular identity at the time they execute axon guidance decisions. Together, these data represent a valuable resource shedding light on transcription factor sequences and guidance cue dynamics during mouse retinal development.


[Effect of damage to the zone of the medial forebrain bundle and preoptic area on the activiy of a penicillin-induced epileptiform focus (phenomenon of the hyperactive determinant dispatch station)].
It was shown in experiments on cats under nembutal anesthesia that a lesion of the medial forebrain bundle (MFB) and partly of the preoptic region at the side of local penicillin application on the cerebral cortex (g. suprasylvius medius) results in depression of the epileptiform activity in the penicillin-induced focus, as well as in the secondary "mirror" focus, which appeared in the symmetrical cortex area of the other hemisphere. The MFB lesion at the "mirror" focus side led to depression of the seizure spike potentials in this focus only and did not change the activity in the primary epileptiform one. The described effects are considered from the aspect of the conception on the role of the determinant dispatch station (DDS) in the central nervous system: the primary epileptiform focus plays the role of the hyperactive DDS which induces the secondary focus and determines the character of its activity. The results of the study substantiate a suggestion that the MFB can take part in the modulation of the cortical epileptiform activity.


Resilience emotions and acute stress reactions in the population of Dimona and the general population of Israel two days after the first suicide bombing attack in Dimona.
On 4 February 2008, two terrorists armed with suicide bombs arrived atthe open market in the southern Israeli city of Dimona. One detonated his bomb at approximately 10:30 a.m. causing multiple casualties. Short-term emotional effects and acute stress reactions usually appear among survivors after such incidents. To compare the differences in emotions and in disturbances of daily life activities that emerge a couple of days following such an event and to identify patterns of stress development among resilient and low-resilient members of the population in Dimona and in the general population of Israel. A telephone survey of two randomly selected representative samples of adults (428 Israeli residents and 250 Dimona residents) was conducted 2 days afterthe event. A higher prevalence of stress and fear and a lower prevalence of joy were reported among the population of Dimona compared to the general population in Israel (P < 0.05). Differences were also recorded when the population of Dimona was categorized by its personal degree of resilience (P < 0.05). A higher prevalence of disturbances in daily life activities and changes in leisure activity was found in the low-resilient population in Dimona (P < 0.01). This study demonstrates that following a public terror event, self-reported low-resilient subjects have a higher prevalence of disturbances in daily life activities, as well as adverse emotional responses. These differences must be addressed by the relevant social service agencies for immediate public intervention.


An approximate model on three-dimensional groundwater infiltration in sewer systems.
Groundwater infiltration through cracked sewer pipes has caused significant economic losses. This paper presents a three-dimensional analytical expression for calculating the steady-state groundwater infiltration rate into sewer systems. As an extension of the previously developed two-dimensional model by the author, this new model can be used to simulate the infiltration through an orifice defect. The derived analytical expression has been validated with experimental results. The new model incorporates all the related resistances during the infiltration process, including the soil head loss and the orifice loss. The soil head loss is assessed with Ergun equation, which involves an inertial loss term in addition to the viscous loss. This has significantly extended the application range of the new expression. A new OS number (the ratio of orifice loss to soil loss) expression is also presented. The order analysis of the OS number expression has demonstrated that in most real cases, the head loss through the soil layer dominates the whole infiltration process.


[The surgical treatment of obstructive cancers of the left colon. Apropos of a series of 66 cases].
From 1977 to 1989, 66 patients were operated on in emergency, without any bowel preparation, for acutely obstructing left-sided colon cancer. Two synchronous cancers were diagnosed and the 68 tumours were located as follows: 13 on the left transverse colon or at the splenic flexure, 7 on the descending colon, 37 on the sigmoid, and 11 at the rectosigmoid junction or below. According to Astler-Coller staging, 15 patients were classified as B, 17 as C and 25 as D. Initial treatment was a colostomy in 58 patients (88%), or a resection with or without anastomosis in 2 and 6 cases respectively. Most patients underwent a two- or more rarely a three-stage resection and 44 patients left the hospital without either tumour or stomy. Cumulative operative mortality was 12%. Five-year survival rates were 21% for the patients with a minimal potential follow-up of 5 years, and 39% for curative resections (disease-free survival of 33%). From these results, we think that two-staged resection, with close proximal colostomy followed by resection and anastomosis, remains an appropriate approach for most obstructing left-sided colon cancers; more tempting procedures such as resection with primary anastomosis or subtotal colectomy are probably indicated in selected patients.


Tentacle probe sandwich assay in porous polymer monolith improves specificity, sensitivity and kinetics.
Nucleic acid sandwich assays improve low-density array analysis through the addition of a capture probe and a specific label, increasing specificity and sensitivity. Here, we employ photo-initiated porous polymer monolith (PPM) as a high-surface area substrate for sandwich assay analysis. PPMs are shown to enhance extraction efficiency by 20-fold from 2 microl of sample. We further compare the performance of labeled linear probes, quantum dot labeled probes, molecular beacons (MBs) and tentacle probes (TPs). Each probe technology was compared and contrasted with traditional hybridization methods using labeled sample. All probes demonstrated similar sensitivity and greater specificity than traditional hybridization techniques. MBs and TPs were able to bypass a wash step due to their 'on-off' signaling mechanism. TPs demonstrated reaction kinetics 37.6 times faster than MBs, resulting in the fastest assay time of 5 min. Our data further indicate TPs had the most sensitive detection limit (<1 nM) as well as the highest specificity (>1 x 10(4) improvement) among all tested probes in these experiments. By matching the enhanced extraction efficiencies of PPM with the selectivity of TPs, we have created a format for improved sandwich assays.


Differential synthesis and binding of hyaluronan by human breast cancer cell lines.
In the present study we investigated a panel of human breast cancer cell lines which were sensitive or resistant to the cytotoxic drug doxorubicin, for their abilities to synthesize and bind hyaluronan. We found that MDA-231 and HS-578T cells which express very low amounts of estrogen and progesterone receptors, both synthesized hyaluronan and expressed hyaluronan binding sites on the cell surface as did their doxorubicin-adapted counterparts MDA-231 Dox and HS-578T Dox. The binding was highly specific with a K-d of 0.48x10(-9) M. Most of the hyaluronan binding activity was blocked by mAbs against Hermes-l antigen indicating that the adhesion molecule CD44 is responsible for hyaluronan binding. Only 0.5% of the total amount of labeled hyaluronan added to the cultures was degraded during a period of 16 h. The hormone positive receptor cell lines, MCF-5, Zr-5-1 and Zr-5-1 Dox synthesized only minute amounts of hyaluronan and did not bind hyaluronan or express CD44 receptors. Expression of CD44-related hyaluronan receptors and synthesized hyaluronan may endow hormone receptor negative cells with a highly hydrated environment that facilitates cell motility and invasiveness. The lack of CD44 and thereby the lack of ability to bind hyaluronan in the extracellular matrix may contribute to the non-invasive behavior of hormone positive cell lines.


In vivo functional characterization of the transmembrane histidine kinase KinC in Bacillus subtilis.
In response to starvation, Bacillus subtilis cells differentiate into different subsets, undergoing cannibalism, biofilm formation or sporulation. These processes require a multiple component phosphorelay, wherein the master regulator Spo0A is activated upon phosphorylation by one or a combination of five histidine kinases (KinA-KinE) via two intermediate phosphotransferases, Spo0F and Spo0B. In this study, we focused on KinC, which was originally identified as a sporulation kinase and was later shown to regulate cannibalism and biofilm formation. First, genetic experiments using both the domesticated and undomesticated (biofilm forming) strains revealed that KinC activity and the membrane localization are independent of both the lipid raft marker proteins FloTA and cytoplasmic potassium concentration, which were previously shown to be required for the kinase activity. Next, we demonstrated that KinC controls cannibalism and biofilm formation in a manner dependent on phosphorelay. For further detailed characterization of KinC, we established an IPTG-inducible expression system in the domesticated strain, in which biofilm formation is defective, for simplicity of study. Using this system, we found that the N-terminal transmembrane domain is dispensable but the PAS domain is needed for the kinase activity. An in vivo chemical cross-linking experiment demonstrated that the soluble and functional KinC (KinC(ΔTM1+2)) forms a tetramer. Based on these results, we propose a revised model in which KinC becomes active by forming a homotetramer via the N-terminal PAS domain, but its activity is independent of both the lipid raft and the potassium leakage, which was previously suggested to be induced by surfactin.


Physiological and psychological effects of viewing forest landscapes in a seated position in one-day forest therapy experimental model.
To clarify the physiological and psychological effects of a one-day forest therapy. The experiments were conducted at three sites, each containing a forest area and an urban area in Japan. Twelve male students participated at each of the three venues (total, 36 subjects). The subjects were randomly assigned to visit either the forest or urban area and were instructed to view the scenery in a seated position for 15 min. Heart rate variability and heart rate were measured to assess physiological response. The semantic differential method, reports of "refreshed" feeling, "state anxiety" in the State-Trait Anxiety Inventory (STAI) and Profile of Mood States (POMS) were used to determine psychological responses. Physiological data revealed that the subjects demonstrated significantly different responses to the forest and urban environments. For heart rate variability, the subjects showed a significantly higher ln(HF) and a lower ln(LF/HF) in the forest environment than in the urban environment. Heart rate decreased in the forest environment relative to that in the urban environment. The forest environment was perceived as significantly more "comfortable," "soothing," and "natural" than the urban environment after viewing. The score for "refreshed" feeling was also significantly higher. The score for the "state anxiety" in STAI was significantly reduced by viewing the scenery in the forested areas. The score for the "vigor" subscale of the POMS was significantly improved by viewing the scenery in the forested areas, whereas scores for negative feelings, such as "tension-anxiety" and "fatigue," were significantly reduced. These results provided scientific evidence of the physiological and psychological effects of a one-day forest therapy.


Cannabidiol for the Treatment of Neonatal Hypoxic-Ischemic Brain Injury.
Each year, more than two million babies die or evolve to permanent invalidating sequelae worldwide because of Hypoxic-Ischemic Brain Injury (HIBI). There is no current treatment for that condition except for therapeutic hypothermia, which benefits only a select group of newborns. Preclinical studies offer solid evidence of the neuroprotective effects of Cannabidiol (CBD) when administered after diffuse or focal HI insults to newborn pigs and rodents. Such effects are observable in the short and long term as demonstrated by functional, neuroimaging, histologic and biochemical studies, and are related to the modulation of excitotoxicity, inflammation and oxidative stress-the major components of HIBI pathophysiology. CBD protects neuronal and glial cells, with a remarkable effect on preserving normal myelinogenesis. From a translational point of view CBD is a valuable tool for HIBI management since it is safe and effective. It is administered by the parenteral route a posteriori with a broad therapeutic time window. Those findings consolidate CBD as a promising treatment for neonatal HIBI, which is to be demonstrated in clinical trials currently in progress.


Apologizing for humiliations in medical practice.
Apologizing to patients and their families for medical mistakes is an increasingly accepted practice. Overlooked is the need to apologize to other members of the treatment team or patients for humiliations inflicted in medical practice, independent of medical mistakes. A humiliated treatment team member or patient is apt to undermine optimal care, particularly when teamwork or patient adherence to treatment is required. This article describes the psychology of humiliation and the history of humiliation in medical practice, including why doctors and patients are vulnerable to being humiliated. Several humiliation narratives are presented. This article presents empirical data based on a sample of 355 subjects that analyze what the offended party seeks in an apology and the magnitude of the importance of each of these desires. The restoration of dignity in response to humiliation emerges as one of the most important functions of apologies. Finally, this article identifies 15 healing forces of apology, a combination of which is necessary for healing any given offense. The final challenge is educating individuals as to how to apply these findings to healing after a humiliating offense.


Vector Analysis of Femtosecond Laser-Assisted Arcuate Keratotomy for Post-Keratoplasty Astigmatic Correction.
To study the astigmatic correction of high post-keratoplasty astigmatism using Femtosecond laser (FSL)-assisted Arcuate Keratotomy (FS-AK). A prospective interventional cohort study. We enrolled 17 eyes with high degree of irregular astigmatism, scheduled for FS-AK. FSL was used to perform paired arcuate incisions 1.00 mm inside the graft. Patients' uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), and astigmatic change were recorded and followed up to 1 year after surgery. Vector analysis using Alpins' method was done to analyze the astigmatic correction. FS-AK reduced the refractive astigmatism at final follow-up visit at 12 months (p = 0.0008, repeated-measures analysis of variance [ANOVA]). The procedure improved the UCVA over the follow-up period (p = 0.007, repeated-measures ANOVA), with a similar effect on the BCVA (p = 0.046, repeated-measures ANOVA). There was a mild correlation between the target-induced astigmatism and the surgically induced astigmatism (R2 = 0.245) with a tendency to overcorrect more than under correct the astigmatism. A constant rotational error in the counterclockwise direction was also detected. FS-AK improves the visual outcome and reduces the refractive cylinder in post-penetrating keratoplasty astigmatism. The predictability of astigmatism correction was variable in reducing post-keratoplasty astigmatism. Refinement of the treatment nomogram for such cases is highly recommended.


The complement system in schizophrenia.
Several lines of evidence suggest that immunological factors contribute to schizophrenia. Since 1989, the role of complement, a major effector of innate immunity and an adjuvant of adaptive immunity, has been explored in schizophrenia. Increased activity of C1, C3, C4 complement components in schizophrenia has been reported by two or more groups. Two studies on different subject cohorts showed increased MBL-MASP-2 activity in patients versus controls. More then one report indicated a significant high frequency of FB*F allotype and low prevalence of the FS phenotype of complement factor B in schizophrenia. From the data reported, it is likely that the disorder is accompanied by alterations of the complement classical and lectin pathways, which undergo dynamic changes, depending on the illness course and the state of neuro-immune crosstalk. Recent findings, implicating complement in neurogenesis, synapse remodeling and pruning during brain development, suggest a reexamination of the potential role of complement in neurodevelopmental processes contributing to schizophrenia susceptibility. It is plausible that the multicomponent complement system has more than one dimensional association with schizophrenia susceptibility, pathopsychology and illness course, understanding of which will bring a new perspective for possible immunomodulation and immunocorrection of the disease.


[Cinnamaldehyde attenuates pressure overload-induced cardiac fibrosis via inhibition of endothelial mesenchymal transition].
Objective: The aim of this study is to investigate the underlying mechanism of cinnamaldehyde attenuating pressure overload-induced cardiac fibrosis. Methods: The mice were randomly divided into control group, model group and treatment group by random number table and each group had 8 mice.Cardiac hypertrophy was induced by aortic banding. Heart vascular density was detected by immunohistochemical staining of CD31.The expression level of stromal cells marker α-smooth muscle actin (α-SMA) was detected by immunofluorescence staining in different groups.The expression levels of endothelial cell associated markers and stromal cell associated markers were detected by using Western blotting.The possible molecular pathway was also screened by using Western blotting. Human umbilical vein endothelial cell (HUVECs) were stimulated with TGFβ1 and cultured with 10 nmol/L cinnamomum for 24 hour to further confirm the mechanism. Results: Eight weeks after operation, the vascular density was significantly decreased in model group mice heart.The expressions of stromal cells markers were increased (α-SMA: 2.57±0.38; Vimentin: 0.58±0.02) and endothelial cell markers were reduced (CD31: 0.58±0.29; CD34: 0.62±0.21). While cinnamicaldehyde treatment significantly increased the mouse heart vascular density, increased endothelial cell markers expression (CD31: 1.51±0.11; CD34: 2.37±0.44; P<0.05), and reduced stromal cells marker expression (α-SMA: 1.22±0.14; Vimentin: 0.35±0.03; P<0.05). Further studies showed that the anti-fibrosis effect of cinnamicaldehyde was mainly through the TGFβ /smad signaling pathway.10 nmol/L cinnamomum attenuated TGFβ1 induced endothelial mesenchymal transition in HUVECs. Conclusion: Cinnamaldehyde may be able to retard the progression of cardiac fibrosis, via blocking endothelial to mesenchymal transition, which, in verse, is through regulating TGFβ /smad signaling pathway.


Quality of life after adjuvant chemotherapy for breast cancer.
To evaluate the quality of life of breast cancer patients previously treated with adjuvant chemotherapy. Registry data were used to recruit a sample of breast cancer patients (N = 61; mean age = 51.6 years) with no current evidence of disease who had completed adjuvant chemotherapy between 3 and 36 months earlier (average = 15.87 months). In addition, a peer nomination procedure was used to recruit an age-matched comparison group of women with no history of cancer (N = 59; mean age = 51.5 years). Both groups were mailed a survey to complete that included the Medical Outcomes Study Short Form 36 (SF-36) and the Center for Epidemiologic Studies Depression Scale (CES-D). These data were used to test the hypothesis that breast cancer patients previously treated with adjuvant chemotherapy experience impaired quality of life relative to their peers and to identify demographic and medical factors associated with individual differences in patient quality of life. Consistent with predictions, the postchemotherapy group scored poorer than the noncancer comparison group on the CES-D and on six of the eight subscales as well as the physical component summary scale of the SF-36 (p < 0.05). With regard to individual differences in patient quality of life, younger age and unmarried status were positively related to poorer mental well-being and greater depressive symptomatology (p < 0.05). Time since cancer diagnosis and chemotherapy completion were also positively related to greater depressive symptomatology (p < 0.05). In contrast, none of the demographic or medical variables assessed were related to physical well-being (p > 0.05). Breast cancer patients appear to experience problems in multiple quality of life domains following the completion of adjuvant chemotherapy treatment. Demographic and medical characteristics explain individual differences in mental but not physical aspects of patient quality of life. These findings demonstrate the need for interventions to improve the quality of life in breast cancer patients previously treated with adjuvant chemotherapy.


Enhanced AMPA receptor-mediated neurotransmission on CA1 pyramidal neurons during status epilepticus.
Status epilepticus (SE) is a common neurological emergency that results from the failure of the mechanisms responsible for seizure termination or the initiation of mechanisms that lead to abnormally prolonged seizures. Although the failure of inhibitory mechanisms during SE is well understood, the seizure-initiating mechanisms are poorly understood. We tested whether hippocampal α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated transmission was enhanced during SE and assessed the underlying molecular mechanism. In animals in self-sustaining limbic SE the amplitudes of the miniature, spontaneous, and AMPA-evoked excitatory currents recorded from the CA1 pyramidal neurons were larger than those recorded in the controls. The evoked EPSCs rectified inwardly. In these animals, the surface expression of GluA1 subunit-containing AMPARs was increased in the CA1 pyramidal neurons. The phosphorylation of the GluA1 subunit on S831 and S845 residues was reduced in animals in SE. In contrast, the GluA1 subunit surface expression and AMPAR-mediated neurotransmission of dentate granule cells (DGCs) was not altered. Treating animals in SE with the NMDAR antagonist MK-801 or with diazaepam blocked the increased surface expression of the GluA1 subunits. NMDAR blockade also prevented the dephosphorylation of the S845 residue but not that of S831. Targeting NMDARs and AMPARs may provide novel strategies to treat benzodiazepine-refractory SE.


Warning criteria for intraoperative neurophysiologic monitoring.
Intraoperative changes in somatosensory (SEP) and motor evoked potentials (MEPs) may indicate potential injury to the spinal cord and will require timely intervention to prevent permanent damage. This review focuses on the validity of currently recommended warning criteria for intraoperative evoked potential monitoring. Current guideline recommends a decrease in SEP amplitude by 50% and MEP amplitude by 50-100% as warning signals for injury to the ascending sensory and descending motor pathway, respectively. On the basis of cohort studies, the diagnostic accuracy of SEP and MEP to predict postoperative neurologic deficits was variable. Importantly, 0.1-4.1% of monitored patients suffered postoperative neurologic deficit despite apparently normal SEP and MEP recordings (i.e. false negative events). These data suggested that the true warning criteria may be lower than previously acknowledged. A systematic review of studies that reported changes in SEP or MEP monitoring and postoperative neurological outcome showed an association between changes in monitoring signals and postoperative neurological deficits. However, the confidence intervals were wide and it is not possible to determine a threshold value in SEP or MEP amplitude beyond which may indicate neurologic deficit. Current recommendations for warning criteria during intraoperative evoked potential monitoring are empirically derived. Until a threshold that predicts spinal cord injury can be accurately determined, it remains difficult to define the clinical utility of intraoperative neurophysiologic monitoring.


The Military Extremity Trauma Amputation/Limb Salvage (METALS) Study: Outcomes of Amputation Compared with Limb Salvage Following Major Upper-Extremity Trauma.
Severe upper-extremity injuries account for almost one-half of all extremity trauma in recent conflicts in the Global War on Terror. Few long-term outcomes studies address severe combat-related upper-extremity injuries. This study's objective was to describe long-term functional outcomes of amputation compared with those of limb salvage in Global War on Terror veterans who sustained severe upper-extremity injuries. Limb salvage was hypothesized to result in better arm and hand function scores, overall functional status, and quality of life, with similar pain interference. This retrospective cohort study utilized data from the Military Extremity Trauma Amputation/Limb Salvage (METALS) study for a subset of 155 individuals who sustained major upper-extremity injuries treated with amputation or limb salvage. Participants were interviewed by telephone 40 months after injury, assessing social support, personal habits, and patient-reported outcome instruments for function, activity, depression, pain, and posttraumatic stress. Outcomes were evaluated for participants with severe upper-extremity injuries and were compared with participants with concomitant severe, lower-extremity injury. The analysis of outcomes comparing limb salvage with amputation was restricted to the 137 participants with a unilateral upper-extremity injury because of the small number of patients with bilateral upper-extremity injuries (n = 18). Overall, participants with upper-extremity injuries reported moderate to high levels of physical and psychosocial disability. Short Musculoskeletal Function Assessment (SMFA) scores were high across domains; 19.4% screened positive for posttraumatic stress disorder (PTSD), and 12.3% were positive for depression. Nonetheless, 63.6% of participants were working, were on active duty, or were attending school, and 38.7% of participants were involved in vigorous recreational activities. No significant differences in outcomes were observed between patients who underwent limb salvage and those who underwent amputation. Severe, combat-related upper-extremity injuries result in diminished self-reported function and psychosocial health. Our results suggest that long-term outcomes are equivalent for those treated with amputation or limb salvage. Addressing or preventing PTSD, depression, chronic pain, and associated health habits may result in less disability burden in this population. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Lactotransferrin Downregulation Serves as a Potential Predictor for the Therapeutic Effectiveness of mTOR Inhibitors in the Metastatic Clear Cell Renal Cell Carcinoma without PTEN Mutation.
Approximately 30% of clear cell renal cell carcinoma (ccRCC) patients develop metastatic spread at the first diagnosis. Therefore, identifying a useful biomarker to predict ccRCC metastasis or therapeutic effectiveness in ccRCC patients is urgently needed. Previously, we demonstrated that lactotransferrin (LTF) downregulation enhanced the metastatic potential of ccRCC. Here, we show that LTF expression conversely associates with the mTORC1 activity as simulated by gene set enrichment analysis (GSEA). Moreover, Western blot analyses revealed that the LTF knockdown promoted, but the inclusion of recombinant human LTF protein suppressed, the phosphorylation of Akt/mTOR proteins in the detected ccRCC cells. Kaplan-Meier analyses demonstrated that the signature of combining an upregulated mTORC1 activity with a downregulated LTF expression referred to a worse overall and progression-free survival probabilities and associated with distant cancer metastasis in TCGA ccRCC patients. Furthermore, we found that the LTF-suppressed Akt/mTOR activation triggered an increased formation of autophagy in the highly metastatic ccRCC cells. The addition of autophagy inhibitor 3-methyadenine restored the LTF-suppressed cellular migration ability of highly metastatic ccRCC cells. Receiver operating characteristic (ROC) analyses showed that the expression of the LTF and MTORC1 gene set, not the autophagy gene set, could be the useful biomarkers to predict 5-year overall survival rate and cancer progression in ccRCC patients. Significantly, the signature of combining mTORC1 upregulation and LTF downregulation was shown as an independent prognostic factor in a multivariate analysis under the progression-free survival condition using the TCGA ccRCC database. Finally, the treatment with mTOR inhibitor rapamycin predominantly reduced the formation of autophagy and ultimately mitigated the cellular migration ability of ccRCC cells with LTF knockdown. Our findings suggest that LTF downregulation is a biomarker for guiding the use of mTOR inhibitors to combat metastatic ccRCC in the clinic.


Radiation biology in brachytherapy.
The biological rationale for the use of brachytherapy, which is undergoing a significant resurgence in the United States, is reviewed with emphasis on low dose rate (LDR brachytherapy). Some of the newer alternatives that have recently been developed, such as pulsed dose rate (PDR) brachytherapy, are discussed.


[Septo-optical dysplasia: oligosymptomatic form (author's transl)].
It is reported on a nine year old boy with the oligosymptomatic form of the septo-optical dysplasia de Morsier: congenital nystagmus with nearly complete loss of visus due to a hypoplasia of the opticus-nerve of both sides, growth retardation (dwarfism) because of STH-deficiency and lack of the gonadotropins. The septum pellucidum is present. The cause of this embryologic malformation within the prosencephalon is not known.


Associations of Father's Lifetime Cannabis Use Disorder with Child's Initiation of Cannabis Use, Alcohol Use, and Sexual Intercourse by Child Gender.
Early initiation of alcohol use, cannabis use, and sexual intercourse among adolescents is an important public health concern in the United States. Parents' history of substance use disorder is an important contributing factor for children's problem behaviors. The associations of fathers' lifetime cannabis use disorder with children's initiation of cannabis use, alcohol use, and sexual intercourse were examined. In addition, child's gender was considered as a moderator of each association. Data from two companion longitudinal studies was utilized, the Rochester Youth Developmental Study and its intergenerational extension, the Rochester Intergenerational Study. Multiple linear regression analyses were conducted to examine the associations of the father's lifetime cannabis use disorder with the child's initiation of cannabis use, alcohol use, and sexual intercourse. To test gender differences in the associations, the study sample was stratified by child's gender. The average age of first cannabis use (b = -3.71, p < .05), alcohol use (b = -3.65, p < .05), and sexual intercourse (b = -2.94, p < .05) among daughters of fathers with a lifetime cannabis use disorder was lower than that of their counterparts after adjusting for all other control variables, whereas no significant differences were detected in a father-son relationship. Homotypic continuity of cannabis use, as well as heterotypic continuity from the father's cannabis use to the child's alcohol use and sexual intercourse existed in a father-daughter relationship. These findings suggest that family-based interventions for female adolescents whose father has suffered from a cannabis use disorder be developed to prevent better adolescents' early substance use and sexual intercourse.


Chromosomal cephalosporinase in Enterobacter hormaechei as an ancestor of ACT-1 plasmid-mediated AmpC β-lactamase.
In this study of the diversity of AmpC β-lactamase in clinical isolates of Enterobacter spp., a strain was found carrying the plasmid-mediated AmpC β-lactamase ACT-1 gene on its chromosome. The strain was identified as Enterobacter hormaechei using phylogenetic analysis of 16S rRNA and hsp60 genes. In addition, the species was confirmed by DNA-DNA hybridization. The genetic environment of the bla(ACT-1) gene was characterized, including the ampR and ampG genes, using a two-step PCR. The amino acid sequences of AmpR at serine 35, arginine 86, glycine 102, aspartic acid 135 and tyrosine 264 were conserved. Measurement of the transcription level of the bla(ACT-1) gene using real-time quantitative PCR showed that it increased 1.98-fold following cefoxitin induction. These results suggest that the plasmid-mediated bla(ACT-1) gene originated from the chromosome of E. hormaechei.


A causal role for ERG in neoplastic transformation of prostate epithelium.
A significant proportion of human prostate cancers carry a chromosomal rearrangement resulting in the overexpression of the ETS transcription factor, ERG; however, the functional significance of this event is poorly understood. We report here that up-regulation of ERG transcript is sufficient for the initiation of prostate neoplasia. In agreement with measurements of ERG transcripts, we found that ERG protein is expressed in neoplastic human prostate epithelium. Overexpression of ERG in prostate cell lines increased cell invasion. Moreover, targeted expression of this transcript in vivo in luminal prostate epithelial cells of transgenic mice results in initiation of prostate neoplasia observed as the development of focal precancerous prostatic intraepithelial neoplasia (PIN). Similar to human cancers, luminal epithelial cells in these PIN lesions displace diminishing in numbers basal epithelial cells and establish direct contact with the stromal cell compartment. Loss of basal cells is considered to be one of the critical hallmarks of human prostate cancer; however, the mechanisms responsible for this event were unknown. We propose that up-regulation of ERG in human prostate cancer activates cell invasion programs that subsequently displace basal cells by neoplastic epithelium. Our data demonstrate that ERG plays an important causal role in the transformation of prostate epithelium and should be considered as a target for prevention or early therapeutic intervention.


An intronless homolog of human proto-oncogene hPTTG is expressed in pituitary tumors: evidence for hPTTG family.
A novel proto-oncogene, PTTG (Pituitary Tumor Transforming Gene), was isolated in our laboratory by virtue of its increased expression in rat pituitary tumor cell lines. Cells which overexpress human or rat PTTG form tumors in athymic mice. hPTTG is highly expressed in cancer cell lines, pituitary adenomas and in normal testis, suggesting that hPTTG protein has different tissue-specific interactions in normal cells and in cancer. Alternatively, different hPTTG gene family members may be functional in normal development and in tumorigenesis. While mapping the chromosomal location of hPTTG to 5q33, we discovered a second gene, hPTTG2, which is intronless and maps to chromosome 4p12. Using gene-specific oligonucleotide hybridization in a PCR-ELISA assay, we determined that hPTTG2 is expressed in both normal and tumorous pituitary. However, high levels of hPTTG mRNA in cancer cell lines are due to increased expression of hPTTG1. Thus, this family of proto-oncogenes appears to differentially participate in tumor-specific pathogenesis.


Phylogenetic analysis of mitochondrial DNA in type 2 diabetes: maternal history and ancient population expansion.
Several studies have suggested a maternal excess in the transmission of type 2 (non-insulin-dependent) diabetes. However, the majority of these reports rely on patients recalling parental disease status and hence are open to criticism. An alternative approach is to study mitochondrial DNA (mtDNA) lineages. The hypervariable region 1 of the rapidly evolving noncoding section of mtDNA is suitable for investigating maternal ancestry and has been used extensively to study the origins of human racial groups. We have sequenced this 347-bp section of mtDNA from leukocytes of subjects with type 2 diabetes (n = 63) and age- and race-matched nondiabetic control subjects (n = 57). Consensus sequences for the two study groups were identical. Pairwise sequence analysis showed unimodal distribution of pairwise differences for both groups, suggesting that both populations had undergone expansion in ancient times. The distributions were significantly different (chi2 = 180, df = 11, P < 0.001); mean pairwise differences were 4.7 and 3.8 for the diabetic and control subjects, respectively. These data suggest that the diabetic subjects belong to an ancient maternal lineage that expanded before the major expansion observed in the nondiabetic population. Phylogenetic trees constructed using maximum parsimony, neighbor-joining, Fitch-Margolish, or maximum likelihood methods failed to show the clustering of all (or a subset) of the diabetic subjects into one or more distinct lineages.


Endovascular coiling versus neurosurgical clipping for people with aneurysmal subarachnoid haemorrhage.
Around 30% of people who are admitted to hospital with aneurysmal subarachnoid haemorrhage (SAH) will rebleed in the initial month after the haemorrhage if the aneurysm is not treated. The two most commonly used methods to occlude the aneurysm for prevention of rebleeding are microsurgical clipping of the neck of the aneurysm and occlusion of the lumen of the aneurysm by means of endovascular coiling. This is an update of a systematic review that was previously published in 2005. To compare the effects of endovascular coiling versus neurosurgical clipping in people with aneurysmal SAH on poor outcome, rebleeding, neurological deficit, and treatment complications. We searched the Cochrane Stroke Group Trials Register (March 2018). In addition, we searched CENTRAL (2018, Issue 2), MEDLINE (1966 to March 2018), Embase (1980 to March 2018), US National Institutes of Health Ongoing Trials Register (March 2018), and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (last searched March 2018). We also contacted trialists. We included randomised trials comparing endovascular coiling with neurosurgical clipping in people with SAH from a ruptured aneurysm. Two review authors independently extracted data, and assessed trial quality and risk of bias using the GRADE approach. We contacted trialists to obtain missing information. We defined poor outcome as death or dependence in daily activities (modified Rankin scale 3 to 6 or Glasgow Outcome Scale (GOS) 1 to 3). In the special worst-case scenario analysis, we assumed all participants in the group with better outcome with missing follow-up information had a poor outcome and those in the other group with missing data a good outcome. We included four randomised trials involving 2458 participants (range per trial: 20 to 2143 participants). Evidence is mostly based on the largest trial. Most participants were in good clinical condition and had an aneurysm on the anterior circulation. None of the included trials was at low risk of bias in all domains. One trial was at unclear risk in one domain, two trials at unclear risk in three domains, and one trial at high risk in one domain.After one year of follow-up, 24% of participants randomised to endovascular treatment and 32% of participants randomised to the surgical treatment group had poor functional outcome. The risk ratio (RR) of poor outcome (death or dependency) for endovascular coiling versus neurosurgical clipping was 0.77 (95% confidence interval (CI) 0.67 to 0.87; 4 trials, 2429 participants, moderate-quality evidence), and the absolute risk reduction was 7% (95% CI 4% to 11%). In the worst-case scenario analysis for poor outcome, the RR for endovascular coiling versus neurosurgical clipping was 0.80 (95% CI 0.71 to 0.91), and the absolute risk reduction was 6% (95% CI 2% to 10%). The RR of death at 12 months was 0.80 (95% CI 0.63 to 1.02; 4 trials, 2429 participants, moderate-quality evidence). In a subgroup analysis of participants with an anterior circulation aneurysm, the RR of poor outcome was 0.78 (95% CI 0.68 to 0.90; 2 trials, 2157 participants, moderate-quality evidence), and the absolute risk decrease was 7% (95% CI 3% to 10%). In subgroup analysis of those with a posterior circulation aneurysm, the RR was 0.41 (95% CI 0.19 to 0.92; 2 trials, 69 participants, low-quality evidence), and the absolute decrease in risk was 27% (95% CI 6% to 48%). At five years, 28% of participants randomised to endovascular treatment and 32% of participants randomised to surgical treatment had poor functional outcome. The RR of poor outcome for endovascular coiling versus neurosurgical clipping was 0.87 (95% CI 0.75 to 1.01, 1 trial, 1724 participants, low-quality evidence). At 10 years, 35% participants allocated to endovascular and 43% participants allocated to surgical treatment had poor functional outcome. At 10 years RR of poor outcome for endovascular coiling versus neurosurgical clipping was 0.81 (95% CI 0.70 to 0.92; 1 trial, 1316 participants, low-quality evidence). The RR of delayed cerebral ischaemia at two to three months for endovascular coiling versus neurosurgical clipping was 0.84 (95% CI 0.74 to 0.96; 4 trials, 2450 participants, moderate-quality evidence). The RR of rebleeding for endovascular coiling versus neurosurgical clipping was 1.83 (95% CI 1.04 to 3.23; 4 trials, 2458 participants, high-quality evidence) at one year, and 2.69 (95% CI 1.50 to 4.81; 1 trial, 1323 participants, low-quality evidence) at 10 years. The RR of complications from intervention for endovascular coiling versus neurosurgical clipping was 1.05 (95% CI 0.44 to 2.53; 2 trials, 129 participants, low-quality evidence). The evidence in this systematic review comes mainly from one large trial, and long-term follow-up is available only for a subgroup of participants within that trial. For people in good clinical condition with ruptured aneurysms of either the anterior or posterior circulation the data from randomised trials show that, if the aneurysm is considered suitable for both neurosurgical clipping and endovascular coiling, coiling is associated with a better outcome. There is no reliable trial evidence that can be used directly to guide treatment in people with a poor clinical condition.


The evaluation and management of monoclonal gammopathy of renal significance and monoclonal gammopathy of neurological significance.
Despite the benign nature of monoclonal gammopathy of undetermined significance (MGUS), mounting data are associating MGUS with the development of organ dysfunction, specifically monoclonal gammopathy of renal significance (MGRS) and monoclonal gammopathy of neurological significance (MGNS), which could be associated with substantial morbidity. Emerging evidence suggests that patients with MGRS and MGNS could benefit from treatments used for myeloma, Waldenström macroglobulinemia, or chronic lymphocytic leukemia, depending on the underlying pathology. However, the treatment of MGRS and MGNS is not standardized, and potentially effective therapies might not be reimbursed because these conditions do not formally meet the criteria for malignant processes. The present review aims at establishing standards for the evaluation and management of MGRS and MGNS, which can facilitate the diagnosis of and provide therapeutic options for treating practitioners and patients affected by these conditions. The careful design and execution of clinical trials for patients with MGRS and MGNS are positively encouraged.


Multiple myeloma in three siblings.
All three siblings of a family developed multiple myeloma. Two siblings had a history of monoclonal gammopathy; in one of these two siblings and in the third sibling, the disease progressed rapidly. A review of the literature shows that of 38 previously reported pairs of siblings with plasma cell disorders, eight families had a third affected sibling and four another affected relative. This clinical clustering suggests that some cases of multiple myeloma may have a hereditary basis and that other family members may be at risk for developing the disease.


Chronic fetal placental embolization and hypoxemia cause hypertension and myocardial hypertrophy in fetal sheep.
To examine the cardiovascular effects on the fetus of an elevated umbilical vascular resistance resulting in fetal hypoxemia, we embolized the fetal side of the placenta in pregnant sheep and measured cardiovascular and hormonal changes and cellular growth in fetal heart. Chronically catheterized fetal sheep were embolized (n = 6) for 21 days between 0.74 and 0.88 of gestation into the descending aorta until arterial oxygen content was decreased by 40-50% of the preembolization value. Control animals (n = 6) received saline only. During embolization, fetuses became chronically hypoxemic (P < 0.001) and hypertensive (P < 0.001), with a progressive increase in umbilical artery resistance index (P < 0.001). There was also an increase in fetal plasma norepinephrine throughout the study period (P < 0.05). On day 21 of embolization, fetuses showed asymmetrical growth restriction, increased heart weight (P < 0.01), and increase in right and left ventricular wall thickness (P < 0.05) compared with control animals. The protein-to-DNA ratio, an index of cell size, increased in the right ventricular myocardium in the embolized group (P < 0.001), suggesting myocardial cell hypertrophy. We conclude that, during chronic placental damage leading to fetal hypoxemia with an increase in umbilical artery resistance index, fetuses developed arterial hypertension and asymmetrical growth restriction and that increases in afterload to the heart and plasma norepinephrine likely caused fetal myocardial hypertrophy.


Modeling the performance of hazardous wastes removal in bioaugmented activated sludge processes.
An enricher-reactor process in which acclimated biomass is grown in an offline reactor on high concentrations of enrichment substrates was used to bioaugment a conventional activated sludge process to a toxic compound, 1-amino naphthalene. Various levels of bioaugmentation, ranging from 1 to 16% mass ratio of augmented cells to indigenous cells, were evaluated in laboratory-scale reactors. The experimental results showed that bioaugmentation can enhance toxic compound removal, increase resistance to shock loading, and reduce the time required for acclimation to the toxic compound. A process model was developed and calibrated using the experimental data. This model was then used to compare the process to an in-situ bioaugmentation process using a reaeration reactor that receives a portion of the recycle activated sludge. The model predicted experimentally observed removals of toxic compound and decreasing relative benefits of bioaugmentation at higher levels. The model suggests that augmented biomass suffers higher decay, which likely is due to the effects of its removal from a substrate-rich to substrate-poor environment. The model shows that the enricher-reactor-process has advantages at lower mean cell retention time (MCRT), and the in-situ process is superior at higher MCRT. Both processes can remove the toxic compound when operating below the washout MCRT that would occur in an unaugmented activated sludge process.


Caregiver strain among non-Hispanic Black and Hispanic male caregivers with self-reported chronic health conditions.
Caregiver strain often stems from unmet needs and is a risk factor for poor physical and psychological health. This study aims to identify factors associated with caregiver strain among middle-aged and older non-Hispanic Black and Hispanic male caregivers living with one or more chronic conditions. Data were analyzed from 418 male caregivers collected through Qualtrics Online Panels using an internet-delivered survey instrument (55.7% non-Hispanic Black, 44.3% Hispanic). Three ordinal regression models were fitted to assess factors associated with Caregiver Strain Scale tertiles: one for all men, one for non-Hispanic Black men only; and one for Hispanic men only. Similarities and differences were observed between the two groups in terms of factors associated with higher caregiver strain (i.e. lower disease self-management efficacy scores, providing ≥20 h of care per week). Uniquely for Non-Hispanic Black male caregivers, higher caregiver strain was associated with living with more children under the age of 18 (β = 0.35, P = 0.011) and feeling more socially disconnected (β = 0.41, P = 0.008). Uniquely for Hispanic male caregivers, higher caregiver strain levels were associated with experiencing lower pain levels (β = -0.14, P = 0.040) and higher fatigue levels (β = 0.23, P < 0.001). Findings from this study suggest that non-Hispanic Black and Hispanic men with chronic conditions have differing caregiving experiences. While bolstering social connectedness and caregiver support services may offset caregiver strain, tailored mental health and disease management programming are needed to meet the specific needs of non-Hispanic Black and Hispanic male caregivers.


Semiparametric model and inference for spontaneous abortion data with a cured proportion and biased sampling.
Evaluating and understanding the risk and safety of using medications for autoimmune disease in a woman during her pregnancy will help both clinicians and pregnant women to make better treatment decisions. However, utilizing spontaneous abortion (SAB) data collected in observational studies of pregnancy to derive valid inference poses two major challenges. First, the data from the observational cohort are not random samples of the target population due to the sampling mechanism. Pregnant women with early SAB are more likely to be excluded from the cohort, and there may be substantial differences between the observed SAB time and those in the target population. Second, the observed data are heterogeneous and contain a "cured" proportion. In this article, we consider semiparametric models to simultaneously estimate the probability of being cured and the distribution of time to SAB for the uncured subgroup. To derive the maximum likelihood estimators, we appropriately adjust the sampling bias in the likelihood function and develop an expectation-maximization algorithm to overcome the computational challenge. We apply the empirical process theory to prove the consistency and asymptotic normality of the estimators. We examine the finite sample performance of the proposed estimators in simulation studies and illustrate the proposed method through an application to SAB data from pregnant women.