[Statement on the lower age limit for outpatient adenotomies and tonsillotomies].
At the beginning of 2023, there have been significant changes to the regulations for outpatient surgery in Germany, which were set out in a trilateral self-administration agreement between the umbrella association of statutory health insurance companies, the German Hospital Association and the Federal Association of Statutory Health Insurance Physicians. Among other things, a catalog stated circumstances under which an operation should not be carried out on an outpatient basis or should only be carried out with doubt. This catalog explains the patient's age: up to the first year of life, inpatient performance of a service can be justified. This formulation in itself means that children from one year of age on should regularly undergo outpatient surgery.In the german scientific societies for otolaryngology, head and neck surgery as well as for anesthesiology and intensive care medicine, doubts arose as to whether this age limit could also be scientifically justified for operations in the throat such as adenotomy or tonsillotomy.A search was carried out in international guidelines and in the international literature and the statements were evaluated. The results of this literature search were discussed with representatives of the Pediatric Otorhinolaryngology Working Group (AG PädHNO) of the German Society for Otorhinolaryngology, Head and Neck Surgery (DGHNO-KHC) and the scientific working group for pediatric anesthesia (WAKKA) of the German Society for Anesthesiology and Intensive Care Medicine (DGAI) in conferences.The consensus revealed that a strict age limit of the first year of life is not appropriate for the outpatient performance of adenotomies and tonsillotomies. First of all, specifying a strict age limit is questionable because, regardless of age, a number of other medical and social factors influence the responsible performance of outpatient operations. Furthermore, the age limit of one year is not considered appropriate in view of literature, guidelines and practical experience in the international area. The assessment of the literature and the consideration of the implementation in the international area make an age limit in the range of 2-3 years seem more appropriate.This review provides the responsible doctors with a variety of insights, aspects and arguments so that they can make their decision to carry out these operations on an outpatient or inpatient basis appropriately and responsibly.


The Use of a Closed Feed Frame for the Development of Near-Infrared Spectroscopic Calibration Model to Determine Drug Concentration.
This study evaluates the use of the closed feed frame as a material sparing approach to develop near-infrared (NIR) spectroscopic calibration models for monitoring blend uniformity. The effect of shear induced by recirculation on NIR spectra was also studied. Calibration models were developed using NIR spectra obtained in the closed feed frame for two cases. For case 2, blends that flowed through the open feed frame were predicted with the model. The shear effect of the feed frame on the blends was assessed through the characterization of powder properties before and after recirculation. The physical characterization of the blends confirmed that the powder properties were not altered after recirculation within the closed feed frame. Both calibration models provided highly accurate predictions of the test sets with low bias (0.03% w/w and -0.06% w/w) and relative standard error of prediction (1.9% and 3.7%), respectively. The predictive performance of the calibration models was not affected by the shear effect. Recirculation within the closed feed frame did not change the physical properties of the blends studied. The prediction of blends flowing through the open feed frame was possible with a calibration model developed in the closed feed frame. The closed feed frame could reduce the materials needed to develop calibration models by more than 90%.


Auditory cortex responses to sequences of normal and reversed squirrel monkey vocalizations.
Responsiveness of auditory cortex (AC) units of awake squirrel monkeys to a natural sequence of species-specific calls was not significantly different from their responsiveness to a reverse playback of the sequence. No dependency was noted between the percentage of responding units and the average intensity of sounds, their spectral content or their order of presentation. The effectiveness of the sounds in eliciting responses was variable even when the sequence was produced in an unchanging behavioral context. Comparison of these findings with earlier results of individual vocalizations presented normally or backward in an isolated manner suggest that responsiveness of AC neurons to continuous sounds is lower than their responsiveness to isolated sounds, whether natural or artificial.


Induction of asthma and the environment: what we know and need to know.
The prevalence of asthma has increased dramatically over the last 25 years in the United States and in other nations as a result of ill-defined changes in living conditions in modern society. On 18 and 19 October 2004 the U.S. Environmental Protection Agency and the National Institute of Environmental Health Sciences sponsored the workshop "Environmental Influences on the Induction and Incidence of Asthma" to review current scientific evidence with respect to factors that may contribute to the induction of asthma. Participants addressed two broad questions: a) What does the science suggest that regulatory and public health agencies could do now to reduce the incidence of asthma? and b) What research is needed to improve our understanding of the factors that contribute to the induction of asthma and our ability to manage this problem? In this article (one of four articles resulting from the workshop), we briefly characterize asthma and its public health and economic impacts, and intervention strategies that have been successfully used to prevent induction of asthma in the workplace. We conclude with the findings of seven working groups that focus on ambient air, indoor pollutants (biologics), occupational exposures, early life stages, older adults, intrinsic susceptibility, and lifestyle. These groups found strong scientific support for public health efforts to limit in utero and postnatal exposure to cigarette smoke. However, with respect to other potential types of interventions, participants noted many scientific questions, which are summarized in this article. Research to address these questions could have a significant public health and economic impact that would be well worth the investment.


Modeling Human Morphological Competence.
One of the central debates in the cognitive science of language has revolved around the nature of human linguistic competence. Whether syntactic competence should be characterized by abstract hierarchical structures or reduced to surface linear strings has been actively debated, but the nature of morphological competence has been insufficiently appreciated despite the parallel question in the cognitive science literature. In this paper, in order to investigate whether morphological competence should be characterized by abstract hierarchical structures, we conducted a crowdsourced acceptability judgment experiment on morphologically complex words and evaluated five computational models of morphological competence against human acceptability judgments: Character Markov Models (Character), Syllable Markov Models (Syllable), Morpheme Markov Models (Morpheme), Hidden Markov Models (HMM), and Probabilistic Context-Free Grammars (PCFG). Our psycholinguistic experimentation and computational modeling demonstrated that "morphous" computational models with morpheme units outperformed "amorphous" computational models without morpheme units and, importantly, PCFG with hierarchical structures most accurately explained human acceptability judgments on several evaluation metrics, especially for morphologically complex words with nested morphological structures. Those results strongly suggest that human morphological competence should be characterized by abstract hierarchical structures internally generated by the grammar, not reduced to surface linear strings externally attested in large corpora.


Structural rearrangements in the parents of children with primary trisomy 21.
A retrospective cytogenetic study was carried out on the parents of children with regular trisomy 21 Down's syndrome. In a total of 128 parents referred routinely to our laboratory after the birth of their affected child, three structural abnormalities, a reciprocal translocation and two pericentric inversions not involving chromosome 21, were detected. This is about 10 times the frequency expected based on current figures from consecutive newborn studies. In addition, the brother of one of nine older people with trisomy 21 referred for cytogenetic analysis for the first time was found to have a reciprocal translocation. This supports the contention made by others that an interchromosomal effect does exist in man. It is suggested that centres who routinely analyse the parents of their trisomy 21 referrals in an unbiased fashion should review their records. They will almost certainly contain useful information regarding the possible existence of this phenomenon and may even contain clues as to its nature. In addition to its undoubted scientific value, such data should prove useful in the genetic counselling of carriers of structural rearrangements.


Regulation of activity of nuclear factor-kappaB and activator protein-1 by nitric oxide, surfactant and glucocorticoids in alveolar macrophages from piglets with acute lung injury.
To investigate whether acute lung injury (ALI) in ventilated piglets with bacterial infection affects NF-kappaB and AP-1 expression in alveolar macrophages (AM) and whether nitric oxide (NO), surfactant (Surf), glucocorticoids (GC) affect NF-kappaB and AP-1 activation in AM in vivo and in vitro. The animals were intraperitoneally injected Escherichia coli, which caused ALI. Nuclear extracts of AM were analyzed by electrophoretic mobility shift assay (EMSA) for the nuclear factor-kappa B (NF-kappaB) and activation protein-1 (AP-1) expression. Detection of IkappaB-alpha protein was from cytoplasmic extract by Western blotting. Immunocytochemistry staining was used for intracellular location of p65 subunits of NF-kappaB. In ex vivo experiments, strikingly higher expression of NF-kappaB and AP-1 by EMSA was found 6 h after bacterial injection in contrast to the Normal group. In the NO, SNO, and GC groups, markedly attenuated NF-kappaB and AP-1 activation was observed. The NF-kappaB and AP-1 activation in Surf group showed lower levels of the expression. Immunoblotting of AM cytoplasmic extract showed low expression of IkappaB-alphaprotein in the Control and Surf groups. The stronger expression was observed in the NO, GC, and SNO groups. AM of the Control and Surf groups showed intense nuclear staining, with decreased nuclear staining in the NO, GC and SNO groups. In in vitro experiment, it caused a significant increase in NF-kappaB and AP-1 activity in AM 1 h after exposure to lipopolysaccharides (LPS). In AM treated by LPS+SNP and LPS+GC, all showed decrease of DNA binding activity of NF-kappaB and AP-1 compared to those exposed to LPS+Surf. Immunoblotting of AM cytoplasmic extract showed that LPS stimulation of AM resulted in the low expression of IkappaB-alpha protein, which was not observed in the presence of SNP and methylprednisolone. However, the surfactant did not show such effect. LPS+Surf-exposed AM had intense nuclear staining, whereas decreased nuclear staining in the LPS+NO and LPS+GC-treated cultures was found, confirming a decrease in NF-kappaB activity. Activation of NF-kappaB was found in AM of ventilated piglets with bacterial ALI. NO and GS could prevent NF-kappaB and AP-1 activation in vivo and in vitro. Surfactant has limited effects on NF-kappaB and AP-1 activity.


Acidogenic pretreatment of wastewaters containing 2-nitrophenol.
Anaerobic Toxicity Assay (ATA) tests were conducted on acidogenic cultures to assess the feasibility of using acidogenic processes to treat wastewaters containing 2-nitrophenol. Results indicated 2-nitrophenol could be removed with a removal efficiency of more than 98%. 2-aminophenol was identified as the major metabolite of the biotransformation of 2-nitrophenol. Reduction in inhibition potential of acidogenic pretreated effluent was observed in the aerobic process. EC50 values of 2-nitrophenol and 2-aminophenol were found to be 0.065 mM and 1.83 mM respectively.


Screening postmenopausal women for ovarian cancer: a systematic review.
To assess ovarian cancer screening in asymptomatic, general-risk postmenopausal women. Outcomes of interest were the screening tests assessed (predictive values, sensitivity, and specificity), the stage of screen-detected disease at diagnosis, psychological effects of screening, and survival. MEDLINE, CANCERLIT, and the Cochrane Library databases were searched to June 2003 using the terms "ovarian," "cancer," "neoplasms," "screening," "clinical trial," "meta-analysis," and "systematic review." Studies were included if they were clinical trials, meta-analyses, or systematic reviews that evaluated tests used to detect ovarian cancer in asymptomatic women in the general population. Studies investigating women at increased risk for ovarian cancer (e.g., family history) and those with symptoms suggestive of ovarian cancer were excluded. Seventeen prospective cohort studies and 3 pilot randomized controlled trials were included in this review. Screening tests for cancer antigen 125 (CA125) and ultrasound had low positive predictive values, resulting in healthy women being recalled and a false-positive rate of 0.01% to 5.8%. Of every 10,000 women participating in an annual screening program with CA125 for 3 years, 800 will have an ultrasound scan because of an elevated CA125, 30 will undergo surgery because of an abnormal ultrasound, and 6 will have ovarian cancer detected at surgery (3 will be diagnosed at early-stage disease and have a chance of a cure). There is insufficient evidence to support the introduction of screening for ovarian cancer in the asymptomatic general-risk postmenopausal population. Screening is associated with increased rates of surgery and patient anxiety.


Multi-Detector Coronary CT Imaging for the Identification of Coronary Artery Stenoses in a "Real-World" Population.
Multi-detector computed tomography (CT) has emerged as a modality for the non-invasive assessment of coronary artery disease (CAD). Prior studies have selected patients for evaluation and have excluded many of the "real-world" patients commonly encountered in daily practice. We compared 64-detector-CT (64-CT) to conventional coronary angiography (CA) to investigate the accuracy of 64-CT in determining significant coronary stenoses in a "real-world" clinical population. A total of 1,818 consecutive patients referred for 64-CT were evaluated. CT angiography was performed using the GE LightSpeed VCT (GE(®) Healthcare). Forty-one patients in whom 64-CT results prompted CA investigation were further evaluated, and results of the two diagnostic modalities were compared. A total of 164 coronary arteries and 410 coronary segments were evaluated in 41 patients (30 men, 11 women, age 39-85 years) who were identified by 64-CT to have significant coronary stenoses and who thereafter underwent CA. The overall per-vessel sensitivity, specificity, positive predictive value, negative predictive value, and accuracy at the 50% stenosis level were 86%, 84%, 65%, 95%, and 85%, respectively, and 77%, 93%, 61%, 97%, and 91%, respectively, in the per-segment analysis at the 50% stenosis level. 64-CT is an accurate imaging tool that allows a non-invasive assessment of significant CAD with a high diagnostic accuracy in a "real-world" population of patients. The sensitivity and specificity that we noted are not as high as those in prior reports, but we evaluated a population of patients that is typically encountered in clinical practice and therefore see more "real-world" results.


New-onset diabetes mellitus in the kidney recipient: diagnosis and management strategies.
Advancing care has markedly improved survival after kidney transplantation, leaving patients susceptible to the effects of chronic transplant-associated morbidities. New-onset diabetes mellitus (NODM) is common in kidney recipients, threatening health and longevity by predisposing to microvascular and cardiovascular disease and by reducing graft survival. A strong rationale therefore exists for the aggressive treatment of NODM in kidney recipients to limit these complications. Screening for diabetes should be systematic and should span the pre- and posttransplantation periods. Once NODM is diagnosed in the kidney transplant patient, a comprehensive plan of therapy should be used to achieve treatment targets. As in the general population, treatment includes lifestyle modification and drug therapy as needed, but transplant-specific factors add complexity to the care of kidney recipients. Among these, minimizing immunosuppression-related toxicity without compromising graft outcomes is of paramount importance. Preexisting allograft functional impairment and the potential for significant interactions with immunosuppressive agents mandate that the expanding armamentarium of hypoglycemic agents be used with care. A team-oriented treatment approach that capitalizes on the collective expertise of transplant physicians, diabetologists, nurse-educators, and dieticians will optimize both glycemic control and the overall health of hyperglycemic kidney recipients.


Experiences of Sex Workers in Chicago during COVID-19: A Qualitative Study.
COVID-19 exacerbated health disparities, financial insecurity, and occupational safety for many within marginalized populations. This study, which took place between 2019 and 2022, aimed to explore the way in which sex workers (n = 36) in Chicago were impacted by COVID-19. We analyzed the transcripts of 36 individual interviews with a diverse group of sex workers using thematic analysis. Five general themes emerged regarding the detrimental impact of COVID-19 on sex workers: (1) the impact of COVID-19 on physical health; (2) the economic impact of COVID-19; (3) the impact of COVID-19 on safety; (4) the impact of COVID-19 on mental health; and (5) adaptive strategies for working during COVID-19. Participants reported that their physical and mental health, economic stability, and safety worsened due to COVID-19 and that adaptive strategies did not serve to improve working conditions. Findings highlight the ways in which sex workers are particularly vulnerable during a public health crisis, such as COVID-19. In response to these findings, targeted resources, an increased access to funding, community-empowered interventions and policy changes are needed to protect the health and safety of sex workers in Chicago.


The nucleotide sequence and genome organization of bovine papillomavirus type 4.
The nucleotide sequence of bovine papillomavirus type 4 (BPV-4) was determined. The viral genome is 7261 base pairs long. Several overlapping open reading frames (ORFs) have been identified both on the basis of amino acid comparison with other papillomaviruses and on their transcriptional pattern. Eight early ORFs (E1 to 8) were recognized, coding for DNA replication and cell transformation functions, and three late ORFs (L1 to 3), coding for structural proteins. Like the E5 ORF of human papillomavirus type 6 the E5 ORF of BPV-4 is discontinuous. Unlike other papillomaviruses, the non-coding region upstream of the early ORFs (ncr-1) is short (385 base pairs), but there is another non-coding region (ncr-2) of nearly 500 base pairs between the L2 and L1 ORFs. Most of the putative regulatory sites are located in the ncr-1, although potential controlling elements are also found in other parts of the genome. Polyadenylation sites are present at the 3' end of both the early and the late transcription units. Comparison between the polypeptides of BPV-4 and other papillomaviruses showed that BPV-4 is evolutionarily closer to the epitheliotropic human and rabbit viruses than to BPV-1.


Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B.
The copper efflux transporters ATP7A and ATP7B sequester intracellular copper into the vesicular secretory pathway for export from the cell. The influence of these transporters on the pharmacodynamics of cisplatin, carboplatin, and oxaliplatin was investigated using human Menkes' disease fibroblasts (Me32a) that do not express either transporter and sublines molecularly engineered to express either ATP7A (MeMNK) or ATP7B (MeWND). Cellular copper levels were significantly higher in the Me32a cells than in the MeMNK and MeWND sublines. These transporter-proficient sublines were resistant to the cytotoxic effect of copper, cisplatin, and carboplatin but were hypersensitive to oxaliplatin. Whole-cell accumulation of platinum after a 24-h exposure was significantly increased in the MeMNK and MeWND cells for all three platinum drugs, but this was accompanied by an increase in the amount of platinum reaching the DNA only for oxaliplatin. Vesicles isolated from MeMNK cells contained more platinum after exposure to cisplatin and carboplatin, whereas the platinum content of vesicles from MeWND cells was increased after exposure to all three drugs. Although copper triggered relocalization of ATP7A from the perinuclear region to more peripheral locations, the platinum drugs did not. These results demonstrate that both ATP7A and ATP7B modulate the pharmacodynamics of all three clinically used platinum drugs. The data are consistent with the hypothesis that these copper exporters sequester the platinum drugs into subcellular compartments, limiting their cytotoxicity, similar to their effect on copper. However, in this model system, although copper is readily exported after vesicular sequestration, the platinum drugs are not.


[Autistic syndrome (Kanner) and vaccination against smallpox (author's transl)].
3-4 weeks following an otherwise uncomplicated first vaccination against smallpox a boy, then aged 15 months and last seen at the age of 5 1/2 years, gradually developed a complete Kanner syndrome. The question whether vaccination and early infantile autism might be connected is being discussed. A causal relationship is considered extremely unlikely. But vaccination is recognized as having a starter function for the onset of autism.


Probe spectrum measurements of Eu3+ ions as a relevant tool for monitoring in vitro hydroxyapatite formation in a new borate biomaterial.
CaB2O4 powders and ceramics were prepared by the conventional solid-state reaction. In vitro hydroxyapatite (HA) mineralization was investigated by soaking the samples in simulated body fluid (SBF) for various time periods. X-ray diffraction and structural refinements, scanning electron microscopy and X-ray energy-dispersive spectra measurements were applied to investigate apatite formation before and after immersion in SBF. HA can easily form flower-like nanostructures with nano-needles even when soaked in SBF for several hours. The in vitro bioactivity of CaB2O4 was attributed to easy formation of B-OH groups in the CaB2O4 structure when soaked in SBF solutions. In the process of mineralization, the luminescence evolution of Eu3+ ions, a well-known structural probe, was detected by photoluminescence spectra and photoluminescence decay curves. This suggested that the process of mineralization can be monitored by the luminescence intensity of Eu3+ ions in the mineralization products. The current study will open up a new and simple in vivo avenue for in situ monitoring of hydroxyapatite conversion using a fiber luminescence spectrometer.


Update on the Management of Infectious Keratitis.
Infectious keratitis is a major global cause of visual impairment and blindness, often affecting marginalized populations. Proper diagnosis of the causative organism is critical, and although culture remains the prevailing diagnostic tool, newer techniques such as in vivo confocal microscopy are helpful for diagnosing fungus and Acanthamoeba. Next-generation sequencing holds the potential for early and accurate diagnosis even for organisms that are difficult to culture by conventional methods. Topical antibiotics remain the best treatment for bacterial keratitis, and a recent review found all commonly prescribed topical antibiotics to be equally effective. However, outcomes remain poor secondary to corneal melting, scarring, and perforation. Adjuvant therapies aimed at reducing the immune response associated with keratitis include topical corticosteroids. The large, randomized, controlled Steroids for Corneal Ulcers Trial found that although steroids provided no significant improvement overall, they did seem beneficial for ulcers that were central, deep or large, non-Nocardia, or classically invasive Pseudomonas aeruginosa; for patients with low baseline vision; and when started early after the initiation of antibiotics. Fungal ulcers often have worse clinical outcomes than bacterial ulcers, with no new treatments since the 1960s when topical natamycin was introduced. The randomized controlled Mycotic Ulcer Treatment Trial (MUTT) I showed a benefit of topical natamycin over topical voriconazole for fungal ulcers, particularly among those caused by Fusarium. MUTT II showed that oral voriconazole did not improve outcomes overall, although there may have been some effect among Fusarium ulcers. Given an increase in nonserious adverse events, the authors concluded that they could not recommend oral voriconazole. Viral keratitis differs from bacterial and fungal cases in that it is often recurrent and is common in developed countries. The Herpetic Eye Disease Study (HEDS) I showed a significant benefit of topical corticosteroids and oral acyclovir for stromal keratitis. HEDS II showed that oral acyclovir decreased the recurrence of any type of herpes simplex virus keratitis by approximately half. Future strategies to reduce the morbidity associated with infectious keratitis are likely to be multidimensional, with adjuvant therapies aimed at modifying the immune response to infection holding the greatest potential to improve clinical outcomes.


Targets of alloantibodies in Alport anti-glomerular basement membrane disease after renal transplantation.
A minority of patients with Alport syndrome develop anti-GBM disease in their allografts after renal transplantation. Clinically, the renal disease appears indistinguishable from Goodpasture's disease of native kidneys, in which the target of autoantibodies had been identified as the NC1 domain of the alpha 3 chain of type IV collagen, alpha 3(IV)NC1. However, in the majority of cases, Alport syndrome is due to mutations in the gene encoding the alpha 5 chain of type IV collagen, located on the X chromosome. Neither chain is detectable in the glomerular basement membrane (GBM) of most patients with Alport syndrome. We investigated the targets of the alloantibodies of 12 Alport patients who developed post-transplant anti-GBM disease by Western blotting onto recombinant NC1 domains made in insect cells. Binding to these antigens, for both typical Goodpasture and Alport anti-GBM antibodies, was strong and conformation-sensitive. Nine antibodies showed selective binding to alpha 5(IV)NC1. This specificity was confirmed by the demonstration of binding to a 26 kDa band of collagenase-solubilized human GBM, and/or binding to normal epidermal as well as renal basement membranes by indirect immunofluorescence. One antibody showed binding to alpha 5 and alpha 3(IV)NC1, while two showed predominant binding to alpha 3(IV)NC1. All seven patients whose pedigree or mutation analysis showed X-linked inheritance had predominant anti-alpha 5 reactivity. One with predominant anti-alpha 3 reactivity had a COL4A3 mutation. These findings show that human anti-GBM disease can be associated with antibodies directed towards different molecular targets. Alpha 5(IV)NC1 is the primary target in most patients with X-linked Alport syndrome who develop post-transplant anti-GBM disease.


Promoting physical activity with people in different places--a Dutch perspective.
This paper describes five recent Dutch studies of the effectiveness of physical activity interventions carried out in diverse settings: general practice (GP), aged care facilities, and workplaces. The stage-based physical activity counselling carried out in the GP setting demonstrated a beneficial effect on the determinants of physical activity, but did not show any additional effect on physical activity behaviour, compared with standard physical activity advice. In contrast, the stage-based intervention through the workplace was effective in increasing physical activity, due mostly to an increase in vigorous-intensity activities. In the aged care setting, functional-skills training alone or in combination with resistance training showed functional improvement only in participants with high participation rates. Functional-skills training appeared to be more feasible than resistance training in this population of frail elderly. The two studies which aimed to promote earlier return-to-work among workers with sick leave due to non-specific low back pain also showed promising results. As a result, it was recommended that occupational physicians (OP) should refer workers with low back pain in the subacute phase of their sick leave to a low intensity intervention consisting of short meetings and exercises aimed at changing behaviour, and that the OPs contact other health care providers (GPs and physiotherapists) about the treatment strategy. Together, the results of these five Dutch studies suggest that it is feasible to successfully promote physical activity to groups of people in diverse places, with benefits in terms of both prevention and management of chronic disease and injury.


Reformulating masculinity: traumatic brain injury and the gendered nature of care and domestic roles.
This article examines the nexus between masculine identity and participation of men living with traumatic brain injury (TBI) in rural New South Wales, Australia. The article considers the impact of adoption of caring and household duties upon identity and participation satisfaction. The focus of this paper is on a finding that emerged from the qualitative phase of a larger project examining participation following TBI in rural and regional areas. During semi-structured interviews, participants were invited to discuss aspects of their participation including their daily occupations, supports, experience of country life and rehabilitation services. A grounded theory methodology shaped the analysis of the interviews. Results, relating to the reformation of masculinity, centred upon eight men drawn from the cohort who moved from the role of breadwinner pre-injury to primarily domestic and caring roles post-injury. Their narratives illustrated three responses to altered life circumstances that necessitated the revision of gendered roles: non-acceptance of reformulated masculinity, accepting reformulated masculinity for the sake of others and accepting and personally valuing a reformulated masculinity. Participation satisfaction for men who take up responsibility for domestic and/or caring duties following TBI is contingent upon successful reformulation of their gendered identity. The research highlights the need for rehabilitation practitioners to adequately support psychosocial adjustment for men following TBI.


Drug repurposing in neurological diseases: an integrated approach to reduce trial and error.
Identifying effective disease-modifying therapies for neurological diseases remains an important challenge in drug discovery and development. Drug repurposing attempts to determine new indications for pre-existing compounds and represents a major opportunity to address this clinically unmet need. It is potentially more cost-effective and time-efficient than de novo drug development and has yielded notable successes in neurological disorders. However, across all medical disciplines, only 30% of repurposed drugs, and 10% of novel candidate molecules, gain market approval. One potentially significant contributor towards this limited success rate is an incomplete knowledge of the exposure-response relationships for the compounds of interest, and how these relate to the new indication, prior to commencing a new trial. We provide an overview of the current approach to early-stage drug repurposing and consider the issues contributing to inconclusive, or possibly falsely negative, Phase II and III trial outcomes in neurological diseases by highlighting examples that illustrate the limitations of empirical evidence generation without a strong scientific basis for the dose rationale. We conclude with a framework suggesting a translational, iterative approach, that integrates pharmacological, pharmaceutical and clinical expertise, towards preclinical and early clinical drug development. This ensures appropriate dosing regimen, route of administration and/or formulation are selected for the new indication before their evaluation in prospective clinical trials.


Multiplex live single-cell transcriptional analysis demarcates cellular functional heterogeneity.
A fundamental goal in the biological sciences is to determine how individual cells with varied gene expression profiles and diverse functional characteristics contribute to development, physiology, and disease. Here, we report a novel strategy to assess gene expression and cell physiology in single living cells. Our approach utilizes fluorescently labeled mRNA-specific anti-sense RNA probes and dsRNA-binding protein to identify the expression of specific genes in real-time at single-cell resolution via FRET. We use this technology to identify distinct myocardial subpopulations expressing the structural proteins myosin heavy chain α and myosin light chain 2a in real-time during early differentiation of human pluripotent stem cells. We combine this live-cell gene expression analysis with detailed physiologic phenotyping to capture the functional evolution of these early myocardial subpopulations during lineage specification and diversification. This live-cell mRNA imaging approach will have wide ranging application wherever heterogeneity plays an important biological role.


Cold- and cryopreservation of human liver and kidney slices.
Tissue slices may provide a rapid and economical way of determining cold ischemic effects on human liver and kidney cell viability and metabolism. In contrast to isolated hepatocyte cultures, tissue slices offer an in vitro system which more closely resembles the in vivo situation because of the differentiation and functional heterogeneity of the slice. In this study, human liver and kidney slices were cold stored for 10 days in Belzers University of Wisconsin (UW), Euro-Collins, and Modified Sacks solutions. Another set of slices was cryopreserved at 1 degree C/min for liver and 12 degrees C/min for kidney using a 10% dimethyl sulfoxide/fetal calf serum (FCS) cryoprotectant solution. The cold- and cryopreserved slices were incubated in roller culture for 4 h using FCS as the media. Liver slice viability was assessed by K+ content, protein synthesis, gluconeogenesis, and urea synthesis. Kidney slice viability was assessed using K+ content, protein synthesis, and organic ion transport (PAH and TEA). Human kidney slices were cold preserved in UW for 4-6 days, while the human liver slices were preserved for 12-24 h depending on the viability parameter. Following cryopreservation, human liver slice viability was retained at between 65 and 90% of control values, while kidney slice viability was maintained between 70 and 90% of control values depending on the viability parameter. These results indicate that this human in vitro tissue slice system can be used to optimize preservation solutions and methods. The ability to cold- and cryopreserve human slices could facilitate the more efficient utilization of human tissue.


Modeling the Tripartite Drug Efflux Pump Archetype: Structural and Functional Studies of the Macromolecular Constituents Reveal More Than Their Names Imply.
It is a remarkable age in molecular biology when one can argue that our current understanding of a process is influenced as much by structural studies as it is by genetic and physiological manipulations. This statement is particularly poignant with membrane proteins for which structural knowledge has been long impeded by the inability to easily obtain crystal structures in a lipid matrix. Thus, several highresolution structures of the components comprising tripartite multidrug efflux pumps from Escherichia coli and Pseudomonas aeruginosa are now available and were received with much acclaim over ever-evolving crystal structures of soluble, aqueous proteins. These structures, in conjunction with functional mutagenesis studies, have provided insight into substrate capture and binding domains and redefined the potential interactions between individual pump constituents. However, correct assembly of the components is still a matter of debate as is the functional contribution of each to the translocation of drug substrates over long distances spanning the Gram-negative cell envelope.


Computed tomography of ununited anconeal process in the dog.
The purpose of this study was to describe computed tomography (CT) features of the ununited anconeal process and relate them with the following elbow dysplasia signs: medial coronoid disease, medial humeral condyle changes, osteoarthritis (OA), and radioulnar incongruence. Computed tomographic images of dogs older than six months with an ununited anconeal process were evaluated (n = 13). Ununited anconeal process features were described as being complete or incomplete, and the degree of displacement, volume, and presence of cysts and sclerosis were also evaluated. Medial coronoid disease was defined as an irregular medial coronoid process shape, presence of sclerosis and fragmentation. Medial humeral condyle changes were defined as subchondral bone flattening, lucencies, and sclerosis. Osteoarthritis was graded depending on the osteophytes size. Radioulnar incongruence was measured on a sagittal view at the base of the medial coronoid process. Eleven elbows had a complete and two had an incomplete ununited anconeal process. All ununited anconeal processes had cystic and sclerotic lesions. Seven ununited anconeal processes were displaced and six were non-displaced. Mean ununited anconeal process volume was 1.35 cm3 (0.61 cm³ - 2.08 cm³). Twelve elbows had signs of medial coronoid disease (4 of them with a fragmented medial coronoid process), and one elbow did not show any evidence of medial coronoid disease. Ten elbows had medial humeral condyle changes. One elbow had grade 1 OA, seven elbows had grade 2, and five elbows grade 3. All elbows had radioulnar incongruence: three elbows had a negative and 10 elbows had a positive radioulnar incongruence. Mean radioulnar incongruence was 1.49 mm (0.63 mm - 2.61 mm). Computed tomographic findings were similar in the majority of the elbows studied: complete ununited anconeal processes with signs of medial coronoid disease, positive radioulnar incongruence, high grade of OA, sclerotic medial humeral condyle changes, and large ununited anconeal process volumes. Incomplete small ununited anconeal process volumes could be associated with a lower incidence of medial coronoid disease or medial humeral condyle changes. We recommend performing preoperative CT of elbows with an ununited anconeal process to evaluate concurrent lesions.


Systemic and mucosal immune response to polio vaccination with additional dose in newborn period.
Administration of supplementary dose of oral polio vaccine (OPV) during neonatal period is recommended by WHO in countries like India, where host response to the regular to the regular three-dose schedule is not satisfactory and poliomyelitis continues to be a problem. The efficacy of this dose +3, and +5 doses of OPV in terms of seropositivity, seroconversion, systemic, and mucosal antibody responses were measured in 51 infants in a follow-up study from birth to 30 weeks. Administration of the additional dose in the newborn period significantly improved seropositivity and seroconversion rates compared to the conventional 3 or 5 dose schedules. Systemic antibody titres improved with each dose of the vaccine and 40-60 per cent of infants had > 1:128 titres to the three types of polioviruses that could prevent re-infection of the gut and 50 per cent of them had mucosal antibodies as evidenced by specific IgA in nasopharyngeal secretions. Therefore, administration of OPV in the neonatal period should be made compulsory in countries where poliomyelitis still continues to be a problem.


Bracing the anterior cruciate ligament deficient knee using the Lenox Hill derotation brace.
The Lenox Hill derotation brace fashioned by Castiglia and his staff at the Lenox Hill Hospital Brace Shop (New York, New York) under the direction of Nicholas during the 1960s has been worn successfully by thousands of patients with unstable knees, including elderly arthritic patients, adolescents with congenital instability, and professional athletes. Nearly 9000 braces were worn by patients in the United States during the period from 1976 to 1980. The brace, with its sliding axis of motion, corresponds to the axis of movement in the knee. The combination Lenox Hill brace includes not only the sliding axis of motion, but also a second below-knee leg pad, second derotation strap, and hyper-extension stop. It is designed to resist the combination anteromedial-rotatory, anterolateral-rotatory, and anteromediolateral-rotatory instabilities. More than 70% of the braces prescribed during the last five years have been the combination type. The derotation brace is a significant advance in brace designs for supporting chronic unstable and surgically reconstructed knees. It can function effectively even when the wearer is actively participating in sports.


Consistently high urine specific gravity in adolescent American football players and the impact of an acute drinking strategy.
The purpose of this study was to determine whether high-school football players showed risks of fluid deficits during two-a-day training (Part 1), and whether implementing a drinking strategy could acutely improve the markers of hydration (Part 2). In Part 1, pre-training urine specific gravity (USG) and pre- and post-training body weight were measured at the morning session for 5 consecutive days of two-a-day practices to monitor the hydration status of 13 varsity players. The mean pre-training body weight was consistently lower (mean decrease of 0.5 kg, p<0.05) following the first day of measurement. Pre-training USG values remained consistently high each day (range for daily means: 1.022+/-0.003 to 1.024+/-0.005). Part 2 consisted of assessing hydration status in 46 varsity and junior varsity players prior to morning training during two-a-day training before and following implementing a drinking strategy. In association with the strategy, mean body weight increased 0.5 kg (p<0.01) and mean USG decreased from 1.021 to 1.016 (p<0.01) following the drinking protocol. The slight decline in body weight and consistently high USG (Part 1) suggested that standard fluid replacement strategies were less than optimal for a majority of the players. Implementing a drinking strategy appeared to improve hydration status based on changes in body weight and USG (Part 2).


[Epithelioid hemangioendothelioma of the mediastinum].
The paper describes a rare case of mediastinal epithelioid hemangioendothelioma characterized by a population of fusiform cells, metaplastic osteogenesis, and aggressive behavior. A 5.5x4-cm encapsulated mass was found in the anterior mediastinum of a 19-year-old female patient. A bone density tumor was sealed with lung tissue and it occluded the lumen of the left subclavian vein. Microscopically, the tumor was composed of foci of the so-called "blister cells" typical of epithelioid hemangioendothelioma, anastomosing chains of epithelioid cells in the microhyaline stroma, diffusely located bone trabeculae, and hemorrhagic stroma. Fusiform cells were present in considerable quantities. A moderate cellular and nuclear polymorphism occurred when mitotic figures were absent. Tumor cells expressed Flil, vimentin, CD31, and CD34. Multiple metastases were detected in the liver and lung. They had the similar morphology.


Histochemical changes in the blood cells of schizophrenic patients under pimozide treatment.
Chromatin structure and nucleohistone pattern were investigated histochemically in the neutrophils of 11 schizophrenics and 16 healthy controls. Compared to controls, all schizophrenic parents prior to medication showed a distinctly different histochemical pattern consisting of increased concentration and abnormal distribution of nucleohistones. This pattern has been attributed to an increase of arginine-rich histones in schizophrenics. Pimozide administration exerted a normalizing effect on the nucleohistone distribution pattern. These findings further support our view that genomic expression abnormalities may be related to schizophrenic illness.


Establishing mutual understanding in interaction: an analysis of conversational repair in psychiatric consultations.
The therapeutic relationship is the greatest predictor of treatment outcome, yet its relationship to communication is largely unevaluated. This study explored how psychiatrists and people with a diagnosis of schizophrenia establish mutual understanding in naturalistic communication, and associations with the therapeutic relationship, patient satisfaction and symptoms. In conversation analysis, the concept of repair focuses on how participants in interaction create mutual understanding and address misunderstanding. A standardized protocol measuring the frequency of repair was applied to 15 outpatient consultations. Correlations between repair and the therapeutic relationship, patients' experience of the consultation and symptoms were explored. Patients made most effort to make their contribution understandable, whereas psychiatrists made most effort to repair misunderstandings. The more positively psychiatrists rated the relationship, the more effort they made to understand patients. Although psychiatrists' efforts were not associated with patients' overall view of the relationship, patients felt better emotionally, despite, feeling less understood. Psychiatrists used fewer repairs when patients were more symptomatic. Both parties prioritized understanding similar topics but psychiatrists focused more on medication and patients on voices. Quantifying repair offers a new way of analyzing how mutual understanding is established in interaction, and links communication processes with treatment outcomes.


The importance of multiple performance criteria for understanding trust in risk managers.
Effective risk management requires balancing several, sometimes competing, goals, such as protecting public health and ensuring cost control. Research examining public trust of risk managers has largely focused on trust that is unspecified or for a single goal. Yet it can be reasonable to have a high level of trust in one aspect of a target's performance but not another. Two studies involving redevelopment of contaminated land (Study 1) and drinking water standards (Study 2) present preliminary evidence on the value of distinguishing between performance criteria for understanding of trust. Study 1 assessed perceptions of several trust targets (councilors, developers, scientists, residents) on their competence (capacity to achieve goals) and willingness to take action under uncertainty for four criteria. Study 2 assessed competence, willingness, and trust for five criteria regarding a single government agency. In both studies overall trust in each target was significantly better explained by considering perceptions of their performance on multiple criteria than on the single criterion of public health. In Study 1, the influence of criteria also varied plausibly across trust targets (e.g., willingness to act under uncertainty increased trust in developers on cost control and councilors on local economic improvement, but decreased it for both targets on environmental protection). Study 2 showed that explained variance in trust increased with both dimension- and trust-based measures of criteria. Further conceptual and methodological development of the notion of multiple trust criteria could benefit our understanding of stated trust judgments.


[The induction of differentiation into dendritic cells from HL-60 cells by calcium ionophore].
To explore whether the promyelocytic leukemia cell line HL-60 may differentiate into activated dendritic cells (DCs) by A23187, a calcium ionophore. The HL-60 cells were cultured in common medium alone or with various concentrations of A23187 (25-1 600 microg/L) and rhGM-CSF (100 microg/L). After culture for 24-96 hours, the cellular morphological change was observed under light microscope and electron microscope. Surface makers on treated HL-60 cells were analyzed by flow cytometry. The proliferation of allogeneic human T cells was detected by MTT colorimetry. Under the condition of a suitable dose (200 microg/L) of A23187 treatment of HL-60 cells for 24 hours, the expression of CD83 molecule, a characteristic marker on DCs, was highest. The typical dendritic outgrowth appeared at a time when HL-60 cells were treated with A23187 for 72 hours. However, when HL-60 cells were treated with A23187 for 96 hours, the expressions of CD80 (B7.1), CD86 (B7.2), MHC-class II molecule and CD54 on HL-60 cells reached peak, and marked activation of allogeneic T cells occurred. Calcium ionophore A23187 can induce the HL-60 cells to differentiate into activated DCs-like cells.


Caregiver descriptions of joint activity routines with young children with autism spectrum disorder in South Africa.
Coaching caregivers to deliver Naturalistic Developmental Behavioral Intervention (NDBI) strategies to their young child with autism spectrum disorder (ASD) could help address the provider capacity barrier in sub-Saharan Africa. However, the behavioral and developmental research that underpins NDBIs is overwhelmingly drawn from high resource settings. Therefore, our understanding of joint activity routines, including play and family routines in which NDBI strategies are embedded, may have limited applicability in low resource, culturally diverse environments. Important questions remain on how to adapt NDBIs to be relevant in the family lives in these settings. This study aimed to elicit descriptions of joint activity routines from caregivers of young children with ASD in South Africa, to understand whether an NDBI-informed caregiver coaching could 'fit' within the multicultural, multilingual South African context. Four focus groups were conducted with 22 caregivers of young children with ASD who were recruited from the Western Cape Education Department autism waiting list. Data were analyzed through directed content analysis, which uses inductive methods to determine salient themes and subthemes. The predetermined initial coding classifications were based on joint activity routine categories of object-based play, sensory social routines, and family routines. Participants' descriptions of caregiver-child interactions aligned with a-priori joint activity routine categories. During object-based play, caregivers engaged in turn-taking, taught developmental skills (for example cognitive, language, and fine motor skills), and participated in child-directed activities. During sensory social routines, caregivers described active, physical play, awareness of child affect, increased child expressive language, and willingness to engage with different play partners. During family routines, caregivers detailed child participation in mealtime and bath time. These data suggest that South African caregivers of young children with ASD use joint activity routines to engage their children and teach them new skills, thus suggesting a degree of 'fit' between South African caregiver-child interactions and an NDBI-informed caregiver coaching approach. However, more information on family routines and which caregiver interacts with the young child with ASD during these routines would help tailor these interventions for low-resource African settings.


East African immigrant children in Australia have poor immunisation coverage.
To provide data on the immunisation status of recently arrived East African children and adolescents in Australia. A prospective audit was conducted at a hospital-based paediatric immigrant health clinic, in Melbourne, Australia, over the time period November 2000-January 2002. Study subjects were consecutive children and adolescents born in East Africa, arriving in Australia after January 1998. Vaccination status was ascertained by parent report and review of patient-held records where available, and by serological testing for immunity to hepatitis B, tetanus, diphtheria, rubella and measles. Among 136 participants, 132 (97%) had incomplete or unknown immunisation status based on parent report and vaccination records; written records were available for 5/136 (4%) of participants. Only 21/136 (15%) had serological immunity to all five of measles, rubella, tetanus, diphtheria and hepatitis B, despite a total of 395 visits to vaccine providers by participants since migration. A higher proportion of children had serological immunity to measles (90%) compared to the proportion with serological immunity to rubella (77%), tetanus (61%), diphtheria (45%) and hepatitis B (33%). The predictive value of parent-reported vaccination status for serological immunity was poor. Paediatric East African immigrants in Victoria are very likely to be inadequately immunised and parent-reported vaccination status does not predict serological immunity. Full catch-up immunisation is recommended where immunisation status is unknown and written records are unavailable. Consideration should be given to policy and program development to provide timely and complete immunisation coverage in this group after arrival in Australia.


Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity.
The role of nitric oxide (NO) in inflammatory bowel diseases has traditionally focused on the inducible form of NO synthase (iNOS). However, the constitutive endothelial (eNOS) and neuronal (nNOS) isoforms may also impact on colitis, either by contributing to the inflammation or by regulating mucosal integrity in response to noxious stimuli. To date, studies examining the roles of the NOS isoforms in experimental colitis have been conflicting, and the mechanisms by which these enzymes exert their effects remain unclear. To investigate and clarify the roles of the NOS isoforms in gut inflammation, we induced trinitrobenzenesulfonic acid colitis in eNOS, nNOS, and iNOS knockout (KO) mice, assessing the course of colitis at early and late times. Both eNOS and iNOS KO mice developed a more severe colitis compared with wild-type mice. During colitis, iNOS expression dramatically increased on epithelial and lamina propria mononuclear cells, whereas eNOS expression remained localized to endothelial cells. Electron and fluorescence microscopy identified bacteria in the ulcerated colonic mucosa of eNOS KO mice, but not in wild-type, iNOS, or nNOS KO mice. Furthermore, eNOS KO mice had fewer colonic goblet cells, impaired mucin production, and exhibited increased susceptibility to an inflammatory stimulus that was subthreshold to other mice. This susceptibility was reversible, because the NO donor isosorbide dinitrate normalized goblet cell numbers and ameliorated subsequent colitis in eNOS KO mice. These results identify a protective role for both iNOS and eNOS during colitis, with eNOS deficiency resulting in impaired intestinal defense against lumenal bacteria and increased susceptibility to colitis.


Organometallic compounds in cancer therapy: past lessons and future directions.
Over the past few years, modern medicinal chemistry has evolved towards providing us new and alternative chemotherapeutic compounds with high cytotoxicity towards tumor cells, alongside with reduced side effects in cancer patients. Organometallic compounds and their unique physic-chemical properties typically used in homogenous catalysis are now being translated as potential candidates for medical purposes. Their structural diversity, ligand exchange, redox and catalytic properties make them promising drug candidates for cancer therapy. Over the last decade this area has witnessed a steady growth and a few organometallic compounds have in fact already entered clinical trials, emphasizing its increasing importance and clinical relevance. Here we intend to stress out the different applications of organometallic compounds in medicine with emphasis on cancer therapy, as well as address setbacks regarding formulation issues, systemic toxicity and off-target effects. Advantages over classical coordination metal complexes, their nanovectorisation and specific molecular targets are also discussed.


Basic mechanisms of fertilization and parthenogenesis in pigs.
Fertilization of the egg, or oocyte, initiates the entire developmental process, but while the mechanism by which the spermatozoa triggers the oocyte to resume meiosis has been studied extensively, conclusions about this process are still elusive. Some workers have suggested that a molecule on the surface of the spermatozoon may interact with a receptor on the plasma membrane of the oocyte, thereby triggering the oocyte to resume meiosis. Other workers have focused on a factor or factors located in the cytoplasm of the spermatozoa that is deposited into the cytoplasm of the oocyte. A hallmark response to fertilization in mammals is an increase in the cytoplasmic concentration of free Ca2+ in the oocyte. Many additional studies have focused on treatments that will induce the oocyte to resume meiosis without being fertilized. The process of resumption of meiosis without a spermatozoon is generally referred to as activation or parthenogenesis. Activation of the oocyte is very important for a number of oocyte- or embryo-related technologies including intracytoplasmic sperm injection (ICSI) and cloning by nuclear transfer. This review will focus on what is known about fertilization and methods to mimic this process, with an emphasis on pigs.


Triamcinolone acetonide loaded-cationic nano-lipoidal formulation for uveitis: Evidences of improved biopharmaceutical performance and anti-inflammatory activity.
Topical administration of corticosteroids is the cornerstone treatment of anterior uveitis, but poor corneal penetration and retention cause hindrance in their therapeutic utility. The conventional eye drops are less valuable in conditions where inflammation reaches deeper regions of the eye. Therefore, there is a clear need for an effective drug delivery system, which can increase corticosteroid penetration after topical application. To address this, cationic nanostructured lipid carriers of the drug triamcinolone acetonide (cTA-NLC) were prepared. The cTA-NLC were prepared by a hot microemulsion method and evaluated for drug release, permeation, cell uptake, cytotoxicity, anti-inflammatory activity and ocular irritancy. The cTA-NLC are nanometric in size (< 200 nm), with a zeta potential of about +35 mv and % drug EE of 88 %. The nanocarriers exhibited slow and sustained release of around 84 % in 24 h and transcorneal drug permeation of 51 % in 8 h. The nanocarriers exhibited no cytotoxicity (% cell viability of>90 %). The cell uptake study showed that nanocarriers could retain inside the cells for 24 h. The developed formulation could significantly reduce the TNF-α level in LPS induced inflamed cells. The studies indicated that cTA-NLC could be a promising option for the topical treatment of uveitis.


Inconsistency between severe substantia nigra degeneration with Lewy bodies and clinical parkinsonism in dementia patients: a cliniconeuropathological study.
In a retrospective cliniconeuropathological study, we reviewed all the cases received in our dementia brain bank during a 4-year period to determine if all patients with severe substantia nigra (SN) degeneration and SN Lewy bodies (LBs) exhibited prominent signs of parkinsonism and were treated for parkinsonism during the disease course. The SN of 426 cases were graded for microscopic degeneration using a semiquantitative five-tiered scale, with grade 0 indicating normal and grade 4 the most severe degeneration. Twenty-nine cases with grade 3 (16) or grade 4 (13) SN degeneration with SN LBs and clinical records were identified. Ten had been treated for parkinsonism (6 grade 3, 4 grade 4) and 19 had not. Whereas most of the patients had exhibited signs of end-stage parkinsonism during their last year, 1 grade 3 and 2 grade 4 patients apparently never exhibited prominent signs of parkinsonism during the course of their dementia. No clear neuropathological differences were noted between these patients that did not have prominent signs and a control group of six patients with clinical Parkinson's disease with dementia (parkinsonism onset at least 1 year before dementia onset). We conclude that in patients with dementia there is an inconsistent relationship between the expression of clinical parkinsonism during life and severe SN degeneration with LBs identified at necropsy.


Ranitidine in the treatment of peptic ulcer.
A randomized, double-blind study was done to determine the efficacy and safety of ranitidine in the short-term treatment of duodenal and benign gastric ulcers. Fifty-one patients with duodenal ulcer and 44 patients with gastric ulcer were admitted to the study. Forty-two duodenal ulcer patients and 36 gastric ulcer patients completed the study. In the duodenal ulcer group, 14 (70%) of 20 patients on ranitidine and one (4.5%) of 22 patients on placebo were healed. In the gastric ulcer group, 12 (75%) of 16 patients on ranitidine and six (30%) of 20 patients on placebo were healed. The healing percentages in both groups significantly favored ranitidine. Ranitidine was also significantly better than placebo in relieving ulcer pain. No side effect could be attributed definitely to ranitidine.


Pretreatment surgical staging of patients with cervical carcinoma: the case for lymph node debulking.
The routine use of extraperitoneal surgical staging prior to radiation therapy in patients with bulky or locally advanced cervical carcinoma remains controversial. A review was performed of 266 patients with cervical carcinoma who underwent extraperitoneal pelvic and paraaortic lymphadenectomy prior to receiving radiotherapy. Patients were divided into groups based on their lymph node status. Group A had negative lymph nodes; Group B had resected, microscopic lymph node metastases; Group C had macroscopically positive lymph nodes that were resectable at the time of surgery; and Group D had unresectable lymph nodes. All patients received standard radiotherapy utilizing external beam and brachy-therapy. Patients with lymph node metastases received extended field irradiation. Survival probabilities were computed by the Kaplan-Meier product limits method with statistical significance determined by the Mantel-Cox log rank test. Lymph node metastases were detected in 50% of patients. Five- and 10-year disease free survival rates were similar for all patients in Groups B and C. All patients in Group D recurred. There was a 10.5% incidence of severe radiation-related morbidity and a 1.1% incidence of treatment-related deaths. Pretreatment extraperitoneal staging of patients with bulky or locally advanced cervical carcinoma may afford a survival benefit via the debulking of macroscopically positive lymph nodes without significantly increasing treatment-related morbidity or mortality.


An APT investigation of an amorphous Cr-B-C thin film.
A magnetron sputtered amorphous Cr-B-C thin film was investigated by means of atom probe tomography (APT). The film is constituted of two phases; a Cr-rich phase present as a few nanometer large regions embedded in a Cr-poor phase (tissue phase). The Cr-rich regions form columnar chains oriented parallel to the growth direction of the film. It was found that the Cr-rich regions have a higher B:C ratio than the Cr-poor regions. The composition of the phases was determined as approximately 35Cr-33B-30C and 15Cr-40B-42C (at%), respectively. The results suggest that this type of nanocomposite films has a more complex structure than previously anticipated, which may have an importance for the mechanical and electrical properties.


Bisexual mating behavior in a diploid of Saccharomyces cerevisiae: evidence for genetically controlled non-random chromosome loss during vegetative growth.
A diploid strain of Saccharomyces cerevisiae has been isolated which exhabits bisexual mating behavior. The strain mates with either a or alpha strains with a relative mating efficiency of 1 to 2%. The efficiency of mating is correlated with the frequency with which subclones of this strain revert to a single mating type. Crosses of the bisexual diploid with a/a or alpha/alpha diploids yield bisexual segregants with a frequency of approximately 3%. Analysis of the segregation of the mating type alleles and other markers on chromosome III indicates that the primary event which leads to the bisexual phenotype is the loss of one homolog of chromosome III during vegetative growth to produce a monosomic (2n-1) diploid. Evidence is presented that the loss of chromosome III and possibly of other chromosomes during vegetative growth is affected by a recessive nuclear gene-her (hermaphrodite)-which is not closely linked to the mating type locus.


Stacking-Order-Dependent Excitonic Properties Reveal Interlayer Interactions in Bulk ReS2.
Rhenium disulfide, a member of the transition metal dichalcogenide family of semiconducting materials, is unique among 2D van der Waals materials due to its anisotropy and, albeit weak, interlayer interactions, confining excitons within single atomic layers and leading to monolayer-like excitonic properties even in bulk crystals. While recent work has established the existence of two stacking modes in bulk, AA and AB, the influence of the different interlayer coupling on the excitonic properties has been poorly explored. Here, we use polarization-dependent optical measurements to elucidate the nature of excitons in AA and AB-stacked rhenium disulfide to obtain insight into the effect of interlayer interactions. We combine polarization-dependent Raman with low-temperature photoluminescence and reflection spectroscopy to show that, while the similar polarization dependence of both stacking orders indicates similar excitonic alignments within the crystal planes, differences in peak width, position, and degree of anisotropy reveal a different degree of interlayer coupling. DFT calculations confirm the very similar band structure of the two stacking orders while revealing a change of the spin-split states at the top of the valence band to possibly underlie their different exciton binding energies. These results suggest that the excitonic properties are largely determined by in-plane interactions, however, strongly modified by the interlayer coupling. These modifications are stronger than those in other 2D semiconductors, making ReS2 an excellent platform for investigating stacking as a tuning parameter for 2D materials. Furthermore, the optical anisotropy makes this material an interesting candidate for polarization-sensitive applications such as photodetectors and polarimetry.


Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man.
The mechanisms for the hypolipidemic action of nicotinic acid were examined in 12 patients with hyperlipidemia. Most patients were studied in the hospital on a metabolic ward. The first month was a control period followed by 1 month on nicotinic acid. During treatment with nicotinic acid, the triglycerides (TG) decreased in total plasma by an average of 52% and in very low density lipoproteins (VLDL) by 36%. Transport rates of VLDL-TG were determined by multicompartmental analysis following injection of [3H]glycerol as a precursor. Nicotinic acid decreased transport (synthesis) of VLDL-TG by an average of 21%. Kinetic modeling of the VLDL-TG data suggested that the TG reduction was due to a decrease in TG content of VLDL and hence a reduction in lipoprotein size more than number. For the whole group, plasma cholesterol fell during nicotinic acid therapy by a mean of 22%. The drug produced no detectable changes in fecal excretions of cholesterol (neutral steroids) or bile acids. However, it induced a small but significant increment in hepatic secretion of biliary cholesterol that might have led to a net loss of cholesterol from the body even though this loss could not be detected by sterol balance. Despite this increase in outputs of biliary cholesterol, there was not a significant increase in molar % cholesterol or in % saturation of gallbladder bile. Therefore, it is doubtful that nicotinic acid enhances the risk for cholesterol gallstones.


Heterogeneity in the physiological states and pharmacological responses of differentiating 3T3-L1 preadipocytes.
Increases in key components of adipogenesis and lipolysis pathways correlate at the population-averaged level during adipogenesis. However, differentiating preadipocytes are highly heterogeneous in cellular and lipid droplet (LD) morphologies, and the degree to which individual cells follow population-averaged trends is unclear. In this study, we analyze the molecular heterogeneity of differentiating 3T3-L1 preadipocytes using immunofluorescence microscopy. Unexpectedly, we only observe a small percentage of cells with high simultaneous expression of markers for adipogenesis (peroxisome proliferator-activated receptor gamma [PPARgamma], CCAAT/enhancer-binding protein alpha, and adiponectin) and lipid accumulation (hormone-sensitive lipase, perilipin A, and LDs). Instead, we identify subpopulations of cells with negatively correlated expressions of these readouts. Acute perturbation of adipocyte differentiation with PPARgamma agonists, forskolin, and fatty acids induced subpopulation-specific effects, including redistribution of the percentage of cells in observed subpopulations and differential expression levels of PPARgamma. Collectively, our results suggested that heterogeneity observed during 3T3-L1 adipogenesis reflects a dynamic mixture of subpopulations with distinct physiological states.


Most Primary Care Physicians Provide Appointments, But Affordability Remains A Barrier For The Uninsured.
The US uninsurance rate has nearly been cut in half under the Affordable Care Act, and access to care has improved for the newly insured, but less is known about how the remaining uninsured have fared. In 2012-13 and again in 2016 we conducted an experiment in which trained auditors called primary care offices, including federally qualified health centers, in ten states. The auditors portrayed uninsured patients seeking appointments and information on the cost of care and payment arrangements. In both time periods, about 80 percent of uninsured callers received appointments, provided they could pay the full cash amount. However, fewer than one in seven callers in both time periods received appointments for which they could make a payment arrangement to bring less than the full amount to the visit. Visit prices in both time periods averaged about $160. Trends were largely similar across states, despite their varying changes in the uninsurance rate. Federally qualified health centers provided the highest rates of primary care appointment availability and discounts for uninsured low-income patients.


Cascade signal amplification using Hg2+-induced oxidation of silver nanoparticles and cation exchange reaction for ICP-MS bioassay.
Combining the Hg2+-induced oxidization of silver nanoparticles with the cation exchange reaction between Ag+ and CuS nanoparticles for cascade signal amplification, a sensitive, universal and label-free ICP-MS bioassay for nucleic acids and proteins was developed. By replacing the loop sequence of the T-Hg-T hairpin structure with specific sequences or aptamers to different biomarkers, it has great promise for the early detection of biomarkers potentially for diagnosis of cancerous diseases.


[Determination of five imidazole pesticide residues in fruits by Turbo flow online purification-ultra performance liquid chromatography-tandem mass spectrometry].
A Turbo flow-ultra performance liquid chromatography-tandem mass spectrometry (TF-UPLC-MS/MS) method was developed for the determination of five imidazole pesticides (imazapyr, triazoxide, rabenzazole, prochloraz and fenamidone) in fruits. The fruit samples were dissolved in saturated sodium chloride solution and extracted by acetonitrile. After the acetonitrile layer was evaporated and redissolved with acetonitrile-water (1 :1, v/v), the fruit samples were analyzed by TF-UPLC-MS/MS. The main factors influencing the purification efficiency including the TF column, mobile phase, elution solution and elution rate were optimized. Under the optimized experimental conditions, the analytes were purified by Turbo flow C18 column (50 mm x 1.0 mm) and separated on a Hypersil GOLD aQ column (100 mm x 2.1 mm) using the mobile phases of acetonitrile and 5 mmol/L ammonium acetate (containing 0.1% (v/v) formic acid) aqueous solution with gradient elution. The compounds were detected by selective reaction monitoring (SRM) via positive electrospray ionization (ESI(+)). The linear range of the method ranged from 0.007 5 to 0.75 mg/L for all the five imidazole pesticides, with the correlation coefficients (r2) greater than 0.99. The limits of quantification were 0.005 mg/kg for all the five imidazole pesticides. The recoveries were in the range from 71.2% to 122.4% at the spiked levels of 0.005, 0.01, 0.05 and 0.5 mg/kg with the relative standard deviations ranging from 0.5% to 8.9% in actual samples. The results indicate that the developed method is simple, efficient and precise, and can be a reliable technique for the determination of the five imidazole pesticides in fruit samples.


Resolution of the DNA strands of the specialized transducing bacteriophage lambda-h80C 1-857 dargF.
The DNA strands of lambdoid phages with deletions or substitutions of the guanine plus cytosine-rich region in the left arm are not resolvable by complexing with poly UG followed by centrifugation in CsCl. This work describes a completely general procedure for the strand resolution of these phages by hybridization with fragments of separated strands of the parent phage. In particular, resolution of the DNA strands of the specialized transducing phage lambda-h80C1-857dargF is described, and evidence is presented which indicates that argF is transcribed from the r strand.


Continuous Stakeholder Engagement: Expanding the Role of Pharmacists in Prevention of Type 2 Diabetes Through the National Diabetes Prevention Program.
The pharmacy sector is a key partner in the National Diabetes Prevention Program (National DPP), as pharmacists frequently care for patients at high risk for type 2 diabetes. The Centers for Disease Control and Prevention aimed to increase pharmacist involvement in the program by leveraging partnerships with national pharmacy stakeholders. Continuous stakeholder engagement helped us to better understand the pharmacy sector and its needs. With stakeholders, we developed a guide and promotional campaign. By following a systematic process and including key stakeholders at every step of development, we successfully engaged these valuable partners in national type 2 diabetes prevention efforts. More pharmacy sites (n = 87) are now offering the National DPP lifestyle change program compared to before release of the guide (n = 27).


Factory performance evaluations of engineering controls for asphalt paving equipment.
This article describes a unique analytical tool to assist the development and implementation of engineering controls for the asphalt paving industry. Through an agreement with the U.S. Department of Transportation, the National Asphalt Pavement Association (NAPA) requested that the National Institute for Occupational Safety and Health (NIOSH) assist U.S. manufacturers of asphalt paving equipment with the development and evaluation of engineering controls. The intended function of the controls was to capture and remove asphalt emissions generated during the paving process. NIOSH engineers developed a protocol to evaluate prototype engineering controls using qualitative smoke and quantitative tracer gas methods. Video recordings documented each prototype's ability to capture theatrical smoke under "managed" indoor conditions. Sulfur hexafluoride (SF6), released as a tracer gas, enabled quantification of the capture efficiency and exhaust flow rate for each prototype. During indoor evaluations, individual prototypes' capture efficiencies averaged from 7 percent to 100 percent. Outdoor evaluations resulted in average capture efficiencies ranging from 81 percent down to 1 percent as wind gusts disrupted the ability of the controls to capture the SF6. The tracer gas testing protocol successfully revealed deficiencies in prototype designs which otherwise may have gone undetected. It also showed that the combination of a good enclosure and higher exhaust ventilation rate provided the highest capture efficiency. Some manufacturers used the stationary evaluation results to compare performances among multiple hood designs. All the manufacturers identified areas where their prototype designs were susceptible to cross-draft interferences. These stationary performance evaluations proved to be a valuable method to identify strengths and weaknesses in individual designs and subsequently optimize those designs prior to expensive analytical field studies.


Transwells with microstamped membranes produce micropatterned two-dimensional and three-dimensional co-cultures.
This article describes a simple and rapid cell patterning method to form co-culture microarrays in commercially available Transwells. A thin poly(dimethylsiloxane) (PDMS) layer is printed on the underside of a Transwell using a PDMS stamp. Arbitrary cellular patterns are generated according to the geometric features of the thin PDMS layer through hydrodynamic forces that guide cells onto the membrane only over the PDMS-uncoated regions. Micropatterns of surface-adhered cells (we refer to this as two-dimensional) or non-surface-adhered clusters of cells (we refer to this as three-dimensional) can be generated depending on the surface treatment of the filter membrane. Additionally, co-cultures can be established by introducing different types of cells on the membrane or in the bottom chamber of the Transwell. We show that this co-culture method can evaluate mouse embryonic stem (mES) cell differentiation based on heterogeneous cell-cell interactions. Co-culture of mES cells and HepG2 cells decreased SOX17 expression of mES cells, and direct cell-cell contact further decreased SOX17 expression, indicating that co-culture with HepG2 cells inhibits endoderm differentiation through soluble factors and cell-cell contact. This method is simple and user-friendly and should be broadly useful to study cell shapes and cell-cell interactions.


Relationships among interleukin-6, tumor necrosis factor-α, adipokines, vitamin D, and chronic periodontitis.
The aim of this study is to explore relationships among serum adipokines, vitamin D, and clinical and microbial parameters of chronic periodontitis before and after treatment. Weight, height, and smoking status were recorded for 56 patients with chronic periodontitis. Plaque, gingivitis, bleeding on probing, suppuration, probing depth, and clinical attachment level were measured at all teeth present. Subgingival biofilm samples from each tooth were analyzed for levels of 40 bacterial species using checkerboard DNA-DNA hybridization. Serum levels of interleukin-6 (IL-6), tumor necrosis factor-α, adiponectin, leptin, resistin, and vitamin D were measured at baseline. Sample collection was then performed in a subset of the population 6 months after therapy (n = 17). Serum samples were analyzed using enzyme-linked immunosorbent assay and immunoassays. Differences in clinical, microbial, and serum factors among groups were sought using the Mann-Whitney U test. Correlations among factors were evaluated using regression analysis. Effects of therapy were sought using the Wilcoxon signed rank test. There were positive correlations between adiponectin/vitamin D and between IL-6/leptin, negative correlations between IL-6/vitamin D and leptin/vitamin D, but no associations between serum analytes and clinical or microbial parameters. Sex and body mass index were associated with levels of adipokines. Periodontal therapy improved clinical and microbiologic parameters but did not influence the levels of serum analytes. Adipokines and IL-6 levels were affected by sex and body mass index. Serum analytes were not influenced by periodontal therapy.


Prevalence and stability of blood-injection-injury phobia in childhood-A prospective community study in Norway.
An individual with a blood-injection-injury (BII) phobia often avoids exposure to triggers, such as blood tests and clinic appointments, leading to potentially serious health complications. This population-based study examined the prevalence, stability and course of BII phobia in children and adolescents. The data came from the Trondheim Early Secure Study, conducted from 2007 to 2018. All children born in Trondheim, Norway, in 2003 and 2004 were invited to attend. Clinical interviews were conducted by trained personnel to assess BII phobia in 1042 children (51% female) every 2 years from 4 to 14 years of age. Latent growth curves and logistic regression analyses were used in the data analysis. Just under 20% of the cohort experienced a BII phobia at least once, with no significant sex differences. The prevalence of BII phobias increased from 3% at 4 years of age and peaked at about 8% at 10 years of age, before levelling off. The two-year stability increased as 12-14 years of age approached. The prevalence of BII was affected by age, but not sex. Early BII phobias often recede with time, but children may need treatment if they persist from 8 years of age.


Predictors of volumetric growth and auditory deterioration in vestibular schwannomas followed in a wait and scan policy.
The purpose of this study was to identify factors predicting growth and audiologic deterioration during follow-up (FU) in a wait and scan (W&S) policy of vestibular schwannomas (VSs) using a novel volumetric measuring tool. So far, only consecutive magnetic resonance imaging (MRI) is able to show growth objectively, and growth, combined with hearing function, generally dictates further intervention. Other factors predicting growth or hearing deterioration would be invaluable and might ease clinical decision making. Retrospective case study. Tertiary referral center. Sixty-three patients diagnosed with VS at Maastricht University Medical Center between 2003 and 2008, with FU data available from 36 patients. A W&S policy for unilateral VS with sequential contrast-enhanced T1- and T2-weighted MRI and audiograms during FU. 1. Patient and radiologic VS features potentially related to growth and auditory function during a W&S policy. 2. The correlation between increase in VS volume and audiologic deterioration during FU. Labyrinthine hypointensity on T2-weighted magnetic resonance images and complaints of hearing loss at presentation are predictive of a faster deterioration of hearing (p < 0.05). Growth during the first FU year predicts further growth. Vestibular schwannoma volume does not correlate with audiologic deterioration significantly. Hypointensity on T2-weighted image of the affected labyrinth will result in a significant faster deterioration of hearing. Hearing loss was more profound, and hearing will deteriorate significantly faster in patients presenting with complaints of hearing loss. Significant growth during the first year of FU predicts further growth during FU. Sequential MRI cannot be substituted by audiologic examinations solely because increase in VS volume does not correlate with audiologic deterioration significantly.


[Relation between the septal nuclei and the amygdaloid complex of the brain of the cat].
By means of retrograde and anterograde transport of horseradish peroxidase method it has been demonstrated in two series of experiments with injecting the enzyme into separate septal nuclei and the amygdaloid complex in cats that most of amygdaloid nuclei (cortico-medial, central and baso-lateral) are reciprocally connected only with two nuclei in the septum: with the nucleus of the diagonal bundle of Broca and with the nucleus of the terminal strip bed. The projections studied are topically organized. The cortico-medial and basal nuclei of the amygdaloid complex are reciprocally connected with the ventral part of the diagonal bundle of Broca and with the terminal strip bed nucleus. The central nucleus of the amygdala has reciprocal projections only with the terminal strip bed nucleus, and with the ventral part of the diagonal bundle of Broca it has only a unilateral connection. On the contrary, the lateral nucleus of the amygdala is reciprocally connected with the ventral part of the diagonal bundle of Broca, and is only projected on the terminal strip bed nucleus without getting any projections from it.


67Ga-metalloprobes: monitoring the impact of geometrical isomers on accumulation profiles in rat cardiomyoblasts and human breast carcinoma cells.
Geometrically similar monocationic gallium(iii) complexes and their radiolabeled SPECT counterparts were obtained from Schiff base precursor ligands using ligand exchange reactions to evaluate the impact of cis and trans-isomers on their cellular accumulation profiles in rat cardiomyoblasts (H9c2(2-1)) and human breast carcinoma (MCF-7neo) cells. 67Ga-metalloprobes comprising trans-phenolates showing an overall octahedral geometry and exhibiting uniform spatial distribution of positive charges on their molecular surface show steady-state accumulation in H9c2(2-1) and MCF-7neo cells, and localize in the mitochondria of the cells. Importantly, the surrogate geometrically similar and monocationic metalloprobe counterparts possessing the cis arrangement of phenolates do not show cellular uptake in H9c2(2-1) and MCF-7neo cells. Exploiting their modest fluorescent traits, live cell imaging indicates that trans-isomers of metalloprobes localize within the mitochondria of cells following their penetration, thereby indicating the excellent correlation of radiotracer data and live-cell microscopy results. Overall, these results indicate that the cell uptake profiles of metalloprobes within this class are mediated by the spatial distribution of charges over their molecular surface and hydrophobicity.


Virgin olive oil phenolic compounds: binding to human low density lipoprotein (LDL) and effect on LDL oxidation.
Oxidation of low density lipoproteins (LDL) appears to occur predominantly in arterial intima in microdomains sequestered from antioxidants of plasma. Therefore phenolic compounds which are able to bind LDL are good drug candidates for the effective prevention of lipid peroxidation and atherosclerotic processes. Plasma from healthy volunteers on nonsupplemented diets was incubated with virgin olive oil phenolic extracts (0-200 mg/l, caffeic acid equivalents). Phenolic compounds in LDL were measured by high-performance liquid chromatography-diode array detection (HPLC-DAD). Copper-mediated LDL oxidation was performed, and conjugated dienes formation was monitored. After plasma preincubation with olive oil phenolic compounds (OOPC), an increased OOPC-concentration dependent was observed in the total phenolic content of LDL (p < 0.001, ANOVA) as well as in the lag time before conjugated diene formation (p < 0.001, ANOVA). Rutin and four phenolics with flavonoid-like spectra were found to be bound to the LDL control. These phenolics, together with tyrosol which was not present in the LDL control, significantly increased in LDL (p < 0.05) after plasma incubation with OOPC. These results show the ability of tyrosol to bind LDL in vitro and the capacity of virgin olive oil phenolics to protect other phenolic compounds previously bound to LDL. These results provide further evidence that phenolic compounds bound to LDL are likely to protect LDL from oxidation.


Differences in lipid characteristics of undifferentiated and enterocytic-differentiated HT29 human colonic cells.
In this paper we compared several lipid characteristics of the homogenate and the corresponding plasma membrane in undifferentiated and differentiated HT29 human colon cancer cells, using normal human colonic cells as a reference. Electron microscopy showed that HT29 cells were morphologically undifferentiated when cultured in the presence of either glucose or inosine without glucose at early confluency. On the contrary, HT29 cells cultured at late confluency in a glucose-free medium containing inosine or grown in nude mice exhibited an enterocytic differentiation with the presence of tight junctions and an apical brush border. The cell homogenate and the plasma membrane were prepared from each cell type. The study of specific marker enzymes showed the same degree of purity in all plasma membranes, with a highly marked increase of brush border-associated hydrolases (N-aminopeptidase and alkaline phosphatase) only in the organelles isolated from differentiated HT29 and colonic cells. Respective similar increases in the amount of free cholesterol and phospholipid and in the free cholesterol:phospholipid molar ratio were found in the plasma membrane as compared with the homogenate in all HT29 cell types. This ratio, due to an increased phospholipid content in both homogenate and plasma membrane, was lowered in colonic cells. No differences in the phospholipid profile were found between the homogenates of all cell types and the plasma membrane of undifferentiated HT29 cells, with the exception of a decrease of cardiolipin in this organelle. On the contrary, the plasma membrane phospholipid composition was different from that of the corresponding homogenate in differentiated HT29 and colonic cells. The most striking changes were a highly increased sphingomyelin amount and concomitant decreases in phosphatidylethanolamine, phosphatidylserine, and cardiolipin. Moreover, differences in the percentage of phosphatidylcholine plus sphingomyelin as well as in phosphatidylcholine:sphingomyelin, phosphatidylethanolamine, and/or phosphatidylcholine molar ratios were also found. The monounsaturated:polyunsaturated fatty acid ratio in phosphatidylethanolamine was similar in differentiated HT29 and colonic cells and lower than in undifferentiated HT29 cells. A decrease in this latter ratio in phosphatidylcholine was also observed in colonic cells and HT29 cells grown in nude mice. These changes were essentially due to opposite variations in the percentage of palmitoleic acid and those of linoleic and/or arachidonic acids in both phospholipids. Thus, these data indicate that undifferentiated HT29 cells were characterized by the absence of a specific phospholipid composition in their plasma membrane, which is suggested to be related to altered phospholipid sorting. The plasma membrane phospholipid profile reversed essentially to the normal pattern when HT29 cells recovered the ability to differentiate.


Thienamycin: development of imipenen-cilastatin.
Thienamycin, a natural product produced by Streptomyces cattleya is the first representative of a unique class of beta-lactam antibiotics, the carbapenems. Despite its outstanding potency and antibacterial spectrum, thienamycin was itself unsuited for further development because of its chemical instability in concentrated solution and in the solid state. Synthesis of the amidine derivative, N-formimidoyl thienamycin (imipenem, MK0787) resulted in a crystalline product with much improved stability and with antibacterial properties significantly superior to thienamycin. Imipenem has an unusually broad antimicrobial spectrum. A high order of bactericidal activity is found against Pseudomonas aeruginosa, Serratia, Bacteroides fragilis, enterococci and numerous other species intrinsically resistant to other antibiotics. Imipenem is refractory to hydrolysis by all important classes of bacterial beta-lactamases and thus exhibits no cross-resistance with penicillins or cephalosporins. Imipenem is distinguished from the new generation of extended-spectrum cephems by its unusually high potency against Gram-positive as well as Gram-negative organisms. Offsetting these excellent antimicrobial properties was an unusual susceptibility exhibited by imipenem to renal metabolism in animal species and in man. Very low urinary recoveries resulted without, however, any significant reduction in the serum half-life of imipenem. A brush-border dipeptidase, dehydropeptidase-I, was shown to be responsible for renal metabolism. Metabolism has been countered with the development of cilastatin (MK0791), a substituted amino-propenoate inhibitor of dehydropeptidase which is specific, potent and well matched in its pharmacokinetic properties for co-administration with imipenem. With the imipenem/cilastatin combination, uniformly high urinary concentrations and recovery are obtained regardless of the varying but often extensive metabolism suffered by imipenem in human populations. An additional benefit conferred by cilastatin results from its ability to exclude imipenem competitively from entry into and subsequent metabolism within the proximal tubular epithelium of the kidney. The tubular necrosis induced by imipenem alone when it is administered at very high doses to susceptible mammalian species is thereby eliminated. Thus the imipenem/cilastatin combination affords reliability and enhanced safety in the application of the antibiotic's unusual antibacterial potential in the treatment of difficult infections regardless of the site of disease.


Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies.
Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span. To examine whether LTL is associated with the life span of contemporary humans. This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019. Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees. The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77). The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.


Increased synovial galectin-3 induce inflammatory fibroblast activation and osteoclastogenesis in patients with rheumatoid arthritis.
Galectin-3 (Gal-3) has been suggested as a proinflammatory mediator in rheumatoid arthritis (RA). We aimed to study clinical and pathogenic aspects of Gal-3 in RA. Plasma samples from healthy controls (n = 48) and patients with newly diagnosed, early RA were assayed for soluble Gal-3. In patients with chronic RA (n = 18), Gal-3 was measured in both plasma and synovial fluid. Synovial fluid mononuclear cells were used to purify fibroblast-like synoviocytes (FLSs) and osteoclasts. Monocultures of FLSs and autologous co-cultures of FLSs and peripheral blood mononuclear cells were established and co-incubated with a Gal-3 inhibitor. Patients with early and chronic RA had persistently increased plasma levels of Gal-3 compared with controls. However, changes in plasma Gal-3 at the level of individuals were associated with long-term disease activity. In seropositive early RA patients, all patients with decreasing plasma Gal-3 from 0 to 3 months had low disease activity after 2 years (p < 0.05). Gal-3 levels in synovial fluid were markedly elevated. In vitro, co-incubation with a Gal-3 inhibitor (GB1107, 10 µM) led to a significant reduction in both interleukin-1β and tumour necrosis factor-α secretion from FLS monocultures (both p < 0.05) and decreased monocyte-derived osteoclastogenesis compared with controls (both p < 0.05). Our findings underscore the role of Gal-3 regarding disease activity and tissue destruction in RA. An initial decrease in plasma Gal-3 levels predicted decreased long-term disease activity. Correspondingly, a Gal-3 inhibitor decreased the activity of inflammatory FLSs and osteoclastogenesis in patients with RA.