Can patients detect hazardous dental practice? A patient complaint study.
The purpose of this paper is to: determine the prevalence and distribution of patient/family-generated, dentistry-related complaints to Regional State Administrative Agencies (AVIs) and the National Supervisory Authority for Welfare and Health (Valvira) in Finland from 2000 to 2011, study patient/family safety incident experiences and other reasons for complaints, assess complaint validity and evaluate factors associated with disciplinary processes against dentists. Data included closed cases handled by AVIs and Valvira (2000-2011) against dental practitioners or dental practice units (n=782). The authors analysed the complaints distribution and examined the antecedent factors and circumstances. This study demonstrated that patients/families can detect many dental treatment hazards, substandard processes and even serious safety risks rather well. The investigation processes revealed some physical harm or potential patient safety (PS) risks in more than half the alleged cases. Many complaints accumulated against certain individuals and statistically significant positive correlations were found between some patient/family complaints, dentist-specific variables and disciplinary actions. Patient/family-generated complaints must be taken seriously and seen as relatively good safety risk indicators. However, more knowledge on how patients might cooperate with dental care providers to prevent errors is needed. This work provides a unique opportunity to learn from several dentistry-related patient complaints. Despite some limitations, patient complaints appear to be useful as a complementary source together with other PS study methods.


Histological evaluation of the adrenal glands of seven dogs with hyperadrenocorticism treated with trilostane.
The lesions in the adrenal glands of seven dogs with hyperadrenocorticism that had been treated with trilostane were studied histologically. The glands of the six dogs with pituitary-dependent hyperadrenocorticism had moderate to severe cortical hyperplasia that was either diffuse or nodular. The lesions were more pronounced in the zona fasciculata than in the zona reticularis, and the zona glomerulosa was normal. In the dog with a functional adrenal tumour the non-tumour bearing adrenal gland showed mild nodular hyperplasia. Five of the seven dogs had variable degrees of adrenal necrosis, which was severe in two of them. The terminal deoxynucleotidyl transferase-mediated DUTP nick-end labelling (TUNEL) reaction specified areas of cell death as apoptosis in three of the dogs, and was positive in one of the dogs without visible areas of cell death. There were variable degrees of cortical haemorrhage in three of the dogs. In some of the dogs the lesions were severe enough to lead to hypoadrenocorticism.


Chronic lymphocytic leukaemia is a risk factor for venous thromboembolism.
Venous thromboembolism (VTE) is a major cause of morbidity and mortality in cancer patients. The literature is sparse on the incidence in the most common lymphoid malignancy, chronic lymphocytic leukaemia (CLL). We calculated the incidence rates for VTE in an unselected UK CLL clinic population at 1.45% per patient year. This represents a tenfold increase over previously published estimates of incidence in the general population and a twofold increase over that of the local hospital inpatient population. In our cohort, the risk of VTE was related to stage C disease. Clinicians should be aware that CLL patients are at risk of VTE.


Chitosan-Based Membranes for Skin Wound Repair in a Dorsal Fold Chamber Rat Model.
Frequently, deep partial and full-thickness skin wounds do not spontaneously regenerate. To restore the normal function of skin, epidermal and dermal components have to be supplied to the wound bed by grafting various substrates. Available options are limited and frequently costly. Herein, authors present a possible approach using 3D skin scaffolds capable of mimicking structure and biological functions of the extracellular matrix, providing, in parallel, a good environment for cell attachment, proliferation and differentiation. Low-molecular weight chitosan-based membranes were prepared by freeze-drying and ionizing radiation techniques to be used as skin scaffolds. Poly (vinyl alcohol), PVA, vinyl pyrrolidone, VP, and gelatin from cold water fish were incorporated. Information regarding membranes' physical-chemical properties from SEM analysis, swelling and weight loss, together with biological response through in vitro assays (using Human Caucasian Fetal Foreskin Fibroblast) allowed the selection of an optimized batch of membranes that was used as skin scaffold in a dorsal rat model wound. The in vivo implantation assays (in Wistar rats) resulted in very promising results: (i) healing process faster than control; (ii) good vascularization; (iii) viable new tissues morphologically functional.


The neurological information network of the National Institute of Neurological Diseases and Blindness.
The National Institute of Neurological Diseases and Blindness (NINDB) has the responsibility of trying to alleviate the morbid and mortal effects of all the diseases of the nervous system and the special senses including speech, hearing, and vision. The information problem facing the NINDB is only a fraction of the total information problem of the biomedical community, but it is probably representative. The NINDB information audience has a core of about 19,000 persons, 10 percent of whom are nonclinical research scientists; 10 percent of whom are engaged in patient care, teaching, and some research; 12 percent in training (post doctoral); and 68 percent chiefly involved in the care of patients. In addition, there is an unknown number of other interested scientists. Fifty to eighty thousand journal articles, an unknown number of technical reports, and other items produced each year are potentially valuable to this group. The exact needs of each subgroup must be identified and ways developed to deliver the required information quickly, accurately, and in an easily useable form. NINDB has undertaken a large information program as a service to the biomedical community to help cope with these information problems. This program is to serve the needs of the practicing physician, the research scientist, and NINDB program analysis and planning. The Neurological Information Network is the core effort of the program.The Neurological Information Network envisions large units incorporating both information storage and retrieval and information analysis. These will be in universities with strong biomedical libraries where there are ongoing research programs in some area relevant to NINDB responsibilities. These units are to be integrated and will interact with each other and with the National Library of Medicine to avoid duplication of work. In addition to their own information analysis activities, the major documentation centers will be able to support information analysis satellites at other research centers where specific categorical research programs are underway.


Brief intervention to promote smoking cessation and improve glycemic control in smokers with type 2 diabetes: a randomized controlled trial.
The aim of the study was to examine the effects of a brief stage-matched smoking cessation intervention group compared with a control group (with usual care) in type 2 diabetes mellitus patients who smoked by randomized controlled trial. There were 557 patients, randomized either into the intervention group (n = 283) who received brief (20- minute) individualized face-to-face counseling by trained nurses and a diabetes mellitus-specific leaflet, or a control group (n = 274) who received standard care. Patient follow-ups were at 1 week, 1 month, 3 months, 6 months, and 12 months via telephone, and assessment of smoking status from 2012 to 2014. Patients smoked an average of 14 cigarettes per day for more than 37 years, and more than 70% were in the precontemplation stage of quitting. The primary outcome showed that both the intervention and control groups had similar 7-day point-prevalence smoking abstinence (9.2% vs. 13.9%; p = 0.08). The secondary outcome showed that HbA1c levels with 7.95% [63 mmol/mol] vs. 8.05% [64 mmol/mol], p = 0.49 at 12 months, respectively. There was no evidence for effectiveness in promoting the brief stage-matched smoking cessation or improving glycemic control in smokers with type 2 diabetes mellitus, particularly those in the pre-contemplation stage.


Targeting G-quadruplexes with Organic Dyes: Chelerythrine-DNA Binding Elucidated by Combining Molecular Modeling and Optical Spectroscopy.
The DNA-binding of the natural benzophenanthridine alkaloid chelerythrine (CHE) has been assessed by combining molecular modeling and optical absorption spectroscopy. Specifically, both double-helical (B-DNA) and G-quadruplex sequences-representative of different topologies and possessing biological relevance, such as telomeric or regulatory sequences-have been considered. An original multiscale protocol, making use of molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations, allowed us to compare the theoretical and experimental circular dichroism spectra of the different DNA topologies, readily providing atomic-level details of the CHE-DNA binding modes. The binding selectivity towards G-quadruplexes is confirmed by both experimental and theoretical determination of the binding free energies. Overall, our mixed computational and experimental approach is able to shed light on the interaction of small molecules with different DNA conformations. In particular, CHE may be seen as the building block of promising drug candidates specifically targeting G-quadruplexes for both antitumoral and antiviral purposes.


An unusual cutaneous infection caused by Mycobacterium marinum.
Introduction.Mycobacterium marinum is a non-tubercular mycobacterium residing in fresh or salt water (in tropical or temperate areas); it is a fish and human pathogen, and in immunocompromised patients can cause severe cutaneous and subcutaneous infections. Case presentation. A 46-year-old white man who underwent immunosuppressive therapy was admitted to our department in May 2016 for skin lesions previously diagnosed as 'unusual erysipelas'. We rejected the hypothesis of erysipelas, due to the clinical features, and our diagnostic hypotheses were oriented towards sporotrichosis, atypical mycobacteriosis, cutaneous tuberculosis and cutaneous sarcoidosis. Histological examination performed after a skin biopsy was compatible with a diagnosis of sporotrichosis. However, PCR performed on fresh tissue demonstrated the presence of M. marinum. Conclusion. The case reported is interesting for the unusual clinical localization and modality of infection. The patient became infected by contact with contaminated remains or in the sea, in a geographical area not endemic for M. marinum. The previous state of immunosuppression favoured infection; however, the presence of M. marinum in this area suggests a possible tropicalization of the water of the Mediterranean Sea. To our knowledge, this case is the only one reported in the literature with this modality of infection and in that geographical area.


Contribution of human hematopoietic stem cells to liver repair.
Immune-deficient mouse models of liver damage allow examination of human stem cell migration to sites of damage and subsequent contribution to repair and survival. In our studies, in the absence of a selective advantage, transplanted human stem cells from adult sources did not robustly become hepatocytes, although some level of fusion or hepatic differentiation was documented. However, injected stem cells did home to the injured liver tissue and release paracrine factors that hastened endogenous repair and enhanced survival. There were significantly higher levels of survival in mice with a toxic liver insult that had been transplanted with human stem cells but not in those transplanted with committed progenitors. Transplantation of autologous adult stem cells without conditioning is a relatively safe therapy. Adult stem cells are known to secrete bioactive factors that suppress the local immune system, inhibit fibrosis (scar formation) and apoptosis, enhance angiogenesis, and stimulate recruitment, retention, mitosis, and differentiation of tissue-residing stem cells. These paracrine effects are distinct from the direct differentiation of stem cells to repair tissue. In patients at high risk while waiting for a liver transplant, autologous stem cell therapy could be considered, as it could delay the decline in liver function.


Budgetary impact of the utilization of buprenorphine/naloxone sublingual film and tablet for Medicaid in the United States.
The buprenorphine/naloxone combination for the treatment of opioid dependence is available in a film or tablet formulation. Recent retrospective studies demonstrated that treatment with the sublingual film formulation is associated with improved treatment retention and lower healthcare costs. In March 2013, generic buprenorphine/naloxone tablets were approved in the US. A budget impact model was built to compare healthcare expenditures for different market shares of sublingual film and tablet. A Markov model was developed to track a cohort of opioid dependent patients treated with sublingual film or tablet through the following treatment phases: initiation, maintenance, discontinuation, off-treatment and reinitiation. Transition probabilities and costs for each phase were estimated from the MarketScan Medicaid database for the period between 1 March 2010 and 30 June 2012. The total expenditure for the plan and expenditure per plan member per month were predicted over 5 years. Two market share scenarios were considered: 1) sublingual film is progressively replaced by generic tablet (current situation) and 2) the sublingual film holds a market share of 100%. Predicted total costs over 5 years were $6400 million when the sublingual film holds a market share of 100% (as per Scenario 2) which is lower than when sublingual film is progressively replaced by generic tablet (current situation as per Scenario 1) by $64 million. These savings were mostly driven by inpatient care ($56 million saved over 5 years), followed by emergency room care ($27 million) and pharmaceutical costs ($24 million). Costs of outpatient care attenuated the difference as they were predicted to be higher by $44 million in Scenario 2. The reduction in total cost per member per month reached $0.027 in the fifth year. Results were most sensitive to price rebates and to the probability of non-psychiatric hospitalization. While using the sublingual film formulation for more patients treated with buprenorphine/naloxone is predicted to increase outpatient care costs, it would generate savings in emergency care and hospitalizations. In the treatment of opioid dependence, total direct medical costs for Medicaid would be lower for sublingual film treated patients, at current drug prices.


Molecular Mechanisms of Zinc as a Pro-Antioxidant Mediator: Clinical Therapeutic Implications.
The essentiality of zinc as a trace mineral in human health has been recognized for over five decades. Zinc deficiency, caused by diet, genetic defects, or diseases, can cause growth retardation, delayed sexual maturation, depressed immune response, and abnormal cognitive functions in humans. Zinc supplementation in zinc-deficient individuals can overcome or attenuate these abnormalities, suggesting zinc is an essential micro-nutrient in the body. A large number of in vitro and in vivo experimental studies indicate that zinc deficiency also causes apoptosis, cellular dysfunction, deoxyribonucleic acid (DNA) damage, and depressed immune response. Oxidative stress, due to the imbalance of reactive oxygen species (ROS) production and detoxification in the anti-oxidant defense system of the body, along with subsequent chronic inflammation, is believed to be associated with many chronic degenerative diseases such as diabetes, heart diseases, cancers, alcohol-related disease, macular degenerative disease, and neuro-pathogenesis. A large number of experimental studies including cell culture, animal, and human clinical studies have provided supportive evidence showing that zinc acts as an anti-oxidative stress agent by inhibition of oxidation of macro-molecules such as (DNA)/ribonucleic acid (RNA) and proteins as well as inhibition of inflammatory response, eventually resulting in the down-regulation of (ROS) production and the improvement of human health. In this article, we will discuss the molecular mechanisms of zinc as an anti-oxidative stress agent or mediator in the body. We will also discuss the applications of zinc supplementation as an anti-oxidative stress agent or mediator in human health and disease.


Excision Arthroplasty With Interpositional Achilles Tendon Autograft: A Novel Approach to Talonavicular Joint Osteoarthritis Associated With Ankle Arthrodesis.
Talonavicular joint arthritis is a great concern after ankle fusion. Although arthrodesis is the gold standard treatment for this complication, it could initiate a vicious cycle of further adjacent joint arthritis. An alternative that may delay or eliminate the need for arthrodesis is excision arthroplasty; however, there are only a few reports on its application on a talonavicular joint. We report 3 cases of excision arthroplasty with interpositional Achilles tendon autograft for the treatment of end-stage talonavicular osteoarthritis in low-demand elderly patients. In 1 patient, excision arthroplasty was performed after tibiotalocalcaneal arthrodesis, and in 2 patients, it was performed after tibiotalar arthrodesis, in which the subtalar joints were also damaged and fused simultaneously on performance of the interpositional arthroplasty of the talonavicular joint. In all cases, pain relief and functional activities of daily living improvement were achieved with this procedure. At a minimum follow-up of 1 year, no patient reported adjacent joint symptoms or flatfoot progression. These cases show that interpositional arthroplasty with Achilles tendon autograft is an effective treatment for end-stage talonavicular arthritis in patients with fused ankle and subtalar joints. This procedure was helpful in relieving pain and improving activities of daily living function in low-demand elderly patients with the preservation of movement of the talonavicular joint. Autograft was considered to be superior to other grafts with respect to availability, graft rejection, or allergy development. Fused subtalar joint resolved the concerning issues, such as flatfoot progression and muscular weakness of ankle plantar flexion, associated with this procedure.


Detection of pre-C and core region mutants of hepatitis B virus in chronic hepatitis B virus carriers.
We analyzed the pre-C and core region of hepatitis B virus (HBV) DNA by a polymerase chain reaction in 22 chronic carriers. In 9 hepatitis B e antigen-positive asymptomatic carriers, a single DNA band was detected at the expected size, whereas additional shorter DNA bands were observed in 7 out of 11 patients with chronic hepatitis. The smaller-sized DNAs from one chronic hepatitis patient had various lengths of deletions spanning from 105 to 183 bp in the middle of the core gene, and all deletions included common nucleotide sequences. All of the smaller-sized DNAs from the other patients proved to be variant core genes. They were deleted in similar regions by Southern analysis using oligonucleotide probes. A follow-up study revealed that four out of seven chronic hepatitis patients with a short core gene seroconverted to antibody to hepatitis B e antigen, but those with only a "wild type" did not. In another set of sequence studies, clones isolated from two chronic carriers displayed heterogeneity of the pre-C and core gene which was more often present in sera with normal alanine aminotransferase levels than with abnormal levels. These results suggest that mutant HBV alters the host immune response, and may modulate the clinical course of HBV infection. An alternative possibility is that chronic hepatitis selects for mutant forms.


An M-like potassium current in the guinea pig cochlea.
Potassium M currents play a role in stabilizing the resting membrane potential. These currents have previously been identified in several cell types, including sensory receptors. Given that maintaining membrane excitability is important for mechano-electrical transduction in the inner ear, the presence of M currents was investigated in outer hair cells isolated from the guinea pig hearing organ. Using a pulse protocol designed to emphasize M currents with the whole-cell patch-clamp technique, voltage- and time-dependent, non-inactivating, low-threshold currents (the hallmarks of M currents) were recorded. These currents were significantly reduced by cadmium chloride. Results from RT-PCR analysis indicated that genes encoding M channel subunits KCNQ2 and KCNQ3 are expressed in the guinea pig cochlea. Our data suggest that guinea pig outer hair cells express an M-like potassium current that, following sound stimulation, may play an important role in returning the membrane potential to resting level and thus regulating outer hair cell synaptic mechanisms.


Blood pressure, edema and proteinuria in pregnancy. 9. Proposal for classification.
The frequency distributions of blood pressures in large populations fail to show two groups, one normotensive and the other hypertensive. In the spectrum of pressures, some people merely have higher levels than others and division of abnormal from normal is artificial and arbitrary, although it is useful for prognosis. The blood pressure of 140/90 as the conventional dividing line does not seem to be appropriate in pregnant women. From the standpoint of fetal prognosis, a level of 125/75 before the thirty-second week and 125/85 thereafter seems more reasonable. Moreover, those levels are close to the 120/80 that Robinson and Brucer specified as the upper limit of normal for all adults and are close to the 130/70 and 120/80 that the eminent British authority, F.J. Browne, used successively in the diagnosis of hypertensive disorders in pregnancy. If the standard of 125/75 were adopted, however, a quarter of all pregnant women would be hypertensive in the second trimester and half in the last month, which are disturbingly high proportions. For the diagnosis of preeclampsia, a rise in blood pressure probably is more significant than an arbitrary level. The usual blood pressure in midpregnancy merely defines the patient's place in the spectrum. Figure 9-1 indicates that in white nulliparas the diastolic pressure rises an average of 10 mm. Hg in the middle of the third trimester. If the mean and median are close together, greater increases would occur in half of the women. The classification of the American Committee on Maternal Welfare and of the Committee on Terminology of the American College of Obstetricians and Gynecologists specify increases of 30 mm. Hg or more in the systolic or 15 mm. Hg or more in the diastolic pressures as criteria of preeclamptic hypertension. pperhaps the rise in diastolic pressure should be set at some greater value. Our analysis of data made thus far cannot decide that issue. The next phase of the study will include analyses in individual women of the times, magnitudes, persistence or transience, and the like of changes in blood pressure, edema, and proteinuria. Such data will afford much more information than can be derived from the preliminary studies reported here. Although edema of the hands and face may be more common in preeclamptic than in normal women, such edema is so common in normal pregnancy as to suggest that it usually is normal. In our data, edema seems to bear no relation to hypertension or proteinuria. The triad of signs -- hypertension, proteinuria, and edema -- is generally accepted as characteristic, though far from specific for preeclampsia. Our data support Hytten's conclusion that edema should by dropped from the triad. There is some indication, however, that some edema is abnormal and that it is associated with an adverse effect when it coincides with proteinuria late in pregnancy.


A novel framework for reflecting on the functioning of research ethics review panels.
In the past decade structures and processes for the ethical review of UK health care research have undergone rapid change. Although this has focused users' attention on the functioning of review committees, it remains rare to read a substantive view from the inside. This article presents details of processes and findings resulting from a novel structured reflective exercise undertaken by a newly formed research ethics review panel in a university school of nursing and midwifery. By adopting and adapting some of the knowledge to be found in the art and science of malt whisky tasting, a framework for critical reflection is presented and applied. This enables analysis of the main contemporary issues for a review panel that is primarily concerned with research into nursing education and practice. In addition to structuring the panel's own literary narrative, the framework also generates useful visual representation for further reflection. Both the analysis of issues and the framework itself are presented as of potential value to all nurses, health care professionals and educationalists with an interest in ethical review.


[The risk of pelvic inflammatory disease associated with urogenital infection with Chlamydia trachomatis; literature review].
To determine the rate of PID in women with genital Chlamydia trachomatis infection. Systematic literature review. MEDLINE and EMBASE were searched over the years 1975-2003 using the keywords 'Chlamydia trachomatis', 'complication', 'pelvic (inflammatory disease)', 'PID', 'endometritis', 'adnexitis', and 'salpingitis'. The reference lists ofthe articles retrieved were checked for other relevant publications. The PID complication rate was determined, as were the characteristics of the study populations and the validity of the diagnostic methods and outcome measures used. 9 prospective studies were identified. The rate of PID in women with a genital C. trachomatis infection varied between o and 72%. Asymptomatic women who were diagnosed with C. trachomatis infection in general screening had the lowest rate of PID: 0-4%. PID occurred in 12-30% of symptomatic women or women with a higher risk of having an STD (e.g. visitor of an STD clinic, double-infection with gonorrhoea, high risk assessed by questionnaire, having a partner with symptomatic C. trachomatis infection). Women who underwent legal abortion had the highest rate of PID (27-72%). The PID rate in women with C. trachomatis varied considerably. Risk depended on whether the infection was symptomatic and the prior probability of having an STD.


APOE ε4 is associated with longer telomeres, and longer telomeres among ε4 carriers predicts worse episodic memory.
Both leukocyte telomere length and the apolipoprotein ε4 allele have been associated with mortality, cardiovascular disease, cognition, and dementia. The authors investigated whether leukocyte telomere length was associated with APOE genotype or cognitive abilities in the context of APOE genotype. The setting for this cross-sectional study was 427 nondemented individuals aged 41-81 yr. The authors found that ε4 carriers overall exhibited significantly longer telomeres compared with non-carriers (difference of 268 bp, p = 0.001). This difference was greatest at the lower limit of the age span and nonsignificant at the upper limit, which translated into a significantly higher telomere attrition rate (p = 0.049) among ε4 carriers (37 bp/years) compared with non-carriers (21 bp/year). Further, longer telomeres among ε4 carriers significantly predicted worse performance on episodic memory tasks. No significant associations were found on tasks tapping semantic and visuospatial ability, or among ε3/ε3 carriers. In conclusion, APOE ε4 carriers had longer telomeres compared with non-carriers, but higher rate of attrition. Among them, longer telomeres predicted worse performance on episodic memory tasks. These observations suggest that the ε4 allele is associated with abnormal cell turnover of functional and possibly clinical significance.


Distinct tissue-specific requirements for the zebrafish tbx5 genes during heart, retina and pectoral fin development.
The transcription factor Tbx5 is expressed in the developing heart, eyes and anterior appendages. Mutations in human TBX5 cause Holt-Oram syndrome, a condition characterized by heart and upper limb malformations. Tbx5-knockout mouse embryos have severely impaired forelimb and heart morphogenesis from the earliest stages of their development. However, zebrafish embryos with compromised tbx5 function show a complete absence of pectoral fins, while heart development is disturbed at significantly later developmental stages and eye development remains to be thoroughly analysed. We identified a novel tbx5 gene in zebrafish--tbx5b--that is co-expressed with its paralogue, tbx5a, in the developing eye and heart and hypothesized that functional redundancy could be occurring in these organs in embryos with impaired tbx5a function. We have now investigated the consequences of tbx5a and/or tbx5b downregulation in zebrafish to reveal that tbx5 genes have essential roles in the establishment of cardiac laterality, dorsoventral retina axis organization and pectoral fin development. Our data show that distinct relationships between tbx5 paralogues are required in a tissue-specific manner to ensure the proper morphogenesis of the three organs in which they are expressed. Furthermore, we uncover a novel role for tbx5 genes in the establishment of correct heart asymmetry in zebrafish embryos.


[The impact of changing the approach of performing episiotomy on perineal trauma in primiparous: a comparison between two periods with different episiotomy rates].
The purpose of this study was to evaluate the impact of changing the approach of performing episiotomy on immediate delivery complications in primiparous women by comparing two periods of time with different episiotomy rates. A retrospective population-based study comparing singleton vaginaL deliveries of nulliparous women for immediate delivery complications during two periods of time: 9192 women during 1994-1999 (period A) with episiotomy rates of 80%-90% and 11,150 women during 2002-2009 (period B) with episiotomy rates of 20%-30%. The study included 20,342 vaginal deliveries. First and second degree perineal tears rate was significantly higher during period B than period A (37.5% vs. 5.8%, p < 0.00). Third degree perineal tears were four times more prevalent in period B than in period A [0.4% vs. 0.1%, p < 0.0001). First and second degree perineal tears rate was significantly higher in women not undergoing episiotomy in both periods. Multiple logistic regression analysis reveals that episiotomy is a significant predictor for first and second degree perineal tears (OR = 0.1, p < 0.001) but not for third degree perineal tears. Since spontaneous first and second degree perineal tears entail no significant morbidity, it is better to manage uncomplicated deLiveries in primiparous women without the use of episiotomy.


Selecting inputs for modeling using normalized higher order statistics and independent component analysis.
The problem of input variable selection is well known in the task of modeling real-world data. In this paper, we propose a novel model-free algorithm for input variable selection using independent component analysis and higher order cross statistics. Experimental results are given which indicate that the method is capable of giving reliable performance and that it outperforms other approaches when the inputs are dependent.


Identification and molecular characterization of alpha-L-iduronidase mutations present in mucopolysaccharidosis type I patients undergoing enzyme replacement therapy.
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of alpha-L-iduronidase (IDUA). Mutations in the gene are responsible for the enzyme deficiency, which leads to the intralysosomal storage of the partially degraded glycosaminoglycans dermatan sulfate and heparan sulfate. Molecular characterization of MPS I patients has resulted in the identification of over 70 distinct mutations in the IDUA gene. The high degree of molecular heterogeneity reflects the wide clinical variability observed in MPS I patients. Six novel mutations, c.1087C>T (p.R363C), c.1804T>A (p.F602I), c.793G>C, c.712T>A (p.L238Q), c.1727+2T>A, and c.1269C>G (p.S423R), in a total of 14 different mutations, and 13 different polymorphic changes, including the novel c.246C>G (p.H82Q), were identified in a cohort of 10 MPS I patients enrolled in a clinical trial of enzyme-replacement therapy. Five novel amino acid substitutions and c.236C>T (p.A79V) were engineered into the wild-type IDUA cDNA and expressed. A p.G265R read-through mutation, arising from the c.793G>C splice mutation, was also expressed. Each mutation reduced IDUA protein and activity levels to varying degrees with the processing of many of the mutant forms also affected by IDUA. The varied properties of the expressed mutant forms of IDUA reflect the broad range of biochemical and clinical phenotypes of the 10 patients in this study. IDUA kinetic data derived from each patient's cultured fibroblasts, in combination with genotype data, was used to predict disease severity. Finally, residual IDUA protein concentration in cultured fibroblasts showed a weak correlation to the degree of immune response to enzyme-replacement therapy in each patient.


Principles of operating room organization.
The importance of the changing health care climate has triggered important changes in the management of high-cost components of acute care facilities. By integrating and better managing various elements of the surgical process, health care institutions are able to rationally trim costs while maintaining high-quality services. The leadership that physicians can provide is crucial to the success of this undertaking (1). The importance of the use of primary data related to patient throughput and related resources should be strongly emphasized, for only when such data are converted to INFORMATION of functional value can participating healthcare personnel be reasonably expected to anticipate and respond to varying clinical demands with ever-limited resources. Despite the claims of specific commercial vendors, no single product will likely be sufficient to significantly change the perioperative process to the degree or for the duration demanded by healthcare reform. The most effective approach to achieving safety, cost-effectiveness, and predictable process in the realm of Surgical Services will occur by appropriate application of the "best of breed" contributions of: (a) medical/patient safety practice/oversight; (b) information technology; (c) contemporary management; and (d) innovative and functional cost-accounting methodology. S "modified activity-based cost accounting method" can serve as the basis for acquiring true direct-cost information related to the perioperative process. The proposed overall management strategy emphasizes process and feedback, rather than specific product, and although imposing initial demands and change on the traditional hospital setting, can advance the strongest competitive position in perioperative services. This comprehensive approach comprises a functional basis for important bench-marking activities among multiple surgical services. An active, comparative process of this type is of paramount importance in emphasizing patient care and safety as the highest priority while changing the process and cost of perioperative care. Additionally, this approach objectively defines the surgical process in terms by which the impact of new treatments, drugs, devices and process changes can be assessed rationally.


Conservation of glycoprotein H (gH) in herpesviruses: nucleotide sequence of the gH gene from herpesvirus saimiri.
We present the nucleotide sequence of the glycoprotein H (gH) gene of herpesvirus saimiri (HVS), a representative of the T lymphotropic herpesviruses of New World monkeys, and compare the predicted amino acid sequence with sequences of homologous proteins from four human herpesviruses. The HVS gH gene is located within a block of genes encoding products conserved in all herpesvirus subgroups as represented by the human herpesviruses herpes simplex virus, varicella-zoster virus, cytomegalovirus and Epstein-Barr virus. In agreement with the biological grouping of HVS as a lymphotropic gammaherpesvirus, its gH amino acid sequence shows greatest similarity to that of the B lymphotropic Epstein-Barr virus, although the nucleotide sequences of their respective gH genes show little similarity given different G + C compositions of 31% and 54%. The similarity observed between the gH amino acid sequences of the two representative gammaherpesviruses is greater than that between the two human alphaherpesviruses varicella-zoster virus and herpes simplex virus. The members of the gH family range in size from 706 to 743 amino acid residues for the beta- and gammaherpesviruses, to 838 to 841 for the alphaherpesviruses, giving non-glycosylated precursors with Mr values of 78,322 to 93,651. The difference in size is due to heterogeneity in the poorly conserved N-terminal regions of the larger alphaherpesviruses compared to the smaller beta- and gammaherpesvirus molecules. Greatest similarity is observed in the C-terminal halves of the proteins including residues surrounding four conserved cysteine residues, a conserved N-linked glycosylation site (within the sequence NGTV) 13 to 18 residues proximal to the membrane-spanning sequences, and a short cytoplasmic domain of seven or eight residues for the beta- and gammaherpesviruses' and 14 or 15 residues for the alphaherpesviruses' gH. Thus, the representatives of all subgroups of herpesviruses, including those with a non-human host, encode gH homologues. Together with the observation that gH of these viruses are major targets for virus neutralization by antibody, this suggests that this glycoprotein family is essential among all herpesviruses and represents a major component involved in herpesvirus infectivity.


HLA haplotype analysis in Finnish patients with rheumatoid arthritis.
To further characterize the HLA gene products that play an important role in the pathogenesis of rheumatoid arthritis (RA). One hundred thirty-four haplotypes from 67 Finnish RA patients and 77 control haplotypes were analyzed for HLA-DRB1 loci, associated alleles of the HLA-DQB1 locus, alleles of the type 2 transporter-associated antigen processing (TAP2) genes, and HLA-B27. In addition, a panel of microsatellite markers within the HLA class I and class III regions was studied. The frequency of HLA-DRB1*04 in the haplotypes of RA patients was found to be 34% (45 of 134) compared with 14% (10 of 72) in control haplotypes (P = 0.004). The frequency of HLA-DRB1*13 was decreased in RA haplotypes (4%, or 5 of 134) in contrast to control haplotypes (24%, or 17 of 72) (P = 0.000031). The decrease in DRB1*13 was not secondary to the increase in DRB1*04, since it was also found among DRB1*04-negative haplotypes (P < 0.001). The DRB1*13-associated DQB1*0604 allele was similarly decreased in RA haplotypes (P = 0.025). The TAP2I allele of I/J dimorphism was increased in RA patients (85%, or 114 of 134) as compared with controls (69%, or 49 of 71) (P = 0.011). Of the tumor necrosis factor (TNF) microsatellite alleles, TNFa6 and TNFb5 were found to be increased in RA haplotypes (for a6 27% versus 5% in controls [P = 0.00043], and for b5 43% versus 26% in controls [P = 0.037]). Both protection-associated and susceptibility-associated alleles can be found among HLA class II genes, and the results suggest that loci outside DR/DQ may contribute to the pathogenesis of RA.


Cation transport in Escherichia coli. IX. Regulation of K transport.
Kinetics of K exchange in the steady state and of net K uptake after osmotic upshock are reported for the four K transport systems of Escherichia coli: Kdp, TrkA, TrkD, and TrkF. Energy requirements for K exchange are reported for the Kdp and TrkA systems. For each system, kinetics of these two modes of K transport differ from those for net K uptake by K-depleted cells (Rhoads, D. B. F.B. Walters, and W. Epstein. 1976. J. Gen. Physiol. 67:325-341). The TrkA and TrkD systems are inhibited by high intracellular K, the TrkF system is stimulated by intracellular K, whereas the Kdp system is inhibited by external K when intracellular K is high. All four systems mediate net K uptake in response to osmotic upshock. Exchange by the Kdp and TrkA systems requires ATP but is not dependent on the protonmotive force. Energy requirements for the Kdp system are thus identical whether measured as net K uptake or K exchange, whereas the TrkA system differs in that it is dependent on the protonmotive force only for net K uptake. We suggest that in both the Kpd and TrkA systems formation of a phosphorylated intermediate is necessary for all K transport, although exchange transport may not consume energy. The protonmotive-force dependence of the TrkA system is interpreted as a regulatory influence, limiting this system to exchange except when the protonmotive force is high.


Diagnosis and treatment of pancreatic exocrine insufficiency.
Pancreatic exocrine insufficiency is an important cause of maldigestion and a major complication in chronic pancreatitis. Normal digestion requires adequate stimulation of pancreatic secretion, sufficient production of digestive enzymes by pancreatic acinar cells, a pancreatic duct system without significant outflow obstruction and adequate mixing of the pancreatic juice with ingested food. Failure in any of these steps may result in pancreatic exocrine insufficiency, which leads to steatorrhea, weight loss and malnutrition-related complications, such as osteoporosis. Methods evaluating digestion, such as fecal fat quantification and the (13)C-mixed triglycerides test, are the most accurate tests for pancreatic exocrine insufficiency, but the probability of the diagnosis can also be estimated based on symptoms, signs of malnutrition in blood tests, fecal elastase 1 levels and signs of morphologically severe chronic pancreatitis on imaging. Treatment for pancreatic exocrine insufficiency includes support to stop smoking and alcohol consumption, dietary consultation, enzyme replacement therapy and a structured follow-up of nutritional status and the effect of treatment. Pancreatic enzyme replacement therapy is administered in the form of enteric-coated minimicrospheres during meals. The dose should be in proportion to the fat content of the meal, usually 40-50000 lipase units per main meal, and half the dose is required for a snack. In cases that do not respond to initial treatment, the doses can be doubled, and proton inhibitors can be added to the treatment. This review focuses on current concepts of the diagnosis and treatment of pancreatic exocrine insufficiency.


Shared Autonomic Pathways Connect Bone Marrow and Peripheral Adipose Tissues Across the Central Neuraxis.
Bone marrow adipose tissue (BMAT) is increased in both obesity and anorexia. This is unique relative to white adipose tissue (WAT), which is generally more attuned to metabolic demand. It suggests that there may be regulatory pathways that are common to both BMAT and WAT and also those that are specific to BMAT alone. The central nervous system (CNS) is a key mediator of adipose tissue function through sympathetic adrenergic neurons. Thus, we hypothesized that central autonomic pathways may be involved in BMAT regulation. To test this, we first quantified the innervation of BMAT by tyrosine hydroxylase (TH) positive nerves within the metaphysis and diaphysis of the tibia of B6 and C3H mice. We found that many of the TH+ axons were concentrated around central blood vessels in the bone marrow. However, there were also areas of free nerve endings which terminated in regions of BMAT adipocytes. Overall, the proportion of nerve-associated BMAT adipocytes increased from proximal to distal along the length of the tibia (from ~3-5 to ~14-24%), regardless of mouse strain. To identify the central pathways involved in BMAT innervation and compare to peripheral WAT, we then performed retrograde viral tract tracing with an attenuated pseudorabies virus (PRV) to infect efferent nerves from the tibial metaphysis (inclusive of BMAT) and inguinal WAT (iWAT) of C3H mice. PRV positive neurons were identified consistently from both injection sites in the intermediolateral horn of the spinal cord, reticular formation, rostroventral medulla, solitary tract, periaqueductal gray, locus coeruleus, subcoeruleus, Barrington's nucleus, and hypothalamus. We also observed dual-PRV infected neurons within the majority of these regions. Similar tracings were observed in pons, midbrain, and hypothalamic regions from B6 femur and tibia, demonstrating that these results persist across mouse strains and between skeletal sites. Altogether, this is the first quantitative report of BMAT autonomic innervation and reveals common central neuroanatomic pathways, including putative "command" neurons, involved in coordinating multiple aspects of sympathetic output and facilitation of parallel processing between bone marrow/BMAT and peripheral adipose tissue.


Detection of bright and dim colours by honeybees.
Honeybees, Apis mellifera, were trained to detect coloured disks with either a strong or a weak intensity difference against the background. Green, blue, ultraviolet-reflecting white and grey papers were reciprocally combined as targets or backgrounds, providing strong chromatic and/or achromatic cues. The behavioural performance of the honeybees was always symmetrical for both reciprocal target/background combinations of a colour pair, thus showing that target detection is independent of whether the colour is presented as a background or as a target in combination with the other colour. Bright targets against dim backgrounds and vice versa were detected more reliably than dim target/background combinations. This result favours the general assumption that the detectability of a coloured stimulus increases with increasing intensity.


In vitro cultivation of embryonic rat tongue cells--a convenient system for oral carcinogenesis studies.
Fine mince of embryonic rat tongue suspended in medium and transferred to culture vessel adhere immediately to surface. Epithelial and fibroblastic cell outgrowth seen in the first few days was overgrown with fibroblasts later. Evidence is presented that these fibroblasts are sensitive to post-confluence inhibition of division and exhibit several properties of normal fibroblasts including limited lifespan. This system may serve as a simple in vitro model for oral carcinogenesis studies.


Incremental value of adenosine-induced stress myocardial perfusion imaging with dual-source CT at cardiac CT angiography.
First, to assess the feasibility of a protocol involving stress-induced perfusion evaluated at computed tomography (CT) combined with cardiac CT angiography in a single examination and second, to assess the incremental value of perfusion imaging over cardiac CT angiography in a dual-source technique for the detection of obstructive coronary artery disease (CAD) in a high-risk population. Institutional review board approval and informed patient consent were obtained before patient enrollment in the study. The study was HIPAA compliant. Thirty-five patients at high risk for CAD were prospectively enrolled for evaluation of the feasibility of CT perfusion imaging. All patients underwent retrospectively electrocardiographically gated (helical) adenosine stress CT perfusion imaging followed by prospectively electrocardiographically gated (axial) rest myocardial CT perfusion imaging. Analysis was performed in three steps: (a)Coronary arterial stenoses were scored for severity and reader confidence at cardiac CT angiography, (b)myocardial perfusion defects were identified and scored for severity and reversibility at CT perfusion imaging, and (c)coronary stenosis severity was reclassified according to perfusion findings at combined cardiac CT angiography and CT perfusion imaging. The sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of cardiac CT angiography before and after CT perfusion analysis were calculated. With use of a reference standard of greater than 50% stenosis at invasive angiography, all parameters of diagnostic accuracy increased after CT perfusion analysis: Sensitivity increased from 83% to 91%; specificity, from 71% to 91%; PPV, from 66% to 86%; and NPV, from 87% to 93%. The area under the receiver operating characteristic curve increased significantly, from 0.77 to 0.90 (P < .005). A combination protocol involving adenosine perfusion CT imaging and cardiac CT angiography in a dual-source technique is feasible, and CT perfusion adds incremental value to cardiac CT angiography in the detection of significant CAD.


Recovery after aerobic exercise is manipulated by tempo change in a rhythmic sound pattern, as indicated by autonomic reaction on heart functioning.
Physical prowess is associated with rapid recovery from exhaustion. Here we examined whether recovery from aerobic exercise could be manipulated with a rhythmic sound pattern that either decreased or increased in tempo. Six men and six women exercised repeatedly for six minutes on a cycle ergometer at 60 percent of their individual maximal oxygen consumption, and then relaxed for six minutes while listening to one of two sound pattern conditions, which seemed to infinitely either decrease or increase in tempo, during which heart and breathing activity was measured. Participants exhibited more high-frequent heart rate variability when listening to decreasing tempo than when listening to increasing tempo, accompanied by a non-significant trend towards lower heart rate. The results show that neuropsychological entrainment to a sound pattern may directly affect the autonomic nervous system, which in turn may facilitate physiological recovery after exercise. Applications using rhythmic entrainment to aid physical recovery are discussed.


AsHC 360 Exposure Influence on Epileptiform Discharges in Hippocampus of Infantile Male Rats In Vitro.
Arsenic-containing hydrocarbons (AsHCs) are typical arsenolipids found in various marine organisms. They can penetrate the blood-brain barrier, specifically affecting synaptic plasticity and the learning and memory ability of hippocampal neurons. Temporal lobe epilepsy often occurs in the hippocampus. Thus, the possible influence of AsHCs exposure to temporal lobe epilepsy garnered attention. The present study investigated the effects of epileptiform discharges (EDs) signals introduced by low-magnesium ACSF in the hippocampus of infantile male rats in vitro, using electrophysiological techniques with multi-electrode arrays under AsHC 360 exposure. In our study of the effects of AsHC 360 on EDs signals, we found that inter-ictal discharges (IIDs) were not significantly impacted. When AsHC 360 was removed, any minor effects observed were reversed. However, when we examined the impact of AsHC 360 on ictal discharges (IDs), distinct patterns emerged based on the concentration levels. For low-concentration groups (5, 20, 60 μg As L-1), both the frequency and duration effects on IDs returned to normal post-elimination of AsHC 360. However, this recovery was not evident for concentrations of 100 μg As L-1 or higher. IDs were only observed in EDs signals during exposures to AsHC 360 concentrations up to 60 μg As L-1. In these conditions, ID frequencies significantly enhanced with the increased of AsHC 360 concentration. At high concentrations of AsHC 360 (≥100 μg As L-1), the transition from IIDs or pre-ictal discharges (PIDs) to IDs was notably inhibited. Additional study on co-exposure of AsHC 360 (100 μg As L-1) and agonist (10 nM (S)-(-)-Bay-K-8644) indicated that the regulation of EDs signals under AsHC 360 exposure could be due to directly interference with the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) expression which influences the binding of excitatory glutamate neurotransmitter to AMPAR. The results suggest that EDs activities in the hippocampus of infantile Sprague Dawley rats are concentration-dependent on AsHC 360 exposure. Thus, it provides a basis for the seafood intake with AsHCs for epileptic patients and those with potential seizures.


Brief Report: COVID-19 Testing, Characteristics, and Outcomes Among People Living With HIV in an Integrated Health System.
Understanding the attributes of COVID-19 clinical severity among people living with HIV (PLWH) compared with those in HIV-uninfected patients is critical for risk stratification and treatment strategies. We conducted a retrospective study at Kaiser Permanente Southern California among PLWH aged 18 years or older. We compared the incidence of SARS-CoV-2 molecular testing, COVID-19 diagnosis, and COVID-19 hospitalization among PLWH and HIV-uninfected adults. A chart review was conducted for PLWH with COVID-19 to examine viral suppression of HIV and most recent CD4+ counts in the year before COVID-19 diagnosis, known exposures to COVID-19, and clinical presentation. Between March 1, 2020, and May 31, 2020, the incidence of SARS-CoV-2 molecular testing, COVID-19 diagnosis, and COVID-19 hospitalization was 551.2, 57.0, and 9.3 per 10,000 PLWH, respectively, compared with 268.4, 34.6, and 5.3 per 10,000 HIV-uninfected individuals, respectively. Among those with COVID-19, the distribution of race/ethnicity, smoking status, and comorbidities was similar in PLWH and HIV-uninfected patients; however, PLWH were mostly men, younger, and less obese than HIV-uninfected individuals. Health care utilization regarding emergency care and hospitalizations in the year before COVID-19-related hospitalization was similar between the groups. Overall, HIV was virologically suppressed in >95% of PLWH with COVID-19, and HIV viral load and CD4+ status did not differ between hospitalized and nonhospitalized patients. In this population of patients with well-controlled HIV infection, the incidence of testing, diagnosis, and hospitalization for COVID-19 was higher in PLWH than that in HIV-uninfected patients.


Association of Body Mass Index and Postoperative Acute Kidney Injury in Patients Undergoing Laparoscopic Surgery.
Whether the deleterious effects of carbon dioxide pneumoperitoneum on the kidneys are exacerbated in the obese population remains unknown. We hypothesized that increased body mass index (BMI) is associated with an increased incidence of postoperative acute kidney injury (AKI) in patients undergoing noncardiac laparoscopic surgery. Following institutional review board approval, we analyzed data on 8,543 adult patients with American Society of Anesthesiologists physical status scores of I-IV who had inpatient noncardiac laparoscopic surgery from 2005-2014. Because the exposure (current BMI) is a chronic condition, we a priori assumed that diabetes mellitus, hypertension, coronary artery disease, and chronic obstructive pulmonary disease might mediate the effect of obesity on outcome. Our primary analysis was a proportional odds logistic regression model with current BMI as a predictor and AKI as an ordinal outcome. After controlling for potential confounding variables, the odds of developing a more serious level of AKI was 7% (95% CI 0%, 15%) greater with a 5-unit increase in BMI (P=0.05). When the analysis was adjusted for the a priori mediators in an attempt to estimate the pure effect of BMI on AKI, the result was no longer significant (Wald test P=0.35), with the residual effect of BMI of 3% (95% CI -4%, 11%). We found a marginal association between BMI and an increased risk of developing AKI in adult patients after having noncardiac laparoscopic surgery. The BMI effect became insignificant when potential mediator variables were considered. The association of BMI and AKI after noncardiac laparoscopic surgery is likely mediated through components of the metabolic syndrome.


Acute sleep deprivation in healthy young men: impact on population diversity and function of circulating neutrophils.
Lack of sleep greatly affects our immune system. The present study investigates the acute effects of total sleep deprivation on blood neutrophils, the most abundant immune cell in our circulation and the first cell type recruited to sites of infection. Thus, the population diversity and function of circulating neutrophils were compared in healthy young men following one night of total sleep deprivation (TSD) or after 8h regular sleep. We found that neutrophil counts were elevated after nocturnal wakefulness (2.0 ± 0.2 × 10(9)/l vs. 2.6 ± 0.2 × 10(9)/l, sleep vs. TSD, respectively) and the population contained more immature CD16(dim)/CD62L(bright) cells (0.11 ± 0.040 × 10(9)/l [5.5 ± 1.1%] vs. 0.26 ± 0.020 × 10(9)/l [9.9 ± 1.4%]). As the rise in numbers of circulating mature CD16(bright)/CD62L(bright) neutrophils was less pronounced, the fraction of this subpopulation showed a significant decrease (1.8 ± 0.15 × 10(9)/l [88 ± 1.8%] vs. 2.1 ± 0.12 × 10(9)/l [82 ± 2.8%]). The surface expression of receptors regulating mobilization of neutrophils from bone marrow was decreased (CXCR4 and CD49d on immature neutrophils; CXCR2 on mature neutrophils). The receptor CXCR2 is also involved in the production of reactive oxygen species (ROS), and in line with this, total neutrophils produced less ROS. In addition, following sleep loss, circulating neutrophils exhibited enhanced surface levels of CD11b, which indicates enhanced granular fusion and concomitant protein translocation to the membrane. Our findings demonstrate that sleep loss exerts significant effects on population diversity and function of circulating neutrophils in healthy men. To which extent these changes could explain as to why people with poor sleep patterns are more susceptible to infections warrants further investigation.


"Allograft-inflammatory-factor-1 is upregulated in microglial cells in human cerebral infarctions".
Allograft inflammatory factor-1 (AIF-1) is a 17-kDa-peptide identified in rat cardiac allografts undergoing chronic rejection and in activated microglial cells in inflammatory autoimune disease of the CNS. We have investigated the expression of AIF-1 in 18 autopsy cases of human focal cerebral infarction. AIF-1-positive cells show the morphology of microglia and are CD68- but not GFAP-positive. The peptide is expressed at a low level in normal brain. In infarctions, activated microglial cells in the area of glial reaction show strongly enhanced cytoplasmic immunoreactivity. The density of AIF-1-expressing cells increases during the first three days post infarction and remains elevated until chronic cystic stages. The upregulation of AIF-1-immunoreactivity precedes the rise in expression of the S-100-protein MRP-8. We conclude that AIF-1 is a sensitive marker of human microglial activation not only in inflammation but also in non-inflammatory lesions of the CNS.


Environmental illness. A clinical review of 50 cases.
A review of 50 patients with a clinical ecology diagnosis of environmentally induced illness is reported. Histories were extremely heterogeneous. Eight patients had no symptoms or disease, 11 had symptoms caused by preexisting nonenvironmental disease, and 31 had multiple subjective symptoms. No consistent physical findings or laboratory abnormalities were found. Serum levels of immunoglobulins and complement, and circulating lymphocyte, B-cell, T-cell, and T-cell subset counts were not significantly abnormal. The diagnostic provocation-neutralization procedure, environmental restrictions, and dietary advice of clinical ecology produced further symptoms and fear of environmental and food contaminants. The patients with chronic multisystem complaints had characteristic symptoms of psychosomatic illness, but this study does not support the clinical ecology theory that psychosomatic illness may be an expression of food and chemical sensitivities induced by the toxic effect of environmental chemicals on the immune system.


Tardive dyskinesia in the aged. Duration of treatment relationships.
Although tardive dyskinesia (TD) is recognized to result from neuroleptic drug exposure, data conflict about the importance of the quantity of that exposure in producing TD. The relationship between duration of neuroleptic treatment (one to 301 months) and TD was studied in 57 elderly psychiatric inpatients. Examinations for TD and parkinsonism were quantified on the Abnormal Involuntary Movement Scale (AIMS) and on a parkinsonism severity scale. Prevalence of presumed TD was 49% and of parkinsonism 51%. Prevalence of TD increased with longer treatment, but parkinsonism was independent of treatment duration. Linear multiple regression analysis showed that the AIMS score was correlated positively with treatment duration and negatively with parkinsonism. Logistic multiple regression analysis verified these relationships and was more successful at predicting TD. The length of neuroleptic treatment necessary to produce TD was calculated from the logistic model at 10.8 months (95% confidence interval, zero to 25.6 months). These analyses showed the greatest rise in risk of TD occurred within the first two years of drug therapy.


Association of A Novel Splice Site Mutation in P/Q-Type Calcium Channels with Childhood Epilepsy and Late-Onset Slowly Progressive Non-Episodic Cerebellar Ataxia.
Episodic ataxia type 2 (EA2) is characterized by paroxysmal attacks of ataxia with typical onset in childhood or early adolescence. The disease is associated with mutations in the voltage-gated calcium channel alpha 1A subunit (Cav2.1) that is encoded by the CACNA1A gene. However, previously unrecognized atypical symptoms and the genetic overlap existing between EA2, spinocerebellar ataxia type 6, familial hemiplegic migraine type 1, and other neurological diseases blur the genotype/phenotype correlations, making a differential diagnosis difficult to formulate correctly and delaying early therapeutic intervention. Here we report a new clinical phenotype of a CACNA1A-associated disease characterized by absence epilepsy occurring during childhood. However, much later in life the patient displayed non-episodic, slowly progressive gait ataxia. Gene panel sequencing for hereditary ataxias led to the identification of a novel heterozygous CACNA1A mutation (c.1913 + 2T > G), altering the donor splice site of intron 14. This genetic defect was predicted to result in an in-frame deletion removing 44 amino acids from the voltage-gated calcium channel Cav2.1. An RT-PCR analysis of cDNA derived from patient skin fibroblasts confirmed the skipping of the entire exon 14. Furthermore, two-electrode voltage-clamp recordings performed from Xenopus laevis oocytes expressing a wild-type versus mutant channel showed that the genetic defect caused a complete loss of channel function. This represents the first description of distinct clinical manifestations that remarkably expand the genetic and phenotypic spectrum of CACNA1A-related diseases and should be considered for an early diagnosis and effective therapeutic intervention.


Exogenous delivery of chaperonin subunit fragment ApiCCT1 modulates mutant Huntingtin cellular phenotypes.
Aggregation of misfolded proteins is characteristic of a number of neurodegenerative diseases, including Huntington disease (HD). The CCT/TRiC (chaperonin containing TCP-1/TCP-1 ring) chaperonin complex can inhibit aggregation and cellular toxicity induced by expanded repeat Huntingtin (mHtt) fragments. The substrate-binding apical domain of CCT/TRiC subunit CCT1, ApiCCT1, is sufficient to inhibit aggregation of expanded repeat mHtt fragments in vitro, providing therapeutic promise for HD. However, a key hurdle in considering ApiCCT1 as a potential treatment is in delivery. Because ApiCCT1 has a region of similarity to the HIV Tat protein cell-transduction domain, we tested whether recombinant ApiCCT1 (ApiCCT1(r)) protein could enter cells following exogenous delivery and modulate an established panel of mHtt-mediated cell-based phenotypes. Cell fractionation studies demonstrate that exogenous ApiCCT1(r) can penetrate cell membranes and can localize to the nucleus, consistent with a strategy that can target both cytosolic and nuclear pathogenic events in HD. ApiCCT1(r) application does indeed modulate HD cellular phenotypes by decreasing formation of visible inclusions, fibrillar oligomers, and insoluble mHtt derived from expression of a truncated mHtt exon 1 fragment. ApiCCT1(r) also delays the onset of inclusion body formation as visualized via live imaging. ApiCCT1(r) reduces mHtt-mediated toxicity in immortalized striatal cells derived from full-length knock-in HD mice, suggesting that therapeutic benefit may extend beyond effects on aggregation. These studies provide the basis for a potentially robust and unique therapeutic strategy to target mHtt-mediated protein pathogenesis.


Disrupted spermatogenesis in a metabolic syndrome model: the role of vitamin A metabolism in the gut-testis axis.
Effects of the diet-induced gut microbiota dysbiosis reach far beyond the gut. We aim to uncover the direct evidence involving the gut-testis axis in the aetiology of impaired spermatogenesis. An excessive-energy diet-induced metabolic syndrome (MetS) sheep model was established. The testicular samples, host metabolomes and gut microbiome were analysed. Faecal microbiota transplantation (FMT) confirmed the linkage between gut microbiota and spermatogenesis. We demonstrated that the number of arrested spermatogonia was markedly elevated by using 10× single-cell RNA-seq in the MetS model. Furthermore, through using metabolomics profiling and 16S rDNA-seq, we discovered that the absorption of vitamin A in the gut was abolished due to a notable reduction of bile acid levels, which was significantly associated with reduced abundance of Ruminococcaceae_NK4A214_group. Notably, the abnormal metabolic effects of vitamin A were transferable to the testicular cells through the circulating blood, which contributed to abnormal spermatogenesis, as confirmed by FMT. These findings define a starting point for linking the testicular function and regulation of gut microbiota via host metabolomes and will be of potential value for the treatment of male infertility in MetS.


Healthy aging as an intervention to minimize injury from falls among older people.
With global trends toward population aging, many countries are adopting healthy aging policies to minimize disability and increase quality in the extended years of life. Falls in older people are a major contributor to functional decline generally associated with aging. Based on a study quantifying the relationship between healthy aging factors and risk of fall-related hip fracture in community-dwelling older people, this paper discusses evidence for the promotion of healthy aging as a population-based intervention for prevention of injuries from falls. To examine the protective effect of healthy aging on the risk of fall-related hip fractures, a case-control study was conducted with 387 participants. Persons aged 65 and over hospitalized with a fall-related hip fracture were matched with community-based controls recruited via electoral roll sampling. A questionnaire designed to assess lifestyle risk factors, identified as determinants of healthy aging, was administered during face-to-face interviews. After adjustment for health status and demographic factors, a number of lifestyle factors were seen to have a significant independent protective effect on the risk of hip fracture. These included never smoking, moderate alcohol consumption, being active, maintaining normal weight, and being proactive in preventive health care. Psychosocial factors included having supportive environments and personal resources to cope with stress. This study identified a range of modifiable lifestyle factors associated with fall-related hip fracture, suggesting that the "healthy aging" paradigm offers a comprehensive approach to falls injury prevention, and thus supports the adoption of healthy aging policies to extend years of quality life among older persons.


Exploring the structural stability and electrochemical performance of B doped T-graphene nanotubes from first-principles calculations.
The structural stability and electrochemical performance of intrinsic and B doped T-graphene nanotubes with different tube lengths are systematically studied by using first-principles calculations within the framework of density functional theory (DFT). The results show that with the increase of tube length, the adsorption energy of both intrinsic and B doped T-graphene nanotubes exhibits regular oscillations, and B doping is beneficial for elevating the adsorption ability of T-graphene nanotubes. The density of states show that intrinsic T-graphene nanotubes are zero band gap semiconductors, and the orbitals' electronic states cross the Fermi level to form a p-type semiconductor, indicating that B doping greatly improves the conductivity of the system. The results of migration behavior demonstrate that B doping can effectively reduce the diffusion barrier of lithium ions on their surface, especially in B doped T-graphene nanotubes with a tube length of N = 1, resulting in more effective migration behavior and excellent rate performance. These findings provide a theoretical basis for the development and application of negative electrode materials for lithium-ion batteries.


Endoscopic ovariohysterectomy in two lions (Panthera leo).
Endoscopic techniques were used to ovariohysterectomize two hybrid Asian lions (Panthera leo) in order to reduce the risk of postoperative wound complications associated with standard surgical techniques. One of the lions was aged, overweight, and considered an anesthetic risk. The animals were anesthetized, intubated, catheterized intravenously, and placed in dorsal recumbency with the head lower (Trendelenburg position). Ventilation was assisted mechanically. Following abdominal insufflation, a surgical trocar was placed in the abdominal cavity. Two additional 12-mm surgical trocars were placed under direct visualization using a videoscope. The ovaries and uterus were removed endoscopically, and the abdominal cavity was inspected for hemorrhage under decreased insufflation pressure before closure. The surgery was complicated by obesity, by uterine enlargement from cystic endometrial hyperplasia and endometrial polyps, and by ovarian enlargement and fragility because of bilateral cystic rete ovarii. The procedure and anesthetic recovery were uneventful. Postsurgical recovery time and convalescence lasted less than 3 days, and the animals were reintroduced to an exhibit mate and placed on exhibit within 8 days. The technique is appropriate for use in lions, even those with pathologic reproductive changes, in zoos.


[Action of ftorafur on the chromosomes of normal and tumorous cells of the Djzungarian hamster in vitro].
The chromosome-breaking effect of antitumor agent ftorafur (0,1 mg/ml) was studied on cell cultures of normal and transformed Djungarian hamster's fibroblasts. After 24 hours of exposition with the drug 79% of aberrant malignant cells was registered, while the chromosomes of normal cells remained undamaged. After ftorafur's action for 2--12 hours and the following removal of the agent the level of aberrant metaphase among normal cells rose to 11--15%. Chromatid breaks were the predominant type of drug-induced aberrations. Thse results confirm the idea that ftorafur blocks the cell cycle of normal fibroblasts and that it's necessary to wash the drug off some period before fuxation in order to reveal its chromosome-breaking effect in metaphase cells. The striking distinctions in susceptibility of normal and malignant cells to the mutagenic effect of ftorafur is partly due to the distrubances of the cell cycle caused by this drug.


Phosphate feeding improves high-cell-concentration NS0 myeloma culture performance for monoclonal antibody production.
Phosphorus depletion was identified in high-cell-concentration fed-batch NS0 myeloma cell cultures producing a humanized monoclonal antibody (MAb). In these cultures, the maximum viable and total cell concentration was generally ca. 5 x 10(9) and 7 x 10(9) cells/L, respectively, without phosphate feeding. Depletion of essential amino acids, such as lysine, was initially thought to cause the onset of cell death. However, further improvement of cell growth was not achieved by feeding a stoichiometrically balanced amino acid solution, which eliminated depletion of amino acids. Even though a higher cell viability was maintained for a longer period, no increase in total cell concentration was observed. Afterwards, phosphorus was found to be depleted in these cultures. By also feeding a phosphate solution to eliminate phosphorus depletion, the cell growth phase was prolonged significantly, resulting in a total cell concentration of ca. 17 x 10(9) cells/L, which is much greater than ca. 7 x 10(9) cells/L without phosphate feeding. The maximum viable cell concentration reached about 10 x 10(9) cells/L, twice as high as that without phosphate feeding. Apoptosis was also delayed and suppressed with phosphate feeding. A nonapoptotic viable cell population of 6.5 x 10(9) cells/L, as compared with 3 x 10(9) cells/L without phosphate feeding, was obtained and successfully maintained for about 70 h. These results are consistent with the knowledge that phosphorus is an essential part of many cell components, including phospholipids, DNA, and RNA. As a result of phosphate feeding, a much higher integral of viable cell concentration over time was achieved, resulting in a correspondingly higher MAb titer of ca. 1.3 g/L. It was also noted that phosphate feeding delayed the cell metabolism shift from lactate production to lactate consumption typically observed in recombinant NS0 cultures. The results highlight the importance of phosphate feeding in high-cell-concentration NS0 cultures.


Proliferating trichilemmal cyst: a simulant of squamous cell carcinoma.
Comparison of 50 proliferating trichilemmal cysts with 50 "ordinary" trichilemmal cysts indicated that both types almost invariably occurred on the scalps of women, were diagnosed clinically as cysts, followed a benign course, and featured trichilemmal keratinization. A spectrum was observed from trichilemmal cyst with minimal hyperplasia, to full-blown proliferating trichilemmal cyst. Occasionally, patients had ordinary trichilemmal cysts on their scalps associated with a proliferating trichilemmal cyst. In addition to trichilemmal keratinization, which is characteristic of the follicular isthmus, proliferating trichilemmal cysts showed a wider range of differentiation, including features of the follicular infundibulum, the lower nonkeratinizing portion of the follicular outer root sheath, and sebaceous cells. Intense inflammatory infiltrate and cellular atypia, sometimes of significant proportions, were also seen in proliferating trichilemmal cysts. It is concluded that trauma and inflammation may induce a trichilemmal cyst to proliferate and show a broader spectrum of pilosebaceous differentiation and cellular atypia of pseudocarcinomatous proportions, while maintaining its benign biologic behavior.


PA utilization on a pediatric bone marrow transplant unit.
Operating without residents or fellows in continuous attendance, The University of Iowa Hospitals and Clinics Pediatric Bone Marrow Transplant Unit utilizes PAs to assume primary responsibility for patients and to assure continuity of care. Major tasks assigned to the PAs include evaluation and assessment, writing notes and orders, and clinic follow-up. Basic PA training in pharmacology, physiology, and pathology has proved to be a sufficient background, supplemented by extensive on-the-job training; a knowledge of hematology is helpful. Severity of illnesses being treated contributes to burnout, which is addressed by staff support groups. This PA utilization model is strongly recommended for other such wards.


U3 snoRNA genes with and without intron in the Kluyveromyces genus: yeasts can accommodate great variations of the U3 snoRNA 3'-terminal domain.
The U3 snoRNA coding sequences from the genomic DNAs of Kluyveromyces delphensis and four variants of the Kluyveromyces marxianus species were cloned by PCR amplification. Nucleotide sequence analysis of the amplification products revealed a unique U3 snoRNA gene sequence in all the strains studied, except for K. marxianus var. fragilis. The K. marxianus U3 genes were intronless, whereas an intron similar to those of the Saccharomyces cerevisiae U3 genes was found in K. delphensis. Hence, U3 genes with and without intron are found in yeasts of the Saccharomycetoideae subfamily. The secondary structure of the K. delphensis pre-U3 snoRNA and of the K. marxianus mature snoRNAs were studied experimentally. They revealed a strong conservation in yeasts of (1) the architecture of U3 snoRNA introns, (2) the 5'-terminal domain of the mature snoRNA, and (3) the protein-anchoring regions of the U3 snoRNA 3' domain. In contrast, stem-loop structures 2, 3, and 4 of the 3' domain showed great variations in size, sequence, and structure. Using a genetic test, we show that, in spite of these variations, the Kluyveromyces U3 snoRNAs are functional in S. cerevisiae. We also show that S. cerevisiae U3A snoRNAs lacking the stem-loop structure 2 or 4 are functional. Hence, U3 snoRNA function can accommodate great variations of the RNA 3'-terminal domain.


Simultaneous K-ras activation and Keap1 deletion cause atrophy of pancreatic parenchyma.
The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system has a wide variety of effects in addition to the oxidative stress response, such as growth promotion and chemoresistance of cancer cells. Nrf2 is constitutively activated in most cancer cells. However, the activation of Nrf2 together with oncogenic mutations does not always result in cancer promotion. K-rasLSL-G12D/+:: p53LSL-R172H/+:: Pdx-1-Cre (KPC) mice are an established model of pancreatic cancer that specifically express mutants of both K-ras and p53 in the pancreas by using Pdx-1-Cre. We here generated Pdx-1-Cre::K-rasLSL-G12D/+:: Keap1fl/fl (KC::Keap1) and KPC:: Keap1fl/fl (KPC::Keap1) mice in which Nrf2 is constitutively activated by Keap1 deletion. KC::Keap1 and KPC::Keap1 mice started to die or showed obvious weakness at approximately around 40 days after birth. Histological examination revealed that KC::Keap1 and KPC::Keap1 mice did not develop pancreatic cancer but, instead, progressive atrophy of the pancreatic parenchyma. In these mice, amylase-positive acinar cells as well as insulin- and glucagon-positive islet cells were decreased and surrounded by fibrotic tissues. KC::Keap1 and KPC::Keap1 mice presented lower body weight and glucose levels than C::Keap1 mice, presumably resulting from pancreatic exocrine insufficiency. Histological changes were not obvious in C::Keap1 and PC::Keap1 mice. The presence of the p53 mutation did not affect the phenotypes in KC::Keap1 mice. Heterologous or homologous Nrf2 deletion ( Nrf2+/- or Nrf2-/-) rescued the pancreatic phenotypes, weight loss, and hypoglycemia in KC::Keap1 mice, suggesting that Nrf2 is a major downstream target of Keap1. In conclusion, simultaneous K-ras activation and Keap1 deletion caused progressive atrophy of the pancreatic parenchyma in mice. NEW & NOTEWORTHY Aberrant activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system usually promotes carcinogenesis, and we assumed that simultaneous activation of K-ras and Nrf2 might promote pancreatic carcinogenesis. Conditional expression of mutant K-ras and Keap1 deletion did not result in pancreatic cancer development. Instead, these mice developed progressive loss of pancreatic parenchyma, accompanied by body weight loss and hypoglycemia, presumably because of pancreatic exocrine insufficiency. Nrf2 activation by Keap1 deletion concomitant with K-ras activation cause pancreatic atrophy.


Individual particle handling in a microfluidic system based on parallel laser trapping.
We present an optical trapping system combining individually addressable multiple laser traps with fluorescence spectroscopy. An in-line set of 64 near-IR laser diodes is used to create a line of individually addressable traps inside a microfluidic chip. This system is completed by an excitation/detection line for spectrally resolved fluorescence imaging of trapped particles. Highly parallel trapping in a constant flow (up to a few millimeters per second), fast particle handling rates (up to a few particles per second), and the possibility of recording fluorescence spectra of trapped objects lead to a performing bioanalytical platform, e.g., for highly parallel analysis and sorting.


A cysteine-rich metal-binding domain from rubella virus non-structural protein is essential for viral protease activity and virus replication.
The protease domain within the RUBV (rubella virus) NS (non-structural) replicase proteins functions in the self-cleavage of the polyprotein precursor into the two mature proteins which form the replication complex. This domain has previously been shown to require both zinc and calcium ions for optimal activity. In the present study we carried out metal-binding and conformational experiments on a purified cysteine-rich minidomain of the RUBV NS protease containing the putative Zn(2+)-binding ligands. This minidomain bound to Zn(2+) with a stoichiometry of approximately 0.7 and an apparent dissociation constant of <500 nM. Fluorescence quenching and 8-anilinonaphthalene-1-sulfonic acid fluorescence methods revealed that Zn(2+) binding resulted in conformational changes characterized by shielding of hydrophobic regions from the solvent. Mutational analyses using the minidomain identified residues Cys(1175), Cys(1178), Cys(1225) and Cys(1227) were required for the binding of Zn(2+). Corresponding mutational analyses using a RUBV replicon confirmed that these residues were necessary for both proteolytic activity of the NS protease and viability. The present study demonstrates that the CXXC(X)(48)CXC Zn(2+)-binding motif in the RUBV NS protease is critical for maintaining the structural integrity of the protease domain and essential for proteolysis and virus replication.


Effects of an ACTH/MSH(4-9) analog (HOE 427) on the sleep EEG and nocturnal hormonal secretion in humans.
The synthetic ACTH/MSH(4-9) analog HOE 427 ("ebiratide"), which is behaviorally the most potent ACTH-derived peptide but which is devoid of endocrine activity, was administered intravenously in a pulsatile mode 4 times (120 micrograms each) at 2200, 2300, 2400 and 0100 to study its effect on the sleep EEG and on concomitant hormonal secretion of cortisol and growth hormone. In comparison to placebo, the peptide produced signs of general activation associated with specific deteriorating effects on the quality of sleep. Sleep onset latency and intermittent wakefulness were increased, slow wave sleep was reduced, but only during the first 3 hours of the sleep period. The nocturnal secretory patterns of cortisol and growth hormone were unaffected by HOE 427. These effects are different from those reported in similar studies in which corticotropin-releasing hormone (CRH) was applied in humans, and they suggest that peripherally administered neuropeptides have specific nonendocrine behavioral effects.


IL-11 is a parietal cell cytokine that induces atrophic gastritis.
IL-is important in gastric damage, mucosal repair and gastric cancer progression. We analysed IL-11 expression in H.pylori infected mouse stomach, the site of gastric IL-11 expression in mice and humans, and the effect of exogenous IL-11 on gastric mucosal homeostasis. IL-11 protein was localised in mouse and human stomach. The impact of chronic, exogenous IL-11 on normal mouse stomach was examined histologically and transcriptionally by microarray, confirmed by mRNA and protein analysis. Functional impact of IL-11 on gastric acid secretion was determined. In mice infected with H.pylori, IL-11 was increased in fundic mucosa with temporal expression similar to IL-1b. IL-11 protein was localised predominantly to parietal cells in mouse and human stomach. Application of exogenous IL-11 to resulted in fundic parietal and chief cell loss, hyperplasia, mucous cell metaplasia and inflammation. Coincident with cellular changes were an increased gastric pH, altered parietal cell ultrastructure and altered gene expression, particularly genes involved in immune response and ion transport which could result in compromised acid secretion. We confirmed that a single dose of IL-11 effectively ablated the gastric response to histamine. IL-11 is a parietal cell cytokine that blocks gastric acid secretion, likely via reducing expression of parietal cell ion transport genes, CCKb and histamine H2 receptors. IL-11 expression is increased in H. pylori infected mouse stomach and treatment of wild type mice with IL-11 induced changes in the gastric fundic mucosa reminiscent of chronic atrophic gastritis, a precursor to gastric cancer.


Carbon in Amazon forests: unexpected seasonal fluxes and disturbance-induced losses.
The net ecosystem exchange of carbon dioxide was measured by eddy covariance methods for 3 years in two old-growth forest sites near Santarém, Brazil. Carbon was lost in the wet season and gained in the dry season, which was opposite to the seasonal cycles of both tree growth and model predictions. The 3-year average carbon loss was 1.3 (confidence interval: 0.0 to 2.0) megagrams of carbon per hectare per year. Biometric observations confirmed the net loss but imply that it is a transient effect of recent disturbance superimposed on long-term balance. Given that episodic disturbances are characteristic of old-growth forests, it is likely that carbon sequestration is lower than has been inferred from recent eddy covariance studies at undisturbed sites.


A case of refractory intestinal Behçet's disease treated with tocilizumab, a humanised anti-interleukin-6 receptor antibody.
We describe a young female patient who had refractory intestinal Behçet's disease that responded to tocilizumab, a humanised anti-interleukin-6 receptor antibody. The patient had suffered from long disease activity courses and was treated with multiple medications, and the disease became refractory when immunosuppressants (e.g., thalidomide, sulfasalazine and azathioprine) were limited for poor remission, methylprednisolone pulse therapy, cyclophosphamide, and biological agents (e.g., adalimumab or infliximab) were restricted due to side effects after administration. Therefore, tocilizumab was considered as a therapeutic option and the symptoms resolved during 9 months of administration. Tocilizumab may be a good choice for intestinal Behçet's disease refractory to conventional treatment.


Perceived complexity of total hip arthroplasty: results of a survey of orthopedic surgeons.
No analysis of the perception of the complexity of total hip arthroplasty (THA) has been performed so far. This study aimed to evaluate the perceived complexity of the disorders faced by orthopedic surgeons in the evaluation process prior to THA. A three-part online survey was administered to orthopedic surgeons. In the first part, the participants were asked questions about demographic and academic knowledge, as well as their experiences with THA. In the second part, it was asked to rate the complexity of certain disorders, such as soft tissue abnormalities, ankylosis/arthrodesis, dysplastic hip, high dislocated hip, post-traumatic arthrosis, protrusio acetabuli, etc., on a scale of one to five. Perceived complexity was classified as mild if the calculated mean score was <1.67, moderate if it was between 1.67 and 3.34, and complex if it was >3.34. In the last section, the effects of perceived complexity on surgical preferences were investigated. THA administered for femoral neck fracture was graded as the least complex surgical challenge (mean score of 1.85±0.99), while high dislocated hip (Crowe III-IV) was scored with the highest mean score of 4.10±0.99. None of the disorders were evaluated as easy by orthopedic surgeons. Disorders of the high dislocated hip (Crowe III-IV) and protrusio acetabuli were identified as the most complicated cases by surgeons. Perception of complexity affected preference for surgical approach. Besides, the level of education after participating in a course related to THA may affect the preferences of orthopedic surgeons when planning an operation.


Expression profiles of cloned channel catfish (Ictalurus punctatus) lymphoid cell lines and mixed lymphocyte cultures.
Clonal channel catfish lymphoid cell lines and mixed lymphocyte cultures (MLCs) have proven extremely useful in examining immune responses at the cellular and molecular levels. To date clonal catfish cell lines and MLCs have been biologically and phenotypically characterized using a variety of techniques including reverse transcription polymerase chain reaction (RT-PCR), as well as Northern and Southern blotting. To expand the molecular characterization of these cultures, microarray analysis was employed. Clonal B (3B11), macrophage (42TA), and cytotoxic T cell (TS32.15 and TS32.17) lines and MLCs were examined using a cDNA array containing approximately 2500 probes derived from EST libraries prepared from the 42TA macrophage cell line, a MLC, and 5-14-day-old catfish fry. Analysis showed that each cell line displayed a unique RNA expression profile that included a variety of immune-related genes. Pearson correlation analysis indicated that one cytotoxic T cell line (TS32.15) clustered with the MLC, whereas a second cytotoxic T cell line (TS32.17) was more closely associated with a second cluster containing B cells and macrophages. This study illustrates the utility of microarray analyses in profiling RNA expression patterns in catfish lymphoid cell lines and will serve as a platform for examining catfish immune responses following virus infection or poly [I:C] treatment.


Adenosine acting on A1 receptors protects NO-triggered rebound potentiation and LTP in rat hippocampal slices.
Exposure of hippocampal slices to nitric oxide (NO) results in a depression of CA1 synaptic transmission. Under 0.2-Hz stimulation, washout of NO leads to a persistent potentiation that depends on N-methyl-D-aspartate (NMDA) receptors and endogenous NO formation and that occludes tetanus-induced long-term potentiation (LTP). The experiments were initially aimed at determining the relationship between the NO-induced synaptic depression and rebound potentiation. The adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) partially inhibited the depression produced by the NO donor diethylamine NONOate (300 microM). It also led to a complete block of both the rebound potentiation and the subsequent tetanus-induced LTP. LTP was preserved in the presence of DPCPX if the stimulation frequency was reduced to 0.033 Hz or if the NO application was omitted. The NO-triggered rebound potentiation was restored if the experiment (DPCPX followed by exogenous NO) was conducted in the presence of an NMDA antagonist. The restored potentiation was completely blocked by the NO synthase inhibitor, L-nitroarginine. It is concluded that the NO-induced depression is partially mediated by increased release of endogenous adenosine acting on A1 receptors. Moreover, tonic A1 receptor activation by adenosine protects LTP and the rebound potentiation from being disabled by untimely NMDA receptor activity. Hence, the NO-induced depression and rebound potentiation are linked in the sense that the depression helps to preserve the capacity of the synapses to undergo potentiation. Finally, the results give the first example of exogenous NO eliciting an enduring potentiation of hippocampal synaptic transmission that is dependent on endogenous NO formation, but not on NMDA receptors.


Resistance to herpes simplex virus type 1 and its latent infection of human T cell lymphotropic virus type I-transformed T cell lines of rabbits.
Fourteen T cell lines of rabbits were infected with herpes simplex virus type 1 (HSV-1) and examined for their susceptibility to lytic infection and ability to support virus replication. T cell lines of CD4+ 8- phenotype were more vulnerable to lysis and supported higher levels of virus replication than those of other phenotypes. Cell lines of CD4+ 8+ and CD4- 8+ phenotypes continued to proliferate, while remaining productively infected, for more than a month. These latently infected cell lines could be established by treatment with anti-HSV-1 serum and complement. Viral genes were only partially expressed and the CD8 membrane antigen was down-regulated. Infected cell lines, as well as peripheral blood lymphocytes, were shown to induce meningoencephalitis when inoculated intravenously into syngeneic hosts, suggesting a possible role for infected lymphocytes in HSV-1 transport in vivo.


Cluster phases of decorated micellar solutions with macrocyclic ligands.
An aqueous self-assembled micellar system (sodium dodecyl sulfate, SDS, decorated with various adhesive sites, cryptand Kryptofix 222 and crown ether 18-Crown-6 molecules) has been investigated by dynamic light scattering (DLS) and small angle x-ray scattering (SAXS) to have insights into the micellar structure, the micellar interactions, and the aggregation properties of the system. DLS demonstrates the existence of populations of aggregates in the submicrometer/micrometer range, while the Guinier analysis of the SAXS curves helps in detailing objects smaller than 30 nm. The aggregates of micelles are here named cluster phases of micelles (CPMs). Considering that SDS micelles in water do not aggregate at low concentration, it is shown that macrocyclic ligands induce the SDS micelle aggregation as a function of the concentration (i.e., investigated ligand/SDS molar ratios are 5.0, 1.5, 1.0, and 0.5) and hydrophobicity of the adhesive sites. The sizes and the percentages of the micelles and the CPMs have been monitored to test the stability and reversibility of the system. DLS results clearly show that the aggregation processes of the decorated micelles are reproducible at time intervals of the order of 1 month, while the stability may not be entirely maintained after a year. As an issue of particular relevance, the higher the ligand/surfactant molar ratio, the larger are the CPMs induced. The K222 ligand results in being more effective in promoting the micellar aggregation than 18C6 as a consequence of the different hydrophobicity.


Identification of Retinoic Acid Receptor Agonists as Potent Hepatitis B Virus Inhibitors via a Drug Repurposing Screen.
Currently available therapies for chronic hepatitis B virus (HBV) infection can efficiently reduce viremia but induce hepatitis B surface antigen (HBsAg) loss in very few patients; also, these therapies do not greatly affect the viral covalently closed circular DNA (cccDNA). To discover new agents with complementary anti-HBV effects, we performed a drug repurposing screen of 1,018 Food and Drug Administration (FDA)-approved compounds using HBV-infected primary human hepatocytes (PHH). Several compounds belonging to the family of retinoic acid receptor (RAR) agonists were identified that reduced HBsAg levels in a dose-dependent manner without significant cytotoxicity. Among them, tazarotene exhibited the most potent anti-HBV effect, with a half-maximal inhibitory concentration (IC50) for HBsAg of less than 30 nM in PHH. The inhibitory effect was also observed in HBV-infected differentiated HepaRG (dHepaRG) models, but not in HepG2.215 cells, and HBV genotypes A to D were similarly inhibited. Tazarotene was further demonstrated to repress HBV cccDNA transcription, as determined by the levels of HBV cccDNA and RNAs and the activation of HBV promoters. Moreover, RNA sequence analysis showed that tazarotene did not induce an interferon response but altered the expression of a number of genes associated with RAR and metabolic pathways. Inhibition of RARβ, but not RARα, by a specific antagonist significantly attenuated the anti-HBV activity of tazarotene, suggesting that tazarotene inhibits HBV in part through RARβ. Finally, a synergistic effect of tazarotene and entecavir on HBV DNA levels was observed. Therefore, RAR agonists as represented by tazarotene were identified as potential novel anti-HBV agents.


Physical activity is a major contributor to the ultra low frequency components of heart rate variability.
To investigate the link between changes in level of physical activity and the pattern of heart rate variability during long term ambulatory monitoring. Heart rate variability was measured simultaneously with a quantitative indicator of muscle activity by electromyography (EMG) in five men and five women while they did activities typical of daily life or while they rested for 2-3 hours. Spectral and cross spectral analyses were performed on both variables with standard fast Fourier transform. There was a marked reduction in spectral power in the ultra low frequency band (< 0.003 Hz) on going from active to rest conditions for both heart rate variability (men 6187 (1801) v 410 (89) ms(2)/Hz; women 4056 (1161) v 2094 (801), mean (SEM); p < 0.01) and EMG (p < 0.001). Cross spectral analysis showed a strong positive gain between the EMG and heart rate variability signal that was virtually eliminated in the resting condition (p < 0.01). A sex-by-condition effect (p = 0.06) was noted with a reduction in total spectral power for heart rate variability during rest in men, while it increased slightly in women. There is a quantitative link between muscle activation and heart rate variability in the lowest frequency band. Voluntary restriction of physical activity in healthy young subjects caused marked reduction in spectral power in the lowest frequency band which is often used to assess patient prognosis. The findings strongly suggest that studies of ambulatory heart rate variability should always include an indication of physical activity patterns.