Present characteristics of symptomatic amebiasis due to Entamoeba histolytica in the east-southeast area of Tokyo.
Admitted medical records, from January 1988 to December 1995, of 28 symptomatic amebic patients who lived in the east-southeast area of Tokyo were studied retrospectively, in order to find the present characteristics of symptomatic amebiasis due to Entamoeba histolytica in this area. Categorized by disease, there were 14 cases of colitis, 9 cases of liver abscess, 4 cases of colitis with liver abscess, and 1 case of liver abscess with brain abscess. Patients consisted of 26 Japanese males, 0 Japanese females, 1 non-Japanese male and 1 non-Japanese female. The mean age of colitis patients and liver abscess patients was 55.4 years old and 41.3 years old, respectively. The presumed place of contraction was Japan in 64% of the patients. Forty-eight percent of male patients indicated that they engaged in homosexual or bisexual practices, and 36% of male patients who denied such sexual practices or did not answer the question had no history of marriage. Positive rate of serum titre for Treponema pallidum hemagglutination test (TPHA) and human immunodeficiency virus antibody was 42.9% and 0%, respectively. Sixty-seven percent of TPHA-positive patients indicated that they engaged in male homosexual or bisexual practices. Zymodeme patterns of E. histolytica isolated from 4 colitis patients were XIV in 1 case and II in 3 cases. Symptomatic amebiasis in the east-southeast area of Tokyo is a disease which predominantly afflicts males, especially those in their middle age, and most patients contract the disease in Japan. The high rates of patients who engaged in male homosexual or bisexual practices and the high rates of patients with positive TPHA suggest that amebiasis is likely to be sexually transmitted disease in homosexual and bisexual men in the east-southeast area of Tokyo, and zymodeme II may be the predominant type in symptomatic amebic colitis in this area.


Gender and the length of time since autologous hematopoietic stem cell transplantation-What is their influence on the immune reconstitution in multiple myeloma patients?
In the literature there is lack of information on the influence of gender and time since autologous hematopoietic stem cell transplantation (HSCT) on the immune reconstitution in multiple myeloma (MM) patients. The aim of this study was to assess the diversity of the immune reconstitution according to gender in MM patients after autologous HSCT on the day of the clinic discharge and on the 29th day after discharge, as well as to investigate the changes in the immune system in females and males after staying at home for 28 days. The studied population comprised 13 females and 13 males after autologous HSCT. On the day of the clinic discharge and on the 29th day after discharge blood samples were taken to analyse 22 immunological parameters. Statistical analysis was performed using STATISTICA 10 StatSoft Poland. For multiple comparisons, the Bonferroni correction was used. No statistically significant differences were observed in the analysed immunological parameters between the studied females and males with MM on the day of the clinic discharge and on the 29th day after discharge. However, on the 29th day after the clinic discharge compared to the day of the clinic discharge, statistically significant differences were found in 8 immunological parameters among females and 6 immunological parameters among males. Our results indicate that the immune reconstitution is similar but not the same in patients of both genders. Statistically significant differences in the immune response in the studied females and males imply that gender may play a role in the immune reconstitution and that the results obtained in MM patients should be analysed separately in females and males. In order to explain the observed changes in the immune system according to gender, further research should be carried out on a larger population. This would most probably make it possible to find their clinical application.


MR imaging of multiple sclerosis.
Owing to its ability to depict the pathologic features of multiple sclerosis (MS) in exquisite detail, conventional magnetic resonance (MR) imaging has become an established tool in the diagnosis of this disease and in monitoring its evolution. MR imaging has been formally included in the diagnostic work-up of patients who present with a clinically isolated syndrome suggestive of MS, and ad hoc diagnostic criteria have been proposed and are updated on a regular basis. In patients with established MS and in those participating in treatment trials, examinations performed with conventional MR pulse sequences provide objective measures to monitor disease activity and progression; however, they have a limited prognostic role. This has driven the application of newer MR imaging technologies, including higher-field-strength MR units, to estimate overall MS burden and mechanisms of recovery in patients at different stages of the disease. These techniques have allowed in vivo assessment of the heterogeneity of MS pathologic features in focal lesions and in normal-appearing tissues. More recently, some of the finer details of MS, including macrophage infiltration and abnormal iron deposition, have become quantifiable with MR imaging. The utility of these modern MR techniques in clinical trial monitoring and in the assessment of the individual patient's response to treatment still need to be evaluated.


Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo.
Human adenoviruses have been developed as an attractive vehicle for in vivo liver-directed gene therapy. Problems with the application of first generation recombinant adenoviruses to liver-directed gene therapy have been transient expression of the recombinant gene and development of hepatitis. Previous studies in mouse models of gene transfer to liver and lung suggested that MHC class I-restricted cytotoxic T lymphocytes (CTLs) to viral antigens may be effectors in the elimination of transgene expression. The goal of this study was to evaluate the importance of viral antigens versus transgene product in inducing CTL mediated hepatocyte destruction in vivo. Immunization of C57BL/6 mice with a lacZ-expressing adenovirus elicited CTL responses to both viral antigens and the transgene product, beta-galactosidase (beta-gal). Adoptive transfer experiments, as well as studies involving lacZ-transgenic mice (ROSA-26) revealed that CTLs to viral antigens are sufficient to destroy virus-infected hepatocytes, indicating that CTLs to beta-gal can not solely account for the observed hepatocyte destruction that has characterized the use of first generation viruses. In addition, we confirmed that B cell-mediated events do not participate in destruction of hepatocytes in vivo, despite the production of virus- and beta-gal-specific antibodies. These data confirm the hypothesis that viral gene expression elicits host responses that contribute to the problem of transgene instability. Recombinant adenoviruses must be redesigned to diminish viral gene expression if they are to be used in the treatment of chronic diseases.


Diagnostics in cystic echinococcosis: serology versus ultrasonography.
Cystic echinococcosis (CE) is the most widespread zoonosis worldwide. The objective of the present study was to compare diagnostic methods in the work-up of suspected cystic echinococcosis of the liver. Data from a total of 68 patients were compiled and analyzed. A diagnosis of cystic echinococcosis was made in 36.8% of patients. Broken down according to WHO criteria, patients with at least one echinococcus cyst were determined in 12.0% of cases to exhibit cysts consistent with stage 1 disease (CE1), while in 24.0%, cysts consistent with CE2 and CE3 were identified. CE4 and CE5 cysts were identified in 32.0% and 8.0% of patients, respectively. Solitary cysts were found in 60.0% of patients with cystic echinococcosis, while in patients with at least one cystic lesion, there were most often multiple cysts. The indirect hemagglutination test (IHA) and echinococcus-specific immunoglobulin E (IgE) concentration showed a higher sensitivity (60.9%, 68.4%) than did the enzyme-linked immunosorbent assay (ELISA) for Echinococcus multilocularis (Em2+) and total IgE (11.1%, 38.9%). The respective specificities of all four serological methods lay between 83.9% and 88.9%. Our data show that ultrasound remains the diagnostic method of choice in the work-up of cystic lesions of the liver suspected to be due to Echinococcus granulosus. Serological methods can serve an adjunctive role.


Signal mingle: Micropatterns of BMP-2 and fibronectin on soft biopolymeric films regulate myoblast shape and SMAD signaling.
In vivo, bone morphogenetic protein 2 (BMP-2) exists both in solution and bound to the extracellular matrix (ECM). While these two modes of presentation are known to influence cell behavior distinctly, their role in the niche microenvironment and their functional relevance in the genesis of a biological response has sparsely been investigated at a cellular level. Here we used the natural affinity of BMP-2 for fibronectin (FN) to engineer cell-sized micropatterns of BMP-2. This technique allowed the simultaneous control of the spatial presentation of fibronectin-bound BMP-2 and cell spreading. These micropatterns induced a specific actin and adhesion organization around the nucleus, and triggered the phosphorylation and nuclear translocation of SMAD1/5/8 in C2C12 myoblasts and mesenchymal stem cells, an early indicator of their osteoblastic trans-differentiation. We found that cell spreading itself potentiated a BMP-2-dependent phosphorylation of SMAD1/5/8. Finally, we demonstrated that FN/BMP-2-mediated early SMAD signaling depended on LIM kinase 2 and ROCK, rather than myosin II activation. Altogether, our results show that FN/BMP-2 micropatterns are a useful tool to study the mechanisms underlying BMP-2-mediated mechanotransduction. More broadly, our approach could be adapted to other combinations of ECM proteins and growth factors, opening an exciting avenue to recreate tissue-specific niches in vitro.


The burden of microstructural damage modulates cortical activation in elderly subjects with MCI and leuko-araiosis. A DTI and fMRI study.
The term leuko-araiosis (LA) describes a common chronic affection of the cerebral white matter (WM) in the elderly due to small vessel disease with variable clinical correlates. To explore whether severity of LA entails some adaptive reorganization in the cerebral cortex we evaluated with functional MRI (fMRI) the cortical activation pattern during a simple motor task in 60 subjects with mild cognitive impairment and moderate or severe (moderate-to-severe LA group, n = 46) and mild (mild LA group, n = 14) LA extension on visual rating. The microstructural damage associated with LA was measured on diffusion tensor data by computation of the mean diffusivity (MD) of the cerebral WM and by applying tract based spatial statistics (TBSS). Subjects were examined with fMRI during continuous tapping of the right dominant hand with task performance measurement. Moderate-to-severe LA group showed hyperactivation of left primary sensorimotor cortex (SM1) and right cerebellum. Regression analyses using the individual median of WM MD as explanatory variable revealed a posterior shift of activation within the left SM1 and hyperactivation of the left SMA and paracentral lobule and of the bilateral cerebellar crus. These data indicate that brain activation is modulated by increasing severity of LA with a local remapping within the SM1 and increased activity in ipsilateral nonprimary sensorimotor cortex and bilateral cerebellum. These potentially adaptive changes as well lack of contralateral cerebral hemisphere hyperactivation are in line with sparing of the U fibers and brainstem and cerebellar WM tracts and the emerging microstructual damage of the corpus callosum revealed by TBSS with increasing severity of LA.


Imaging Threading Dislocations and Surface Steps in Nitride Thin Films Using Electron Backscatter Diffraction.
Extended defects, like threading dislocations, are detrimental to the performance of optoelectronic devices. In the scanning electron microscope, dislocations are traditionally imaged using diodes to monitor changes in backscattered electron intensity as the electron beam is scanned over the sample, with the sample positioned so the electron beam is at, or close to the Bragg angle for a crystal plane/planes. Here, we use a pixelated detector instead of single diodes, specifically an electron backscatter diffraction (EBSD) detector. We present postprocessing techniques to extract images of dislocations and surface steps, for a nitride thin film, from measurements of backscattered electron intensities and intensity distributions in unprocessed EBSD patterns. In virtual diode (VD) imaging, the backscattered electron intensity is monitored for a selected segment of the unprocessed EBSD patterns. In center of mass (COM) imaging, the position of the center of the backscattered electron intensity distribution is monitored. Additionally, both methods can be combined (VDCOM). Using both VD and VDCOM, images of only threading dislocations, or dislocations and surface steps can be produced, with VDCOM images exhibiting better signal-to-noise. The applicability of VDCOM imaging is demonstrated across a range of nitride semiconductor thin films, with varying surface step and dislocation densities.


LDL receptors in coated vesicles isolated from bovine adrenal cortex: binding sites unmasked by detergent treatment.
Coated vesicles isolated from bovine adrenal cortex contain specific binding sites that recognize 125I-labeled human low density lipoprotein (LDL). These sites share the properties of the functional LDL receptors previously demonstrated on the surface of adrenal cells and in unfractionated adrenal membranes. Approximately 90% of the LDL receptors of the isolated coated vesicles were initially masked. Binding of 125I-LDL increased 10 fold after the vesicles were disrupted with the detergent octylglucoside. The LDL receptors of intact coated vesicles were also shielded from destruction by pronase; proteolytic destruction occurred only after the vesicles had been disrupted with octylglucoside. The adrenal coated vesicles measured 60 nm in diameter, suggesting that they were derived from the Golgi apparatus. Like the previously studied coated vesicles from brain and other tissues, the coated vesicles from adrenal cortex contained clathrin as the major protein component. In contrast to the coated vesicles of adrenal cortex, however, the brain coated vesicles failed to reveal masked LDL receptor activity when treated with octylglucoside. The current data indicate that isolated coated vesicles from the adrenal cortex contain LDL receptors and that these receptors exist in a masked form, apparently because their binding sites face the interior of the vesicle.


Determination of Bacteroides melaninogenicus serogroups by fluorescent antibody staining.
Fluorescein isothiocyanate-labeled antibody reagents (conjugates) were prepared to one strain of each of the three subspecies of Bacteroides melaninogenicus: B. melaninogenicus subsp. melaninogenicus, B. melaninogenicus subsp. asaccharolyticus, and B. melaninogenicus subsp. intermedius. These three conjugates were specific; thus, they provided a new serological classification of B. melaninogenicus. The three serogroups were designated A, B, and C. Most test strains (98%) isolated from human clinical specimens were assigned to a specific serogroup by immunofluorescence, and the serogroup of these test strains corroborated the biochemical characterization of the three subspecies of B. melaninogenicus. The conjugates failed to cross-react with other anaerobes or aerobes tested. This fluorescent antibody technique provided a more rapid classification of the three subspecies of B. melaninogenicus than did conventional biochemical methods.


Coagulopathies and osteonecrosis.
Intravascular coagulation of the intraosseous microcirculation (capillaries and venous sinusoids) progressing to generalized venous thrombosis, and less commonly retrograde arterial occlusion, now appears to be the cause of nontraumatic osteonecrosis. However, this coagulopathy is only an intermediary event, which is always activated by some underlying etiologic risk factor(s). Conditions capable of triggering intravascular coagulation include familial thrombophilia (resistance to activated protein C, decreased protein C, protein S, or antithrombin III), hyperlipemia and embolic lipid (alcoholism and hypercortisonism), hypersensitivity reactions (allograft organ rejection, immune complexes, and antiphospholipid antibodies), bacterial endotoxic (Shwartzman) reactions and various viral infections, proteolytic enzymes (pancreatitis), tissue factor release (inflammatory bowel disease, malignancies, neurotrauma, and pregnancy), and other prothrombotic and hypofibrinolytic conditions.


Efficient enantiorecognition of amino acids under a stimuli-responsive system: synthesis, characterization and application of electroactive rotaxane.
In this study, an electroactive rotaxane, (S,S)-crown-3, consisting of a polymeric chiral ionic liquid as a flexible axle and 18-crown-6 as the wheel, was designed and synthesized. It is worth noting that a stimuli-responsive system was developed, in which the wheel could switch its location between the chiral carbamido group and ionic pair of the ionic polymers under an external force. Next, (S,S)-crown-3 was employed as a modification on the surface of glassy electrode. In contrast to previous study, the developed probe presented a clear discrimination of an electrochemical signal in the absence of Cu(ii). Under the external force (different pH values), l-isomers of amino acids (tryptophan, tyrosine, and cysteine) could form stable host-guest interactions with the chiral carbamido group, producing higher peak currents than the d-isomers. Compared to the absence of the crown, (S,S)-crown-3 showed much better recognition efficiency. The value of IL/ID for tryptophan could reach 39.8. In brief, the present study describes a powerful method for the synthesis of an electroactive rotaxane with great enantiorecognition capability.


[The "culture of survival" and international public health in Latin America: the Cold War and the eradication of diseases in the mid-twentieth century].
This article analyzes the main campaigns run by international agencies and national health bodies to eradicate infectious diseases in rural Latin America in the 1940s and 1950s. The political dimensions of the period have been studied but there has been little attention as yet to the health dimensions. This article proposes the concept of a "culture of survival" to explain the official public health problems of states with limited social policies that did not allow the exercise of citizenship. Public health, as part of this culture of survival, sought a temporary solution without confronting the social problems that led to infections and left a public health legacy in the region.


Carotid chemoreceptor reflex parasympathetic coronary vasodilation in the dog.
The hypothesis that carotid body chemoreceptor activation with hypoxic-hypercapnic blood elicits reflex coronary vasodilation was investigated. Circumflex or anterior descending coronary artery blood flow was measured in alpha-chloralose-anesthetized, closed-chest dogs. To minimize changes in cardiac metabolism, the heart was paced at a constant rate after atrioventricular heart block, propranolol (1 mg/kg) was given to prevent beta-receptor-mediated alterations in cardiac contractility, and aortic blood pressure was stabilized by means of a blood reservoir. The carotid body regions were vascularly isolated and perfused at constant pressure with arterial blood or hypoxic-hypercapnic blood. Under these conditions, carotid body chemoreceptor stimulation with hypoxic or hypoxic-hypercapnic blood for 90 s produced atrial bradycardia and a transient increase in coronary blood flow of 36-53% above prestimulation values. The augmented coronary flow was accompanied by a transient increase in coronary sinus O2 tension of 4.6-5.7 mmHg. Aortic blood pressure varied less than 10 mmHg. Intracarotid injections of nicotine (0.1 microgram/kg) or cyanide (150 micrograms) produced similar results. The coronary response to chemoreceptor stimulation with hypoxic blood or drugs was abolished when the reflex arc was interrupted with atropine (0.5 mg/kg). It is concluded that transient reflex parasympathetic coronary vasodilation is elicited by hypoxic or hypoxic-hypercapnic stimulation of carotid body chemoreceptors.


Epidemiology of bacteremia in young hospitalized infants in Vientiane, Laos, 2000-2011.
As data about the causes of neonatal sepsis in low-income countries are inadequate, we reviewed the etiology and antibiotic susceptibilities of bacteremia in young infants in Laos. As Staphylococcus aureus is the leading cause of bacteremia in Lao infants, we also examined risk factors for this infection, in particular the local practice of warming mothers during the first weeks postpartum with hot coals under their beds (hot beds). Clinical and laboratory data regarding infants aged 0-60 days evaluated for sepsis within 72 h of admission to Mahosot Hospital in Vientiane, Laos, were reviewed, and 85 of 1438 (5.9%) infants' blood cultures grew a clinically significant organism. Most common were S. aureus, Escherichia coli and Klebsiella pneumoniae. Whereas no methicillin-resistant S. aureus was found, only 18% of E. coli isolates were susceptible to ampicillin. A history of sleeping on a hot bed with mother was associated with S. aureus bacteremia (odds ratio 4.8; 95% confidence interval 1.2-19.0).


The olivocochlear reflex strength and cochlear sensitivity are independently modulated by auditory cortex microstimulation.
In mammals, efferent projections to the cochlear receptor are constituted by olivocochlear (OC) fibers that originate in the superior olivary complex. Medial and lateral OC neurons make synapses with outer hair cells and with auditory nerve fibers, respectively. In addition to the OC system, there are also descending projections from the auditory cortex that are directed towards the thalamus, inferior colliculus, cochlear nucleus, and superior olivary complex. Olivocochlear function can be assessed by measuring a brainstem reflex mediated by auditory nerve fibers, cochlear nucleus neurons, and OC fibers. Although it is known that the OC reflex is activated by contralateral acoustic stimulation and produces a suppression of cochlear responses, the influence of cortical descending pathways in the OC reflex is largely unknown. Here, we used auditory cortex electrical microstimulation in chinchillas to study a possible cortical modulation of cochlear and auditory nerve responses to tones in the absence and presence of contralateral noise. We found that cortical microstimulation produces two different peripheral modulations: (i) changes in cochlear sensitivity evidenced by amplitude modulation of cochlear microphonics and auditory nerve compound action potentials and (ii) enhancement or suppression of the OC reflex strength as measured by auditory nerve responses, which depended on the intersubject variability of the OC reflex. Moreover, both corticofugal effects were not correlated, suggesting the presence of two functionally different efferent pathways. These results demonstrate that auditory cortex electrical microstimulation independently modulates the OC reflex strength and cochlear sensitivity.


Health related quality of life 5-7 years after minor and severe burn injuries: a multicentre cross-sectional study.
Burn injury can affect health-related quality of life (HRQL). Knowledge concerning long-term HRQL in burn patients is limited. Therefore our aim was to evaluate long-term HRQL and to study predictors of impaired long-term HRQL. All adults with a length of stay (LOS) of ≥1 day (2011-2012) were invited. Also, adults with severe burns, i.e., >20% total body surface area (TBSA) burned or TBSA full thickness>5% (2010-2013) were invited. Participants completed the EuroQol(EQ)-5 D-5L + C and visual analogue scale (EQ-VAS) 5-7 years after burns. This study included 256 patients (mean %TBSA 10%); 187 patients with minor burns and 69 patients with severe burns. Mean EQ-5D summary was 0.90 and EQ-VAS 83.2 in the minor burn patients, and 0.79 and 78.1 in the severe burn patients. Some problems in at least one dimension were experienced by 81% of patients with severe burns and 45% of those with minor burns. However, a minority reported severe or extreme problems; 15% of those with severe burns and 6% of those with minor burns. Patients with severe burns reported significantly more problems, except for anxiety/depression. In both patient groups most problems were reported on pain/discomfort. Length of hospital stay, gender and age were associated with lower long-term HRQL (EQ-VAS) in multivariate analyses, whereas only length of stay was associated with a lower summary score. The majority of patients experienced some problems with HRQL 5-7 years post burn. This emphasizes that burns can have a negative impact on an individual's HRQL, particularly in more severely burned patients, that persists for years. The HRQL dimensions most frequently affected include pain/discomfort and anxiety/depression. Patients with a prolonged hospital stay, females and older patients are at higher risk of poor HRQL in the long-term.


Flies dynamically anti-track, rather than ballistically escape, aversive odor during flight.
Tracking distant odor sources is crucial to foraging, courtship and reproductive success for many animals including fish, flies and birds. Upon encountering a chemical plume in flight, Drosophila melanogaster integrates the spatial intensity gradient and temporal fluctuations over the two antennae, while simultaneously reducing the amplitude and frequency of rapid steering maneuvers, stabilizing the flight vector. There are infinite escape vectors away from a noxious source, in contrast to a single best tracking vector towards an attractive source. Attractive and aversive odors are segregated into parallel neuronal pathways in flies; therefore, the behavioral algorithms for avoidance may be categorically different from tracking. Do flies plot random ballistic or otherwise variable escape vectors? Or do they instead make use of temporally dynamic mechanisms for continuously and directly avoiding noxious odors in a manner similar to tracking appetitive ones? We examine this question using a magnetic tether flight simulator that permits free yaw movements, such that flies can actively orient within spatially defined odor plumes. We show that in-flight aversive flight behavior shares all of the key features of attraction such that flies continuously 'anti-track' the noxious source.


Different types of exercise induce differential effects on neuronal adaptations and memory performance.
Different exercise paradigms show differential effects on various forms of memory. We hypothesize that the differential effects of exercises on memory performance are caused by different neuroplasticity changes in relevant brain regions in response to different exercise trainings. We examined the effects of treadmill running (TR) and wheel running (WR) on the Pavlovian fear conditioning task that assesses learning and memory performance associated with the amygdala (cued conditioning) and both the amygdala and hippocampus (contextual conditioning). The skeletal muscle citrate synthase activity, an indicator of aerobic capacity, was elevated in rats received 4 w of TR, but not WR. While both TR and WR elevated the contextual conditional response, only TR facilitated the cued conditional response. Using a single-neuron labeling technique, we found that while both TR and MR enlarged the dendritic field and increased the spine density in hippocampal CA3 neurons, only TR showed these effects in basolateral amygdalar neurons. Moreover, both types of exercise upregulated synaptic proteins (i.e., TrkB and SNAP-25) in the hippocampus; however only TR showed similar effects in the amygdala. Injection of K252a, a TrkB kinase inhibitor, in the dorsal hippocampus or basolateral amygdala abolished the exercise-facilitated contextual or cued fear learning and memory performance, respectively, regardless of the types of exercise. In summary, our results supported that different types of exercise affect the performance of learning and memory via BDNF-TrkB signaling and neuroplasticity in specific brain regions. The brain region-specific neuronal adaptations are possibly induced by various levels of intensity/stress elicited by different types of exercise.


Awareness of chronic viral hepatitis in the United States: An update from the National Health and Nutrition Examination Survey.
The World Health Organization has set the goal of reducing the hepatitis-related mortality rate by 65% between 2015 and 2030. Diagnosis and awareness of infection is the first essential step towards achieving this goal. Our study examined the current awareness rate of chronic viral hepatitis in the United States and the potentially associated factors. In the National Health Nutrition and Examination Survey 2013-2016, there were 11 488 persons who participated in serology testing for chronic viral hepatitis. We defined chronic hepatitis B virus (HBV) infection by HbsAg, HBV past exposure by anti-HBc and hepatitis C virus (HCV) infection by HCV RNA. At risk for significant fibrosis was determined by AST to Platelet Ratio Index >0.7. Awareness of chronic HBV infection, past HBV exposure and HCV infection were present in 33.9%, 11.7% and 55.6% of participants, respectively. Among HCV-infected baby boomers, the awareness was in 61.5%. The awareness of HBV infection was significantly higher in individuals with high education level. Age group (40-60 years), women, non-Black race/ethnicity and those with high household income who were born in the United States with insurance plans tend to be aware of their infection. For HCV, awareness was the lowest in Hispanics and Asians, foreign-born who lived below the federal poverty level and low education level. Awareness among chronic viral hepatitis patients at risk for significant fibrosis was 62.0% in HBV and 38.2% in HCV infection. In conclusion, current awareness of chronic viral hepatitis in the United States remains suboptimal. Active public health policy to identify persons at risk and provide appropriate management is warranted.


Potential anatomical basis for attentional modulation of hippocampal neurons.
Lesions of the hippocampus and related structures produce profound anterograde amnesia. The amnesia is specific to what has been called "explicit," "declarative," and "episodic" memory. These memories are frequently believed to be central to the human condition, requiring such advanced cognitive functions as attention and even consciousness. However, the hippocampus and associated structures are evolutionarily conserved, which argues that the memories of lower mammals should be qualitatively similar in nature. Just as attention and arousal are critical components of appropriate memory formation in humans, an emerging body of evidence suggests that these processes bear on the firing patterns of hippocampal neurons in rodents. Here the evidence favoring this hypothesis is discussed and then the potential anatomical basis for such modulation is considered.


Serious violence by people with mental illness: national clinical survey.
This study aimed to estimate the prevalence of mental disorder in offenders convicted of serious violence, examine their social and clinical characteristics, and compare them with patients convicted of homicide. We examined a national clinical survey of all people convicted of serious violence in England and Wales in 2004. Mental disorder was measured by contact with mental health services within 12 months of the offense. Of the 5,966 serious violent offenders, 293 (5%) had been in recent contact with mental health services. Personality disorder (63, 22%) and schizophrenia (55, 19%) were the most common diagnoses. Most had previous convictions for violence (168, 61%). Seventy-two (25%) patients were at high risk of violence and 34 (49%) were not subject to the Care Programme Approach. Compared with serious violence offenders, homicide offenders were more likely to have been patients (293, 5% vs. 65, 10%; p < .01). We conclude that patients were responsible for a small proportion of serious violent offenses; however, high-risk patients require closer supervision, and regular inquiry about changing delusional beliefs, thoughts of violence, and weapon carriage.


'Doing with …' rather than 'doing for …' older adults: rationale and content of the 'Stay Active at Home' programme.
Owing to increasing age, accidents or periods of illness, home care services are provided to community-dwelling older adults. Traditionally, these services focus on doing things for older adults rather than with them; though from a rehabilitative perspective, it is important to assist older adults to attain and maintain their highest level of functioning. Consequently, a re-orientation of home care services is required away from treating disease and creating dependency towards focusing on capabilities and opportunities and maximising independence. To achieve this behavioural change in home care professionals, the 'Stay Active at Home' programme was developed. The aim of this article is to give a detailed description of the rationale and content of the 'Stay Active at Home' programme by making use of the TIDieR (Template for Intervention Description and Replication) Checklist. 'Stay Active at Home' is a comprehensive training programme that aims to equip home care professionals (i.e. community nurses and domestic support workers) with the necessary knowledge, attitude, skills and social and organisational support to deliver day-to-day services at home from a more rehabilitative perspective. More specifically, home care professionals are expected to deliver goal-oriented, holistic and person-centred services focusing on supporting older adults to maintain, gain or restore their competences to engage in physical and daily activities so that they can manage their everyday life as independently as possible.


The transcriptomic response of the coral Acropora digitifera to a competent Symbiodinium strain: the symbiosome as an arrested early phagosome.
Despite the ecological significance of the relationship between reef-building corals and intracellular photosynthetic dinoflagellates of the genus Symbiodinium, very little is known about the molecular mechanisms involved in its establishment. Indeed, microarray-based analyses point to the conclusion that host gene expression is largely or completely unresponsive during the establishment of symbiosis with a competent strain of Symbiodinium. In this study, the use of Illumina RNA-Seq technology allowed detection of a transient period of differential expression involving a small number of genes (1073 transcripts; <3% of the transcriptome) 4 h after the exposure of Acropora digitifera planulae to a competent strain of Symbiodinium (a clade B strain). This phenomenon has not previously been detected as a consequence of both the lower sensitivity of the microarray approaches used and the sampling times used. The results indicate that complex changes occur, including transient suppression of mitochondrial metabolism and protein synthesis, but are also consistent with the hypothesis that the symbiosome is a phagosome that has undergone early arrest, raising the possibility of common mechanisms in the symbiotic interactions of corals and symbiotic sea anemones with their endosymbionts.


An examination of relationship satisfaction as a predictor of outcomes of brief couple therapy for posttraumatic stress disorder.
The pretreatment quality of intimate relationships can promote or interfere with couple therapy for posttraumatic stress disorder (PTSD) treatment response. We tested whether baseline relationship satisfaction predicted clinical and process outcomes in two dyadic treatments for PTSD. Using data from a randomized trial comparing brief cognitive behavioral conjoint therapy (bCBCT) for PTSD to PTSD family education (PFE) among 137 military veterans and their partners (N = 274, Mage = 42.3 years, 46.7% White, 81.0% male veteran partner), we examined whether baseline relationship satisfaction (Couples Satisfaction Index; CSI-32) predicted change in PTSD symptom severity (Clinician Administered PTSD Scale for DSM-5; CAPS-5), psychosocial functioning (Brief Inventory of Psychosocial Functioning; B-IPF), and relationship satisfaction at posttreatment and 6-month follow-up. We also explored associations with process outcomes (working alliance, treatment satisfaction, dropout). In both treatment conditions, neither partner's baseline CSI-32 score moderated change in veteran CAPS-5 or B-IPF score or any process variable. However, baseline CSI-32 scores moderated both partners' CSI-32 score change during bCBCT and PFE; participants who scored in the distressed range at baseline (n = 123) experienced significant improvements in relationship satisfaction, β = .199, whereas there was no change among those in the nondistressed range at baseline (n = 151), β = .025. Results suggest bCBCT and PFE are effective in improving PTSD symptoms and psychosocial functioning regardless of whether a couple is experiencing clinically significant relationship distress; further, these treatments improve relationship satisfaction for the most distressed individuals.


The global burden of anxiety disorders in 2010.
Despite their high prevalence, the global burden of anxiety disorders has never been calculated comprehensively. The new Global Burden of Disease (GBD) study has estimated burden due to morbidity and mortality caused by any anxiety disorder. Prevalence was estimated using Bayesian meta-regression informed by data identified in a systematic review. Years of life lived with disability (YLDs) were calculated by multiplying prevalent cases by an average disability weight based on severity proportions (mild, moderate and severe). Disability-adjusted life years (DALYs) were then calculated and age standardized using global standard population figures. Estimates were also made for additional suicide mortality attributable to anxiety disorders. Findings are presented for YLDs, DALYs and attributable burden due to suicide for 21 world regions in 1990 and 2010. Anxiety disorders were the sixth leading cause of disability, in terms of YLDs, in both high-income (HI) and low- and middle-income (LMI) countries. Globally, anxiety disorders accounted for 390 DALYs per 100,000 persons [95% uncertainty interval (UI) 191-371 DALYs per 100,000] in 2010, with no discernible change observed over time. Females accounted for about 65% of the DALYs caused by anxiety disorders, with the highest burden in both males and females experienced by those aged between 15 and 34 years. Although there was regional variation in prevalence, the overlap between uncertainty estimates means that substantive differences in burden between populations could not be identified. Anxiety disorders are chronic, disabling conditions that are distributed across the globe. Future estimates of burden could be further improved by obtaining more representative data on severity state proportions.


Role of hepatic metallothionein during perinatal development in the rat.
The concentration of metallothionein (MT) in the liver of the perinatal rat is relatively high at term and 7 days after birth and then decreases to barely detectable levels by day 28. The developmental pattern MT-zinc parallels that of MT. When challenged with a single injection of cadmium chloride, the 26-day-old rat responds with a dose-related increase in hepatic MT which sequesters both cadmium and zinc. When the 5-day-old rat is similarly challenged, induction of MT occurs only at the highest dose tested (6 mg Cd/kg); however, due to the pre-existence of MT in these younger rats, cadmium administered at the lower doses still binds to the MT in a dose-related manner. Despite the induction of MT seen in both age groups following the 6.0 mg/kg dose, exposure to that level of the metal produced death in 30% of the younger animals but in only 4% of the older animals. When cadmium was administered to pregnant rats on day 19 of gestation, it was found to produce a dose-related induction of maternal hepatic MT over the following 48 hr. In contrast, maternal exposure to the metal led to a significant depression of fetal hepatic MT over the same time interval.


Structure elucidation and synthesis of dioxolanes emitted by two Triatoma species (Hemiptera: Reduviidae).
Volatiles from the metasternal glands of two species of true bugs of the Triatominae subfamily, Triatoma brasiliensis and Triatoma infestans, were analyzed by SPME-GC/MS. Two sets of new natural products were found: (4S,5S)- and (4R,5R)-2,2,4-triethyl-5-methyl-1,3-dioxolane (1) (major component) and (4S*,5S*)-2,4-diethyl-2,5-dimethyl-1,3-dioxolane (2) (trace component), (2R/S,4S,5S)- as well as (2R/S,4R,5R)-4-ethyl-5-methyl-2-(1-methylethyl)-1,3-dioxolane (3) (minor component), (2R/S,4S*,5S*)-4-ethyl-5-methyl-2-(1-methylpropyl)-1,3-dioxolane (4) (trace component), and (2R/S,4S*,5S*)-4-ethyl-5-methyl-2-(2-methylpropyl)-1,3-dioxolane (5) (trace component). Syntheses of optically active 1 and 3 were carried out by reacting pure enantiomers of 2,3-pentanediol with 3-pentanone or 2-methylpropanal. The preparation of pure stereoisomers of 2,3-pentanediol involved a novel key step for the synthesis of secondary alcohols: the reduction of a carboxylic ester by means of DIBAH and in situ alkylation of the intermediate by Grignard reaction at low temperature. Starting from the pure enantiomers of methyl lactate, all four stereoisomers of 2,3-pentanediol were synthesized and transformed to the corresponding isomers of 1 and 2. Relative configurations of the natural products and enantiomeric compositions of naturally occurring 1 and 2 were determined by comparison of their mass spectra and gas chromatographic retention times (co-injection) with those of authentic reference samples.


Cross-linking of the mannose receptor on monocyte-derived dendritic cells activates an anti-inflammatory immunosuppressive program.
Immature monocyte-derived dendritic cells (DC) strongly express the endocytic mannose receptor (MR). Addition of a specific anti-MR mAb (clone PAM-1) for 24 h to cultures of immature DC induced phenotypical and functional maturation of the cells, assessed as up-regulation of costimulatory molecules and CD83, and chemotactic response to CCL19. A different isotype-matched anti-MR mAb (clone 19.2) had no significant effect. Engagement of MR with mAb PAM-1 induced the production of the anti-inflammatory cytokines IL-10, IL-1R antagonist, and of the nonsignaling IL-1R type II. In contrast IL-1beta, TNF, and IL-12 were not produced. PAM-1-treated DC were unable to polarize Th1 effector cells and did not secrete the chemokines CXCL10 and CCL19; in turn, they produced large amounts of CCL22 and CCL17, thus favoring the amplification of Th2 circuits. T cells cocultured with PAM-1-matured DC initially proliferated but later became anergic and behaved as suppressor/regulatory cells. Natural ligands binding to MR had differential effects. MUC III (a partially purified mucin), biglycan (a purified complex proteoglycan), and mannosylated lipoarabinomannan from Mycobacterium tuberculosis affected cytokine production with high IL-10, IL-1R antagonist, IL-1R type II, and inhibition of IL-12. In contrast, mannan, dextran, and thyroglobulin had no significant effect. In conclusion, the appropriate engagement of the MR by mAb PAM-1 and selected natural ligands elicit a secretory program in mono-derived DC characterized by a distinct profile of cytokines/chemokines with the ability to dampen inflammation and to inhibit the generation of Th1-polarized immune responses.


Molecularly Engineered Room-Temperature Phosphorescence for Biomedical Application: From the Visible toward Second Near-Infrared Window.
Phosphorescence, characterized by luminescent lifetimes significantly longer than that of biological autofluorescence under ambient environment, is of great value for biomedical applications. Academic evidence of fluorescence imaging indicates that virtually all imaging metrics (sensitivity, resolution, and penetration depths) are improved when progressing into longer wavelength regions, especially the recently reported second near-infrared (NIR-II, 1000-1700 nm) window. Although the emission wavelength of probes does matter, it is not clear whether the guideline of "the longer the wavelength, the better the imaging effect" is still suitable for developing phosphorescent probes. For tissue-specific bioimaging, long-lived probes, even if they emit visible phosphorescence, enable accurate visualization of large deep tissues. For studies dealing with bioimaging of tiny biological architectures or dynamic physiopathological activities, the prerequisite is rigorous planning of long-wavelength phosphorescence, being aware of the cooperative contribution of long wavelengths and long lifetimes for improving the spatiotemporal resolution, penetration depth, and sensitivity of bioimaging. In this Review, emerging molecular engineering methods of room-temperature phosphorescence are discussed through the lens of photophysical mechanisms. We highlight the roles of phosphorescence with emission from visible to NIR-II windows toward bioapplications. To appreciate such advances, challenges and prospects in rapidly growing studies of room-temperature phosphorescence are described.


Ultrastructural neuronal pathology in transgenic mice expressing mutant (P301L) human tau.
Transgenic mice expressing mutant (P301L) human tau develop neurofibrillary tangles, amyotrophy and progressive motor disturbance. We present ultrastructural features of neuronal degeneration in this model that suggests involvement of both neurofibrillary and autophagic processes in neurodegeneration. Neurons undergoing neurofibrillary degeneration contain tau-immunoreactive, 15-20 nm-wide straight or wavy filaments with no periodic twists. Tau filaments were found in two types of affected neurons. One type resembled neurons with neurofibrillary tangles (NFT) that were filled with numerous filaments that displaced sparse cytoplasmic organelles to the periphery. Microtubules were almost completely absent. The nucleus remained centrally located, but showed lobulations due to deep infoldings. The other type resembled ballooned neurons seen in some human tauopathies. The nucleus was peripherally placed, but normal appearing. The cytoplasmic organelles were dispersed throughout the swollen perikarya, the Golgi complex was fragmented and duplicated, while mitochondria and other organelles appeared normal. Tau filaments similar to those in NFT were sparse and not tightly packed. Microtubules were also sparse. Many autophagic vacuoles were present in these cells. Heterogeneous appearing axonal swellings resembling spheroids in human tauopathies were present in gray and white matter. Unlike normal appearing axons, axonal spheroids were filled with tau-immunoreactive filaments and autophagic vacuoles, in addition to normal appearing neurofilaments and microtubules. These P301L transgenic mice exhibit many features common to human tauopathies, making them a valuable model to study the pathogenesis of these uncommon disorders.


Expression of the prolactin gene in normal and neoplastic human breast tissues and human mammary cell lines: promoter usage and alternative mRNA splicing.
Prolactin (PRL) has been implicated in the development of mammary cancer in rodents and humans. Although PRL and its mRNA have been detected in breast tissues and some mammary cell lines, the role of PRL as an autocrine/paracrine growth factor within the breast is not clear. A second, more distal, promoter has recently been identified in the human PRL gene. We have used reverse transcription-polymerase chain reaction (RT-PCR) to determine whether the distal or the proximal promoter directs expression of the PRL gene in normal and neoplastic breast tissues and in mammary cell lines. Total RNA was isolated from 10 normal and 20 neoplastic breast tissue samples and from 8 mammary cell lines; MDA-MB-231, SK-BR-3, T-47D, MCF10, MCF10T2, and 3 MCF7 derivatives. The RNA was reverse transcribed to cDNA using random hexamers as primers. PCR amplification of the cDNAs was performed, using a variety of PRL-specific primer pairs, and the DNA products were subjected to agarose gel electrophoresis and Southern blotting. The resulting data indicate that the PRL gene is expressed in the majority of both normal and neoplastic breast tissue samples, as well as all of the mammary cell lines. PRL-specific PCR products corresponding to transcripts that originated from the distal promoter were observed in a subset of the normal and neoplastic breast tissue samples and mammary cell lines. Together these data indicate that PRL transcripts in human breast tissues and human mammary cell lines originate, at least in part, from the distal PRL promoter. In addition, data are presented which suggest that PRL transcripts in breast tissues and mammary cell lines may undergo alternative splicing.


The mouse age phenome knowledgebase and disease-specific inter-species age mapping.
Similarities between mice and humans lead to generation of many mouse models of human disease. However, differences between the species often result in mice being unreliable as preclinical models for human disease. One difference that might play a role in lowering the predictivity of mice models to human diseases is age. Despite the important role age plays in medicine, it is too often considered only casually when considering mouse models. We developed the mouse-Age Phenotype Knowledgebase, which holds knowledge about age-related phenotypic patterns in mice. The knowledgebase was extensively populated with literature-derived data using text mining techniques. We then mapped between ages in humans and mice by comparing the age distribution pattern for 887 diseases in both species. The knowledgebase was populated with over 9800 instances generated by a text-mining pipeline. The quality of the data was manually evaluated, and was found to be of high accuracy (estimated precision >86%). Furthermore, grouping together diseases that share similar age patterns in mice resulted in clusters that mirror actual biomedical knowledge. Using these data, we matched age distribution patterns in mice and in humans, allowing for age differences by shifting either of the patterns. High correlation (r(2)>0.5) was found for 223 diseases. The results clearly indicate a difference in the age mapping between different diseases: age 30 years in human is mapped to 120 days in mice for Leukemia, but to 295 days for Anemia. Based on these results we generated a mice-to-human age map which is publicly available. We present here the development of the mouse-APK, its population with literature-derived data and its use to map ages in mice and human for 223 diseases. These results present a further step made to bridging the gap between humans and mice in biomedical research.


Is the context specificity of latent inhibition a sufficient explanation of learned irrelevance?
In three experiments, rats were pre-exposed either to uncorrelated presentations of a light and sucrose pellets (group CS/US) or to equivalent presentations of the light and pellets in separate sessions (control). In Experiment 1, subsequent conditioning to the light proceeded more slowly in group CS/US than in the control group, whether this conditioning was excitatory, with the light signalling the delivery of pellets, or inhibitory, with the light signalling their absence. Bonardi and Hall (1996) have argued that this learned irrelevance effect may be reducible to latent inhibition, which would be stronger in group CS/US because they are both pre-exposed and conditioned to the CS in the presence of traces of previous USs occurring in the same session. This analysis implies that group CS/US should have conditioned more rapidly to the CS than controls on the first trial of each session in Experiment 1, but this did not happen. It also implies that the learned irrelevance effect should be reversed if conditioning trials are given at a rate of one per day. Experiments 2 and 3 found no support for this prediction. We conclude that learned irrelevance effects cannot always be reduced to latent inhibition.


Research methodology: cancer cachexia syndrome.
Cachexia is a syndrome and therefore does not have a specific definition. Patients are characterized by the presence of anorexia, early satiety, weight loss, weakness, anaemia and oedema. These features occur to a variable extent in different patients and may change in severity during the course of a patient's illness. The multifactorial origin of cachexia precludes a uniform pathophysiological definition. Taken together these factors have hindered clinical studies both at a fundamental level and in terms of the introduction of effective therapy. The advent of novel therapeutic targets (e.g., ubiquitin-proteasome pathway) and biological response modifiers has opened possibilities for new clinical trials in cachexia. Regulatory authorities feel it is important not only to demonstrate efficacy in terms of patients' nutritional status (e.g., lean body mass) but also functional status (e.g., performance status). This article reviews current methods to assess the latter. Methods focused on measuring physical activity level (e.g., doubly labelled water technique or physical activity meters) promise objective data which can be readily interpreted in terms of clinically meaningful benefit.


Sonographically guided alcohol injection in painful stump neuroma.
Stump neuroma is a common cause of pain from disorganized proliferation of nerve fascicles occurring after limb amputation. Ultrasound guided alcohol injection in painful stump neuroma has been tried as a new treatment approach. Herein, we report 2 male patients, who had traumatic amputation and claimed severe and diffuse burning pain in the stump area. Neuroma at the distal end of an amputated nerve was clearly identified on sonography. The patients gradually developed increasing severe pain that could not be managed with conservative care. They were treated with neurolysis using alcohol solution. Using ultrasonographical guidance, 1.2 ml of 100% dehydrated alcohol was injected into the nerves proximal to neuroma. No complications occurred. The patients were initially pain free. After a few months, however, their stump pain recurred slightly. Repeat neurolysis was performed using 0.3 ml of 100% dehydrated alcohol. During the three months follow-up period, mild stump pain occurred but the patients did not require any analgesics.


Hydrocephalus due to idiopathic stenosis of the foramina of Magendie and Luschka. Report of three cases.
Idiopathic stenosis of the foramina of Magendie and Luschka is a rare cause of obstructive hydrocephalus involving the four ventricles. Like other causes of noncommunicating hydrocephalus, it can be treated with endoscopic third ventriculostomy (ETV). Three patients who were 21, 53, and 68 years of age presented with either headaches (isolated or associated with raised intracranial pressure) or vertigo, or a combination of gait disorders, sphincter disorders, and disorders of higher functions. In each case, magnetic resonance (MR) imaging demonstrated hydrocephalus involving the four ventricles (mean transverse diameter of third ventricle 14.15 mm; mean sagittal diameter of fourth ventricle 23.13 mm; and mean ventricular volume 123.92 ml) with no signs of a Chiari Type I malformation (normal posterior fossa dimensions, no herniation of cerebellar tonsils). The diagnosis of obstruction was confirmed using ventriculography (in two patients) and/or MR flow images (in two patients). All patients presented with marked dilation of the foramen of Luschka that herniated into the cisterna pontis. All patients were treated using ETV. No complications were observed. All three patients became asymptomatic during the weeks following the surgical procedure and remained stable at a mean follow-up interval of 36 months. Postoperative MR images demonstrated regression of the hydrocephalus (mean transverse diameter of third ventricle 7.01 mm; mean sagittal diameter of fourth ventricle 16.6 mm; and mean ventricular volume 79.95 ml), resolution of dilation of the foramen of Luschka, and good patency of the ventriculostomy (flow sequences). These results confirm the existence of hydrocephalus caused by idiopathic fourth ventricle outflow obstruction without an associated Chiari Type I malformation, and the efficacy of ETV for this rare indication.


Erythromycin resistance genes in group A streptococci in Finland. The Finnish Study Group for Antimicrobial Resistance.
Streptococcus pyogenes isolates (group A streptococcus) of different erythromycin resistance phenotypes were collected from all over Finland in 1994 and 1995 and studied; they were evaluated for their susceptibilities to 14 antimicrobial agents (396 isolates) and the presence of different erythromycin resistance genes (45 isolates). The erythromycin-resistant isolates with the macrolide-resistant but lincosamide- and streptogramin B-susceptible phenotype (M phenotype) were further studied for their plasmid contents and the transferability of resistance genes. Resistance to antimicrobial agents other than macrolides, clindamycin, tetracycline, and chloramphenicol was not found. When compared to our previous study performed in 1990, the rate of resistance to tetracycline increased from 10 to 93% among isolates with the inducible resistance (IR) phenotype of macrolide, lincosamide, and streptogramin B (MLSB) resistance. Tetracycline resistance was also found among 75% of the MLSB-resistant isolates with the constitutive resistance (CR) phenotype. Resistance to chloramphenicol was found for the first time in S. pyogenes in Finland; 3% of the isolates with the IR phenotype were resistant. All the chloramphenicol-resistant isolates were also resistant to tetracycline. Detection of erythromycin resistance genes by PCR indicated that, with the exception of one isolate with the CR phenotype, all M-phenotype isolates had the macrolide efflux (mefA) gene and all the MLSB-resistant isolates had the erythromycin resistance methylase (ermTR) gene; the isolate with the CR phenotype contained the ermB gene. No plasmid DNA could be isolated from the M-phenotype isolates, but the mefA gene was transferred by conjugation.


Repeated measures dose-finding design with time-trend detection in the presence of correlated toxicity data.
Phase I trials are designed to determine the safety, tolerability, and recommended phase 2 dose of therapeutic agents for subsequent testing. The dose-finding paradigm has thus traditionally focused on identifying the maximum tolerable dose of an agent or combination therapy under the assumption that there is a non-decreasing relationship between dose-toxicity and dose-efficacy. The dose is typically determined based on the probability of severe toxicity observed during the first treatment cycle. A novel endpoint, the total toxicity profile, was previously developed to account for the multiple toxicity types and grades experienced in the first cycle. More recently, this was extended to a repeated measures design based on the total toxicity profile to account for longitudinal toxicities over multiple treatment cycles in the absence of within-patient correlation. In this work, we propose to extend the design in the presence of within-patient correlation. Furthermore, we provide a framework to detect a toxicity time trend (toxicity increasing, decreasing, or stable) over multiple treatment cycles. We utilize a linear mixed model in the Bayesian framework, with the addition of Bayesian risk functions for decision-making in dose assignment. The performance of this design was evaluated using simulation studies and real data from a phase I trial. We demonstrated that using available toxicity data from all cycles of treatment improves the accuracy of maximum tolerated dose identification and allows for the detection of a time trend. The performance is consistent regardless of the strength of the within-patient correlation. In addition, the use of a quasi-continuous total toxicity profile score significantly increased the power to detect time trends compared to when binary data only were used. The increased interest in molecularly targeted agents and immunotherapies in oncology necessitates innovative phase I study designs. Our proposed framework provides a tool to tackle some of the challenges presented by these novel agents, specifically through the ability to understand patterns of toxicity over time, which is important in the cases of cumulative or late toxicities.


Management involvement on the board of directors and hospital financial performance.
Agency theory is used to investigate the relationship between top management team involvement on not-for-profit hospitals' boards of directors (BODs) and hospital financial performance. Governance data collected in 2011 by The Governance Institute was merged with hospital financial performance data from the 2011 Medicare Cost Reports. Then, an ordinary least squares regression model, using propensity score adjustments, was used to evaluate the relationship between management involvement on the BOD and three financial performance profitability ratios: total margin, operating margin, and return on assets. The sample included 637 not-for-profit hospitals, most of which (74.1%) were not government owned. As hypothesized, we found that having a larger number of managers with voting rights on the BOD was associated with lower total margin (β = -0.011, p < .065). Similarly, we found that having a greater percentage of voting BOD members who were managers was associated with lower total margin (β = -0.296, p < .002) and return on assets (β = -0.337, p < .072). We did not find support for the notion that CEO involvement onthe BOD is associated with poorer hospital financial performance (β = -0.008, p < .437). Consistent with agency theory, our findings suggest that management involvement on the BOD is associated with poorer hospital financial performance. This finding suggests that management involvement on the BOD may impair the BOD's ability to effectively monitor the actions of management, which may lead managers to make decisions that are more consistent with their own interests than those of the organization.


Statistical approach for assessing the influence of calcium silicate and HPMC on the formulation of novel alfuzosin hydrochloride mucoadhesive-floating beads as gastroretentive drug delivery systems.
Multiparticulate floating drug delivery systems have proven potential as controlled-release gastroretentive drug delivery systems that avoid the "all or none" gastric emptying nature of single-unit floating dosage forms. An objective of the presence investigation was to develop calcium silicate (CaSi)/calcium alginate (Ca-Alg)/hydroxypropyl methylcellulose (HPMC) mucoadhesive-floating beads that provide time- and site-specific drug release of alfuzosin hydrochloride (Alf). Beads were prepared by simultaneous internal and external gelation method utilizing 3(2) factorial design as an experimental design; with two main factors evaluated for their influence on the prepared beads; the concentration of CaSi as floating aid (X (1)) and the percentage of HPMC as viscosity enhancer and mucoadhesive polymer (X (2)), each of them was tested in three levels. Developed formulations were evaluated for yield, entrapment efficiency, particle size, surface topography, and buoyancy. Differential scanning calorimetry, Fourier transform infrared spectroscopy, in vitro drug release, as well as in vitro mucoadhesion using rat stomach mucosal membrane were also conducted. Percentage yield and entrapment efficiency ranged from 57.03% to 78.51% and from 49.78% to 83.26%, respectively. Statistical analysis using ANOVA proved that increasing the concentration of either CaSi or HPMC significantly increased the beads yield. Both CaSi and HPMC concentrations were found to significantly affect Alf release from the beads. Additionally, higher CaSi concentration significantly increased the beads diameter while HPMC concentration showed significant positive effect on the beads mucoadhesive properties. CaSi/Ca-Alg/HPMC beads represent simple floating-mucoadhesive gastroretentive system that could be useful in chronopharmacotherapy of benign prostatic hyperplasia.


The effect of the colour red in 20 years of Olympic taekwondo.
The objectives of this study were (1) to analyse the relationship between the colour of the protectors and the outcome of 895 matches in the six Olympic Games in which taekwondo has been included, and (2) to analyse the effect of confounding factors through the different degrees of asymmetry between contestants. Data were recorded on the colour of each athlete's protectors, the scoring system, the sex of the athlete, the weight category, the round of competition, the winner of the match, the method of victory and the points scored by each athlete. Among the main results, a relationship emerged between male athletes wearing red and winning the match (p = 0.034) under the manual scoring system. There were relationships between female athletes wearing blue and winning the match in the quarterfinal (p = 0.014) and last 16 rounds (p = 0.021) using the manual and electronic scoring systems respectively. In female athletes, relationships emerged between wearing blue and winning the match with small (p = 0.008) and medium (p = 0.047) asymmetry under the manual system and with large (p = 0.036) asymmetry under the electronic system. The electronic system had a positive impact on the fairness of Olympic competition. Red tends to gain in importance as the asymmetry between the two athletes decreases, but not enough to give a competitive advantage. The results for Olympic competition held in the now concluded era of the manual system confirmed the presence of the colour effect as a result of psychological factors attributable to referees and judges.


Gene repertoire of amoeba-associated giant viruses.
Acanthamoeba polyphaga mimivirus, Marseillevirus, and Sputnik, a virophage, are intra-amoebal viruses that have been isolated from water collected in cooling towers. They have provided fascinating data and have raised exciting questions about viruses definition and evolution. Mimivirus and Marseillevirus have been classified in the nucleo-cytoplasmic large DNA viruses (NCLDVs) class. Their genomes are the largest and fifth largest viral genomes sequenced so far. The gene repertoire of these amoeba-associated viruses can be divided into four groups: the core genome, genes acquired by lateral gene transfer, duplicated genes, and ORFans. Open reading frames (ORFs) that have homologs in the NCLDVs core gene set represent 2.9 and 6.1% of the Mimivirus and Marseillevirus gene contents, respectively. A substantial proportion of the Mimivirus, Marseillevirus and Sputnik ORFs exhibit sequence similarities to homologs found in bacteria, archaea, eukaryotes or viruses. The large amount of chimeric genes in these viral genomes might have resulted from acquisitions by lateral gene transfers, implicating sympatric bacteria and viruses with an intra-amoebal lifestyle. In addition, lineage-specific gene expansion may have played a major role in the genome shaping. Altogether, the data so far accumulated on amoeba-associated giant viruses are a powerful incentive to isolate and study additional strains to gain better understanding of their pangenome.


ANMCO/SIC/SICI-GISE/SICCH Executive Summary of Consensus Document on Risk Stratification in elderly patients with aortic stenosis before surgery or transcatheter aortic valve replacement.
Aortic stenosis is one of the most frequent valvular diseases in developed countries, and its impact on public health resources and assistance is increasing. A substantial proportion of elderly people with severe aortic stenosis is not eligible to surgery because of the advanced age, frailty, and multiple co-morbidities. Transcatheter aortic valve implantation (TAVI) enables the treatment of very elderly patients at high or prohibitive surgical risk considered ineligible for surgery and with an acceptable life expectancy. However, a significant percentage of patients die or show no improvement in quality of life (QOL) in the follow-up. In the decision-making process, it is important to determine: (i) whether and how much frailty of the patient influences the risk of procedures; (ii) how the QOL and the individual patient's survival are influenced by aortic valve disease or from other associated conditions; and (iii) whether a geriatric specialist intervention to evaluate and correct frailty or other diseases with their potential or already manifest disabilities can improve the outcome of surgery or TAVI. Consequently, in addition to risk stratification with conventional tools, a number of factors including multi-morbidity, disability, frailty, and cognitive function should be considered, in order to assess the expected benefit of both surgery and TAVI. The pre-operative optimization through a multidisciplinary approach with a Heart Team can counteract the multiple damage (cardiac, neurological, muscular, respiratory, and kidney) that can potentially aggravate the reduced physiological reserves characteristic of frailty. The systematic application in clinical practice of multidimensional assessment instruments of frailty and cognitive function in the screening and the adoption of specific care pathways should facilitate this task.


IgM-rheumatoid factors cross-reactive with IgG and a cell nuclear antigen: immunopathological implications?
The cross-reaction of IgM-rheumatoid factors (IgM-RF) with a cell nuclear antigen has been further investigated by immunofluorescence procedures. This reaction appears to be optimal at pH 8-9, and fails to occur at pH 6.5. No evidence was obtained by immunofluorescence that IgM-RF bound to the cell nuclear antigen fixes complement. It would appear that the nuclear reactivity of IgM-RF may be of limited immunopathological significance, though this reaction is of note in understanding the behavioural nature of rheumatoid factors.


Mediastinal Teratoma with Pulmonary Parenchyma Fistula: A Rare Diagnostic Endeavour.
Teratoma is the most frequent mediastinal germ cell tumour amongst young population. They are often detected due to pressure symptoms or as an incidental finding on chest X-ray done for any other reason. Mediastinal teratoma is usually benign and rarely possesses diagnostic or therapeutic challenge unless they rupture into surrounding viscera. In such scenario, they may lead to acute life threatening condition and need prompt diagnosis and surgical extirpation. Here, we are reporting our experience of managing a young lady, who presented with short duration breathing difficulty and cough, and was diagnosed with ruptured mediastinal teratoma on imaging, which was further confirmed intraoperatively and histopathologically.


[Esophageal mucoceles complicating double exclusion of the esophagus after ingestion of caustics].
A mucocele is rarely observed after esophageal exclusion for corrosive burns. It may represent a contra-indication to esophageal conservation in case of a total gastric resection for necrosis and perforation of the stomach. To evaluate this risk, 15 patients, operated between January 1970 and December 1988, were reviewed: they underwent total gastric resection with esophageal exclusion, followed by a secondary colon transplant between the cervical esophagus and the duodenum. A plain chest film was performed for 13 patients and a CT scan for 11 patients. Mean follow-up was 5.7 years (2 months - 17 years). Four patients died, one of them after resection of a compressive esophageal mucocele. Six mucoceles were detected on 13 chest films and 7 were described on 11 CT scans. On the whole, 8 mucoceles were diagnosed on 15 patients; one of them was complicated by tracheal compression. The formation of a secondary esophageal mucocele is a late sign of incomplete destruction of the esophageal wall. It is a frequent complication of esophageal exclusion performed after total gastrectomy for corrosive burns of the stomach. It must be detected on a chest film which shows the largest dilatations or on a CT scan, which is a better investigation. When the diameter of the mucocele is equal of superior to 50 mm, it can be compressive and must be treated by resection of internal diversion.


Molecular Mechanisms of the Anti-Obesity and Anti-Diabetic Properties of Flavonoids.
Obesity and diabetes are the most prevailing health concerns worldwide and their incidence is increasing at a high rate, resulting in enormous social costs. Obesity is a complex disease commonly accompanied by insulin resistance and increases in oxidative stress and inflammatory marker expression, leading to augmented fat mass in the body. Diabetes mellitus (DM) is a metabolic disorder characterized by the destruction of pancreatic β cells or diminished insulin secretion and action insulin. Obesity causes the development of metabolic disorders such as DM, hypertension, cardiovascular diseases, and inflammation-based pathologies. Flavonoids are the secondary metabolites of plants and have 15-carbon skeleton structures containing two phenyl rings and a heterocyclic ring. More than 5000 naturally occurring flavonoids have been reported from various plants and have been found to possess many beneficial effects with advantages over chemical treatments. A number of studies have demonstrated the potential health benefits of natural flavonoids in treating obesity and DM, and show increased bioavailability and action on multiple molecular targets. This review summarizes the current progress in our understanding of the anti-obesity and anti-diabetic potential of natural flavonoids and their molecular mechanisms for preventing and/or treating obesity and diabetes.


Aggressive pterygium growth and corneal scarring after hyperopic photorefractive keratectomy.
To describe a patient who noticed a corneal growth and accompanying rapid decrease in visual acuity soon after undergoing hyperopic photorefractive keratectomy (PRK). Interventional case report. A healthy 47-year-old white woman presented with a corneal growth after undergoing PRK. Visual acuity became progressively worse over 2 years. The growth transected the visual axis, measuring 180 μm centrally and 310 μm nasally. She underwent excisional biopsy, application of mitomycin C on the limbus and adjacent corneal tissue, and grafting with cryopreserved multilayer amniotic membrane. The pathologist reported findings consistent with pterygium. The patient initially experienced improvement in uncorrected visual acuity but then became noncompliant with topical steroids. The central anterior stroma became opacified to the extent of obscuring iris details. Best-corrected visual acuity at the last follow-up was 20/30. Because ultraviolet exposure is a risk factor for development and growth of pterygium, 1 possible explanation for this patient's findings is the effect of the excimer laser (which has a wavelength in the ultraviolet spectrum) on a previously insignificant corneal growth and/or the corneal limbal stem cells. Patients with corneal lesions suggestive of pterygia may be at increased risk for rapid lesion growth and aggressive corneal scarring after photorefractive keratectomy with a large ablation zone.


Comparison of three methods for the purification of the delta haemolysin of Staphylococcus aureus.
Three methods for the purification of Staphylococcus aureus delta haemolysin were compared (Kantor et al., 1972; Kreger et al., 1971; Heatley, 1971). The products of these purifications from the culture supernatant of S. aureus strain RN25 were compared by electrophoresis, amino acid analysis, amino-terminal sequence analysis and thin-layer chromatography. The method of Heatley (1971) was found to be superior in terms of recovery and purity of the product. Delta haemolysin prepared by the method of Kreger et al. (1971) could not be sequenced successfully prior to treatment aimed at the removal of the N-formyl group at the amino-terminus. Delta haemolysin appears to exist in two distinct molecular forms, one with N-formylmethionine and the other with un-formylated methionine in the amino-terminal position. The former polypeptide species is purified preferentially by the method of Kreger et al. (1971). Thin-layer chromatography of the products of each method of purification revealed that they were all heterogeneous, although the major component from the product of the method of Heatley (1971) represented not less than 70% of the product.


Intrahepatic and adrenal hemorrhage as a rare cause of neonatal anemia.
Vaginal delivery of the macrosomic fetus may result in hemorrhage of intra-abdominal organs. Mostly affected organs are the liver and adrenal glands. Hemorrhage of liver is usually occurs as a subcapsular hemorrhage and it is clinically presented an abdominal mass without symptoms of anemia. But intraparenchymal hemorrhage of liver is very rare and there is no sign of abdominal mass. However, in contrast to subcapsular hemorrhage, symptoms of anemia are rapidly developed in newborns. A macrosomic newborn by vaginal delivery at term. Within 6 h after delivery, the patient showed pallor without tachycardia and hypotension. In laboratory studies, hemoglobin level failed from 14 g/dL to 10 g/dL within 6 h. Physical examination revealed no signs of abdominal mass. Intraparenchymal hemorrhage in the sixth segment of liver and right adrenal hemorrhage were detected on the ultrasonographic scan. Hepatic function tests were normal in the whole follow-up period, and hemorrhage resolved within two weeks. Following months after discharge, adrenal hemorrhage also resolved without any complication. Hepatic hemorrhages, causing hemorrhagic anemia in neonates, usually occur in subcapsular form. Intraparenchymal hepatic hemorrhage should especially be considered in those newborns, which are rapidly developed symptoms of anemia without any abdominal mass.


[HIV transmission and risk behavior among drug addicts at a treatment institution in Copenhagen (Klub 47)].
From autumn 1985 until 31.12.1988, 127 drug addicts were examined for HIV-antibodies. Twenty-five (19.7%) were positive. No connection was found between age, sex and HIV-status. The incidence of positive test results fell from 32.8% in 1985/1986 to 0% in 1988. From autumn 1987, 49 drug addicts completed a questionnaire about risk behaviour as regards sharing syringes or needles during the month prior to commencement of treatment. Thirty-nine had no risk behaviour and the remainder very limited risk behaviour. The majority had reduced their risk behaviour on account of AIDS. Drug addicts have shown their will and abilities to reduce their risk behaviour. It is thus important to continue the informative efforts and prescription of syringes and needles. The therapeutic efforts should be extended with the object of preventing further infection in drug addicts and heterosexual and perinatal infection from the infected drug addicts.


The role of splanchnic congestion and the intestinal microenvironment in the pathogenesis of advanced heart failure.
Right-sided heart failure, which is often present in the setting of advanced heart failure, is associated with cardiac cachexia, the cardiorenal syndrome, and adverse outcomes. Improved understanding of venous congestion of the splanchnic circulation, which may play a key role in the pathogenesis of right-sided heart failure, could lead to novel therapeutics to ameliorate heart failure. Here we provide an overview of right-sided heart failure, splanchnic hemodynamics, fluid homeostasis, and the intestinal microenvironment. We review recent literature to describe pathophysiologic mechanisms and possible therapeutics. Several possible mechanisms centered around upregulation of sodium-hydrogen exchanger-3 (NHE3) may form a causal link between right ventricular dysfunction, splanchnic congestion, and worsening heart failure. These include an anaerobic environment in enterocytes, resulting in reduced intracellular pH; increased sodium absorption by the gut via NHE3; decreased pH at the intestinal brush border thus altering the gut microbiome profile; increased bacterial synthesis of trimethylamine N-oxide; and decreased bacterial synthesis of short-chain fatty acids causing abnormal intestinal barrier function. Splanchnic congestion in the setting of right-sided heart failure may serve an important role in the pathogenesis of advanced heart failure, and further exploration of these mechanisms may lead to new therapeutic advances.


Environment and primary biliary cirrhosis: electrophilic drugs and the induction of AMA.
Environmental stimulation is a major factor in the initiation and perpetuation of autoimmune diseases. We have addressed this issue and focused on primary biliary cirrhosis (PBC), an autoimmune disease of the liver. Immunologically, PBC is distinguished by immune mediated destruction of the intra hepatic bile ducts and the presence of high titer antimitochondrial autoantibodies (AMA) directed against a highly specific epitope within the lipoic acid binding domain of the pyruvate dehydrogenase E2 subunit (PDC-E2). We submit that the uniqueness of AMA epitope specificity and the conformational changes of the PDC-E2 lipoyl domain during physiological acyl transfer could be the lynchpin to the etiology of PBC and postulate that chemical xenobiotics modification of the lipoyl domain of PDC-E2 is sufficient to break self-tolerance, with subsequent production of AMA in patients with PBC. Indeed, using quantitative structure activity relationship (QSAR) analysis on a peptide-xenobiotic conjugate microarray platform, we have demonstrated that when the lipoyl domain of PDC-E2 was modified with specific synthetic small molecule lipoyl mimics, the ensuing structures displayed highly specific reactivity to PBC sera, at levels often higher than the native PDC-E2 molecule. Hereby, we discuss our recent QSAR analysis data on specific AMA reactivity against a focused panel of lipoic acid mimic in which the lipoyl di-sulfide bond are modified. Furthermore, data on the immunological characterization of antigen and Ig isotype specificities against one such lipoic acid mimic; 6,8-bis(acetylthio)octanoic acid (SAc), when compared with rPDC-E2, strongly support a xenobiotic etiology in PBC. This observation is of particular significance in that approximately one third of patients who have taken excessive acetaminophen (APAP) developed AMA with same specificity as patients with PBC, suggesting that the lipoic domain are a target of APAP electrophilic metabolites such as NAPQI. We submit that in genetically susceptible hosts, electrophilic modification of lipoic acid in PDC-E2 by acetaminophen or similar drugs can facilitate loss of tolerance and lead to the development of PBC.


Symptom clusters associated with complementary and alternative medicine use by cancer patients: A cross-sectional study.
Complementary and alternative medicine (CAM) is a commonly used approach among cancer patients, with a reported prevalence of 14.8 to 73.1% depending on multiple factors. Even though a typical patient-reported reason for using CAM is symptom control, no conclusive evidence could be established for specific symptoms being a predictor for CAM use. Symptom clusters are a novel approach for assessing a multidimensional symptom burden, reflecting the impact of diseases on the patient's quality of life and considering the tendency of symptoms to occur in groups. A single-center cross-sectional study on cancer patients during oncological or palliative care was conducted to identify socio-demographical and clinical characteristics, including symptom clusters of CAM users and non-users. Symptom clusters were defined using latent profile analysis, and multivariable analyses were performed to assess significant factors influencing CAM use. Of 171 cancer patients in this study, 63.7% used CAM alongside oncological treatment or palliative care. The most common CAM therapies were biological and physical therapies, including homeopathy (30.3%), supplements (27.4%), herbs (26.6%), massage (24.8%), and acupuncture (22.0%). Four distinct symptom clusters were identified, of which the cluster drowsiness-depression-anxiety was associated with a 3.83-fold increased chance of using CAM compared to low-symptomatic cancer patients. Multivariate analysis did not show any additional significant predictors of socio-demographical factors. Using the concept of symptom clusters revealed a significant predictor for CAM use, suggesting to be a more conclusive method for assessing symptom burden in cancer patients. In addition, understanding why and how cancer patients turn to CAM can enhance the quality of multidisciplinary communication about its use.


Treatment of arterial thromboembolic disease.
Prevention of thrombus formation and embolization remains a therapeutic challenge. Recent advances in the treatment of arterial thromboembolic disease include prevention of thromboembolism in patients with nonrheumatic atrial fibrillation with warfarin or aspirin, and combined therapy with low-dose aspirin, and anticoagulants for prosthetic heart valves and coronary artery disease. The potential of direct thrombin inhibition for treatment of acute coronary syndromes is also discussed.


Long-term morbidity after a negative sentinel node in breast cancer patients.
Morbidity after sentinel lymph node biopsy is often underestimated. The aim of this study was to inventory arm and shoulder complaints in sentinel node-negative breast cancer patients post-surgery after long-term follow-up. Sentinel node-negative breast cancer patients with at least 2 years of follow-up after surgery were included in this study. Self-reported arm and shoulder morbidities were assessed using a survey. Patients (n = 126) were asked if they ever developed complaints, if these complaints were still present and whether they were ever treated for these complaints. After a mean follow-up of 55.5 months (range 25-86 months), the prevalence of the self-reported arm and shoulder complaints was 25.8% for pain, 12.0% for numbness, 6.4% for paraesthesias, 7.1% for lymphedema, 8.0% for axillary web syndrome, 26.2% for loss of strength and 19.5% for limitations in range of motion. About 38.1% of the patients were treated by a physical therapist concerning the experienced complaints after SLNB. Up to 7 years post-surgery a considerable amount of sentinel node-negative patients still suffer from arm and shoulder complaints. These complaints affect the activities of daily living. Therefore, more research is needed regarding the value of early detection and treatment of these complaints.


The P2Y13 receptor regulates extracellular ATP metabolism and the osteogenic response to mechanical loading.
ATP release and subsequent activation of purinergic receptors has been suggested to be one of the key transduction pathways activated by mechanical stimulation of bone. The P2Y(13) receptor, recently found to be expressed by osteoblasts, has been suggested to provide a negative feedback pathway for ATP release in different cell types. Therefore, we hypothesized that the P2Y(13) receptor may contribute to the mediation of osteogenic responses to mechanical stimulation by regulating ATP metabolism by osteoblasts. To test this hypothesis, wild-type (WT) and P2Y(13) receptor knockout (P2Y(13)R-/-) mice were subject to non-invasive axial mechanical loading of the left tibiae to induce an osteogenic response. Micro-computed tomography analysis showed mechanical loading induced an osteogenic response in both strains of mice in terms of increased total bone volume and cortical bone volume, with the P2Y(13)R-/- mice having a significantly greater response. The extent of the increased osteogenic response was defined by dynamic histomorphometry data showing dramatically increased bone formation and mineral apposition rates in P2Y(13)R-/- mice compared with controls. In vitro, primary P2Y(13)R-/- osteoblasts had an accumulation of mechanically induced extracellular ATP and reduced levels of hydrolysis. In addition, P2Y(13)R-/- osteoblasts also had a reduction in their maximal alkaline phosphatase (ALP) activity, one of the main ecto-enzymes expressed by osteoblasts, which hydrolyzes extracellular ATP. In conclusion, deletion of the P2Y(13) receptor leads to an enhanced osteogenic response to mechanical loading in vivo, possibly because of the reduced extracellular ATP degradation by ALP. The augmented osteogenic response to mechanical stimulation, combined with suppressed bone remodeling activities and protection from OVX-induced bone loss after P2Y(13) receptor depletion as previously described, suggests a potential role for P2Y(13) receptor antagonist-based therapy, possibly in combination with mechanical loading, for the treatment of osteoporosis.


Application of the Combination of Soybean Lecithin and Whey Protein Concentrate 80 to Improve the Bile Salt and Acid Tolerance of Probiotics.
To improve the bile salt and acid tolerance of probiotics against gastrointestinal stresses, we investigated the effects of soybean lecithin and whey protein concentrate (WPC) 80 on the bile salt tolerance of Lacticaseibacillus paracasei L9 using a single-factor methodology, which was optimized using response surface methodology (RSM). The survival rate of L. paracasei L9 treated with 0.3% (w/v) bile salt for 2.5 h, and combined with soybean lecithin or WPC 80, was lower than 1%. After optimization, the survival rate of L. paracasei L9 incubated in 0.3% bile salt for 2.5 h reached 52.5% at a ratio of 0.74% soybean lecithin and 2.54% WPC 80. Moreover, this optimized method improved the survival rate of L. paracasei L9 in low pH condition and can be applied to other lactic acid bacteria (LAB) strains. Conclusively, the combination of soybean lecithin and WPC 80 significantly improved the bile salt and acid tolerance of LAB. Our study provides a novel approach for enhancing the gastrointestinal tolerance of LAB by combining food-derived components that have different properties.


Effects of hormonal contraceptive use on HIV acquisition and transmission among HIV-discordant couples.
The risk of HIV associated with hormonal contraceptives is controversial. We assessed hormonal contraceptive use and HIV incidence in HIV-discordant couples in Rakai, Uganda. HIV-discordant couples were retrospectively identified from a cohort between 1999 and 2009. Hormonal contraception included oral contraception, depomedroxyprogesterone acetate (DMPA), and implants (Norplant). Poisson regression estimated adjusted incidence rate ratios (adjIRRs) associated with hormonal contraceptive methods. A case-control subanalysis estimated odds ratios (ORs) of HIV associated with hormonal contraceptive, adjusted for viral load and age. We identified 190 male HIV-positive/female HIV-negative (M+F-) and 159 male HIV- negative/female HIV-positive (M-F+) couples not using antiretroviral therapy or condoms. Female HIV incidence was 5.8/100 person-years (py) among nonhormonal contraceptive users, 12.0/100 py among oral contraceptive users [adjIRR 2.65, 95% confidence interval (CI) 0.82-8.60], 4.5 among Norplant users (adjIRR: 0.89, 95% CI 0.11-7.10), and 7.5/100 py among DMPA users (adjIRR 1.42, 95% CI 0.60-3.36). Male HIV incidence was 7.4/100 py during nonhormonal contraceptive use, 16.5/100 py during female oral contraceptive use (adjIRR 2.52, 95% CI 0.49-12.95), and 4.9/100 py with DMPA use (adjIRR 0.57, 95% CI 0.19-1.70). The number of female seroconverters was three among oral contraceptive users, one among Norplant users, and seven among DMPA users. Male seroconverters were two during female oral contraceptive use, none with Norplant use, and three with DMPA use. In a nested case-control analysis after adjustment for HIV viral load, the adjOR associated with oral contraceptive use was 1.59 (95% CI 0.32-97.85) for M+F- and 2.11 (95% CI 0.18-25.26) for M-F+ couples. For DMPA use, the adjOR was 1.44 (95% CI 0.46-4.51) for M+F- and 1.40 (95% CI 0.30-6.49) for M-F+ couples. We did not observe significant risk of HIV acquisition or transmission with oral contraceptives or DMPA use in HIV discordant couples, but several point estimates were above 1.0 and statistical power was limited.


Asylum-seekers' experiences of trauma-focused cognitive behaviour therapy for post-traumatic stress disorder: a qualitative study.
Trauma-focused CBT (TFCBT) is an evidence-based treatment for posttraumatic stress disorder (PTSD), but little is known about whether it is an acceptable and effective treatment for asylum-seekers presenting with PTSD. This study considers the acceptability of TFCBT for asylum-seekers with PTSD by exploring their experiences of this treatment. Seven asylum-seekers who had received CBT involving a TFCBT component were interviewed using a semi-structured schedule. The transcribed interviews were analysed using interpretative phenomenological analysis (IPA). Interpretative themes were developed iteratively to closely reflect participants' common and distinct experiences. Six super-ordinate interlinking themes are discussed: Staying where you are versus engaging in therapy; Experiences encouraging engagement in therapy; Experiences impeding engagement in therapy; Importance of the therapeutic relationship; "Losing oneself" and "Regaining life". Participants described their ambivalence about engaging in TFCBT. Such treatment was experienced as very challenging, but most participants also reported finding it helpful. Various experiences that appeared to encourage or impede engagement are outlined. These preliminary findings suggest that fear of repatriation can impede engagement in TFCBT, but that some asylum-seekers with PTSD still report finding TFCBT beneficial. The clinical implications are discussed, including the special importance of the therapeutic relationship.


Potentials of two-photon based 3-D optical memories for high performance computing.
The advent of optoelectronic computers and highly parallel electronic processors has brought about a need for storage systems with enormous memory capacity and memory bandwidth. These demands cannot be met with current memory technologies (i.e., semiconductor, magnetic, or optical disk) without having the memory system completely dominate the processors in terms of the overall cost, power consumption, volume, and weight. As a solution, we propose an optical volume memory based on the two-photon effect which allows for high density and parallel access. In addition, the two-photon 3-D memory system has the advantages of having high capacity and throughput which may overcome the disadvantages of current memories.


Transcription mapping of the Escherichia coli chromosome by electron microscopy.
The distinctive double Christmas tree morphology of rRNA operons as visualized by electron microscopy makes them easy to recognize in chromatin spreads from Escherichia coli. On the basis of the pattern of nascent transcripts on nearby transcription units and the relative distances of the operons from one another and the replication origin, we are now able to specifically identify five of the seven rRNA operons in E. coli. The use of rRNA operons as markers of both position and distance has resulted in the morphological mapping of a significant portion of the E. coli chromosome; over 600 kilobase pairs in the 84- to 90-min and 72-min regions can now be recognized. Since individual rRNA operons could be identified, direct comparisons could be made of their transcriptional activities. As judged by the densities of RNA polymerases along the operons, rrnA, rrnB, rrnC, rrnD, and rrnE were all transcribed at similar levels, with one RNA polymerase every 85 base pairs. The ability to recognize individual operons and specific regions of the chromosome allows direct comparisons of various genetic parameters.


Self-audits. First step in TQM.
In the fall of 1987, West Paces Medical Center (WPMC), a 294-bed hospital in Atlanta, made a commitment to a new way of management, one that would make it a learning organization. The commitment would not be just to a higher quality of service, but would be a change in the way of doing business. The three components included in the hospital's quality improvement process were customer mindedness, process mindedness and statistical mindedness. West Paces employees concentrated on understanding customers and their needs, learning how they should perform each day to satisfy those needs, and routinely measuring the improvements made in daily processes. Led by Vicki S. Davis, director of quality resources, WPMC implemented, in November 1987, a program based on W. Edwards Deming's quality management method. One year later, 54 department managers had been trained in quality improvement. Davis shares her account of the quality improvement process on the following pages.


Lack of effects of lesions of the dorsal noradrenergic bundle on behavioral vigilance.
The effects of 6-hydroxydopamine (6-OHDA)-induced lesions of the dorsal noradrenergic bundle (DNB) were assessed in animals trained in a task designed to measure sustained attention, or vigilance. Infusions of 6-OHDA reduced frontal cortical noradrenaline contents but did not significantly affect striatal and hypothalamic noradrenaline contents. The performance of lesioned animals did not differ significantly from sham-lesioned controls. The performance of both the lesioned and sham-lesioned animals was impaired by the presentation of a visual distractor and by a decrease in the probability for a signal. The results from this study largely coincide with the results from previous studies on the effects of noradrenergic lesions on various aspects of attention. In contrast to the attentional functions assessed in this experiment, the ability to detect and select stimuli that are associated with activation of sympathetic functions is hypothesized to be sensitive to the effects of DNB lesions.