Protein disulfide isomerase inhibition synergistically enhances the efficacy of sorafenib for hepatocellular carcinoma.
Sorafenib is the only approved targeted drug for hepatocellular carcinoma (HCC), but its effect on patients' survival gain is limited and varies over a wide range depending on pathogenetic conditions. Thus, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCCs. In this study, we utilized a systems approach by combining transcriptome analysis of the mRNA changes in HCC cell lines in response to sorafenib with network analysis to investigate the action and resistance mechanism of sorafenib. Gene list functional enrichment analysis and gene set enrichment analysis revealed that proteotoxic stress and apoptosis modules are activated in the presence of sorafenib. Further analysis of the endoplasmic reticulum stress network model, combined with in vitro experiments, showed that introducing an additional stress by treating the orally active protein disulfide isomerase (PDI) inhibitor (PACMA 31) can synergistically increase the efficacy of sorafenib in vitro and in vivo, which was confirmed using a mouse xenograft model. We also found that HCC patients with high PDI expression show resistance to sorafenib and poor clinical outcomes, compared to the low-PDI-expression group. These results suggest that PDI is a promising therapeutic target for enhancing the efficacy of sorafenib and can also be a biomarker for predicting sorafenib responsiveness. (Hepatology 2017;66:855-868).


Effects of somatostatin and testosterone on the hepatic monooxygenase system in castrated male rats.
In male rats exogenous growth hormone (GH) (5 mg . kg-1, twice a day for 7 days) reduced (p less than 0.05) the in vitro hepatic microsomal metabolism of ethylmorphine (EM) and hexobarbital (HB) by 59 and 33%; aniline (AN) metabolism and microsomal P-450 levels were unaltered but GH reduced (p less than 0.001) NADPH-cytochrome c reductase by 17%. GH had no effects in females. Castrated males receiving subreplacement doses of testosterone propionate (2 mg, three times weekly) were injected (280 micrograms . kg-1, three times a day for 4 days) with somatostatin (SS), an inhibitor of GH release: EM and HB metabolism was increased (p less than 0.01) 8 and 18%; AN hydroxylation and P-450 levels were unchanged; the reductase was elevated (p less than 0.01) 9%. In nonandrogenized castrates, SS effected greater changes: EM and HB metabolism was increased (p less than 0.01) 47 and 21%; AN metabolism and P-450 levels were unchanged; the reductase was increased (p less than 0.01) 27%. Conversely, SS had no effects in intact males at doses up to 1120 micrograms . kg-1, three times a day for 4 days. These data support the view that endogenous GH is a modulator of "feminized" drug metabolism in the adult male and that it is antagonized by testosterone. Attempts to inhibit drug metabolism with SS in the female were unsuccessful and may reflect the ineffectiveness of the preparations as they failed to inhibit growth in young rats.(ABSTRACT TRUNCATED AT 250 WORDS)


"Understanding AIDS"--the national AIDS mailer.
The Centers for Disease Control (CDC) of the Public Health Service made public health history in 1988 by mailing the pamphlet, "Understanding AIDS," to every household in the United States. Approximately 126 million copies were distributed, reaching at least 60 percent of the population according to several national polls. The pamphlet was produced and mailed at a cost of about 20 cents per copy. The impact of "Understanding AIDS" by itself on AIDS-related behavior was not fully assessed. Extensive message pretesting and other commercial marketing techniques to improve the effectiveness of the brochure, however, helped "Understanding AIDS" achieve an increase in awareness and concern about AIDS. A number of lessons were learned during the process. They included the importance in such an enterprise of setting a deadline, doing formative research, receiving active support from senior management, achieving a consensus on scientific knowledge, using communications experts, centralizing the final decision-making function, maximizing publicity surrounding the mailing, building a base of support among constituency groups, planning distribution logistics from the very start, and designing evaluation into the process from the beginning.


Why Is There No Cure for Tinnitus?
Tinnitus is unusual for such a common symptom in that there are few treatment options and those that are available are aimed at reducing the impact rather than specifically addressing the tinnitus percept. In particular, there is no drug recommended specifically for the management of tinnitus. Whilst some of the currently available interventions are effective at improving quality of life and reducing tinnitus-associated psychological distress, most show little if any effect on the primary symptom of subjective tinnitus loudness. Studies of the delivery of tinnitus services have demonstrated considerable end-user dissatisfaction and a marked disconnect between the aims of healthcare providers and those of tinnitus patients: patients want their tinnitus loudness reduced and would prefer a pharmacological solution over other modalities. Several studies have shown that tinnitus confers a significant financial burden on healthcare systems and an even greater economic impact on society as a whole. Market research has demonstrated a strong commercial opportunity for an effective pharmacological treatment for tinnitus, but the amount of tinnitus research and financial investment is small compared to other chronic health conditions. There is no single reason for this situation, but rather a series of impediments: tinnitus prevalence is unclear with published figures varying from 5.1 to 42.7%; there is a lack of a clear tinnitus definition and there are multiple subtypes of tinnitus, potentially requiring different treatments; there is a dearth of biomarkers and objective measures for tinnitus; treatment research is associated with a very large placebo effect; the pathophysiology of tinnitus is unclear; animal models are available but research in animals frequently fails to correlate with human studies; there is no clear definition of what constitutes meaningful change or "cure"; the pharmaceutical industry cannot see a clear pathway to distribute their products as many tinnitus clinicians are non-prescribing audiologists. To try and clarify this situation, highlight important areas for research and prevent wasteful duplication of effort, the British Tinnitus Association (BTA) has developed a Map of Tinnitus. This is a repository of evidence-based tinnitus knowledge, designed to be free to access, intuitive, easy to use, adaptable and expandable.


ICN--past and present.
When Dame Sheila Quinn became director of ICN's newly established Social and Economic Welfare Division in 1961, Daisy Bridges retired as general secretary, only to emerge later on as an ICN historian. It was during the years that Bridges spent delving into ICN archives that Quinn passed many hours with her reminiscing about ICN's fascinating past. Quinn's interest in ICN's history grew when she became executive director and was later refueled by her eight years on the ICN Board. Quinn's real chance came when the Board in 1985 gave her a new assignment: updating ICN's history, the result being ICN--Past and Present, which was launched at the 19th Quadrennial Congress in Seoul in 1989. Below, her reflections.


Mechanism of threshold size assessment: Metamorphosis is triggered by the TGF-beta/Activin ligand Myoglianin.
Although the mechanisms that control growth are now well understood, the mechanism by which animals assess their body size remains one of the great puzzles in biology. The final larval instar of holometabolous insects, after which growth stops and metamorphosis begins, is specified by a threshold size. We investigated the mechanism of threshold size assessment in the tobacco hornworm, Manduca sexta. The threshold size was found to change depending on the amount of exposure to poor nutrient conditions whereas hypoxia treatment consistently led to a lower threshold size. Under these various conditions, the mass of the muscles plus integuments was correlated with the threshold size. Furthermore, the expression of myoglianin (myo) increased at the threshold size in both M. sexta and Tribolium castaneum. Knockdown of myo in T. castaneum led to larvae that underwent supernumerary larval molts and stayed in the larval stage permanently even after passing the threshold size. We propose that increasing levels of Myo produced by the growing tissues allow larvae to assess their body size and trigger metamorphosis at the threshold size.


Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex.
Neurotrophins (NTs) are important regulators for the survival, differentiation and maintenance of different peripheral and central neurons. NTs bind to two distinct classes of glycosylated receptor: the p75 neurotrophin receptor (p75(NTR)) and tyrosine kinase receptors (Trks). Whereas p75(NTR) binds to all NTs, the Trk subtypes are specific for each NT. The question of whether NTs stimulate p75(NTR) by inducing receptor homodimerization is still under debate. Here we report the 2.6-A resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75(NTR). In contrast to the previously reported asymmetric complex structure, which contains a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75(NTR) (ref. 3), we show that NT-3 forms a central homodimer around which two glycosylated p75(NTR) molecules bind symmetrically. Symmetrical binding occurs along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand-receptor interactions and p75(NTR) conformations. Biochemical experiments indicate that both NT-3 and NGF bind to p75(NTR) with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. We therefore propose that the symmetrical 2:2 complex reflects a native state of p75(NTR) activation at the cell surface. These results provide a model for NTs-p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and Trks.


Entamoeba histolytica in male homosexuals.
The mobility patterns of four enzymes using cultured trophozoites of Entamoeba histolytica were examined by electrophoresis. By this means the stocks of amoebae isolated from male homosexuals were characterised into zymodemes. No amoebic stock isolated corresponded to a pathogenic zymodeme.


Increased anxiety in corticotropin-releasing factor type 2 receptor-null mice requires recent acute stress exposure and is associated with dysregulated serotonergic activity in limbic brain areas.
Corticotropin-releasing factor type 2 receptors (CRFR2) are suggested to facilitate successful recovery from stress to maintain mental health. They are abundant in the midbrain raphe nuclei, where they regulate serotonergic neuronal activity and have been demonstrated to mediate behavioural consequences of stress. Here, we describe behavioural and serotonergic responses consistent with maladaptive recovery from stressful challenge in CRFR2-null mice. CRFR2-null mice showed similar anxiety levels to control mice before and immediately after acute restraint stress, and also after cessation of chronic stress. However, they showed increased anxiety by 24 hours after restraint, whether or not they had been chronically stressed.Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) contents were quantified and the level of 5-HIAA in the caudal dorsal raphe nucleus (DRN) was increased under basal conditions in CRFR2-null mice, indicating increased 5-HT turnover. Twenty-four hours following restraint, 5-HIAA was decreased only in CRFR2-null mice, suggesting that they had not fully recovered from the challenge. In efferent limbic structures, CRFR2-null mice showed lower levels of basal 5-HT in the lateral septum and subiculum, and again showed a differential response to restraint stress from controls.Local cerebral glucose utilization (LCMRglu) revealed decreased neuronal activity in the DRN of CRFR2-null mice under basal conditions. Following 5-HT receptor agonist challenge, LCMRglu responses indicated that 5-HT1A receptor responses in the DRN were attenuated in CRFR2-null mice. However, postsynaptic 5-HT receptor responses in forebrain regions were intact. These results suggest that CRFR2 are required for proper functionality of 5-HT1A receptors in the raphe nuclei, and are key to successful recovery from stress. This disrupted serotonergic function in CRFR2-null mice likely contributes to their stress-sensitive phenotype. The 5-HT content in lateral septum and subiculum was notably altered. These areas are important for anxiety, and are also implicated in reward and the pathophysiology of addiction. The role of CRFR2 in stress-related psychopathologies deserves further consideration.


Predictors of toxicity associated with stereotactic body radiation therapy to the central hepatobiliary tract.
To identify dosimetric predictors of hepatobiliary (HB) toxicity associated with stereotactic body radiation therapy (SBRT) for liver tumors. We retrospectively reviewed 96 patients treated with SBRT for primary (53%) or metastatic (47%) liver tumors between March 2006 and November 2013. The central HB tract (cHBT) was defined by a 15-mm expansion of the portal vein from the splenic confluence to the first bifurcation of left and right portal veins. Patients were censored for toxicity upon local progression or additional liver-directed therapy. HB toxicities were graded according to Common Terminology Criteria for Adverse Events version 4.0. To compare different SBRT fractionations, doses were converted to biologically effective doses (BED) by using the standard linear quadratic model α/β = 10 (BED10). Median follow-up was 12.7 months after SBRT. Median BED10 was 85.5 Gy (range: 37.5-151.2). The median number of fractions was 5 (range: 1-5), with 51 patients (53.1%) receiving 5 fractions and 29 patients (30.2%) receiving 3 fractions. In total, there were 23 (24.0%) grade 2+ and 18 (18.8%) grade 3+ HB toxicities. Nondosimetric factors predictive of grade 3+ HB toxicity included cholangiocarcinoma (CCA) histology (P<.0001), primary liver tumor (P=.0087), and biliary stent (P<.0001). Dosimetric parameters most predictive of grade 3+ HB toxicity were volume receiving above BED10 of 72 Gy (VBED1072) ≥ 21 cm(3) (relative risk [RR]: 11.6, P<.0001), VBED1066 ≥ 24 cm(3) (RR: 10.5, P<.0001), and mean BED10 (DmeanBED10) cHBT ≥14 Gy (RR: 9.2, P<.0001), with VBED1072 and VBED1066 corresponding to V40 and V37.7 for 5 fractions and V33.8 and V32.0 for 3 fractions, respectively. VBED1072 ≥ 21 cm(3), VBED1066 ≥ 24 cm(3), and DmeanBED10 cHBT ≥14 Gy were consistently predictive of grade 3+ toxicity on multivariate analysis. VBED1072, VBED1066, and DmeanBED10 to cHBT are associated with HB toxicity. We suggest VBED1072 < 21 cm(3) (5-fraction: V40 < 21 cm(3); 3-fraction: V33.8 < 21 cm(3)), VBED1066 < 24 cm(3) (5-fraction: V37.7 < 24 cm(3); 3-fraction: V32 < 24 cm(3)) as potential dose constraints for the cHBT when clinically indicated.


Posttraumatic stress disorder and the use of general health services in postwar Kosovo.
Studies conducted in high-income countries have demonstrated that posttraumatic stress symptoms are positively correlated with increased use of general health services; however, comparative data are lacking in postwar settings. This survey was conducted in Kosovo after the end of the conflict; 996 people, age 16 or older, were interviewed. Older age, lower education level, worse physical health, and current diagnosis of posttraumatic stress disorder (PTSD) were associated with higher use of any health services. After adjusting for gender, age, place of residence, type of education, poverty, refugee status, and subjective physical health, PTSD remained associated with an increased use of most health care services. Our results underline the importance of taking into account PTSD when restoring health services in postwar countries.


Potential risk of drug-drug interactions with hormonal contraceptives and antiretrovirals: prevalence in women living with HIV.
Family planning services are vital for women living with HIV (WLH); however, the use of concomitant antiretroviral therapy (ART) and hormonal contraceptives (HCs) may pose challenges due to the risk of potential drug-drug interactions (DDIs). The objectives of this study were to assess ART and HC use among WLH and quantify the frequency of potential DDIs between ART and HCs. This was a retrospective, observational, cohort study of WLH aged 18-55 years, prescribed ART, with at least one clinic visit from January 1, 2010 to April 30, 2014. Potential DDIs between HCs and ART were assessed using the University of Liverpool HIV Drug Interactions website (www.hiv-druginteractions.org) and categorized as 'weak potential interaction,' 'potential interaction,' or 'do not co-administer.' Overall, a contraceptive method was reported in 167 (54%) of the 309 women included in the study. Of those using contraception, 73 (43.7%) reported using HCs, which was most frequently a progestin intrauterine device (n=43), progestin injection (n=17), or combination oral contraceptive pills (n=9). Out of a total of 449 ART regimens, a potential DDI was identified in 21 of 115 (18.3%) ART-HC combinations from 19 women using ART and HCs. Atazanavir/ritonavir was the most common potentially interacting ART (10, 47.6%); for HCs, these were combination oral contraceptive pills (16, 76.2%) and progestin implants (2, 9.5%). In this cohort, one-quarter of WLH on ART-HCs had a potential DDI. Future studies should investigate the impact of DDIs on unintended pregnancies, the side effects of DDIs, and the effects of HC DDIs on ART concentrations.


A negative association between plasma phylloquinone and all-cause mortality in Chinese adults with hypertension: a nested case-control study.
Previous studies have revealed that vitamin K is essential for preventing various chronic diseases. Phylloquinone is the primary dietary and circulating form of vitamin K. However, data concerning the association between plasma phylloquinone and all-cause mortality are limited. This study aimed to evaluate the association between plasma phylloquinone and the risk of all-cause mortality, and examine some potential confounders. This study is a post hoc analysis of the RCT and a nested, case-control design was used. Enrolled participants had to have hypertension at baseline. Study initiation was May 19, 2008, and the median follow-up was 4.5 years. A total of 604 mortality cases and 604 controls matched for age, sex, treatment group, and study site were included in this study. Odds ratios (OR) and 95% confidence intervals (CI) of all-cause mortality were calculated using conditional or unconditional logistic regression, without or with adjusting for pertinent covariates, respectively. The concentration of phylloquinone was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The mean and median phylloquinone levels were 1.62 nmol/L and 0.89 nmol/L, respectively. There was a significant negative association between log-transformed plasma phylloquinone and all-cause mortality after controlling for potential confounders (per 1 unit increase-OR: 0.79; 95% CI: 0.66-0.95). Furthermore, the association of plasma phylloquinone with the risk of all-cause mortality differed by body mass index (BMI) (<25 kg/m2 vs. ≥25 kg/m2, P-interaction=0.004). A significant trend of decreasing risk with increasing concentration of phylloquinone was observed in participants with higher BMI (per 1 unit increase-OR: 0.71; 95%CI: 0.56-0.90; P=0.004). No significant correlation was found between phylloquinone and the risk of all-cause mortality in those with BMI<25 kg/m2. In Chinese patients with hypertension, there was a significant negative association between baseline plasma phylloquinone and all-cause mortality, especially among those with higher BMI.


Lack of effect of atrial natriuretic peptide on vasopressin release.
This study was designed to investigate the effects of intracerebroventricular or intravenous atrial natriuretic peptide (ANP) on plasma arginine-vasopressin (AVP) levels, plasma renin activity (PRA), blood pressure (BP) and heart rate (HR) in conscious rats. No changes were observed in plasma AVP levels and PRA after intracerebroventricular injection of ANP (0.3 nmol/kg). Also no changes were found in BP and HR after intracerebroventricular ANP injection in the dose range 0.01-0.3 nmol/kg. No significant changes were observed in plasma AVP levels after the intravenous administration of ANP at 2.5 nmol/kg to hydrated rats or at 0.1 nmol/kg and 2.5 nmol/kg to dehydrated rats, although the larger dose was sufficient to cause a small fall in BP. Even after 30 min intravenous infusion of ANP at 0.1 nmol min-1 kg-1, a dose sufficient to produce very high plasma ANP levels, no change in plasma AVP could be detected, although haemodynamic changes were observed. Intravenous ANP injection (2.5 nmol/kg) inhibited basal renin secretion in hydrated rats and also inhibited renin secretion which had been stimulated by prior dehydration. From these studies in hydrated and dehydrated rats, there was no evidence that either intracerebroventricular or intravenous ANP administration affected AVP release in vivo.


Care of the skin at midlife: diagnosis of pigmented lesions.
Intrinsic skin changes with advancing years include dryness, decreasing elasticity, increasing skin fragility, and more prominent vasculature. Extrinsic skin aging, caused primarily by cigarette smoking and exposure to sunlight, includes mottled pigmentation and yellow discoloration, rough leathery textural changes, and wrinkling. Major premalignant and malignant neoplasms in photodamaged skin are actinic keratosis, basal cell carcinoma, squamous cell carcinoma, and melanoma. Nonmalignant lesions include solar lentigines and seborrheic keratoses. The A, B, C, D criteria can assist in the evaluation of pigmented nevi. Physicians play an important role in educating patients about the health risks associated with excessive sun exposure and about sun protection to prevent further skin damage.


Everything is not everywhere: can marine compartments shape phytoplankton assemblages?
The idea that 'everything is everywhere, but the environment selects' has been seminal in microbial biogeography, and marine phytoplankton is one of the prototypical groups used to illustrate this. The typical argument has been that phytoplankton is ubiquitous, but that distinct assemblages form under environmental selection. It is well established that phytoplankton assemblages vary considerably between coastal ecosystems. However, the relative roles of compartmentalization of regional seas and site-specific environmental conditions in shaping assemblage structures have not been specifically examined. We collected data from coastal embayments that fall within two different water compartments within the same regional sea and are characterized by highly localized environmental pressures. We used principal coordinates of neighbour matrices (PCNM) and asymmetric eigenvector maps (AEM) models to partition the effects that spatial structures, environmental conditions and their overlap had on the variation in assemblage composition. Our models explained a high percentage of variation in assemblage composition (59-65%) and showed that spatial structure consistent with marine compartmentalization played a more important role than local environmental conditions. At least during the study period, surface currents connecting sites within the two compartments failed to generate sufficient dispersal to offset the impact of differences due to compartmentalization. In other words, our findings suggest that, even for a prototypical cosmopolitan group, everything is not everywhere.


To Advance Population Health, We Need to Be "Well Behaved": The Science of Health Behaviour Change.
As technological innovations continue to be developed and introduced within healthcare, public health, and our daily lives, human beings now have access to sophisticated and powerful tools that could be used in a variety of ways to change health behaviours. Information and communications technology (ICT) features prominently among 21st century innovations, and we must consider how they may be used to help or hinder our efforts to address population health challenges. There are numerous relevant challenges that need to be addressed within healthcare, public health, and other areas relevant to population health. The Australian population is aging (increasing in both the absolute number, and also proportion of older adults), along with having greater levels of obesity, diabetes, cardiovascular diseases, cancers, and other chronic diseases that will take a large toll on Australia. There are many lifestyle determinants of chronic disease that could potentially be addressed through ICT-based intervention efforts to improve diet, physical activity, alcohol, tobacco, sleep, and sexual behaviour. Challenges also include better delivery of what innovations or interventions have been shown to work, how we can best help those who need help the most, and how to implement policy, systems, or environmental interventions that can help to make healthy behaviours more convenient, attractive, and normative. As the name suggests, ICT involves any technology that allows us to store, retrieve, manipulate, transmit, or receive information electronically in a digital form. Although such technologies may allow us to reach more people than we could without them, and to do so in more rapid manner, with better geographic reach than ever before, ICT does not automatically provide any advantage in addressing the key drivers of health behaviour. Information itself could be useful-but is almost never sufficient-to facilitate health behaviour change; rather, information must instead be placed within the context of the key drivers of behaviour change. These drivers can be described most simply as factors that enhance people's capability, opportunity, and motivation to engage in health promoting behaviour, or their obverse, behaviours that undermine health. Beyond the storage, retrieval, manipulation, transmission, or receipt of information, we must ensure that key drivers of behaviour are built into ICT approaches. Understanding, predicting, and influencing human behaviour is crucially important if we aim to address relevant population health challenges, and to achieve better health and wellness within populations. In other words, if we want to be well, we need to be "well behaved." Illustrative examples will be shared from the author's research studies, primarily focused on motivating and building the capability of adult leaders to provide better opportunities for children to be physically active, eat healthfully, and to establish health promoting habits. These studies range from interventions set in girl scouts, schools, and whole communities, with a variety of ICT approaches.


Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection.
We examined the longitudinal effects of primary HIV infection (PHI) and responses to early antiretroviral therapy (ART) on the brain using high-field magnetic resonance spectroscopy (MRS). Cerebral metabolites were measured longitudinally with 4T proton MRS and assessed for ART effects in participants with PHI. Levels of glutamate (Glu), N-acetylaspartate (NAA), myo-inositol (MI), and choline-containing metabolites (Cho) were measured relative to creatine + phosphocreatine (Cr) in anterior cingulate, basal ganglia, frontal white matter, and parietal gray matter. Fifty-three participants recruited at median 3.7 months post HIV transmission were followed a median 6.0 months. A total of 23 participants initiated ART during follow-up. Prior to ART, increases per month were observed in Cho/Cr (slope = 0.0012, p = 0.005) and MI/Cr (slope = 0.0041, p = 0.005) in frontal white matter as well as increases in MI/Cr (slope = 0.0041, p < 0.001) and NAA/Cr (slope = 0.0024, p = 0.030) in parietal gray matter. After initiation of ART, prior positive slopes were no longer significantly different from zero, while Glu/Cr in basal ganglia decreased (slope = -0.0038, p = 0.031). Early in HIV infection, increases of Cho/Cr and MI/Cr in treatment-naive participants suggest progressive inflammation and gliosis in the frontal white matter and parietal gray matter, which is attenuated after initiation of ART. Elevated baseline Glu/Cr in basal ganglia may signal excitotoxicity; its subsequent stabilization and downward trajectory with ART may lend further support for early ART initiation.


Formulation and in vitro, in vivo evaluation of extended- release matrix tablet of zidovudine: influence of combination of hydrophilic and hydrophobic matrix formers.
The aim of the present study was to prepare and characterize extended-release matrix tablets of zidovudine using hydrophilic Eudragit RLPO and RSPO alone or their combination with hydrophobic ethyl cellulose. Release kinetics was evaluated by using United States Pharmacopeia (USP)-22 type I dissolution apparatus. Scanning electron microscopy was used to visualize the effect of dissolution medium on matrix tablet surface. Furthermore, the in vitro and in vivo newly formulated sustained-release zidovudine tablets were compared with conventional marketed tablet (Zidovir, Cipla Ltd, Mumbai, India). The in-vitro drug release study revealed that either Eudragit preparation was able to sustain the drug release only for 6 hours (94.3% +/- 4.5% release). Combining Eudragit with ethyl cellulose sustained the drug release for 12 hours (88.1% +/- 4.1% release). Fitting the in vitro drug release data to Korsmeyer equation indicated that diffusion along with erosion could be the mechanism of drug release. In vivo investigation in rabbits showed sustained-release pharmacokinetic profile of zidovudine from the matrix tablets formulated using combination of Eudragits and ethylcellulose. In conclusion, the results suggest that the developed sustained-release tablets of zidovudine could perform therapeutically better than conventional dosage forms, leading to improve efficacy and better patient compliance.


Mild hypoglycemia and impairment of brain stem and cortical evoked potentials in healthy subjects.
To evaluate the impact of mild hypoglycemia on CNS function in healthy adults, we measured brain stem auditory evoked potentials and P300 potentials (elicited by cognitive processing of auditory stimuli) during hypoglycemic or euglycemic insulin clamps (80 mU.m-2.min-1). In the hypoglycemic clamp study (n = 8), plasma glucose was allowed to fall from 4.6 to 3 mM in hourly approximately 0.5-mM steps and subsequently returned to euglycemic baseline levels. In the euglycemic clamp study (n = 8), plasma glucose was maintained at baseline levels throughout. Neither brain stem nor P300 responses changed during the euglycemic control study; symptoms and counterregulatory hormones were also unaffected. During the hypoglycemia study, epinephrine and growth hormone rose once plasma glucose reached 3.4 +/- 0.1 mM. Brain stem and P300 potentials remained unchanged until the 3-mM glucose step, when neurophysiological changes suddenly developed in conjunction with reported symptoms. At this glucose level, the wave V component of the brain stem potential was selectively altered in 7 of 8 subjects. Furthermore, P300 latency significantly increased, and amplitude diminished. Changes in both brain stem and cortical (P300) responses reversed when euglycemia was restored. We conclude that modest reductions in plasma glucose (to 3 mM) produce marked alterations in both brain stem and cortical responses to auditory stimuli. These changes in neural function appear at the same time as symptoms and follow rather than precede the rise in counterregulatory hormones during hypoglycemia. Our data suggest that the adverse effects of mild hypoglycemia on brain function are not limited to higher centers but also involve the brain stem.


Three-dimensional analysis of dental casts based on a newly defined palatal reference plane.
The purpose of this study was to establish a new method for orthodontic diagnosis that integrates the three-dimensional (3-D) shape of a dental cast and the craniofacial morphology using a newly defined palatal reference plane. We also measured the accuracy of this new palatal reference plane as a reference for measurement and its spatial relationship to the framework of the craniofacial skeleton using lateral and frontal cephalometric radiography and maxillary dental casts, which were transferred using an anatomical face-bow. Eighteen female subjects were included in this study. The new reference plane in dental cast analysis corresponded to the A-PNS plane in the lateral view and to the J-J' plane in the frontal view, which have been shown to be sufficiently accurate as a reference for measurement. These results indicate that the application of this palatal reference plane, as a reference structure, should provide accurate and abundant 3-D data concerning malocclusion.


Sexual dimorphism in the synchrony of joint growth hormone and cortisol dynamics in children with classic 21-hydroxylase deficiency.
In humans, growth hormone (GH) and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/insulin-like growth factor (IGF)-I axis and hypothalamic-pituitary-adrenal (HPA) axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. In view of the sexually dimorphic pattern in GH secretion, we investigated the GH-cortisol bihormonal secretory dynamics in male and female children with classic CAH. Thirty-eight children with classic 21-hydroxylase deficiency (M: 13, F: 25; age range: 6.1-18.8 yr) were studied prospectively. Serum GH and cortisol concentrations were determined at 20 min intervals for 24 hours. The irregularity of GH and cortisol pattern was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol dynamics was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol concentrations was computed at various time lags covering the 24-h period. There was no gender difference in mean 24-hour serum GH (males vs females: 5.25 +/- 4.72 vs 4.44 +/- 2.64 mIU/l) or cortisol (156.2 +/- 44.6 vs 172.0 +/- 58.5 nmol/l) concentrations. For GH, ApEn values were significantly higher in females (0.66 +/- 0.14) than in males (0.53 +/- 0.16) (p = 0.009). No difference in cortisol ApEn values was noted between sexes (0.53 +/- 0.21 vs 0.54 +/- 0.12). Cross-ApEn values of paired GH-cortisol, with cortisol leading GH, were significantly higher in females (0.94 +/- 0.14) than in males (0.83 +/- 0.20) (p = 0.03). These findings suggest that females with classic 21-hydroxylase deficiency have a more irregular pattern of GH secretion and a more asynchronous joint GH and cortisol dynamics than their male counterparts.


Blood loss in the minimally invasive posterior approach to total hip arthroplasty: a comparative study.
Our primary aim was to evaluate whether there is really less bleeding in patients for whom the minimally invasive posterior approach is used in comparison with the direct lateral approach for primary total hip arthroplasty. Our secondary aim was to evaluate the clinical functional results after six months as well as the postoperative radiographic result. In a comparative non-random prospective study, 76 adult patients underwent elective total hip arthroplasty using one of two approaches. The minimally invasive posterior approach (34 cases; mini-incision group) was compared with the standard direct lateral approach (42 cases; control group). Lower total estimated bleeding (means of 1083.5 ml versus 1682.3 ml; p < 0.001) and lower intraoperative bleeding (means of 745.6 ml versus 1282.8 ml; p < 0.001) were found in the mini-incision group. There was, however, no difference in the volume of blood drained after the operation (means of 340 ml and 399 ml; p = 0.77). There was also a difference between the two groups regarding the need for allogenic transfusion (8.8% in the mini-incision group versus 28.6%, p = 0.02). We observed a better clinical result in the mini-incision group (p = 0.002) despite the lack of difference between the two groups in relation to the radiographic result. Our results draw attention to the possibility that other authors may have underestimated blood losses when using minimally invasive approaches. The minimally invasive approach gave rise to a positive final impression with regard to lower blood loss.


Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala.
Fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL) catalyse the hydrolysis of the endocannabinoids anandamide and 2-arachidonoyl glycerol. We investigated their ultrastructural distribution in brain areas where the localization and effects of cannabinoid receptor activation are known. In the hippocampus, FAAH was present in somata and dendrites of principal cells, but not in interneurons. It was located mostly on the membrane surface of intracellular organelles known to store Ca(2+) (e.g. mitochondria, smooth endoplasmic reticulum), less frequently on the somatic or dendritic plasma membrane. MGL immunoreactivity was found in axon terminals of granule cells, CA3 pyramidal cells and some interneurons. In the cerebellum, Purkinje cells and their dendrites are intensively immunoreactive for FAAH, together with a sparse axon plexus at the border of the Purkinje cell/granule cell layers. Immunostaining for MGL was complementary, the axons in the molecular layer were intensively labelled leaving the Purkinje cell dendrites blank. FAAH distribution in the amygdala was similar to that of the CB(1) cannabinoid receptor: evident signal in neuronal somata and proximal dendrites in the basolateral nucleus, and hardly any labelling in the central nucleus. MGL staining was restricted to axons in the neuropil, with similar relative signal intensities seen for FAAH in different nuclei. Thus, FAAH is primarily a postsynaptic enzyme, whereas MGL is presynaptic. FAAH is associated with membranes of cytoplasmic organelles. The differential compartmentalization of the two enzymes suggests that anandamide and 2-AG signalling may subserve functional roles that are spatially segregated at least at the stage of metabolism.


Gelatin Nanoparticles for Complexation and Enhanced Cellular Delivery of mRNA.
Messenger RNA (mRNA) is increasingly gaining interest as a modality in vaccination and protein replacement therapy. In regenerative medicine, the mRNA-mediated expression of growth factors has shown promising results. In contrast to protein delivery, successful mRNA delivery requires a vector to induce cellular uptake and subsequent endosomal escape to reach its end destination, the ribosome. Current non-viral vectors such as lipid- or polymer-based nanoparticles have been successfully used to express mRNA-encoded proteins. However, to advance the use of mRNA in regenerative medicine, it is required to assess the compatibility of mRNA with biomaterials that are typically applied in this field. Herein, we investigated the complexation, cellular uptake and maintenance of the integrity of mRNA complexed with gelatin nanoparticles (GNPs). To this end, GNPs with positive, neutral or negative surface charge were synthesized to assess their ability to bind and transport mRNA into cells. Positively charged GNPs exhibited the highest binding affinity and transported substantial amounts of mRNA into pre-osteoblastic cells, as assessed by confocal microscopy using fluorescently labeled mRNA. Furthermore, the GNP-bound mRNA remained stable. However, no expression of mRNA-encoded protein was detected, which is likely related to insufficient endosomal escape and/or mRNA release from the GNPs. Our results indicate that gelatin-based nanomaterials interact with mRNA in a charge-dependent manner and also mediate cellular uptake. These results create the basis for the incorporation of further functionality to yield endosomal release.


Retinol and retinol-binding protein in lung cancer screening.
Human epidemiology studies demonstrate an inverse correlation between serum levels of vitamin A and the incidence of lung cancer. While such studies suggest that vitamin A may have a role in cancer prevention, the intent of this study was to investigate the use of vitamin A status parameters as markers for detection of occult lung cancer. In the first of two phases of this study, we established criteria for a prospective screening study. Serum levels of retinol-binding protein (RBP), zinc, retinol, and beta-carotene in lung cancer patients were compared to levels in controls. For the second phase, a prospective screening study, 100 ambulatory male cigarette smokers over the age of 45 were enrolled. Subjects were excluded if they had a known diagnosis of cancer, recent weight loss, or serum albumin less than 3.5 g/dl. Subjects with RBP less than 4.2 mg/dl and retinol less than 42 micrograms/dl were classified as high-risk; those remaining were classified as controls. A chest X-ray (CXR) was obtained on all 17 high-risk subjects and on 26 of the 83 controls. CXR was read and follow-up was performed by physicians without knowledge of this study. Lung cancer was detected in 24% (4/17) of the high-risk subset, and 4% (1/26) of the controls. These data suggest that retinol and RBP may be useful in lung cancer screening for selecting a high-risk population that warrants further examination.


Assessment of progress towards universal health coverage for people with disabilities in Afghanistan: a multilevel analysis of repeated cross-sectional surveys.
Since 2002, Afghanistan has made much effort to achieve universal health coverage. According to the UN Sustainable Development Goal 3, target eight, the provision of quality care to all must include usually underserved groups, including people with disabilities. We investigated whether a decade of international investment in the Afghan health system has brought quality health care to this group. We used data from two representative household surveys, one done in 2005 and one in 2013, in 13 provinces of Afghanistan, that included questions about activity limitations and functioning difficulties, socioeconomic factors, perceived availability of health care, and experience with coverage of health-care needs. We used multilevel modelling and tests for interaction to investigate factors associated with differences in perception between timepoints and whether village remoteness affected changes in perception. The 2005 survey included 334 people, and the 2013 survey included 961 people. Mean age, employment, and asset levels of participants with disabilities increased slightly between 2005 and 2013, but the level of education decreased. Formal education and higher asset level were associated with improved availability of health care and positive experience with coverage of health-care needs, whereas being employed was only associated with the latter. Perceived availability of health care and positive experience with coverage of health-care needs significantly worsened in 2013 compared with in 2005 (227 [69%] perceived that services were available in 2005 vs 405 [44%] in 2013, p<0·0001; 255 [78%] perceived a positive experience in 2005 vs 410 [45%] in 2013, p<0·0001). Village remoteness increased in 2013 (no connectivity by paved road 186 [57%] in 2005 vs 797 [87%] in 2013, p<0·0001; mean time to reach health-care facility 64·3 min [SD 167·7] vs 84·4 min [107·7], p<0·0001) and negatively affected perception of health-care availability. Perceived availability of health care and experience with health-care coverage have not greatly improved for people with disabilities in Afghanistan, particularly in remote areas. Health policy in Afghanistan will need to address attitudinal, social, and accessibility barriers to health care. Swedish International Development Agency.


The casparian strip as a barrier to the movement of lanthanum in corn roots.
The effectiveness of the Casparian strip as a barrier to apoplastic movement of solutes from cortex to stele of corn roots was investigated by using lanthanum in combination with electron microscopy. Lanthanum deposits were found only in cell walls and on the outside of the plasma membrane of epidermal, cortical, and endodermal cells up to the Casparian strip. Lanthanum was completely absent from the stele, indicating that the Casparian strip provides an effective barrier to apoplastic movement of solutes. Inhibitory effects of trivalent lanthanum ions on the absorption of potassium ions are discussed in relation to the nature of the lanthanum ion binding site on membranes.


Laser light delivery systems for medical applications.
For medical applications, the choice of a delivery system will be governed by the characteristics of the laser system on the one hand and the tissue application on the other. The most important parts are the beam guide and the target optics. Most lasers have wavelengths in the visible and near-infrared and can be transported by silica fibres. For the mid- and far-IR other fibre materials or hollow waveguides are used. At the end of the waveguide or fibre, an optically active component is present to direct the beam and to control the power density on the target tissue. The laser beam can be delivered either by focusing handpieces and scanning devices to treat superficial areas or through microscopes, endoscopes and flexible fibres to treat areas almost anywhere inside the human body. The characteristics of the delivery systems can be determined looking at beam properties, transmission and thermal properties. The delivery of continuous wave or pulsed laser energy, contact or non-contact, will determine the contribution of optical, thermal and mechanical effects to the tissue. The practical use of laser delivery systems is illustrated by various clinical applications.


Dilution of Fluon Before Trap Surface Treatment Has No Effect on Longhorned Beetle (Coleoptera: Cerambycidae) Captures.
Several studies have observed that trap captures of longhorned beetles (Coleoptera: Cerambycidae) can be increased by treating the surface of intercept traps with a lubricant. In addition to being expensive, these treatments can alter the spectral properties of intercept traps when applied neat. These surface treatments, particularly Fluon, are commonly used diluted as a low friction coating to prevent insects from climbing out of rearing containers. The purpose of this study was to examine the effect of diluting Fluon on the spectral properties of treated corrugated plastic traps and the capture of longhorned beetles including Monochamus scutellatus (Say), Monochamus mutator (LeConte), and Monochamus notatus (Drury). Intercept panel traps were baited with attractant semiochemicals and treated with either undiluted (i.e., 100%) Fluon, a 1:1 mixture of Fluon and water (50%), a 1:9 mixture of Fluon and water (10%), or untreated. There were no obvious differences in the relative reflectance of untreated black Coroplast plastic or black Coroplast plastic treated with 50 or 10% Fluon. Traps treated with 100% Fluon had similar patterns of peak reflectance to the other treatments but overall had higher relative reflectance. In general, no effect of diluting the Fluon was observed for male or female M. scutellatus or M. mutator , but an effect of treating traps with Fluon was observed. Similar results were observed for the combined captures of Clytus ruricola Olivier, Cyrtophorus verrucosus Olivier, Megacyllene caryae (Gahan), Xylotrechus colonus (F.), Neoclytus acuminatus (F.), Neoclytus mucronatus (F.), and Phymatodes testaceus (L.). No treatment effect was observed for M. notatus .


11C-Iodoantipyrine for the measurement of regional cerebral blood flow by positron emission tomography. Validation studies.
Positron emission tomography (PET) makes it possible to employ an in vivo autoradiographic paradigm to measure regional cerebral blood flow (rCBF) in man. In this study, we synthesized the positron-emitting radiopharmaceutical 11C-iodoantipyrine (11C-IAP) and validated its suitability as a CBF tracer. 11C ( T and one-half 20.4 min) was produced by the (p,alpha) nuclear reaction on 14N. 11C-methyl iodide was used to methylate 3-methyl-1-phenyl-2-pyrazolin-5-one to form 11C-antipyrine, which was iodinated. Radiochemical purity of the 11C-IAP product was 93-98% except as described below. rCBF was measured with 11C-IAP in nitrous oxide-anesthetized Wistar rats by the method of indicator fractionation, and values were compared with rCBF values measured with simultaneously administered commercially produced 14C-IAP. rCBF was studied over a range of arterial Pco2 values (31-58 mm Hg, mean 43.0 +/- 3.5). Mean rCBF data for the 2 tracers agreed to within 4.8% for cerebral hemispheral samples, 3.8% for cerebellum, and 5.3% for brainstem. Mean values (+/- SEM) for rCBF using 11C-IAP were 1.67 +/- 0.20 ml gm-1 min-1 for cerebral hemispheres; 1.32 +/- 0.17 for cerebellum; and 1.50 +/- 0.21 for brainstem. When chromatographic analysis revealed tracer impurity, rCBF, as measured with 11C-IAP, fell consistently below values obtained with 14C-IAP. The data indicate that 11C-IAP, when properly synthesized and submitted to batch-by-batch quality control, may be suitable for measuring rCBF in man by emission tomography.


Prognostic value of microalbuminuria on admission in patients with acute pulmonary embolism.
There have been no studies examining the effect of microalbuminuria on outcomes of patients with acute pulmonary embolism (APE). This study aimed to assess the association between microalbuminuria and in-hospital mortality in patients with APE. This retrospective study included all adult patients hospitalized due to APE between June 2015 and May 2018. Blood and urine samples were collected before the diagnostic procedures on admission. Patients were divided into 3 groups according to urinary albumin to creatinine ratio (UACR) levels: normoalbuminuria (<30 mg/g), microalbuminuria (30-299 mg/g), and macroalbuminuria (> 300 mg/g). The primary endpoint of the study was in-hospital mortality. A total of 154 consecutive patients (mean age 69.8 ± 13.4 years, 51.9% female) were included, and 21 (13.6%) of the patients died during their in-hospital course. The prevalence of normoalbuminuria, microalbuminuria, macroalbuminuria was 70.1%, 23.4%, and 6.5%, respectively. Patients with in-hospital mortality had significantly lower estimated glomerular filtration rate (eGFR), but higher UACR at admission than those patients who survived. As compared with patients with normoalbuminuria, multivariate analyses showed that the patients with microalbuminuria and macroalbuminuria had 2.38-, and 3.48-fold higher risk for in-hospital mortality, respectively (p < 0.001). Multivariate analyses also showed that UACR >102.6 mg/g (OR: 1.76; 95% CI, 0.99-3.16; p = 0.011) was independently associated with in-hospital mortality, while a low eGFR was not associated. Microalbuminuria at admission may allow rapid prediction of prognosis in patients with APE.


Network Differential in Gaussian Graphical Models from Multimodal Neuroimaging Data.
Multimodal brain network analysis has the potential to provide insights into the mechanisms of brain disorders. Most previous studies have analyzed either unimodal brain graphs or focused on local/global graphic metrics with little consideration of details of disrupted paths in the patient group. As we show, the combination of multimodal brain graphs and disrupted path-based analysis can be highly illuminating to recognize path-based disease biomarkers. In this study, we first propose a way to estimate multimodal brain graphs using static functional network connectivity (sFNC) and gray matter features using a Gaussian graphical model of schizophrenia versus controls. Next, applying the graph theory approach we identify disconnectors or connectors in the patient group graph that create additional paths or cause absent paths compared to the control graph. Results showed several edges in the schizophrenia group graph that trigger missing or additional paths. Identified edges associated with these disrupted paths were identified both within and between dFNC and gray matter which highlights the importance of considering multimodal studies and moving beyond pairwise edges to provide a more comprehensive understanding of brain disorders.Clinical Relevance- We identified a path-based biomarker in schizophrenia, by imitating the structure of paths in a multimodal (sMIR+fMRI) brain graph of the control group. Identified cross-modal edges associated with disrupted paths were related to the middle temporal gyrus and cerebellar regions.


Broadband acoustic scattering measurements of underwater unexploded ordnance (UXO).
In order to evaluate the potential for detection and identification of underwater unexploded ordnance (UXO) by exploiting their structural acoustic response, we carried out broadband monostatic scattering measurements over a full 360 degrees on UXO's (two mortar rounds, an artillery shell, and a rocket warhead) and false targets (a cinder block and a large rock). The measurement band, 1-140 kHz, includes a low frequency structural acoustics region in which the wavelengths are comparable to or larger than the target characteristic dimensions. In general, there are aspects that provide relatively high target strength levels ( approximately -10 to -15 dB), and from our experience the targets should be detectable in this structural acoustics band in most acoustic environments. The rigid body scattering was also calculated for one UXO in order to highlight the measured scattering features involving elastic responses. The broadband scattering data should be able to support feature-based separation of UXO versus false targets and identification of various classes of UXO as well.


Arterioportal fistulas: twelve cases.
During the last 20 years, we encountered 14 arterioportal fistulas in 12 patients. Gastrointestinal hemorrhage or mesenteric artery insufficiency were the most frequent conditions found after the diagnosis. Arterioportal arterial fistulas were congenital in two cases and acquired in 10; seven of these 10 were iatrogenic. One patient had three successive and different sites of arterioportal fistula. The fistula originated from a branch of the celiac axis in nine cases, the superior mesenteric artery in three, and the inferior mesenteric artery in two. One patient died of massive anal bleeding before any treatment was possible. Eight fistulas were treated surgically and five by arterial embolization. After treatment there was no early mortality, while hemorrhagic and ischemic complications regressed in all cases. Three hemorrhagic recurrences were observed in patients with preexisting cirrhosis (two cases) or by recurrence of a congenital arteriovenous fistula (one case). Closure of symptomatic arterioportal fistula is justified. The choice of the most appropriate method for each patient should be discussed between the surgeon and interventional radiologist on a case by case basis.


CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage.
The CDC7 kinase is essential for the activation of DNA replication origins and has been implicated in the replication stress response. Using a highly specific chemical inhibitor and a chemical genetic approach, we now show that CDC7 activity is required to coordinate multiple MRE11-dependent processes occurring at replication forks, independently from its role in origin firing. CDC7 localizes at replication forks and, similarly to MRE11, mediates active slowing of fork progression upon mild topoisomerase inhibition. Both proteins are also retained on stalled forks, where they promote fork processing and restart. Moreover, MRE11 phosphorylation and localization at replication factories are progressively lost upon CDC7 inhibition. Finally, CDC7 activity at reversed forks is required for their pathological MRE11-dependent degradation in BRCA2-deficient cells. Thus, upon replication interference CDC7 is a key regulator of fork progression, processing and integrity. These results highlight a dual role for CDC7 in replication, modulating both initiation and elongation steps of DNA synthesis, and identify a key intervention point for anticancer therapies exploiting replication interference.


"One-stop shop" for the evaluation of the infertile patient: hystero-salpingo foam sonography combined with two and three dimensional ultrasound and sonohysterography.
Hysterosalpingo-foam sonography (HyFoSy) is considered an acceptable alternative for hysterosalpingography (HSG). By combining HyFoSy with two and three-dimensional (2D and 3D) ultrasound and hysterosonography, a complete fertility work-up can be done. We aimed to evaluate the value of a combined ultrasound examination for fertility work-up. During the study period 113 women were examined. Five of 113 (4.4%) examinations were abandoned due to intra-uterine adhesions that were detected by hysterosonography, and five (4.4%) were abandoned due to technical difficulties. Of 103 women who had completed the examination, 2D ultrasound revealed six patients with hydrosalpinx (5.8%) and sonographic signs of adenomyosis in 13 (12.6%) patients. By combining 2D ultrasound with hysterosonography, two (1.9%) fibroids that were penetrating the uterine cavity and seven (6.8%) endometrial polyps were detected. HyFoSy showed bilateral patent tubes in 58 patients (56.3%), unilateral tubal occlusion in 29 (28.1%) and bilateral tubal occlusion in 16 (15.5%). This study shows that the 'one-stop shop' examination is feasible. The combined examination had detected 16 pathological findings that would have not been detected by HyFoSy alone. Hence, it should be offered to couples undergoing routine infertility work-up.IMPACT STATEMENTWhat is already known on this subject? The accuracy of the HyFoSy alone has been evaluated in different studies, but this presented ultrasound scan is integrating 4 different modalities in one exam (2D scanning of the pelvis, 3D scanning of the uterus, hysterosonography and HyFoSy) and we were able to evaluate the female pelvic organs, including the uterine cavity, the tubes and the ovaries, in order to expand the range of diagnosed pathologies.What do the results of this study add? The concept of 'one-stop shop' for the evaluation of female pelvis in couples suffering from infertility is feasible, has comparable accuracy as HSG for tubal occlusion, and higher detection rate for uterine malformations.What are the implications of these findings for clinical practice and/or further research? We suggest to incorporate this examination in routine fertility work-up.


Development of suppressor T lymphocytes for Epstein-Barr virus-induced B-lymphocyte outgrowth during acute infectious mononucleosis: assessment by two quantitative systems.
A system of 3H-thymidine incorporation by lymphocytes in culture for 3 wk has been utilized for quantitative assessment of the ability of T lymphocytes to inhibit outgrowth of autologous Epstein-Barr virus (EBV) transformed B lymphocytes. Lymphocytes from EBV-seronegative individuals lack the ability to suppress outgrowth of autologous EBV-transformed B lymphocytes. This capability appears during the course of primary EBV-induced infectious mononucleases (IM) as the atypical lymphocytosis is subsiding and persists for years after recovery from primary EBV infection. The ability of T lymphocytes from EBV-seropositive subjects or convalescent IM patients to inhibit B-lymphocyte outgrowth is not HLA restricted. Thus, T lymphocytes capable of inhibition of in vitro EBV-induced B-cell outgrowth emerge during the acute stage of IM and may represent an important control mechanism of EBV-induced B-lymphocyte proliferation in vivo. The system provides a highly sensitive quantitative means for in vitro assessment of cell-mediated immunity to EBV.


Incidence and predictors of post-cardiotomy delirium.
To determine the incidence and predictors of delirium after cardiac surgery. A prospective, observational study of postcardiotomy surgical patients was conducted during a 5 month period at the Minneapolis, MN, VAMC. Of the 53 patients who completed the study, 12 patients (23%) met criteria for postoperative delirium and 18 patients (34%) met criteria for postoperative subsyndromal delirium. Significant predictors of postoperative delirium included a history of cerebrovascular disease (Charlson Index item, VA CICSP), high medical comorbidity (VA morbidity risk score, Charlson Index), increased preoperative creatinine level, and an increased preoperative pain rating. When delirium and subsyndromal delirium patients were combined, a history of cerebrovascular disease, left ventricular dysfunction, or diabetes predicted the development of delirious symptoms. Incident delirium occurred in 23% of patients after cardiac surgery and incident delirium symptoms, in 57%. The strongest predictor of both incident delirium and delirium symptoms was a history of cerebrovascular disease.


Growth hormone improves weight velocity and height velocity in prepubertal children with cystic fibrosis.
We undertook this study to determine if growth hormone treatment of prepubertal children with cystic fibrosis could improve their height and weight. Nine prepubertal children with cystic fibrosis were treated with human recombinant growth hormone for one year. Results obtained during this year were compared to similar measurements made for each patient for the one year prior to the treatment year. Anthropometric data including: height, height velocity, weight, weight velocity and skin fold thickness were measured at three month intervals. Pulmonary function and skeletal muscle strength were measured at three month intervals. Glucose tolerance was evaluated by HbAlc and by fasting blood glucose and insulin levels every three months. Our results demonstrate that growth hormone treatment resulted in significant improvement in height velocity and height Z scores. Weight increased in all subjects, with a significant increase in weight velocity (year prior to treatment = 1.7+/-1.0 kg/yr, treatment year = 3.8+/-1.6 kg/yr; p=0.03). Measurements of skin fold thickness suggests that lean body mass improved with growth hormone treatment. Pulmonary function improved in all but two patients, whose pulmonary function remained the same and muscle strength improved in all subjects. These results suggest that growth hormone used in prepubertal children with cystic fibrosis can improve height and weight and may improve lean body mass.


An efficient region of interest acquisition method for dynamic magnetic resonance imaging.
Motivated by work in the area of dynamic magnetic resonance imaging (MRI), we develop a new approach to the problem of reduced-order MRI acquisition. Efforts in this field have concentrated on the use of Fourier and singular value decomposition (SVD) methods to obtain low-order representations of an entire image plane. We augment this work to the case of imaging an arbitrarily-shaped region of interest (ROI) embedded within the full image. After developing a natural error metric for this problem, we show that determining the minimal order required to meet a prescribed error level is in general intractable, but can be solved under certain assumptions. We then develop an optimization approach to the related problem of minimizing the error for a given order. Finally, we demonstrate the utility of this approach and its advantages over existing Fourier and SVD methods on a number of MRI images.


Genetic Analyses Suggest Separate Introductions of the Pine Pathogen Lecanosticta acicola Into Europe.
Lecanosticta acicola is a heterothallic ascomycete that causes brown spot needle blight on native and nonnative Pinus spp. in many regions of the world. In this study we investigated the origin of European L. acicola populations and estimated the level of random mating of the pathogen in affected areas. Part of the elongation factor 1-α gene was sequenced, 11 microsatellite regions were screened, and the mating type idiomorphs were determined for 201 isolates of L. acicola collected from three continents and 17 host species. The isolates from Mexico and Guatemala were unique, highly diverse and could represent cryptic species of Lecanosticta. The isolates from East Asia formed a uniform and discrete group. Two distinct populations were identified in both North America and Europe. Approximate Bayesian computation analyses strongly suggest independent introductions of two populations from North America into Europe. Microsatellite data and mating type distributions indicated random recombination in the populations of North America and Europe. Its intercontinental introduction can most likely be explained as a consequence of the movement of infected plant material. In contrast, the spread of L. acicola within Europe appears to be primarily due to conidial dispersion and probably also ascospore dissemination.


Physiotherapy-led triage clinic for low back pain.
The aims of this study were to evaluate a physiotherapy-led triage clinic (PLTC) and investigate general practitioner satisfaction with the PLTC. A retrospective cohort study was undertaken from January to December 2005 at a Melbourne tertiary teaching hospital. Outcomes assessed included waiting times to first appointment, patient attendance and surgery conversion rates. Outcomes were compared with the hospital 2002 benchmark data. GP satisfaction was evaluated by a survey. One-hundred and five new patients attended the PLTC clinic during the evaluation period. Patients waited 9 weeks for a PLTC appointment compared with 26 weeks for the general orthopaedic clinic and 23 weeks for the spinal orthopaedic clinic. Sixty-seven percent of the patients triaged in the PLTC were discharged from the orthopaedic outpatient department without requiring an orthopaedic surgeon consultation. Referring GPs were at least as satisfied with the management of their patients through the PLTC as with usual management in the general orthopaedic clinic. A PLTC can significantly reduce waiting times for orthopaedic outpatient appointments in a public hospital. Many patients can be managed by these experienced physiotherapists and their GPs, without the need for face-to-face contact with an orthopaedic surgeon. Pilot results indicated that GPs whose patients are managed in this PLTC were satisfied with this model for their patients with low back conditions.


Being Female and in a Romantic Relationship Enhances the Association between Satisfaction with Love Life and Capacity to Love.
This study aims to evaluate if the relation between love life satisfaction, assessed by the satisfaction with love life scale (SWLLS), and capacity to love, assessed by the capacity to love inventory (CTL-I), is moderated by gender and by being or not in a romantic relationship, in a Portuguese sample. To this end, the adaptation and validation of CTL-I for this population were carried out through an exploratory factorial analysis (EFA) followed by a Robust Maximum Likelihood (MLR) confirmatory factorial analysis (CFA). A multi-group analysis for measurement invariance depending on being in a romantic relationship or not was assessed. The model's reliability was also evaluated. The associations between SWLLS and CTL-I were tested by correlations, regressions and moderations. At last, differences between means and distributions concerning sociodemographic variables were determined. The results showed that a good model fit for the Portuguese version of the CTL-I was found, as well as good psychometric properties. Results also showed that satisfaction with love life contributes to explaining the capacity to love and all its dimensions, and that gender and being in a romantic relationship moderate the association between love life satisfaction and the capacity to love. Being female and being in a romantic relationship make the relationship between love life satisfaction and the capacity to love stronger and more meaningful.


[A serious complication of ritual circumcision of a 'buried' penis].
The buried penis is a rare congenital anomaly in which a circumcision can result in deformity and functional disorder of the penis. We describe the case history of a one-year-old boy with this anomaly who underwent ritual circumcision by a layman.


Continuous lumbar erector spinae plane block as an alternative to epidural analgesia in pain treatment in patients undergoing hip replacement surgery - a prospective pilot study.
Postoperative pain associated with hip replacement surgery can be severe, decreasing the patient's mobility and satisfaction with perioperative treatment. Regional techniques are commonly used as postoperative analgesia in hip surgery patients. We performed a prospective pilot study on patients undergoing hip replacement surgery. We anesthetized each participant with spinal technique and allocated patients according to postoperative analgesia to the continuous epidural group and the continuous lumbar erector spinae plane block (ESPB) group. We measured postope-rative oxycodone consumption with patient-controlled analgesia (PCA) demands. At several points, we evaluated the patients' pain at rest and during activity on the visual analog scale (VAS, 0-10), their quadriceps femoris' muscle strength on the Lovett scale (0-5), and their ability to sit, stand upright, and walk on the Timed Up and Go test. Moreover, we assessed the patients' recovery through the Quality of Recovery 40 (QoR-40) questionnaire on the first postoperative day. We found lower oxycodone consumption via PCA in the epidural than in the ESPB group (9.1 (mean) mg (5.2-13.0) (confidence interval) vs. 15.5 mg (9.8-21.3), P = 0.049). Patients in the ESPB group had more demands with PCA than participants in the epidural group (10.5 (median) (6-16) (interquartile range) vs. 25 (16-51), P = 0.016). We did not find differences between the groups in the other outcomes or in terms of postoperative complications. The results suggest that the continuous lumbar ESPB group is equivalent to epidural analgesia as a pain treatment technique in patients undergoing hip replacement surgery.


Litigation in Anesthesia and Intensive Care Units: An Italian Retrospective Study.
Anesthesiologists consider professional insurance and its medico-legal problems as a remarkable aspect of their job. "Associazione Anestesisti Rianimatori Ospedalieri Italiani-Emergenza ed Area Critica" (AAROI-EMAC) is the Italian professional association of anesthesiologists and intensivists that works to train its subscribers on safety measures. This is a retrospective observational study on an insurance complaints database for anesthetic accidents that result in injuries to patients. The analyzed period runs from 1 January 2014 to 31 December 2016. A total of 1309 complaints related to 873 insurance claims were analyzed. Criminal complaints comprised 805 (64.4%) of the total, and civil complaints were 445 (35.6%). The iatrogenic damage claimed included: death (58% of the cases); peripheral nerve damage (8%); spinal cord injuries (5%); unspecified injuries (7%); dental damage (4%); infections (3%); needing second surgical procedure (2%); and other injuries (13%). There is a statistical significance between the size of the hospital and the number of the claims: small hospital complaints comprised 40.1% of the cases, while complaints against medium-sized and large hospitals constituted 20.6% of the cases (χ2GL = 8 = 39.87, p = 0.00). In Italy, anesthesiologists and intensivists are often involved in litigation even when they are not directly responsible for iatrogenic injuries, and the most frequent claims in ICU are related post-operative complications.


In Crohn's Disease, Anti-TNF-α Treatment Changes the Balance between Mucosal IL-17, FOXP3, and CD4 Cells.
Aim. In Crohn's disease (CD), anti-TNF-α treatment is a potent medication. We aimed to characterize the effect of anti-TNF-α treatment on T effector and regulatory cells. Material and Methods. We studied T-effector and regulatory cells on cellular and mRNA levels in intestinal biopsy samples from 13 Crohn's disease patient. Biopsies were obtained at baseline and 3 months after anti-TNF-α treatment, and from 14 inflammation-free control subjects. Results. Patients had higher numbers of ileal IL-17(+) and forkhead box P3 (FOXP3)(+) cells than did control subjects, both before ( P ≤ 0.001 and P ≤ 0.05, resp.) and after the anti-TNF-α treatment (P ≤ 0.01, P ≤ 0.01). Intestinal interferon-γ and IL-17 mRNA expression was higher in Crohn's disease and remained elevated after anti-TNF-α treatment. The ratio of IL-17(+) cells to CD4(+) cells decreased (P ≤ 0.05) and compared to baseline the ratio of IL-17(+) cells to FOXP3(+) was lower after treatment (P ≤ 0.05). Conclusions. TNF-α-blocking agents improved intestinal balance between IL-17(+) T-effector and regulatory T cells, although intestinal IL-17 upregulation remained elevated.


A vector radiative transfer model for coupled atmosphere and ocean systems based on successive order of scattering method.
A vector radiative transfer model has been developed for coupled atmosphere and ocean systems based on the Successive Order of Scattering (SOS) Method. The emphasis of this study is to make the model easy-to-use and computationally efficient. This model provides the full Stokes vector at arbitrary locations which can be conveniently specified by users. The model is capable of tracking and labeling different sources of the photons that are measured, e.g. water leaving radiances and reflected sky lights. This model also has the capability to separate florescence from multi-scattered sunlight. The delta - fit technique has been adopted to reduce computational time associated with the strongly forward-peaked scattering phase matrices. The exponential - linear approximation has been used to reduce the number of discretized vertical layers while maintaining the accuracy. This model is developed to serve the remote sensing community in harvesting physical parameters from multi-platform, multi-sensor measurements that target different components of the atmosphere-oceanic system.


Persistence and expression of Marek's disease virus DNA in tumour cells and peripheral nerves studied by in situ hybridization.
We have used cloned fragments of Marek's disease virus (MDV) DNA and in situ hybridization to search for virus DNA and study its expression in infected chick embryo fibroblasts (CEF), lymphoblastoid cell lines, tumours and neural lesions. DNA from the HPRS 16/att strain of MDV was cleaved with EcoRI endonuclease and several fragments were cloned in Escherichia coli using the vector PBR322. Seven fragments ranging in size from 2.6 to 11 kbp representing approx. 25% of the MDV genome were labelled in vitro and annealed to EcoRI digests of DNA from infected cells and tumours following separation and transfer according to the Southern blotting procedure. Most of the selected MDV DNA fragments hybridized to fragments of corresponding sizes in EcoRI digests of DNA from cell lines and tumours and failed to hybridize to digests of uninfected chick cell DNA. In situ hydridization using 3H-labelled DNA with specific activity of 10(8) d/min/microgram as probe showed intranuclear MDV DNA in infected CEF, in every cell of two lymphoblastoid cell lines and in the majority of infiltrating or proliferating lymphoid cells found in type 'A' lesions of grossly enlarged peripheral nerves. Both intranuclear and cytoplasmic RNA were detected in cells that contained virus DNA. However, comparatively little virus RNA appears to be transcribed in cell lines and in infected tissues from the regions of virus DNA (25% of genome) used as probe in this study. Our results favour the hypothesis that the accumulation of lymphoid cells in nerves is not the result of an inflammatory response to infected nerve cells but is rather the consequence of proliferating transformed cells.


A Culturally Relevant Smartphone-Delivered Physical Activity Intervention for African American Women: Development and Initial Usability Tests of Smart Walk.
Smart Walk is a culturally relevant, social cognitive theory-based, smartphone-delivered intervention designed to increase physical activity (PA) and reduce cardiometabolic disease risk among African American (AA) women. This study aimed to describe the development and initial usability testing results of Smart Walk. Smart Walk was developed in 5 phases. Phases 1 to 3 focused on initial intervention development, phase 4 involved usability testing, and phase 5 included intervention refinement based on usability testing results. In phase 1, a series of 9 focus groups with 25 AA women (mean age 38.5 years, SD 7.8; mean BMI 39.4 kg/m2, SD 7.3) was used to identify cultural factors associated with PA and ascertain how constructs of social cognitive theory can be leveraged in the design of a PA intervention. Phase 2 included the analysis of phase 1 qualitative data and development of the structured PA intervention. Phase 3 focused on the technical development of the smartphone app used to deliver the intervention. Phase 4 consisted of a 1-month usability trial of Smart Walk (n=12 women; mean age 35.0 years, SD 8.5; mean BMI 40 kg/m2, SD 5.0). Phase 5 included refinement of the intervention based on the usability trial results. The 5-phase process resulted in the development of the Smart Walk smartphone-delivered PA intervention. This PA intervention was designed to target social cognitive theory constructs of behavioral capability, outcome expectations, social support, self-efficacy, and self-regulation and address deep structure sociocultural characteristics of collectivism, racial pride, and body appearance preferences of AA women. Key features of the smartphone app included (1) personal profile pages, (2) multimedia PA promotion modules (ie, electronic text and videos), (3) discussion boards, and (4) a PA self-monitoring tool. Participants also received 3 PA promotion text messages each week. The development process of Smart Walk was designed to maximize the usability, cultural relevance, and impact of the smartphone-delivered PA intervention.


[Is research in Germany up for sale? Results of a study of Transparency International Germany].
The intransparency of the complex Public Health System opens up the possibility for the abuse of all groups acting in this system. Some of them damage this system without hesitation even by corruption, and keep their focus on the personal interests instead of public interests. Particularly within research there are medical scientists and experts, who work and publish being dependant on grants from the pharmaceutical industries.


The drivers of sea lice management policies and how best to integrate them into a risk management strategy: An ecosystem approach to sea lice management.
The control of sea lice infestations on cultivated Atlantic salmon is a major issue in many regions of the world. The numerous drivers which shape the priorities and objectives of the control strategies vary for different regions/jurisdictions. These range from the animal welfare and economic priorities of the producers, to the mitigation of any potential impacts on wild stocks. Veterinary ethics, environmental impacts of therapeutants, and impacts for organic certification of the produce are, amongst others, additional sets of factors which should be considered. Current best practice in both EU and international environmental law advocates a holistic ecosystem approach to assessment of impacts and risks. The issues of biosecurity and ethics, including the impacts on the stocks of species used as cleaner fish, are areas for inclusion in such a holistic ecosystem assessment. The Drivers, Pressures, State, Impacts, Responses (DPSIR) process is examined as a decision-making framework and potential applications to sea lice management are outlined. It is argued that this is required to underpin any integrated sea lice management (ISLM) strategy to balance pressures and outcomes and ensure a holistic approach to managing the issue of sea lice infestations on farmed stock on a medium to long-term basis.


Maternal work and child-care strategies in peri-urban Guatemala: nutritional effects.
Associations of 293 mothers' work for earnings and child-care arrangements with the anthropometric status of their children were examined in urban Guatemala. It was hypothesized that during the period of life in which growth often falters (8 through 35 months), maternal employment could be beneficial for children. Informal workers tended to be poorer, less educated, and have more undernourished children than formal workers or nonworkers. When poverty and mother's education were controlled for, no effects of maternal employment on children's anthropometric growth patterns were seen. However, the percent of the family income the mother earned was positively associated with all anthropometric indicators, controlling for confounds. Children taken care of by preteen siblings had significantly lower weight for height than those in other situations, even controlling for SES and maternal employment status. These effects were not found in a 36-48-month-old sample.


Antibody response and viraemia during the course of severe acute respiratory syndrome (SARS)-associated coronavirus infection.
To understand the time-course of viraemia and antibody responses to severe acute respiratory syndrome-associated coronavirus (SARS-CoV), RT-PCR and ELISA were used to assay 376 blood samples from 135 SARS patients at various stages of the illness, including samples from patients who were in their early convalescent phase. The results showed that IgM antibodies decreased and became undetectable 11 weeks into the recovery phase. IgG antibodies, however, remained detectable for a period beyond 11 weeks and were found in 100 % of patients in the early convalescent phase. SARS-CoV viraemia mainly appeared 1 week after the onset of illness and then decreased over a period of 1 month, becoming undetectable in the blood samples of the convalescent patients. At the peak of viraemia, viral RNA was detectable in 75 % of blood samples from patients who were clinically diagnosed with SARS 1 or 2 weeks before the test.


Childhood language skills and adolescent self-esteem in preterm survivors.
Fifty-seven percent of children with poor language skills are affected by socio-emotional problems. Despite the importance of language skills to interpersonal functioning and school performance, relatively little is known about how they affect self-esteem in adolescence. Data on youth at high risk for language problems (e.g. those born extremely low birth weight (ELBW; <1000 grams)) are even more scarce. This prospective study examined associations between language skills at age 8 and self-esteem during adolescence (12-16 years) in individuals born at ELBW ( N = 138) or normal birth weight (NBW; >2500 grams) ( N = 111). Participants' language skills were assessed using the Verbal Scale of the Wechsler Intelligence Scale for Children-Revised and the Token Test at age 8. In adolescence, participants completed the Harter Self-Perception Profile for Adolescents. Birth weight status was found to moderate associations between childhood language and adolescent global self-esteem (Token Test ( p = .006), Verbal Intelligence Quotient ( p = .033)) such that better language skills were associated with higher self-esteem in adolescent ELBW survivors, but not in NBW participants. Language skills may play a protective role in the development and maintenance of self-esteem in ELBW youth and could be an important target for optimizing their functioning, particularly before transitioning to the critical adolescent period.


Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses.
Multiple mitochondrial DNA (mtDNA) deletions have been described in patients with autosomal dominant progressive external ophthalmoplegia (AD-PEO) and in autosomal recessive disorders including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and autosomal recessive cardiomyopathy ophthalmoplegia (ARCO). The pathogenic bases of these disorders are unknown. We studied three patients with AD-PEO and three patients with autosomal recessive (AR)-PEO (two patients with MNGIE and one patient with ARCO). Histochemistry and Southern blot analyses of DNA were performed in skeletal muscle from the patients. Muscle mtDNA was used to characterize the pattern and amounts of the multiple mtDNA rearrangements; PCR analysis was performed to obtain finer maps of the deleted regions in both conditions. The patients with AD-PEO had myopathic features; the patients with AR-PEO had multisystem disorders. The percentage of ragged-red and cytochrome c oxidase-negative fibers tended to be higher in muscle from the patients with AD-PEO (19% +/- 13.9, 29.7 +/- 26.3) than in muscle from the patients with AR-PEO (1.4% +/- 1.4, 3.3% +/- 3.2; p < 0.10). The sizes of the multiple mtDNA deletions ranged from approximately 4.0 to 10.0 kilobases in muscle from both groups of patients, and in both groups, we identified only deleted and no duplicated mtDNA molecules. Patients with AD-PEO harbored a greater proportion of deleted mtDNA species in muscle (31% +/- 5.3) than did patients with AR-PEO (9.7% +/- 9.1; p < 0.05). In the patients with AD-PEO, we identified a deletion that included the mtDNA heavy strand promoter (HSP) region, which had been previously described as the HSP deletion. The HSP deletion was not present in the patients with AR-PEO. Our findings show the clinical, histologic, and molecular genetic heterogeneity of these complex disorders. In particular, the proportions of multiple mtDNA deletions were higher in muscle samples from patients with AD-PEO than in those from patients with AR-PEO.


Diagnosis and prognosis of primary breast cancer.
The diagnosis of breast cancer should be made in the context of a multidisciplinary team: preoperative diagnosis can be made in over 90% of patients with symptomatic and screen-detected cancers. A preoperative diagnosis allows patients the opportunity to come to terms with the diagnosis of breast cancer and to consider their treatment options before progressing to therapeutic surgery. Surgery remains the primary therapeutic treatment for operable breast cancer with radiotherapy and systemic therapies as adjuvant treatments. Surgery in addition provides pathological specimens from which important prognostic information may be obtained. The traditional TNM classification in itself is no longer sufficient although there is still considerable prognostic information to be gained in staging patients. However, markers of tumour biology provide prognostic data independent of TNM staging. Both need to be considered in any overall assessment of patient prognosis.


Metabolic Bone Disease of Prematurity: Diagnosis and Management.
Metabolic Bone Disease (MBD) of prematurity is a multifactorial disorder commonly observed in very low birth weight (VLBW, <1,500 g) newborns, with a greater incidence in those extremely low birth weight (ELBW, <1,000 g). MBD is characterized by biochemical and radiological findings related to bone demineralization. Several antenatal and postnatal risk factors have been associated to MBD of prematurity, although the main pathogenetic mechanism is represented by the reduced placental transfer of calcium and phosphate related to preterm birth. The diagnosis of MBD of prematurity requires the assessment of several biochemical markers, radiological, and ultrasonographic findings. However, the best approach is the prevention of the symptomatic disease, based on the screening of subjects exposed to the risks of developing MBD. Regarding the subjects who need to be screened, there is a substantial agreement on the potential risk factors for MBD. On the contrary, different recommendations exist on the diagnosis, management and treatment of this disorder of bone metabolism. This review was aimed at: (1) identifying the subjects at risk for MBD of prematurity; (2) indicating the biochemical findings to take in consideration for the prevention of MBD of prematurity; (3) suggesting practical recommendations on nutritional intake and supplementation in these subjects. We searched for papers which report the current recommendations for biochemical assessment of MBD of prematurity and for its prevention and treatment. The majority of the authors suggest that MBD of prematurity is a disease which tends to normalize overtime, thus it is not mandatory to mimic the rate of mineral fetal accretion through parenteral or enteral supplementation. The optimization of total parenteral nutrition (TPN) and the early achievement of a full enteral feeding are important goals for the prevention and management of MBD of prematurity.


Ordered water molecules as key allosteric mediators in a cooperative dimeric hemoglobin.
One of the most remarkable structural aspects of Scapharca dimeric hemoglobin is the disruption of a very well-ordered water cluster at the subunit interface upon ligand binding. We have explored the role of these crystallographically observed water molecules by site-directed mutagenesis and osmotic stress techniques. The isosteric mutation of Thr-72-->Val in the interface increases oxygen affinity more than 40-fold with a surprising enhancement of cooperativity. The only significant structural effect of this mutation is to destabilize two ordered water molecules in the deoxy interface. Wild-type Scapharca hemoglobin is strongly sensitive to osmotic conditions. Upon addition of glycerol, striking changes in Raman spectrum of the deoxy form are observed that indicate a transition toward the liganded form. Increased osmotic pressure, which lowers the oxygen affinity in human hemoglobin, raises the oxygen affinity of Scapharca hemoglobin regardless of whether the solute is glycerol, glucose, or sucrose. Analysis of these results provides an estimate of six water molecules lost upon oxygen binding to the dimer, in good agreement with eight predicted from crystal structures. These experiments suggest that the observed cluster of interfacial water molecules plays a crucial role in communication between subunits.


Spread of vimentin-immunoreactive cells within the plaque-like lesion in the spinal anterior horn of a patient with post-poliomyelitis syndrome.
A Japanese man in the present study experienced acute weakness in his right leg as a two year old. The strength in his leg gradually recovered and developed, and he could play golf and climb mountains up to around the age of 50. From approximately 55 years of age, he became unable to stand up from a stooped position. Muscle weakness and atrophy spread to his right arm, and an electromyography revealed a neurogenic pattern in his lower and upper extremities. The patient was diagnosed as having post-poliomyelitis syndrome (PPS). Numbness in both the legs and pain in the buttocks occurred after 60 years of age. Computed tomography and magnetic resonance imaging at that time revealed spondylosis and protrusion of an osteophye in lower thoracic vertebrae compressing the second lumbar segment of the spinal cord. He died of malignant lymphoma and acute interstitial pneumonia at 80 years of age. Pathological examination revealed transverse myelopathy at the second lumbar segment of the spinal cord and total necrosis. The anterior horn and the intermediate zone of the third and fourth lumbar segments of the spinal cord on the right side were atrophic and diffusely gliotic. An oval-shaped plaque-like lesion was observed in the right anterior horn at the third and fourth lumbar segments of the spinal cord. Neurons and synaptophysin immunoreactivity had completely disappeared in the plaque-like lesion. A striking spread of vimentin-immunoreactive cells was found corresponding to the lesion, while glial fibrillary acidic protein-immunoreactive astrocytes existed evenly in the anterior horn and intermediate zone on both sides of the third and fourth lumber segments of the spinal cord. Virological examination using the autopsied materials was negative for poliovirus. Neither transactivation response DNA-binding protein of 43 kDa-immunoreactive inclusion nor Bunina body was seen in the spinal cord. The present paper demonstrates new findings of a noteworthy response of the vimentin-immunoreactive cells within the peculiar "plaque-like lesion" in the PPS.


Protein kinase C overexpression suppresses calcineurin-associated defects in Aspergillus nidulans and is involved in mitochondrial function.
In filamentous fungi, intracellular signaling pathways which are mediated by changing calcium levels and/or by activated protein kinase C (Pkc), control fungal adaptation to external stimuli. A rise in intracellular Ca2+ levels activates calcineurin subunit A (CnaA), which regulates cellular calcium homeostasis among other processes. Pkc is primarily involved in maintaining cell wall integrity (CWI) in response to different environmental stresses. Cross-talk between the Ca2+ and Pkc-mediated pathways has mainly been described in Saccharomyces cerevisiae and in a few other filamentous fungi. The presented study describes a genetic interaction between CnaA and PkcA in the filamentous fungus Aspergillus nidulans. Overexpression of pkcA partially rescues the phenotypes caused by a cnaA deletion. Furthermore, CnaA appears to affect the regulation of a mitogen-activated kinase, MpkA, involved in the CWI pathway. Reversely, PkcA is involved in controlling intracellular calcium homeostasis, as was confirmed by microarray analysis. Furthermore, overexpression of pkcA in a cnaA deletion background restores mitochondrial number and function. In conclusion, PkcA and CnaA-mediated signaling appear to share common targets, one of which appears to be MpkA of the CWI pathway. Both pathways also regulate components involved in mitochondrial biogenesis and function. This study describes targets for PkcA and CnaA-signaling pathways in an A. nidulans and identifies a novel interaction of both pathways in the regulation of cellular respiration.


Iodine-Catalyzed Radical C-H Amination of Nonaromatic Imidazole Oxides: Access to Cyclic α-Aminonitrones.
A straightforward cross-dehydrogenative coupling approach to incorporate alicyclic amino residues into the structure of model cyclic aldonitrones, 2H-imidazole oxides, is reported. The elaborated C(sp2)-H functionalization is achieved by employing cyclic amines in the presence of the I2-tert-butyl hydroperoxide (TBHP) reagent system. As a result, a series of 19 novel heterocyclic derivatives were obtained in yields of up to 97%. A mechanistic study involving electron paramagnetic resonance spectroscopic experiments allowed the radical nature of the reaction to be confirmed. In particular, the envisioned mechanistic rationale comprises N-iodination of a cyclic amine, followed by N-I bond homolysis of the resulting intermediate and subsequent amination of the nitrone moiety via the newly generated nitrogen-centered radical.


Polymorphism at the rad gene is not associated with NIDDM in Finns.
Recently, a trinucleotide repeat polymorphism at the rad (ras associated with diabetes) locus (RAD1) on chromosome 16q was described in association with NIDDM in white Americans. In an attempt to replicate this finding, we screened RAD1 and another microsatellite marker at the D16S265 loci, which is located near the rad locus, with a radioactive polymerase chain reaction method in 290 unrelated Finnish NIDDM patients and 270 control subjects and related the findings to measures of insulin sensitivity. Both groups were randomly selected from the western (189 NIDDM patients and 184 control subjects) and southern (101 NIDDM and 86 control subjects) parts of Finland. The allele frequency distributions of RAD1 and D16S265 did not differ between NIDDM patients and control subjects in the studied population groups. The genotype distribution was also analyzed by structural classes of the RAD1 polymorphism, and no difference was detected between the NIDDM and control groups. In addition, carriers of allele classes I, II, and IV (reported to be preferentially associated with NIDDM in white Americans) did not differ from the class III homozygotes with respect to age at onset of NIDDM, BMI, or rates of insulin-stimulated glucose disposal. In conclusion, we found no association between the rad locus and NIDDM or insulin resistance in Finnish NIDDM patients.


The predictive value of arterial and valvular calcification for mortality and cardiovascular events.
A review of the predictive ability of arterial and valvular calcification has shown an additive effect of calcification in more than 1 location in predicting mortality and coronary heart disease, with mitral annual calcification being a particularly strong predictor. In individual arteries and valves there is a clear association between calcification presence, extent and progression and future cardiovascular events and mortality in asymptomatic, symptomatic and high risk patients, although adjustment for calcification in other arterial beds generally renders associations non-significant. Furthermore, in acute coronary syndrome, culprit plaque is normally not calcified. This would tend to reduce the validity of calcification as a predictor and suggest that the association with cardiovascular events and mortality may not be causal. The association with stroke is less clear; carotid and intracranial artery calcification show little predictive ability, with symptomatic plaques tending to be uncalcified.