Dyslexia and music: measuring musical timing skills.
Over the last few decades, a growing amount of research has suggested that dyslexics have particular difficulties with skills involving accurate or rapid timing, including musical timing skills. It has been hypothesised that music training may be able to remediate such timing difficulties, and have a positive effect on fundamental perceptual skills that are important in the development of language and literacy skills (Overy, 2000). In order to explore this hypothesis further, the nature and extent of dyslexics' musical difficulties need to be examined in more detail. In the present study, a collection of musical aptitude tests (MATs) were designed specifically for dyslexic children, in order to distinguish between a variety of musical skills and sub-skills. 15 dyslexic children (age 7-11, mean age 9.0) and 11 control children (age 7-10, mean age 8.9) were tested on the MATs, and their scores were compared. Results showed that the dyslexic group scored higher than the control group on 3 tests of pitch skills (possibly attributable to slightly greater musical experience), but lower than the control group on 7 out of 9 tests of timing skills. Particular difficulties were noted on one of the tests involving rapid temporal processing, in which a subgroup of 5 of the dyslexic children (33%) (mean age 8.4) was found to account for all the significant error. Also, an interesting correlation was found between spelling ability and the skill of tapping out the rhythm of a song, which both involve the skill of syllable segmentation. These results support suggestions that timing is a difficulty area for dyslexic children, and suggest that rhythm skills and rapid skills may need particular attention in any form of musical training with dyslexics.


[On X-ray diagnosis of pathologic conditions of paranasal sinuses].
A method for X-ray examination of paranasal sinuses is proposed ensuring an optimal possibility for the assessment of their condition regardless of anatomical structure of the skull. X-ray imaging is performed with the skull sagittal plane being perpendicular to the plane of the X-ray cassette and the X-ray beam directed strictly into its centre through the selected anatomical structures. High quality of X-ray images irrespective of the patient's somatic status is ensured due to the absence of projective overlap between temporal bone pyramids and lower portions of maxillary sinuses. Another advantage of the method is reduced radiation exposure of the patient. To date, a total of 86 patients has been examined by the proposed method in the clinical hospital No 1, Southern Medical Centre of the Federal agency for healthcare and social development.


Case Report: Pulmonary and Liver Sarcoidosis Suspected of Metastasis.
Introduction: Sarcoidosis is a granulomatous disease with unknown cause that can vary from an asymptomatic condition. Almost half of the patients with sarcoidosis have no symptoms. In this article, we describe a sarcoidosis patient with lung and liver engagement; it may be confused with metastasis. Case report: A 39-year-old man, with known as hypothyroidism who had come to the emergency ward with dyspnea and coughing after exposure to detergents in a closed environment. The patient smoked for 10 years (3 pack/year). No other findings were found in clinical examinations except for wheezing in the right lung. The patient's chest radiography was shown a mass. For further investigation, spiral CT scan was performed. Large lymph nodes on the right side of the trachea, measuring about 23 mm and a mass of 70 × 77 mm in the vicinity of the right lung hilum and a hypodense nodule in the posterior part of the liver with malignancy suspicious were reported. After several biopsy results was shown chronic granulomatous inflammation, the most important differential diagnosis is tuberculosis (TB) and sarcoidosis. Sputum smear, culture, and PCR were performed for tuberculosis. Also, the level of angiotensin-converting enzyme (ACE) was measured for sarcoidosis. the results ruled out TB and shown a higher level of ACE (ACE = 88 IU/L).After diagnosis treatment started with prednisolone. Now, the patient is in the follow- up. Conclusion: In hilar lymphadenopathy of lung sarcoidosis is the importance differential diagnosis that should be considered.


Behavior of centrosomes during fertilization and cell division in mouse oocytes and in sea urchin eggs.
The forms and locations of centrosomes in mouse oocytes and in sea urchin eggs were followed through the whole course of fertilization and first cleavage by immunofluorescence microscopy. Centrosomes were identified with an autoimmune antiserum to centrosomal material. Staining of the same preparations with tubulin antibody and with the DNA dye Hoechst 33258 allowed the correlation of the forms of the centrosomes with the microtubule structures that they generate and with the stages of meiosis, syngamy, and mitosis. The results with sea urchin eggs conform to Boveri's view on the paternal origin of the functional centrosomes. Centrosomes are seen in spermatozoa and enter the egg at fertilization. Initially, the centrosomes are compact, but as the eggs enter the mitotic cycle the forms of the centrosomes go through a cycle in which they spread during interphase, apparently divide, and condense into two compact poles by metaphase. In anaphase, they spread to form flat poles. In telophase and during reconstitution of the daughter nuclei, the centrosomal material is disposed as hemispherical caps around the poleward surfaces of the nuclei. Mouse sperm lack centrosomal antigen. In the unfertilized mouse oocyte, the meiotic spindle poles are displayed as broad-beaded centrosomes. In addition, centrosomal material is detected in the cytoplasm as particles, about 16 in number, which are foci of small aster-like arrays of microtubules. The length and number of astral microtubules correlate with the size of the centrosomal foci. After sperm incorporation, as the pronuclei develop and more cytoplasmic microtubules assemble, a few of the foci associate with the peripheries of the nuclei. The number of foci multiplies during the first cell cycle. At the end of interphase, all of the centrosomal foci have concentrated on the nuclear peripheries and the cytoplasmic microtubules have disappeared. At prophase, the centrosomes are seen as two irregular clusters, marking the poles which, at metaphase and anaphase, appear as rough bands with foci, and the spindle is typically barrel-shaped. At telophase, the centrosomes are seen as arcs that lie on the nuclear peripheries after cleavage. The ordering of microtubules in all the stages reflects the shapes of the centrosomes. The findings on the sea urchin confirm the classical theory of the paternal origin of centrosomes and contrast with observations tracing the mitotic poles of the mouse egg to maternal centrosomal material. This evidence strengthens the conclusion that mouse centrosomes derive from the oocyte.


The structure of the teleost Immunoglobulin M core provides insights on polymeric antibody evolution, assembly, and function.
Polymeric (p) immunoglobulins (Igs) serve broad functions during vertebrate immune responses. Typically, pIgs contain between two and six Ig monomers, each with two antigen binding fragments and one fragment crystallization (Fc). In addition, many pIgs assemble with a joining-chain (JC); however, the number of monomers and potential to include JC varies with species and heavy chain class. Here, we report the cryo-electron microscopy structure of IgM from a teleost (t) species, which does not encode JC. The structure revealed four tIgM Fcs linked through eight C-terminal tailpieces (Tps), which adopt a single β-sandwich-like domain (Tp assembly) located between two Fcs. Remarkably, two of eight heavy chains fold uniquely, resulting in a structure distinct from mammalian IgM, which typically contains five IgM monomers, one JC and a centrally-located Tp assembly. Together with mutational analysis, structural data indicate that pIgs have evolved a range of assembly mechanisms and structures, each likely to support unique antibody effector functions.


The diagnosis of GI stromal tumors with EUS-guided fine needle aspiration with immunohistochemical analysis.
With the advent of immunohistochemical analysis, the term "gastrointestinal stromal tumor" (GIST) was proposed to designate the largest category of primary nonepithelial neoplasms. EUS-guided fine needle aspiration (EUS-FNA) is useful for diagnosis of GISTs. The aim of this study was to evaluate the phenotyping of GISTs and diagnosis of malignant GISTs by using EUS-FNA with immunohistochemical analysis. A diagnosis of GIST was made in 23 patients by using EUS-FNA with immunohistochemical analysis. The accuracy of EUS-FNA diagnosis compared with the EUS imaging alone was analyzed. Additionally, immunophenotyping of specimens obtained by EUS-FNA and surgical resection specimens was compared. Factors that were diagnostic for malignant GISTs were also analyzed. The overall accuracy for the diagnosis of malignant GIST was 78% (18/23) by EUS imaging alone and 91% (21/23) by histopathologic evaluation (H&E staining) of specimens obtained by EUS-FNA. In 21 of 23 cases (91%) the immunohistochemical expressions of c-kit, CD34, muscle actin, and S-100 coincided for the FNA and surgical specimens. The presence of mitotic cells (p = 0.011) and the Ki-67 labeling index (p < 0.0001) with respect to the FNA specimens were significant predictive factors for malignant GIST. For the diagnosis of malignant GIST, the accuracy, sensitivity, and specificity of EUS-FNA with the addition of Ki-67 immunohistochemical staining were 100%. EUS-FNA with immunohistochemical analysis is useful in the preoperative diagnosis of GIST. It provides abundant information on immunohistochemical subtyping and on the capacity of the tumor for cellular progression.


Presenting symptoms of nonerosive and erosive esophagitis in pediatric patients.
Children and adolescents with symptomatic gastroesophageal reflux disease (GERD) and erosive esophagitis (EE) of grade >/=2 (n=45) or nonerosive esophagitis (NEE) (n=45) were assessed to determine the relationship between presenting symptoms, esophagitis severity, and patient age. Overall, regurgitation/vomiting, abdominal pain, and cough were the most frequent symptoms. The prevalence and severity of anorexia/feed refusal was significantly greater in EE versus NEE children; this symptom was also significantly more prevalent in younger (1-5 years) children (both NEE and EE groups) compared to older children. Cough was significantly less severe in NEE adolescents than in younger children. Cough, anorexia/feed refusal, and regurgitation/vomiting were more severe and heartburn was less severe in EE children aged 1-5 years compared with older patients. In conclusion, GERD in children manifests differently than that in adults and symptoms vary with patient age. Symptoms were not predictive of presence or lack of mucosal damage.


A qualitative study of veterans on long-term opioid analgesics: barriers and facilitators to multimodality pain management.
The aim of this study was to examine barriers and facilitators to multimodality chronic pain care among veterans on high-dose opioid analgesics for chronic non-cancer pain. A Veterans Health Administration clinic in San Antonio. Twenty-five veterans taking at least 50 mg morphine equivalent daily oral opioid doses for more than 6 months. Three semi-structured focus groups, each with seven to nine veterans. Interview guide addressed: chronic pain effects on quality of life, attitudes/experiences with multimodality pain care, social support, and interest in peer support. In an iterative process using grounded theory, three reviewers reviewed de-identified transcripts for themes. The theory of planned behavior (TPB) framework was used to classify barriers and facilitators to multimodal pain management. The 25 participants had a mean age of 54 years (39-70); 32% were women and 24% non-white. The three TPB dimensions (attitudes, social norms, and perceived behavioral control) were reflected in emergent themes: 1) uncontrollable impact of pain in all aspects of life; 2) reliance on opioids and challenges in obtaining these drugs despite ambivalence about benefits; 3) poor access to and beliefs about non-pharmacologic therapies; 4) frustrations with Department of Veterans Affairs health care; and 5) poor social support and isolation reflected by limited interest in peer support. Veterans with chronic pain on long-term opioids hold pervasive attitudes that prevent them from using multimodality pain management options, lack social support and social norms for non-opioid-based pain treatment options, and have poor perceived control due to poor access to multimodality care.


Petite mutagenesis in Saccharomyces cerevisiae by a series of bis-cationic trypanocidal drugs.
A group of bis-cationic imidazo[1,2-a]pyridinium salts and related compounds, some of which exhibit in vivo trypanocidal activity, have been investigated for induction of petite mutagenesis in Saccharomyces cerevisiae. All of the compounds which are active trypanocides induce mutagenesis. There appears to be a correlation between trypanocidal activity and mutagenic activity which may have its structural origin in the spatial separation of the cationic centers.


What's up with my neck? Ultrasound and surgical findings in cervical midline tumors.
Evaluate ultrasound (US) sensitivity and specificity in suspected thyroglossal duct cysts (TGDC) undergoing surgery in our hospital, and their correlation with surgical findings. Retrospective study of 150 patients undergoing surgery for midline neck mass suggestive of TGDC (2008-2018). We analyzed epidemiological variables and compared the correlation between diagnostic ultrasound imaging and surgical findings, considering previous episodes of local infection. Mean age at surgery was 3.96 years (0.75-12.58 years). Of the 150 patients, 81 were male and 69 were female. Following ultrasound examination, 110 were suspected to have TGDC, and diagnosis was confirmed after surgery in 80 cases. Of the remaining 40 cases without TGDC-compatible US examination, TGDC was confirmed in 15 cases. The rest were diagnosed with dermoid cyst (49), lymphadenopathy (4), and vascular malformation (2). US sensitivity was 84%, while specificity was 45%, with a positive predictive value of 73%, and a negative predictive value of 62%. In 62.1% (59) of TGDCs, a previous infection episode had been described, with 16.7% of cases requiring surgical drainage. 13.6% had recurrence after Sistrunk technique. There was no statistically significant relationship between previous infection episodes and postsurgical recurrence, or between surgical or spontaneous drainage and cyst recurrence. Even though US role in eutopic thyroid gland identification cannot be doubted, it provides with low specificity in the study of midline neck masses. Therefore, the physician's opinion should be prioritized.


Lymphocyte cultures of Macaca mulatta and Macaca fascicularis.
Lymphocytes of Macaca mulatta and Macaca fascicularis were cultured using a microculture technic. The use of RPMI-1640 with fetal calf serum as a culture medium and an extra dose of phytohemagglutinin produced excellent results. Staining of the chromosomes by the Gemsa banding technic did not reveal any differences between the karyotypes of the Macaca species.


[A comparative study of the role of atresia and stenosis of the outflow duct of a salivary gland in the pathogenesis of dystrophic and inflammatory changes].
Experiments were carried out with submandibular salivary glands of 20 dogs. Complete obturation of the submandibular duct (in 10 animals) was achieved by binding this duct. Partial impairment of the saliva flow from the gland was induced in 10 animals by fixing a metal ring on the duct. The experiment has demonstrated that both complete and partial obturation of the salivary duct result in the development of chronic sialadenitis. Partial obturation of salivary outflow from the gland did not result in an acute inflammation but in a flaccid process, slowly developing dystrophic changes in acinar cells, gradually developing sclerosis of the glandular parenchyma and stroma. These data indicate a direct relationship between the intensity of dystrophic changes in the salivary gland and the severity of impairment of salivary discharge.


Prefrontal serotonin transporter availability is positively associated with the cortisol awakening response.
Stress sensitivity and serotonergic neurotransmission interact, e.g. individuals carrying the low-expressing variants (S and LG) of the 5-HTTLPR promoter polymorphism of the serotonin transporter (SERT) gene are at higher risk for developing mood disorders when exposed to severe stress and display higher cortisol responses when exposed to psychosocial stressors relative to high expressing 5-HTTLPR variants. However, it is not clear how the relation between SERT and cortisol output is reflected in the adult brain. We investigated the relation between cortisol response to awakening (CAR) and SERT binding in brain regions considered relevant to modify the cortisol awakening response. thirty-two healthy volunteers underwent in vivo SERT imaging with [(11)C]DASB-Positron Emission Tomography (PET), genotyping, and performed home-sampling of saliva to assess CAR. CAR, defined as the area under curve with respect to increase from baseline, was positively coupled to prefrontal SERT binding (p=0.02), independent of adjustment for 5-HTTLPR genotype. Although S- and LG-allele carriers tended to show a larger CAR (p=0.07) than LA homozygous, 5-HTTLPR genotype did not modify the coupling between CAR and prefrontal SERT binding as tested by an interaction analysis (genotype×CAR). prefrontal SERT binding is positively associated with cortisol response to awakening. We speculate that in mentally healthy individuals prefrontal serotonergic neurotransmission may exert an inhibitory control on the cortisol awakening response.


Oral hibernoma along with multiple lipomas.
'Hibernoma' is a neoplasm that arises from vestiges of fetal brown fat, and its occurrence in oral cavity is extremely rare. Its most common locations include thighs, the inter-scapular region, and the cervical region. In the present case, a 37-year-old male patient reported to our department with a localized swelling on his lower left labial mucosa along with multiple cutaneous well-defined swellings on his right arm and abdominal region. Incisional biopsy was carried out. Histopathological examination revealed sheets of multi-vacuolated eosinophilic cells with the granular cytoplasm interspersed with fat cells suggestive of oral hibernoma. These are rare lesions and could be often a missed-out diagnosis. Therefore, it is imperative to consider oral hibernoma among the commonly considered differential diagnosis of oral mucosal swellings.


Role of mTORC1 in intestinal epithelial repair and tumorigenesis.
mTORC1 signaling is the prototypical pathway regulating protein synthesis and cell proliferation. mTORC1 is active in stem cells located at the base of intestinal crypts but silenced as transit-amplifying cells differentiate into enterocytes or secretory cells along the epithelium. After an insult or injury, self-limiting and controlled activation of mTORC1 is critical for the renewal and repair of intestinal epithelium. mTORC1 promotes epithelial cell renewal by driving cryptic stem cell division, and epithelial cell repair by supporting the dedifferentiation and proliferation of enterocytes or secretory cells. Under repeated insult or injury, mTORC1 becomes constitutively active, triggering an irreversible return to stemness, cell division, proliferation, and inflammation among dedifferentiated epithelial cells. Epithelium-derived cytokines promulgate inflammation within the lamina propria, which in turn releases inflammatory factors that act back on the epithelium where undamaged intestinal epithelial cells participate in the pervading state of inflammation and become susceptible to tumorigenesis.


Identification and characterization of a specific autoantiphosphatidylinositol immune response during the time course of benzo(a)pyrene-induced malignant tumors in female Sprague-Dawley rats.
High levels of anti-phosphatidylinositol (PtdIns) autoantibodies (autoAb) have been previously described in sera of cancer patients and in plasma of dimethylbenzanthracene-treated female Sprague-Dawley rats. The presence of anti-PtdIns autoAb was tested in a model of highly malignant sarcomas induced by a single dose of benzo(a)pyrene [B(a)P] diluted in sesame oil and injected in female Sprague-Dawley rats. Significantly elevated levels of anti-PtdIns autoAb were found in sera of B(a)P-treated rats 40 days after B(a)P administration, whereas no significant levels of anti-PtdIns autoAb were noted in oil- or benzo(e)pyrene-treated rats. After day 60, autoantibody levels plateaued in B(a)P-treated rats, and highly malignant sarcomas appeared with 100% efficiency around day 100. Anti-PtdIns autoAb avidity and specificity were found to be high.


Initiation of Moderately Frequent Cannabis use in Adolescence and Young Adulthood is Associated with Declines in Verbal Learning and Memory: A Longitudinal Comparison of Pre- versus Post-Initiation Cognitive Performance.
Cannabis use is associated with relative cognitive weaknesses as observed by cross-sectional as well as longitudinal research. Longitudinal studies, controlling for relevant confounds, are necessary to differentiate premorbid from post-initiation contributions to these effects. We followed a sample of adolescents and young adults across ten years. Participants provided neurocognitive data and substance use information at two-year intervals. Participants who initiated cannabis and/or alcohol use were identified (n = 86) and split into alcohol-only initiators (n = 39) and infrequent (n = 29) and moderately frequent (n = 18) cannabis initiators. Participants completed the Rey Auditory Verbal Learning Task (RAVLT) and the Iowa Gambling Task (IGT). Group differences before and after substance use initiation and the extent to which alcohol, nicotine, and cannabis use frequencies contributed to cognitive functions over time were examined. After controlling for parental education, RAVLT new learning was worse in moderately frequent cannabis users prior to use initiation. RAVLT total learning and delayed recall showed significant declines from pre- to post-initiation in moderately frequent cannabis users. Regression analyses confirmed that frequencies of cannabis, but not alcohol, use contributed to post-initiation variations. Nicotine use showed an independent negative association with delayed memory. Findings for the IGT were not significant. Verbal learning and memory may be disrupted following the initiation of moderately frequent cannabis use while decreased new learning may represent a premorbid liability. Our use of a control group of alcohol-only users adds interpretive clarity to the findings and suggests that future studies should carefully control for comorbid substance use.


FR121196, a potential antidementia drug, ameliorates the impaired memory of rat in the Morris water maze.
We investigated the effects of FR121196 N-(4-acetyl-1-piperazinyl)-4-fluorobenzenesulfonamide on the performance of rats in the Morris water maze using a two-trial-per-day regimen. Escape latency to find the platform was significantly prolonged in young rats subjected to scopolamine (1 mg/kg) treatment or to nucleus basalis magnocellularis (NBM) or fimbria-fornix (FF) lesioning compared with the respective control animals. Similar memory deficit was observed in aged rats (24-26 months old) compared with young rats. Daily treatment with FR121196 (0.1-1.0 mg/kg i.p.) ameliorated all the memory deficits except in the FF-lesioned rats, whereas physostigmine (0.032-0.32 mg/kg) ameliorated the memory deficits in scopolamine-treated rats but not in the NBM-lesioned, FF-lesioned or aged rats. Methamphetamine (0.32-3.2 mg/kg) hardly ameliorated the memory deficits and, rather, aggravated those in the scopolamine-treated, NBM-lesioned and aged rats. Neurochemical analysis of the brain showed that dopamine, norepinephrine and serotonin levels were significantly reduced in the hippocampus of the FF-lesioned rats compared with the sham control, and a significant reduction of dopamine level in the cortex was also observed in the aged rats compared with young rats. None of these parameters were changed after NBM lesioning. We concluded that FR121196 ameliorates the memory deficits of rats with cholinergic dysfunction through the action on the hippocampal monoaminergic (possibly serotonergic) neurons.


Hydrogen-rich water attenuates oxidative stress in rats with traumatic brain injury via Nrf2 pathway.
Several studies have recently found that oxidative stress plays a pivotal role in the pathogenesis of traumatic brain injury (TBI) and may represent a target in TBI treatment. Hydrogen-rich water was recently shown to exert neuroprotective effects in various neurological diseases through its antioxidant properties. However, the mechanisms underlying its effects in TBI are not clearly understood. The purpose of our study was to evaluate the neuroprotective role of hydrogen-rich water in rats with TBI and to elucidate the possible mechanisms underlying its effects. The TBI model was constructed according to the modified Feeney weight-drop method. In part 1 of the experiment, we measured oxidative stress levels by observing the changes in catalase (CAT), glutathione peroxidase (GPx), and malondialdehyde (MDA) expressions. We also evaluated nuclear factor erythroid 2-related factor 2 (Nrf2) levels to determine the role of the protein in the neuroprotective effects against TBI. In part 2, we verified the neuroprotective effects of hydrogen-rich water in TBI and observed its effects on Nrf2. All the experimental rats were divided into sham group, TBI group, and TBI + hydrogen-rich water-treated (TBI + HW) group. We randomly chose 20 rats from each group and recorded their 7-d survival rates. Modified neurological severity scores were recorded from an additional six rats per group, which were then sacrificed 24 h after testing. Spectrophotometry was used to measure GPx, CAT, and MDA levels, whereas western blotting, reverse transcription polymerase chain reaction, and immunohistochemistry were used to measure the expression of Nrf2 and downstream factors like heme oxygenase 1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). GPx and CAT activity was significantly decreased, and MDA content was increased in the TBI group compared with the sham group at 6 h after TBI. MDA content peaked at 24 h after TBI. Nrf2 nucleoprotein levels were upregulated in the TBI group compared with the sham group and peaked at 24 h after TBI; however, no significant changes in Nrf2 mRNA levels were noted after TBI. Hydrogen-rich water administration significantly increased 7-d survival rates, reduced neurologic deficits, and lowered intracellular oxidative stress levels. Moreover, hydrogen-rich water caused Nrf2 to enter the cell nucleus, which resulted in increases in the expression of downstream factors such as HO-1 and NQO1. Our results indicate that hydrogen-rich water has neuroprotective effects against TBI by reducing oxidative stress and activating the Nrf2 pathway.


Planning for sustainability in China's urban development: status and challenges for Dongtan eco-city project.
With the rapid urbanization in China, the country faces significant challenges in sustainable urban development and actively explores novel ways to expand urban areas while conserving natural resources. Radical changes in city planning are being made to switch to sustainable development, with new cities being designed to be ecologically friendly guided by principles like carbon neutrality and self-sufficiency. This paper introduces the development of the Dongtan eco-city project on Chongming Island, Shanghai and describes how it addresses issues including energy, water, waste, transportation, ecosystem, and social and economic development in its design. The lessons and challenges of eco-city development based on the Dongtan experience are also discussed. If the vision of a zero-carbon emissions sustainable city is successfully realized, Dongtan will serve as a model for developing similar cities across China and the rest of the developing world. Currently, the development of this project is behind schedule and whether the eco-city plan will materialize or not is in question. Even though the project remains mostly on the drawing boards, the planning and preliminary development of Dongtan eco-city have generated significant enthusiasm for green buildings and influenced plans for other sustainable urban development projects in China.


No effect of histamine on human bronchial epithelial cell permeability and tight junctional integrity in vitro.
Both animal and human studies have suggested that histamine increases airway epithelial cell permeability in vivo. In order to study the effect of histamine on paracellular epithelial permeability and tight junctional integrity, we have cultured human bronchial epithelial cells to confluency and investigated the effect of topically applied 0.1-20.0 microM histamine. Cultures were established on microporous membranes of tissue culture cell inserts and used for the assessment of: 1) transepithelial movement of radiolabelled mannitol (14C-mannitol) and bovine serum albumin (14C-BSA), in the luminal to serosal direction and 2) changes in electrical resistance of the cultures. Epithelial cell cultures were also established on plastic coverslips, in order to determine tight junction morphology by freeze-fracture electron microscopy, and to assess junctional integrity by lanthanum penetration, using thin sections. Compared with untreated control cultures, 0.1-10 microM histamine did not significantly alter the movement of either 14C-mannitol or 14C-BSA across the epithelial cultures at any time during incubation, but caused an increase in the electrical resistance of the cultures, which was maximal by 6 h of incubation. The morphology of the tight junctions revealed by freeze-fracture and junctional integrity (the latter determined by the degree of lanthanum penetration) were similar in untreated control cultures and cultures incubated with histamine. These studies indicate that histamine does not have a direct effect on paracellular bronchial epithelial permeability in vitro.


The potency of inducers of NAD(P)H:(quinone-acceptor) oxidoreductase parallels their efficiency as substrates for glutathione transferases. Structural and electronic correlations.
Induction of glutathione transferases (EC. 126.96.36.199), NAD(P)H:(quinone-acceptor) oxidoreductase (EC 184.108.40.206; quinone reductase) and other detoxification enzymes is a major mechanism for protecting cells against the toxicities of electrophiles, including many carcinogens. Although inducers of these two enzymes belong to many different chemical classes, they nevertheless contain (or acquire by metabolism) electrophilic centres that appear to be essential for inclusive activity, and many inducers are Michael reaction acceptors [Talalay, De Long & Prochaska (1988) Proc. Natl. Acad. Sci. U.S.A., 85, 8261-8265]. The inducers therefore share structural and electronic features with glutathione transferase substrates. To define these features more precisely, we examined the inductive potencies (by measuring quinone reductase in murine hepatoma cells) of two types of glutathione transferase substrates: a series of 1-chloro-2-nitrobenzenes bearing para-oriented electron-donating or -withdrawing substituents and a wide variety of other commonly used and structurally unrelated glutathione transferase substrates. We conclude that virtually all glutathione transferase substrates are inducers, and their potencies in the nitrobenzene series correlate linearly with the Hammett sigma or sigma- values of the aromatic substituents, precisely as previously reported for their efficiencies as glutathione transferase substrates. More detailed information on the electronic requirements for inductive activity was obtained with a series of methyl trans-cinnamates bearing electron-withdrawing or -donating substituents on the aromatic ring, and in which the electronic densities at the olefinic and adjacent carbon atoms were measured by 13C n.m.r. Electron-withdrawing meta-substituents markedly enhance inductive potency in parallel with their increased non-enzymic reactivity with GSH. Thus, methyl 3-bromo-, 3-nitro- and 3-chloro-cinnamates are 21, 14 and 8 times more potent inducers than the parent methyl cinnamate. This finding permits the design of more potent inducers, which are important for elucidation of the molecular mechanisms of induction.


A protein constructed de novo enables cell growth by altering gene regulation.
Recent advances in protein design rely on rational and computational approaches to create novel sequences that fold and function. In contrast, natural systems selected functional proteins without any design a priori. In an attempt to mimic nature, we used large libraries of novel sequences and selected for functional proteins that rescue Escherichia coli cells in which a conditionally essential gene has been deleted. In this way, the de novo protein SynSerB3 was selected as a rescuer of cells in which serB, which encodes phosphoserine phosphatase, an enzyme essential for serine biosynthesis, was deleted. However, SynSerB3 does not rescue the deleted activity by catalyzing hydrolysis of phosphoserine. Instead, SynSerB3 up-regulates hisB, a gene encoding histidinol phosphate phosphatase. This endogenous E. coli phosphatase has promiscuous activity that, when overexpressed, compensates for the deletion of phosphoserine phosphatase. Thus, the de novo protein SynSerB3 rescues the deletion of serB by altering the natural regulation of the His operon.


The genetic basis of female reproductive disorders: etiology and clinical testing.
With the advent of improved molecular biology techniques, the genetic basis of an increasing number of reproductive disorders has been elucidated. Mutations in at least 20 genes cause hypogonadotropic hypogonadism including Kallmann syndrome in about 35-40% of patients. The two most commonly involved genes are FGFR1 and CHD7. When combined pituitary hormone deficiency includes hypogonadotropic hypogonadism as a feature, PROP1 mutations are the most common of the six genes involved. For hypergonadotropic hypogonadism, mutations in 14 genes cause gonadal failure in 15% of affected females, most commonly in FMR1. In eugonadal disorders, activating FSHR mutations have been identified for spontaneous ovarian hyperstimulation syndrome; and WNT4 mutations have been described in mullerian aplasia. For other eugonadal disorders, such as endometriosis, polycystic ovary syndrome, and leiomyomata, specific germline gene mutations have not been identified, but some chromosomal regions are associated with the corresponding phenotype. Practical genetic testing is possible to perform in both hypogonadotropic and hypergonadotropic hypogonadism and spontaneous ovarian hyperstimulation syndrome. However, clinical testing for endometriosis, polycystic ovary syndrome, and leiomyomata is not currently practical for the clinician.


Depressive symptoms among mothers of children with epilepsy: a review of prevalence, associated factors, and impact on children.
The impact of epilepsy is not limited to the child experiencing seizures, but affects all members of the family. As primary caregivers, mothers are particularly at risk for experiencing increased depressive symptoms and risk for clinical depression. The objective of this systematic review was to critically assess available evidence regarding the prevalence, associated factors, and impact of maternal depressive symptoms on child outcomes in epilepsy. Using a modified version of the Quality Index, studies were rigorously evaluated in terms of reporting, external validity, and internal validity. Limitations in the study designs and analytic techniques of previous research are discussed, and study methods to overcome these barriers are presented in order to advance this research area. Up to 50% of mothers of children with epilepsy are at risk for clinical depression. Correlates of maternal depressive symptoms include a number of modifiable risk factors such as role ambiguity, worry, and satisfaction with relationships. In addition, studies suggest that depressive symptoms in mothers have a negative impact on child outcomes in epilepsy including behavior problems and health-related quality of life. The overall mean score on the Quality Index was 9.7, indicating a midrange quality score, suggesting a need for more methodologically robust studies.


Noninvasive diagnosis of incomplete endovascular aneurysm repair: D-dimer assay to detect type I endoleaks and nonshrinking aneurysms.
To test the hypothesis that D-dimer (D-D), a cross-linked fibrin degradation product of an ongoing thrombotic event, could be a marker for incomplete aneurysm exclusion after endovascular abdominal aortic aneurysm (AAA) repair. In a multicenter study, 83 venous blood samples were collected from 74 AAA endograft patients and controls. Twenty subjects who were >6 months postimplantation and had evidence of an endoleak and/or an unmodified or increasing AAA sac diameter formed the test group. Controls were 10 nondiseased subjects >65 years old, 18 AAA surgical candidates, and 26 postoperative endograft patients with no endoleak and a shrinking aneurysm. Blood samples were analyzed for D-D through a latex turbidimetric immunoassay. The endograft patients were stratified into 5 clinical groups for analysis: no endoleak and decreasing sac diameter, no endoleak and increasing/unchanged sac diameter, type II endoleak and decreasing sac diameter, type II endoleak and increasing/unchanged sac diameter, and type I endoleak. Individual D-D values were highly variable, but differences among clinical groups were statistically significant (p < 0.0001). D-D values did not vary significantly between patients with stable, untreated AAAs and age-matched controls (238 +/- 180 ng/mL versus 421 +/- 400 ng/mL, p > 0.05). Median D-D values increased at 4 days postoperatively (963 ng/mL versus 382 ng/mL, p > 0.05) and did not vary thereafter if there was no endoleak and the aneurysm sac decreased. D-D mean values were higher in patients with type I endoleak (1931 +/- 924 ng/mL, p < 0.005) and those with unchanged/increasing sac diameters (1272 +/- 728 ng/mL) than in cases with decreasing diameters (median 638 +/- 238 ng/mL) despite the presence of endoleak (p < 0.0005). Elevated D-D may prove to be a useful marker for fixation problems after endovascular AAA repair and may help rule out type I endoleak, thus excluding patients from unnecessary invasive tests.


Electronic liquid crystal contact lenses for the correction of presbyopia.
Presbyopia, the age-related reduction in near vision acuity, is one of the leading issues facing the contact lens industry due to an increasingly ageing population and limitations associated with existing designs. A plastic-based liquid crystal contact lens is described which is designed to allow switchable vision correction. The device is characterized by low operating voltages (<5V(rms)) and has curvatures suitable for placement upon the cornea. Imaging and Point Spread Function analysis confirm that the lens provides an increase in optical power of + 2.00 ± 0.25 D when activated, ideal for presbyopia correction.


Multiple ADH genes are associated with upper aerodigestive cancers.
Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.


Distribution of Radioactive Cesium during Milling and Cooking of Contaminated Buckwheat.
To clarify the behavior of radioactive cesium (Cs) in buckwheat grains during milling and cooking processes, parameters such as processing factor (Pf) and food processing retention factor (Fr) were evaluated in two lots of buckwheat grains, R1 and R2, with different concentrations of radioactive Cs. Three milling fractions, the husk, bran, and flour fractions, were obtained using a mill and electric sieve. The radioactive Cs (134Cs + 137Cs) concentrations in husk and bran were higher than that in grain, whereas the concentration in flour was lower than that in grain. Pf values for the flours of R1 and R2 were 0.60 and 0.80, respectively. Fr values for the flours of R1 and R2 were 0.28 and 0.53, respectively. Raw buckwheat noodles (soba) were prepared using a mixture of buckwheat flour and wheat flour according to the typical recipe and were cooked with boiling water for 0.5, 1, and 2 min, followed by rinsing with water. Pf values for the soba boiled for 2 min (optimal for eating) made with R1 and R2 were 0.34 and 0.40, respectively. Fr values for these R1 and R2 samples were 0.55 and 0.66, respectively. Pf and Fr values for soba boiled for different times for both R1 and R2 were less than 0.6 and 0.8, respectively. Thus, buckwheat flour and its product, soba, cooked by boiling, are considered acceptable for human consumption according to the standard limit for radioactive Cs in buckwheat grains.


Influence of antioxidants on arachidonic acid metabolism and platelet function.
Studies from our laboratory demonstrated that the free radical scavenger, nitro blue tetrazolium, and iron chelators, such as dypyrydil, are potent inhibitors of arachidonic acid oxidation and platelet function. In the present study, we have evaluated the effects of known antioxidants, such as butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), and diphenylamine, on arachidonic acid metabolism and platelet function. Diphenylamine, a common dye intermediate used in hair color formulations, was the most potent inhibitor of arachidonic acid metabolism by platelet cyclooxygenases. Diphenyl and BHA were also potent inhibitors of arachidonic acid oxidation. Other diphenyl analogues and BHT were relatively poor inhibitors of arachidonic-mediated platelet activation. Results of this study, as well as those of our earlier studies, suggest that antioxidants and iron chelators prevent arachidonic acid metabolism and alter platelet function by interfering with the heme/arachidonic acid interaction and blocking cyclooxygenase metabolites essential for the formation of thromboxane A2, a potent platelet agonist.


Introducing interventional pain services in a large african teaching hospital: challenges and opportunities.
There is a need for interventional pain management in the developing world; however, there are many barriers to the introduction of interventional pain therapies. This brief report describes one approach to the introduction of interventional pain medicine to a Nigerian teaching hospital. Although many barriers exist, interventional pain medicine can be brought to the developing world, as demonstrated in this case series.


The efficacy of conjoint behavioral consultation in the home setting: Outcomes and mechanisms in rural communities.
This study reports the results of a randomized controlled trial examining the effect of Conjoint Behavioral Consultation (CBC), a family-school partnership intervention, on children's behaviors, parents' skills, and parent-teacher relationships in rural community and town settings. Participants were 267 children, 267 parents, and 152 teachers in 45 Midwestern schools. Using an Intent to Treat approach and data analyzed within a multilevel modeling framework, CBC yielded promising results for some but not all outcomes. Specifically, children participating in CBC experienced decreases in daily reports of aggressiveness, noncompliance, and temper tantrums; and increases in parent-reported adaptive skills and social skills at a significantly greater pace than those in a control group. Other outcomes (e.g., parent reports of internalizing and externalizing behaviors) suggested a nonsignificant effect at post-test. CBC parents reported using more effective parenting strategies, gaining more competence in their problem-solving practices, and feeling more efficacious for helping their child succeed in school than parents in the control group. Parents participating in CBC also reported significant improvements in the parent-teacher relationship, and the parent-teacher relationship mediated the effect of CBC on children's adaptive skills. Implications for practice in rural communities, study limitations, and directions for future research are discussed.


Climate change winners: receding ice fields facilitate colony expansion and altered dynamics in an Adélie penguin metapopulation.
There will be winners and losers as climate change alters the habitats of polar organisms. For an Adélie penguin (Pygoscelis adeliae) colony on Beaufort Island (Beaufort), part of a cluster of colonies in the southern Ross Sea, we report a recent population increase in response to increased nesting habitat as glaciers have receded. Emigration rates of birds banded as chicks on Beaufort to colonies on nearby Ross Island decreased after 2005 as available habitat on Beaufort increased, leading to altered dynamics of the metapopulation. Using aerial photography beginning in 1958 and modern satellite imagery, we measured change in area of available nesting habitat and population size of the Beaufort colony. Population size varied with available habitat, and both increased rapidly since the 1990s. In accord with glacial retreat, summer temperatures at nearby McMurdo Station increased by ~0.50 °C per decade since the mid-1980s. Although the Ross Sea is likely to be the last ocean with an intact ecosystem, the recent retreat of ice fields at Beaufort that resulted in increased breeding habitat exemplifies a process that has been underway in the Ross Sea during the entire Holocene. Furthermore, our results are in line with predictions that major ice shelves and glaciers will retreat rapidly elsewhere in the Antarctic, potentially leading to increased breeding habitat for Adélie penguins. Results further indicated that satellite imagery may be used to estimate large changes in Adélie penguin populations, facilitating our understanding of metapopulation dynamics and environmental factors that influence regional populations.


Cell cycle specific effects of tumor necrosis factor alpha in monocyte mediated leukemic cell death and the role of beta 2-integrins.
Human monocytes are involved in host defense against neoplastic cells. In view of cellular immunotherapy with cytotoxic monocytes in minimal residual disease of acute myeloid leukemia we have studied the role of monocytes in cell cycle dependent leukemic cell death of U937, THP-1, and HL-60 cells in vitro. Leukemic cells separated in G1 of the cell cycle by countercurrent centrifugal elutriation were highly susceptible to monocyte mediated cytotoxicity, whereas cells in S and G2-M were less sensitive or completely resistant as compared to unfractionated control cells. HL-60 cells resistant to cytotoxic monocytes became sensitive to monocyte mediated cytotoxicity upon differentiation induction with 1,25-dihydroxyvitamin D3 which paralleled an accumulation of cells in G1 of the cell cycle. The differences in susceptibility of cell phase separated populations to monocyte mediated cytotoxicity paralleled differences in sensitivity to the cytotoxic effects of tumor necrosis factor alpha, as secreted by gamma-interferon activated monocytes. Furthermore, monocyte mediated cytotoxicity was markedly inhibited in the presence of anti-CD11/CD18 monoclonal antibodies recognizing the alpha and beta chains of the beta 2-integrin adhesion proteins. By fluorescence activated cell sorter immunofluorescence a marked increase in mean fluorescence density of the beta 2-integrins could be demonstrated on cells in G1 of the cell cycle as compared to unseparated leukemic cells. A decrease in mean fluorescence density was shown for cells in G2-M. By blocking experiments with anti-CD11/CD18 monoclonal antibodies, the differences in mean fluorescence density were functionally relevant since cells in G1 were shown to be the most sensitive cells to beta 2-integrin dependent monocyte mediated cytotoxicity. In conclusion these data show that differences in sensitivity to tumor necrosis factor and in the expression of beta 2-integrins may play a central role in cell cycle dependent monocyte mediated antileukemic activity.


Early external-environmental and internal-health predictors of risky sexual and aggressive behavior in adolescence: An integrative approach.
External predictive adaptive response (PAR) models assume that developmental exposures to stress carry predictive information about the future state of the environment, and that development of a faster life history (LH) strategy in this context functions to match the individual to this expected harsh state. More recently internal PAR models have proposed that early somatic condition (i.e., physical health) critically regulates development of LH strategies to match expected future somatic condition. Here we test the integrative hypothesis that poor physical health mediates the relation between early adversity and faster LH strategies. Data were drawn from a longitudinal study (birth to age 16; N = 1,388) of mostly African American participants with prenatal substance exposure. Results demonstrated that both external environmental conditions early in life (prenatal substance exposure, socioeconomic adversity, caregiver distress/depression, and adverse family functioning) and internal somatic condition during preadolescence (birthweight/gestational age, physical illness) uniquely predicted the development of faster LH strategies in adolescence (as indicated by more risky sexual and aggressive behavior). Consistent with the integrative hypothesis, the effect of caregiver distress/depression on LH strategy was mostly mediated by worse physical health. Discussion highlights the implications of these findings for theory and research on stress, development, and health.


Genetic evidence for a common enzyme catalyzing the second step in the degradation of proline and hydroxyproline.
The initial step in the degradation pathways of proline and hydroxyproline is catalyzed by proline oxidase and hydroxyproline oxidase, yielding delta 1-pyrroline-5-carboxylate and delta 1-pyrroline-3-hydroxy-5-carboxylate, respectively. The second step is the oxidation of delta 1-pyrroline-5-carboxylate to glutamate and delta 1-pyrroline-3-hydroxy-5-carboxylate to gamma-hydroxy-glutamate. To determine if this second step in the degradation of proline and hydroxyproline is catalyzed by a common or by separate enzyme(s), we developed a radioisotopic assay for delta 1-pyrroline-3-hydroxy-5-carboxylate dehydrogenase activity. We then compared delta1-pyrroline-3-hydroxy-5-carboxylate dehydrogenase activity with that of delta 1-pyrroline-5-carboxylate dehydrogenase in fibroblasts and leukocytes from type II hyperprolinemia patients, heterozygotes, and controls. We found that cells from type II hyperprolinemia patients were deficient in both dehydrogenase activities. Furthermore, these activities were highly correlated over the range found in the normals, heterozygotes, and patients. We conclude from these data that a common delta 1-pyrroline-5-carboxylate dehydrogenase catalyzes the oxidation of both delta 1-pyrroline-5-carboxylate and delta 1-pyrroline-3-hydroxy-5-carboxylate, and that this activity is deficient in type II hyperprolinemia.


Developmental Modulation of a beta myosin heavy chain promoter-driven transgene.
The molecular mechanisms underlying heart and skeletal muscle-specific gene expression during development and in response to physioloic stimuli are largely unknown. Using a novel immunohistochemical procedure to detect chloramphenicol acetyltransferase (CAT), we have investigated, in vivo at high resolution, the ability of cis-acting DNA sequences within the 5' flanking region of the mouse beta myosin heavy chain (MyHC) gene (beta-MyHC) to direct appropriate gene expression throughout development. A 5.6-kb fragment 5' to the beta-MyHC's transcriptional start site was linked to the reporter gene encoding CAT (cat) and used to generate transgenic mice. The anti-CAT in situ assay described in this report allowed us to define the ability of the promoter fragment to direct appropriate temporal, tissue- and muscle fiber type-specific gene expression throughout early development. In skeletal muscles, the transgene expression profile mimics the endogenous beta-myHC's at all developmental stages and is appropriately restricted to slow (type I) skeletal fibers in the adult. Surprisingly, transgene expression was detected in both the atria and ventricles during embryonic and fetal development, indicating that ventricular specification involves elements outside the 5.6-kb fragment. In contrast, in the adult, hypothyroid conditions led to transgene induction specifically in the ventricles, suggesting that distinct regulatory mechanisms control fetal versus adult beta-MyHC expression in the cardiac compartment.


Genetic analysis of milk urea nitrogen and lactose and their relationships with other production traits in Canadian Holstein cattle.
The objective of this research was to estimate heritabilities of milk urea nitrogen (MUN) and lactose in the first 3 parities and their genetic relationships with milk, fat, protein, and SCS in Canadian Holsteins. Data were a random sample of complete herds (60,645 test day records of 5,022 cows from 91 herds) extracted from the edited data set, which included 892,039 test-day records of 144,622 Holstein cows from 4,570 herds. A test-day animal model with multiple-trait random regression and the Gibbs sampling method were used for parameter estimation. Regression curves were modeled using Legendre polynomials of order 4. A total of 6 separate 4-trait analyses, which included MUN, lactose, or both (yield or percentage) with different combinations of production traits (milk, fat and protein yield, fat and protein percentages, and somatic cell score) were performed. Average daily heritabilities were moderately high for MUN (from 0.384 to 0.414), lactose kilograms (from 0.466 to 0.539), and lactose percentage (from 0.478 to 0.508). Lactose yield was highly correlated with milk yield (0.979). Lactose percentage and MUN were not genetically correlated with milk yield. However, lactose percentage was significantly correlated with somatic cell score (-0.202). The MUN was correlated with fat (0.425) and protein percentages (0.20). Genetic correlations among parities were high for MUN, lactose percentage, and yield. Estimated breeding values (EBV) of bulls for MUN were correlated with fat percentage EBV (0.287) and EBV of lactose percentage were correlated with lactation persistency EBV (0.329). Correlations between lactose percentage and MUN with fertility traits were close to zero, thus diminishing the potential of using those traits as possible indicators of fertility.


[Alcohol oxidation by Candida guilliermondii yeasts grown on hexadecanol].
A number of enzyme systems involved in the first steps of hexadecane oxidation can be induced by hexadecanol, an intermediate product of hexadecane degradation. It has also been found that, in Candida guilliermondii cells and in their mitochondrial fraction, an oxidase system is induced when the cells are grown on hexadecanol. This system is similar to that in cells grown on hexadecane; it oxidises higher alcohols at a high rate and is not inhibited by the inhibitors of the man phosphorylating respiration chain. The membrane-bound alcohol dehydrogenase and aldehyde dehydrogenase activities resistant to pyrazole, an inhibitor of cytosol ethanol dehydrogenase, are induced together with the oxidase activity when the cells are grown on hexadecanol as well as on hexadecane. The oxidation of higher alcohols by whole cells is entirely inhibited by azide although their oxidation by mitochondria is resistant to the action of azide; apparently, azide inhibits the transport of alcohols into the cell.


Femtosecond laser tagging in R134a with trace quantities of air.
Femtosecond laser tagging is demonstrated for the first time in R134a (1,1,1,2-Tetrafluoroethane) gas, and in mixtures of R134a with small quantities of air. A systematic study of this tagging method is explored through the adjustment of gas pressure, mixture ratio and laser properties. It is found that the signal strength and lifetime are greatest at low pressures for excitation at both the 400 nm and 800 nm laser wavelengths. The relative intensities of two spectral peaks in the near-UV emission change as a function of gas pressure and can potentially be used for local pressure measurements. Single shot precision in pure R134a and R134a with 5% air is demonstrated in quiescent gas and at the exit of a subsonic pipe flow. One standard deviation (68%) of the uncertainty lies within 5 m/s of the mean velocity in a low pressure quiescent flow using a delay time of 3μs, and 18 m/s in a 230 m/s flow using a delay of 5 μs. The parameter space of these results are chosen to mimic conditions used in the NASA Langley Research Center's Transonic Dynamics Tunnel. The precision and signal lifetime demonstrate the feasibility of using this technique for measuring flowfields that induce airfoil flutter.


Protection reduces loss of natural land-cover at sites of conservation importance across Africa.
There is an emerging consensus that protected areas are key in reducing adverse land-cover change, but their efficacy remains difficult to quantify. Many previous assessments of protected area effectiveness have compared changes between sets of protected and unprotected sites that differ systematically in other potentially confounding respects (e.g. altitude, accessibility), have considered only forest loss or changes at single sites, or have analysed changes derived from land-cover data of low spatial resolution. We assessed the effectiveness of protection in reducing land-cover change in Important Bird Areas (IBAs) across Africa using a dedicated visual interpretation of higher resolution satellite imagery. We compared rates of change in natural land-cover over a c. 20-year period from around 1990 at a large number of points across 45 protected IBAs to those from 48 unprotected IBAs. A matching algorithm was used to select sample points to control for potentially confounding differences between protected and unprotected IBAs. The rate of loss of natural land-cover at sample points within protected IBAs was just 42% of that at matched points in unprotected IBAs. Conversion was especially marked in forests, but protection reduced rates of forest loss by a similar relative amount. Rates of conversion increased from the centre to the edges of both protected and unprotected IBAs, but rates of loss in 20-km buffer zones surrounding protected IBAs and unprotected IBAs were similar, with no evidence of displacement of conversion from within protected areas to their immediate surrounds (leakage).


Genomic Heterogeneity of the Naga and Kuki Tribal Populations of Manipur, Northeast India.
Manipur, one of the northeastern states of India, lies on the ancient silk route and serves as a meeting point between Southeast Asia and South Asia. The origin and migration histories of Naga and Kuki tribal populations are not clearly understood. Moreover, Kukis have been traced to two different ancestries, which has created confusion among the people. The present study examined genomic affinities and differentiation of the Naga and Kuki tribal populations of Manipur, Northeast India. Twenty autosomal markers (8 Alu insertion-deletions, 12 restriction-fragment-length polymorphisms) were analyzed. Findings show genetic differences between Naga and Kuki tribal populations with respect to the allele distribution pattern, which was substantiated by genetic differentiation (GST = 5.2%) and molecular variance (AMOVA), where the highest percentage of among-group variances was observed between Naga and Kuki tribal groups (7.09%). However, genetic similarities with respect to allele distribution patterns in most of the loci were seen among their respective groups (Rongmei and Inpui, Thadou and Vaiphei). Rongmei and Inpui tribal populations (Naga group) belong to the Naga-Bodo linguistic group, and Thadou and Vaiphei (Kuki group) belong to the Northern Kuki-Chin linguistic group, suggesting that genetic similarities may not be independent of linguistic affinities. Despite differential genetic affinities, both Naga and Kuki tribal populations in Manipur show more proximity with Southeast Asian populations and Northeast Indian populations than with other Indian populations and global populations taken for comparison.


Production in Vero cells of an inactivated rabies vaccine from strain FRV/K for animal and human use.
A new concentrated and purified rabies vaccine was produced in Vero cells. Two rabies virus strains, the fixed rabies virus Pasteur (FRV) and Pittman Moore (PM) were adapted to Vero cells by 20 cycles of alternating passages in the brain of weaning mice. Intracerebral (i.c.) inoculation of weaning mice was followed then by 17 and 20 serial passages in Vero cells of RFV and PM strains, respectively. The adapted strains designated as FRV/K and PM/K gave titres of 10(6) +/- 1.5 log (LD50/ml for i.c. inoculated mice) in several harvests taken from one infected cell culture. Pooled harvests were concentrated 20-fold by ultrafiltration and were tested as animal vaccine after inactivation with beta-propiolactone (BPL). Another vaccine preparation destined for human use, in addition to concentration and inactivation, was also purified by gel filtration. Control tests revealed that the antigenic content of different strain FRV/K harvests was very high in comparison with that of strain PM/K and the reference tissue culture vaccine (RIV, Netherland). In sheep the antibody response induced by the FRV/K strain was very high; serum neutralizing index (NI) higher than 4 was reached 40 days after the second vaccine dose, whereas the vaccine preparation from strain PM/K gave NI of 2.3 and the reference vaccine NI of 3.8, respectively. Safety tests in rabbits and guinea pigs showed neither pyrogenicity nor toxicity.


Promotion of osteoclast survival and antagonism of bisphosphonate-induced osteoclast apoptosis by glucocorticoids.
Glucocorticoids depress bone formation by inhibiting osteoblastogenesis and increasing osteoblast apoptosis. However, the role of bone resorption in the initial rapid phase of bone loss characteristic of glucocorticoid-induced osteoporosis is unexplained, and the reason for the efficacy of bisphosphonates in this condition remains unknown. We report that in murine osteoclast cultures, glucocorticoids prolonged the baseline survival of osteoclasts and antagonized bisphosphonate-induced caspase activation and apoptosis by a glucocorticoid receptor-mediated action. Consistent with the in vitro evidence, in a murine model of glucocorticoid-induced osteoporosis, the number of cancellous osteoclasts increased, even though osteoclast progenitor number was reduced. Moreover, in mice receiving both glucocorticoids and bisphosphonates, the expected proapoptotic effect of bisphosphonates on osteoclasts was abrogated, as evidenced by maintenance of osteoclast numbers and, additionally, loss of bone density. In contrast, bisphosphonate administration prevented glucocorticoid-induced osteoblast apoptosis. These results indicate that the early loss of bone with glucocorticoid excess is caused by extension of the life span of pre-existing osteoclasts, an effect not preventable by bisphosphonates. Therefore, the early beneficial effects of these agents must be due, in part, to prolonging the life span of osteoblasts.


Systematic studies of the structures and magnetic properties for a family of cubane complexes with the formula: [M2Ln2] (Ln = Dy, Gd; M = Ni, Zn) and [Ni2Y2].
Studies of magnetic properties of a family of tetranuclear M(II)(2)Ln(III)(2) (M = Ni, Zn; Ln = Dy, Gd and Y) complexes with hmp (anion of 2-hydroxymethylpyridine) and benzoate as ligands are reported. In these complexes, metal ions (M or Ln) occupy the four alternative corners of a distorted cubane with oxygen atoms from alkoxyl groups on the others. Complexes 1, 2 and 3 crystallized in P2(1)/c and complexes 4 and 5 in C2/c space groups. Although in different space groups, complexes 1-5 have very similar structures which permit the magnetic interactions to be systematically compared with respect to metal ion pairs. In complex 3 (Ni(2)Y(2)), clear ferromagnetic coupling between Ni(II) ions can be seen, with: g = 2.16, S = 2, D = -0.95 cm(-1), J = +3.77 cm(-1) (or g = 2.20, S = 2, D = +1.51 cm(-1)). In complex 5 (Zn(2)Gd(2)), a very weak antiferromagnetic coupling between the Gd(III) ions was observed: g = 2.08, J = -0.05 cm(-1). Based on these data, we concluded that the decrease in χ(M)T-T upon cooling for complex 2 (Zn(2)Dy(2)) might be partly due to antiferromagnetic coupling between Dy(III) ions. The data from complex 4 (Ni(2)Gd(2)) were analyzed based on the preceding results and gave moderate ferromagnetic coupling between Ni(II) and Gd(III) with J = 0.26 cm(-1). A detailed study of magnetic properties of complex 1 (Ni(2)Dy(2)) was not possible, because of its strong orbital contributions from Dy(III) ions. In addition, frequency-dependent out-of-phase signals were clearly observed for both complexes 1 and 2 which can be attributed to magnetoanisotropy contributions from Dy(III) ions.


Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis.
Arthrogenic alphaviruses, such as Ross River virus (RRV), chikungunya, Sindbis, mayaro and o'nyong-nyong viruses circulate endemically worldwide, frequently causing outbreaks of polyarthritis. The exact mechanisms of how alphaviruses induce polyarthritis remain ill defined, although macrophages are known to play a key role. Macrophage migration inhibitory factor (MIF) is an important cytokine involved in rheumatoid arthritis pathogenesis. Here, we characterize the role of MIF in alphavirus-induced arthritides using a mouse model of RRV-induced arthritis, which has many characteristics of RRV disease in humans. RRV-infected WT mice developed severe disease associated with up-regulated MIF expression in serum and tissues, which corresponded to severe inflammation and tissue damage. MIF-deficient (MIF(-/-)) mice developed mild disease accompanied by a reduction in inflammatory infiltrates and muscle destruction in the tissues, despite having viral titers similar to WT mice. In addition, reconstitution of MIF into MIF(-/-) mice exacerbated RRV disease and treatment of mice with MIF antagonist ameliorated disease in WT mice. Collectively, these findings suggest that MIF plays a critical role in determining the clinical severity of alphavirus-induced musculoskeletal disease and may provide a target for the development of antiviral pharmaceuticals. The prospect being that early treatment with MIF-blocking pharmaceuticals may curtail the debilitating arthritis associated with alphaviral infections.


Transglutaminase and polyamination of tubulin: posttranslational modification for stabilizing axonal microtubules.
Neuronal microtubules support intracellular transport, facilitate axon growth, and form a basis for neuronal morphology. While microtubules in nonneuronal cells are depolymerized by cold, Ca(2+), or antimitotic drugs, neuronal microtubules are unusually stable. Such stability is important for normal axon growth and maintenance, while hyperstability may compromise neuronal function in aging and degeneration. Though mechanisms for stability are unclear, studies suggest that stable microtubules contain biochemically distinct tubulins that are more basic than conventional tubulins. Transglutaminase-catalyzed posttranslational incorporation of polyamines is one of the few modifications of intracellular proteins that add positive charges. Here we show that neuronal tubulin can be polyaminated by transglutaminase. Endogenous brain transglutaminase-catalyzed polyaminated tubulins have the biochemical characteristics of neuronal stable microtubules. Inhibiting polyamine synthesis or transglutaminase activity significantly decreases microtubule stability in vitro and in vivo. Together, these findings suggest that transglutaminase-catalyzed polyamination of tubulins stabilizes microtubules essential for unique neuronal structures and functions.


Short versus longer term effectiveness of an outreach program for the homeless mentally ill.
Presents 12-month follow-up results from an outreach/linkage intervention with persons who are homeless and mentally ill, contrasting these with results obtained at 4 months. Both sets reflect the success of the program in placing individuals in independent housing. However, longer term data provide useful information regarding client movement patterns and increased tenure in nonhomeless living arrangements beyond the termination of specialized services. Analyses of 12-month residential outcomes identified four variables as significant predictors: recruitment source, project service duration, CMH service duration, and client age. In contrast to 4-month predictors, variables reflecting baseline client functioning were no longer significantly related to outcome, suggesting that the positive effects of the intervention may take longer to achieve with some clients. Discussion focuses on the implications of these effectiveness results for future research designs and measures as well as the utility and limitations of preexperimental approaches for evaluating innovative service models when implementation and efficacy experiences are lacking.


Design and initiation of a study to assess the direct and indirect effects of influenza vaccine given to children in rural India.
The burden of disease due to influenza is not well characterized for children in developing countries and the effectiveness of available influenza vaccines in lower resource settings has not been established. We initiated a prospective, longitudinal, phase IV, household-randomized, controlled, observer-blinded three year study (2009-2011) in a rural community of India to measure the total and indirect household protective effects of immunizing children ages 6 months through 10 years with seasonal inactivated trivalent influenza vaccine (TIV) or a control vaccine (n=3697). Active weekly surveillance was conducted year round with home visits for identification of febrile acute respiratory illness (FARI) conducted for all vaccine recipients and household members (n=18,220). Nasal and throat swabs were collected from each FARI episode for influenza detection by real-time reverse transcription polymerase chain reaction. The primary outcome was reduction in laboratory confirmed influenza infections in the influenza vaccine versus control vaccine group, with secondary outcome assessing indirect effects among the entire study population. This report describes the study site, cluster study design, choice of study and control vaccines, and the initial enrollment in the study.


Regulation of risky decision making by gonadal hormones in males and females.
Psychiatric diseases characterized by dysregulated risky decision making are differentially represented in males and females. The factors that govern such sex differences, however, remain poorly understood. Using a task in which rats make discrete trial choices between a small, "safe" food reward and a large food reward accompanied by varying probabilities of footshock punishment, we recently showed that females are more risk averse than males. The objective of the current experiments was to test the extent to which these sex differences in risky decision making are mediated by gonadal hormones. Male and female rats were trained in the risky decision-making task, followed by ovariectomy (OVX), orchiectomy (ORX), or sham surgery. Rats were then retested in the task, under both baseline conditions and following administration of estradiol and/or testosterone. OVX increased choice of the large, risky reward (increased risky choice), an effect that was attenuated by estradiol administration. In contrast, ORX decreased risky choice, but testosterone administration was without effect in either ORX or sham males. Estradiol, however, decreased risky choice in both groups of males. Importantly, none of the effects of hormonal manipulation on risky choice were due to altered shock sensitivity or food motivation. These data show that gonadal hormones are required for maintaining sex-typical profiles of risk-taking behavior in both males and females, and that estradiol is sufficient to promote risk aversion in both sexes. The findings provide novel information about the mechanisms supporting sex differences in risk taking and may prove useful in understanding sex differences in the prevalence of psychiatric diseases associated with altered risk taking.


Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial.
Hepatic steatosis is a common histologic feature in patients with chronic hepatitis C (CHC) but there are no large longitudinal studies describing the progression of steatosis in CHC. We examined changes in steatosis on serial biopsies among CHC patients participating in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All 1050 patients in the trial had advanced fibrosis at baseline biopsy and were documented not to have had a sustained virological response to peginterferon and ribavirin. Most (94%) patients had genotype 1 infection. At least one protocol follow-up biopsy was read on 892 patients, and 699 had the last biopsy performed 3.5 years after randomization. At enrollment, 39% had cirrhosis and 61% had bridging fibrosis; 18%, 41%, 31%, and 10% had steatosis scores of 0, 1, 2, and 3 or 4, respectively. The mean steatosis score decreased in the follow-up biopsies in both the interferon-treated patients and controls with no effect of treatment assignment (P = 0.66). A decrease in steatosis score by > or =1 point was observed in 30% of patients and was associated with both progression to cirrhosis and continued presence of cirrhosis (P = 0.02). Compared to patients without a decrease in steatosis, those with a decrease in steatosis had worse metabolic parameters at enrollment, and were more likely to have a decrease in alcohol intake, improvement in metabolic parameters, and worsening liver disease (cirrhosis, esophageal varices, and deterioration in liver function). Serial biopsies demonstrated that in patients with CHC, steatosis recedes during progression from advanced fibrosis to cirrhosis. Decreased alcohol intake and improved metabolic parameters are associated with a decline in steatosis and may modulate hepatitis C progression.


Clinical evaluation of acupuncture in 129 patients.
The scope of effectiveness of acupuncture in relieving pain was tested in an Acupuncture Clinic for nonemergency care: 129 patients were treated, mainly for intractable pain associated with a wide variety of conditions. Only mechanical stimulation was used. Acupuncture anesthesia was not evaluated. Response was excellent or good in 87 patients. Acupuncture was most effective in conditions attributable to musculoskeletal or visceral muscle spasm. In some situations it inhibited pain recurrence, such as menstrual cramps in subsequent periods. It did not mask pathology: pain recurred promptly if underlying stimulus persisted. Relief of pain was usually immediate; side effects were negligible. Neurophysiologic principles appear to offer a basis for explaining the mechanism of action. Acupuncture is sufficiently promising as an adjunct to standard medical methods to deserve clinical and theoretical investigation.


Malignant bone tumor management. 30 years of achievement.
Malignant bone tumor management has changed drastically over the last three decades. Orthopedic surgery has been in the forefront of these major advances. Amputation is now much less common than other forms of limb reconstruction. Oncologists have come to play a much larger role than do radiotherapists. Indeed, radiotherapy is seldom used now except for its undoubted value in palliation. The development of adjuvant chemotherapy is now prolonging life, assisting the surgeon in local resection, and almost certainly increasing the chances of survival. When one considers the valuable role of thoracic surgery in lung metastectomy and the advances in pathology, imaging, and the staging of bone tumors, it can be seen there has been a revolutionary change in the care of those who suffer from primary malignancy of bone.


Trans-ethnic fine mapping identifies a novel independent locus at the 3' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population.
Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population. A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression. We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10(-12) for KCNQ1; p = 5.0 × 10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1. These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.


CASE SERIES OF HYPERBARIC OXYGEN THERAPY FOR CENTRAL RETINAL ARTERY OCCLUSION.
To retrospectively report the outcomes of patients presenting to our facility with central retinal artery occlusion and receiving therapy with hyperbaric oxygen (HBO). This was a retrospective, chart review at a single hospital center. Patients with diagnosed central retinal artery occlusion were treated with HBO twice daily for 5 days during their inpatient stay for a total of 10 HBO treatments. Main outcome was change from the documented presenting best-corrected visual acuity to discharge best-corrected visual acuity. Thirty-nine patients with central retinal artery occlusion were included in the analysis during a 30-month period. Twenty-eight of 39 patients (72%) had some improvement in acuity. There was a mean of 5.05 lines of improvement using a modified Snellen chart after completing their HBO treatment course. Patients treated within 12 hours of symptom onset showed the greatest improvement in their visual acuity (6.11 mean lines of improvement). Complications of therapy included middle ear barotrauma (10/39) and confinement anxiety (1/39) and did not interfere with the therapy regimen or hospital course. This retrospective case series supports the use of emergent HBO therapy as a viable treatment option for patients with central retinal artery occlusion. Hyperbaric oxygen therapy was safely administered and well tolerated.


Pharmacokinetic parameters for single- and multi-dose regimens for subcutaneous administration of a high-dose ceftiofur crystalline-free acid to neonatal foals.
The objective of this study was to determine the pharmacokinetics of single- and multi-dose ceftiofur crystalline-free acid (CCFA) administered subcutaneously at a dose of 13.2 mg/kg to 12 neonatal foals 1-3 days of age. Six foals received a single subcutaneous dose, while 6 additional foals received 4 doses of CCFA at 48-h intervals. Blood samples were collected at pre-determined times following drug administration, and plasma concentrations of ceftiofur free acid equivalents (CFAE) were measured using high-performance liquid chromatography. Following single-dose administration of CCFA, the mean ± standard deviation maximum observed plasma concentration was 3.1 ± 0.6 μg/mL and observed time to maximal plasma concentration was 14.0 ± 4.9 h. Following multi-dose administration of CCFA, the mean ±standard deviation times above CFAE concentrations of ≥0.5 μg/mL and ≥2.0 μg/mL were 192.95 ± 15.86 h and 78.80 ± 15.31 h, respectively. The mean ± standard deviation area under the concentration vs time curve (AUC0→∝ ) was 246.2 ± 30.7 h × μg/mL and 172.7 ± 27.14 h × μg/mL following single- and multi-dose CCFA administrations, respectively. Subcutaneous administration of CCFA at 13.2 mg/kg in neonatal foals was clinically well- tolerated and resulted in plasma concentrations sufficient for the treatment of most bacterial pathogens associated with neonatal foal septicemia. Multi-dose administration of four doses at dosing interval of 48 h between treatments maintains appropriate therapeutic concentrations in neonatal foals.


Detection of myocardial viability by dobutamine stress echocardiography: incremental value of diastolic wall thickness measurement.
To assess the diagnostic accuracy of baseline diastolic wall thickness (DWT) alone and as an adjunct to dobutamine stress echocardiography (DSE) for prediction of myocardial viability in patients with ischaemic left ventricular (LV) dysfunction, with the recovery of resting function after revascularisation as the yardstick. 24 patients with ischaemic LV dysfunction (ejection fraction < 40%) scheduled for surgical revascularisation. Regional cardiothoracic centre. All patients underwent DSE before and resting echocardiography six months after revascularisation. DWT was measured in each of the 16 LV segments. A receiver operating characteristic (ROC) and a multi-ROC curve were generated to assess the ability of DWT alone and in combination with DSE to predict myocardial viability. DWT > 0.6 cm provided a sensitivity of 80%, a specificity of 51%, and a negative predictive value of 80% for the prediction of viability in akinetic segments. DSE had an excellent specificity (92%) but a modest sensitivity (60%) in akinetic segments. A combination of improvement at DSE or DWT > 0.8 cm improved sensitivity (90% v 60%, p < 0.001) and negative predictive value (92% v 78%, p = 0.03) in akinetic segments compared with DSE alone. This was achieved with some loss in specificity (75% v 92%, p = 0.01) and positive predictive value (71% v 82%, p = 0.79). DWT measurement may improve the sensitivity of DSE for the detection of myocardial viability. Akinetic segments with DWT > 0.8 cm have a good chance of recovery despite the absence of contractile reserve during DSE. Further testing may be required before excluding myocardial viability in these cases.


Metoclopramide treatment of tardive dyskinesia.
Five patients with tardive dyskinesia (average age, 64 years) were treated with a central dopamine blocking agent, metoclopramide hydrochloride. The duration of symptoms ranged from four to 30 months. A pretreatment disability score was graded (0 to 4) for buccolingual, extremity, and truncal movements and for duration of tongue protrusion. A 59% improvement was achieved in total disability scores. Tongue protrusion demonstrated the most noticeable improvement. The average daily dosage ranged from a minimum of 20 mg to a maximum of 80 mg given in divided doses. Duration of follow-up ranged from three to eight months. Preliminary data suggest that metoclopramide may be effective in the treatment of tardive dyskinesia.


A computational network control theory analysis of depression symptoms.
Rumination and impaired inhibition are considered core characteristics of depression. However, the neurocognitive mechanisms that contribute to these atypical cognitive processes remain unclear. To address this question, we apply a computational network control theory (NCT) approach to structural brain imaging data acquired via diffusion tensor imaging in a large sample of participants, to examine how NCT relates to individual differences in subclinical depression. Recent application of this theory at the neural level is built on a model of brain dynamics, which mathematically models patterns of inter-region activity propagated along the structure of an underlying network. The strength of this approach is its ability to characterize the potential role of each brain region in regulating whole-brain network function based on its anatomical fingerprint and a simplified model of node dynamics. We find that subclinical depression is negatively related to higher integration abilities in the right anterior insula, replicating and extending previous studies implicating atypical switching between the default mode and executive control networks in depression. We also find that subclinical depression is related to the ability to "drive" the brain system into easy to reach neural states in several brain regions, including the bilateral lingual gyrus and lateral occipital gyrus. These findings highlight brain regions less known in their role in depression, and clarify their roles in driving the brain into different neural states related to depression symptoms.


Deconstructing the landscape of fear in stable multi-species societies.
Animal distributions are influenced by variation in predation risk in space, which has been described as the "landscape of fear." Many studies suggest animals also reduce predation risk by eavesdropping on heterospecific alarm calls, allowing them to occupy otherwise risky habitats. One unexplored area of study is understanding how different species' alarms vary in quality, and how this variation is distributed in the landscape. We tested this phenomenon in a unique system of avian mixed species flocks in Amazonian rainforests: flock mates (eavesdropping species) strongly associate with alarm-calling antshrikes (genus Thamnomanes), which act as sentinel species. Up to 70 species join these flocks, presumably following antshrike behavioral cues. Since flocks in this region of the Amazon are exclusively led by a single antshrike species, this provides a unique natural system to compare differences in sentinel quality between flocks. We simulated predation threat by flying three species of live trained raptors (predators) towards flocks to compare sentinel probability to (1) produce alarm calls, and (2) encode information about magnitude and type of threat within such alarm calls. Our field experiments show significant differences in the probability of different sentinel species to produce alarm calls and distinguish predators. This variation may have important fitness consequences and shape the "landscape of fear" for eavesdropping species.


Congenital macrostomia--transverse facial cleft.
Congenital macrostomia or transverse facial cleft is a rare congenital craniofacial anomaly. It is usually associated with deformities of other structures developed from the first and second branchial arches and is thought to be part of the manifestations of hemifacial microsomia, the second most common congenital craniofacial anomaly. There were several methods to repair this deformity. All the methods emphasize the importance of restoration of the integrity of cheek and lip muscles. The role of vermilion flap and the size and direction of skin Z-plasty remained controversial. A retrospective review on the 16 congenital macrostomia patients repaired in this hospital by 4 different surgeons with 5 different methods was made. The symmetry of lip, commissural shape and scar quality were evaluated among different methods. It was felt that accurate positioning of the oral commissure and reconstruction of a functional oral musculature were quite important to a good result. The skin Z-plasty could lengthen the deficient transverse distance of the cheek tissue and prevent later scar contracture. But a Z-plasty needed careful design and good postoperative care to minimize visible scar. A vermilion flap across the commissure could also prevent the lateral migration of the commissure from a linear scar contracture. The flap also needed careful design to give a better commissural shape.


Proliferative response in necrotising enterocolitis is insufficient to prevent disease progression.
Necrotising enterocolitis (NEC) is characterised by severe mucosal loss and therefore gastrointestinal (GI) cell proliferation is essential for survival, epithelial repair and recovery of function. Trefoil peptides play a key role in epithelial restitution and repair, and we previously reported a down-regulation of these peptides in NEC. Oral administration of epidermal growth factor has a protective effect in a rat model of colitis. These observations raised the question of a link between the pathogenesis of NEC and decreased mucosal cell proliferation. This study investigates the pattern of mucosal cell proliferation in the GI tract of fetuses, normal neonatal controls, infants with NEC and those recovering from NEC. Parents of neonates up to 44 weeks' gestation undergoing laparotomy and bowel resection were approached for consent. Bowel samples from resection specimens, and GI tract extractions from products of conception at termination of pregnancy, were fixed in formalin and then embedded in paraffin blocks. Patterns of small and large bowel mucosal proliferation were assessed by immunohistochemical staining for Ki67. Seventeen foetal and 58 postnatal bowel samples [34 with NEC (22 acute, 12 recovery) and 24 controls] were analysed. The pattern of proliferation seen in the fetus and normal neonate was identical to that in mature bowel. In NEC severe mucosal necrosis was observed, but in viable crypts remaining, there was crypt hyperplasia and a relative increase in the proportion of cells staining positive for Ki67. In those patients recovering from NEC the pattern of proliferation was returning towards the normal range. In those patients with post-NEC strictures the recovery of normal bowel morphology was delayed. In NEC there is massive loss of potential proliferative tissue. The remaining viable tissue shows an increase in proliferative activity in the small and large bowel. Failure of rapid regeneration of functional mucosa may therefore be related to an inability of increased proliferative activity to match the losses from the surface; alternatively there may be rapid production of immature, short-lived cells. This study shows that the proliferative response, although present, is insufficient to rapidly reverse the mucosal insult observed in NEC.


Adopting Patient Portals in Hospitals: Qualitative Study.
Theoretical models help to explain or predict the adoption of electronic health (eHealth) technology and illustrate the complexity of the adoption process. These models provide insights into general factors that influence the use of eHealth technology. However, they do not give hospitals much actionable knowledge on how to facilitate the adoption process. Our study aims to provide insights into patient portal adoption processes among patients and hospital staff, including health care professionals (HCPs), managers, and administrative clerks. Studying the experiences and views of stakeholders answers the following question: How can hospitals encourage patients and HCPs to adopt a patient portal? We conducted 22 semistructured individual and group interviews (n=69) in 12 hospitals and four focus groups with members of national and seminational organizations and patient portal suppliers (n=53). The effort hospitals put into adopting patient portals can be split into three themes. First, inform patients and HCPs about the portal. This communication strategy has four objectives: users should (1) know about the portal, (2) know how the portal works, (3) know that action on the portal is required, and (4) know where to find help with the portal. Second, embed the patient portal in the daily routine of HCPs and management. This involves three forms of support: (1) hospital policy, (2) management by monitoring the numbers, and (3) a structured implementation strategy that includes all staff of one department. Third, try to adjust the portal to meet patients' needs to optimize user-friendliness in two ways: (1) use patients' feedback and (2) focus on optimizing for patients with special needs (eg, low literacy and low digital skills). Asking stakeholders what they have learned from their efforts to stimulate patient portal use in hospitals elicited rich insights into the adoption process. These insights are missing in the theoretical models. Therefore, our findings help to translate the relatively abstract factors one finds in theoretical models to the everyday pragmatics of eHealth projects in hospitals.


Gene Conversion Facilitates the Adaptive Evolution of Self-Resistance in Highly Toxic Newts.
Reconstructing the histories of complex adaptations and identifying the evolutionary mechanisms underlying their origins are two of the primary goals of evolutionary biology. Taricha newts, which contain high concentrations of the deadly toxin tetrodotoxin (TTX) as an antipredator defense, have evolved resistance to self-intoxication, which is a complex adaptation requiring changes in six paralogs of the voltage-gated sodium channel (Nav) gene family, the physiological target of TTX. Here, we reconstruct the origins of TTX self-resistance by sequencing the entire Nav gene family in newts and related salamanders. We show that moderate TTX resistance evolved early in the salamander lineage in three of the six Nav paralogs, preceding the proposed appearance of tetrodotoxic newts by ∼100 My. TTX-bearing newts possess additional unique substitutions across the entire Nav gene family that provide physiological TTX resistance. These substitutions coincide with signatures of positive selection and relaxed purifying selection, as well as gene conversion events, that together likely facilitated their evolution. We also identify a novel exon duplication within Nav1.4 encoding an expressed TTX-binding site. Two resistance-conferring changes within newts appear to have spread via nonallelic gene conversion: in one case, one codon was copied between paralogs, and in the second, multiple substitutions were homogenized between the duplicate exons of Nav1.4. Our results demonstrate that gene conversion can accelerate the coordinated evolution of gene families in response to a common selection pressure.


Plasmon-induced nonlinear response of silver atomic chains.
Nonlinear response of a linear silver atomic chain upon ultrafast laser excitation has been studied in real time using the time-dependent density functional theory. We observe the presence of nonlinear responses up to the fifth order in tunneling current, which is ascribed to the excitation of high-energy electrons generated by Landau damping of plasmons. The nonlinear effect is enhanced after adsorption of polar molecules such as water due to the enhanced damping rates during plasmon decay. Increasing the length of atomic chains also increases the nonlinear response, favoring higher-order plasmon excitation. These findings offer new insights towards a complete understanding and ultimate control of plasmon-induced nonlinear phenomena to atomic precision.


Clonal evolution of multidrug resistant hepatitis B virus during entecavir rescue therapy.
Analysing the mutation pattern of multidrug resistance (MDR) is important in the treatment of chronic hepatitis B (CHB). In this study, the evolutionary pattern of MDR mutations was investigated in patients receiving entecavir (ETV) rescue therapy. Eight CHB patients with lamivudine (LAM)- and adefovir (ADV)-resistant mutations showing suboptimal response to ETV and to subsequent ETV-plus-ADV therapy were enrolled. The clonal evolution of the mutation pattern was investigated through direct sequencing, multiplex restriction fragment mass polymorphism (RFMP), and clonal analysis and the utility of these methods was compared. Among 160 clones at baseline, wild-type hepatitis B virus (HBV) was present in 62 (38.8%), LAM-resistant mutations in 92 (57.6%) and ADV-resistant mutations in 55 (34.4%). LAM-resistant mutations increased to 70.6% at the end of ETV therapy and increased to 74.4% at the 12th month of ETV-plus-ADV therapy. During the same time periods, ETV-resistant mutations were present in 46.3% and 38.8%, and ADV-resistant mutations were present in 3.1% and 9.4% respectively. When 256 nucleotides from 32 samples were examined for mutations, clonal analysis detected 93 mutations (36.3%), direct sequencing detected 36 mutations (14.1%) and RFMP detected 73 mutations (28.5%). The sensitivity (73.1%, 95% CI; 64.1-82.1%) and specificity (96.9%, 95% CI; 94.4-99.4%) of RFMP were high, showing a concordance rate of 88.3% with the results from clonal analysis. All mutations exceeding 40% of the total clones detected by clonal analysis were also detected by RFMP. The clonal evolution of the mutation pattern in MDR HBV showed the selection of LAM-resistant (±ETV-resistant) HBV during ETV rescue therapy, which may be the primary reason for patients' suboptimal response. Multiplex RFMP is a useful method for detecting MDR mutations in clinical practice.