Noninvasive brain stimulation in stroke rehabilitation.
Stroke is a common disorder that produces a major burden to society, largely through long-lasting motor disability in survivors. Recent studies have broadened our understanding of the processes underlying recovery of motor function after stroke. Bilateral motor regions of the brain experience substantial reorganization after stroke, including changes in the strength of interhemispheric inhibitory interactions. Our understanding of the extent to which different forms of reorganization contribute to behavioral gains in the rehabilitative process, although still limited, has led to the formulation of novel interventional strategies to regain motor function. Transcranial magnetic (TMS) and DC (tDCS) electrical stimulation are noninvasive brain stimulation techniques that modulate cortical excitability in both healthy individuals and stroke patients. These techniques can enhance the effect of training on performance of various motor tasks, including those that mimic activities of daily living. This review looks at the effects of TMS and tDCS on motor cortical function and motor performance in healthy volunteers and in patients with stroke. Both techniques can either enhance or suppress cortical excitability, and may move to the clinical arena as strategies to enhance the beneficial effects of customarily used neurorehabilitative treatments after stroke.


Stand-alone front-end system for high- frequency, high-frame-rate coded excitation ultrasonic imaging.
A stand-alone front-end system for high-frequency coded excitation imaging was implemented to achieve a wider dynamic range. The system included an arbitrary waveform amplifier, an arbitrary waveform generator, an analog receiver, a motor position interpreter, a motor controller and power supplies. The digitized arbitrary waveforms at a sampling rate of 150 MHz could be programmed and converted to an analog signal. The pulse was subsequently amplified to excite an ultrasound transducer, and the maximum output voltage level achieved was 120 V(pp). The bandwidth of the arbitrary waveform amplifier was from 1 to 70 MHz. The noise figure of the preamplifier was less than 7.7 dB and the bandwidth was 95 MHz. Phantoms and biological tissues were imaged at a frame rate as high as 68 frames per second (fps) to evaluate the performance of the system. During the measurement, 40-MHz lithium niobate (LiNbO(3)) single-element lightweight (<;0.28 g) transducers were utilized. The wire target measure- ment showed that the -6-dB axial resolution of a chirp-coded excitation was 50 μm and lateral resolution was 120 μm. The echo signal-to-noise ratios were found to be 54 and 65 dB for the short burst and coded excitation, respectively. The contrast resolution in a sphere phantom study was estimated to be 24 dB for the chirp-coded excitation and 15 dB for the short burst modes. In an in vivo study, zebrafish and mouse hearts were imaged. Boundaries of the zebrafish heart in the image could be differentiated because of the low-noise operation of the implemented system. In mouse heart images, valves and chambers could be readily visualized with the coded excitation.


Large-scale and high-resolution mass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting.
Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes-S1 and S2-based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC.


Transient oral microflora in Greeks attending day centres for the elderly and residents in homes for the elderly.
To examine the isolation frequency and the carriage of yeasts, Enterobacteriaceae, Staphylococcus and Enterococcus species in oral samples from elderly Greeks living alone or in institutions. Ageing may promote changes in the oral ecosystem, which lead to colonisation of the mouth by microbes found less commonly or only transiently in younger subjects. Previous studies indicate a geographical variation in the isolation frequency of such bacteria in elderly populations. Medical and dental records were obtained from 66 attenders at elderly people's day centres (EPDC), and 82 residents of elderly people's homes (EPH), 66-95 years old. Mucosa smear samples were cultured on appropriate media for enumeration of the above species. Microbial identification was performed by conventional microbiological tests. The results were analysed using the Multiple Correspondence Analysis (MCA), ANOVA and other traditional statistical tests. No statistically significant association was found between the place of residence and the wearing of dentures. The isolation frequencies of Staphylococcus aureus, Enterococcus and Enterobacteriaceae species were 21.6, 20.3 and 7.4% respectively. MCA, and further statistical analysis, revealed that the place of residence affected the isolation frequency of years (54.9% in EPH vs. 37.9% in EPDC). Moreover, ANOVA showed that living in EPH increased the carriage of yeasts. Elderly Greeks exhibit a moderate to high oral carriage of transient bacteria compared with other elderly populations. Living in EPH seems to increase both the isolation frequency and carriage of yeasts.


Automated quantification of 99mTc sestamibi myocardial perfusion compared with visual analysis.
The visual interpretation of 99mTc sestamibi single photon emission computed tomography (SPECT) myocardial perfusion images can be challenging due to the quantity of scan information generated, the large number of normal variants, attenuation artifacts and gender differences. The development of automated, computer derived, quantitative indices of perfusion can assist in this interpretation by providing an objective measure. It is important to verify that similar results can be obtained when the software is used in centres outside those where the algorithms were initially developed. Our objective was to assess the degree of concordance between the visual and automated diagnostic assessments of 99mTc sestamibi SPECT. We studied 718 patients referred for 99mTc sestamibi SPECT myocardial perfusion imaging. The SPECT studies were initially interpreted visually without benefit of computer based analysis, and were then subjected to blinded reprocessing to extract quantitative indices of perfusion. There was very good agreement between the visual and quantitative diagnostic classifications. When a visual abnormality was taken to be the reference standard, the automated summed stress score (SSS) showed agreement (SSS>3) in 80% (kappa 0.60, P<0.0001). The area under the receiver operating characteristic (ROC) curve was 0.89 (95% confidence interval (CI), 0.86-0.91). Concordance was greater in those with previous myocardial infarction or severe perfusion defects, but was not affected by age, prior revascularization, stress procedure or heart rate. Concordance over the presence or absence of visual reversibility and the summed difference score (SDS) in abnormal scans was slightly lower (overall agreement 73% (kappa 0.36, P<0.00001) and ROC area 0.84 (95% CI, 0.77-0.90)). Automated quantification of 99mTc sestamibi SPECT myocardial perfusion with the SSS and SDS provides objective diagnostic information and concordance when compared with conventional visual image interpretation.


Pain Treatment in the Companion Canine Model to Validate Rodent Results and Incentivize the Transition to Human Clinical Trials.
One of the biggest challenges for analgesic drug development is how to decide if a potential analgesic candidate will work in humans. What preclinical data are the most convincing, incentivizing and most predictive of success? Such a predicament is not unique to analgesics, and the pain field has certain advantages over drug development efforts in areas like neuropsychiatry where the etiological origins are either unknown or difficult to ascertain. For pain, the origin of the problem frequently is known, and the causative peripheral tissue insult might be observable. The main conundrum centers around evaluation of translational cell- and rodent-based results. While cell and rodent models are undeniably important first steps for screening, probing mechanism of action, and understanding factors of adsorption, distribution metabolism and excretion, two questions arise from such studies. First, are they reliable indicators of analgesic performance of a candidate drug in human acute and chronic pain? Second, what additional model systems might be capable of increasing translational confidence? We address this second question by assessing, primarily, the companion canine model, which can provide particularly strong predictive information for candidate analgesic agents in humans. This statement is mainly derived from our studies with resiniferatoxin (RTX) a potent TRPV1 agonist but also from protein therapeutics using a conjugate of Substance P and saporin. Our experience, to date, is that rodent models might be very well suited for acute pain translation, but companion canine models, and other large animal studies, can augment initial discovery research using rodent models for neuropathic or chronic pain. The larger animal models also provide strong translational predictive capacity for analgesic performance in humans, better predict dosing parameters for human trials and provide insight into behavior changes (bladder, bowel, mood, etc.) that are not readily assessed in laboratory animals. They are, however, not without problems that can be encountered with any experimental drug treatment or clinical trial. It also is important to recognize that pain treatment is a major veterinary concern and is an intrinsically worthwhile endeavor for animals as well as humans.


When Feeding Difficulties Are due to Genetics: The Case of Familial Partial 9q Duplication.
Chromosomal abnormalities may cause growth failure before or since birth. 9q duplication is reported as a cause of intrauterine growth restriction, mild dysmporphism, and intellectual disabilities. We report a case of a maternally inherited 9q21.31q21.33 duplication causing prenatal and postnatal growth restriction with feeding refusal and mild facial dysmorphisms, prenatally diagnosed by single-nucleotide polymorphism array analysis. Hypothesis of the possible pathogenic mechanisms are discussed.


Medicinally Used Asarum Species: High-Resolution LC-MS Analysis of Aristolochic Acid Analogs and In vitro Toxicity Screening in HK-2 Cells.
Species of Asarum are used in traditional Chinese medicine and, similar to members of the genus Aristolochia, they contain aristolochic acid analogs (AAAs). These compounds are known for their nephrotoxic and carcinogenic effects. So far, the phytochemistry and nephrotoxicity of species of Asarum is not well studied. A high-resolution LC-MS-based metabolomic approach was used to study the phytochemical variation in medicinally used Asarum species. The cytotoxicity of the samples was assessed using human kidney (HK-2) cells. The majority of samples contained potentially nephrotoxic AAAs, including 9-methoxy aristolactam (AL) IV, AL I, and AL IV. These compounds were present in methanol as well as water extracts. AAAs were detected in all parts of the plant. The majority of the extracts were not cytotoxic to HK-2 cells at the doses tested. However, other mechanisms relating to aristolochic acid nephropathy and cancer development, such as DNA adduct formation may occur. The results of this study provide a model for assessing lesser-known plant species for toxicity.


Immunohistochemical studies on specificity and affinity of the BB5-antibody against human parathyroid tissue.
Localisation of parathyroid tissue in hyperparathyroidism may be difficult with standard methods. Immunoscintigraphy, using radiolabeled antibodies against epitopes of human parathyroid cells, could be a promising alternative. Therefore, we studied the necessary preconditions, whether the so-called BB5-antibody, directed against parathyroid cell membranes possesses sufficient specificity and affinity to be employed in immunoscintigraphy. Specificity was tested immunohistochemically with APAAP-staining of 39 different human tissues. Additionally, an immunoscore-based quantitative comparison was performed to test the affinity of BB5-antibody for normal and pathologic parathyroid tissue. Specificity was proven by the fact that of all 39 tested tissue-types only the parathyroid tissue was BB5-positive. Normal parathyroid tissue showed a significantly higher affinity to the BB5-antibody than pathologic parathyroid tissue (p < 0.03). However, all tissue samples from primary or secondary hyperparathyroidism exhibited sufficient staining. We conclude that the BB5-antibody fulfills the necessary conditions to be tried for immunoscintigraphical localisation of the parathyroid glands.


Oxaliplatin-Induced Tonic-Clonic Seizures.
Oxaliplatin is a common chemotherapy drug used for colon and gastric cancers. Common side effects are peripheral neuropathy, hematological toxicity, and allergic reactions. A rare side effect is seizures which are usually associated with posterior reversible leukoencephalopathy syndrome (PRES). A 50-year-old male patient presented with severe abdominal pain. CT scan of the abdomen showed acute appendicitis. Appendectomy was done and pathology showed mixed adenoneuroendocrine carcinoma. Adjuvant chemotherapy was started with Folinic acid, Fluorouracil, and Oxaliplatin (FOLFOX). During the third cycle of FOLFOX, the patient developed tonic-clonic seizures. Laboratory workup was within normal limits. EEG and MRI of the brain showed no acute abnormality. The patient was rechallenged with FOLFOX but he had tonic-clonic seizures for the second time. His chemotherapy regimen was switched to Folinic acid, Fluorouracil, and Irinotecan (FOLFIRI). After 5 cycles of FOLFIRI, the patient did not develop any seizures, making Oxaliplatin the most likely culprit for his seizures. Oxaliplatin-induced seizures rarely occur in the absence of PRES. One case report has been described in the literature. We present a rare case of tonic-clonic seizures in a patient receiving Oxaliplatin in the absence of PRES.


Na+-H+ exchange and Na+-dependent transport systems in streptozotocin diabetic rat kidneys.
The streptozotocin-induced diabetic rat was used to test the hypothesis that Na+-H+ exchange activity in the proximal tubule luminal membrane would be increased in association with renal hypertrophy, altered glomerular hemodynamics, enhanced filtered load and tubular reabsorption of Na+, and stimulated Na+ pump activity in the basolateral membrane, previously reported characteristics of this experimental animal model. Amiloride-sensitive H+ gradient-dependent Na+ uptake and Na+ gradient-dependent H+ flux were increased in brush-border membrane vesicles from the streptozotocin-treated animals. Na+ gradient-dependent uptakes of phosphate, D-glucose, L-proline, and myoinositol were decreased in the drug-induced diabetic animals. These membrane transport alterations were not found when the streptozotocin-diabetic animals were treated with insulin.


The mathematician's control toolbox for management of type 1 diabetes.
Blood glucose levels are controlled by well-known physiological feedback loops: high glucose levels promote insulin release from the pancreas, which in turn stimulates cellular glucose uptake. Low blood glucose levels promote pancreatic glucagon release, stimulating glycogen breakdown to glucose in the liver. In healthy people, this control system is remarkably good at maintaining blood glucose in a tight range despite many perturbations to the system imposed by diet and fasting, exercise, medications and other stressors. Type 1 diabetes mellitus (T1DM) results from loss of the insulin-producing cells of the pancreas, the beta cells. These cells serve as both sensor (of glucose levels) and actuator (insulin/glucagon release) in a control physiological feedback loop. Although the idea of rebuilding this feedback loop seems intuitively easy, considerable control mathematics involving multiple types of control schema were necessary to develop an artificial pancreas that still does not function as well as evolved control mechanisms. Here, we highlight some tools from control engineering used to mimic normal glucose control in an artificial pancreas, and the constraints, trade-offs and clinical consequences inherent in various types of control schemes. T1DM can be viewed as a loss of normal physiologic controls, as can many other disease states. For this reason, we introduce basic concepts of control engineering applicable to understanding pathophysiology of disease and development of physiologically based control strategies for treatment.


Growth of Infants Fed Formula with Evolving Nutrition Composition: A Single-Arm Non-Inferiority Study.
The nutritional composition of human milk evolves over the course of lactation, to match the changing needs of infants. This single-arm, non-inferiority study evaluated growth against the WHO standards in the first year of life, in infants consecutively fed four age-based formulas with compositions tailored to infants' nutritional needs during the 1st, 2nd, 3rd-6th, and 7th-12th months of age. Healthy full-term formula-fed infants (n = 32) were enrolled at ≤14 days of age and exclusively fed study formulas from enrollment, to the age of four months. Powdered study formulas were provided in single-serving capsules that were reconstituted using a dedicated automated preparation system, to ensure precise, hygienic preparation. The primary outcome was the weight-for-age z-score (WAZ) at the age of four months (vs. non-inferiority margin of -0.5 SD). Mean (95% CI) z-scores for the WAZ (0.12 (-0.15, 0.39)), as well as for the length-for-age (0.05 (-0.19, 0.30)), weight-for-length (0.16 (-0.16, 0.48)), BMI-for-age (0.11 (-0.20, 0.43)), and head circumferencefor-age (0.41 (0.16, 0.65)) at the age of four months, were non-inferior. Throughout the study, anthropometric z-scores tracked closely against the WHO standards (within ±1 SD). In sum, a fourstage, age-based infant formula system with nutritional compositions tailored to infants' evolving needs, supports healthy growth consistent with WHO standards, for the first year of life.


Efficacy and Safety of Modified Banxia Xiexin Decoction (Pinellia Decoction for Draining the Heart) for Gastroesophageal Reflux Disease in Adults: A Systematic Review and Meta-Analysis.
Modified Banxia Xiexin decoction (MBXD) is a classical Chinese herbal formula in treating gastroesophageal reflux disease (GERD) for long time, but the efficacy of it is still controversial. This study is to evaluate the efficacy and safety of MBXD for the treatment of GERD in adults. The search strategy was carried out for publications in seven electronic databases. RevMan software version 5.3 and the Cochrane Collaboration's risk of bias tool were performed for this review. Twelve RCTs were included for the analysis. The results of overall clinical efficacy and efficacy under gastroscope demonstrated that MBXD was superior to conventional western medicine. Meanwhile, the results of subgroup analysis showed clinical heterogeneity between the two groups. However, there was no statistically significant difference in acid regurgitation between the two groups. But in the improvement of heartburn and sternalgia, the results showed statistically significant differences for the comparison between two groups. In addition, the adverse reactions of the experiment groups were not different from those of the control groups. This systematic review indicates that MBXD may have potential effects on the treatment of patients with GERD. But because the evidence of methodological quality and sample sizes is weak, further standardized researches are required.


A new chiral uranyl phosphonate framework consisting of achiral building units generated from ionothermal reaction: structure and spectroscopy characterizations.
The ionothermal reactions of uranyl nitrate and 1,3-pbpH4 (1,3-pbpH4 = 1,3-phenylenebis(phosphonic acid) ligand in ionic liquids of [C4mim][Dbp], [C4mpyr][Br], and [Etpy][Br], respectively, afforded three new uranyl phosphonates, namely [C4mim][(UO2)2(1,3-pbpH)(1,3-pbpH)·Hmim] (1), [UO2(1,3-pbpH2)H2O·mpr] (2), and [Etpy][UO2(1,3-pbpH2)F] (3). Compound 1 exhibits a rare example of a chiral uranyl phosphonate 3D framework structure built from achiral building units of tetragonal bipyramidal uranium polyhedra and 1,3-pbp ligands. The structure adopts a network with channels extending along the b axis, which are filled with C4mim(+) and protonated 1-methylimidazole. In sharp contrast, compounds 2 & 3 both show pillared topology composed of uranyl pentagonal bipyramid polyhedra and phosphonate ligands. The layers are neutral in compound 2 with N-methylpyrrole molecules in the interlayer space, while compound 3 adopts anionic layer, and the charge is compensated with N-ethyl-pyridinium cations between the layers. Although compounds 1, 2, and 3 were synthesized under identical conditions with sole variation of the ionic liquid species, the resulting structures show a rich diversity in the local coordination environment of uranyl ions, the protonation of the phosphonate ligand, the conformation of ionic liquid ions, and the overall arrangement of the structure. All compounds were characterized by absorption, temperature dependent fluorescence, as well as infrared and Raman spectroscopies.


Repair of a cheek defect with the tissue expander method: a case report.
A 28-year-old female had a severe depressed deformity of the left cheek due to false local injection of ZnCl2 into her buccal mucosa instead of an anesthetic. After several attempts at plastic surgery in another hospital with unsatisfactory results, she was treated surgically in our clinic using cheek skin expanded by a tissue expander. The outcome was satisfactory.


The role of IL-10 in iNOS and cytokine mRNA expression during in vitro differentiation of bovine mononuclear phagocytes.
In the study reported here, we used RT-PCR with primers specific for interleukin-1 (IL-1), IL-6, IL-10, tumor necrosis factor-alpha (TNF-alpha), and nitric oxide synthase (iNOS) to assess the cytokine mRNA expression associated with bovine blood monocytes during their differentiation to macrophages cultured on plastic (1 week). In addition, we used RT-PCR to assess the contribution of gammadelta T cells as a source of interferon-gamma (IFN-gamma), the induction signal for iNOS. Further, we evaluated cytocentrifuge preparations from the cultures for the production of IL-10 using specific antibody. We previously demonstrated that iNOS can be induced in cultured bovine monocytes in response to IFN-gamma and TNF-alpha but lose this capability in a short period of time. However, we demonstrate here that iNOS induction from monocytes cultured with IFN-gamma secreting gammadelta T cells is prolonged, suggesting that this source of IFN-gamma primes the monocytes before exogenous stimulation. Based on mRNA expression, placement of monocytes in culture resulted in activation, followed by quiescence. By 6 days in culture, the iNOS message was reduced below the basal level. In addition, the TNF-alpha message was substantially reduced, and IL-1 and IL-6 messages were reduced below detectable levels. This correlated with an increase in IL-10 message. Downregulation of these same cytokine messages as well as IFN-gamma message occurred within a 20-h period when IL-10 was added exogenously to cultures of total leukocytes. At the same time, there was an increase in the number of IL-10-positive cells and an increase in the intensity of anti-IL-10 staining within adherent cells. These results provide evidence for IL-10 regulation of some bovine mononuclear phagocyte effector functions.


Surveillance of Kawasaki disease in Taiwan and review of the literature.
Kawasaki disease affects mainly children younger than five years, leading to coronary artery lesions, even to life-threatening myocardial infarctions. Since 1976, Kawasaki disease has occurred in thousands of children in Taiwan; some of them died. Questionnaire forms for the survey of epidemiological features of Kawasaki disease were designed and sent to the hospitals of 100 or more beds in Taiwan, in 1987, 1992, 1994, and 2001, for retrospective reviews of their patients with Kawasaki disease encountered during 1976-2000. A school-based mass survey, on the prevalence of children with history of Kawasaki disease was conducted every year from 1990 to 2000. Since 1976, the number of Kawasaki disease patients increased, totaling to 8,267 patients in 2000. The ratio of the incidence increased by 1.15 times annually (Poisson regression), reaching the highest incidence of 54.9 per 100,000 children <5 years of age in 1998. Of them, 85.1% were under 5 years of age. The male-to-female ratio was 1.6. Coronary artery lesions were noted during acute, subacute and convalescent stages in 25.8% of the patients. The fatality rate decreased from 0.4% to 0.06%. There was no student with history of Kawasaki disease among students surveyed in 1990. Subsequent school surveys showed the prevalence was 24.6 in 1991, 74.6 in 1996, then reached to 103.9 per 100,000 school children in 2000, with an annual increase of 1.24 times (Poisson regression). In Taiwan, Kawasaki disease, first diagnosed in 1976, continued to occur with several outbreaks reaching to a peak incidence of 54.9 per 100,000 population less than 5 years of age in 1998. Epidemiological features of Kawasaki disease in Taiwan were similar to the Japanese experiences and the incidence was, next only to Japan, the second highest in the world.


Potentiation of PIEZO2 mechanically-activated currents in sensory neurons mediates vincristine-induced mechanical hypersensitivity.
Vincristine, a widely used chemotherapeutic agent for treating different cancer, often induces severe peripheral neuropathic pain. A common symptom of vincristine-induced peripheral neuropathic pain is mechanical allodynia and hyperalgesia. However, mechanisms underlying vincristine-induced mechanical allodynia and hyperalgesia are not well understood. In the present study, we show with behavioral assessment in rats that vincristine induces mechanical allodynia and hyperalgesia in a PIEZO2 channel-dependent manner since gene knockdown or pharmacological inhibition of PIEZO2 channels alleviates vincristine-induced mechanical hypersensitivity. Electrophysiological results show that vincristine potentiates PIEZO2 rapidly adapting (RA) mechanically-activated (MA) currents in rat dorsal root ganglion (DRG) neurons. We have found that vincristine-induced potentiation of PIEZO2 MA currents is due to the enhancement of static plasma membrane tension (SPMT) of these cells following vincristine treatment. Reducing SPMT of DRG neurons by cytochalasin D (CD), a disruptor of the actin filament, abolishes vincristine-induced potentiation of PIEZO2 MA currents, and suppresses vincristine-induced mechanical hypersensitivity in rats. Collectively, enhancing SPMT and subsequently potentiating PIEZO2 MA currents in primary afferent neurons may be an underlying mechanism responsible for vincristine-induced mechanical allodynia and hyperalgesia in rats. Targeting to inhibit PIEZO2 channels may be an effective analgesic method to attenuate vincristine-induced mechanical hypersensitivity.


Effect of infertility on quality of life of women: a validation study of the Turkish FertiQoL.
The fertility quality of life (FertiQoL) measure specifically evaluates the impact of fertility problems in various life areas. The aim of this study was to examine the relationship between FertiQoL and the hospital anxiety and depression scale (HADS) in the Turkish population. All female patients who underwent various fertility treatments in our infertility clinic from May 2011 to May 2014 were approached to participate in the study and 389 completed the questionnaires. Our results showed that the four core scales of the FertiQoL measure had a Cronbach's α value that was between 0.70 and 0.89. Two scales (anxiety and depression) of HADS both had a Cronbach's α value of 0.80. These values present a reliable usage of FertiQoL and HADS measures (α > 0.60). Significant negative correlations were found between the FertiQoL scales and HADS scales, ranging from -0.27 (between relational scale of FertiQoL and anxiety scale of HADS) to -0.65 (between mind-body scale of FertiQoL and depression scale of HADS). The results of this study provide supportive data to confirm that the Turkish version of FertiQol can accurately evaluate QoL in women who seek fertility treatment in Turkey.


Anaphylaxis to scorpion antivenin and its management following envenomation by Indian red scorpion, Mesobuthus tamulus.
Mesobuthus tamulus is an Indian red scorpion that is responsible for numerous cases of scorpion stings in the Indian subcontinent. Antivenin, vasodilators, and benzodiazepines are medications of choice in the treatment of scorpion bites. Adverse reactions such as anaphylaxis to antivenin have been infrequently described in the literature. We, herein, present a case of a 42-year-old man stung by Indian red scorpion while gardening at home in India, who presented with extreme pain at the sting site and signs of cardio-toxicity. He was treated with scorpion antivenin and vasodilators but developed anaphylaxis to antivenin. We discuss management strategies. Anaphylaxis to antivenin should be on the differential during management of scorpion bites because classical signs of anaphylaxis may be absent.


Dynamics of human protein arginine methyltransferase 1(PRMT1) in vivo.
Arginine methylation is a posttranslational protein modification catalyzed by a family of protein arginine methyltransferases (PRMT), the predominant member of which is PRMT1. Despite its major role in arginine methylation of nuclear proteins, surprisingly little is known about the subcellular localization and dynamics of PRMT1. We show here that only a fraction of PRMT1 is located in the nucleus, but the protein is predominantly cytoplasmic. Fluorescence recovery after photobleaching experiments reveal that PRMT1 is highly mobile both in the cytoplasm and the nucleus. However, inhibition of methylation leads to a significant nuclear accumulation of PRMT1, concomitant with the appearance of an immobile fraction of the protein in the nucleus, but not the cytoplasm. Both the accumulation and immobility of PRMT1 is reversed when re-methylation is allowed, suggesting a mechanism where PRMT1 is trapped by unmethylated substrates such as core histones and heterogeneous nuclear ribonucleoprotein proteins until it has executed the methylation reaction.


Exploring the interaction of N/S compounds with a dicopper center: tyrosinase inhibition and model studies.
Tyrosinase (Ty) is a copper-containing enzyme widely present in plants, bacteria, and humans, where it is involved in biosynthesis of melanin-type pigments. Development of Ty inhibitors is an important approach to control the production and the accumulation of pigments in living systems. In this paper, we focused our interest in phenylthiourea (PTU) and phenylmethylene thiosemicarbazone (PTSC) recognized as inhibitors of tyrosinase by combining enzymatic studies and coordination chemistry methods. Both are efficient inhibitors of mushroom tyrosinase and they can be considered mainly as competitive inhibitors. Computational studies verify that PTSC and PTU inhibitors interact with the metal center of the active site. The KIC value of 0.93 μM confirms that PTSC is a much more efficient inhibitor than PTU, for which a KIC value of 58 μM was determined. The estimation of the binding free energies inhibitors/Ty confirms the high inhibitor efficiency of PTSC. Binding studies of PTSC along with PTU to a dinuclear copper(II) complex ([Cu2(μ-BPMP)(μ-OH)](ClO4)2 (1); H-BPMP = 2,6-bis-[bis(2-pyridylmethyl)aminomethyl]-4-methylphenol) known to be a structural and functional model for the tyrosinase catecholase activity, have been performed. Interactions of the compounds with the dicopper model complex 1 were followed by spectrophotometry and electrospray ionization (ESI). The molecular structure of 1-PTSC and 1-PTU adducts were determined by single-crystal X-ray diffraction analysis showing for both an unusual bridging binding mode on the dicopper center. These results reflect their adaptable binding mode in relation to the geometry and chelate size of the dicopper center.


Taurolidine peritoneal lavage as prophylaxis against infection after elective colorectal surgery.
A total of 300 patients undergoing elective colorectal surgery over a 3-year period were randomly assigned to receive intraoperative peritoneal lavage with either taurolidine or saline. Culture swabs were taken from the region of surgery before and after lavage and the development of postoperative infection monitored. Of the positive culture swabs before lavage, a significantly higher proportion were negative after lavage with taurolidine than after that with saline. However, there was no difference in the incidence of postoperative infection between groups, suggesting that taurolidine intraoperative peritoneal lavage confers no clinical benefit over that with saline.


Forgotten goiter. Our experience and a review of the literature.
"Forgotten" goiter is an extremely rare disease which is defined as a mediastinal thyroid mass found after total thyroidectomy. The authors report their experience of 7 cases of residual mediastinal goiter after total thyroidectomy for substernal goiter. Six patients were female and one male with a median age of 56 years (range: 25-70 years). Four patients were asymptomatic, 2 patients showed signs of mediastinal compression, and one patient had persistent hyperthyroidism. A sternal splitting incision associated with a cervical incision was required in 3 patients while an exclusively cervical incision was sufficient in 4 patients. Histology did not show neoplasia. Postoperative outcome was uncomplicated in 6 patients and in one patient a transient recurrent laryngeal nerve paralysis occurred. In the majority of cases forgotten goiter is the consequence of the incomplete removal of a plunging goiter, although sometimes it may be attributed to a concomitant, unrecognized mediastinal goiter which is not connected to the thyroid. The residual goiter has the same clinical presentation as an ordinary intrathoracic goiter. Our experience confirms that surgical treatment of forgotten goiter is associated with only minimal morbidity although a sternal split is sometimes required. Forgotten goiter is a rare pathology which can be prevented if particular attention is paid to preoperative imaging and intraoperative management during the first operation. However surgical treatment for forgotten goiter, when performed in specialized centers, is associated with low morbidity.


Leukemic and lymphomatous meningitis: incidence, prognosis and treatment.
Neoplastic meningitis (NM) is a common problem in neuro-oncology occurring in approximately 5% of all patients with cancer. Notwithstanding frequent focal signs and symptoms in NM, NM is a disease affecting the entire neuraxis and therefore staging and treatment need encompass all cerebrospinal fluid (CSF) compartments. Central nervous system (CNS) staging of NM includes contrast enhanced cranial computerized tomography (CE-CT) or magnetic resonance imaging (MR-Gd), contrast enhanced spine magnetic resonance imaging (MR-S) or computerized tomographic myelography (CT-M) and radionuclide CSF flow study (FS). Treatment of NM involves involved-field radiotherapy of bulky or symptomatic disease sites and intra-CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with NM and may obviate the need for intra-CSF chemotherapy. At present, intra-CSF drug therapy is confined to three chemotherapeutic agents (i.e. methotrexate, cytosine arabinoside and thio-TEPA) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Although treatment of NM is palliative with an expected median patient survival of 4 to 6 months, it often affords stabilization and protection from further neurologic deterioration in patients with NM. In patients with leukemia or lymphoma, prophylaxis of the CNS is used (utilizing a combination of high-dose systemic chemotherapy and intra-CSF chemotherapy) for patients at high risk as defined by specific tumor-related laboratory markers. Using such a risk-stratified approach, the late occurrence of CNS relapse has decreased dramatically attesting to the value of CNS prophylaxis.


Rate of Parental Consanguineous Marriage among Patients with Visual Impairments in Turkey.
We aimed to describe the causes, characteristics, and rate of parental consanguineous marriage associated with patients with visual impairments in Turkey. This study involved 236 patients with visual impairments. The 10th revision of the International Classification of Diseases was used to categorize the causes of visual impairments (based on the main cause in both eyes). The mean age of the patients was 38.5 ± 24.2 years (range, 6-95 years), and most were in the 15-30-year age group (35.6%). There were more male patients (65%) than female patients. Blindness, severe visual impairment, and mild to moderate visual impairment were observed in 30 (12.7%), 84 (35.6%), and 122 (51.6%) patients, respectively. Choroidal and retinal diseases were identified as the main underlying cause of visual impairment (62.7%), followed by nystagmus (23.7%), optic tract and nerve diseases (11.0%), congenital cataracts (0.8%), and glaucoma (1.7%). Parental consanguinity was present for 26.3% of the patients, and it was significantly more common in the 15-30-year age group (50%) compared to the other age groups. In Turkey, the main cause of visual impairment was choroid and retinal diseases in all the age groups above 14 years, while nystagmus was the most common cause in the age group below 15 years. Parental consanguinity was significantly higher among the patients with macular dystrophy and those with retinitis pigmentosa than with retinopathy of prematurity, optic nerve diseases, age-related macular degeneration, and diabetic retinopathy. Genetic factors are known to be involved in the development of these diseases, indicating that the issue of consanguineous marriage remains a problem in Turkey.


Trust as a mechanism of system justification.
People are motivated to hold favorable attitudes about the systems on which they depend, so they justify (i.e., rationalize, defend and bolster) forms of social and economic inequality, even if the inequality is disadvantageous to them. This paper examines how this system-justifying motivation is reflected in behaviors involving interpersonal trust. In a series of three experiments using the trust game I manipulate income inequality by providing participants with higher (advantaged position) or lower (disadvantaged position) initial endowments and measure their trust toward individuals on the same or on different positions. Results show that higher income individuals trust other higher income individuals more than lower income individuals (ingroup favoritism), while lower income individuals trust higher income individuals more than lower income individuals (outgroup favoritism). It is also shown that the strength of these biases is dependent on the level of endorsement of system justifying ideology and the legitimacy of the system. More trust toward those in advantaged positions within a social system, expressed both by equally advantaged as well as by disadvantaged others, not only secures the advantaged in their positions but also reinforces the underlying inequality.


Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2.
We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu2 positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters kon, koff and residence time (RT) were determined. The PAMs showed various kinetic profiles; kon values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant kon was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu2 PAMs with high values for kon but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.


[Posterior osteotomy and long-segment internal fixation for the treatment of senile thoracolumbar kyphotic deformity].
To explore the therapeutic effects of posterior osteotomy and long-segment internal fixation in the treatment of senile thoracolumbar kyphotic deformity and provide the reference for operative treatment. From April 2007 to April 2010, 19 older patients with thoracolumbar kyphotic deformity were respectively analyzed. There were 12 males and 7 females with an average age of 62 years (ranged, 58 to 74 years). Among patients, 11 cases were old fracture, 3 cases were ankylosing spondylitis, and 5 cases were old spinal tuberculosis. According to preoperative Frankel classification, 12 cases were grade E, 4 cases were grade D, 2 cases were C and 1 case was grade B. All patients were treated by posterior osteotomy and long-segment internal fixation and followed up above 1 year. VAS score preoperative, 2 weeks and 1 year after operation, Cobb's angle,n erve function and complication were observed. VAS score preoperative, 2 weeks and 1 year after operation separately was (7.0 +/- 1.2),(1.1 +/= .7) and (1.3 +/- .8); while Cobb's angle separately was (44.1 +/- .9), (10.9 +/- .1) and (11.5 +/- .8); there was significant difference in VAS score and Cobb's angle between preoperative and 2 weeks after operation (P < 0.05) w hile no significant difference between 2 weeks and 1 year after operation (P > 0.05). Eighteen cases met the standard of osseous fusion, 1 case occurred nonunion, but not looseness 1 year after operation. Nerve function: 3 cases changed grade E from 4 cases with grade D, 2 cases with grade C changed to grade D, 1 case with grade B changed to grade Posterior osteotomy and long-segment internal fixation for the treatment of senile thoracolumbar kyphotic deformity can receive a good short-time effects.


[Island flap in the surgical treatment of hypospadias].
Surgery of hypospadias represents an interesting field of innovatory ideas. Many methods may be suitable and many modifications can be performed. There is no one method for all kinds of hypospadias. It is necessary to find the right method for each patient. The result often depends upon the experience of the surgeon with a particular method. The choice between straightening and urethroplasty in one or two stages depends on cost-benefit ratio and evolution at distance of the straightening must be taken into account as well tissue consumption imposed by the urethroplasty, with one stage straightening that makes reintervention very difficult. In the latter case, a multi-stage operation will be necessary with flaps for urethroplasty after the straightening, or, in a more developed penis, a shortening operation according to Nesbit. With two-stage method, in case of relapsed curvature, this can easily be treated, if tissue is available. For a good result of urethroplasty the ability of surgeon, a constant calibration of the canal, plenty of elastic tissue for the neo-urethra, care not to suture on these planes, are highly important. In our opinion Duplay's method observes these requisites. Two-stages surgery allows easy correction of any eventual relapsing incurvature, with no problems for the following urethroplasty. One-stage surgery allows the problems to be resolved in a single surgical Step, but involves the risk of tissue consumption and proximal stricture.


Local Methotrexate Injection Followed by Dilation and Curettage for Cesarean Scar Pregnancy: A Prospective Non-randomized Study.
To evaluate the clinical effects and outcomes of local intra-gestational sac methotrexate injection followed by dilation and curettage for treatment of cesarean scar pregnancies (CSP). This prospective non-randomized study was conducted on patients diagnosed with CSP between 2018 and 2020 at the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region. Patients were categorized into two groups according to the treatments, i.e., local intra-gestational sac methotrexate injection followed by dilation and curettage (group A), and uterine artery embolization in combination with dilation and curettage (group B). The choices of treatment reflect the patients' decision after they thoroughly understood the benefits and risks of the two therapies. Clinical data were then collected and compared between these two alternatives. Seventy-seven patients with CSP were enrolled in the study. Of this total, 41 vs. 36 were respectively categorized into group A and group B. Similar success rates were observed between these two groups (92.7 vs. 97.2%; RR = 27.362, 95% CI: 0.496-1.51E3, p = 0.106). However, the overall occurrence of complications in group A was significant lower when compared with group B (17.1 vs. 52.8%; RR = 0.236, 95% CI: 0.077-0.728, p = 0.012). Lower abdominal pain (unrelated to infection) and intrauterine adhesions were the two primary complications exhibited in group B of the present study, with rates of 38.9 and 22.2% respectively. Local intra-gestational sac methotrexate injection followed by dilation and curettage is an effective and safe treatment for CSP that also drastically reduces the risks of complications. Further multiple center randomized trials with large series are warranted to confirm these findings.


Selective targeting of HDAC1/2 elicits anticancer effects through Gli1 acetylation in preclinical models of SHH Medulloblastoma.
SHH Medulloblastoma (SHH-MB) is a pediatric brain tumor characterized by an inappropriate activation of the developmental Hedgehog (Hh) signaling. SHH-MB patients treated with the FDA-approved vismodegib, an Hh inhibitor that targets the transmembrane activator Smoothened (Smo), have shown the rapid development of drug resistance and tumor relapse due to novel Smo mutations. Moreover, a subset of patients did not respond to vismodegib because mutations were localized downstream of Smo. Thus, targeting downstream Hh components is now considered a preferable approach. We show here that selective inhibition of the downstream Hh effectors HDAC1 and HDAC2 robustly counteracts SHH-MB growth in mouse models. These two deacetylases are upregulated in tumor and their knockdown inhibits Hh signaling and decreases tumor growth. We demonstrate that mocetinostat (MGCD0103), a selective HDAC1/HDAC2 inhibitor, is a potent Hh inhibitor and that its effect is linked to Gli1 acetylation at K518. Of note, we demonstrate that administration of mocetinostat to mouse models of SHH-MB drastically reduces tumor growth, by reducing proliferation and increasing apoptosis of tumor cells and prolongs mouse survival rate. Collectively, these data demonstrate the preclinical efficacy of targeting the downstream HDAC1/2-Gli1 acetylation in the treatment of SHH-MB.


Protective effect of zinc preconditioning against renal ischemia reperfusion injury is dose dependent.
Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and chronic kidney disease. Two promising preconditioning methods for the kidney, intermittent arterial clamping (IC) and treatment with the hypoxia mimetic cobalt chloride, have never been directly compared. Furthermore, the protective efficacy of the chemically related transition metal Zn2+ against renal IRI is unclear. Although Co2+ ions have been shown to protect the kidney via hypoxia inducible factor (HIF), the effect of Zn2+ ions on the induction of HIF1α, HIF2α and HIF3α has not been investigated previously. The efficacy of different preconditioning techniques was assessed using a Sprague-Dawley rat model of renal IRI. Induction of HIF proteins following Zn2+ treatment of the human kidney cell lines HK-2 (immortalized normal tubular cells) and ACHN (renal cancer) was measured using Western Blot. Following 40 minutes of renal ischemia in rats, cobalt preconditioning offered greater protection against renal IRI than IC as evidenced by lower peak serum creatinine and urea concentrations. ZnCl2 (10 mg/kg) significantly lowered the creatinine and urea concentrations compared to saline-treated control rats following a clinically relevant 60 minutes of ischemia. Zn2+ induced expression of HIF1α and HIF2α but not HIF3α in HK-2 and ACHN cells. ZnCl2 preconditioning protects against renal IRI in a dose-dependent manner. Further studies are warranted to determine the possible mechanisms involved, and to assess the benefit of ZnCl2 preconditioning for clinical applications.


Association of the 5A/6A promoter polymorphism of the MMP-3 gene with the radiographic progression of rheumatoid arthritis.
Matrix metalloproteinases (MMPs) as a family of zinc-dependent endopeptidases have been involved in remodeling the extracellular matrix (ECM) in rheumatoid arthritis (RA). In RA patients synovial fluid and serum include enhanced levels of MMP-3. The 5A/6A polymorphism in the MMP-3 gene promoter can contribute to the severity of RA on account of a higher promoter activity of the 5A allele in vitro. The aim of the study was to associate the 5A/6A polymorphism of the MMP-3 gene with radiographic progression of RA. A total of 128 RA patients according to the ACR criteria were available for the study. Radiographs of both hands, obtained from all RA patients, were scored using the modified Sharp/van der Heijde method and the Steinbrocker method. The total Sharp score (TSS) and the annual radiographic progression rate (TSS/year) were calculated. Significant association with the 5A/6A polymorphism was found between patients with TSS/year <or= 1.00 and those with TSS/year > 1.00 in allelic frequencies (Pa = 0.046) and also in genotype distribution (Pg = 0.04). Compared to other genotypes the prevalence of 5A/5A genotype was lower within patients with TSS/year <or= 1.00 (odds ratio [OR] = 0.2; 95% confidence interval [CI] 0.04-0.85; P = 0.01). Also, in comparison to genotypes 5A/6A and 5A/5A, the prevalence of 6A/6A genotype was higher within patients with nonerosive RA (OR = 2.65; 95% CI 1.03-6.83, P = 0.02). Results obtained in this study provide the evidence of an association of the 5A/6A promoter polymorphism of the MMP-3 gene to the radiographic progression of RA.


The microtubule-associated kinase-like protein RUNKEL functions in somatic and syncytial cytokinesis.
The microtubule (MT)-associated putative kinase RUNKEL (RUK) is an important component of the phragmoplast machinery involved in cell plate formation in Arabidopsis somatic cytokinesis. Since loss-of-function ruk mutants display seedling lethality, it was previously not known whether RUK functions in mature sporophytes or during gametophyte development. In this study we utilized RUK proteins that lack the N-terminal kinase domain to further examine biological processes related to RUK function. Truncated RUK proteins when expressed in wild-type Arabidopsis plants cause cellularization defects not only in seedlings and adult tissues but also during male meiocyte development, resulting in abnormal pollen and reduced fertility. Ultrastructural analysis of male tetrads revealed irregular and incomplete or absent intersporal cell walls, caused by disorganized radial MT arrays. Moreover, in ruk mutants endosperm cellularization defects were also caused by disorganized radial MT arrays. Intriguingly, in seedlings expressing truncated RUK proteins, the kinesin HINKEL, which is required for the activation of a mitogen-activated protein kinase signaling pathway regulating phragmoplast expansion, was mislocalized. Together, these observations support a common role for RUK in both phragmoplast-based cytokinesis in somatic cells and syncytial cytokinesis in reproductive cells.


The use of minigrafts in hair transplantation surgery.
With the conventional hair transplantation method of Okuda-Orentreich, the tuft effect and the creation of an abrupt hairline have been major problems. In the method presented here, minigrafts are exclusively distributed and transplanted over the entire surface. Through the use of this technique a more aesthetic pattern of hair growth is achieved than was possible before, even after only one treatment.


Vicarious resilience in sexual assault and domestic violence advocates.
There is little research related to sexual assault and domestic violence advocates' experiences, with the bulk of the literature focused on stressors and systemic barriers that negatively impact efforts to assist survivors. However, advocates participating in these studies have also emphasized the positive impact they experience consequent to their work. This study explores the positive impact. Vicarious resilience, personal trauma experiences, peer relational quality, and perceived organizational support in advocates (n = 222) are examined. Also, overlap among the conceptual components of vicarious resilience is explored. The first set of multiple regressions showed that personal trauma experiences and peer relational health predicted compassion satisfaction and vicarious posttraumatic growth, with organizational support predicting only compassion satisfaction. The second set of multiple regressions showed that (a) there was significant shared variance between vicarious posttraumatic growth and compassion satisfaction; (b) after accounting for vicarious posttraumatic growth, organizational support accounted for significant variance in compassion satisfaction; and (c) after accounting for compassion satisfaction, peer relational health accounted for significant variance in vicarious posttraumatic growth. Results suggest that it may be more meaningful to conceptualize advocates' personal growth related to their work through the lens of a multidimensional construct such as vicarious resilience. Organizational strategies promoting vicarious resilience (e.g., shared organizational power, training components) are offered, and the value to trauma-informed care of fostering advocates' vicarious resilience is discussed. (PsycINFO Database Record


Respiratory syncytial virus-associated hospitalizations in pre-mature infants in Lima, Peru.
We conducted a prospective cohort study in four hospitals in Lima, Peru in infants with a birth weight ≤ 1,500 g followed from birth hospital discharge up to 1 year of age to determine the incidence of respiratory syncytial virus (RSV) hospitalizations. We enrolled 222 infants from March of 2009 to March of 2010: 48 infants with a birth weight < 1,000 g and 174 infants with a birth weight of 1,000-1,500 g (birth weight = 1,197 ± 224 g; gestational age = 30.1 ± 2.6 weeks). There were 936 episodes of respiratory infections; the incidence of respiratory infections during the first 1 year of life was 5.7 episodes/child-years. The incidence of RSV respiratory infections that required emergency room management was 103.9 per 1,000 child-years, and the incidence of RSV hospitalizations was 116.2 per 1,000 child-years (244.9 in infants with a birth weight < 1,000 g and 88.9 in infants 1,000-1,500 g; P < 0.05). The incidence of RSV respiratory infections that required emergency management or hospitalization is high among pre-mature infants in Lima.


[Detection by hemagglutination of antibodies to group A and group E streptococci by the use of O-stearoyl derivatives of their cell wall carbohydrate-grouping antigens].
The streptococcal group A and group E cell wall polysaccharide antigens were extracted with trichloroacetic acid from the cell or cell wall and esterified with stearic acid. The stearoyl derivatives contained 5 to 8% (by weight) of the ester. Sheep or human red blood cells were sensitized with the esterified antigens and were shown to agglutinate in the presence of specific rabbit antisera. Sera from (i) children hospitalized with group A streptococcal respiratory disease and (ii) swine possessing group E streptococcal lymphadenitis were shown to possess antibody titers significantly higher than the controls. The use of the two esterified antigens as controls for each other established the specificity of the reaction in each case. The general shape of the antigen-antibody precipitin curves was not changed when the stearoyl antigens were used; however, the quantitative aspects differed markedly. Oligosaccharides which inhibit the normal antigen-antibody precipitin reaction did not inhibit the hemagglutination reaction. The adsorption of antisera with whole streptococcal cells reduced the hemagglutination titer in relation to the quantity of cells employed. Data are given on the (i) optimal concentration of stearoyl antigen for sensitization, (ii) time of adsorption of antigen to red cells, (iii) use of albumin as diluting fluid, and (iv) condition of red cells. Properties of the esterified antigens and the mechanism of the agglutination reaction are discussed. The results indicate that polysaccharide antigens of other bacteria may be esterified and employed in a similar manner.


Environmental tobacco smoke exposure in children: parental perception of smokiness at home and other factors associated with urinary cotinine in preschool children.
Parental smoking behavior at home and sociodemographic variables may influence exposure to environmental tobacco smoke (ETS) in children. A sample of 115 preschool children aged 3-6 years was enrolled in this study. ETS exposure was evaluated through a questionnaire about parents' smoking behavior and determinations of urinary cotinine -- a biomarker of exposure -- in children. Bivariate and multiple regression analyses were used to evaluate the association between the smoking behavior of each parent at home, sociodemographic factors and cotinine levels in children. The parental perception of smokiness in the home was significantly associated with urinary cotinine in children (r-partial coefficient=0.324; P<0.002). The father's education, mother's smoking status, and day of the week when urine was sampled (Tuesday) were also independently associated with levels of cotinine. These four variables explained 26.4% of the variance in the cotinine levels of children. In designing educational programs to reduce passive smoking among children, it is necessary to take into account those factors related with cotinine levels in children. Our results support the influence of the mothers' smoking status, the fathers' educational level, and the day of the week of sampling on cotinine in children. The perception of parents (smokers and nonsmokers) about the smokiness in the home could also be a useful indicator of the cotinine in children exposed to environmental tobacco smoke in the household.


What are infants learning about race? A look at a sample of infants from multiple racial groups.
Little empirical knowledge exists about the importance of culture and the sociopolitical context of race's influence on the social development of infants and young children. In this article, we review current research on the transmission of race and culture to the developing child. Utilizing a historical theoretical framework proposed by Margaret Mahler and colleagues' (1975) theory of infant's development of a separate self, we will examine the potential influence of racial context on children's development. Observational videotaped research methods will be used to describe several young children ages 6 months to 36 months from several racial/ethnic groups and their preferences for "same-race" and "different-race" dolls during structured play. How infants at different stages of social development notice differences associated with racial phenotype of toys during their play, how parents of these young children discuss issues of culture and race with their children, and the reasons underlying these discussions will be described for this sample. Finally, we discuss future research questions and areas of study suggested by the findings of this pilot study.


Immunoglobulin superfamily proteins: structure, mechanisms, and drug discovery.
We review the recent progress made in our laboratories in structure-based drug design targeting proteins of the immunoglobulin superfamily (IgSF). We will focus on the CD4 protein, which is involved in T cell function, as a specific example of how the general concept and methodologies can be applied. Recent studies of CD4 structure and function have revealed new insight into possible mechanisms for CD4 self-association and its role in binding to major histocompatibility complex (MHC) class II molecules and initiation of T cell activation. This has led to the formulation of a hypothetical model of co-oligomerization of CD4, MHC class II, and T cell receptor (TCR). Such a basic understanding of CD4 structure and mechanisms has aided the development of a new generation of potential immunotherapeutics targeting specific CD4 surface functional sites. The design and discovery of small molecular inhibitors of CD4 and other IgSF proteins, in peptide, peptidomimetic, and nonpeptidic organic forms have opened new avenues for chemical research in which peptide, organic, and more recently combinatorial chemistry techniques can be used to further develop these promising lead analogs into a new generation of effective pharmaceuticals.


Parvovirus B19 NS1 protein induces cell cycle arrest at G2-phase by activating the ATR-CDC25C-CDK1 pathway.
Human parvovirus B19 (B19V) infection of primary human erythroid progenitor cells (EPCs) arrests infected cells at both late S-phase and G2-phase, which contain 4N DNA. B19V infection induces a DNA damage response (DDR) that facilitates viral DNA replication but is dispensable for cell cycle arrest at G2-phase; however, a putative C-terminal transactivation domain (TAD2) within NS1 is responsible for G2-phase arrest. To fully understand the mechanism underlying B19V NS1-induced G2-phase arrest, we established two doxycycline-inducible B19V-permissive UT7/Epo-S1 cell lines that express NS1 or NS1mTAD2, and examined the function of the TAD2 domain during G2-phase arrest. The results confirm that the NS1 TAD2 domain plays a pivotal role in NS1-induced G2-phase arrest. Mechanistically, NS1 transactivated cellular gene expression through the TAD2 domain, which was itself responsible for ATR (ataxia-telangiectasia mutated and Rad3-related) activation. Activated ATR phosphorylated CDC25C at serine 216, which in turn inactivated the cyclin B/CDK1 complex without affecting nuclear import of the complex. Importantly, we found that the ATR-CHK1-CDC25C-CDK1 pathway was activated during B19V infection of EPCs, and that ATR activation played an important role in B19V infection-induced G2-phase arrest.


Allostatic Load and Biomarkers of Stress in the Preterm Infant: An Integrative Review.
Every year, an estimated 15 million babies are born preterm (<37 weeks' gestational age) globally. These preterm infants are exposed to repeated stressful and often painful procedures as part of routine life-saving care within the neonatal intensive care unit (NICU). Low thresholds for tactile and nociceptive input make it more difficult for neonates to discriminate between noxious and nonnoxious stimuli, which can result in continuous activation of stress responses in an attempt to achieve stability through adaptation, or allostasis. Rapidly reoccurring stressors can render stress-response systems over- or underactive, creating wear and tear, or allostatic load. A better understanding of biomarkers related to allostatic load might aid in early detection and prevention/alleviation of allostatic load in this population. To identify stress biomarkers that have been studied in preterm infants at different time points in the NICU and as long-term outcome measures. Systematic searches were conducted of PubMed, CINAHL, SCOPUS, and PsychInfo databases. Twenty-one studies met inclusion criteria for this review. Several putative biomarkers were identified, including cortisol levels, epigenetic markers, brain microstructure, markers of oxidative stress, and the brain-gut-microbiome axis. The interaction of disease with therapeutic interventions may inadvertently increase infant allostatic load. In addition to human studies, future research should leverage newly available large data sets to conduct additional analyses.


The composition and physicochemical properties of hyaluronic acids prepared from ox synovial fluid and from a case of mesothelioma.
1. Materials containing hyaluronic acid have been prepared by filtration (Ogston & Stanier, 1950) from ox synovial fluid and from a protein-rich human mesothelioma fluid. The ox material has been deproteinized by treatment with chloroform and pentanol and by gradient elution on DEAE-Sephadex; several fractions were obtained by the latter method. These materials can be stored in solution at -20 degrees without change of properties. The ox material contained 21% of protein; all other preparations contained less than 6% of protein. 2. The two materials have been compared by sedimentation and viscosity and shown to be closely similar. Treatment of the ox material with neuraminidase caused no change in its viscosity behaviour. 3. Information about the molecular configuration of the ox material has been obtained from measurements of light-scattering and viscosity. The results, though consistent with a highly extended configuration, are not consistent with a linear random-coil configuration. It is tentatively suggested that the structure may have some degree of branching and of cross-linking, which give it a rigidity with respect to expansion of the molecular domain that would not be possessed by a random coil. 4. The deproteinized material recovered from DEAE-Sephadex, though polydisperse, showed unchanged average molecular weight; however, the average radius of gyration was greater than before this treatment. 5. Acidification to approx. pH3 resulted in a contraction of the structure, with only a slight degree of expansion when the pH was restored to 6.8-7.0. 6. Measurements of optical rotatory dispersion qualitatively support a structure less simple than a linear random coil. 7. Colloid osmotic pressures of mixed solutions of bovine serum albumin and of hyaluronic acid prepared by filtration from ox synovial fluid have been measured. The results agree approximately with those of Laurent & Ogston (1963) but are in quantitative disagreement with the partition measurements of Ogston & Phelps (1960). The relationships between thermodynamic quantities in a quaternary system of electrolytes are discussed in Appendix 2. 8. Refractometric measurements have been made in connexion with light-scattering measurements, as the basis for a convenient method of determining the concentrations of solutions of hyaluronic acids, and to measure the partition of sodium chloride in dialysis experiments. The theory of the last use is discussed in Appendix 1. 9. Sedimentation measurements on the ox preparation have been made up to a concentration of 1.4x10(-2)g./ml. The form of the sedimentation coefficient-concentration relationship is discussed. The value of the sedimentation coefficient at higher concentration is the basis of an illustration of the likely effect of hyaluronic acid on the flow of water through narrow channels in connective tissue. 10. Available colorimetric methods have been shown to give low estimates for glucuronic acid when applied to highly polymerized materials, as compared with estimates by decarboxylation. A spectrophotometric titration with cetylpyridinium bromide has been shown to give estimates of carboxyl groups that agree well with those of decarboxylation when applied to preparations of hyaluronic acid under suitable conditions; the results are not affected by the presence of protein. 11. Estimates of glucosamine (Ogston, 1964) have been found to be low compared with those of total acetyl, independently of the presence of protein. The magnitude of the discrepancy is characteristically different for preparations from ox synovial fluid and from mesothelioma. 12. Sialic acid was estimated in several preparations. It is likely that this forms part of the protein. 13. Analyses of preparations for total nitrogen, amino acids, total acetyl, glucuronic acid (by decarboxylation) and ash account for at least 95.7% of the dry weight in terms of N-acetylglucosaminyl, glucuronyl, protein and metal ions. Previously published analyses of hyaluronic acids are reviewed. 14. The estimated molar ratios of glucuronic acid to glucosamine were all significantly greater than unity. 15. The analytical results are interpreted as agreeing with the physicochemical measurements in suggesting a more complex structure, for at least some hyaluronic acids, than that of an alternate linear copolymer in random-coil configuration.


Rapid and accurate determination of MYCN copy number and 1p deletion in neuroblastoma by quantitative PCR.
MYCN amplification and 1p36 deletion are adverse prognostic factors in neuroblastoma, and rapid accurate determination of MYCN amplification is essential for risk stratification. MYCN copy number and 1p36 deletion status were determined by fluorescence in situ hybridization (FISH) and real time PCR in a diagnostic pathology laboratory setting on 35 consecutive patients with neuroblastoma. The PCR technique was technically successful in all cases and results were generally available within 24 hr of biopsy. There was no discordance between FISH and PCR results. Real time PCR is a reliable, accurate, and simple technique that can be applied to small neuroblastoma biopsies allowing rapid diagnosis.


Evaluation of MR cisternography of the cerebellopontine angle using a balanced fast-field-echo sequence: preliminary findings.
We evaluated the feasibility of MR cisternography by the balanced fast-field-echo (bFFE) sequence, comparing with that by a turbo-spin-echo (TSE) sequence, for cerebellopontine angle lesions on a 1.5-T imager (Gyroscan Intera, Philips, Best, The Netherlands). The bFFE MR cisternograms depicted target cranial nerves with less cerebrospinal fluid pulsation artifacts than TSE cisternograms and visualized an acoustic schwannoma in 6 of 44 patients with suspicion and a causative vessel of hemifacial spasm in all of 3 patients in a short scanning time (1 min 53 s). The bFFE sequence can be promising for MR cisternography in the diagnosis of cerebellopontine angle lesions.


Blockade of reflex venous capacitance responses in liver and spleen by hexamethonium, atropine, and surgical section.
Since hexamethonium and surgical section have been used to prevent reflex splanchnic capacitance responses, we examined the effectiveness of these procedures in blocking responses to direct stimulation of preganglionic fibres in the splanchnic nerves. Liver blood volume was measured by plethysmography and splenic blood volume by weighing in cats anesthetized by pentobarbital. The cats were adrenalectomized to prevent adrenal catecholamine secretion in response to splanchnic nerve stimulation. Hexamethonium (10 and 20 mg/kg) alone or atropine (1 mg/kg) alone caused only a small variable block of the responses to preganglionic nerve stimulation. A combination of the two drugs essentially produced a complete block of the liver capacitance response, but a significant response still persisted in the spleen. Surgical section of the postganglionic nerve bundles around the hepatic and splenic arteries completely abolished the responses to preganglionic stimulation. It is concluded that a relatively complete block of reflex splanchnic capacitance responses requires either a combination of hexamethonium and atropine or surgical section of the postganglionic nerves.


Guarana (Paullinia cupana var. sorbilis), an anciently consumed stimulant from the Amazon rain forest: the seeded-fruit transcriptome.
Guarana (Paullinia cupana var. sorbilis) is a plant native to the central Amazon basin. Roasted seed extracts have been used as medicinal beverages since pre-Colombian times, due to their reputation as stimulants, aphrodisiacs, tonics, as well as protectors of the gastrointestinal tract. Guarana plants are commercially cultivated exclusively in Brazil to supply the national carbonated soft-drink industry and natural product stores around the world. In this report, we describe and discuss the annotation of 15,387 ESTs from guarana seeded-fruits, highlighting sequences from the flavonoid and purine alkaloid pathways, and those related to biotic stress avoidance. This is the largest set of sequences registered for the Sapindaceae family.


Small steps to new drugs for bugs.
Governments, academics and industry are beginning to listen to the medical communities call for new anti-bacterials. This special issue brings together diverse review articles on topics from economics and pricing to new discovery methods.


Caffeine-induced impairment of glucose tolerance is abolished by beta-adrenergic receptor blockade in humans.
The caffeine-induced impairment of insulin action is commonly attributed to adenosine receptor (AR) antagonism in skeletal muscle. However, epinephrine, a potent inhibitor of insulin actions, is increased after caffeine ingestion. We tested the hypothesis that the insulin antagonistic effects of caffeine are mediated by epinephrine, and not by AR antagonism, in seven healthy men. On four separate occasions, they received 1) dextrose (placebo, PL), 2) 5 mg/kg caffeine (CAF), 3) 80 mg of propranolol (PR), and 4) 5 mg/kg caffeine + 80 mg of propranolol (CAF + PR) before an oral glucose tolerance test (OGTT). Blood glucose was similar among trials before and during the OGTT. Plasma epinephrine was elevated (P < 0.05) in CAF and CAF + PR. Areas under the insulin and C-peptide curves were 42 and 39% greater (P < 0.05), respectively, in CAF than in PL, PR, and CAF + PR. In the presence of propranolol (CAF + PR), these responses were similar to PL and PR. These data suggest that the insulin antagonistic effects of caffeine in vivo are mediated by elevated epinephrine rather than by peripheral AR antagonism.


Dose effect of caffeine on control of breathing and respiratory response to CO2 in cats.
The dose effect of caffeine (10-70 mg/kg iv) on pulmonary ventilation (VE), mean inspiratory flow (VT/TI), and tracheal pressure generated 0.3 and 0.5 s (P0.3 and P0.5, respectively) after the onset of inspiration against airway occluded at end expiration was studied in cats anesthetized with pentobarbital sodium (35 mg/kg ip) breathing various gas mixtures. With air and 50% O2 (balance N2), increasing doses of caffeine caused a progressive increase in VE that was associated with a reduction in end-tidal PCO2. When the latter was maintained at control (precaffeine) level by inhalation of CO2, the increase in VE was, at all caffeine levels, about three times that under nonisocapnic conditions. Both under isocapnic and nonisocapnic conditions the greatest incremental changes of VE were observed after administration of the first 10-mg/kg aliquot of caffeine, i.e., the current acceptable clinical dose. In all instances, the changes in VE were proportionally the same as the corresponding changes in VT/TI, P0.3, and P0.5, suggesting that caffeine did not appreciably alter either the shape of the inspiratory driving pressure waveform or the impedance of the respiratory system but simply acted by increasing the amplitude of the neuromuscular inspiratory output. An additive interaction between caffeine and end-tidal PCO2 was observed in the VE, VT/TI, and P0.3 responses at levels of CO2 at or below the eucapnic range.


Inactivation of influenza virus by solar radiation.
Influenza virus is readily transmitted by aerosols and its inactivation in the environment could play a role in limiting the spread of influenza epidemics. Ultraviolet radiation in sunlight is the primary virucidal agent in the environment but the time that influenza virus remains infectious outside its infected host remains to be established. In this study, we calculated the expected inactivation of influenza A virus by solar ultraviolet radiation in several cities of the world during different times of the year. The inactivation rates reported here indicate that influenza A virions should remain infectious after release from the host for several days during the winter "flu season" in many temperate-zone cities, with continued risk for reaerosolization and human infection. The correlation between low and high solar virucidal radiation and high and low disease prevalence, respectively, suggest that inactivation of viruses in the environment by solar UV radiation plays a role in the seasonal occurrence of influenza pandemics.


Reappraisal of geographic atrophy patterns seen on fundus autofluorescence using a latent class analysis approach.
To reappraise fundus autofluorescence (FAF) patterns in patients with geographic atrophy (GA) with the aim of simplifying the existing classification and to evaluate their stability with time using a data-driven approach, latent class analysis (LCA). One hundred seventy-one patients in the prospective, natural history study on GA (GAIN, NCT01694095) with a minimum follow-up of 12 months were screened. Five experienced observers independently evaluated FAF patterns according to the original classification, and LCA was used to determine the new, emerging categories (classes). A set of prespecified FAF features was then used to characterize each resulting class. Seventy-five eyes of 59 subjects with a median follow-up of 19 months were included. The optimal LCA model resulted in five classes, which showed an association with GA size, among others. The classes did not change in a given individual during the study period, but the time frame may have been too short to evaluate hypothetical transitions. The original description of FAF patterns, which is based exclusively on distribution of hyperautofluorescence around GA, ultimately classifies patients according to area of atrophy. These results suggest that FAF patterns are not true phenotypes and that they rather represent different stages of the disease. This may have implications regarding the role of lipofuscin on disease pathogenesis.


Low-cost phantom for stereotactic breast biopsy training.
This article reports on the construction of a low-cost phantom to be used for training technologists, residents, and radiologists to perform stereotactic breast biopsy. The model is adaptable to a variety of biopsy devices and realistically simulates the aspects of stereotactic breast biopsy. We believe our model provides an excellent alternative to more expensive commercial products.


Virulence factors in fungal pathogens.
Fungal pathogens possess virulence factors that allow them to cause disease in humans and animals. Combinations of properties such as temperature tolerance, evasion of host defences, dimorphism, and enzymatic activities may serve as virulence mechanisms for fungi.


Changes in epidemiological indices following the introduction of WHO MDT into the Guyana leprosy control programme.
In December 1981 the multidrug regimen recommended by the WHO Study Group of October 1981, was introduced into the Guyana Hansen's Disease Programme. This paper examines the changes that occurred in epidemiological indices over the 6 years following the introduction of MDT and also evaluates changing work loads and staffing patterns.


Antimicrobial assesment of aroylhydrazone derivatives in vitro.
Aroylhydrazones 1-13 were screened for antimicrobial and antibiofilm activities in vitro. N'-(2-hydroxy-phenylmethylidene)-3-pyridinecarbohydrazide (2), N'-(5-chloro-2-hydroxyphenyl-methylidene)-3-pyridinecarbohydrazide (10), N'-(3,5-chloro-2-hydroxyphenylmethylidene)-3-pyridinecarbohydrazide (11), and N'-(2-hydroxy-5-nitrophenylmethylidene)-3-pyridinecarbohydrazide (12) showed antibacterial activity against Escherichia coli, with MIC values (in µmol mL-1) of 0.18-0.23, 0.11-0.20, 0.16-0.17 and 0.35-0.37, resp. Compounds 11 and 12, as well as N'-(2-hydroxy-3-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (6) and N'-(2-hydroxy-5- methoxyphenylmethylidene)-3-pyridinecarbohydrazide (8) showed antibacterial activity against Staphylococcus aureus, with the lowest MIC values of 0.005-0.2, 0.05-0.12, 0.06-0.48 and 0.17-0.99 µmol mL-1. N'-(2-hydroxy-5-methoxyphenylmethylidene)-3-pyridinecarbohydrazide (7) showed antifungal activity against both fluconazole resistant and susceptible C. albicans strains with IC90 range of 0.18-0.1 µmol mL-1. Only compound 11 showed activity against C. albicans ATCC 10231 comparable to the activity of nystatin (the lowest MIC 4.0 ×10-2 vs. 1.7 × 10-2 µmol mL-1). Good activity regarding multi-resistant clinical strains was observed for compound 12 against MRSA strain (MIC 0.02 µmol mL-1) and compounds 2, 6 and 12 against ESBL+ E. coli MFBF 12794, with the lowest MIC for compound 12 (IC50 0.16 µmol mL-1). Anti-biofilm activity was found for compounds 2 (MBFIC 0.015-0.02 µmol mL-1 against MRSA) and 12 (MBFIC 0.013 µmol mL-1 against EBSL+ E. coli). In the case of compound 2 against MRSA biofilm formation, MBFIC values were comparable to those of gentamicin sulphate, whereas in the case of compound 12 and EBSL+ E. coli even more favourable activity compared to gentamicin was observed.


The inhibition of antigen-presenting activity of dendritic cells resulting from UV irradiation of murine skin is restored by in vitro photorepair of cyclobutane pyrimidine dimers.
Exposing skin to UVB (280-320 nm) radiation suppresses contact hypersensitivity by a mechanism that involves an alteration in the activity of cutaneous antigen-presenting cells (APC). UV-induced DNA damage appears to be an important molecular trigger for this effect. The specific target cells in the skin that sustain DNA damage relevant to the immunosuppressive effect have yet to be identified. We tested the hypothesis that UV-induced DNA damage in the cutaneous APC was responsible for their impaired ability to present antigen after in vivo UV irradiation. Cutaneous APC were collected from the draining lymph nodes of UVB-irradiated, hapten-sensitized mice and incubated in vitro with liposomes containing a photolyase (Photosomes; Applied Genetics, Freeport, NY), which, upon absorption of photoreactivating light, splits UV-induced cyclobutane pyrimidine dimers. Photosome treatment followed by photoreactivating light reduced the number of dimer-containing APC, restored the in vivo antigen-presenting activity of the draining lymph node cells, and blocked the induction of suppressor T cells. Neither Photosomes nor photoreactivating light alone, nor photoreactivating light given before Photosomes, restored APC activity, and Photosome treatment did not reverse the impairment of APC function when isopsoralen plus UVA (320-400 nm) radiation was used instead of UVB. These controls indicate that the restoration of APC function matched the requirements of Photosome-mediated DNA repair for dimers and post-treatment photoreactivating light. These results provide compelling evidence that it is UV-induced DNA damage in cutaneous APC that leads to reduced immune function.


CT scan evidence of dysthyroid optic neuropathy.
To determine the utility of CT imaging in identifying patients with dysthyroid optic neuropathy. Orbital CT scans of 12 randomly selected patients with dysthyroid optic neuropathy and 15 control subjects with Graves orbitopathy were retrospectively reviewed by two investigators blinded to the clinical data. The clinical diagnosis of optic neuropathy was made by one author before obtaining CT images and was based on clinical features. Optic nerve crowding (P<0.001) and intracranial fat prolapse (P<0.05) were the imaging features independently related to optic neuropathy. A muscle index greater than 50% had excellent sensitivity (100%) but did not have high specificity (47%) for dysthyroid optic neuropathy. Superior ophthalmic vein dilation and proptosis did not show significant relations with optic neuropathy. This study suggests that patients with Graves orbitopathy who have severe optic nerve crowding, intracranial fat prolapse, and/or muscle index greater than 50% present on orbital CT scans are more likely to have coexisting optic neuropathy.


Recombinant E1-deleted adenovirus-mediated gene therapy for cancer: efficacy studies with p53 tumor suppressor gene and liver histology in tumor xenograft models.
Type 5 adenoviral (Ad) vectors have been the "vector-of-choice" for preclinical studies on p53 tumor suppressor gene therapy of cancer. Previous studies have examined the in vivo efficacy of p53 Ad when given intratumorally. However published information does little to guide clinicians in the design of intraperitoneal (i.p.) dosing trials for i.p. tumors, e.g., ovarian, or clinical trials using regional organ perfusion, e.g., for lung tumors. Therefore, we examined several parameters with special significance for these routes of administration. Lung metastases from p53mut MDA-MB-231 mammary xenografts were treated with therapeutic levels of intravenous buffer, beta-galactosidase (beta-Gal) Ad, or p53 Ad. Treatment with intravenous p53 Ad significantly reduced the number of metastases per lung and there was a dramatic reduction in the surface area occupied by these tumors as compared to control groups. Two types of i.p. tumor xenografts were used for preclinical modeling of i.p. gene therapy, the p53null SK-OV-3 ovarian and the p53mut DU-145 prostate human cancers. In a study examining the effect of different vehicle volumes on the efficacy of a constant drug dose, all mice treated with p53 Ad had reduced tumor burden compared to controls. Dosing volumes between 0.2 and 1 ml were equally effective and all were more effective than a dosing volume of 0.1 ml. However, reduced efficacy was observed when a volume of 1.5 ml was used. When the effect of dosing frequency on antitumor efficacy was examined, fractionated doses of p53 Ad had somewhat greater efficacy than fewer, bolus injections. One of the significant elements in the emerging toxicology associated with recombinant adenoviruses is the hepatocyte pathology caused by high systemic concentrations of adenovirus. For recombinant Ad used in this study, there was a pronounced dose-dependence for the liver response, with very high, repeated doses causing significant hepatocellular insult. Expression of cytoplasmic beta-Gal protein coincided with areas of greatest damage in mice treated with high doses of beta-Gal Ad. Ultrastructural examination of hepatocyte intranuclear inclusions revealed moderately electron-dense, tightly packed granular material interspersed with more electron-dense nuclear material. Human tumor xenografts, but not mouse tissues, expressed viral hexon protein. In summary, hepatic toxicity caused by high concentrations of recombinant adenovirus was observed in murine cancer models. However, therapeutic levels of p53 Ad could be achieved which had dramatic efficacy without significant pathology.


Status of countrywide laboratory services quality and capacity in primary healthcare facilities in Tanzania: Findings from Star Rating Assessment.
Accurate disease diagnosis relies on a well-organized and reliable laboratory system. This study assesses the quality of laboratory services in Tanzania based on the nationwide Star Rating Assessment (SRA) of Primary Healthcare (PHC) facilities conducted in 2017/18. This cross-sectional study utilized secondary data from all the country's PHC facilities stored in the SRA database. Laboratory service quality was assessed by aggregating scores as percentages of the maximum achievable score across various indicators: dedicated laboratory department/room, adequate equipment, staffing levels, adherence to testing protocols, establishment of turnaround times, internal and external quality controls, and safety and supplies management. Scores equal to or exceeding 80% were deemed compliant. Multiple linear regression was used to determine the influence of facility characteristics (level, ownership, location, staffing) on quality scores, with statistical significance set at p < 0.05. The study included 6,663 PHC facilities (85.9% dispensaries, 11% health centers, 3.2% hospital-level-1), with the majority being public (82.3% vs. 17.7%) and located in rural areas (77.1% vs. 22.9%). On average, facilities scored 30.8% (SD = 35.7), and only 26.6% met staffing requirements. Compliance with quality standards was higher in private (63% vs. 19%, p<0.001) and urban facilities (62% vs. 16%, p<0.001). More than half of the facilities did not meet either of the eight quality indicators. Quality was positively linked to staffing compliance (Beta = 5.770) but negatively impacted by dispensaries (Beta = -6.342), rural locations (Beta = -0.945), and public ownership (Beta = -1.459). A score of 30% falls significantly short of the national target of 80%. Improving laboratory staffing levels at PHC facilities could improve the quality of laboratory services, especially in public facilities that are based in rural areas. There is a need to further strengthen laboratory services in PHC facilities to ensure the quality of laboratory services and clients' satisfaction.


Computational NMR Spectroscopy of Ionic Liquids: [C4C1im]Cl/Water Mixtures.
In this work, I have analyzed the structure of binary mixtures of 1-butyl-3-methylimidazolium chloride ionic liquid, [C4C1im]Cl, and water, using computational NMR spectroscopy. The structure of the complex fluid phase, where the ionic and hydrophobic nature of ionic liquids is further complicated by the addition of water, is first generated by classical Molecular Dynamics (MD) and then validated by calculating the NMR properties with DFT at the ONIOM(B3LYP/cc-pVTZ//B3LYP/3-21G) on clusters extracted during the MD trajectories. Three ionic liquid/water mixtures have been considered with the [C4C1im]Cl mole fraction of 1.00, 0.50, and 0.01, that is the pure ionic liquid [C4C1im]Cl, the equimolar [C4C1im]Cl/water mixture, and a diluted solution of [C4C1im]Cl in water. A good agreement is obtained with published experimental data that, at the same time, validates the structural features obtained from the MD and the force field used, and provides an example of the power of NMR spectroscopy applied to complex fluid phases.


Lipid biosynthesis and its coordination with cell cycle progression.
The activation of cell cycle regulators at the G1/S boundary has been linked to the cellular protein synthesis rate. It is conceivable that regulatory mechanisms are required to allow cells to coordinate the synthesis of other macromolecules with cell cycle progression. The availability of highly synchronized cells and flow cytometric methods facilitates investigation of the dynamics of lipid synthesis in the entire cell cycle of the heterotrophic dinoflagellate Crypthecodinium cohnii. Flow cytograms of Nile red-stained cells revealed a stepwise increase in the polar lipid content and a continuous increase in neutral lipid content in the dinoflagellate cell cycle. A cell cycle delay at early G1, but not G2/M, was observed upon inhibition of lipid synthesis. However, lipid synthesis continued during cell cycle arrest at the G1/S transition. A cell cycle delay was not observed when inhibitors of cellulose synthesis and fatty acid synthesis were added after the late G1 phase of the cell cycle. This implicates a commitment point that monitors the synthesis of fatty acids at the late G1 phase of the dinoflagellate cell cycle. Reduction of the glucose concentration in the medium down-regulated the G1 cell size with a concomitant forward shift of the commitment point. Inhibition of lipid synthesis up-regulated cellulose synthesis and resulted in an increase in cellulosic contents, while an inhibition of cellulose synthesis had no effects on lipid synthesis. Fatty acid synthesis and cellulose synthesis are apparently coupled to the cell cycle via independent pathways.


Perhydroquinolylbenzamides as novel inhibitors of 11beta-hydroxysteroid dehydrogenase type 1.
High-throughput screening identified 5 as a weak inhibitor of 11beta-HSD1. Optimization of the structure led to a series of perhydroquinolylbenzamides, some with low nanomolar inhibitory potency. A tertiary benzamide is required for biological activity and substitution of the terminal benzamide with either electron-donating or -withdrawing groups is tolerated. The majority of the compounds show selectivity of >20 to >700-fold over 11beta-HSD2. Analogues which showed >50% inhibition of 11beta-HSD1 at 1 muM in an cellular assay were screened in an ADX mouse model. A maximal response of >70% reduction of liver corticosterone levels was observed for three compounds; 9m, 25 and 49.


Individual differences in ethanol self-administration following withdrawal are associated with asymmetric changes in dopamine and serotonin in the medial prefrontal cortex and amygdala.
Ethanol withdrawal alters brain neurochemistry, causes asymmetric activation of neurons in the medial prefrontal cortex (mPFC) and amygdala (AMY), and increases ethanol craving and drinking. Rats with intrinsic rightward-turning preferences drink more ethanol than those with left or no preferences; they also exhibit an ethanol-induced neurochemical activation that favors the right side of the mPFC. Our experiments used rats with different turning preferences to assess differences in withdrawal effects on mPFC and AMY neurochemistry as well as ethanol self-administration. Rats with left-turning, right-turning, and nonturning preferences were fed a 6% ethanol-containing liquid diet (WD) or a pair-fed control diet for 14 days. Differences in dopamine (DA), serotonin (5HT), norepinephrine (NE), and metabolite [3,4-dihydroxphenylacetic acid, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid) concentrations were assessed in each side of the mPFC and AMY during acute withdrawal. Similar groups were fed the same diets and tested for consumption of 10% ethanol versus water and 1% sucrose versus water. WD increased HVA/DA in the mPFC and caused depletions of DA and 5HT in the mPFC and 5HT in the AMY. These effects were greater in the right than in the left side of these structures in rats with right-turning preferences. WD reduced ethanol drinking but right turners drank significantly more than left turners on day 2 of testing and drank more on days 2 and 3 than on day 1. No effects were observed on sucrose drinking. Similar groups were also trained to self-administer ethanol using a sucrose-fade sipper tube procedure that separated measures of ethanol seeking (bar pressing) and consumption. Following 14 days of vapor chamber exposure to ethanol, rats of all turning preferences had a lower rate of bar pressing on the first postwithdrawal day and shorter latencies to begin bar pressing on the third withdrawal day versus prewithdrawal baseline. Only right-turning-preference rats consumed more ethanol following withdrawal. These studies show that individual rats differ in postwithdrawal brain neurochemistry and ethanol consumption and that these differences are associated with differences in functional brain asymmetry.


Challenges to developing diabetes self-management skills in a low-income sample in North Carolina, USA.
High rates of diabetes diagnosis and poor diabetes outcomes are particularly significant in low-income, socially disadvantaged populations. Although many social and economic predictors of poor self-management outcomes are known, few studies have examined how these elements impact the ability to develop self-management capacities in low-income populations. This article presents new insights into low-income women's challenges and successes to becoming more adept self-managers. Interview data were collected in 2012 with a sample of low-income, middle-age women with type II diabetes recruited from a non-profit medical clinic serving low-income clients in North Carolina, United States. Data were analysed using a grounded theory approach. Developing self-management skills within disadvantaged life contexts involved negotiating three related, overlapping sub-processes: negotiating access to care systems, negotiating disruptions to diabetes self-management patterns, and negotiating self-care knowledge. Developing diabetes self-management skills is a long and arduous process. Data and analysis presented here help explain how disadvantaged life contexts can impact self-managers' efforts to develop self-management skills and why continued support is important for reducing and preventing future problems. These initial findings suggest that future studies and intervention development on the topic are warranted.


Hydrogen atom formation from the photodissociation of water ice at 193 nm.
The TOF spectra of photofragment hydrogen atoms from the 193 nm photodissociation of amorphous ice at 90-140 K have been measured. The spectra consist of both a fast and a slow components that are characterized by average translational energies of 2k(B)T(trans)=0.39+/-0.04 eV (2300+/-200 K) and 0.02 eV (120+/-20 K), respectively. The incident laser power dependency of the hydrogen atom production suggests one-photon process. The electronic excitation energy of a branched cluster, (H(2)O)(6+1), has been theoretically calculated, where (H(2)O)(6+1) is a (H(2)O)(6) cyclic cluster attached by a water molecule with the hydrogen bond. The photoabsorption of this branched cluster is expected to appear at around 200 nm. The source of the hydrogen atoms is attributed to the photodissociation of the ice surface that is attached by water molecules with the hydrogen bond. Atmospheric implications are estimated for the photodissociation of the ice particles (Noctilucent clouds) at 190-230 nm in the region between 80 and 85 km altitude.