Partial characterization and anticoagulant activity of a heterofucan from the brown seaweed Padina gymnospora.
The brown algae Padina gymnospora contain different fucans. Powdered algae were submitted to proteolysis with the proteolytic enzyme maxataze. The first extract of the algae was constituted of polysaccharides contaminated with lipids, phenols, etc. Fractionation of the fucans with increasing concentrations of acetone produced fractions with different proportions of fucose, xylose, uronic acid, galactose, and sulfate. One of the fractions, precipitated with 50% acetone (v/v), contained an 18-kDa heterofucan (PF1), which was further purified by gel-permeation chromatography on Sephadex G-75 using 0.2 M acetic acid as eluent and characterized by agarose gel electrophoresis in 0.05 M 1,3 diaminopropane/acetate buffer at pH 9.0, methylation and nuclear magnetic resonance spectroscopy. Structural analysis indicates that this fucan has a central core consisting mainly of 3-beta-D-glucuronic acid 1-> or 4-beta-D-glucuronic acid 1 ->, substituted at C-2 with alpha-L-fucose or beta-D-xylose. Sulfate groups were only detected at C-3 of 4-alpha-L-fucose 1-> units. The anticoagulant activity of the PF1 (only 2.5-fold lesser than low molecular weight heparin) estimated by activated partial thromboplastin time was completely abolished upon desulfation by solvolysis in dimethyl sulfoxide, indicating that 3-O-sulfation at C-3 of 4-alpha-L-fucose 1-> units is responsible for the anticoagulant activity of the polymer.


Transforming activity of DNA fragments from normal human lymphocytes results from spontaneous activation of a c-Ha-ras1 gene.
An activated human Ha-ras gene was present in a secondary NIH 3T3 transformant isolated after serial transfection of originally low-molecular-weight DNA fragments from normal human cells. This gene appeared to have acquired its transforming properties by a spontaneous mutation in codon 12 by substitution of a deoxythymidine residue for a deoxyguanosine residue. DNA rearrangements in the flanking sequences of the transferred Ha-ras gene were not involved in the activation of the protooncogene.


The acute and post-discontinuation effects of a glucocorticoid receptor (GR) antagonist probe on sleep and the HPA axis in chronic insomnia: a pilot study.
Hypothalamic-pituitary-adrenal axis (HPA) hyperactivity has been reported in patients with chronic insomnia without depression. Aglucocorticoid receptor (GR) antagonist may re-regulate HPA axis activity even after discontinuation and may have clinical benefit. Ten subjects with chronic insomnia participated in a placebo controlled double-blinded prospective 30-day pilot study of the acute and post-discontinuation effects of a 5-day course of 600 mg of the glucocorticoid antagonist, mifepristone. Sleep outcome measures were polysomnogram and Insomnia Severity Index. Hormonal outcome measures were mean overnight cortisol and ACTH (23:00-07:00). We predicted sleep would improve and that overnight cortisol and ACTH would decrease at 2 weeks post-treatment discontinuation. At 2 weeks post-discontinuation, Insomnia Severity Index (ISI) decreased by 4.0 points (effect size = 0.97). Polysomnogram findings were limited. Mean cortisol (0.84 microg/dL, effect size = 0.91) and ACTH (5.50 pg/mL, effect size = 0.96) were still mildly increased (23:00 to 07:00). Post hoc analysis revealed that, the ratio of cortisol/ ACTH decreased (-0.21, effect size = 1.15) as did mean cortisol from 18:00 to 23:00 (-0.47 microg/dL, effect size = 0.56). This is the first study of a GR antagonist in chronic insomnia. Sleep improvement manifests in terms of decreased ISI post-treatment discontinuation. The decrease in cortisol in the early evening (18:00 to 23:00) in combination with the decrease in cortisol/ ACTH ratio may be an indicator of the longer-term biological mode of action of the drug.


Trends and Predictors of Longitudinal Hearing Aid Use for Children Who Are Hard of Hearing.
Children who are hard of hearing (CHH) have restricted access to acoustic and linguistic information. Increased audibility provided by hearing aids (HAs) influences language outcomes, but the advantages of appropriately fit HAs can only be realized if children wear their devices on a consistent basis. The purpose of this article was to characterize long-term HA use in CHH, based on parent-report measures, and identify factors that influence longitudinal trends in HA use. Participants were parents of 290 children with mild to severe hearing loss. At every visit, parents estimated the average amount of time the child used HAs per day during the week and on the weekends. Parent reports of daily HA use were analyzed to determine if different patterns of HA use were observed longitudinally during the study. Independent predictor variables were then related to longitudinal trends in HA use within three age groups (infant, preschool, school age). On average across multiple visits, parents reported that their children wore their HAs for 10.63 hr per day (SD = 3.29). Data logging values were lower than parent-report measures (M = 8.44, SD = 4.06), suggesting that parents overestimated daily HA use. The majority of children in each age group wore HAs at least 8 hr per day from their first research testing interval to their last, based on parent-report measures. Maternal education level predicted longitudinal trends in HA use for infants and school-age CHH. Degree of hearing loss was related to trends in school-age children only. These results indicated that the majority of CHH increased HA use over time, but a sizable minority demonstrated a low level of use or decreased use in the time period studied. Maternal education level influenced longitudinal trends in daily HA use. Degree of hearing loss influenced trends in school-age children only. Audiologists and early intervention service providers might aid in improving HA use by providing regular hands-on training with the HAs and individualized problem-based strategies to address the challenges families experience with attaining a high level of use. Families may also benefit from practical demonstrations of the benefits of consistent HA use, such as hearing loss simulations, examples of listening in noise with and without HAs, or listening to malfunctioning HAs.


Role of Conformational Dynamics of Sulfotransferases SULT1A1 and SULT1A3 in Substrate Specificity.
Sulfotransferases (SULTs) are phase II metabolizing enzymes catalyzing the sulfoconjugation from the co-factor 3'-Phosphoadenosine 5'-Phosphosulfate (PAPS) to a wide variety of endogenous compounds, drugs and natural products. Although SULT1A1 and SULT1A3 share 93% identity, SULT1A1, the most abundant SULT isoform in humans, exhibits a broad substrate range with specificity for small phenolic compounds, while SULT1A3 displays a high affinity toward monoamine neurotransmitters like dopamine. To elucidate the factors determining the substrate specificity of the SULT1 isoenzymes, we studied the dynamic behavior and structural specificities of SULT1A1 and SULT1A3 by using molecular dynamics (MD) simulations and ensemble docking of common and specific substrates of the two isoforms. Our results demonstrated that while SULT1A1 exhibits a relatively rigid structure by showing lower conformational flexibility except for the lip (loop L1), the loop L2 and the cap (L3) of SULT1A3 are extremely flexible. We identified protein residues strongly involved in the recognition of different substrates for the two isoforms. Our analyses indicated that being more specific and highly flexible, the structure of SULT1A3 has particularities in the binding site, which are crucial for its substrate selectivity.


NO mediates postjunctional inhibitory effect of neurogenic ACh in guinea pig small intestinal microcirculation.
The present study was designed to evaluate the role of the endothelium as an effector organ of neurally mediated inhibition of vascular tone. Acetylcholine (ACh), either released by stimulation of the submucosal ganglia or applied exogenously, inhibited phenylephrine (PE)-induced constrictions in arterioles of the guinea pig intestinal submucosa. N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, attenuated the response to superfused ACh by 74% compared with 94% attenuation obtained with N(G)-nitro-L-arginine (L-NNA). L-NNA attenuated the response to neurally released ACh by 98% and that to iontophoretically applied ACh by 92%. L-Arginine reversed the effects of both L-NMMA and L-NNA. Functional integrity of the endothelium was essential for the neurally mediated inhibition of PE-induced constrictions. However, neurogenic inhibition of neurally evoked constrictions was preserved despite endothelial disruption. It was concluded that at the postjunctional level, the mechanism of action of neurally released ACh was almost exclusively via a NO-dependent pathway, with the source of NO being the vascular endothelium.


A novel composite formulation of palmitoylethanolamide and quercetin decreases inflammation and relieves pain in inflammatory and osteoarthritic pain models.
Osteoarthritis (OA) is a common progressive joint disease in dogs and cats. The goal of OA treatment is to reduce inflammation, minimize pain, and maintain joint function. Currently, non-steroidal anti-inflammatory drugs (e.g., meloxicam) are the cornerstone of treatment for OA pain, but side effects with long-term use pose important challenges to veterinary practitioners when dealing with OA pain. Palmitoylethanolamide (PEA) is a naturally-occurring fatty acid amide, locally produced on demand by tissues in response to stress. PEA endogenous levels change during inflammatory and painful conditions, including OA, i.e., they are typically increased during acute conditions and decreased in chronic inflammation. Systemic treatment with PEA has anti-inflammatory and pain-relieving effects in several disorders, yet data are lacking in OA. Here we tested a new composite, i.e., PEA co-ultramicronized with the natural antioxidant quercetin (PEA-Q), administered orally in two different rat models of inflammatory and OA pain, namely carrageenan paw oedema and sodium monoiodoacetate (MIA)-induced OA. Oral treatment with meloxicam was used as benchmark. PEA-Q decreased inflammatory and hyperalgesic responses induced by carrageenan injection, as shown by: (i) paw oedema reduction, (ii) decreased severity in histological inflammatory score, (iii) reduced activity of myeloperoxidase, i.e., a marker of inflammatory cell infiltration, and (iv) decreased thermal hyperalgesia. Overall PEA-Q showed superior effects compared to meloxicam. In MIA-treated animals, PEA-Q exerted the following effects: (i) reduced mechanical allodynia and improved locomotor function, (ii) protected cartilage against MIA-induced histological damage, and (iii) counteracted the increased serum concentration of tumor necrosis factor alpha, interleukin 1 beta, metalloproteases 1, 3, 9 and nerve growth factor. The magnitude of these effects was comparable to, or even greater than, those of meloxicam. The present findings shed new light on some of the inflammatory and nociceptive pathways and mediators targeted by PEA-Q and confirm its anti-inflammatory and pain-relieving effects in rodent OA pain models. The translatability of these observations to canine and feline OA pain is currently under investigation.


Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors.
Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis. There is much evidence that direct inhibition of the kinase activity of vascular endothelial growth factor receptor-2 (VEGFR-2) will result in the reduction of angiogenesis and the suppression of tumor growth. Attempts to optimize a cyclin-dependent kinase-1 (CDK1) inhibitor by using palladium-catalyzed C-C bond, C-N bond formation reactions to assemble diverse biheteroaryl molecules led to the unexpected discovery of a pyrazine-pyridine biheteroaryl as a novel series of potent VEGFR-2 inhibitors. Compound 15, which had IC(50) = 0.084 microM at VEGFR-2, showed very modest selectivity against fibroblast growth factor receptor-2 (IC(50) = 0.21 microM), platelet-derived growth factor receptor (IC(50) = 0.36 microM), and glycogen synthase kinase-3 (IC(50) = 0.478 microM), while it exhibited more than 10-fold selectivity against epidermal growth factor receptor (IC(50) = 1.36 microM) and insulin-R kinase (IC(50) = 1.69 microM). On the other hand, compound 15 exhibited more than 100-fold selectivity against calmodulin kinase 2; casein kinase-1 and -2; CDK1 and -4; mitogen-activated protein kinase; and protein kinase A, Cbeta2, and Cgamma (IC(50) >10 microM). Compound 15 also displayed high inhibitory potency on VEGF-stimulated human umbilical vein endothelial cell (HUVEC) proliferation (IC(50) = 0.005 microM) and good selectivity against cell lines such as HUVEC, human aortic smooth muscle cells, and MRC5 lung fibroblasts. Molecular docking studies were conducted in an attempt to rationalize the unexpected high VEGFR-2 selectivity of 15.


Bioaerosols from composting facilities--a review.
Bioaerosols generated at composting plants are released during processes that involve the vigorous movement of material such as shredding, compost pile turning, or compost screening. Such bioaerosols are a cause of concern because of their potential impact on both occupational health and the public living in close proximity to such facilities. The biological hazards potentially associated with bioaerosol emissions from composting activities include fungi, bacteria, endotoxin, and 1-3 β-glucans. There is a major lack of knowledge concerning the dispersal of airborne microorganisms emitted by composting plants as well as the potential exposure of nearby residents. This is due in part to the difficulty of tracing specifically these microorganisms in air. In recent years, molecular tools have been used to develop new tracers which should help in risk assessments. This review summarizes current knowledge of microbial diversity in composting aerosols and of the associated risks to health. It also considers methodologies introduced recently to enhance understanding of bioaerosol dispersal, including new molecular indicators and modeling.


Association between SIRT1 Gene Polymorphisms and Breast Cancer in Egyptians.
Breast cancer is reported to cause the highest mortality among female cancer patients. Previous studies have explored the association of silent mating-type information regulator 2 homolog 1 (SIRT1) gene expression with prognosis in breast cancer. However, no studies exist, so far, on the role of SIRT1 gene polymorphism in breast cancer risk or prognosis. The present study aimed to assess the association between SIRT1 gene polymorphisms and breast cancer in Egyptians. The study comprised 980 Egyptian females divided into a breast cancer group (541 patients) and a healthy control group (439 subjects). SIRT1 gene single nucleotide polymorphisms (SNPs) rs3758391, rs3740051 and rs12778366 were genotyped using real-time polymerase chain reaction (RT-PCR). Allelic and genotypic frequencies were determined in both groups and association with breast cancer and clinicopathological characteristics was assessed. Breast cancer patients exhibited elevated serum SIRT1 levels which varied among different tumor grades. SIRT1 rs3758391 and rs12778366 TT genotypes were more frequent, exhibited higher SIRT1 levels than CC and CT genotypes and were associated with histologic grade and lymph node status. SIRT1 rs12778366 TT genotype also correlated with negative estrogen receptor (ER) and progesterone receptor (PR) statuses. The T allele frequency for both SNPs was higher in breast cancer patients than in normal subjects. Combined GG and AG genotypes of rs3740051 were more frequent, showed higher serum SIRT1 levels than the AA genotype, and were associated with ER and PR expression. Furthermore, inheritance of the G allele was associated with breast cancer. Our findings reveal that rs3758391 and rs12778366 polymorphisms of SIRT1 gene are associated with breast cancer risk and prognosis in the Egyptian population.


The evolution from cardiac physiologists to clinical scientists in the UK: a guide to attaining equivalence.
At its inception, transthoracic echocardiography (TTE) was employed as a basic screening tool for the diagnosis of heart valve disease and as a crude indicator of left ventricular function. Since then, echocardiography has developed into a highly valued non-invasive imaging technique capable of providing extremely complex data for the diagnosis of even the subtlest cardiac pathologies. Its role is now pivotal in the diagnosis and monitoring of heart disease. With the evolution of advanced practice and devolving care, ordinarily performed by senior doctors, to the cardiac physiology workforce in the UK, significant benefits in terms of timely patient care and cost savings are possible. However, there needs to be appropriate level of accountability. This accountability is achieved in the UK with statutory regulation of healthcare professionals and is a crucial element in the patient protection system, particularly for professions in patient facing roles. However, statutory regulation for staff practising echocardiography is not currently mandatory in the UK, despite the level of responsibility and influence on patient care. Regulators protect the public against the risk of poor practice by setting agreed standards of practice and competence and registering those who are competent to practice. Regulators take action if professionals on their register do not meet their standards. The current cardiac physiology workforce can be recognised as registered clinical scientists using equivalence process through the Academy for Healthcare Science, and this review aims to describe the process in detail.


Urine drug testing: current recommendations and best practices.
The precise role of urine drug testing (UDT) in the practice of pain medicine is currently being defined. Confusion exists as to best practices, and even to what constitutes standard of care. A member survey by our state pain society revealed variability in practice and a lack of consensus. The authors sought to further clarify the importance of routine UDT as an important part of an overall treatment plan that includes chronic opioid prescribing. Further, we wish to clarify best practices based on consensus and data where available. A 20-item membership survey was sent to Texas Pain Society members. A group of chronic pain experts from the Texas Pain Society undertook an effort to review the best practices in the literature. The rationale for current UDT practices is clarified, with risk management strategies outlined, and recommendations for UDT outlined in detail. A detailed insight into the limitations of point-of-care (enzyme-linked immunosorbent assay, test cups, test strips) versus the more sensitive and specific laboratory methods is provided. Our membership survey was of a limited sample size in one geographic area in the United States and may not represent national patterns. Finally, there is limited data as to the efficacy of UDT practices in improving compliance and curtailing overall medication misuse. UDT must be done routinely as part of an overall best practice program in order to prescribe chronic opioid therapy. This program may include risk stratification; baseline and periodic UDT; behavioral monitoring; and prescription monitoring programs as the best available tools to monitor chronic opioid compliance.


Treatment of acquired bilateral nevus of Ota-like macules (Hori's nevus) using a combination of scanned carbon dioxide laser followed by Q-switched ruby laser.
Acquired bilateral nevus of Ota-like macules (Hori's nevus) is a dermal pigmented lesion commonly seen in middle-aged women of Asian descent. The Q-switched ruby laser (QSRL) has been used successfully to treat a variety of benign pigmented lesions. Multiple, sequential treatments are typically required for complete clearance of the dermal pigmented dermatoses. The purpose of this study was to determine the efficacy of QSRL in the treatment of Hori's nevus and the beneficial effect of epidermal ablation using the scanned carbon dioxide (CO(2)) laser before QSRL. A total of 13 women from Thailand with Hori's nevus were randomly treated with the scanned CO(2) laser followed by QSRL on one side of their face, and QSRL alone on the other side. The same fluence of QSRL was used on both sides in individual patients. The treatment response was objectively evaluated by measuring the melanin index using a Mexameter (Courage & Khazaka Electronic GmbH, Köln, Germany), and subjectively assessed by the patients before treatment and 3 and 16 months after treatment. Adverse sequelae of the treatment and the patients' tolerance were also evaluated at the same follow-up visit. The 3- and 16-month posttreatment melanin index was significantly decreased compared with that of pretreatment on both treated sites and this corresponded to the patients' subjective evaluations. The response rate, defined as "the percentage of reduction in melanin index," was significantly higher on the sides treated with scanned CO(2) laser followed by QSRL, compared with the sides irradiated with QSRL alone at both follow-up visits. At the 3-month follow-up, the most common adverse effect was hypopigmentation, found in 15% (2 of 13) of the patients on the sites treated with QSRL alone, and on the sites treated with scanned CO(2) laser followed by QSRL (8%, 1/13). Erythema was observed in 15% (2/13) of the patients only on the sites that received combination treatment. However, no adverse sequelae were observed at the 16-month posttreatment follow-up. Epidermal ablation with scanned CO(2) laser before the use of the pigment-specific laser may be an effective technique for increasing therapeutic efficacy in the treatment of dermal pigmented dermatoses.


Similarities in the polypeptide composition of glyoxysomal and endoplasmic-reticulum membranes from castor-bean endosperm.
Microsomal fractions, glyoxysomes and mitochondria were isolated from homogenates of germinating castor-bean (Ricinus communis) endosperm by sucrose-density-gradient centrifugation. Washed membrane preparations from these cellular fractions were examined by sodium dodecyl sulphate/polyacrylamide-gel electrophoresis. At corresponding developmental stages the endoplasmic-reticulum and glyoxysomal membranes were strikingly similar in polypeptide composition, at least 16 polypeptides being present in membranes isolated from 3-day-old tissue. Supplying [35S]methionine to intact endosperm tissue resulted in the labelling of all membrane polypeptides, the specific radioactivity in the endoplasmic reticulum being greater than for equivalent polypeptides of the glyoxysomal membrane. Washing these membranes with sodium deoxycholate solution extensively solubilized protein components, with the exception of a predominant polypeptide of mol.wt. 55000. Mitochondrial membrane preparations differed from those of the endoplasmic reticulum and glyoxysomes in polypeptide molecular-weight distribution and the [35S]methionine-labelling pattern. The similarity in polypeptide composition between endoplasmic-reticulum and glyoxysomal membranes is discussed in relation to glyoxysome biogenesis.


Hepatopancreatobiliary manifestations of inflammatory bowel disease.
Inflammatory bowel disease (IBD) is frequently associated with extraintestinal manifestations such as hepatopancreatobiliary manifestations (HPBMs), which include primary sclerosing cholangitis (PSC), pancreatitis, and cholelithiasis. PSC is correlated with IBD, particularly ulcerative colitis (UC); 70-80% of PSC patients in Western countries and 20-30% in Japan have comorbid UC. Therefore, patients diagnosed with PSC should be screened for UC by total colonoscopy. While symptoms of PSC-associated UC are usually milder than PSC-negative UC, these patients have a higher risk of colorectal cancer, particularly in the proximal colon. Therefore, regular colonoscopy surveillance is required regardless of UC symptoms. Administration of 5-aminosalicylic acid or ursodeoxycholic acid may prevent colorectal cancer and cholangiocarcinoma. While PSC is diagnosed by diffuse multifocal strictures on cholangiography, it must be carefully differentiated from immunoglobulin G4 (IgG4)-associated cholangitis, which shows a similar cholangiogram but requires different treatment. When PSC is suspected despite a normal cholangiogram, the patient may have small-duct PSC, which requires a liver biopsy. IBD patients have a high incidence of acute and chronic pancreatitis. Most cases are induced by cholelithiasis or medication, although some patients may have autoimmune pancreatitis (AIP), most commonly type 2 without elevation of serum IgG4. AIP should be accurately identified based on characteristic image findings, because AIP responds well to corticosteroids. Crohn's disease is frequently associated with gallstones, and several risk factors are indicated. HPBMs may influence the management of IBD, therefore, accurate diagnosis and an appropriate therapeutic strategy are important, as treatment depends upon the type of HPBM.


Distribution and elimination of palladium in rats after 90-day oral administration.
This study determined the distribution in internal organs and the elimination routes in rats after oral administration of potassium hexachloro-palladate. Forty male Wistar rats were exposed for 90 days to 0, 10, 100 and 250 ng/mL of the palladium (Pd) salt in drinking water. Samples of urine and feces were collected on days 1, 30, 60 and 90, while organs (kidney, liver, lung, spleen and bones) and blood were collected at the end of the experiment. Quantification method was based on the sector-field inductively coupled plasma mass spectrometry. Results indicated that Pd ions were rapidly eliminated from the body. The principal excretion was through the feces (650 +/- 72.7 ng/g dry weight, at the Pd dose of 250 ng/mL), but at the higher dosing Pd was also eliminated through the urine (6.16 +/- 1.91 ng/mL for the Pd intake of 250 ng/mL). A clear relationship between the Pd ingested dose and the Pd excretion amount was observed mainly in the feces. Absorbed Pd was mostly found in the kidney of rats (124.4 +/- 23.0 ng/g dry weight, following the highest dose), while liver, lung, spleen and bones did not accumulate the metal. At the higher dosing, Pd content in the kidney raised proportionally with the Pd dose. Our findings may be useful to help in the understanding of the health impact of Pd dispersed in the environment as well as in identifying appropriate biological indices of Pd exposure.


An investigation of G-quadruplex structural polymorphism in the human telomere using a combined approach of hydrodynamic bead modeling and molecular dynamics simulation.
Guanine-rich oligonucleotides can adopt noncanonical tertiary structures known as G-quadruplexes, which can exist in different forms depending on experimental conditions. High-resolution structural methods, such as X-ray crystallography and NMR spectroscopy, have been of limited usefulness in resolving the inherent structural polymorphism associated with G-quadruplex formation. The lack of, or the ambiguous nature of, currently available high-resolution structural data, in turn, has severely hindered investigations into the nature of these structures and their interactions with small-molecule inhibitors. We have used molecular dynamics in conjunction with hydrodynamic bead modeling to study the structures of the human telomeric G-quadruplex-forming sequences at the atomic level. We demonstrated that molecular dynamics can reproduce experimental hydrodynamic measurements and thus can be a powerful tool in the structural study of existing G-quadruplex sequences or in the prediction of new G-quadruplex structures.


Histomorphological investigation regarding to malignant transformation of pleomorphic adenoma (so-called malignant mixed tumor) of the salivary gland origin: special reference to carcinosarcoma.
Pleomorphic adenoma is the best-recognized tumor among those of salivary gland origin that also has the highest incidence. However, it is not uncommon for it to become malignant, and it has been noted that the frequency of malignancy increases as a result of the tumor persisting without being treated following the onset of adenoma. Carcinomatous components demonstrate various histological appearances, and in particular, there have been sporadic reports of carcinosarcoma in which malignant findings are not only observed in epithelial components, but in mesenchymal components as well. We conducted a histopathological study on cases of malignant-transformed pleomorphic adenoma, namely so-called malignant mixed tumor observed in our department. The subject cases consisted of a total of 19 cases registered in the diagnostic files of our department and included 12 males and 7 females. Age ranged from 46 to 87 (average 67.7) years old. The sites of occurrence consisted of the parotid gland in 17 cases, and palatal and buccal minor salivary glands in one case each. Histological types consisted of 7 cases of adenocarcinoma not otherwise specified, 3 cases of squamous cell carcinoma, 3 cases of salivary duct carcinoma, and one case each of polymorphous low-grade adenocarcinoma and epithelial-myoepithelial carcinoma, while the remaining were 2 cases of sarcomatoid carcinoma and 2 carcinosarcoma. We described herein their histological characteristics, discussed diagnostic problems in various instants in which each phenotype on this setting, and reviewed the literature, especially as to carcinosarcoma in contrast with those derived from other organs.


Use of unsolicited first-person written illness narratives in research: systematic review.
This paper is a report of a methodological systematic review conducted to critically analyze the use of unsolicited first-person written illness narratives for research purposes. Documenting illness experiences through written narratives enables individuals to record the impact of illness on themselves and those closest to them. In health research, unsolicited first-person written illness narratives are recognized increasingly as legitimate data sources. To date there has been no critical evaluation of the method. The ISI Web of Knowledge; CINAHL; PubMed; MEDLINE; PsycINFO; Science Direct; Cochrane Library databases and the internet metasearch engine 'Dogpile' were searched for the period up to 2009. The search terms were: 'patient experience', 'narratives', 'autobiography', 'pathography', 'written narratives', 'illness narratives', 'internet', 'published', 'unsolicited'. Recommendations within the Centre for Reviews and Dissemination guidance informed the review. Eligible studies were evaluated according to inclusion/exclusion criteria. The data were extracted by one reviewer and monitored by the second reviewer. Eighteen papers met the inclusion criteria, 12 from the original search in 2008 and six from the updated search in October 2009. Nine used unpublished (internet) narratives, eight used published (print) accounts and one drew on both genres. The method has been used to explore a wide range of illness experiences. There was lack of agreement on key terminology. Methodological issues were often poorly-described, and confused ethical stances were reported. The lack of methodological detail in published papers requires attention if this method is to be used effectively in healthcare research. The confused ethical stance adopted needs to be addressed and clarified. A theoretical conceptual framework to define and describe the method accurately is urgently required.


Rhinitis patients with sputum eosinophilia show decreased lung function in the absence of airway hyperresponsiveness.
Sputum eosinophilia is observed frequently in patients with rhinitis. Sputum eosinophilia in patients with non-asthmatic allergic rhinitis has been suggested to be related to nonspecific airway hyperresponsiveness (AHR). However, the clinical significance of sputum eosinophilia in patients with non-asthmatic rhinitis without AHR has not been determined. We conducted a retrospective study examining the influence of sputum eosinophilia in patients with non-asthmatic rhinitis without AHR on pulmonary function and expression of fibrosis-related mediators. Eighty-nine patients with moderate-to-severe perennial rhinitis without AHR were included. All underwent lung function tests (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]), skin tests to inhalant allergens, methacholine bronchial challenge tests, and hypertonic saline-induced sputum to determine eosinophil counts. Sputum mRNA levels for transforming growth factor-β (TGF-β), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) were also examined. Patients were divided into two groups according to the presence of sputum eosinophilia (≥3%, eosinophilia-positive [EP] and <3%, eosinophilia-negative [EN] groups). FEV1 was significantly lower (P=0.04) and FEV1/FVC tended to be lower (P=0.1) in the EP group than in the EN group. In sputum analyses, the MMP-9 mRNA level (P=0.005) and the ratio of MMP-9 to TIMP-1 expression (P=0.01) were significantly higher in the EP group than in the EN group. There was no significant difference in TGF-β mRNA expression between the two groups. Sputum eosinophilia in patients with moderate-to-severe perennial rhinitis without AHR influenced FEV1 and the expression pattern of fibrosis-related mediators.


Prognostic factors in small cell lung cancer: multivariate model based on 778 patients treated with chemotherapy with or without irradiation.
The relationships between prognostic factors and duration of survival in small cell lung cancer were investigated in a consecutive series of 874 patients treated with combination chemotherapy with or without irradiation. The series included 443 patients with limited and 431 patients with extensive stage disease based on staging including bone marrow examination and peritoneoscopy with liver biopsy but no routine scans. The median durations of survival for the two disease categories were 48 and 30 weeks, respectively. The influence on survival of various pretreatment factors was investigated by use of univariate methods and Cox's multivariate regression model. Patients in each stage were treated according to one of three controlled trials. Variations among the applied treatment regimens did not result in significant differences in duration of survival among patients with limited disease. An alternating regimen was superior to continuous therapy in patients with extensive disease and raised serum lactate dehydrogenase. Prognosis was correlated with disease extent. Surgical resection as well as limited stage disease thus both contributed to survival. Poor performance status, reduced hemoglobin concentration, and raised values for serum lactate dehydrogenase were significantly associated with a reduced duration of survival in both stages. Females with limited disease lived significantly longer than males while advanced age was a negative prognostic factor in extensive disease. Plasma sodium and serum urate were both predictive of survival in limited disease. Proved metastatic disease affecting specific sites or total number of metastatic sites did not carry significant prognostic information in a model including a general variable characterizing stage of disease. Fifty of the 778 patients, on whom the multiple regression model was based, were alive and disease free 2 years after the start of the treatment. Two-year survival rates were strongly correlated to groupings based on prognostic factors, and information about disease extent was not mandatory for predicting the probability of long term disease-free survival.


Intestinal parasites in Malaysian children with cancer.
In this prospective study, we examined stool specimens from children with cancer receiving chemotherapy who were admitted for fever to the Universiti Sains Malaysia Hospital in Kota Baru, Kelantan. Stool specimens were examined for ova and cysts of parasites. Over a period of 15 months, there were 129 febrile episodes in 50 children with cancer and, in all, 237 stool specimens were examined. Sixty-six per cent of febrile episodes were associated with neutropenia and 9 per cent were associated with diarrhoea. Stool parasites were found in 42 per cent of children. The most common were helminths, followed by protozoa. Trichuris trichiura was the most common parasite (24 per cent), followed by Ascaris lumbricoides (22 per cent). Hookworm was found in 2 per cent. Giardia lamblia was found in 6 per cent of children, Blastocystis hominis in 4 per cent, and Cryptosporidium parvum in 2 per cent.


Research on Classification of Primary Liver Cancer Syndrome Based on Data Mining Technology.
This study is based on the analysis of the status quo of the research on liver cancer syndromes, starting with the clinical objective and true four-diagnosis information of TCM inpatients with primary liver cancer, using computer data mining technology to analyze and summarize the syndrome rules from the bottom to the top. Let the data itself show the essence of liver cancer syndrome. First, with the help of hierarchical cluster analysis, we can understand the general characteristics through the rough preliminary classification of the four-diagnosis information of liver cancer patients. Then, with the help of the emerging and mature hidden structure model analysis in recent years, through data modeling, the classification of common syndromes of liver cancer and the corresponding relationship with the four-diagnosis information are comprehensively analyzed. Finally, considering the inherent shortcomings of implicit structure and hierarchical clustering based on the assumption that there is a unique one-to-one correspondence between the four diagnostic information factors and the class (or hidden class) when classifying, we plan to use factor analysis and joint cluster analysis, as supplementary means to further explore the classification of liver cancer syndromes and the corresponding relationship with the four-diagnosis information.


The characteristics, occurrence, and toxicological effects of patulin.
Mycotoxins are the secondary metabolites secreted by different types of fungi to which humans can get exposed mainly via ingestion. Patulin (C7H6O4) is a polyketide lactone produced by various fungal specifies, including Penicillium expansum as the main producer. P. expansum can infect different fruits and vegetables yet it has preference to apples in which they cause blue rot. Therefore, apples and apple-based food products are the main source of Patulin exposure for humans. Patulin was first identified in 1943 under the name of tercinin as a possible antimicrobial agent. Although it is categorized as a non-carcinogen, Patulin has been linked, in the last decades, to neurological, gastrointestinal, and immunological adverse effects, mainly causing liver and kidney damages. In this review, the characteristics of and possible human exposure pathways to Patulin are discussed. Various surveillance and toxicity studies on the levels of Patulin in various food products and effects of Patulin on cells and animal models have been documented as well. Importance of epidemiological studies and a summary of the possible toxicity mechanisms are highlighted with a case study. The commonly used control methods as described in the literature are also discussed to guide future researchers to focus on mitigating mycotoxins contamination in the food industry.


Using quality improvement methods to improve door-to-balloon time at an academic medical center.
1) Describe a quality improvement (QI) process to decrease door-to-balloon time (D2B); 2) Explain implementation of evidence-based strategies to improve D2B. The ACC/AHA 2006 guideline target for ST-elevation myocardial infarction (STEMI) is a D2B of 90 minutes (min). QI methods can be used to identify areas for improvement, measure current processes, and provide rapid-cycle feedback about which strategies are effective. We studied all STEMI patients presenting to Vanderbilt University Medical Center from July 2005 through November 2006. A process flow chart was created and all D2B process steps were analyzed. In February 2006, evidence-based strategies were implemented to address bottlenecks and decrease D2B. Statistical process control (SPC) was used to monitor D2B time in real-time. Targeted changes led to a 44 min decrease (p < 0.001) in overall median D2B time from 108 min (interquartile range [IQR] = 94-122 min) to 64 min (IQR = 56-94 min). Subinterval time periods for emergency department (ED)-to-electrocardiogram (ECG) time decreased by 7 min (p = 0.008), ECG-to-cardiac catheterization laboratory (CCL) time decreased by 18 min (p = 0.01), and CCL-to-balloon time decreased by 4 min (p = 0.19). After implementation, SPC charts revealed a 50% decrease in the central mean line and narrower control limits indicating more reliable performance. Using QI methods of flow-charting, identifying bottlenecks, targeting strategies to bottleneck areas, and real-time monitoring with SPC and rapid-cycle feedback, D2B processes can be systematically redesigned for improvement. QI methods can be used by individual institutions to customize and implement strategies for their particular context.


The Accuracy of Temperature Measurements Provided by the Edwards Lifesciences Pulmonary Artery Catheter.
Pulmonary artery catheters (PACs) are frequently used for monitoring patient temperatures in the intensive care unit. Nevertheless, data regarding the accuracy of these measurements are lacking, and few data testify to the accuracy of temperatures recorded after the PAC has been in place for several days. The absolute values of such measurements are relevant for critical care because patient temperatures are often used as diagnostic criteria for sepsis and antibiotic therapy. We thus hypothesized that the Edwards Lifesciences PAC would accurately measure blood temperature. To test our hypothesis, we compared temperature measurements obtained from PACs inserted in patients for different lengths of time with measurements of a reference platinum resistance thermometer (PRT). PACs were removed and analyzed in 39 patients in whom PACs were inserted for 0 to 5 days. The PACs were placed in calibration baths, and 10 consecutive measurements at each of 7 different temperatures were obtained (36°C, 36.5°C, 37°C, 38°C, 38.3°C, 39°C, and 40°C). The temperature measurements obtained using PACs were compared with measurements obtained using a PRT. Bland-Altman statistical analyses were performed. Outliers, defined as PAC temperature measurements that varied more than ±0.3°C from PRT measurements, were identified. We considered a catheter unfit for clinical diagnostic or therapeutic use if ≥15% of data pairs were outliers. A total of 2730 data pairs were analyzed. Overall, the bias was -0.15°C; the precision was +0.13°C; and the limits of agreement were -0.45°C to +0.13°C. The bias and limits of agreement did not differ according to the age of the catheter or the temperature tested. One hundred fourteen data pairs (4.2% [95% confidence interval, 2.0%-6.4%]), involving 13 PACs and mostly from 4 PACs, were outliers. We conclude that temperature measurements obtained using the Edwards Lifesciences PACs are thus sufficiently accurate to be used for clinical temperature monitoring in critically ill patients.


Facile synthesis of β-lactoglobulin capped Ag2S quantum dots for in vivo imaging in the second near-infrared biological window.
Effective in vivo fluorescence imaging for cancer screening and diagnostics requires bright and biocompatible fluorophores whose emission can effectively penetrate biological tissues. Recent studies have confirmed that the second near-infrared window (NIR-II, 1000-1400 nm) is the most sensitive spectral range for in vivo imaging due to ultralow tissue absorption and autofluorescence. We report herein a facile synthesis of Ag2S quantum dots (QDs) that emit at ∼1100 nm using β-lactoglobulin (β-LG) as a biological template. The β-LG protein coating improves water-solubility, faciliates rapid biodistribution and reduces in vivo toxicity of the QDs. Compared to other currently used NIR emitters, β-LG capped Ag2S QDs exhibit superior photostability and biocompatibility, making them promising probes for in vivo NIR-II imaging.


[Effects of intranasal insulin and serotonin on functional activity of the adenylyl cyclase system in the myocardium, ovaries, and uterus of rats with prolonged neonatal model of diabetes mellitus].
Disturbances in hormonal signaling systems, in the adenylyl cyclase system (ACS) in particular, occur at early stages of diabetes mellitus (DM) and are one of the key causes of its complications. Since there is a correlation between the severity of DM and of disturbances in the ACS, the study of the ACS activity can be used to monitor DM and its complications and to evaluate effectiveness of their treatment. Comparatively recently, for treatment of the type 2 DM, there began to be used the intranasal insulin (I-I) and drugs increasing brain serotonin level, which effectively restore CNS functions. However, mechanisms of their action on peripheral tissues and organs with DM remain to be not understood. The goal of this work was to study effects. of I-I and intranasal serotonin (I-S) on the ACS functional activity in myocardium, ovary, and uterus of rats with a neonatal model of the type 2 DM. In tissues of diabetic rats there were revealed changes in regulation of adenylyl cyclase (AC) by guanine nucleotides and hormones that both stimulated and inhibited this enzyme, such changes being characterized by the receptor and tissue specificity. In diabetic rats, I-I restored the AC stimulating effects of isoproterenol in the myocardium, guanine nucleotides and gonadotropin in ovaries and relaxin in uterus, as well as the AC inhibitory effects of somatostatin in all tissues, and of noradrenaline in myocardium. Treatment with IS led to a partial restoration of the AC-inhibitory effect of noradrenalin in the diabetic myocardium, but did not affect regulation of AC by other hormones. These data indicate that I-I normalizes the ACS functional activity in myocardium and in tissues of the reproductive system of female rats with neonatal DM, whereas the effect of I-S on in the studied tissues is less pronounced. These results are necessary to be taken into account at development and optimization of strategy of use of I-I and I-S for treatment of DM and of its complications.


Restoration of hip anatomy using computer modelling prior to total hip arthroplasty and its potential consequences in terms of lower limb-length difference.
Restoring hip anatomy during total hip arthroplasty (THA) is the gold standard. The general goal is for hips to be symmetrical in terms of height. This study aimed to analyse the effect of simulating hip length (HL) equalisation on leg-length difference (LLD) before and after THA with a computerised plan. 141 consecutive patients were enrolled following THA. Outcomes of interest were preoperative hip-length difference (HLD) and LLD as determined on CT and final LLD as determined by simulating HL equalisation. We divided patients into 3 groups: no LLD, LLD >5 mm and LLD ⩾10 mm. The rate of preoperative LLD >5 mm and LLD ⩾10 mm was 37.5% and 14.8%, respectively. HL equalisation did not change LLD distribution in the overall cohort. Among patients with smaller preoperative HLs and LLDs, HL equalisation changed the rate of LLD >5 mm from 100% (n = 24) to 41.7% (n = 10) (p < 0.0001) and of LLD ⩾10 mm from 100% (n = 12) to 16.7% (n = 2) (p < 0.0001). Among patients with no preoperative LLD, HL equalisation changed the rate of LLD ⩽5 mm from 100% (n = 64) to 59.3% (n = 38) (p < 0.0001) and of LLD<10 mm from 100% (n = 76) to 89.5% (n = 68) (p = 0.006). Restoring biomechanical hip anatomy by HL equalisation may not be the correct goal for all patients. In patients with no LLD and shorter HLs, equalisation could result in LLD >5 mm in 40% of patients and LLD >10 mm in 10%, demonstrating the necessity to further analyse individuals and propose a personalised stem position.


Progressive immune dysfunction with advancing disease stage in renal cell carcinoma.
The tumor immune microenvironment plays a critical role in cancer progression and response to immunotherapy in clear cell renal cell carcinoma (ccRCC), yet the composition and phenotypic states of immune cells in this tumor are incompletely characterized. We performed single-cell RNA and T cell receptor sequencing on 164,722 individual cells from tumor and adjacent non-tumor tissue in patients with ccRCC across disease stages: early, locally advanced, and advanced/metastatic. Terminally exhausted CD8+ T cells were enriched in metastatic disease and were restricted in T cell receptor diversity. Within the myeloid compartment, pro-inflammatory macrophages were decreased, and suppressive M2-like macrophages were increased in advanced disease. Terminally exhausted CD8+ T cells and M2-like macrophages co-occurred in advanced disease and expressed ligands and receptors that support T cell dysfunction and M2-like polarization. This immune dysfunction circuit is associated with a worse prognosis in external cohorts and identifies potentially targetable immune inhibitory pathways in ccRCC.


Effect of increased magnesium on recovery from ischemia in rat and rabbit hearts.
Perfusates containing high magnesium concentrations have been suggested to have a protective effect for ischemic myocardium, but the mechanism for such an effect is unclear. We investigated the recovery of isolated perfused rabbit and rat hearts from ischemia under varied conditions of increased Mg. Hearts were made ischemic in the presence of normal 1.2 mM Mg or elevated 15 mM Mg. Rabbit hearts, which show minimal alteration in contractility in the presence of 15 mM Mg, were not protected from ischemia by high Mg perfusate. Rat hearts, which have a large negative inotropic response to 15 mM Mg, exhibited significantly better recovery of mechanical function following ischemia in the presence of high Mg than following ischemia with normal Mg. This protective effect was abolished by increasing both Ca and Mg in the perfusate to prevent the decline in contractility that normally occurred with Mg. Reperfusion with 15 mM Mg after ischemia also had no protective effect if the rat heart had been made ischemic in the presence of normal Mg. We conclude that elevated Mg protects ischemic myocardium only under circumstances in which it has a negative inotropic effect before the onset of ischemia, i.e., in the rat heart perfused with normal Ca. These results suggest that the mechanism of protection by high Mg involves sparing of ATP. However, the different responses to Mg of the species studied in these experiments should be a caution against extrapolating such results from rat hearts to other species.


Temsirolimus combined with cisplatin or bevacizumab is active in osteosarcoma models.
Mammalian target of rapamycin (mTOR) is a new promising oncological target. However, most clinical studies reported only modest antitumor activity during mTOR-targeted monotherapies, including studies in osteosarcomas, emphasizing a need for improvement. We hypothesized that the combination with rationally selected other therapeutic agents may improve response. In this study, we examined the efficacy of the mTOR inhibitor temsirolimus combined with cisplatin or bevacizumab on the growth of human osteosarcoma xenografts (OS-33 and OS-1) in vivo, incorporating functional imaging techniques and microscopic analyses to unravel mechanisms of response. In both OS-33 and OS-1 models, the activity of temsirolimus was significantly enhanced by the addition of cisplatin (TC) or bevacizumab (TB). Extensive immunohistochemical analysis demonstrated apparent effects on tumor architecture, vasculature, apoptosis and the mTOR-pathway with combined treatments. 3'-Deoxy-3'-(18) F-fluorothymidine ((18) F-FLT) positron emission tomography (PET) scans showed a remarkable decrease in (18) F-FLT signal in TC- and TB-treated OS-1 tumors, which was already noticeable after 1 week of treatment. No baseline uptake was observed in the OS-33 model. Both immunohistochemistry and (18) F-FLT-PET demonstrated that responses as determined by caliper measurements underestimated the actual tumor response. Although (18) F-FLT-PET could be used for accurate and early response monitoring for temsirolimus-based therapies in the OS-1 model, we could not evaluate OS-33 tumors with this molecular imaging technique. Further research on the value of the use of (18) F-FLT-PET in this setting in osteosarcomas is warranted. Overall, these findings urge the further exploration of TC and TB treatment for osteosarcoma (and other cancer) patients.


[Antimicrobial resistance of uropathogens among outpatients, 2000-2004].
A retrospective study based on the electronic database of a university hospital was carried out to investigate the prevalence of etiological agents and their susceptibilities to antibiotics, among adult outpatients (> 18 years old) with urinary tract infections. Nine hundred and fifty-seven positive urine cultures were identified between January 2000 and December 2004. Escherichia coli, Proteus mirabilis and Klebsiella sp were the three principal bacterial etiological agents. Trimethoprim-sulfamethoxazole presented the highest prevalence of bacterial resistance (46.9%), followed by cefalotin (46.7%), nalidixic acid (27.6%) and nitrofurantoin (22.3%). Over the study period, nalidixic acid presented annual increases of 5.9% in the rate of bacterial resistance (p = 0.02). Ciprofloxacin also showed an increasing trend, of 3.3% per year (p = 0.07). This study demonstrated that the antibiotics that are widely recommended for empirical treatment of urinary tract infection in adults presented high rates of bacterial resistance among the population studied.


Molecular motors and a spectrin matrix associate with Golgi membranes in vitro.
Cytoplasmic dynein is a microtubule minus-end-directed motor that is thought to power the transport of vesicles from the TGN to the apical cortex in polarized epithelial cells. Trans-Golgi enriched membranes, which were isolated from primary polarized intestinal epithelial cells, contain both the actin-based motor myosin-I and dynein, whereas isolated Golgi stacks lack dynein but contain myosin-I (Fath, K.R., G.M. Trimbur, and D.R. Burgess. 1994. J. Cell Biol. 126:661-675). We show now that Golgi stacks in vitro bind dynein supplied from cytosol in the absence of ATP, and bud small membranes when incubated with cytosol and ATP. Cytosolic dynein binds to regions of stacks that are destined to bud because dynein is present in budded membranes, but absent from stacks after budding. Budded membranes move exclusively towards microtubule minus-ends in in vitro motility assays. Extraction studies suggest that dynein binds to a Golgi peripheral membrane protein(s) that resists extraction by ice-cold Triton X-100. In the presence of cytosol, these membrane ghosts can move towards the minus-ends of microtubules. Detergent-extracted Golgi stacks and TGN-containing membranes are closely associated with an amorphous matrix composed in part of spectrin and ankyrin. Although spectrin has been proposed to help link dynein to organellar membranes, we found that functional dynein may bind to extracted membranes independently of spectrin and ankyrin.


Preparing pharmacy students to communicate effectively with adolescents.
To develop an elective workshop designed to equip pharmacy students with skills to effectively communicate with adolescents. To conduct preliminary evaluation of the workshop to assess its impact on pharmacy student perceived confidence and knowledge relating to the importance of adolescent counselling and counselling techniques. Academics from three universities in three countries collaborated on the workshop development and evaluation. The workshop structure was designed upon the foundations of communication best practices and established techniques, and it consisted of two online modules and an in-person tutorial. Pharmacy students undertaking a 4-year Bachelor, Master or Doctor of Pharmacy degree from all three participating universities evaluated the workshop via pre- and post-questionnaires. A total of 81 pharmacy students volunteered to attend and evaluate the workshop. Of these 81 students, 31 completed paired pre- and post-questionnaires, 44 students completed unpaired questionnaires and six students were lost to follow-up. Of the paired pre- and post-questionnaires, students were mostly female (67.7%) with an average age of 24.9 years (standard deviation, SD = 5.6) and were in the first (32.3%), second (16.1%) or third (51.6%) year of their pharmacy programme. Over 80% of students somewhat or strongly agreed that the workshop made them feel more comfortable speaking with young people in pharmacy settings. Mean (SD) perceived confidence (pre = 21.7 (4.0) and post = 24.9 (4.5)) and knowledge scores (pre = 5.2 (1.5) and post = 6.6 (1.6)) significantly improved after undertaking the workshop. The workshop increased pharmacy student perceived confidence and knowledge relating to the importance of adolescent counselling and counselling techniques.


Frequency of Hepatorenal Syndrome Among Patients With Cirrhosis and Outcome After Treatment.
Introduction Hepatorenal syndrome is the third most common cause of admissions among patients with liver cirrhosis and has a high mortality rate. It is a progressive deterioration of renal function in a patient with acute or chronic liver failure. The only definite curative treatment of choice for hepatorenal syndrome is liver transplantation. This study aimed to determine the frequency of hepatorenal syndrome among patients with liver cirrhosis and to determine its outcome after treatment. Patients and Methods This case series prospective study was conducted at the Department of Medicine, CMH Lahore Medical College and Institute of Dentistry, Pakistan, from January 2019 to December 2019. The study included 136 patients of cirrhosis who were identified and worked up for hepatorenal syndrome. The patients with liver cirrhosis diagnosed as having hepatorenal syndrome were given treatment comprising injection terlipressin 2 mg four times a day and injection Haemaccel twice a day for two weeks, and after that the outcome was measured with a follow-up of six weeks. Results A total of 136 patients of cirrhosis were included in the study. Of the patients, 14 (10.3%) were diagnosed as suffering from hepatorenal syndrome. These diagnosed cases were given treatment for two weeks. Three (21.4%) of the patients having hepatorenal syndrome did not show any response, two (14.3%) patients recovered partially, four (28.6%) patients recovered fully, and four (28.6%) expired within one month of the treatment. One (7.14%) patient was referred during the treatment for liver transplant. Conclusions Hepatorenal syndrome is a common complication of cirrhosis. The treatment of systemic vasoconstrictors for hepatorenal syndrome proved to be effective in our study and should be the first priority for treating hepatorenal syndrome especially in places like Pakistan where liver transplantation is not that easily available.


Back Grafting the Split-Thickness Skin Graft Donor Site.
Split-thickness skin grafting is a useful method of wound repair in burn and reconstructive operations. However, skin grafts require a donor site injury that creates a secondary wound at risk for delayed wound healing. Though in young healthy patients such donor sites have minimal risk, patients with risk factors for delayed wound healing are more challenging. We present a method for graft donor site management that offers an alternative to healing by secondary intention for patients with higher risk of poor wound healing. In those patients considered to be at high risk for donor site healing complications, we chose to treat the donor site with a split-thickness skin graft, or "graft back" procedure. An additional graft is taken adjacent to the initial donor site, and meshed 4:1 to cover both donor sites at once. Out of the 17 patients who received this procedure, 1 patient had a complication from the procedure that did not require an operation, and all patients appear to have good functional and cosmetic outcomes. No patients had any graft loss or graft infection. Histologic analysis showed complete epithelialization of the back-grafted area. The graft back method converts an open wound to a covered wound and may result in decreased wound healing time, improved cosmetic outcomes, and fewer complications, particularly in patients where wound healing is a concern. Importantly, it seems to have minimal morbidity. More detailed prospective studies are needed to ensure no additional risk is incurred by this procedure.


Development of a Computational Model of the Mechanical Behavior of the L4-L5 Lumbar Spine: Application to Disc Degeneration.
Degenerative changes in the lumbar spine significantly reduce the quality of life of people. In order to fully understand the biomechanics of the affected spine, it is crucial to consider the biomechanical alterations caused by degeneration of the intervertebral disc (IVD). Therefore, this study is aimed at the development of a discrete element model of the mechanical behavior of the L4-L5 spinal motion segment, which covers all the degeneration grades from healthy IVD to its severe degeneration, and numerical study of the influence of the IVD degeneration on stress state and biomechanics of the spine. In order to analyze the effects of IVD degeneration on spine biomechanics, we simulated physiological loading conditions using compressive forces. The results of modeling showed that at the initial stages of degenerative changes, an increase in the amplitude and area of maximum compressive stresses in the disc is observed. At the late stages of disc degradation, a decrease in the value of intradiscal pressure and a shift in the maximum compressive stresses in the dorsal direction is observed. Such an influence of the degradation of the geometric and mechanical parameters of the tissues of the disc leads to the effect of bulging, which in turn leads to the formation of an intervertebral hernia.


[Reversal of malignant transformation induced by the oncogenic virus SV40. I. Induction of reversal to normal type for the contact inhibition trait].
The possibility of induction by the oncogenic DNA-containing virus SV40 of reversions to normal phenotype as regards contact inhibition ("flat" revertants), was studied in spontaneously transformed chinese hamster fibroblasts. Negative selection was used for detection of revertants. The method adopted allowed to study the mutagenic activity of the virus, while excluding its transforming effect. In all experiments the frequency of revertants after infection exceeded that in control series. The value of induction varied from 1.2 to 28.4 X 10(-6). The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) known to increase the frequency of mutations induced by carcinogens in vitro, displayed no enhancing effect on the frequency of revertants induced by SV40. The lack of enhancement of virus-induced reversions after TPA treatment might be explained by the lack of the transforming effect of SV40 in the system studied. Some of the normal "flat" colonies were T-antigen positive, i. e. the viral oncogene was expressed. The role of mutations induced by SV40 in cellular genes controlling malignancy is discussed.


Does increased topside conformity in modular total knee arthroplasty lead to increased backside wear?
Modular metal-backed tibia components allow surgeons intraoperative flexibility. Although it is known that modular tibia components introduce the possibility for backside wear resulting from relative motion between the polyethylene insert and the tibial baseplate, it is not known to what degree variability in the conformity of the tibial polyethylene liner itself might contribute to backside wear. The purpose of this study was to determine whether a flat, cruciate-retaining tibial polyethylene bearing generates less backside wear than a more conforming (curved) tibial polyethylene bearing in an analysis of specimens explanted during revision surgery. The study included 70 total knee inserts explanted at revision surgery, all implanted and explanted by the same surgeon. Two different cruciate-retaining insert options in an otherwise similar knee system were used: one with a curved-on-flat (17) articular geometry and one with a highly conforming curved-on-curved design (53); both groups were sequential cohorts. The composite backside wear depth for the insert as well as the volume of backside wear was measured and compared between groups. The median linear backside-normalized wear for the posterior lipped inserts was 0.0063 mm/year (range, 0-0.085 mm/year), which was lower than for the curved inserts at 0.05 mm/year (range, 0.00003-0.14 mm/year) (p<0.001). The median calculated volumetric backside-normalized wear for the posterior lipped inserts was 14.2 mm3/year (range, 0-282.8 mm3/year) compared with 117 mm3/year (range, 2.1-312 mm3/year) for the curved inserts (p<0.001). In this retrieval study, more conforming tibial inserts demonstrated more backside-normalized wear than the flatter designs. This suggests that in this modular total knee arthroplasty design, higher articular conformity to address the issues of high bearing contact stress comes at a price: increased torque transmitted to the backside insert-to-tray interface. We suggest further work be undertaken to examine newer insert designs to evaluate if our conclusions hold true with the newer generation locking mechanism, tibial tray finish and polyethylene designs, as more highly conforming tibial inserts are introduced into the market. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.


Electrochemical Screening Spot Test Method for Detection of Nickel and Cobalt Ion Release From Metal Surfaces.
Present screening methods to rapidly detect release of nickel and cobalt ions from metallic surfaces involve colorimetric dimethylglyoxime (DMG)- and disodium-1-nitroso-2-naphthol-3,6-disulfonate-based spot tests with a cotton bud. There is a risk of false-negative test reactions because test outcomes are dependent on the pressure, area, and duration of surface wiping. The aim of the study was to develop a miniaturized electrochemical device that uses a voltage to accelerate nickel and cobalt release from the tested item and perform an initial validation. A device was built in plastic, and its performance was investigated using 0.5 mL of test solutions of, respectively, DMG and disodium-1-nitroso-2-naphthol-3,6-disulfonate. Cotton buds that had been wetted in test solution were pressed against different metal surfaces at various voltages (0-9 V) and a range of test durations (0-120 seconds). Duplicate testing for nickel and cobalt release was also performed on a sample of 163 jewelry items. This novel electrochemical device makes it possible to perform nickel and cobalt ion release testing without rubbing, thereby reducing interindividual differences in testing technique. The nickel testing with the device seemed to be superior to conventional DMG spot testing.


Metal assisted chemical etching of silicon in the gas phase: a nanofabrication platform for X-ray optics.
High aspect ratio nanostructuring requires high precision pattern transfer with highly directional etching. In this work, we demonstrate the fabrication of structures with ultra-high aspect ratios (up to 10 000 : 1) in the nanoscale regime (down to 10 nm) by platinum assisted chemical etching of silicon in the gas phase. The etching gas is created by a vapour of water diluted hydrofluoric acid and a continuous air flow, which works both as an oxidizer and as a gas carrier for reactive species. The high reactivity of platinum as a catalyst and the formation of platinum silicide to improve the stability of the catalyst pattern allow a controlled etching. The method has been successfully applied to produce straight nanowires with section size in the range of 10-100 nm and length of hundreds of micrometres, and X-ray optical elements with feature sizes down to 10 nm and etching depth in the range of tens of micrometres. This work opens the possibility of a low cost etching method for stiction-sensitive nanostructures and a large range of applications where silicon high aspect ratio nanostructures and high precision of pattern transfer are required.


Complexation of Polyelectrolytes with Hydrophobic Drug Molecules in Salt-Free Solution: Theory and Simulations.
The delivery and dissolution of poorly soluble drugs is challenging in the pharmaceutical industry. One way to significantly improve the delivery efficiency is to incorporate these hydrophobic small molecules into a colloidal polyelectrolyes(PE)-drug complex in their ionized states. Despite its huge application value, the general mechanism of PE collapse and complex formation in this system has not been well understood. In this work, by combining a mean-field theory with extensive molecular simulations, we unveil the phase behaviors of the system under dilute and salt-free conditions. We find that the complexation is a first-order-like phase transition triggered by the hydrophobic attraction between the drug molecules. Importantly, the valence ratio between the drug molecule and PE monomer plays a crucial role in determining the stability and morphology of the complex. Moreover, the sign of the zeta potential and the net charge of the complex are found to be inverted as the hydrophobicity of the drug molecules increases. Both theory and simulation indicate that the complexation point and complex morphology and the electrostatic properties of the complex have a weak dependence on chain length. Finally, the dynamics aspect of PE-drug complexation is also explored, and it is found that the complex can be trapped into a nonequilibrium glasslike state when the hydropobicity of the drug molecule is too strong. Our work gives a clear physical picture behind the PE-drug complexation phenomenon and provides guidelines to fabricate the colloidal PE-drug complex with the desired physical characteristics.


Urea Is Both a Carbon and Nitrogen Source for Microcystis aeruginosa: Tracking 13C Incorporation at Bloom pH Conditions.
The use of urea as a nitrogenous fertilizer has increased over the past two decades, with urea itself being readily detected at high concentrations in many lakes. Urea has been linked to cyanobacterial blooms as it is a readily assimilated nitrogen (N) - source for cyanobacteria that possess the enzyme urease. We tested the hypothesis that urea may also act as a carbon (C) source to supplemental growth requirements during the alkaline conditions created by dense cyanobacterial blooms, when concentrations of dissolved CO2 are vanishingly low. High rates of photosynthesis markedly reduce dissolved CO2 concentrations and drive up pH. This was observed in Lake Erie during the largest bloom on record (2015) over long periods (months) and short periods (days) of time, suggesting blooms experience periods of CO2-limitation on a seasonal and daily basis. We used 13C-urea to demonstrate that axenic cultures of the model toxic cyanobacterium, Microcystis aeruginosa NIES843, assimilated C at varying environmentally relevant pH conditions directly into a spectrum of metabolic pools during urea hydrolysis. Primarily, 13C from urea was assimilated into central C metabolism and amino acid biosynthesis pathways, including those important for the production of the hepatotoxin, microcystin, and incorporation into these pathways was at a higher percentage during growth at higher pH. This corresponded to increased growth rates on urea as the sole N source with increasing pH. We propose this ability to incorporate C from urea represents yet another competitive advantage for this cyanobacterium during dense algal blooms.


Left ovarian gonadoblastoma with yolk sac tumor in a young woman.
Gonodoblastomas with ovarian germ cell tumors other than dysgerminoma coexists very rarely with yolk sac tumor (YST). Because of this rarity, we report a case of gonadoblastoma with YST. An 18-year-old female patient was admitted to our hospital with an abdomino-pelvic mass. Ultrasonographical examinations revealed a 15X14 cm heterogenous pelvic mass with calcific foci in the left adnexal area. Macroscopically, the resected mass was oval and measured 18X15X15 cm and weighed 3150 gm. Histological examination showed both gonadoblastic and YST areas. There were many gonadoblastic nests in the subcapsular areas of the tumor. The gonadoblastic nests were composed of large and small cells. The YST areas showed enteric differentiation and numerous hyaline globules. Immunohistochemical examination may help in the diagnosis of these gonadoblastoma with YST.


Computational Underpinnings of Neuromodulation in Humans.
We summarize a new approach to neuromodulator detection that provides colocalized detection of dopamine, serotonin, and norepinephrine at subsecond timescales and promises to provide submillisecond estimates of the same. The methodology, elastic net electrochemistry, is used to estimate dopamine and serotonin in the striatum of conscious human subjects during active decision-making. We show a proof-of-principle example of the same method working on commercially available depth electrodes in common use for epilepsy monitoring and neurosurgical planning in humans, which further promises to make such electrodes sources of fast neuromodulator information never before available in human subjects. We discuss the implications of this methodology for making direct tests in humans of the computations carried by these three important neuromodulatory systems. The methods also promise great utility in model organisms, but this chapter focuses on the possibilities for human use.


Synthesis and SERS application of gold and iron oxide functionalized bacterial cellulose nanocrystals (Au@Fe3O4@BCNCs).
Bacterial cellulose nanocrystals (BCNCs) are biocompatible cellulose nanomaterials that can host guest nanoparticles to form hybrid nanocomposites with a wide range of applications. Herein, we report the synthesis of a hybrid nanocomposite that consists of plasmonic gold nanoparticles (AuNPs) and superparamagnetic iron oxide (Fe3O4) nanoparticles supported on BCNCs. As a proof of concept, the hybrid nanocomposites were employed to isolate and detect malachite green isothiocyanate (MGITC) via magnetic separation and surface-enhanced Raman scattering (SERS). Different initial gold precursor (Au3+) concentrations altered the size and morphology of the AuNPs formed on the nanocomposites. The use of 5 and 10 mM Au3+ led to a heterogenous mix of spherical and nanoplate AuNPs with increased SERS enhancements, as compared to the more uniform AuNPs formed using 1 mM Au3+. Rapid and sensitive detection of MGITC at concentrations as low as 10-10 M was achieved. The SERS intensity of the normalized Raman peak at 1175 cm-1 exhibited a log-linear relationship for MGITC concentrations between 2 × 10-10 and 2 × 10-5 M for Au@Fe3O4@BCNCs. These results suggest the potential of these hybrid nanocomposites for application in a broad range of analyte detection strategies.


Shunt Tapping Versus Lumbar Puncture for Evaluating Cerebrospinal Fluid Infections in a Pediatric Population.
To compare the results of lumbar puncture (LP) and shunt tapping in pediatric patients with suspected ventriculoperitoneal shunt infection. Medical records of pediatric patients with suspected shunt infections were retrospectively analyzed. All patients had cerebrospinal fluid samples obtained either via shunt tapping, LP or both. The diagnosis of infection was made when at least one cerebrospinal fluid had positive culture results. The patients with negative cerebrospinal fluid culture results were followed up for at least 6 months to monitor the occurrence of central nervous system infection. There were 20 patients in the study (12 males, 8 females). Cerebrospinal fluid was obtained by shunt tapping in 11, by lumbar puncture in 9 and by both methods in one patient. Thirteen patients [ Shunt tapping: 5/11 (45%), LP: 7/9 (78%), Both: 1) ] were diagnosed with shunt infection on the basis of cerebrospinal fluid culture. Seven patients with negative cerebrospinal fluid culture were found to have infections unrelated to shunts and did not show evidence of cerebrospinal fluid infection during the follow-up period. Although the percentage of detecting the infection was higher in LP group, both groups showed negative predictive value of 100%. Both shunt tapping and LP are effective in establishing the diagnosis of shunt infection in suspected patients.


Migraine attacks as a result of hypothalamic loss of control.
Migraine is a complex neurological disorder affecting approximately 12% of the population. The pathophysiology is not yet fully understood, however the clinical features of the disease, such as the cyclic behaviour of attacks and vegetative symptoms, suggest a prominent role of the hypothalamus. Previous research has observed neuronal alterations at different time points during the migraine interval, specifically just before the headache is initiated. We therefore aimed to assess the trajectory of migraineurs' brain activity over an entire migraine cycle. Using functional magnetic resonance imaging (fMRI) with pseudo-continuous arterial spin labelling (ASL), we designed a longitudinal intra-individual study to detect the rhythmicity of (1) the cerebral perfusion and (2) the hypothalamic connectivity over an entire migraine cycle. Twelve episodic migraine patients were examined in 82 sessions during spontaneous headache attacks with follow-up recordings towards the next attack. We detected cyclic changes of brain perfusion in the limbic circuit (insula and nucleus accumbens), with the highest perfusion during the headache attack. In addition, we found an increase of hypothalamic connectivity to the limbic system over the interictal interval towards the attack, then collapsing during the headache phase. The present data provide strong evidence for the predominant role of the hypothalamus in generating migraine attacks. Due to a genetically-determined cortical hyperexcitability, migraineurs are most likely characterised by an increased susceptibility of limbic neurons to the known migraine trigger. The hypothalamus as a metronome of internal processes is suggested to control these limbic circuits: migraine attacks may occur as a result of the hypothalamus losing control over the limbic system. Repetitive psychosocial stress, one of the leading trigger factors reported by patients, might make the limbic system even more vulnerable and lead to a premature triggering of a migraine attack. Potential therapeutic interventions are therefore suggested to strengthen limbic circuits with dedicated medication or psychological approaches.


4q21.2q21.3 Duplication: Molecular and Neuropsychological Aspects.
During the last decades, a large amount of newly described microduplications and microdeletions associated with intellectual disability (ID) and related neuropsychiatric diseases have been discovered. However, due to natural limitations, a significant part of them has not been the focus of multidisciplinary approaches. Here, we address previously undescribed chromosome 4q21.2q21.3 microduplication for gene prioritization, evaluation of cognitive abilities and estimation of genomic mechanisms for brain dysfunction by molecular cytogenetic (cytogenomic) and gene expression (meta-) analyses as well as for neuropsychological assessment. We showed that duplication at 4q21.2q21.3 is associated with moderate ID, cognitive deficits, developmental delay, language impairment, memory and attention problems, facial dysmorphisms, congenital heart defect and dentinogenesis imperfecta. Gene-expression meta-analysis prioritized the following genes: ENOPH1, AFF1, DSPP, SPARCL1, and SPP1. Furthermore, genotype/phenotype correlations allowed the attribution of each gene gain to each phenotypic feature. Neuropsychological testing showed visual-perceptual and fine motor skill deficits, reduced attention span, deficits of the nominative function and problems in processing both visual and aural information. Finally, emerging approaches including molecular cytogenetic, bioinformatic (genome/epigenome meta-analysis) and neuropsychological methods are concluded to be required for comprehensive neurological, genetic and neuropsychological descriptions of new genomic rearrangements/diseases associated with ID.


Ionotropic glutamate receptor-mediated responses in the rat primary somatosensory cortex evoked by noxious and innocuous cutaneous stimulation in vivo.
To examine the involvement of different ionotropic glutamate receptors in the mediation of responses evoked by noxious cutaneous stimulation, single unit recordings were made from 31 neurons in the primary somatosensory (SI) cortex of rats anesthetized with urethane. To compare synaptic receptor pharmacology across somatosensory submodalities, 13 of the neurons were also tested with an innocuous, cutaneous air jet stimulus. Mechanical (HT) responses, evoked by a 5-s noxious pinch, decayed gradually upon termination of the stimulus and lasted on average for 15.1+/-1.9 s (+/-SEM; n=10). An increase in baseline activity was also observed during noxious stimulus trials of 5-min stimulus intervals. A correlation between increase in mechanical or thermal HT responses and baseline activity was found for some neurons. However, the normalized ratios of the mechanical or thermal HT response to baseline activity during iontophoretic application of (RS)-3-(2-carboxypiperazine-4-yl)-propyl-l-phosphonic acid (CPP), an N-methyl-D-aspartic acid (NMDA) receptor antagonist (0.6+/-0.1; n=11, or 6-nitro-7-sulfamoylbenz[f]quinoxaline-2,3-dione (NBQX), an (RS)-alpha-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonist (0.8+/-0.1; n=11), suggest that the reductions in baseline activity did not account for the reductions of the mechanical or thermal HT responses observed, which were reduced proportionally more than the baseline activity. A 10-ms air jet evoked a biphasic increase in action potentials above an average background activity of 7+/-2 spikes/s (n=13). The early phase of this low-threshold (LT) response was within two or three 10-ms bins and had an average firing rate of 74+/-11 spikes/s evoked in the first 10-ms bin (n=13). In eight neurons, the early LT response was followed by a lower frequency excitatory component lasting an average of 415+/-92 ms. Iontophoretic application of CPP reduced responses evoked by a noxious pinch (21+/-10% of control responses; n=19) and a noxious thermal stimulus (24+/-18%; n=5). The fast component of the LT responses was only reduced to 85+/-4% (n=12). A slower component of the LT responses, when present, was also reduced by CPP (15+/-19%; n=4). Iontophoretic application of NBQX reduced responses evoked by a noxious pinch (42+/-12%; n=19) and a noxious thermal stimulus (63+/-16%; n=8). The fast component of the LT responses was reduced to 43+/-6% (n=12) and the slower component to 32+/-20% (n=6). These data show that both NMDA and AMPA/kainate receptors are involved in the mediation of SI high-threshold responses. This same combination of glutamate receptors also mediates low-threshold synaptic responses.


Costing analysis of a point-of-care drug checking program in Rhode Island.
Drug checking is a harm reduction strategy that provides greater awareness and information about the drug supply to the community. While fentanyl test strips are low-cost and available in most parts of the U.S., community-based organizations are considering using more sophisticated technologies, such as Fourier-transform infrared (FTIR) spectroscopy to test drugs. FTIR can detect multiple substances in a non-destructive manner that can be rapidly communicated to the program client by a trained technician, however implementation costs in community-based settings have not been assessed. We conducted a costing analysis of a new pilot drug checking service that employed an FTIR spectrometer, fentanyl test strips and confirmatory testing in Rhode Island from January 2023-May 2023. We used microcosting methods to determine the overall cost during this period and cost per drug checked, reflecting realistic service capacity. Among 101 drug samples that were voluntarily submitted and tested, 53% tested positive for fentanyl, 39% for cocaine, 9% for methamphetamine and 13% for xylazine, a powerful sedative. The total cost during this period was $71,044 and the cost per drug checked was $474, though sensitivity analyses indicated that the cost would rise to $78,058 - $83,058 or $544 - $593 for programs needing to pay for specialized training. These findings demonstrate feasibility and inform the resources needed to scale-up drug checking services to reduce overdose risk.


No evidence for a bioenergetic advantage from forced swimming in rainbow trout under a restrictive feeding regime.
Sustained swimming at moderate speeds is considered beneficial in terms of the productive performance of salmonids, but the causative mechanisms have yet to be unequivocally established. In the present study, the effects of moderate exercise on the bioenergetics of rainbow trout were assessed during a 15 week growth experiment, in which fish were reared at three different current speeds: 1 BL s(-1), 0.5 BL s(-1) and still water (≈ 0 BL s(-1)). Randomly selected groups of 100 fish were distributed among twelve 600 L tanks and maintained on a restricted diet regime. Specific growth rate (SGR) and feed conversion ratio (FCR) were calculated from weight and length measurements every 3 weeks. Routine metabolic rate (RMR) was measured every hour as rate of oxygen consumption in the tanks, and was positively correlated with swimming speed. Total ammonia nitrogen (TAN) excretion rates showed a tendency to decrease with increasing swimming speeds, yet neither they nor the resulting nitrogen quotients (NQ) indicated that swimming significantly reduced the fraction of dietary protein used to fuel metabolism. Energetic budgets revealed a positive correlation between energy expenditure and the current speed at which fish were reared, fish that were forced to swim and were fed restrictively consequentially had poorer growth and feed utilization. The results show that for rainbow trout, water current can negatively affect growth despite promoting minor positive changes in substrate utilization. We hypothesize that this may be the result of either a limited dietary energy supply from diet restriction being insufficient for both covering the extra costs of swimming and supporting enhanced growth.


Atypical porokeratosis developing following bone marrow transplantation in a patient with myelodysplastic syndrome.
Porokeratosis is an abnormal disease of keratinization of epidermis. It is clinically characterized by margins covered with keratin layer and it typically has an atrophied macule with a protruded, circular form. Histopathologically, it shows the findings of cornoid lamella. Risk factors for its development include organ transplantation, long-term use of corticosteroids, immunocompromised status, including AIDS, and exposure to ultraviolet light. We herein report a case of atypical porokeratosis in a 38-year-old man who developed porokeratosis involving multiple sites following bone marrow transplantation for myelodysplastic syndrome.


Comparative analysis of marine ecosystems: international production modelling workshop.
Understanding the drivers that dictate the productivity of marine ecosystems continues to be a globally important issue. A vast literature identifies three main processes that regulate the production dynamics of such ecosystems: biophysical, exploitative and trophodynamic. Exploring the prominence among this 'triad' of drivers, through a synthetic analysis, is critical for understanding how marine ecosystems function and subsequently produce fisheries resources of interest to humans. To explore this topic further, an international workshop was held on 10-14 May 2010, at the National Academy of Science's Jonsson Center in Woods Hole, MA, USA. The workshop compiled the data required to develop production models at different hierarchical levels (e.g. species, guild, ecosystem) for many of the major Northern Hemisphere marine ecosystems that have supported notable fisheries. Analyses focused on comparable total system biomass production, functionally equivalent species production, or simulation studies for 11 different marine fishery ecosystems. Workshop activities also led to new analytical tools. Preliminary results suggested common patterns driving overall fisheries production in these ecosystems, but also highlighted variation in the relative importance of each among ecosystems.


Molecular genetics of human chromosome 16.
The major diseases mapped to chromosome 16 are adult polycystic kidney disease and those resulting from mutations in the alpha globin complex. There are at least six other less important genetic diseases which map to this chromosome. The adenine phosphoribosyltransferase gene allows for selection of chromosome 16 in somatic cell hybrids and a hybrid panel is available which segments the chromosome into six regions to facilitate gene mapping. Genes which have been mapped to this chromosome or which have had their location redefined since HGM8 include APRT, TAT, MT, HBA, PKD1, CTRB, PGP, HAGH, HP, PKCB, and at least 19 cloned DNA sequences. There are RFLPs at 13 loci which have been regionally mapped and can be used for linkage studies.


Lung cancer and positron emission tomography with fluorodeoxyglucose.
Over the past years, positron emission tomography (PET) with fluoro-2-deoxy-D-glucose (FDG) has emerged as an important imaging modality. In the thorax, FDG-PET has been shown to differentiate benign from malignant pulmonary lesions and stage lung cancer. Preliminary studies have shown its usefulness in assessing tumor recurrence, and assisting in radiotherapy planning. FDG-PET is often more accurate than conventional imaging studies, and has been proven to be cost-effective in evaluating lung cancer patients. This review will discuss the current applications of FDG-PET as compared with conventional imaging in diagnosing, staging, and following patients with lung cancer.


Delamanid or pretomanid? A Solomonic judgement!
Given the low treatment success rates of drug-resistant tuberculosis (TB), novel TB drugs are urgently needed. The landscape of TB treatment has changed considerably over the last decade with the approval of three new compounds: bedaquiline, delamanid and pretomanid. Of these, delamanid and pretomanid belong to the same class of drugs, the nitroimidazoles. In order to close the knowledge gap on how delamanid and pretomanid compare with each other, we summarize the main findings from preclinical research on these two compounds. We discuss the compound identification, mechanism of action, drug resistance, in vitro activity, in vivo pharmacokinetic profiles, and preclinical in vivo activity and efficacy. Although delamanid and pretomanid share many similarities, several differences could be identified. One finding of particular interest is that certain Mycobacterium tuberculosis isolates have been described that are resistant to either delamanid or pretomanid, but with preserved susceptibility to the other compound. This might imply that delamanid and pretomanid could replace one another in certain regimens. Regarding bactericidal activity, based on in vitro and preclinical in vivo activity, delamanid has lower MICs and higher mycobacterial load reductions at lower drug concentrations and doses compared with pretomanid. However, when comparing in vivo preclinical bactericidal activity at dose levels equivalent to currently approved clinical doses based on drug exposure, this difference in activity between the two compounds fades. However, it is important to interpret these comparative results with caution knowing the variability inherent in preclinical in vitro and in vivo models.


Effects of metformin versus placebo on vitamin B12 metabolism in non-diabetic breast cancer patients in CCTG MA.32.
Metformin is associated with low levels of vitamin B12 (VitB12) in patients with diabetes. The CCTG/MA.32 trial investigates the effects of metformin vs placebo on breast cancer (BC) outcomes in non-diabetic high-risk BC patients. We analyzed VitB12 at baseline and after 6 months of metformin (versus placebo) in the first 492 patients with paired blood samples. VitB12 was analyzed centrally in baseline and 6-month fasting plasma. Levels <181 pmol/L were considered deficient, 181-221 pmol/L borderline, and ≥222 pmol/L sufficient. Methylmalonic acid (MMA) and homocysteine (HC) were assayed in those with VitB12 levels <222 pmol/L. Statistical analyses used Spearman's rank correlation coefficients and Wilcoxon signed-rank test for continuous variables and Chi-square test for categorical variables. 237 patients received metformin and 255 received placebo; median (inter quartile range) baseline VitB12 levels were 390 (290, 552) and 370 (290, 552) pmol/L in the metformin and placebo arms, respectively (p = 0.97). At 6 months, the median levels were 320 (244, 419) in the metformin versus 380 (286, 546) pmol/L in the placebo arm (p = 0.0001). At baseline, 15 patients (11 metformin and 4 placebo) had VitB12 <181 pmol/L, and at 6 months, 18 patients (15 metformin and 3 placebo) (p = 0.004). Median hemoglobin was similar at baseline, metformin, 130 g/L (124-137), and placebo arms, 131 g/L (124-137) (p = 0.38), and at 6 months, metformin, 131 g/L (91-162), and 131 g/L (106-169) in placebo group (p = 0.11). Of the 74 subjects with vitamin B12 <222 pmol/L at either time point (45 metformin, 29 placebo), at baseline MMA was normal in all patients and two had elevated HC (>15μmol/L). At 6 months, one patient (metformin) had MMA >0.4μmol/L and 3 (2 metformin, 1 placebo) had HC > 15μmol/L. There was an increased rate of biochemical VitB12 deficiency after 6 months of metformin; this was not associated with anemia. Further research will investigate VitB12 levels in all subjects at baseline and at 6 and 60 months.


In Vitro and in Vivo Characterization of MOD-4023, a Long-Acting Carboxy-Terminal Peptide (CTP)-Modified Human Growth Hormone.
MOD-4023 is a novel long-acting version of human growth hormone (hGH), containing the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG). MOD-4023 is being developed as a treatment for adults and children with growth hormone deficiency (GHD), which would require fewer injections than currently available GH formulations and thus reduce patient discomfort and increase compliance. This study characterizes MOD-4023's binding affinities for the growth hormone receptor, as well as the pharmacokinetic and pharmacodynamics, toxicology, and safety profiles of repeated dosing of MOD-4023 in Sprague-Dawley rats and Rhesus monkeys. Although MOD-4023 exhibited reduced in vitro potency and lower affinity to the GH receptor than recombinant hGH (rhGH), administration of MOD-4023 every 5 days in rats and monkeys resulted in exposure comparable to daily rhGH, and the serum half-life of MOD-4023 was significantly longer. Repeated administration of MOD-4023 led to elevated levels of insulin-like growth factor 1 (IGF-1), and twice-weekly injections of MOD-4023 resulted in larger increase in weight gain with fewer injections and a lower accumulative hGH dose. Thus, the increased half-life of MOD-4023 in comparison to hGH may increase the frequency of protein-receptor interactions and compensate for its decreased in vitro potency. MOD-4023 was found to be well-tolerated in rats and monkeys, with minimal adverse events, suggesting an acceptable safety profile. These results provide a basis for the continued clinical development of MOD-4023 as a novel treatment of GHD in children and adults.


Burst analysis spectroscopy: a versatile single-particle approach for studying distributions of protein aggregates and fluorescent assemblies.
Many essential cellular functions depend on the assembly and disassembly of macromolecular complexes. The size, form, and distribution of these assemblies can be heterogeneous and complex, rendering their detailed characterization difficult. Here we describe a simple non-correlation-based method capable of directly measuring population distributions at very low sample concentrations. Specifically, we exploit the highest signal-to-noise light bursts from single fluorescent particles transiting a confocal excitation spot to recursively determine the brightness and size distribution of complex mixtures of fluorescent objects. We refer to this method as burst analysis spectroscopy (BAS) and demonstrate the sensitivity of this technique by examining the free-solution, time-resolved distribution of assembled protein aggregates by using two fluorescently labeled proteins: the aggregation-prone, chaperonin-dependent, folding model protein ribulose-bisphosphate carboxylase/oxygenase (RuBisCO), and an amyloidogenic fragment of the yeast prion protein Sup35. We find that the assembly kinetics of both proteins display complex multimodal behavior not readily quantifiable with other methods.


[The modifying effect of novocaine on the clinical manifestations of the intestinal form of radiation sickness].
On rats and dogs exposed to absolute lethal doses of X-irradiation (rats--10, 12 Gy; dogs--15 Gy sublethally) it has been shown that novocaini injection to animals immediately after radiation exposure reduces the primary radiation reaction and at the same time shifts the changes in morphofunctional state of peripheric blood on 24 hours, reduces the symptoms of acute radiation sickness, increases the average life length of the animals on 1,5 days. A conclusion concerning the expressed therapeutic influence of intraperitoneal novocaini injection immediately after radiation has been drawn.