Anemia following Roux-en-Y gastric bypass for morbid obesity; a 5-year follow-up study.
Patients are at risk of anemia post Roux-en-Y gastric bypass (RYGB). We sought to determine the prevalence of anemia and related nutritional deficiencies 5 years after RYGB and to evaluate adherence to nutritional supplements with iron, vitamin B12, and folate. Patients operated with RYGB 2004-2006 were eligible for evaluation. Blood samples were collected and use of nutritional supplements was recorded preoperatively, and at outpatients' consultations 1, 2, and 5 years postoperatively. Of 203 patients operated, 184 (91%) completed the 5 year follow-up and were included in the study. Of these, 97% had valid measurements of hemoglobin both at baseline and after 5 years. During the 5 years after RYGB, the prevalence of anemia increased from 4% preoperatively to 24% in females, and from 0% to 7% in males. Ferritin levels decreased gradually in both genders. Iron deficiency increased from 6% preoperatively to 42% at 5 years in females, and from 0% to 9% in males. Vitamin B12 deficiency was not altered while folate deficiency decreased from 10% preoperatively to 1% at 5 years. Five years after surgery 25% reported the use of supplements with iron, while 83% used vitamin B12 and 65% used multivitamins with folate. We observed a long-term increase in anemia and iron deficiency after RYGB in both genders, but most pronounced in women. Our postoperative protocol for prevention of vitamin B12 and folate deficiencies appear acceptable. Iron status and iron supplementation seems to need stronger emphasis during follow-up after RYGB.


Effects of L-canavanine, an inhibitor of inducible nitric oxide synthase, on endotoxin mediated shock in rats.
The effects of L-canavanine, an inhibitor of nitric oxide synthase, on endotoxin-induced shock was investigated in the pentobarbitone anesthetized rat. Endotoxin infusion (2.5 mg kg-1 h-1 over 6 h) produced progressive and marked hypotension and hypoglycemia. Electron microscopy showed marked changes in the kidney, comprising severe endothelial cell disruption and the accumulation of platelets in the blood vessels. In the lung, there was marked accumulation of polymorphonuclear leukocytes in small blood vessels and endothelial disruption. Treatment with L-canavanine (10 mg kg-1 by bolus injection each hour starting 70 min after endotoxin or saline infusion) significantly reduced endotoxin-induced hypotension, without any effect on the hypoglycemia. This treatment markedly reduced the endotoxin-induced electron microscopical changes in the kidneys and lungs. Although L-canavanine, like L-NAME, inhibited both cerebellar constitute and splenic inducible nitric oxide synthase in vitro, in contrast to L-NAME it did not modify either arterial blood pressure or carotid artery blood flow in control rats. The data are consistent with L-canavanine being a selective inhibitor of inducible nitric oxide synthase, at least in vivo, and suggest that inhibitors of this enzyme may be beneficial in endotoxin-induced shock.


Targeted delivery of colloids by swimming bacteria.
The possibility of exploiting motile microorganisms as tiny propellers represents a fascinating strategy for the transport of colloidal cargoes. However, delivery on target sites usually requires external control fields to steer propellers and trigger cargo release. The need for a constant feedback mechanism prevents the design of compact devices where biopropellers could perform their tasks autonomously. Here we show that properly designed three-dimensional (3D) microstructures can define accumulation areas where bacteria spontaneously and efficiently store colloidal beads. The process is stochastic in nature and results from the rectifying action of an asymmetric energy landscape over the fluctuating forces arising from collisions with swimming bacteria. As a result, the concentration of colloids over target areas can be strongly increased or depleted according to the topography of the underlying structures. Besides the significance to technological applications, our experiments pose some important questions regarding the structure of stationary probability distributions in non-equilibrium systems.


A model for the RNA-catalyzed replication of RNA.
A shortened form of the self-splicing ribosomal RNA intervening sequence of Tetrahymena thermophila has enzymatic activity as a poly(cytidylic acid) polymerase [Zaug, A.J. & Cech, T.R. (1986) Science 231, 470-475]. Based on the known properties of this enzyme, a detailed model is developed for the template-dependent synthesis of RNA by an RNA polymerase itself made of RNA. The monomer units for RNA synthesis are tetra- and pentanucleotides of random base sequence. Polymerization occurs in a 5'-to-3' direction, and elongation rates are expected to approach two residues per minute. If the RNA enzyme could use another copy of itself as a template, RNA self-replication could be achieved. Thus, it seems possible that RNA catalysts might have played a part in prebiotic nucleic acid replication, prior to the availability of useful proteins.


Who's cheating? Agreements about sexual exclusivity and subsequent concurrent partnering in Australian heterosexual couples.
Background Concurrent relationships are a driver of generalised epidemics of sexually transmissible infections (STIs). In Australia, explicit negotiation of agreements about sex outside regular relationships has been recommended in health promotion for gay men but not for heterosexuals. To ascertain the annual incidence of concurrency among people in ongoing male-female relationships according to their reported expectations of exclusivity. In a national cohort recruited by household random digit dialling in 2004-05, people aged 16-64 years completed computer-assisted telephone interviews including questions about expectations of sexual exclusivity, discussion and agreements. A year later, those in ongoing sexual relationships (5323 people) were asked about sexual partner numbers in the past year. The huge majority (96%) expected sexual exclusivity of themselves and their partner. However, only 48% of men and 64% of women had discussed the matter and explicitly agreed. Older respondents were less likely to report discussion. Only 1% reported mutually nonexclusive ('open') relationships. A year later, 93% of respondents were still in the same relationship, among whom 4% of men and 2% of women had had sex outside the relationship. Those with agreements that one or both partners could have sex with others were more likely to do so, but the majority of respondents who had sex with someone else were in relationships that were explicitly or implicitly expected to be exclusive. Sexual health promotion should stress the importance of STI testing and establishing agreements about exclusivity before condoms are abandoned in new relationships.


Rational drug repurposing using sscMap analysis in a HOX-TALE model of leukemia.
Drug discovery and development are often hampered by lack of target identification and clinical tractability. Repurposing of approved drugs to life-threatening diseases such as leukemia is emerging as a promising alternative approach. Connectivity mapping systems link approved drugs with disease-related gene signatures. Relevant preclinical models provide essential tools for system validation and proof-of-concept studies. Herein we describe procedures aimed at generating disease-based gene signatures and applying them to established cross-referencing databases of potential candidate drugs. As a proof of principle, we present the identification of Entinostat as a candidate drug for the treatment of HOX-TALE-related leukemia.


The BUFFET Program: Development of a Cognitive Behavioral Treatment for Selective Eating in Youth with Autism Spectrum Disorder.
Selective eating (often referred to as "picky" eating) is common in individuals with autism spectrum disorder (ASD) across the lifespan. Behavioral interventions are widely used to treat selective eating; however, most of these programs are time intensive, have not been evaluated for use in outpatient settings, and do not typically include youth beyond early childhood. Despite the functional impact and risk for negative outcomes associated with selective eating, there are no empirically supported treatments available for older children, adolescents, or adults, either with or without ASD. To address this treatment gap, we developed BUFFET: the Building Up Food Flexibility and Exposure Treatment program. BUFFET is a 14-week, multi-family group cognitive behavioral treatment for selective eating in children (8-12 years) with ASD. In this paper, we will (1) discuss the theoretical conceptualization of BUFFET, (2) describe the treatment content and structure, (3) present feasibility data from the initial pilot trial, and (4) consider next steps in treatment development.


The production of antibodies to pentosanpolysulfate (ELMIRON, SP-54).
Pentosanpolysulfate (PPS) represents the product obtained after sulfation of xylan and is composed of beta 1----4-D-xylopyranose residues sulfated at C2 and C3. Studies have shown that this compound can often be effective in relieving the symptoms of interstitial cystitis (IC). In order to elucidate the mode of action of PPS in IC, a sensitive and reliable assay was needed. To this end we prepared an immunogenic form of PPS by coupling it to methylated bovine serum albumin (MBSA). This complex was used to immunize NZW rabbits (1 mg, IM). Four of five animals responded with anti-PPS antibodies, three of which had high titer (greater than 1/2000) as measured by an enzyme-linked immunosorbent assay (ELISA). All sera were routinely absorbed with an MBSA-Sepharose immunoadsorbent to remove anti-MBSA antibodies. ELISA inhibition tests were used to determine the sensitivity and specificity of the sera. At least 50 ng/ml of PPS could be routinely detected by this assay. A number of naturally occurring proteoglycans, polysaccharides, monosaccharides and disaccharides were examined for reactivity with the antibodies but only heparin was an effective inhibitor. Absorption with heparin immunoadsorbents reduced, but did not eliminate, the ability of heparin to inhibit anti-PPS binding. This activity could be destroyed by treatment with heparinase without affecting PPS inhibition. Normal urine did not affect the ELISA or ELISA inhibition tests and thus allowed the determination of PPS levels in IC patient urines. Initial analysis of seven IC patients receiving oral PPS revealed urine concentration of 0.8-16.0 micrograms/ml. No inhibition could be detected in pre-treatment urine samples.


Birth weight influences long-term catch-up growth and height prognosis of GH-deficient children treated before the age of 2 years.
To investigate which pretreatment variables most significantly affect long-term growth response to GH therapy in children with apparently idiopathic GH deficiency (GHD) treated from a similar and very young age (less than 2 years), for the same period (7 years) and with the same therapeutic protocol. Twelve children with either isolated GHD or multiple pituitary hormone deficiency were treated with biosynthetic human GH (0.7IU/kg per week) and were examined every 6 months. Height measurements were performed by Harpenden stadiometers. Bone age was evaluated every 12 months. The onset of therapy was followed in all patients by an important height gain, which attained its zenith during the first year of treatment and became progressively less evident during the next 4 years. Cumulative height gain was 3.0+/-1.7SDS. Thanks to the therapy, at the end of the 7-year treatment period, average height in the entire series was not significantly far from mean target height (TH) (-0.7+/-1.3 vs -0. 3+/-0.4SDS) and average predicted height (PH) (-0.2+/-1.4SDS) was very close to TH. A stepwise regression analysis showed that both catch-up growth under therapy and PH at the end of the 7-year treatment period were positively influenced by birth weight (BW). a) Our 7-year prospective study on GHD infants treated with GH from less than 2 years of age confirmed the importance of early diagnosis and treatment of GHD in childhood. b) The influence of BW on growth response to GH therapy in GHD children persists over time, at least when treatment is begun from less than 2 years of age.


Impact of geriatric home screening services on mental state: a systematic review.
The purpose of this report was to determine the impact of geriatric home screening services on mental state. Two computer databases, MEDLINE and HealthSTAR, were searched for relevant articles published from January 1975 to June 1997, and the bibliographies of retrieved articles were searched for additional references. Seven trials were located that met the four inclusion criteria: (a) original study; (b) published in English or French; (c) controlled trial (randomized or nonrandomized) of a geriatric home screening service; and (d) the trial included at least one measure of mental state. All trials met most of the validity criteria for intervention studies of the Evidence-Based Medicine Working Group. Two trials reported a small effect on morale or self-perceived health and five trials reported no effect. Thus, there was little evidence that geriatric home screening services had an impact on the mental state of aged subjects.


Endogenous production of tumour necrosis factor is required for manganese superoxide dismutase expression by irradiation in the human monocytic cell line THP-1.
Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme that scavenges superoxide (O2-) ions. We studied the regulation of MnSOD gene expression by irradiation and the mechanisms in human monocytic cell line THP-1. We found that irradiation induced expression of the MnSOD gene through the autocrine mechanism, involving the production of tumour necrosis factor (TNF). Irradiation increased TNF production in THP-1 cells, and TNF increased the levels of MnSOD transcripts. Supernatant from irradiated THP-1 cells induced the expression of MnSOD mRNA, and anti-TNF antibody blocked the induction of MnSOD mRNA. Irradiation also increased the levels of MnSOD mRNA in other myelocytic cell lines, HL60 and KG-1, and the ovarian cancer cell line SK-OV-3. Moreover, increased levels of MnSOD mRNA were observed in mature myeloid cells, including macrophages and granulocytes, as well as in immature cells. However, irradiation did not increase the level of MnSOD mRNA in THP-1 cells with prolonged exposure to PMA. We also found that irradiation increased the rate of MnSOD transcription, and irradiation stabilized MnSOD mRNA in THP-1 cells. Our results indicate that the endogenous production of TNF is required, at least in part, for the induction of MnSOD mRNA expression by irradiation in THP-1 cells, and the increased levels of MnSOD transcripts on irradiation occur through a pathway involving protein kinase C activation. Our results also indicate that the increase in MnSOD mRNA caused by irradiation is regulated by both transcriptional and post-transcriptional mechanisms.


Multiple structural alignment and core detection by geometric hashing.
A Multiple Structural Alignment algorithm is presented. The algorithm accepts an ensemble of protein structures and finds the largest substructure (core) of C alpha atoms whose geometric configuration appear in all the molecules of the ensemble (core). Both the detection of this core and the resulting structural alignment are done simultaneously. Other large enough multistructural superimpositions are detected as well. Our method is based on the Geometric Hashing paradigm and a superimposition clustering technique which represents superimpositions by sets of matching atoms. The algorithm proved to be efficient on real data in a series of experiments. The same method can be applied to any ensemble of molecules (not necessarily proteins) since our basic technique is sequence order independent.


The anisotropic nanomovement of azo-polymers.
Nanoscale polymer movement is induced by a tightly focused laser beam in an azo-polymer film just at the diffraction limit of light. The deformation pattern that is produced by photoisomerization of the azo dye is strongly dependent on the incident laser polarization and the longitudinal focus position of the laser beam along the optical axis. The anisotropic photo-fluidity of the polymer film and the optical gradient force played important roles in the light induced polymer movement. We also explored the limits of the size of the photo-induced deformation, and we found that the deformation depends on the laser intensity and the exposure time. The smallest deformation size achieved was 200 nm in full width of half maximum; a value which is nearly equal to the size of the diffraction limited laser spot.


Modifiable individual and work-related factors associated with neck pain in 740 office workers: a cross-sectional study.
Office workers have the highest incidence of neck pain of all occupations. However, the relationship between symptoms and the risk factors is unclear. To examine the relationship between self-reported neck pain with a comprehensive range of individual and work-related risk factors. This study utilised a cross-sectional study design. Office workers with and without neck pain (n=763) were recruited. Participants completed a survey which included a Pain Numerical Rating Scale (dependent variable), and measures of independent variables including demographic, individual, work-related factors, neck/shoulder muscle strength, endurance, and range of motion (ROM). The relationships between the independent and dependent variables were analysed in a logistic regression model. Neck pain was significantly associated with more senior occupational categories, working more than six hours per day on the computer, female sex, greater fear avoidance beliefs for work, greater psychological distress, and reduced cervical flexion ROM. The low severity of neck pain of the participants in this study may limit a robust determination of their association with the risk factor variables, but the studied sample is a realistic representation of the office worker population. Several potentially modifiable individual and work-related factors were identified to be associated with the presence of self-reported neck pain in office workers. Future studies will be needed to investigate whether strategies to alter these modifiable risk factors translate to changes in neck pain. ACTRN12612001154897 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363209).


Uncinate fasciculus and word selection processing in Parkinson's disease.
We explored with Diffusion Tensor Imaging (DTI) technique whether the ability to select words among competitive alternatives during word production is related to the integrity of the left uncinate fasciculus (UF) in Parkinson's disease (PD). Nineteen PD patients (10 right-sided and 9 left-sided) and 17 matched healthy controls (HC) took part in the study. Participants were asked to derive nouns from verbs (reading from to read) or to generate verbs from nouns (to build from building). Noun and verb production, in this task, differ in the number of lexical entries among which the response is selected, as the noun must be selected from a larger number of alternatives compared to the verb, and thus is more demanding of processing resources. DTI evaluation was obtained for each subject. Fractional anisotropy (FA) and mean diffusivity (MD) maps were derived from DTI and median FA and MD values were computed within the left and right UF. Then, FA and MD of the left and right UF were correlated with noun and verb production. Both the left and right UF-FA correlated with the global (noun + verb) production and noun production in the whole PD group. In right-sided PD, correlations were found with the contralateral UF-FA; in left-sided PD the correlations emerged with both the left and right UF-FA. The most difficult task, noun production, significantly correlated with the right UF-FA in left-sided PD. The left UF is involved in word selection processes, and the right UF intervenes when the selection is particularly demanding of attentional resources.


[Holter analysis of ventricular arrhythmias and its treatment with propafenone].
We studied 20 patients with ventricular premature beats. All of them underwent 16-24 hs Holter monitoring before and during propafenone treatment at an average dosage of 600 mgs P.O. We observed 86% decrease in the ectopic beats. In two cases there was a complete abolition of the ventricular beats. The Lown's type 3 ventricular beats had a 50% reduction. The were not significant modifications of the heart rate of blood pressure. There were not significant side effects. We consider propafenone as a potent agent for the treatment of ventricular ectopic beats.


[The influence of stress-strain processes in tooth enamel on the marginal permeability of class i restorations with a different design of the edge of the carious cavity].
Introduction: Of the factors affecting the marginal permeability of restorations in the teeth, the state of stress-strain processes in the enamel with different design of the edge of the carious cavity has been poorly studied. The aim of this research was to study the influence of stress-strain processes in tooth enamel on the marginal permeability of class I restorations with a different design of the edge of the carious cavity. Materials and methods: We have examined 45 pulled out intact third molars, which were divided into three groups of 15 each, depending on class 1 carious cavities formed in them. In I group we formed a carious cavity without a bevel of enamel, in II - with external bevel of enamel, in III - with internal bevel of enamel. Carious cavities were restored with a microhybrid composite light curing material. The teeth were undergone thermocycling and a single vertical mechanical load, were covered with nail polish, placed in a 1% aqueous solution of methylene blue, separated in the medio-distal direction, and the depth of dye penetration was studied. The stress-strain state of the enamel was modelled by the finite elements method. Results: Nonparametric statistical analysis showed that there is a close relationship between the values of stress and strain in enamel and the marginal permeability of restorations. The higher are these values, the deeper is the penetration of the dye. When the edge of the carious cavity is formed with external bevel of enamel, the lowest penetration of the dye is observed, with the internal bevel - the maximal. The results obtained can be useful for clinicians in the preparation of class I carious cavities. Conclusions: The higher the values of stress and strain in enamel, the deeper the marginal permeability of restorations. When the external bevel of the enamel is formed, the dye penetrates least, and when the internal bevel is formed - the maximal.


S-glycoprotein-like protein regulates defense responses in Nicotiana plants against Ralstonia solanacearum.
RsRGA4 (for Ralstonia solanacearum-responsive gene A4) encodes a polypeptide similar to S-locus glycoprotein (SGP) from Brassica rapa and SGP-like proteins from Ipomoea trifida and Medicago truncatula. Therefore, we designated RsRGA4 as NtSGLP (for Nicotiana tabacum SGP-like protein) and NbSGLP (its Nicotiana benthamiana ortholog). NbSGLP is expressed in root, leaf, petal, gynoecium, and stamen. Expression of NbSGLP was strongly induced by inoculation with an avirulent strain of R. solanacearum (Rs8107) and slightly enhanced by inoculation with virulent R. solanacearum (RsOE1-1). Expression of NbSGLP was induced by inoculation with an hrpY-deficient mutant of RsOE1-1 and Rs8107. Expression was also induced by aminocyclopropane carboxylic acid and salicylic acid. Virus-induced gene silencing of NbSGLP enhanced the growth of Rs8107. Growth of RsOE1-1 and appearance of wilt symptoms were also accelerated in silenced plants. Expression of PR-1a and EREBP was reduced, and markers for basal defense, such as callose deposition and reduced vascular flow, were compromised in NbSGLP-silenced plants. Moreover, growth of Pseudomonas cichorii, Pseudomonas syringae pv tabaci, and P. syringae pv mellea was also enhanced in the silenced plants. On the other hand, silencing of NbSGLP did not interfere with the appearance of the hypersensitive response. NbSGLP was secreted in a signal peptide-dependent manner. Agrobacterium tumefaciens-mediated expression of NbSGLP induced PR-1a and EREBP expression, callose deposition, and reduced vascular flow. NbSGLP-induced callose deposition and reduced vascular flow were not observed in salicylic acid-deficient N. benthamiana NahG plants. Taken together, SGLP might have a role in the induction of basal defense in Nicotiana plants.


Immune responsiveness in chronic fatigue syndrome.
We have endeavoured to find immunological indications of chronic virus infection in patients with chronic fatigue syndrome (myalgic encephalomyelitis) and to investigate immune responsiveness to viruses in such patients in comparison with normal subjects and patients with muscular dystrophy. Levels of circulating IgM immune complexes were elevated (above the 95% normal control range) in 10 (17%) of 58 patients with chronic fatigue syndrome, which was not significantly different from the normal controls or from dystrophy controls (by Mann Whitney U test). Levels of IgG complexes were only increased in 10% of patients. Lymphocyte proliferation in response to concanavalin A (Con A), assessed by increase in 3H-thymidine incorporation, did not differ between 14 patients and 18 normal subjects. The proliferative response to Coxsackie B virus antigen did not differ between chronic fatigue patients and normal subjects when expressed either as an increase in counts or as a stimulation index. Adjustment of the counts in relation to the proliferation response to Con A, as an indication of the overall proliferative response of the cell preparation, did not reveal any hidden difference. IgM antibodies to Coxsackie B viruses were not found in any of 20 patients and in 1 of 20 dystrophy controls. Significant levels of neutralizing antibodies to Coxsackie B viruses 1-5 were found in 6 out of 19 (32%) patients compared with 4 out of 17 (24%) dystrophy controls, which does not differ from currently expected normal incidence. Antibody titres to other respiratory viruses were also not notably different between the patient and control groups. In conclusion we can find no evidence for a definable viral aetiology for the chronic fatigue syndrome, neither in terms of a persistent infection nor an altered ability to respond to virus.


Age-related changes of monoaminooxidases in rat cerebellar cortex.
Age-related changes of the monoaminoxidases, evaluated by enzymatic staining, quantitative analysis of images, biochemical assay and statistical analysis of data were studied in cerebellar cortex of young (3-month-old) and aged (26-month-old) male Sprague-Dawley rats. The enzymatic staining shows the presence of monoamino-oxidases within the molecular and granular layers as well as within the Purkinje neurons of the cerebellum of young and aged animals. In molecular layer, and in Purkinje neurons the levels of monoaminooxidases were strongly increased in old rats. The granular layer showed, on the contrary, an age-dependent loss of enzymatic staining. These morphological findings were confirmed by biochemical results. The possibility that age-related changes in monoaminooxidase levels may be due to impaired energy production mechanisms and/or represent the consequence of reduced energetic needs is discussed.


Effects of early gestational undernutrition on fetal growth, organ development, and placentomal composition in the bovine.
Fetal intrauterine growth restriction (IUGR) is known to negatively affect offspring health postnatally. This study evaluated the impacts of early gestational undernutrition followed by realimentation on bovine fetal and placental growth. Thirty multiparous beef cows bred to a single sire and gestating female fetuses were fed to meet NRC recommendations (control; n = 15) or fed below NRC recommendations (68.1% of NE(m) and 86.7% of MP recommendations; nutrient restricted, NR; n = 15) from d 30 to 125 of gestation. On d 125 of gestation, 10 control and 10 NR cows were necropsied. The remaining 5 NR cows were realimented to achieve similar BW and BCS with the remaining 5 control cows by d 190 of gestation; both groups were necropsied at d 245 of gestation. Fetal weight at d 125 of gestation was 948 +/- 14 g (n = 10) for control cows; however, fetal weights of NR cows fell into 2 distinct groups: NR non-IUGR cows had fetal weights similar to control cows (974 +/- 20 g, n = 6), whereas fetal weights of NR IUGR cows were reduced (773 +/- 23 g, n = 4; P < 0.01). Fetal brain weight as a percentage of fetal weight was increased (approximately 11%; P < 0.01) in the NR IUGR fetuses compared with fetuses from the other 2 groups, which were similar. Fetal heart weight as a percentage of fetal weight also tended to be increased (approximately 10%; P = 0.08) in NR IUGR fetuses compared with control fetuses. Nutrient-restricted IUGR cows exhibited reduced (P < 0.01) cotyledonary weights compared with NR non-IUGR and control cows, which were similar (192 +/- 27 vs. 309 +/- 22, and 337 +/- 17 g, respectively). Total placentome surface area also tended to be reduced (P = 0.07) in NR IUGR cows compared with NR non-IUGR and control cows, which again were similar (685.0 +/- 45.6 vs. 828.7 +/- 37.2 and 790.7 +/- 28.9 mm(2), respectively). On d 245 of gestation, fetal weights and caruncle weight were similar for NR and control cows; cotyledonary weights, however, were reduced in NR vs. control cows (1,430 +/- 133 vs. 2,137 +/- 133 g, P < 0.01). Decreased fetal growth in NR IUGR cows on d 125 of gestation was associated with decreased cotyledonary weights and reduced placentomal surface areas. The return of NR cows to a BW and BCS similar to that of control cows through realimentation beginning on d 126 resulted in similar fetal weights of NR and control cows by d 245 of gestation. Thus, a bout of fetal IUGR may go undetected if cows undernourished during early gestation receive feed supplementation in the second half of gestation to assure normal birth weight.


Sclerosing Pneumocytoma of the Lung: A Case Report.
Pulmonary Sclerosing Pneumocytoma (PSP) is a rare tumour of the lung and is always benign. Diagnosis is made incidentally following chest X-ray or chest CT scan performed for other clinical conditions. We report a case of PSP in a seven-year-old girl who got admitted for evaluation of an anterior mediastinal mass. Clinically, thought of teratoma or other germ cell tumour the mass was excised and sent for histopathological examination. Grossly, we received a pneumonectomy specimen measuring 13x11x8 cm with a nodular firm grey white lesion in the medial aspect of lower and middle lobe measuring 7.5x5.5x5 cm. Macroscopically, pleura was involved and adherent to the lung. Microscopy showed, an ill-defined lesion in the lung with extensive fibrosis and lymphoplasmacytic infiltrate. The lesion was composed of round to oval cells with ill defined cell border, moderate eosinophilic cytoplasm and bland nuclei. A panel of Immunohistochemical (IHC) markers was performed and the lesional cells were positive for Epithelial Membrane Antigen (EMA) and Thyroid Transcription Factor-1 (TTF-1). The prognosis after surgical resection is good and the patient is doing well.


Physician behavior in the care of pediatric chronic illness: association with health outcomes and treatment adherence.
Physician behavior is an important but understudied influence on child and parental adherence to medical treatment. To address this need, research was reviewed in the following topic areas: child and adolescent perceptions of physicians' behavior in pediatric chronic illness management, parental perceptions of physicians' behavior in pediatric chronic illness management; physicians' adherence to guidelines for pediatric chronic illness management; physicians' communication of information concerning pediatric chronic illness treatment; the relationship of physician behavior to treatment adherence; and interventions to enhance physicians' management of pediatric chronic illness. Findings underscore discrepancies between the needs of parents and adolescents and physician behavior as well as inconsistencies in physician behavior, including adherence to practice guidelines, which may limit children's adherence to medical treatment. However, results of interventions designed to enhance physicians' management of pediatric asthma have been promising. Future research should be guided by a comprehensive model of physician behavior in chronic illness management that considers contextual determinants (e.g., culture and socioeconomic status), identifies clinically relevant targets for intervention, and documents the impact on health outcomes. Approaches to chronic illness management that involve physicians in active communication, support, and decision making with children with chronic illness and their parents should be developed and evaluated.


Raising livestock in resource-poor communities of the North West Province of South Africa--a participatory rural appraisal study.
A participatory research model was used in six village communities in the Central Region of the North West Province of South Africa in order to achieve the following broad objectives: to obtain information on the challenges owners face in raising livestock in these areas and to evaluate the livestock owners' level of knowledge of internal parasites in their animals. Information obtained at participatory workshops clearly indicated a need for improvements in water supply, schools, job creation, and health services. Lack of pasture for grazing livestock was also cited as being important. Other most frequently mentioned livestock problems included 'gall sickness' (a vaguely defined condition not necessarily referring to anaplasmosis), parasites (both external and internal), chicken diseases and ingestion of plastic bags discarded in the environment. When livestock owners were questioned during individual interviews, most were able to identify the presence of parasites in either the live or dead animal. However, it seems likely that this is limited to the identification of tapeworms. It was found that most livestock owners use a combination of treatments, ranging from traditional to folklore to commercial. There were some difficulties in using the participatory methods since it was the first time that the facilitators and the communities had been exposed to them. Many communities had difficulty in dealing with the concept of finding solutions within the community, which is such an integral part of participatory methods.


Patients' perspectives on interprofessional collaboration between health care professionals during hospitalization: a qualitative systematic review.
The objective of this review was to gain a better understanding of the interprofessional collaboration between health care professionals from the patients' point of view during hospitalisation; the influence of interprofessional collaboration on patient care, safety, and well-being; and patients' perspectives of their role in the interprofessional collaboration process. Interprofessional collaboration is a key factor in improving patient health care outcomes and safety through better communication between health care professionals, better teamwork, and better care coordination. However, implementing interprofessional collaboration in the clinical setting can prove complex. Patients are increasingly interested in becoming partners within the health care system. They have the potential to contribute to their own safety and to observe professionals during the care process, thus gaining a better understanding of the interprofessional collaboration process and facilitating changes in the behavior of health care professionals. This review considered qualitative research and mixed-method studies. Participants were hospitalized patients. Studies were included when they explored i) patients' perceptions of interprofessional collaboration, ii) the influence of interprofessional collaboration on patients' care, safety, or well-being, or iii) patients' perceptions of their own role in interprofessional collaboration. Qualitative studies focusing only on the care process or families' points of view were excluded. Searches of six databases including MEDLINE, CINAHL, Embase, Web of Science, PsycINFO, and Sociological Abstract, limited to English, French, and German were conducted from March 2017 to June 2018. Assessment of methodological quality of studies was performed using the JBI Qualitative Assessment and Review Instrument. Data were extracted using the standardized data extraction tool from JBI. Data synthesis following the JBI approach of meta-aggregation was performed. The level of confidence for each synthesized finding was established based on ConQual. A total of 22 studies were included, which resulted in 89 findings and 24 categories. Eight synthesized findings were generated: patients' perceptions of interprofessional collaboration based on personal experiences and observations; patients' experiences with effective or ineffective interprofessional communication; patients' experience with power imbalance and paternalistic attitudes; patients' perceptions of key factors for a confident relationship with the interprofessional health care team; patients' need for comprehension of discussions between health care professionals; patients' perceptions of their role in an interprofessional health care team; patients' perceptions of opportunities for empowerment in interprofessional health care teams; and patients' need for humanizing care from interprofessional health care teams. The level of confidence of synthesized findings varied from low to moderate according to ConQual. This systematic review synthesized the perspectives of hospitalized patients regarding interprofessional collaboration and their perceived role in collaborative practices. Hospitalized patients observe interprofessional collaboration, either directly or indirectly, and the way interprofessional collaboration is performed may impact both their care and their well-being. However, little evidence has been found regarding the impact of interprofessional collaboration on patient safety. Patients' perspectives on their perceived role is not unanimous; some patients want to play an active role in the collaborative process, whereas others prefer to trust the health care professionals' expertise. Health care professionals should consider patients' preferences and act accordingly regarding both the collaborative process and the inclusion of the patients in collaborative practices.


Efficacy of ketamine as an adjunct to lidocaine in intravenous regional anesthesia.
This study aims to compare and evaluate the effect of adding ketamine as an adjunct to lidocaine for intravenous regional anesthesia (IVRA) on intraoperative and postoperative analgesia, the onset and recovery times of sensory and motor block, and tourniquet pain. Forty patients undergoing surgery of the hand or forearm under IVRA were randomly assigned to receive lidocaine 3 mg/kg (group 1) or lidocaine 3 mg/kg plus ketamine 50 mg (group 2) diluted to 40 mL with normal saline. Assessment parameters included the onset and recovery times of sensory and motor block, tourniquet pain, intraoperative hemodynamics, surgeon and patient satisfaction, postoperative pain, time of first analgesic request, total analgesic consumption, and adverse effects in the first 24 hours postoperatively. Groups 1 and 2 were comparable in demographic and surgical parameters. There were no differences between groups in intraoperative hemodynamics, onset and recovery times of sensory and motor block, or surgeon satisfaction index. Compared with group 1, group 2 patients showed less tourniquet pain, prolonged time to first request for postoperative rescue analgesia (5.5 ± 1.3 vs 20.4 ± 3.7 hours, P < 0.001), lower postoperative diclofenac consumption (120.00 ± 45.23 vs 55.1 ± 0.00 mg, P < 0.001), lower scores for postoperative pain as measured by the Verbal Rating Scale, higher patient satisfaction index, and a nonsignificant difference in the incidence of postoperative adverse effects between groups. The addition of ketamine to lidocaine in patients receiving IVRA significantly reduced intraoperative and postoperative analgesic requirements and improved patient satisfaction without causing significant adverse effects.


Long-term potentiation of hippocampal synaptic transmission affects rate of behavioral learning.
Electrical stimulation techniques were used to produce a long-lasting potentiation of synaptic transmission in the hippocampus of naïve rabbits. Animals were then classically conditioned. Long-term potentiation of the hippocampus before training increased the rate at which animals subsequently learned the conditioning task. This result has significance for potential cellular mechanisms of associative learning.


Calcifying Pseudoneoplasm of the Neuraxis: From Pathogenesis to Diagnostic and Therapeutic Considerations.
Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumefactive lesion that can develop anywhere within the neuraxis. The incidence is likely underreported, given its nonspecific imaging features and because CAPNON has often been overwhelmed by the presence of comorbid disease. CAPNON is typically diagnosed by the histopathological examination findings. However, the histopathological diagnosis is often challenging owing to the existence of similar calcifying pathological entities. Although the pathogenesis of CAPNON has remained elusive, emerging evidence supports a reactive proliferative and immune-mediated process involving the aggregation of neurofilament light chain protein and the infiltration of immune cells. The management of CAPNON is largely dependent on the symptoms, which are mainly related to the location and associated mass effects. Maximal surgical resection will result in excellent patient outcomes with rare recurrence, especially in patients presenting with epilepsy. The discovery of neurofilament light chain protein within CAPNON suggests that neurofilament might be implicated in the pathogenesis of CAPNON, serve as an immunohistochemical marker to improve the diagnostic accuracy of CAPNON, and hold therapeutic potential for the treatment of CAPNON.


ASSESSMENT OF MECHANICAL AND MANUAL SUTURE IN THE SURGICAL TREATMENT OF THE PHARYNGOESOPHAGEAL DIVERTICULUM.
The occurrence of the pharyngoesophageal, or Zenker diverticulum is not frequent in the national scenario, and the technique of the diverticulectomy with cricomyotomy in medium and great dimension diverticula is still the most indicated. Because the resection of the diverticulum requires the suture of the pharynx, dehiscence can occur, thereafter delaying swallowing. Hence, the idea is to accomplish this surgical procedure, comparing the manual and mechanical suture, in order to evaluate the real benefit of the mechanical technique. To evaluate the results of the pharyngoesophageal diverticulectomy with cricomyotomy using manual and mechanical suture with regard to local and systemic complications. Fifty-seven patients with pharyngoesophageal diverticula diagnosed through high digestive endoscopy and pharyngeal esophagogram were studied. The applied surgical technique was diverticulectomy with myotomy of the cricopharyngeal muscle, done in 24 patients (42.2%) the mechanical suture (group A) with the mechanical linear suture device and in 33 (57.8%) a manual closure of the pharynx (group B). In the postoperative period, one patient of group A (4.1%) presented fistula caused by dehiscence of the pharyngeal suture, and three of group B (15.1%) presented the same complication, with a good outcome using a conservative treatment. In the same group, three patients (9.0%) presented stenosis of the suture of the pharynx, with good outcome and with endoscopic dilatations, and no patient from group A presented such complication. Lung infection was present in five patients, being two (8.3%) of group A and three (9.0%) on B, having good outcomes after specific treatment. In the late review, done with 43 patients (94.4%) of group A and 22 (88.0%) on B, the patients declared to be pleased with the surgical procedure, because they were able to regain normal swallowing. The diverticulectomy with myotomy and pharyngeal closure using mechanical suture was proven appropriate, for having restored regular swallowing in most of the patients, and the mechanical closure of the pharynx proved to be more effective in comparison to the manual one, because it provided a lower index of local post-surgical complications.


Feeding behaviour of Belminus ferroae (Hemiptera: Reduviidae), a predaceous Triatominae colonizing rural houses in Norte de Santander, Colombia.
Belminus ferroae (Hemiptera: Reduviidae) was collected from houses in the localities of San Alberto and Santa Catalina in the municipality of Toledo, Department of Norte de Santander, Colombia. Precipitin tests revealed that the main hosts of B. ferroae are insects belonging to the order Blattodea, whose haemolymph serves as food (89.43%). A low rate of haematophagy was indicated on rodents, dogs and humans (7.32%) and no natural infection with Trypanosoma cruzi was found by either microscopic examination or polymerase chain reaction. The finding of B. ferroae inside houses, feeding primarily on Blattodea with only a minor tendency to feed on vertebrate blood, is indicative of both the evolutionary path from predator to blood-sucker taken by Triatominae and their tendency to adapt from silvatic to domestic habitats.


Negative regulation of AbetaPP gene expression by pur-alpha.
The nucleic acid binding protein, Pur-alpha, is best characterized as a transcription factor with affinity to single stranded G/C rich regions. Pur-alpha exhibits developmental and tissue-specific regulation and plays a critical role in neuronal development and differentiation. Similar to Pur-alpha, the amyloid-beta protein precursor (AbetaPP) is a developmentally regulated protein which promotes neuronal survival. Both the human and mouse AbetaPP promoters contain multiple G/C rich sequences which regulate AbetaPP at the transcriptional and translational levels. Using an in vitro reporter assay, we confirmed that Pur-alpha consensus binding sites within the human AbetaPP promoter down-regulate AbetaPP transcription. Electrophoretic mobility shift and chromatin immunoprecipitation assays (ChIP) showed direct binding of Pur-alpha to the AbetaPP promoter. Down regulation of AbetaPP went beyond the transcriptional level as overexpression of Pur-alpha in glial and fibroblast cell lines decreased basal levels of AbetaPP while siRNA targeting Pur-alpha increased basal levels of AbetaPP. Similar findings were observed in brain tissue and fibroblasts from mice with targeted deletion of Pur-alpha. These data point to a novel mechanism of controlling AbetaPP levels by the transcriptional regulatory protein, Pur-alpha, and suggest that Pur-alpha may be involved in the dysregulation of AbetaPP in Alzheimer's disease.


Value of histopathology, culture and guinea pig inoculation in osteoarticular tuberculosis.
Evaluation of histopathology, culture and guinea pig inoculation in 58 patients provisionally diagnosed as having osteoarticular tuberculosis in the Department of Orthopedics, P.B.M. Hospital, Bikaner is presented. The following conclusions were reached. Where facilities exist, all the investigations should be carried out in each case to obviate chances of missing the diagnosis and if possible all the pathological material available should be used. Otherwise histopathology plus guinea pig inoculation or histopathology plus culture should be mandatory. Clinical examination, radiological evidence and gross appearances of the lesion can only serve as an aid to preliminary diagnosis and/or prognosis.


Human papillomavirus genotype distribution in Madrid and correlation with cytological data.
Cervical cancer is the second most common cancer in women worldwide. Infection with certain human papillomavirus (HPV) genotypes is the most important risk factor associated with cervical cancer. This study analysed the distribution of type-specific HPV infection among women with normal and abnormal cytology, to assess the potential benefit of prophylaxis with anti-HPV vaccines. Cervical samples of 2,461 women (median age 34 years; range 15-75) from the centre of Spain were tested for HPV DNA. These included 1,656 samples with normal cytology (NC), 336 with atypical squamous cells of undetermined significance (ASCUS), 387 low-grade squamous intraepithelial lesions (LSILs), and 82 high-grade squamous intraepithelial lesions (HSILs). HPV detection and genotyping were performed by PCR using 5'-biotinylated MY09/11 consensus primers, and reverse dot blot hybridisation. HPV infection was detected in 1,062 women (43.2%). Out of these, 334 (31%) samples had normal cytology and 728 (69%) showed some cytological abnormality: 284 (27%) ASCUS, 365 (34%) LSILs, and 79 (8%) HSILs. The most common genotype found was HPV 16 (28%) with the following distribution: 21% in NC samples, 31% in ASCUS, 26% in LSILs, and 51% in HSILs. HPV 53 was the second most frequent (16%): 16% in NC, 16% in ASCUS, 19% in LSILs, and 5% in HSILs. The third genotype was HPV 31 (12%): 10% in NC, 11% in ASCUS, 14% in LSILs, and 11% in HSILs. Co-infections were found in 366 samples (34%). In 25%, 36%, 45% and 20% of samples with NC, ASCUS, LSIL and HSIL, respectively, more than one genotype was found. HPV 16 was the most frequent genotype in our area, followed by HPV 53 and 31, with a low prevalence of HPV 18 even in HSILs. The frequency of genotypes 16, 52 and 58 increased significantly from ASCUS to HSILs. Although a vaccine against HPV 16 and 18 could theoretically prevent approximately 50% of HSILs, genotypes not covered by the vaccine are frequent in our population. Knowledge of the epidemiological distribution is necessary to predict the effect of vaccines on incidence of infection and evaluate cross-protection from current vaccines against infection with other types.


Isolation and characterization of novel soil- and plant-associated bacteria with multiple phytohormone-degrading activities using a targeted methodology.
Ethylene (ET), salicylic acid (SA) and indole-3-acetic acid (IAA) are important phytohormones regulating plant growth and development, as well as plant-microbe interactions. Plant growth-promoting bacteria (PGPB) naturally associate with plants and facilitate plant growth through a variety of mechanisms, including the ability to modulate the concentrations of these phytohormones in planta. Importantly, the wide presence of phytohormone degradation mechanisms amongst symbiotic and other soil- and plant-associated bacteria indicates that the ability to modulate phytohormone concentrations plays an important role in bacterial colonization and plant-growth promotion abilities. Obtaining phytohormone-degrading bacteria is therefore key for the development of novel solutions aiming to increase plant growth and protection. In this paper, we report an optimized targeted methodology and the consequent isolation of novel soil- and plant-associated bacteria, including rhizospheric, endophytic and phyllospheric strains, with the ability to degrade the phytohormones, SA and IAA, as well as the ET precursor, 1-aminocyclopropane-1-carboxylic acid (ACC). By using an optimized targeted methodology, we rapidly isolated diverse soil- and plant-associated bacteria presenting phytohormone-degrading abilities from several plants, plant tissues and environments, without the need for prior extensive and laborious isolation and maintenance of large numbers of isolates. The developed methodology facilitates PGPB research, especially in developing countries. Here, we also report, for the first time, the isolation of bacterial strains able to concomitantly catabolize three phytohormones (SA, IAA and ACC). Ultimately, the described targeted methodology and the novel phytohormone-degrading bacteria obtained in this work may be useful tools for future plant-microbe interaction studies, and in the development of new inoculant formulations for agriculture and biotechnology.


THYROTOXIC PERIODIC PARALYSIS IN A COMPETITIVE BODYBUILDER WITH THYROTOXICOSIS FACTITIA.
We report a case of thyrotoxic periodic paralysis (TPP) in a bodybuilder who developed paralysis secondary to thyrotoxicosis factitia after taking a supplement containing thyroid hormone. Interestingly, the patient had no intrinsic thyroid disease. Prompt recognition of thyrotoxicosis is critical to avoid progression of paralysis and subsequent complications. We discuss a 27-year-old body builder who presented after a 3-day bodybuilding competition with sudden upper and lower extremity paralysis. He admitted to taking anabolic steroids, a supplement containing an unknown amount of thyroid hormone for 2 weeks, and furosemide 40 mg twice daily with near-complete fluid restriction for 3 days. Laboratory results showed a thyroid-stimulating hormone (TSH) level of <0.010 μIU/mL (normal, 0.3 to 5.8 μIU/mL), normal total triiodothyronine level, elevated free thyroxine level of 3.6 ng/dL (normal, 0.8 to 1.9 ng/dL), and potassium level of 1.9 mEq/L (normal, 3.7 to 5.2 mEq/L). Thyroid peroxidase antibody, thyroid-stimulating immunoglobulin, and thyroglobulin antibody levels were normal. Thyroid uptake was 1% (normal, 8 to 25%) after administration of I-123 and thyroglobulin level was 9 ng/mL (normal, 1.4 to 29.2 ng/mL). The patient was treated with normal saline infusion, magnesium supplementation and a total of 230 mEq of potassium within 12 hours of hospitalization. Muscle weakness resolved within this time period and potassium level normalized. By the third day of hospitalization free thyroxine level also normalized and TSH improved to 0.1 mIU/L. TPP is a rare complication of thyrotoxicosis that should be considered in bodybuilders who are presenting with acute muscle weakness.


Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients.
Splenectomy has been used in patients with common variable immunodeficiency disorders (CVID), mainly in the context of refractory autoimmune cytopenia and suspected lymphoma, but there are understandable concerns about the potential of compounding an existing immunodeficiency. With increasing use of rituximab as an alternative treatment for refractory autoimmune cytopenia, the role of splenectomy in CVID needs to be re-examined. This retrospective study provides the largest cohesive data set to date describing the outcome of splenectomy in 45 CVID patients in the past 40 years. Splenectomy proved to be an effective long-term treatment in 75% of CVID patients with autoimmune cytopenia, even in some cases when rituximab had failed. Splenectomy does not worsen mortality in CVID and adequate immunoglobulin replacement therapy appears to play a protective role in overwhelming post-splenectomy infections. Future trials comparing the effectiveness and safety of rituximab and splenectomy are needed to provide clearer guidance on the second-line management of autoimmune cytopenia in CVID.


Alternatively spliced ltk mRNA in neurons predicts a receptor with a larger putative extracellular domain.
Ltk is a new member of the ros/insulin receptor family of tyrosine kinases that is expressed in murine B-lymphocyte precursors and forebrain neurons. We previously reported that lymphoid ltk cDNAs predict a 69 kDa transmembrane glycoprotein, which uses a CUG translational start codon and has a 110 amino acid putative extracellular domain. We now show that the predominant ltk mRNA in brain is alternatively spliced and predicts a protein with a substantially larger extracellular part. The human ltk gene maps to chromosome 15, bands q13-21, a region containing the breakpoint of a recurring chromosomal abnormality in B-cell non-Hodgkin lymphomas.


Hydroxysafflor Yellow A mitigated myocardial ischemia/reperfusion injury by inhibiting the activation of the JAK2/STAT1 pathway.
Hydroxysafflor Yellow A (HSYA) may reduce ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms remain unclear. The present study explored the effect and the mechanisms of HSYA on myocardial injury in vivo and in vitro. Myocardial infarct size was assessed by Evans blue/2,3,5‑triphenyltetrazoliumchloride staining. Levels of cardiac troponin I (cTnI), interleukin‑6 (IL‑6), lactate dehydrogenase (LDH), superoxide dismutase (SOD) and malondialdehyde (MDA) were measured using commercial kits. Alteration of mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) generation was determined by fluorescent signals. Apoptosis was detected by terminal deoxynucleotidyl‑transferase‑mediated dUTP nick‑end labeling staining, flow cytometry assay and caspase‑3 activity. Expression levels of the apoptosis‑associated proteins were detected by reverse transcription quantitative polymerase chain reaction and western blot analysis. In vivo, animals treated with HSYA presented less severe myocardial injury and decreased janus kinase 2 (JAK2)/signal transducer and activator of transcription 1 (STAT1) activity, improved antioxidant capacity and decreased apoptosis. In vitro, compared with the hypoxia (H)/reoxygenation (R) + HSYA group, AG490 and S1491 treatment decreased the releases of cTnI, IL‑6 and LDH and enhanced the resistance to oxidative stress by maintaining MMP and decreasing ROS generation. In addition, AG490 and S1491 were also identified to alleviate the H/R‑induced apoptosis by inhibiting caspase 3 activity and modulating the expression levels of cleaved caspase‑3, tumor necrosis factor receptor superfamily member 6 (Fas), Fas ligand, B‑cell lymphoma 2 (Bcl‑2) and Bcl‑2‑associated X protein. These data suggested that inactivation of the JAK2/STAT1 pathway strengthened the HSYA‑induced protective effect in H/R‑induced myocardial injury. In conclusion, the treatment of HSYA was effective in decreasing IR‑induced myocardial injury, and this may be largely dependent on the JAK2/STAT1 pathway. Therefore, the present study provided a potential strategy to prevent myocardial I/R injury.


Treatment of multiple sclerosis with the monoclonal anti-CD4 antibody cM-T412: results of a randomized, double-blind, placebo-controlled, MR-monitored phase II trial.
We report the results of a randomized, double-blind, placebo-controlled exploratory trial of the chimeric monoclonal anti-CD4 antibody cM-T412 in 71 patients suffering from active relapsing-remitting and secondary progressive multiple sclerosis. Infusion of the antibody produced frequent but usually minor side effects and resulted in a long-lasting reduction of circulating CD4-positive T cells. There was no significant effect on the primary measure of efficacy, the number of active lesions on monthly gadolinium-enhanced MRI over 9 months. Further statistical evaluation provided evidence that the degree of depletion of CD4-positive cells was important with regard to treatment efficacy; using CD4 counts as a covariate there was a statistically significant effect on the number of active lesions over 18 months (p = 0.04). There was a statistically significant reduction of 41% in the number of clinical relapses (a secondary efficacy parameter) after 9 months (p = 0.02), which was still present after 18 months, but this finding may be partly due to physician unblinding. Other secondary efficacy parameters (Expanded Disability Status Scale progression, number of courses of methylprednisolone) were not influenced by anti-CD4 treatment. We conclude that intravenous treatment with the monoclonal antibody cM-T412 in the dosage we used results in a substantial and sustained reduction of the number of circulating CD4-positive cells, but is not able to reduce MS activity as measured by monthly gadolinium-enhanced MRI, and is therefore unlikely to have a beneficial effect on the clinical disease course. We found preliminary evidence suggesting that more aggressive depletion of CD4-positive cells might lead to a more substantial reduction in MRI activity.


cDNA cloning confirms the polyadenylation of RNA decay intermediates in Streptomyces coelicolor.
In Escherichia coli the poly(A) tails of messenger and rRNAs are a major determinant of RNA stability. These tails are formed primarily by poly(A) polymerase I (PAP I) in wild-type strains or by polynucleotide phosphorylase (PNPase) in PAP I-deficient strains. In Streptomyces coelicolor it has been shown that mycelial RNAs display biochemical characteristics consistent with the presence of poly(A) tails. To confirm the occurrence of polyadenylation, rRNA and mRNA transcripts from S. coelicolor were isolated by oligo(dT)-dependent RT-PCR followed by cDNA cloning. One of the clones obtained was polyadenylated at a site corresponding to the mature 3' terminus of 16S rRNA, while two 23S rRNA cDNA clones were polyadenylated at precursor processing sites. Other clones identified polyadenylation sites internal to the coding regions of both 16S and 23S rRNAs, and redD and actII-orf4 mRNAs. While most rRNA cDNA clones displayed adenosine homopolymer tails, the poly(A) tails of three rRNAs and all the redD and actII-orf4 clones consisted of a variety of heteropolymers. These results suggest that the enzyme primarily responsible for polyadenylation in S. coelicolor is PNPase rather than a PAP I homologue.


RNA and RNA-protein complexes as targets for therapeutic intervention.
Today, the majority of pharmaceuticals developed to treat cancers and viral/bacterial infections target cellular, bacterial or viral proteins known to be associated with a given pathology. Although proteins are the focus of most current drug discovery efforts, exciting new research has recently begun which aims to exploit ribonucleic acid (RNA) and RNP particles as novel targets for pharmaceutical development. These RNA-targeted research efforts have been fueled by an increased appreciation for the central role played by RNA and RNA-protein interactions in many biological processes and diseases, together with a better understanding of RNA structure and an improvement in biophysical/biochemical techniques available to study RNA. As for protein targets, genome sequencing is greatly accelerating the identification of human and microbial RNA transcripts for targeted drug discovery. With this explosion in the number of potential RNA and RNP targets, the effective development of specific small molecule RNA-based drugs requires robust and general approaches for detecting and quantifying RNA-ligand interactions, which can be used as high-throughput screens (HTS) and for obtaining rapid structural information to guide rational drug design. In this review, an overview of the potential for therapeutic intervention based on RNA and RNP targets is presented, together with recent efforts to develop generally useful nuclear magnetic resonance (NMR) and fluorescence binding assays for screening and optimizing drugs aimed at RNA and RNP targets.


Dabigatran is effective with a favourable safety profile in normal and overweight patients undergoing major orthopaedic surgery: a pooled analysis.
Three pivotal phase 3 trials have demonstrated that oral dabigatran etexilate showed similar safety and efficacy to enoxaparin 40 mg once daily (qd) for venous thromboembolism (VTE) prevention in patients undergoing total knee or hip replacement. Obesity is an established independent risk factor for VTE. A post-hoc pooled analysis of the three trials was performed to evaluate the safety and efficacy of dabigatran 220 mg qd versus enoxaparin 40 mg qd in patients with a normal body mass index (BMI) of >20-25 kg/m(2), pre-obese patients (BMI >25-30 kg/m(2)) and obese patients (BMI >30 kg/m(2)). The primary efficacy endpoint was major VTE and VTE-related mortality; safety endpoints included major, clinically relevant, or any bleeding events. The mean BMIs for patients in the dabigatran and enoxaparin arms from all three trials, separately, were between 27.5 and 29.9 kg/m(2). Of the participants, 1417 (24.9%) had a normal BMI, 2373 (41.7%) were pre-obese and 1826 (32.1%) obese. In patients with normal BMI, the rates of the primary efficacy endpoint were significantly lower in the dabigatran than in the enoxaparin group (2.1% versus 4.3%; OR 0.48; 95% CI 0.24-0.97, P=0.037). No significant difference between dabigatran and enoxaparin in the primary efficacy endpoint was observed in the other subgroups. Bleeding rates were also similar between treatments for BMI subgroups. Dabigatran is an effective thromboprophylactic therapy for normal, pre-obese and obese patients, and outcomes in patients with a BMI >25 kg/m(2) do not differ from the overall population.


Comparison of Aerobic Preservation by Venous Systemic Oxygen Persufflation or Oxygenated Machine Perfusion of Warm-Ischemia-Damaged Porcine Kidneys.
The global shortage of donor organs for transplantation has necessitated the expansion of the organ pool through increased use of organs from less ideal donors. Venous systemic oxygen persufflation (VSOP) and oxygenated machine perfusion (OMP) have previously demonstrated beneficial results compared to cold storage (CS) in the preservation of warm-ischemia-damaged kidney grafts. The aim of this study was to compare the efficacy of VSOP and OMP for the preservation of warm-ischemia-damaged porcine kidneys using the recently introduced Ecosol preservation solution compared to CS using Ecosol or histidine-tryptophan-ketoglutarate solution (HTK). Kidneys from German Landrace pigs (n = 5/group) were retrieved and washed out with either Ecosol or HTK after 45 min of clamping of the renal pedicle. As controls, kidneys without warm ischemia, cold stored for 24 h in HTK, were employed. Following 24 h of preservation by VSOP, OMP, CS-Ecosol, or CS-HTK, renal function and damage were assessed during 1 h using the isolated perfused porcine kidney model. During reperfusion, urine production was significantly higher in the VSOP and OMP groups than in the CS-HTK group; however, only VSOP could demonstrate lower urine protein concentrations and fractional excretion of sodium, which did not differ from the non-warm-ischemia-damaged control group. VSOP, CS-Ecosol, and controls showed better maintenance of the acid-base balance than CS-HTK. Reduced lipid peroxidation, as reflected in postreperfusion tissue thiobarbituric acid-reactive substance levels, was observed in the VSOP group compared to the OMP group, and the VSOP and CS-Ecosol groups had concentrations similar to the controls. The ratio of reduced to oxidized glutathione was higher in the VSOP, OMP, and CS-Ecosol groups than in the CS-HTK group and controls, with a higher ratio in the VSOP than in the OMP group. VSOP was associated with mitigation of oxidative stress in comparison to OMP and CS. Preservation of warm-ischemia-damaged porcine kidneys by VSOP was improved compared to OMP and CS, and was comparable to preservation of non-warm-ischemia-damaged cold-stored kidneys.


Spline regression hashing for fast image search.
Techniques for fast image retrieval over large databases have attracted considerable attention due to the rapid growth of web images. One promising way to accelerate image search is to use hashing technologies, which represent images by compact binary codewords. In this way, the similarity between images can be efficiently measured in terms of the Hamming distance between their corresponding binary codes. Although plenty of methods on generating hash codes have been proposed in recent years, there are still two key points that needed to be improved: 1) how to precisely preserve the similarity structure of the original data and 2) how to obtain the hash codes of the previously unseen data. In this paper, we propose our spline regression hashing method, in which both the local and global data similarity structures are exploited. To better capture the local manifold structure, we introduce splines developed in Sobolev space to find the local data mapping function. Furthermore, our framework simultaneously learns the hash codes of the training data and the hash function for the unseen data, which solves the out-of-sample problem. Extensive experiments conducted on real image datasets consisting of over one million images show that our proposed method outperforms the state-of-the-art techniques.


Modulatory effects of low- and high-frequency repetitive transcranial magnetic stimulation on visual cortex of healthy subjects undergoing light deprivation.
The aim of the present study was to explore further the effects of light deprivation (LD) on visual cortex excitability. Healthy subjects reporting reliable induction of phosphenes by occipital transcranial magnetic stimulation (TMS) underwent 60 min of complete LD. Phosphene threshold (PT) was measured before (T0), after 45 min (T1) and 60 min (T2) of LD, and then every 10 min after light re-exposure until recovery to T0 values. Repetitive TMS (rTMS) (at 1 or 10 Hz) was applied in separate sessions during the last 15 min of LD. PTs significantly decreased after 45 min of LD. rTMS differentially modified the effects of 60 min LD on PTs depending on stimulation frequency. One hertz rTMS did not change the decreasing of PT values as observed in baseline condition, but significantly prolonged the time to recover T0 PT values after light re-exposure. By contrast, 10 Hz rTMS significantly increased PT and the time to recover T0 PT values after light re-exposure was shortened. The results of this study show that the modulatory effects of different rTMS frequencies on visual cortex critically depend on the pre-existing excitability state of inhibitory and facilitatory circuits, and provide novel insights into the neurophysiological changes that take place in the visual cortex following functional visual deafferentation.


Absence of detectable serum interferon in acute and chronic viral hepatitis.
Amounts of interferon were measured in sera from 59 patients with acute viral hepatitis and 49 patients with chronic hepatitis B and compared to those from patients with nonviral liver disease or influenza, and from healthy controls. In all patients with acute and chronic viral hepatitis, no serum interferon could be detected, confirming data from earlier studies of acute viral hepatitis in which no circulating interferon was found. Our results disprove the view that the amounts of serum interferon, detected at the time of the acute clinical illness, may be a determinant of outcome.


How Do We Allocate Our Resources When Listening and Memorizing Speech in Noise? A Pupillometry Study.
Actively following a conversation can be demanding and limited cognitive resources must be allocated to the processing of speech, retaining and encoding the perceived content, and preparing an answer. The aim of the present study was to disentangle the allocation of effort into the effort required for listening (listening effort) and the effort required for retention (memory effort) by means of pupil dilation. Twenty-five normal-hearing German speaking participants underwent a sentence final word identification and recall test, while pupillometry was conducted. The participants' task was to listen to a sentence in four-talker babble background noise and to repeat the final word afterward. At the end of a list of sentences, they were asked to recall as many of the final words as possible. Pupil dilation was recorded during different list lengths (three sentences versus six sentences) and varying memory load (recall versus no recall). Additionally, the effect of a noise reduction algorithm on performance, listening effort, and memory effort was evaluated. We analyzed pupil dilation both before each sentence (sentence baseline) as well as the dilation in response to each sentence relative to the sentence baseline (sentence dilation). The pupillometry data indicated a steeper increase of sentence baseline under recall compared to no recall, suggesting higher memory effort due to memory processing. This increase in sentence baseline was most prominent toward the end of the longer lists, that is, during the second half of six sentences. Without a recall task, sentence baseline declined over the course of the list. Noise reduction appeared to have a significant influence on effort allocation for listening, which was reflected in generally decreased sentence dilation. Our results showed that recording pupil dilation in a speech identification and recall task provides valuable insights beyond behavioral performance. It is a suitable tool to disentangle the allocation of effort to listening versus memorizing speech.


Comparative modeling of 25-hydroxycholesterol-7α-hydroxylase (CYP7B1): ligand binding and analysis of hereditary spastic paraplegia type 5 CYP7B1 mutations.
CYP7B1 mutations have been linked directly with the neurodegenerative disease hereditary spastic paraplegia (HSP), with mutations in the CYP7B1 gene identified as being directly responsible for autosomal recessive HSP type 5A (SPG5). To evaluate the potential impact of CYP7B1 mutations identified in SPG5 on binding and protein function, a comparative model of cytochrome P450 7B1 (CYP7B1) was constructed using human CYP7A1 as a template during model construction. The secondary structure was predicted using the PSIPRED and GOR4 prediction methods, the lowest energy CYP7B1 model was generated using MOE, and then this model was assessed in terms of stereochemical quality and the side chain environment using RAMPAGE, Verify3D and ProSA. Evaluation of the active site residues of the CYP7B1 model and validation of the active site architecture were performed via molecular docking experiments: the docking of the substrates 25-hydroxycholesterol and 27-hydroxycholesterol and the inhibitor 3α-Adiol identified structurally and functionally important residues. Mutational analysis of CYP7B1 amino acid mutations related to hereditary spastic paraplegia type 5 considered phosphorylation, ligand/substrate binding and the structural roles of mutated amino acid residues, with R112, T297 and S363 mutations expected to have a direct impact on ligand binding, while mutations involving R417 would indirectly affect ligand binding as a result of impairment in catalytic function.


Patterns of Surgically Treated Thyroid Disease: A Two Years Review at St. Paul Hospital Millennium medical Collage, Addis Ababa, Ethiopia.
Thyroid disease is a common disorder of the endocrine system worldwide. It is a common problem in developing countries, including Ethiopia. The aim of this study was to determine the burden and the pattern of thyroid disease in St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. A retrospective review of patients' medical records over a two-year period, January 2013-december 2014, was done. OR log books, and individual patient medical records was used for the review. Data was analyzed with SPSS version 20. A total of 2201 general surgical operations were done in a two-year period. Of these, 250(11%) were for thyroid surgery. Records of 222(88.8%) patients were found and used for analysis. Females accounted for 91.4% with F: M ratio of 10.7:1. The common mode of presentations were anterior neck swelling (91.4%) and toxic (29.7%) and pressure symptoms(19.4%). The common physical findings identified were multi nodular goiter (57.2%), diffuse goiter (23.9%) and solitary nodule (5.8%). FNAC showed that Nodular colloid goiter was common diagnosis (68.5%). Neoplasms accounted for 15.9% of the diagnosis; of this follicular neoplasm make (54%) and papillary cancer (20%). Functionally, hyperthyroid goiter 28.8% and euthyroid goiters (64 %). Transient hypocalcaemia (3.2%) and hoarseness of voice (1.8%) were the commonest complications. There was no postoperative mortality. Hyperthyroidism and neoplasms make significant proportions of the patients. Follicular neoplasm is the commonest tumor. Morbidity and mortality rates are comparable to the literature.


The farm level economic and environmental contribution of Intacta soybeans in South America: the first five years.
This study assesses the economic and environmental impacts that have arisen from the adoption and use of genetically modified (GM) herbicide tolerant (HT) and insect resistant (IR) soybeans in South America in the five years since first planted in 2013/14. A total of 73.6 million hectares have been planted to soybeans containing these traits since 2013/14, with farmers benefiting from an increase in income of $7.64 billion. For every extra $1 spent on this seed relative to conventional seed, farmers have gained an additional $3.88 in extra income. These income gains have arisen from a combination of higher yields (+ 9.2% across the four countries using the technology) and lower costs of weed and pest control. The seed technology has reduced pesticide spraying by 10.44 million kg (-15.1%) and, as a result, decreased the environmental impact associated with herbicide and insecticide use on these crops (as measured by the indicator, the Environmental Impact Quotient (EIQ)) by 30.6%. The technology has also facilitated important cuts in fuel use and tillage changes, resulting in a significant reduction in the release of greenhouse gas emissions from the GM cropping area. In 2017/18, this was equivalent to removing 3.3 million cars from the roads.


Characterization of cytokine mRNA transcripts in conjunctival cells in patients with allergic conjunctivitis.
The host response to allergens appears to be regulated by specific patterns of local cytokine production. More than 20,000 conjunctival superficial cells were collected with a special brush, a smaller version of the Cytobrush used in cervical cytology, from the upper palpebral conjuntiva. Samples were obtained by cytology brush from seven patients with allergic conjunctivitis and from seven healthy volunteers. Giemsa staining, immunocytochemistry, and flow cytometric analysis were performed. Cytokine gene expression was assayed by the reverse-transcription-polymerase chain reaction method. Giemsa staining of cytocentrifuged preparations from patients with allergic conjunctivitis showed conjunctival epithelial cells with lymphocytes, mast cells, and eosinophils. In an immunohistochemical study, a few CD3- and CD4-bearing cells, but not CD20- and CD14-bearing cells, were seen in patients. In 82.6 +/- 17% of the samples obtained from allergic patients, HLA-DR was present, but it was present in only 34.2 +/- 17.8% of samples from control subjects (P = 0.0001) using flow cytometric analysis. Steady state transcripts of mRNA for cytokines were analyzed with RT-PCR in conjunctival cell samples, and results showed that samples from allergic conjunctivitis expressed increased transcripts of interleukin 4 and interleukin 13 but virtually no interleukin 2 or interferon-gamma; six samples from seven healthy subjects expressed no interleukin 2, interleukin 4, interleukin 13, or interferon-gamma transcripts. These results suggest that the clinical features of allergic conjunctivitis in humans are associated with a specific local pattern of proinflammatory cytokine expression.


Medial conchal excision in otoplasty.
The most common cartilaginous deformities in protruding ears include an inadequate antihelical fold and an enlarged concha. We have employed medial conchal excision to correct deep conchas in 25 patients, all of whom were pleased with the postoperative result. Obvious wrinkling of the anterior skin occurred in four patients, and several patients displayed slight distortion of the helical crus. Medial conchal excision does not impede management of the antihelical fold with mattress sutures or by other means. We consider the risk of minor alterations of the concha justified if even slight distortion of the more conspicuous lateral auricle can be avoided.


WHO Surgical Safety Checklist and Anesthesia Equipment Checklist efficacy in war-affected low-resource settings: a prospective two-arm multicenter study.
The Russian invasion of Ukraine has caused huge damage to all medical infrastructure and impairs patient safety. The aim of our study was to assess the impact of implementation of the WHO Surgical Safety Checklist and Anesthesia Equipment Checklist on patient outcomes and adherence to safety standards in low-resource settings, affected by an ongoing war. A prospective multicenter study was conducted in 6 large Ukrainian hospitals. The study was conducted in two phases: a control period, lasting five months, followed by a study period, when the two checklists (the WHO Surgical Safety Checklist and Anesthetic Equipment Checklist) were introduced in the designated operating rooms. The primary outcomes were any major complications, including death, during 30 days after surgery. A total of 2237 surgical procedures were recorded - 1178 in the control group and 1059 in the intervention group. Major postoperative complications occurred in 82 (6.9%) patients in the control group and in 25 (2.4%) in the study group (OR = 0.32 [0.19-0.52], P < 0.001). The effect on the incidence of specific postoperative complications was statistically significant for the "surgical infection" (1.5% vs. 0.1%; OR = 0.31 [0.1-0.8], P = 0.01) and "reoperation" (1.7% vs. 0.5%; OR = 0.32 [0.1-0.8], P = 0.01) cate-gories as well as for the 30-day mortality (1.3% vs. 0.3%; OR = 0.35 [0.1-0.9], P = 0.03). Better adherence to basic WHO surgical safety recommendations was observed for every check mentioned in the WHO Surgical Safety Checklist ( P < 0.05). The WHO Surgical Safety Checklist and the Anesthesia Equipment Checklist improve patient outcomes in war-affected low-resource settings.


Somatomedins/insulin-like growth factors, their receptors and binding proteins are present during mouse embryogenesis.
Somatomedins/insulin-like growth factors (Sm/IGFs) are considered to have important roles in regulating fetal growth; however, because of limited quantities of tissue, few studies have been performed on their effects on embryonic growth. To assess a potential role for these factors, we evaluated mouse embryonic tissues for the presence of Sm/IGF and insulin receptors and Sm/IGF-binding proteins by chemical affinity labelling. In addition, we measured extractable Sm-C/IGF-I radioimmunoactivity in mouse embryonic tissues. Finally, we compared these data with those from the embryonal carcinoma cell line, PC13. All embryos from day 9 (3-4 somites) to day 12 (45 somites) possessed both Sm-C/IGF-I and IGF-II receptors in apparent greater abundance than insulin receptors. The visceral yolk sac appeared to have proportionally more insulin receptors than the corresponding embryonic tissue. Extracts from the embryos contained immunoreactive Sm-C/IGF-I and binding proteins of 30-45 X 10(3) Mr. PC13 cells possessed all three receptors and the apparent abundance of the insulin and IGF-II receptors was reduced after differentiation was induced with retinoic acid. PC13 cells released both immunoreactive Sm-C/IGF-I- and Sm-C/IGF-I-binding proteins into their medium. When differentiated, the binding proteins resembled the native ones extracted from the intact embryos. The presence of Sm/IGF activity, receptors and binding proteins in early embryogenesis suggests a role for these factors in embryonic growth. The PC13 cell line appears to only partially reflect normal development.


Military participants at U.S. Atmospheric nuclear weapons testing--methodology for estimating dose and uncertainty.
Methods were developed to calculate individual estimates of exposure and dose with associated uncertainties for a sub-cohort (1,857) of 115,329 military veterans who participated in at least one of seven series of atmospheric nuclear weapons tests or the TRINITY shot carried out by the United States. The tests were conducted at the Pacific Proving Grounds and the Nevada Test Site. Dose estimates to specific organs will be used in an epidemiological study to investigate leukemia and male breast cancer. Previous doses had been estimated for the purpose of compensation and were generally high-sided to favor the veteran's claim for compensation in accordance with public law. Recent efforts by the U.S. Department of Defense (DOD) to digitize the historical records supporting the veterans' compensation assessments make it possible to calculate doses and associated uncertainties. Our approach builds upon available film badge dosimetry and other measurement data recorded at the time of the tests and incorporates detailed scenarios of exposure for each veteran based on personal, unit, and other available historical records. Film badge results were available for approximately 25% of the individuals, and these results assisted greatly in reconstructing doses to unbadged persons and in developing distributions of dose among military units. This article presents the methodology developed to estimate doses for selected cancer cases and a 1% random sample of the total cohort of veterans under study.


Fetal organ growth in response to oesophageal infusion of amniotic fluid, colostrum, milk or gastrin-releasing peptide: a study in fetal sheep.
The hypothesis of the present study was that the infusion of the biological fluids to which the developing gut is normally exposed (i.e. amniotic fluid, colostrum, milk) and a single growth factor (gastrin-releasing peptide), which is found in high concentrations in fetal fluids and milk, could ameliorate the altered growth induced by the elimination of swallowed input secondary to ligation of the oesophagus. At 108-110 days of gestation the fetal oesophagus was ligated and a catheter inserted towards the stomach (32 fetuses). At 117-119 days of gestation saline (n = 5), amniotic fluid (n = 5), colostral whey (n = 5), milk whey (n = 5) or gastrin-releasing peptide (3.6 nmol day(-1), n = 6), was infused for 7 days (4 x 20 mL day(-1)), or no infusion was given (ligated group, n = 6). A further 15 fetuses were not ligated (normal group, n = 15). All fetuses had carotid artery and/or jugular vein catheters implanted. At 124-126 days of gestation the fetus was delivered and fetal body and organ weights recorded. Analysing the results by ANOVA, there were no effects of either ligation alone or infusion after ligation on fetal weight, crown-rump length, or weight relative to bodyweight of heart, adrenal, pancreas, large intestine and cecum. There were significant differences between the infusion groups for lungs, kidney, pancreas, total gut, abomasum, small intestine, spleen, chest and neck thymus, and mesenteric lymph nodes. Ligation alone significantly reduced small intestinal growth and increased kidney and spleen growth. Colostrum infusion enhanced growth of most organs. Gastrin-releasing peptide significantly increased growth of all the immune organs studied. It was concluded that at an age when premature delivery could be encountered, the fetal gut is capable of significant adaptive growth, to varying degrees, depending on the enteral diet. Growth effects in organs distant to the gut suggest that either gastrointestinal uptake and transport of growth factors or altered nutrient uptake and/or availability can affect the growth of other major fetal organs.


Clinical benign disorders of the breast and carcinoma of the breast.
Among 2,506 women with breast disorders seen in consecutive consultations, 345 had carcinoma. Clinical benign breast disorders occurred 6.3 times as frequently as carcinoma of the breast. The lifetime risk of clinical benign breast disorder was calculated to be more than 50 per cent. Clinical benign breast disorders occurred chiefly in young women and carcinoma occurred chiefly in older women. Thus, clinical benign breast disorders precede carcinoma because of the age at which the disorders occur. The incidence of a previous benign biopsy in women with carcinoma was 10.4 per cent and was estimated to be at least 8.2 per cent in the general population. Only a small number of women with carcinoma had previous benign biopsy. The likelihood of finding carcinoma in those women with a previous benign biopsy was 9.2 per cent and in those without 14.6 per cent. Thirty-one of the 36 patients with carcinoma of the breast with a previous benign biopsy were more than 50 years old and 18 were more than 60 years old. It is concluded that women with clinical benign breast disorders do not have an increased risk of having carcinoma of the breast develop.


Respiratory Pathogens in Infants Diagnosed with Acute Lower Respiratory Tract Infection in a Tertiary Care Hospital of Western India Using Multiplex Real Time PCR.
To determine the frequency of respiratory pathogens in infants diagnosed with acute lower respiratory tract infections. A prospective cross-sectional observational study was conducted in infants hospitalized with a diagnosis of acute lower respiratory tract infection (ALRTI), in a tertiary care hospital in a metropolitan city of Western India. Nasopharyngeal swabs were analyzed by multiplex real time polymerase chain reaction, for 18 viruses and 3 bacteria (H. influenzae type b, C. pneumoniae and M. pneumoniae). The entire data was entered in Microsoft excel sheet and frequencies were determined. One hundred eligible infants were enrolled. Pathogens were detected in 82 samples, which included Respiratory syncytial viruses (RSV) A / B (35.4%), Human rhinovirus (25.6%), Adenovirus (22%), Human Parainfluenza viruses (11%), Human bocavirus (9.8), Human metapneumovirus A / B (8.5%), Influenza A (H1N1) pdm 09 (6.1%), Parechovirus (3.7%), Human coronaviruses (3.66%), Haemophilus influenzae type b (6.1%), Chlamydia pneumoniae (2.4%) and Mycoplasma pneumoniae (2.4%). Influenza A (other than H1N1), Influenza B, Human Coronavirus 229E and Enterovirus were not detected. The rate of coinfection was 34% and rhinovirus was the most common of the multiple pathogens. Spectrum of viral etiologies of ALRTI is highlighted. Etiological diagnosis of ALRTI would enable specific antiviral therapy, restrict antibiotic use and help in knowing burden of disease.


Recurrence patterns of locally advanced head and neck squamous cell carcinoma after 3D conformal (chemo)-radiotherapy.
To establish recurrence patterns among locally advanced head and neck non-nasopharyngeal squamous cell carcinoma (HNSCC) patients treated with radical (chemo-) radiotherapy and to correlate the sites of loco-regional recurrence with radiotherapy doses and target volumes 151 locally advanced HNSCC patients were treated between 2004-2005 using radical three-dimensional conformal radiotherapy. Patients with prior surgery to the primary tumour site were excluded. The sites of locoregional relapses were correlated with radiotherapy plans by the radiologist and a planning dosimetrist. Median age was 59 years (range:34-89). 35 patients had stage III disease, 116 patients had stage IV A/B. 36 patients were treated with radiotherapy alone, 42 with induction chemotherapy, 63 with induction and concomitant chemoradiotherapy and 10 concomitant chemoradiotherapy. Median follow-up was 38 months (range 3-62). 3-year cause specific survival was 66.8%. 125 of 151 (82.8%) achieved a complete response to treatment. Amongst these 125 there were 20 local-regional recurrence, comprising 8 local, 5 regional and 7 simultaneous local and regional; synchronous distant metastases occurred in 7 of the 20. 9 patients developed distant metastases in the absence of locoregional failure. For the 14 local recurrences with planning data available, 12 were in-field, 1 was marginal, and 1 was out-of-field. Of the 11 regional failures with planning data available, 7 were in-field, 1 was marginal and 3 were out-of-field recurrences. The majority of failures following non-surgical treatment for locally advanced HNSCC were loco-regional, within the radiotherapy target volume. Improving locoregional control remains a high priority.


Evaluating PVALB as a candidate gene for SLC12A3-negative cases of Gitelman's syndrome.
Loss-of-function mutations in SLC12A3 coding for the thiazide-sensitive NaCl cotransporter (NCC) cause Gitelman's syndrome (GS), a recessively inherited salt-losing tubulopathy. Most GS patients are compound heterozygous. However, up to 30% of GS patients carry only a single mutant allele, and a normal SLC12A3 screening is also observed in a small subset of patients. Locus heterogeneity could explain the lack of detection of mutant SLC12A3 alleles in GS patients. The renal phenotype of the parvalbumin knockout mice pointed to PVALB as a candidate gene for GS for SLC12A3-negative cases. PCR and direct sequencing of PVALB was performed in 132 GS patients in whom only one or no (N = 79) mutant SLC12A3 allele was found. The possible interference of biallelic SNPs (single nucleotide polymorphisms) on normal transcription or normal splicing was investigated. Genotyping of 110 anonymous blood donors was performed to determine the allelic frequency in the normal population. No sequence variants resulting in amino acid substitution or truncated protein within the PVALB gene were found in the 264 chromosomes tested. Ten biallelic SNPs, including six novel polymorphisms, were identified: five in the 5' UTR, none of them affecting predicted regulatory elements; three in the coding region, without alteration of the consensus splice sites, and two in the 3' UTR. The observed allelic frequencies did not differ significantly between GS patients and controls. Our results strongly suggest that mutations in the PVALB gene are not involved in GS patients who harbour a single or no mutant SLC12A3 allele.


Revisit of the Ramp Filter.
An important part of the filtered backprojection (FBP) algorithm is the ramp filter. This paper derives the discrete version of the ramp filter in the Fourier domain and studies the windowing effects. When a window function is used to control the noise, the image amplitude will be affected and reduced. A simple remedy is proposed to improve the image accuracy when a window function must be used.


The status of Nrf2-based therapeutics: current perspectives and future prospects.
This mini-review presents the authors' vision on the current status and future trends in the development of neuroprotective agents working via activation of nuclear factor erythroid 2-related factor 2 (Nrf2), and in particular, via disruption of Nrf2-Keap1 interaction. There are two opposite "chemical" mechanisms underlying such activation: the first one is a non-specific covalent modification of Keap1 thiols, resulting in side effects of varied severity, and the second one is the shift of the Nrf2-Kelch-like ECH associated protein-1 (Keap1) binding equilibrium in the presence of a competitive and chemically benign displacement agent. At this point, no displacement activators exhibit sufficient biological activity in comparison with common Nrf2 activators working via Keap1 thiol modification. Hence, the hope in therapeutics is now linked to the FDA approved dimethylfumarate, whose derivative, monomethylfumarate, as we demonstrated recently, is much less toxic but equally biologically potent and an ideal candidate for clinical trials right now. A newly emerging player is a nuclear inhibitor of Nrf2, BTB domain and CNC homolog 1 (Bach1). The commercially developed Bach1 inhibitors are currently under investigation in our laboratory showing promising results. In our viewpoint, the perfect future drug will present the combination of a displacement activator and Bach1 inhibitor to insure safety and efficiency of Nrf2 activation.


Relationship between preferred orientation and ordinal position in neurones of cat striate cortex.
Striate cortical cells were classified according to whether or not their preferred orientation was close to one of the "primary" orientations (horizontal, vertical or radial, i.e. directed to the area centralis) and according to their ordinal position on the afferent pathway from the dorsal lateral geniculate nucleus (dLGN). Among the neurones that could be driven monosynaptically from the dLGN, there was a high representation of those with a preference for the primary orientations. This was particularly evident in the case of C (complex) cells. There was no such preponderance of primary orientations among the polysynaptically activated cells. It is proposed that the asymmetry of distribution seen among the first-order cells reflects the asymmetry seen subcortically in neurones that show orientation biases. It may be that the cortex elaborates a more uniform representation of orientations only at the higher ordinal levels.


Monitoring disease progression using high-density motor unit number estimation in amyotrophic lateral sclerosis.
In amyotrophic lateral sclerosis (ALS), progressive motor neuron loss causes severe weakness. Functional measurements tend to underestimate the underlying pathology because of collateral reinnervation. A more direct marker of lower motor neuron loss is of significant importance. We evaluated high-density motor unit number estimation (MUNE), as compared with the ALS Functional Rating Scale (ALSFRS) and maximal compound muscle action potential (CMAP) amplitude, for monitoring and classifying disease progression. MUNE showed good reproducibility (intraclass correlation coefficient = 0.86). MUNE showed a significantly greater decrease than the ALSFRS, the Medical Research Council (MRC) scale, and CMAP amplitude. Patients could be stratified into groups with rapidly or slowly progressive disease based on a decrement in MUNE at 4 months from baseline; ALSFRS score at 8 months was significantly lower in the rapidly progressive group. MUNE was sensitive to motor neuron loss early in the disease course when compared to other clinical measures. Stratification of patients based on a decrease in MUNE seems feasible.