Continuous intraoperative nerve monitoring in thyroidectomy using automatic periodic stimulation in 256 at-risk nerves.

INTRODUCTION: Automatic periodic stimulation of the vagal nerve during thyroidectomy provides real-time feedback of recurrent laryngeal nerve function intraoperatively. To assess the validity of this device, the ability of monitoring to predict recurrent laryngeal nerve palsy was determined and the incidence of recurrent laryngeal nerve palsy recorded. MATERIALS AND METHODS: All thyroidectomies using APS® (Automatic Periodic Stimulation, Medtronic) nerve monitoring were reviewed over a 27-month period. Changes in signal amplitude and latency during thyroidectomy were recorded from saved data. Postoperative fibreoptic laryngoscopy determined the incidence of vocal cord immobility and recovery of nerve function was assessed from follow-up letters. RESULTS: A total of 256 at-risk nerves were examined (132 hemi- and 62 total thyroidectomies) in cases involving benign and malignant disease. Permanent recurrent laryngeal nerve palsy occurred in six (2.3%) lobectomies and transient recurrent laryngeal nerve palsy occurred in two lobectomies (< 1%). Sensitivity for detecting postoperative vocal cord immobility was 100% and specificity 85% if the end amplitude was 50% below baseline. The positive predictive value when amplitude was 50% below baseline was 18%. The negative predictive value when amplitude was 50% above or equal to baseline was 100%. Intraoperatively, the amplitude was 50% below baseline more frequently in the vocal cord immobility group (t-test, P < 0.015). No vagal nerve complications occurred. CONCLUSION: Whilst the incidence of recurrent laryngeal nerve palsy is comparable to rates in the literature, the incidence of transient palsy is lower than published averages. APS is able to reliably predict recurrent laryngeal nerve palsy based on end amplitude.

Right colic artery anatomy: a systematic review of cadaveric studies.

BACKGROUND: Complete mesocolic excision for right-sided colon cancer may offer an oncologically superior excision compared to traditional right hemicolectomy through high vascular tie and adherence to embryonic planes during dissection, supported by preoperative scanning to accurately define the tumour lymphovascular supply and drainage. The authors support and recommend precision oncosurgery based on these principles, with an emphasis on the importance of understanding the vascular anatomy. However, the anatomical variability of the right colic artery (RCA) has resulted in significant discord in the literature regarding its precise arrangement. METHODS: We systematically reviewed the literature on the incidence of the different origins of the RCA in cadaveric studies. An electronic search was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations up to October 2016 using the MESH terms 'right colic artery' and 'anatomy' (PROSPERO registration number CRD42016041578). RESULTS: Ten studies involving 1073 cadavers were identified as suitable for analysis from 211 articles retrieved. The weighted mean incidence with which the right colic artery arose from other parent vessels was calculated at 36.8% for the superior mesenteric artery, 31.9% for the ileocolic artery, 27.7% for the root of the middle colic artery and 2.5% for the right branch of the middle colic artery. In 1.1% of individuals the RCA shared a trunk with the middle colic and ileocolic arteries. The weighted mean incidence of 2 RCAs was 7.0%, and in 8.9% of cadavers the RCA was absent. CONCLUSIONS: This anatomical information will add to the technical nuances of precision oncosurgery in right-sided colon resections.

The right colic artery: An anatomical demonstration and its relevance in the laparoscopic era.

INTRODUCTION Hemicolectomies are not tailored in right-sided colon cancer resections, despite significant variation in the incidence and origin of the right colic artery (RCA). Early evidence suggests that removal of the relevant lymphovascular package and associated cancer as part of complete mesocolic excision (CME), rather than the entire right colon, may produce better outcomes. Advancing laparoscopic techniques are making this possible, and so it is increasingly important to more precisely define the anatomy of the RCA. METHODS To demonstrate the incidence and variation of the RCA, 25 formalin embalmed cadavers were dissected. Consent to dissection and photography was obtained under Human Tissue Act regulations. RESULTS Eleven female and 14 male cadavers (mean age 79.7 years, range 41-95 years) were included. The RCA originated from the right branch of the middle colic artery in nine cadavers (36%), while it arose from the superior mesenteric artery in eight cases (32%) and from the ileocolic or root of the middle colic artery in a smaller number of specimens. The RCA was absent in two individuals. CONCLUSIONS The RCA arises from the right branch of the middle colic artery in a considerable number of cases. The literature to date does not reflect the precision of anatomical understanding required for CME; hence, a new definition for the right colic vessel is proposed.

Mine waste disposal leads to lower coral cover, reduced species richness and a predominance of simple coral growth forms on a fringing coral reef in Papua New Guinea.

A large gold mine has been operating at the Lihir Island Group, Papua New Guinea since 1997. The mine disposes of waste rock in nearshore waters, impacting nearby coral communities. During 2010, 2012 we conducted photographic surveys at 73 sites within 40 km of the mine to document impacts of mining operations on the hard coral communities. Coral communities close to the mine (∼2 km to the north and south of the mine) were depaurperate, but surprisingly, coral cover and community composition beyond this range appeared to be relatively similar, suggesting that the mine impacts were limited spatially. In particular, we found mining operations have resulted in a significant decrease in coral cover (4.4% 1.48 km from the disposal site c.f. 66.9% 10.36 km from the disposal site), decreased species richness and a predominance of less complex growth forms within ∼2 km to the north and south of the mine waste disposal site. In contrast to the two 'snapshot' surveys of corals performed in 2010 and 2012, long term data (1999-2012) based on visual estimates of coral cover suggested that impacts on coral communities may have been more extensive than this. With global pressures on the world's coral reefs increasing, it is vital that local, direct anthropogenic pressures are reduced, in order to help offset the impacts of climate change, disease and predation.

Overlapping BXSB congenic intervals, in combination with microarray gene expression, reveal novel lupus candidate genes.

The BXSB mouse strain is an important model of glomerulonephritis observed in systemic lupus erythematosus (SLE). Linkage studies have successfully identified disease-susceptibility intervals; however, extracting the identity of the susceptibility gene(s) in such regions is the crucial next step. Congenic mouse strains present a defined genetic resource that is highly amenable to microarray analysis. We have performed microarray analysis using a series of chromosome 1 BXSB congenic mice with partially overlapping disease-susceptibility intervals. Simultaneous comparison of the four congenic lines allowed the identification of expression differences associated with both the initiation and progression of disease. Thus, we have identified a number of novel SLE disease gene candidates and have confirmed the identity of Ifi202 as a disease candidate in the BXSB strain. Sequencing of the promoter regions of Gas5 has revealed polymorphisms in the BXSB strain, which may account for the differential expression profile. Furthermore, the combination of the microarray results with the different phenotypes of these mice has allowed the identification of a number of expression differences that do not necessarily map to the congenic interval, but may be implicated in disease pathways.

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene.

The activation-induced differentiation of naive CD4+ T cells generates functionally divergent type 1 helper T cells (Th1) or type 2 helper T cells (Th2) effector cell populations, characterized by secretion of Interferon (IFN)-gamma or Interleukin (IL)-4, respectively. Inappropriate generation of Th subsets may contribute to immune dysfunction. The decision to generate Th1/Th2 lineages is critically regulated by cytokines, such that IL-12 induces Th1 differentiation, while IL-4 induces Th2 differentiation. Genetic factors influence the pathway of Th differentiation, as displayed by the preferential generation of divergent Th populations by different inbred strains of mice. We employ two complementary genetic techniques to identify genes that regulate the default IL-4 secretion profiles of T cells from BALB/c and B6 mice. We performed a genome-wide linkage analysis of the progeny of a backcross between BALB/c and B6 mice to identify three loci, T-cell secretion of interleukin-4 (Tsi)1-3, on chromosomes 7, 19 and 15, respectively, which regulate in vitro T-cell IL-4 production. We have also employed mRNA representational difference analysis to isolate a gene, Flj20274, which is differentially expressed in T cells that secrete high levels of IL-4. Significantly, Flj20274 was mapped to the point of peak linkage within Tsi1 and is a strong candidate for Tsi1.

Cervical HPV infection and neoplasia in a large population-based prospective study: the Manchester cohort.

Cytology and histology records and cervical samples for HPV assay were obtained from a prospective cohort of 49 655 women attending clinics for routine cervical cytology in or near Manchester between 1988 and 1993. The women were followed up for cytological abnormality and neoplasia through the cytology laboratory's records. HPV at entry was assayed in an age- and period-stratified random sample of 7278 women and in prevalent and incident CIN3 cases. The prevalence of newly diagnosed CIN3 increased with time since last normal smear, indicating that most cases persist for several years. CIN3 prevalence did not increase further for screening intervals exceeding 5 years, however, suggesting that CIN3 eventually regresses cytologically. CIN2 prevalence increased less steeply with screening interval, while the prevalence of lesser abnormality was almost independent of screening interval. The prevalence of oncogenic HPV at entry declined from 19% among women aged under 25 to less than 3% at age 40 or above. Oncogenic HPV infection was strongly predictive of subsequent CIN3 (OR 17.2, 95% CI 10.4-28.4), but only weakly related to CIN2 (OR 2.3, 95% CI 0.5-10.7) and lesser abnormality (OR 1.4, 95% CI 0.8-2.5). At current incidence rates, the lifetime risk of developing CIN3 will be 9% in this population. The cumulative risk of CIN3 diagnosis among cytologically normal women with oncogenic HPV detected at entry was 28% (CI 18-43%) after 14 years. Persistence of oncogenic HPV may be more sensitive and specific than cytology for early detection of CIN3 and invasive cancer.

Autoantigen glycoprotein 70 expression is regulated by a single locus, which acts as a checkpoint for pathogenic anti-glycoprotein 70 autoantibody production and hence for the corresponding development of severe nephritis, in lupus-prone PXSB mice.

Retroviral envelope glycoprotein gp70 is present in the sera of immunologically normal and autoimmune-prone strains of mice. However, only lupus-prone mice spontaneously develop gp70-anti-gp70 immune complexes (gp70IC), and these have been implicated in the development of nephritis. We investigated the genetic factors that affect the production of both free serum gp70 and gp70IC in the lupus-prone BXSB mouse strain by analyzing (BXSB x (C57BL/10 x BXSB)F(1))- and (C57BL/10 x (C57BL/10 x BXSB)F(1))-backcrossed male mice. Production of gp70 mapped to a single major locus located on chromosome 13 (Bxs6) with a maximum log likelihood of the odds of 36.7 (p = 1.6 x 10(-38)). The level of gp70IC was highly dependent on Bxs6-related gp70 production, and high titer autoantibody production only occurred when serum gp70 levels were greater than a threshold value of approximately 4.0 microg/ml. The subdivision of the (BXSB x (C57BL/10 x BXSB)F(1))-backcrossed mice into those homozygous or heterozygous for Bxs6 enabled a remarkable association to be observed between high levels of gp70IC and severe nephritis in the Bxs6 homozygote population. A further mapping study in these two subgroups identified a previously unrecognized interval associated with the production of autoantibodies.

A novel transgenic model to characterize the specific effects of follicle-stimulating hormone on gonadal physiology in the absence of luteinizing hormone actions.

Gonadal function is wholly reliant on the two pituitary-derived gonadotropins, FSH and LH. Identifying the specific effects of FSH has been difficult because of the intimate relationship between LH and FSH action and inherent limitations of classic research paradigms. We describe a novel transgenic model to characterize the definitive actions of FSH alone, distinct from LH effects, created by combining transgenic FSH expression with the gonadotropin-deficient background of the hypogonadal (hpg) mouse. A tandem transgene construct encoding each alpha- and beta-subunit of human FSH, under the rat insulin II promoter, expressed biologically active heterodimers at serum levels, by immunoassay, equivalent to circulating FSH concentrations in fertile humans (0.1-25 IU/liter). Transgenic mice were crossed into the hpg mouse genotype to obtain LH-deficient animals secreting FSH alone. Testis weights of adult FSHxhpg mice were increased up to 5-fold, relative to nontransgenic hpg controls (P < 0.001). However, only transgenic males with serum FSH levels more than 1 IU/liter showed testis weights increased relative to hpg controls, indicating a physiological FSH threshold for the testicular response. Histology of enlarged FSHxhpg testes revealed round spermatids and sparse numbers of elongated spermatids, demonstrating that the testosterone-independent FSH response targeting the Sertoli cell can facilitate completion of meiosis and minimal initiation, but not completion, of spermiogenesis. Transgenic FSH also induced inhibin B secretion in FSHxhpg mice, but showed a distinct sexual dimorphism with only females exhibiting a strong FSH dose-dependent increase in serum inhibin B levels (r(2) = 0.84). In addition, ovaries of FSHxhpg females were enlarged up to 10-fold (P < 0.001), characterized by increased follicular recruitment and development to type 7 antral follicles. Thus, these findings show that the transgenic FSHxhpg mouse provides a unique model for detailed investigations of the definitive in vivo actions of FSH alone.

Neglect dyslexia with a stimulus-centred deficit and without visuospatial neglect.

This paper reports a single case of ipsilesional left neglect dyslexia and interprets it according to the three-level model of visual word recognition proposed by Caramazza and Hillis (1990). The three levels reflect a progression from the physical stimulus to an abstract representation of a word. RR was not impaired at the first, retinocentric, level, which represents the individual features of letters within a word according to the location of the word in the visual field: She made the same number of errors to words presented in her left visual field as in her right visual field. A deficit at this level should also mean the patient neglects all stimuli. This did not occur with RR: She did not neglect when naming the items in rows of objects and rows of geometric symbols. In addition, although she displayed significant neglect dyslexia when making visual matching judgements on pairs of words and nonwords, she did not do so to pairs of nonsense letter shapes, shapes which display the same level of visual complexity as letters in words. RR was not impaired at the third, graphemic, level, which represents the ordinal positions of letters within a word: She continued to neglect the leftmost (spatial) letter of words presented in mirror-reversed orientation and she did not neglect in oral spelling. By elimination, these results suggest RR's deficit affects a spatial reference frame where the representational space is bounded by the stimulus: A stimulus-centred level of representation. We define five characteristics of a stimulus-centred deficit, as manifest in RR. First, it is not the case that neglect dyslexia occurs because the remaining letters in a string attract or capture attention away from the leftmost letter(s). Second, the deficit is continuous across the letter string. Third, perceptually significant features, such as spaces, define potential words. Fourth, the whole, rather than part, of a letter is neglected. Fifth, category information is preserved. It is concluded that the Caramazza-Hillis model accounts well for RR's data, although we conclude that neglect dyslexia can be present when a more general visuospatial neglect is absent.

Diversion of Anopheles gambiae from children to other hosts following exposure to permethrin-treated bednets.

Permethrin-treated bednets reduce mortality and morbidity from malaria in Gambian children. However, it is not certain how this effect is achieved, as neither mosquito numbers nor the human blood index of indoor-resting female Anopheles gambiae Giles sensu lato (Diptera: Culicidae) mosquitoes have been reduced when treated bednets were introduced into a community. One possibility is that insecticide-treated bednets divert mosquitoes from children to adults. To investigate this hypothesis, a cross-over trial with insecticide-treated bednets was undertaken in two small Gambian villages. To differentiate mosquitoes that had fed on children from those that had fed on adults, all children in the study villages were immunized with rabies vaccine before the trial. Using the detection of rabies antibody in a bloodmeal as an indicator that a mosquito had bitten a child, it was found that the percentage of blood-fed mosquitoes caught indoors that had bitten a child fell significantly from 30.8% to 9.2% and from 28.0% to 6.9% in each village after insecticide-treated bednets were introduced. To investigate the possibility that some diversion to animals had occurred, a PCR analysis for human beta-globin DNA was undertaken on selected samples. The results of this investigation were confusing, as some rabies-antibody positive bloodmeals were negative for human DNA. This may have been due to cross-reacting antibodies in animal sera and/or DNA degradation by digestion in the mosquito. Although good evidence for diversion of mosquitoes away from children was obtained, it remains uncertain whether diversion was mainly to adult humans, to animals or to both.

Identification of intervals on chromosomes 1, 3, and 13 linked to the development of lupus in BXSB mice.

OBJECTIVE: To identify intervals containing systemic lupus erythematosus (SLE) susceptibility alleles in the BXSB strain of mice. METHODS: We analyzed 286 (B10 x [B10 x BXSB]F1) backcross mice for a range of phenotypic traits associated with the development of SLE in BXSB mice. The mice were genotyped using 93 microsatellite markers, and the linkage of these markers to disease was studied by extreme-phenotype and quantitative trait locus analysis. RESULTS: The disease phenotype in these backcross mice was less severe than that in BXSB mice. However, antinuclear antibody production was increased compared with the parental strain. We identified 4 areas of genetic linkage to disease on chromosome 1 (Bxs1-4), 1 on chromosome 3 (Bxs5), and another interval on chromosome 13 which were associated with various aspects of the phenotype. Bxs4 and Bxs5 are located in regions not previously linked to disease in other models of SLE. CONCLUSION: SLE in the BXSB mouse model has a complex genetic basis and involves at least 5 distinct intervals located on chromosomes 1 and 3. There is evidence that different intervals affect particular aspects of the SLE phenotype.

Corrosion of and changes in biological effects of cobalt chrome alloy and 316L stainless steel prosthetic particles with age.

The biological response to prosthetic wear particles is thought to stimulate the bone loss that often leads to prosthetic joint failure. This in vitro study investigates how metal particles corrode under physiological conditions and how biological responses to particles may change as particles age. Cobalt chrome alloy (CoCr) and 316L stainless steel (SS) particles of a similar size, shape, and concentration to those found in revision tissues were used. The release of soluble metal (Co and Cr from CoCr particles and Fe from 316L SS) was markedly reduced with time under physiological conditions. CoCr particles released far more Co than Cr. The biological responses to aged and freshly produced particles were tested using human monocytes because wear particles are usually associated with this type of cell in the periarticular tissues. Aged particles of both metals were markedly less toxic to monocytes than freshly produced particles. Aged particles also appeared to stimulate the release of more IL-6 and prostaglandin E(2) from monocytes. The results show that CoCr and 316L SS particles become less toxic but may induce more bone resorbing mediators as they age in vivo.

Reduction in the mean number of Plasmodium falciparum genotypes in Gambian children immunized with the malaria vaccine SPf66.

SPf66, a synthetic peptide Plasmodium falciparum vaccine, did not protect young Gambian children against clinical attacks of malaria. Nevertheless, Gambian children who had been vaccinated with SPf66 and who were parasitaemic at the end of the first malaria transmission season after vaccination had significantly fewer detectable P. falciparum genotypes than control children, as determined by polymerase chain reaction analysis of 3 polymorphic loci--the msp1 block 2 repeat region, the msp2 repeat region, and the R11 region of the glutamate-rich protein gene (glurp). Geometric mean numbers of genotypes were 1.66 vs. 1.87, 1.95 vs. 2.43, and 1.21 vs. 1.50 for msp1, msp2 and glurp, respectively (P = 0.31, P = 0.04 and P < 0.01). Differences between groups became a little more marked for msp1 and msp2 when children with symptomatic malaria were excluded. No significant difference was found between parasites obtained from SPf66-vaccinated or control children in the prevalences of amino acid alleles at positions 44 and 47 in the 11 amino acid sequence of the merozoite surface protein 1 molecule, which is present in SPf66. The reduction in the number of genotypes observed could not be explained by a difference in parasite densities between SPf66-vaccinated and control children, as geometric mean parasite densities were almost identical in the 2 groups. These observations suggest that SPf66 vaccine may have induced an immune response which reduced the incidence of new infections in immunized children or accelerated the rate of clearance of parasites of individual genotypes. However, no reduction in the prevalence or density of parasitaemia was recorded in SPf66-vaccinated children, suggesting the existence of some kind of density-dependent mechanism for controlling low levels of malaria parasitaemia.

Serological responses of Gambian children to immunization with the malaria vaccine SPf66.

Antibody responses to the malaria vaccine SPf66 and to its constituent peptides were measured over a period of 2 years in Gambian children who had been immunized with SPf66 or with a control vaccine (inactivated polio vaccine). Three hundred and six of 308 children (99%) who had received three doses of SPf66 vaccine had antibodies to SPf66 at a level above that found in European controls who had not been exposed to malaria. Responses to the constituent peptides derived from 35.1, 55.1 and 83.1-kDa proteins were found in 88%, 97% and 97% of children, respectively; 26% had an antibody response to the NANP repeat peptide of circumsporozoite protein which is also included in the SPf66 vaccine. A response to SPf66 was found in 22% of children who had received the control vaccine. Antibody responses to NANP, 35.1, 55.1 and 83.1-kDa peptide were found in 3%, 33%, 49% and 33% of these children. Overall, no significant correlation was found between the level of anti-SPf66 antibody at the beginning of the malaria transmission season following vaccination and the subsequent risk of malaria. However, further analysis showed that among the control children who had acquired antibodies to SPf66 as a result of natural exposure to malaria, those with high levels of anti-SPf66 were less at risk of malaria, perhaps reflecting their greater previous exposure and thus immunity. In contrast, among children who had received three doses of SPf66, those with high antibody levels were at greater risk of have malaria during the subsequent malaria transmission season.

New reference allelic ladders to improve allelic designation in a multiplex STR system.

This paper reports the composition of a new reference allelic ladder mixture for use with a multiplex DNA profiling system consisting of six short tandem repeat loci. The loci included in this mixture are HUMTH01, D21S11, D18S51, D8S1179, HUMVWAF31/A, HUMFIBRA/FGA and an amelogenin sex test. Sequence analysis of individual ladder alleles was carried out and allelic designations made in accordance with the recommendations of the International Society of Forensic Haemogenetics (1992; 1994). A series of rare alleles which increase the range of alleles previously reported were identified. By including some of the rare alleles into the ladder marker system, we have significantly improved the ability to identify new alleles in unknown samples.

A randomized controlled trial of artemether/benflumetol, a new antimalarial and pyrimethamine/sulfadoxine in the treatment of uncomplicated falciparum malaria in African children.

We report here the results of a randomized double blind trial comparing coartemether (CGP56697), a combination of artemether and benflumetol, with pyrimethamine/sulfadoxine (P/S). Two hundred eighty-seven children 1-5 years of age with uncomplicated falciparum malaria were enrolled at two centers in The Gambia between July 1996 and December 1996. Following treatment, children were visited at home every 24 hr until a blood film free of asexual parasites was obtained. Genotyping of parasites was used to distinguish recrudescence from new infections. Three days after the start of treatment, 133 (100%) of the CGP56697-treated children compared with 128 (93.4%) of children treated with P/S had cleared their parasites (P = 0.003). The day 15 cure rate was 93.3% for CGP56697 and 97.7% for P/S (P = 0.13). Within the third and fourth week after initiation of therapy, 20 children treated with CGP56697 and one of the P/S-treated children returned with second malaria episodes (P < 0.0001). Genotyping suggested that the majority (19 of 23 [82.6%]) of these second episodes were due to new infections, supporting the World Health Organization recommendation that longer follow-up is not relevant for the assessment of drug efficacy. At the two-week follow-up, 28.9% of the P/S treated children but none of the CGP56697-treated children carried gametocytes (P < 0.0001). This study showed that CGP56697 is safe in African children with acute uncomplicated falciparum malaria, clears parasites more rapidly than P/S, and results in fewer gametocyte carriers. More frequent new infections within the third and fourth week following treatment with CGP56697 than treatment with P/S are likely to be due to the short prophylactic effect of CGP56697.

Treatment of African children with uncomplicated falciparum malaria with a new antimalarial drug, CGP 56697.

New antimalarial drugs are urgently needed. The use of short courses of the new antimalarial drug artemether as monotherapy has been limited by secondary malaria episodes following parasite clearance. Therefore, a new antimalarial drug, CGP 56697, has been developed, which combines artemether with a longer-acting antimalarial agent, benflumetol. A safety trial was undertaken in 60 Gambian children 1-6 years old with uncomplicated Plasmodium falciparum malaria. All children treated with CGP 56697 cleared their parasites 72 h after the start of treatment. No neurologic, cardiac, or other adverse reactions were observed. Second episodes of falciparum malaria were recorded in 16 (27%) of the children. Second infections were more frequent during the rainy season than during the dry season. Molecular epidemiologic studies suggested that 12 of the 14 second episodes of malaria in children treated with CGP 56697 were due to new infections. CGP 56697 proved to be a safe and effective antimalarial drug in African children.