Spatiotemporal Profile of Voltage-Sensitive Dye Responses in the Visual Cortex of Tree Shrews Evoked by Electric Microstimulation of the Dorsal Lateral Geniculate and Pulvinar Nuclei.

The primary visual cortex (V1) receives its main thalamic drive from the dorsal lateral geniculate nucleus (dLGN) through synaptic contacts terminating primarily in cortical layer IV. In contrast, the projections from the pulvinar nucleus to the cortex are less clearly defined. The pulvinar projects predominantly to layer I in V1, and layer IV in extrastriate areas. These projection patterns suggest that the pulvinar nucleus most strongly influences (drives) activity in cortical areas beyond V1. Should this hypothesis be true, one would expect the spatiotemporal responses evoked by pulvinar activation to be different in V1 and extrastriate areas, reflecting the different connectivity patterns. We investigated this issue by analyzing the spatiotemporal dynamics of cortical visual areas' activity following thalamic electrical microstimulation in tree shrews, using optical imaging and voltage-sensitive dyes. As expected, electrical stimulation of the dLGN induced fast and local responses in V1, as well as in extrastriate and contralateral cortical areas. In contrast, electrical stimulation of the pulvinar induced fast and local responses in extrastriate areas, followed by weak and diffuse activation in V1 and contralateral cortical areas. This study highlights spatiotemporal cortical activation characteristics induced by stimulation of first (dLGN) and high-order (pulvinar) thalamic nuclei. SIGNIFICANCE STATEMENT: The pulvinar nucleus represents the main extrageniculate thalamic visual structure in higher-order mammals, but its exact role remains enigmatic. The pulvinar receive prominent inputs from virtually all visual cortical areas. Cortico-thalamo-cortical pathways through the pulvinar nuclei may then provide a complementary route for corticocortical information flow. One step toward the understanding of the role of transthalamic corticocortical pathways is to determine the nature of the signals transmitted between the cortex and the thalamus. By performing, for the first time, high spatiotemporal mesoscopic imaging on tree shrews (the primate's closest relative) through the combination of voltage-sensitive dye recordings and brain stimulation, we revealed clear evidence of distinct thalamocortical functional connectivity pattern originating from the geniculate nucleus and the pulvinar nuclei.

Thalamic burst firing propensity: a comparison of the dorsal lateral geniculate and pulvinar nuclei in the tree shrew.

Relay neurons in dorsal thalamic nuclei can fire high-frequency bursts of action potentials that ride the crest of voltage-dependent transient (T-type) calcium currents [low-threshold spike (LTS)]. To explore potential nucleus-specific burst features, we compared the membrane properties of dorsal lateral geniculate nucleus (dLGN) and pulvinar nucleus relay neurons using in vitro whole-cell recording in juvenile and adult tree shrew (Tupaia) tissue slices. We injected current ramps of variable slope into neurons that were sufficiently hyperpolarized to de-inactivate T-type calcium channels. In a small percentage of juvenile pulvinar and dLGN neurons, an LTS could not be evoked. In the remaining juvenile neurons and in all adult dLGN neurons, a single LTS could be evoked by current ramps. However, in the adult pulvinar, current ramps evoked multiple LTSs in >70% of recorded neurons. Using immunohistochemistry, Western blot techniques, unbiased stereology, and confocal and electron microscopy, we found that pulvinar neurons expressed more T-type calcium channels (Ca(v) 3.2) and more small conductance potassium channels (SK2) than dLGN neurons and that the pulvinar nucleus contained a higher glia-to-neuron ratio than the dLGN. Hodgkin-Huxley-type compartmental models revealed that the distinct firing modes could be replicated by manipulating T-type calcium and SK2 channel density, distribution, and kinetics. The intrinsic properties of pulvinar neurons that promote burst firing in the adult may be relevant to the treatment of conditions that involve the adult onset of aberrant thalamocortical interactions.

Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients.

BACKGROUND: The CALYPSO phase III trial compared CD (carboplatin-pegylated liposomal doxorubicin (PLD)) with CP (carboplatin-paclitaxel) in patients with platinum-sensitive recurrent ovarian cancer (ROC). Overall survival (OS) data are now mature. METHODS: Women with ROC relapsing > 6 months after first- or second-line therapy were randomised to CD or CP for six cycles in this international, open-label, non-inferiority trial. The primary endpoint was progression-free survival. The OS analysis is presented here. RESULTS: A total of 976 patients were randomised (467 to CD and 509 to CP). With a median follow-up of 49 months, no statistically significant difference was observed between arms in OS (hazard ratio = 0.99 (95% confidence interval 0.85, 1.16); log-rank P = 0.94). Median survival times were 30.7 months (CD) and 33.0 months (CP). No statistically significant difference in OS was observed between arms in predetermined subgroups according to age, body mass index, treatment-free interval, measurable disease, number of lines of prior chemotherapy, or performance status. Post-study cross-over was imbalanced between arms, with a greater proportion of patients randomised to CP receiving post-study PLD (68%) than patients randomised to CD receiving post-study paclitaxel (43%; P < 0.001). CONCLUSION: Carboplatin-PLD led to delayed progression and similar OS compared with carboplatin-paclitaxel in platinum-sensitive ROC.

Barriers to prenatal detection of congenital heart disease: a population-based study.

OBJECTIVE: To evaluate the extent and determinants of missed prenatal detection of congenital heart disease (CHD) in a population-based setting. METHODS: This was a retrospective cohort study of cases with CHD, excluding minor defects, identified between 1997 and 2007 by a statewide surveillance program. We examined a comprehensive list of potential risk factors for which data were available in the surveillance database from abstracted medical charts. We analyzed the association of fetal, maternal and encounter factors with 1) whether a prenatal ultrasound was performed and 2) prenatal detection of CHD. RESULTS: CHD was detected prenatally in only 39% of 1474 cases, with no improvement in detection rate over the 10-year period. Among the 97% (n = 1431) of mothers who underwent one or more ultrasound examinations, 35% were interpreted as abnormal; fetal echocardiography was performed in 27% of the entire cohort. Maternal and encounter factors increasing the adjusted odds of prenatal detection included: family history of CHD (OR, 4.3 (95% CI, 1.9-9.9)), presence of extracardiac defects (OR, 2.7 (95% CI, 1.9-3.9)) and ultrasound location i.e. high risk clinic vs clinic (OR, 2.1 (95% CI, 1.3-3.1)). Defects that would be expected to have an abnormal outflow-tract view were missed more often (64%) than were those that would be expected to have an abnormal four-chamber view (42%). CONCLUSION: The majority of CHD cases over the 10-year study period were missed prenatally and detection rates did not increase materially during that time. The failure to detect CHD prenatally was related to encounter characteristics, specifically involving screening ultrasound examinations, which may be targeted for improvement.

Synaptic organization of connections between the temporal cortex and pulvinar nucleus of the tree shrew.

We examined the synaptic organization of reciprocal connections between the temporal cortex and the dorsal (Pd) and central (Pc) subdivisions of the tree shrew pulvinar nucleus, regions innervated by the medial and lateral superior colliculus, respectively. Both Pd and Pc subdivisions project topographically to 2 separate regions of the temporal cortex; small injections of anterograde tracers placed in either Pd or Pc labeled 2 foci of terminals in the temporal cortex. Pulvinocortical pathways innervated layers I-IV, with beaded axons oriented perpendicular to the cortical surface, where they synapsed with spines that did not contain gamma amino butyric acid (GABA), likely located on the apical dendrites of pyramidal cells. Projections from the temporal cortex to the Pd and Pc originate from layer VI cells, and form small terminals that contact small caliber non-GABAergic dendrites. These results suggest that cortical terminals are located distal to tectopulvinar terminals on the dendritic arbors of Pd and Pc projection cells, which subsequently contact pyramidal cells in the temporal cortex. This circuitry could provide a mechanism for the pulvinar nucleus to activate subcortical visuomotor circuits and modulate the activity of other visual cortical areas. The potential relation to primate tecto-pulvino-cortical pathways is discussed.

Immunocytochemical and ultrastructural organization of the taste thalamus of the tree shrew (Tupaia belangeri).

Ventroposterior medialis parvocellularis (VPMP) nucleus of the primate thalamus receives direct input from the nucleus of the solitary tract, whereas the homologous thalamic structure in the rodent does not. To reveal whether the synaptic circuitries in these nuclei lend evidence for conservation of design principles in the taste thalamus across species or across sensory thalamus in general, we characterized the ultrastructural and molecular properties of the VPMP in a close relative of primates, the tree shrew (Tupaia belangeri), and compared these to known properties of the taste thalamus in rodent, and the visual thalamus in mammals. Electron microscopy analysis to categorize the synaptic inputs in the VPMP revealed that the largest-size terminals contained many vesicles and formed large synaptic zones with thick postsynaptic density on multiple, medium-caliber dendrite segments. Some formed triads within glomerular arrangements. Smaller-sized terminals contained dark mitochondria; most formed a single asymmetric or symmetric synapse on small-diameter dendrites. Immuno-EM experiments revealed that the large-size terminals contained VGLUT2, whereas the small-size terminal populations contained VGLUT1 or ChAT. These findings provide evidence that the morphological and molecular characteristics of synaptic circuitry in the tree shrew VPMP are similar to that in nonchemical sensory thalamic nuclei. Furthermore, the results indicate that all primary sensory nuclei of the thalamus in higher mammals share a structural template for processing thalamocortical sensory information. In contrast, substantial morphological and molecular differences in rodent versus tree shrew taste nuclei suggest a fundamental divergence in cellular processing mechanisms of taste input in these two species.

Evolutionary shifts dramatically reorganized the human hippocampal complex.

The hippocampal complex (HC) is central to long-term memory storage and retrieval as well as spatial navigation across many species. Notably, humans appear to have greatly enhanced and possibly unique HC-mediated capacities such as constructive episodic simulation. Key studies have shown that the human HC is disproportionately large amongst hominoids, but much remains unknown at the levels of substructural evolutionary reorganization and ecological selection. Here, we calculated relative sizes of 12 HC subregions in a diverse sample of 44 primate species. We then used a Bayesian phylogenetic method, selective regime analysis, to identify 27 separate evolutionary shifts in HC organization across 65 million years of primate evolution. Additionally, a series of multivariate phylogenetic regressions using HC-related ecological variables as predictors (Diet Breadth, Population Density, Group Size, Home Range Size, and Residual Home Range) revealed that relative fascia dentata and CA1 size were both significantly predicted by species' home range size (after correcting for body size). However, perhaps the most notable finding of this study was that the shifts in HC size and subregional organization in the human lineage were the largest seen in all of primate evolution, rendering modern humans with a HC that is a clear outlier amongst all nonhuman primates investigated here. Given the extensive literature confirming the relationship between HC organization and function, these selective shifts are likely to have played a significant role in the emergence of human-specific capacities, such as constructive episodic simulation.

The Second Visual System of The Tree Shrew.

This review provides a historical account of the discovery of secondary visual pathways (from retina to the superior colliculus to the dorsal thalamus and extrastriate cortex), and Vivien Casagrande's pioneering studies of this system using the tree shrew as a model. Subsequent studies of visual pathways in the tree shrew are also reviewed, beginning with a description of the organization and central projections of the tree shrew retina. The organization and connectivity of second visual system components that include the retino-recipient superior colliculus, tecto-recipient pulvinar nucleus and its projections, and the tecto-recipient dorsal lateral geniculate nucleus and its projections are detailed. Potential functions of the second visual system are discussed in the context of this work and in the context of the behavioral studies that initially inspired the secondary visual system concept.

Vision improvement in retinal degeneration patients by implantation of retina together with retinal pigment epithelium.

PURPOSE: To demonstrate efficacy and safety of the implantation of neural retinal progenitor cell layers (sheets) with its retinal pigment epithelium (RPE) in retinitis pigmentosa (RP) and dry age-related macular degeneration (AMD) patients with 20/200 or worse vision in the surgery eye. DESIGN: Interventional nonrandomized clinical trial. METHODS: Ten patients (six RP, four AMD) received retinal implants in one eye and were followed in a phase II trial conducted in a clinical practice setting. Early Treatment Diabetic Retinopathy Study (EDTRS) was the primary outcome measure. All implant recipients and nine of 10 tissue donors were deoxyribonucleic acids typed. RESULTS: Seven patients (three RP, four AMD) showed improved EDTRS visual acuity (VA) scores. Three of these patients (one RP, two AMD) showed improvement in both eyes to the same extent. Vision in one RP patient remained the same, while vision in two RP patients decreased. One RP patient has maintained an improvement in vision from 20/800 to 20/200 ETDRS for more than five years; at the six-year examination, it was still maintained at 20/320 while the nonsurgery eye had deteriorated to hand motion vision. This patient also showed a 22.72% increase in light sensitivity at five years compared to microperimetry results at two years; the other patients showed no improved sensitivity. Although no match was found between donors and recipients, no rejection of the implanted tissue was observed clinically. CONCLUSIONS: Seven (70%) of 10 patients showed improved VA. This outcome provides clinical evidence of the safety and beneficial effect of retinal implants and corroborates results in animal models of retinal degeneration.

Synaptic organization of striate cortex projections in the tree shrew: A comparison of the claustrum and dorsal thalamus.

The tree shrew (Tupaia belangeri) striate cortex is reciprocally connected with the dorsal lateral geniculate nucleus (dLGN), the ventral pulvinar nucleus (Pv), and the claustrum. In the Pv or the dLGN, striate cortex projections are thought to either strongly "drive", or more subtly "modulate" activity patterns respectively. To provide clues to the function of the claustrum, we compare the synaptic arrangements of striate cortex projections to the dLGN, Pv, and claustrum, using anterograde tracing and electron microscopy. Tissue was additionally stained with antibodies against γ-aminobutyric acid (GABA) to identify GABAergic interneurons and non-GABAergic projection cells. The striate cortex terminals were largest in the Pv (0.94 ± 0.08 µm2 ), intermediate in the claustrum (0.34 ± 0.02 µm2 ), and smallest in the dLGN (0.24 ± 0.01 µm2 ). Contacts on interneurons were most common in the Pv (39%), intermediate in the claustrum (15%), and least common in the dLGN (12%). In the claustrum, non-GABAergic terminals (0.34 ± 0.01 µm2 ) and striate cortex terminals were not significantly different in size. The largest terminals in the claustrum were GABAergic (0.51 ± 0.02 µm2 ), and these terminals contacted dendrites and somata that were significantly larger (1.90 ± 0.30 µm2 ) than those contacted by cortex or non-GABAergic terminals (0.28 ± 0.02 µm2 and 0.25 ± 0.02 µm2 , respectively). Our results indicate that the synaptic organization of the claustrum does not correspond to a driver/modulator framework. Instead, the circuitry of the claustrum suggests an integration of convergent cortical inputs, gated by GABAergic circuits. J. Comp. Neurol. 525:1403-1420, 2017. © 2016 Wiley Periodicals, Inc.

Ultrastructure of geniculocortical synaptic connections in the tree shrew striate cortex.

To determine whether thalamocortical synaptic circuits differ across cortical areas, we examined the ultrastructure of geniculocortical terminals in the tree shrew striate cortex to compare directly the characteristics of these terminals with those of pulvinocortical terminals (examined previously in the temporal cortex of the same species; Chomsung et al. [] Cereb Cortex 20:997-1011). Tree shrews are considered to represent a prototype of early prosimian primates but are unique in that sublaminae of striate cortex layer IV respond preferentially to light onset (IVa) or offset (IVb). We examined geniculocortical inputs to these two sublayers labeled by tracer or virus injections or an antibody against the type 2 vesicular glutamate antibody (vGLUT2). We found that layer IV geniculocortical terminals, as well as their postsynaptic targets, were significantly larger than pulvinocortical terminals and their postsynaptic targets. In addition, we found that 9-10% of geniculocortical terminals in each sublamina contacted GABAergic interneurons, whereas pulvinocortical terminals were not found to contact any interneurons. Moreover, we found that the majority of geniculocortical terminals in both IVa and IVb contained dendritic protrusions, whereas pulvinocortical terminals do not contain these structures. Finally, we found that synaptopodin, a protein uniquely associated with the spine apparatus, and telencephalin (TLCN, or intercellular adhesion molecule type 5), a protein associated with maturation of dendritic spines, are largely excluded from geniculocortical recipient layers of the striate cortex. Together our results suggest major differences in the synaptic organization of thalamocortical pathways in striate and extrastriate areas.

Vision change after sheet transplant of fetal retina with retinal pigment epithelium to a patient with retinitis pigmentosa.

OBJECTIVE: To report the subjective and objective improvement in vision in a patient with autosomal dominant retinitis pigmentosa after transplantation of a sheet of fetal neural retina together with its retinal pigment epithelium. DESIGN: A sheet of fetal neural retina with its retinal pigment epithelium was transplanted into the subretinal space under the fovea unilaterally in a patient with retinitis pigmentosa with visual acuity of 20/800 in the treated eye. Early Treatment Diabetic Retinopathy Study visual acuity testing, scanning laser ophthalmoscope, tissue typing of the donor and recipient, fluorescein angiography, multifocal electroretinogram, multifocal visually evoked potential, and clinical examination were used. RESULTS: No clinical evidence of rejection was observed. There was no retinal edema or scarring. The transplant sheet lost its pigmentation by 6 months. MAIN OUTCOME MEASURES: A change in visual acuity from 20/800 to 20/400 (7 months), 20/250 (9 months), and 20/160 (1 year) was observed by Early Treatment Diabetic Retinopathy Study visual acuity testing. Independently, scanning laser ophthalmoscope testing at a different institution at 9 months showed a visual acuity of 20/270 at a 40 degrees field of view. CONCLUSION: This study indicates that fetal retina transplanted with its retinal pigment epithelium can survive 1 year without apparent clinical evidence of rejection and show continued improvement in Early Treatment Diabetic Retinopathy Study visual acuity.

Treatment of recurrent and metastatic adenocarcinoma of the endometrium with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate.

We conducted a retrospective review of 44 patients with metastatic or recurrent endometrial carcinoma treated with cisplatin, doxorubicin, cyclophosphamide, and medroxyprogesterone acetate. Thirty-six women had metastatic disease; eight had recurrent disease. In the metastatic group, 12 women had positive peritoneal cytology as the only criterion for metastatic disease. Grade 1 tumors represented 25%, grade 2, 47.7%, and grade 3, 27.3%. The series was divided into four groups based on disease volume before chemotherapy: positive peritoneal cytology only (N = 12), microscopic (N = 11), macroscopic less than 2 cm (N = 6), and macroscopic greater than 2 cm (N = 15). Fifteen patients had measurable disease and eight (53%) had an objective response. The median survival was 31 months for the whole group. Median survivals were not reached for the positive peritoneal cytology only and the microscopic groups. Median survival for the macroscopic less than 2 cm and greater than 2 cm groups were 15 and 10 months, respectively (P less than .0001). The volume of disease was the most important factor in determining survival as well as the time to progression (P less than .0001). The distribution of grade was similar in all groups (P = .88), and grade did not predict survival (P = .80) or recurrence (P = .87). The significant number of low-grade lesions in our series as well as the importance of positive cytology as a predictor of survival underscore the need for surgical pathologic staging in an effort to identify those patients in need of adjuvant therapy.

Peritoneovenous shunt for palliation of gynecologic malignant ascites.

BACKGROUND: Ascites is a common sequela of advanced or recurrent gynecologic malignancies, such as carcinoma of the ovary, fallopian tube, or endometrium. Symptomatic treatment with repeated paracentesis is the initial management after failure of chemotherapy. STUDY DESIGN: This study was done to evaluate the safety and effectiveness of a peritoneovenous shunt (PVS) in the palliation of these patients with recurrent ascites. A retrospective review of 25 patients having a PVS between 1982 and 1992 was performed. RESULTS: The 25 patients consisted of 21 patients with carcinoma of the ovary, two with primary carcinoma of the peritoneum, one with carcinoma of the endometrium, and one patient with carcinoma of the fallopian tube. The mean weight and abdominal girth decreased after shunt insertion (p < 0.001). Gastrointestinal dysfunction and dyspnea also improved with PVS insertion. There was no change in mean Karnofsky score after placement of a PVS. Two patients died within ten days postoperatively. The median survival period was 80 days and shunt occlusion occurred in four patients. CONCLUSIONS: The insertion of a PVS is effective in relieving refractory malignant ascites in gynecologic malignancies. The impact on quality of life requires further study.

Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients.

PURPOSE: To show the safety of transplanting sheets of fetal neural retina together with its retinal pigment epithelium (RPE) to patients with retinitis pigmentosa. DESIGN: Interventional case series. METHODS: Sheets of fetal neural retina and RPE were transplanted together into the subretinal space near the fovea unilaterally in the eyes of five patients with retinitis pigmentosa who had only light perception in both eyes. The patients were followed for 6 months. The main outcome measures were tissue typing of both donors and recipients, fluorescein angiography, multifocal electroretinogram (mfERG) testing, and clinical examination. No immunosuppressive medications were given. RESULTS: No evidence of rejection was observed. Up to 6 months there was no evidence of tissue disintegration, retinal edema, or scarring. There was no change in vision both by Snellen acuity and with mfERGs. Growth of the transplant was noted in two of five patients at 6 months vs. 2 weeks. All patients typed were HLA mismatched with donor tissue. CONCLUSIONS: This study indicates that fetal retina can be transplanted together with its RPE and survive for at least 6 months without evidence of rejection. However, no improvements in vision were observed, possibly due to the severe retinal degeneration of the patients.

Early ovarian cancer: what is the staging impact of retroperitoneal node sampling?

BACKGROUND: Comprehensive surgical staging of apparent early-stage epithelial ovarian cancer includes peritoneal washings, biopsies, and retroperitoneal lymph node dissection. Unresolved is the relative frequency or importance of the lymph node dissection. OBJECTIVES: (1) To determine the site(s) of microscopic metastatic disease in women undergoing a comprehensive staging for apparent early-stage cancer of the ovary; (2) to identify those women with metastases in the retroperitoneal lymph nodes alone. METHODS: Between 1985 and 2000, we reviewed all records of women at cancer centres in Winnipeg, Ottawa, and Saskatoon who had undergone a "staging laparotomy" for an apparent early-stage IA epithelial cancer of the ovary. Histology, tumour grade, initial and final surgical stage, and the site(s) of metastatic disease were recorded for all cases. RESULTS: Forty-three of the 128 women (34%) had a final surgical stage of II or III. Sixteen women had positive pelvic biopsies, while 19 had microscopic upper abdominal disease. Eight women had positive retroperitoneal nodes, and in only 2 of these women, disease was found in the retroperitoneal nodes alone. In the 8 women with nodal disease, 5 had grade 3 tumours and 6 had serous histology tumours. CONCLUSION: Comprehensive staging is important to identify women with metastatic disease. Solitary nodal metastases are predominantly found in grade 3 and serous tumours.

A framework for improved training of Sigma-Pi networks.

This paper proposes and demonstrates a framework for Sigma-Pi networks such that the combinatorial increase in product terms is avoided. This is achieved by only implementing a subset of the possible product terms (sub-net Sigma-Pi). Application of a dynamic weight pruning algorithm enables redundant weights to be removed and replaced during the learning process, hence permitting access to a larger weight space than employed at network initialization. More than one learning rate is applied to ensure that the inclusion of higher order descriptors does not result in over description of the training set (memorization). The application of such a framework is tested using a problem requiring significant generalization ability. Performance of the resulting sub-net Sigma-Pi network is compared to that returned by optimal multi-layer perceptrons and general Sigma-Pi solutions.

Early ovarian cancer: value of a negative staging laparotomy.

OBJECTIVE: To assess the risk of recurrence in patients with stage I (negative cytology) epithelial ovarian cancer receiving no adjuvant therapy. METHODS: Between 1976 and 1991, 51 patients with apparent stage I ovarian cancer underwent a comprehensive surgical staging that included: peritoneal cytology, omentectomy, pelvic and para-aortic lumphadenectomy, peritoneal biopsies and either unilateral salpingo-oophorectomy or TAH and BSO. RESULTS: Eleven of 51 patients (22%) were found to have stage II or III disease based on a positive staging laparotomy. Thirty-seven of 40 patients with stage I disease received no further therapy. There was one recurrence (stage 1C - grade 1) in patients with surgical stage 1C while there were no recurrences in patients with either stage 1A or 1B disease. CONCLUSION: This study concludes that surgical staging in apparent early stage ovarian cancer can identify a group of patients that require surgical therapy alone.

Randomised trial of subcuticular suture versus metal clips for wound closure after thyroid and parathyroid surgery.

A randomised trial was conducted to compare the results of neck wound closure using metal (Michel) clips or subcuticular suture. All operations were performed using a standardised technique, which included wound infiltration with 10 ml bupivacaine and adrenaline solution, no strap muscle division and the use of suction drains. All the collar incisions and wound closures were performed by the same surgeon. At the end of each operation patients were randomised to wound closure by either metal clips (n = 38) or a continuous 3/0 prolene subcuticular suture (n = 42). Daily postoperative pain scores and the discomfort caused by clip/suture removal were recorded. The cosmetic appearance of each wound was scored by the patient, the surgeon, and an independent observer using verbal response and linear analogue scales. The two study groups were well matched for age, sex, indication for surgery and operation performed. There were no differences in postoperative pain scores between clips and sutures. Removal of subcuticular sutures was performed more quickly (P < 0.0001) and caused less pain (P < 0.0001, visual analogue scale; P = 0.0042, verbal response scale) than the removal of clips. At the time of discharge, the cosmetic appearance scores generated by the surgeon, patient and independent observer were higher for suture closed wounds than clips. However, by 3 and 6 months follow-up there were no differences in cosmetic appearance between the two methods of closure. Only very short-term cosmetic results are influenced by the type of wound closure in thyroid and parathyroid surgery, but sutures are quicker and less painful to remove than Michel clips.

Dynamic page based crossover in linear genetic programming.

Page-based linear genetic programming (GP) is proposed in which individuals are described in terms of a number of pages. Pages are expressed in terms of a fixed number of instructions, which is constant for all individuals in the population. Pairwise crossover results in the swapping of single pages, and thus, individuals are of a fixed number of instructions. Head-to-head comparison with Tree-structured GP and block-based linear GP indicates that the page-based approach evolves succinct solutions without penalizing generalization ability.