A shared neural integrator for human posture control.

Control of standing posture requires fusion of multiple inputs including visual, vestibular, somatosensory, and other sensors, each having distinct dynamics. The semicircular canals, for example, have a unique high-pass filter response to angular velocity, quickly sensing a step change in head rotational velocity followed by a decay. To stabilize gaze direction despite this decay, the central nervous system supplies a neural "velocity storage" integrator, a filter that extends the angular velocity signal. Similar filtering might contribute temporal dynamics to posture control, as suggested by some state estimation models. However, such filtering has not been tested explicitly. We propose that posture control indeed entails a neural integrator for sensory inputs, and we test its behavior with classic sensory perturbations: a rotating optokinetic stimulus to the visual system and a galvanic vestibular stimulus to the vestibular system. A simple model illustrates how these two inputs and body tilt sensors might produce a postural tilt response in the frontal plane. The model integrates these signals through a direct weighted sum of inputs, with or without an indirect pathway containing a neural integrator. Comparison with experimental data from healthy adult subjects (N = 16) reveals that the direct weighting model alone is insufficient to explain resulting postural transients, as measured by lateral tilt of the trunk. In contrast, the neural integrator, shared by sensory signals, produces the dynamics of both optokinetic and galvanic vestibular responses. These results suggest that posture control may involve both direct and indirect pathways, which filter sensory signals and make them compatible for sensory fusion.NEW & NOTEWORTHY Control of standing posture requires fusion of multiple inputs including visual, vestibular, somatosensory, and other sensors, each having distinct dynamics. We propose that postural control also entails a shared neural integrator. To test this theory, we perturbed standing subjects with classic sensory stimuli (optokinetic and galvanic vestibular stimulation) and found that our proposed shared filter reproduces the dynamics of subjects' postural responses.

Six month outcomes in patients experiencing weight gain after gastric bypass who underwent gastrojejunal revision using an endoluminal suturing device.

BACKGROUND: Weight gain after Roux-en-Y gastric bypass occurs in approximately 25 % of cases, and this may contribute to recurrence of comorbid conditions. Currently, adequate treatment strategies for this group of patients are limited. Endoscopic narrowing of the gastrojejunal anastomosis may result in a low-risk, minimally invasive treatment alternative compared to standard surgical revision. We assessed short-term outcomes in patients undergoing endoscopic gastrojejunal revisions (EGJR) using an endoluminal suturing device. METHODS: We performed an institutional review board-approved retrospective analysis of 25 consecutive patients who underwent EGJR. Patients preoperatively presented with a dilated gastrojejunal anastomosis of greater than 15 mm and weight gain. An endoluminal suturing device (Overstitch(TM), Apollo Endosurgery, Austin TX) was used to reduce the diameter of the anastomosis. Follow-up occurred at 2 and 6 weeks, 3 and 6 months, and 1 year RESULTS: Prior to EGJR, patients regained an average of 23.4 ± 13.2 kg from their weight loss nadir and had a mean body mass index of 42.2 ± 6.6 kg/m(2). At 6 weeks, 100 % of patients experienced weight loss (average 5.8 ± 4.4 kg; p < .001). At 3 months, 94 % had weight loss (average 7.0 ± 6.2 kg; p < .001). At 6 months, 91 % maintained weight loss (average 5.6 ± 6.2 kg; p = 0.013). Lastly, at 1 year following EGJR, 100 % of available cases maintained weight loss (average 7.5 ± 6.4 kg; p = 0.057). The average percent excess weight loss was 12.5, 15.4, 12.4, and 17.1 % at 6 weeks, 3 and 6 months, and 1 year, respectively. There was a negative time effect in the mixed effect model using both on-treatment and intent-to-treat analyses, illustrating a significant weight reduction over time. The average follow-up per patient was 146 days. There were no complications reported during the follow-up period. CONCLUSIONS: Six month follow-up for EGJR patients demonstrated a low-risk, minimally invasive treatment option to reverse weight gain subsequent to a failed gastric bypass. Procedures presented no complications and may provide an attractive alternative to standard surgical revision.

Identification of fifty-seven novel loci for abdominal wall hernia development and their biological and clinical implications: results from the UK Biobank.

PURPOSE: Familial aggregation is known for both hernia development and recurrence. To date, only one genome-wide association study (GWAS) limited to inguinal hernia has been reported that identified four risk-associated loci. We aim to investigate polygenic architecture of abdominal wall hernia development and recurrence. METHODS: A GWAS was performed in 367,394 subjects from the UK Biobank to investigate the polygenic architecture of abdominal wall hernia subtypes (inguinal, femoral, umbilical, ventral) and identify specific single nucleotide polymorphisms (SNPs) that are associated with their risk. Expression quantitative trait loci (eQTL) analysis was performed to identify genes whose expression levels are associated with these SNPs. A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent risk-associated SNPs on hernia development and recurrence in independent subjects (n = 82,064). RESULTS: Heritability (h2) was 0.12, 0.06, 0.16, and 0.07 for inguinal, femoral, umbilical, and ventral hernias, respectively. A high-level of genetic correlation (rg) was found among these subtypes of hernia. We confirmed the aforementioned four loci and identified 57 novel loci (P < 5 × 10-8), including 55, 3, 5, and 3 loci for inguinal, femoral, umbilical, and ventral hernias, respectively. Significantly different expression levels between risk/reference alleles of SNPs were found for 145 genes, including TGF-ß2 and AIG1 for inguinal hernia risk and CALD1 for umbilical hernia risk. Finally, higher GRS deciles were significantly associated with increased risk for hernia development (Ptrend = 3.33 × 10-38) and recurrent hernia repair surgery (Ptrend = 3.64 × 10-14). CONCLUSION: These novel results have potential biological and clinical implications for hernia management in high-risk patients.

Ultradeep (greater than 300 kilometers), ultramafic upper mantle xenoliths.

Geophysical discontinuities in Earth's upper mantle and experimental data predict the structural transformation of pyroxene to garnet and the solid-state dissolution of pyroxene into garnet with increasing depth. These predictions are indirectly verified by omphacitic pyroxene exsolution in pyropic garnet-bearing xenoliths from a diamondiferous kimberlite. Conditions for silicon in octahedral sites in the original garnets are met at pressures greater than 130 kilobars, placing the origin of these xenoliths at depths of 300 to 400 kilometers. These ultradeep xenoliths support the theory that the 400-km seismic discontinuity is marked by a transition from peridotite to eclogite.

Ultradeep (>300 kilometers) ultramafic xenoliths: petrological evidence from the transition zone.

The seismologically delineated transition zone, at depths between 400 and 670 kilometers, is a fundamental discontinuity in the earth that separates the upper mantle from the lower mantle. Xenoliths from within or close to the transition zone are dominated by pyropic garnet and associated pyroxene or mineralogically heterogeneous garnet lherzolite. These xenoliths show evidence for the high-pressure (90 to 120 kilobars) transformation of pyroxene to a solid solution of pyroxene in garnet (majorite) and silicon in octahedral coordination; low-pressure (less than 80 kilobars) exsolution of clinopyroxene or orthopyroxene from the original majorite is preserved. Although mineral modes and rock proportions below the transition zone and the relative amount of eclogite present cannot be accurately assessed from the xenoliths, it is likely that both majorite and beta-spinel help produce the observed seismic gradient of the transition zone.

Native iron in the continental lower crust: petrological and geophysical implications.

Lower crustal granulite xenoliths recovered from a kimberlite pipe in western Africa contain native iron (Fe(0)) as a decomposition product of garnet and ilmenite. Magnetic measurements show that less than 0.1 percent (by volume) of iron metal is present. Data from geothermometry and oxygen geobarometry indicate that the oxide and metal phases equilibrated between iron-wüstite and magnetite-wüstite buffers, which may represent the oxidation state of the continental lower crust, and the depleted lithospheric upper mantle. Ferromagnetic native iron could be stable to a depth of approximately 95 kilometers and should be considered in the interpretation of long-wavelength static magnetic anomalies.

Primary oxidation variation and distribution of uranium and thorium in a lava flow.

An Icelandic basalt lava flow has a systematic oxidation variation, formed during the initial cooling, with a resultant maximum oxidation just below the center of the lava. The ratio of thorium to uranium shows a clear dependence on this primary oxidation variation. Between-lava comparisons of thorium and uranium may be critically dependent on the position of the samples in each lava.

Iron-titanium oxides and olivine from 10020 and 10071.

A new mineral (approximately Fe(0.5)Mg(0.5)Ti(2)O(5)) related to the pseudobrookite series has been discovered in section 10071,28. Electron-probe analyses for this mineral, a coexisting ilmenite, and a chromian ulvöspinel-ilmenite assemblage in section 10020,40 indicate crystallization under highly reducing conditions. Analytical and optical absorption studies of the olivine in 10020 show it to contain unusually high Cr (1400 parts per million) probably as Cr(2+).

Rectus abdominis atrophy after ventral abdominal incisions: midline versus chevron.

PURPOSE: Although many outcomes have been compared between a midline and chevron incision, this is the first study to examine rectus abdominis atrophy after these two types of incisions. METHODS: Patients undergoing open pancreaticobiliary surgery between 2007 and 2011 at our single institution were included in this study. Rectus abdominis muscle thickness was measured on both preoperative and follow-up computed tomography (CT) scans to calculate percent atrophy of the muscle after surgery. RESULTS: At average follow-up of 24.5 and 19.0 months, respectively, rectus abdominis atrophy was 18.9% greater in the chevron (n = 30) than in the midline (n = 180) group (21.8 vs. 2.9%, p < 0.0001). Half the patients with a chevron incision had >20% atrophy at follow-up compared with 10% with a midline incision [odds ratio (OR) 9.0, p < 0.0001]. No significant difference was observed in incisional hernia rates or wound infections between groups. CONCLUSION: In this study, chevron incisions resulted in seven times more atrophy of the rectus abdominis compared with midline incisions. The long-term effects of transecting the rectus abdominis and disrupting its innervation creates challenging abdominal wall pathology. Atrophy of the abdominal wall can not be readily fixed with an operation, and this significant side effect of a transverse incision should be factored into the surgeon's decision-making process when choosing a transverse over a midline incision.

Predominance of distinct viral genotypes in brain and lymph node compartments of HIV-1-infected individuals.

A modified polymerase chain reaction protocol was used to amplify the entire envelope-coding region of HIV-1 directly from brain and lymph node tissue obtained at autopsy from three HIV-1-infected individuals. Molecular analysis of amplified DNA by digestion with 18 restriction endonucleases, singly and in combination, revealed different HIV-1 genotypes in the brain and lymph node compartments in each of the three individuals. This anatomic compartmentalization of HIV-1 populations may reflect different viral genomic sequences that determine tropism or differences in host immune selection pressures in the brain and lymphoid compartments that drive the emergence of distinct viral populations.

HIV-1 replication and potential targets for intervention.

Intense research into fundamental processes of human immunodeficiency syndrome type 1 (HIV-1) replication has yielded knowledge that in many aspects equals or exceeds that of the oncogenic retroviruses. The availability of sensitive virus detection methods has allowed a more thorough characterization of the biology of virus persistence and latency in vivo and removed the dependence on in vitro models. As a clearer picture of the pattern of HIV-1 replication in vivo evolves, it becomes apparent that HIV-1 biology is distinct from that of the prototypic oncogenic retroviruses in several key aspects, particularly with regard to host cell range and determinants of viral permissiveness. In this respect it may be appropriate to examine the lentivirus, rather than the oncovirus model system to better understand the biology and pathogenesis of HIV-1 infection. This synopsis of recent and ongoing research developments in HIV-1 replication and pathogenesis emphasizes the determinants of host cell permissiveness, early events in virus replication, and underlying features in HIV-1 cytopathogenesis. In addition, basic viral replication processes which can be exploited for therapeutic intervention are discussed.

Posttranslational modifications within the HIV-1 envelope glycoprotein which restrict virus assembly and CD4-dependent infection.

Alterations in two highly conserved N-linked glycosylation sites within the gp120 envelope glycoprotein of human immunodeficiency virus type I (HIV-1) implicated in the phenotype of a noncytopathic HIV-1 variant were introduced independently and in combination into a cytopathic, infectious HIV-1 clone by site-specific mutagenesis. Neither mutation affected the synthesis of HIV-1 envelope glycoproteins. However, one of the mutations restricted the ability of HIV-1 envelope to localize on the cell membrane and thus markedly impaired virus assembly. The HIV-1 assembly defect could be overcome in trans if site-specific mutants were packaged in HeLa cells constitutively producing wild-type HIV-1 envelope glycoprotein. In addition to inefficient virus assembly, this mutation impaired the ability of the virus to infect CD4+ T cells, but did not affect CD4-independent infection of muscle cells. These results suggest additional functions of posttranslational modification in virus replication (i.e., envelope glycoprotein transport). Given that such modifications can restrict CD4-mediated uptake without affecting CD4-independent uptake, variations in posttranslational env processing between different HIV-1 genotypes may affect virus tropism in vivo.

Lack of cardioplegia uniformity in clinical myocardial preservation.

Advances in myocardial preservation have led to improved patient survival after open heart operations. However, few studies have detailed the nature of national or regional patterns of cardioplegia use. To determine the regional pattern, all open heart surgery programs in Missouri were surveyed. During 1 year, it was found that cardioplegia was administered to 8,382 patients by 61 cardiothoracic surgeons at ten academic affiliated hospitals and 16 nonteaching hospitals. All cardioplegic solutions were hospital produced. Of 13 crystalloid solutions, 11 differed from one another and eight were intracellular formulations. Of 28 multidose blood-based cardioplegic solutions, there were 23 different mixtures. Most crystalloid (69%) and blood-based (89%) solutions differed substantially from commonly reported formulations. The incidences of the various additives to crystalloid solutions were as follows: bicarbonate, 92%; glucose, 69%; lidocaine, 54%; mannitol, 46%; magnesium, 31%; calcium, 23%; methylprednisolone, 15%; heparin, 8%; and acetate, 8%. Of the common blood-based cardioplegic solution additives, the following incidences were observed: glucose, 79%; bicarbonate, 43%; trishydroxyaminomethane, 36%; acetate, 29%; magnesium, 29%; procaine (or lidocaine), 25%; citrate-phosphate-dextrose, 18%; mannitol/albumin, 14%; nitroglycerin, 11%; glutamate/aspartate, 11%; calcium, 7%; insulin, 3%; and methylprednisolone, 3%. No calcium channel blocker or high-energy phosphate additives were reported. We conclude that many different cardioplegic admixtures that have not been tested experimentally are used routinely in clinical practice, presumably with acceptable results. Because the salutary effects of induced cardiac arrest and hypothermia may mask suboptimal solutions, further study of customized cardioplegia should be considered, particularly with regard to high-risk patients.

Should pulmonary lesions be resected at the time of open heart surgery?

The prevalence and malignant potential of pulmonary lesions found preoperatively in patients undergoing coronary artery bypass grafting (CABG) surgery are poorly defined. In a review of 3364 consecutive patients undergoing CABG, 191 (5%) were found to have pulmonary lesions. Granulomatous disease was suspected in all patients who had only calcified lesions (n = 151). These were empirically observed with no changes seen at follow-up. The 40 patients with noncalcified lesions (NCLs) were managed variously. Twenty patients underwent resection of the suspicious pulmonary lesion at the time of cardiac surgery. One patient underwent wedge resection of a pulmonary lesion (benign granuloma) 4 days before CABG. Eighteen patients underwent concomitant pulmonary resection and CABG through the median sternotomy (7 benign, 11 malignant). A delayed pneumonectomy was performed 17 days after CABG in another patient. Three of 40 patients died during the perioperative period without pathologic diagnosis. The remaining 17 were followed with serial roentgenograms. Three of 17 (18%) had lesional enlargement in the follow-up period their lesions were found to be malignant. The remaining 14 patients have been observed without surgical intervention now with a mean follow-up of 5.7 years (range, 20 months to 13 years). The prevalence of malignancy in lesions found on CABG preoperative chest roentgenograms was 15 out of 191 (7.8%); however, among patients with NCL the prevalence of malignancy was 15 out of 40 (37%), and malignancy was present in 12/13 (92%) of patients with NCLs that were >/= 2 cm in diameter. When malignancy is diagnosed in an NCL before CABG surgery, the decision to proceed with CABG should be based upon the coronary pathophysiology and the stage and cell type of the malignancy. Concomitant CABG and pulmonary resection is possible in most cases; however, we prefer a staged resection of all newly diagnosed NCLs when these are identified in patients requiring emergent revascularization or when these lesions are difficult to access through sternotomy. The mortality rate may be slightly increased in patients having concomitant procedures (5.47%) versus isolated CABG (3%). The incidence of malignancy in these NCLs is related to size. If a staged resection is not undertaken after CABG, careful observation of NCLs is important, as 18 per cent of these so managed were ultimately found to be malignant.

JC virus-simian virus 40 genomes containing heterologous regulatory signals and chimeric early regions: identification of regions restricting transformation by JC virus.

The papovavirus JC virus (JCV) is highly oncogenic in experimental animals but, unlike simian virus 40 (SV40), is severely restricted in its ability to transform cells in culture. We exploited the close genetic relatedness of these two viruses to delimit region(s) of the T protein which can restrict transforming activity. Novel chimeric genomes were produced by exchanging various segments of the JCV and SV40 T-protein-coding regions. These DNA constructs specified early proteins with in-frame substitutions of analogous amino acid sequences. A second set of genomes was prepared which, in addition to chimeric early proteins, contained substituted regulatory regions. The transformation efficiencies of these chimeric genomes were intermediate between those of SV40 and JCV, with the source of T protein exerting a greater effect than that of the regulatory region. The ability of certain constructs to induce efficient transformation required the presence of an SV40 regulatory region or specific sequences within the SV40 early coding region. Cloned cell lines prepared from representative transformants were characterized; the ability to form colonies in soft agarose was investigated, and the presence of viral T and cellular p53 proteins was determined. The various T proteins differed in amount, stability, and the ability to form stable complexes with p53.

Isolation of Corynebacterium aquaticum from spinal fluid of an infant with meningitis.

A 4-week-old female was hospitalized because of vomiting, irritability, and nuchal rigidity. A spinal fluid culture yielded Corynebacterium aquaticum. The diagnosis of C. aquaticum meningitis in this infant was supported by the following cerebrospinal fluid findings: Gram stain, elevated protein, hypoglycorrhachia, positive C-reactive protein, and polymorphonuclear leukocytosis. Antigen studies for common bacterial causes of meningitis were negative. C. aquaticum is a rare cause of human disease and may be initially confused with Listeria monocytogenes, which is a more common gram-positive, motile rod associated with meningitis in infants.

DNA replication of chimeric JC virus-simian virus 40 genomes.

The ubiquitous virus JCV is the etiologic agent of the human brain disease progressive multifocal leukoencephalopathy. Although infection usually occurs early in life and the virus can remain latent in human tissues, including brain, little information is available regarding its replication. It is known that DNA replication of primate polyomaviruses is dependent upon the synthesis of T antigen and the subsequent interactions of this protein with cellular factors and the viral origin of replication. We constructed chimeric genomes between JCV and SV40, two genetically similar viruses with distinct biologies, in which segments of the T antigen coding region and the replication origin were exchanged. Because the engineering of these genomes created a defect in the structural protein VP1, their DNA replicating activities could be compared without the complication of secondary infection of adjacent cells and amplification of the replication signal. The ability of the JCV-SV40 hybrid T antigens to initiate replication from the two viral origins in primate cells was investigated. A region of the JCV T antigen that includes the DNA binding and zinc finger domains was found to be responsible for the failure of JCV T antigen to interact productively with the SV40 origin. In addition, the ability to replicate in monkey cells was limited to constructs expressing T antigens which contained the carboxy-terminal host range domain of SV40.