RESUMO
The multifactorial nature of head and neck squamous cell carcinoma (HNSCC) has led to increased efforts in establishing various risk factors. Well-known environmental risk factors for HNSCC include tobacco use, heavy alcohol consumption, immunosuppression, and more recently human papillomavirus infection. Familial clustering has been observed in cancers occurring at other sites, but not so much with oral squamous cell carcinoma (OSCC) without exposure to shared environmental risk factors. An unusual case of identical twins who presented with OSCC involving an identical site and exhibiting similar histological features is reported here. The two patients underwent identical surgery with curative intent, culminating in good outcomes. It appears that no other cases of identical twins with a similar presentation in time, anatomical site, and histopathology have been reported in the literature.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Infecções por Papillomavirus , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/cirurgia , Humanos , Neoplasias Bucais/patologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Gêmeos MonozigóticosRESUMO
PURPOSE: For oropharynx squamous cell carcinoma (OPSCC) this study aimed to: (i) compare 5-year overall survival (OS) stratification by AJCC/UICC TNM versions 7 (TNMv7) and 8 (TNMv8), (ii) determine whether changes to T and N stage groupings improve prognostication and (iii) develop and validate a model incorporating additional clinical characteristics to improve 5-year OS prediction. MATERIAL AND METHODS: All OPSCC treated with curative-intent at our institution between 2011 and 2017 were included. The primary endpoint was 5-year OS. Survival curves were produced for TNMv7 and TNMv8. A three-way interaction between T, N stage and p16 status was evaluated for improved prognostication. Cox proportional hazards modelling was used to derive a new predictive model. RESULTS: Of 750 OPSCC cases, 574 (77%) were p16-positive. TNMv8 was more prognostic than TNMv7 (concordance probability estimate [CPE]⯱â¯SEâ¯=â¯0.72⯱â¯0.02 vs 0.53⯱â¯0.02). For p16-positive disease, TNMv8 discriminated stages II vs I (HR 2.32, 95% CI 1.47-3.67) and III vs II (HR 1.75, 95% CI 1.13-2.72). For p16-negative disease, TNMv7 and TNMv8 demonstrated poor hazard discrimination. Different T, N stage and p16-status combinations did not improve prognostication after adjusting for other factors (CPEâ¯=â¯0.79 vs 0.79, pâ¯=â¯0.998). A model for p16-positive and p16-negative OPSCC including additional clinical characteristics improved 5-year OS prediction beyond TNMv8 (c-index 0.76⯱â¯0.02). CONCLUSIONS: TNMv8 is superior to TNMv7 for p16-positive OPSCC, but both performed poorly for p16-negative disease. A novel model incorporating additional clinical characteristics improved 5-year OS prediction for both p16-positive and p16-negative disease.
Assuntos
Neoplasias Orofaríngeas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/patologia , PrognósticoRESUMO
A replication-deficient chimpanzee adenovirus expressing Ag85A (ChAdOx1.85A) was assessed, both alone and in combination with modified vaccinia Ankara also expressing Ag85A (MVA85A), for its immunogenicity and protective efficacy against a Mycobacterium tuberculosis (M.tb) challenge in mice. Naïve and BCG-primed mice were vaccinated or boosted with ChAdOx1.85A and MVA85A in different combinations. Although intranasally administered ChAdOx1.85A induced strong immune responses in the lungs, it failed to consistently protect against aerosol M.tb challenge. In contrast, ChAdOx1.85A followed by MVA85A administered either mucosally or systemically, induced strong immune responses and was able to improve the protective efficacy of BCG. This vaccination regime has consistently shown superior protection over BCG alone and should be evaluated further.
Assuntos
Aciltransferases/imunologia , Adenovirus dos Símios/genética , Antígenos de Bactérias/imunologia , Portadores de Fármacos , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Vaccinia virus/genética , Aciltransferases/genética , Animais , Antígenos de Bactérias/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos , Esquemas de Imunização , Camundongos Endogâmicos BALB C , Resultado do Tratamento , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/genética , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologiaRESUMO
BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a better prognosis than those with HPV-negative tumours. There is interest in de-escalating their treatment but strategies are needed for risk stratification to identify subsets with a poor prognosis. This study investigated tumour-infiltrating lymphocytes (TILs) in relation to HPV tumour status and patient survival. METHODS: Biopsies from 218 patients diagnosed with OPSCC between 2002 and 2011, who underwent chemo/radiotherapy were analysed for HPV by PCR, in-situ hybridisation and p16 immunohistochemistry (IHC). One hundred and thirty-nine samples with concordant HPV detection were analysed for CD3, CD4, CD8 and FoxP3 expression in tumour and stromal regions using multiplexIHC and multispectral image analysis. Labelling of smooth muscle actin (SMA) identified activated stroma. RESULTS: Human papillomavirus-positive compared with HPV-negative OPSCC had higher infiltration in both tumour and stromal areas of CD4 and CD8 T cells but not FoxP3 T regulatory cells. Only CD3+CD8+ stromal and not tumour area infiltration was associated with increased survival (P=0.02). There was significantly higher SMA expression in HPV-positive compared with -negative tumours, which did not correlate with survival. CONCLUSIONS: Studies of TILs for risk stratification in OPSCC should assess stromal infiltration.
Assuntos
Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/virologia , Subpopulações de Linfócitos/imunologia , Linfócitos do Interstício Tumoral , Neoplasias Orofaríngeas/imunologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae/isolamento & purificação , Actinas/análise , Antígenos de Neoplasias/análise , Biópsia , Complexo CD3/análise , Antígenos CD4/análise , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/análise , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Fatores de Transcrição Forkhead/análise , Humanos , Imuno-Histoquímica/métodos , Linfócitos do Interstício Tumoral/imunologia , Músculo Liso/química , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/radioterapia , Orofaringe/imunologia , Orofaringe/patologia , PrognósticoRESUMO
Tuberculosis (TB) is a reemerging disease. The only available vaccine, Mycobacterium bovis BCG, is delivered intradermally and confers highly variable efficacy against pulmonary disease. There is an urgent need for improved vaccination strategies. Murine studies suggest that immunizations delivered directly to the respiratory mucosa might be a more effective route of vaccination. This study compared the immunogenicity of a leading candidate tuberculosis (TB) vaccine, modified vaccinia virus Ankara expressing antigen 85A (MVA85A), in rhesus macaques, delivered either as an aerosol or as an intradermal boost immunization 12 weeks after an intradermal BCG prime vaccine. Aerosol vaccination was well tolerated. MVA85A delivered by aerosol or by intradermal injection induced antigen-specific immune responses in the periphery and the lung, with a trend toward the highest response when the compartment and route of delivery were matched. The ability of poxvirus-vectored vaccines delivered by the systemic route to induce responses in the mucosal immune compartment in macaques is in contrast to the independent compartmentalization of mucosal and systemic immune systems described in mice. Unlike intradermal vaccination, aerosol vaccination did not induce a detectable serum anti-vector antibody response. The delivery of vaccines to the lungs might provide an immunization strategy that limits the induction of systemic anti-vector immunity, which would be extremely useful in the development of improved vaccine strategies. This is the first study to show a recombinant MVA-vectored vaccine to be highly immunogenic when delivered by the aerosol route to nonhuman primates. These results provide important safety and proof-of-concept data for further evaluation of this route of immunization for use in human clinical trials.
Assuntos
Vacinas contra a Tuberculose , Tuberculose/imunologia , Tuberculose/prevenção & controle , Administração por Inalação , Animais , Antígenos de Bactérias/imunologia , Líquido da Lavagem Broncoalveolar/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas/imunologia , Imunização Secundária , Macaca , Mycobacterium bovis/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/imunologia , Vacinação , Vacinas Atenuadas/administração & dosagem , Vacinas Atenuadas/efeitos adversos , Vacinas Atenuadas/imunologia , Vacinas de DNA , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologiaRESUMO
AIMS: Nasopharyngeal cancer (NPC) is relatively uncommon, especially in the Western world. We report our single institution experience of 20 years of data in 128 patients with NPC, including responses to different treatment modalities and outcomes by histological subtype. MATERIALS AND METHODS: NPC patients presenting from 1992 to 2005 were located on the cancer registry database. Demographic data included age, gender, length of presenting symptoms and stage. World Health Organization classification (2005) was used for histological subtyping. The date of recurrence and survival outcomes were analysed using Kaplan-Meier curves. RESULTS: Presentation data were analysed from 128 patients; the survival analysis included 123 patients. The median age at presentation was 57.7 years. Stage III and IV presentation rates were 34 and 38%, respectively. The most common presenting symptom was a palpable neck lump (55%) and the median duration of symptoms was 16 weeks. Forty-eight patients received radiotherapy alone and 75 received chemoradiotherapy. The median overall survival in chemoradiotherapy patients was 80.3 months versus 28.5 months with radiotherapy alone (P = 0.003). A significant difference was also seen with recurrence-free survival (RFS) (P = 0.017). Type 1 keratinising carcinoma had a significantly worse overall survival (P = 0.04) and a similar but non-statistically significant trend was seen for RFS (P = 0.051). The multivariate analysis for overall survival showed that histological subtype (hazard ratio 2.7, 95% confidence interval 1.3-5.5, P = 0.034), age (hazard ratio 2.3, 95% confidence interval 1.1-4.9, P = 0.018) and N stage (hazard ratio 3.7, 95% confidence interval 1.4-9.4, P = 0.024) were prognostic factors. CONCLUSIONS: We present the first large-scale, single-centre retrospective review of NPC in a UK-based population. Demographic data were similar to that in other Western populations, with a significantly worse survival outcome in the keratinising group. Further prospective study of outcome in Western populations accounting for newer radiotherapy techniques such as intensity-modulated radiotherapy and dose escalation, particularly in the keratinising population who were more likely to present with an isolated local recurrence, is recommended.
Assuntos
Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Criança , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Nasofaríngeas/patologia , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: To investigate small-nucleolar RNAs (snoRNAs) as reference genes when measuring miRNA expression in tumour samples, given emerging evidence for their role in cancer. METHODS: Four snoRNAs, commonly used for normalisation, RNU44, RNU48, RNU43 and RNU6B, and miRNA known to be associated with pathological factors, were measured by real-time polymerase chain reaction in two patient series: 219 breast cancer and 46 head and neck squamous cell carcinoma (HNSCC). SnoRNA and miRNA were then correlated with clinicopathological features and prognosis. RESULTS: Small-nucleolar RNA expression was as variable as miRNA expression (miR-21, miR-210, miR-10b). Normalising miRNA PCR expression data to these recommended snoRNAs introduced bias in associations between miRNA and pathology or outcome. Low snoRNA expression correlated with markers of aggressive pathology. Low levels of RNU44 were associated with a poor prognosis. RNU44 is an intronic gene in a cluster of highly conserved snoRNAs in the growth arrest specific 5 (GAS5) transcript, which is normally upregulated to arrest cell growth under stress. Low-tumour GAS5 expression was associated with a poor prognosis. RNU48 and RNU43 were also identified as intronic snoRNAs within genes that are dysregulated in cancer. CONCLUSION: Small-nucleolar RNAs are important in cancer prognosis, and their use as reference genes can introduce bias when determining miRNA expression.
Assuntos
Neoplasias da Mama/genética , MicroRNAs/análise , RNA Nucleolar Pequeno/fisiologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma/genética , Carcinoma de Células Escamosas , Feminino , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias de Células Escamosas/genética , Prognóstico , RNA Nucleolar Pequeno/análise , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
BACKGROUND: Mitochondrial DNA (mtDNA) mutations occur in head and neck squamous cell carcinoma (HNSCC) and are most frequently detected in the displacement-loop (D-loop) region. The D-loop is considered to be important because it controls mitochondrial gene expression and mtDNA replication. There is currently no evidence that mtDNA mutations can be used as prognostic or predictive biomarkers in HNSCC. METHODS: We used denaturing high performance liquid chromatography to screen the entire mitochondrial genome of six oral squamous cell carcinoma-derived cell lines and then focused on detecting D-loop abnormalities in 34 HNSCC tissue samples. RESULTS: Mitochondrial DNA mutations are not ubiquitous in HNSCC because only half of the cell lines had detectable mtDNA abnormalities following screening of the entire mitochondrial genome and only 18% (6 of 34) of tissue samples had D-loop mutations. There was no correlation between D-loop mutations and determinates of clinical outcome; specifically, tumour stage and the expression of hypoxia-inducible genes included in a highly prognostic hypoxia metagene. CONCLUSIONS: Taken together, these data suggest that mtDNA D-loop mutations are stochastic events that may not significantly influence the biology of HNSCC and supports the hypothesis that mtDNA mutations in cancer represent bystander genotoxic damage as a consequence of tumour development and progression.
Assuntos
Carcinoma/diagnóstico , Carcinoma/genética , DNA Mitocondrial/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Mutação , Adulto , Idoso , Linhagem Celular , Análise Mutacional de DNA , DNA Mitocondrial/análise , Feminino , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , PrognósticoRESUMO
Burnet proposed in the 1950's that the immune system is engaged in identifying and destroying abnormal cancerous cells. This process, termed immune surveillance, has been at the centre of intense debate for decades. Results using immunodeficient mice lend support to the immune surveillance hypothesis. We surmised that immune surveillance would be hampered by the inhibitory effect of naturally occurring FoxP3(+) regulatory T cells, a population of T cells shown to be present at an increased frequency in a variety of human tumours. The carcinogen, methylcholanthrene was injected subcutaneously into mice and the steady development of fibrosarcomas was observed over approximately 200 days. These fibrosarcomas were strikingly infiltrated with FoxP3(+) regulatory T cells implying that these cells impinge upon immune-mediated rejection of the tumour. This was confirmed by partial ablation of FoxP3(+) regulatory T-cell activity, which resulted in a marked reduction in tumour incidence. The reduction of tumour incidence was ablated in mice that lacked interferon gamma. These data offer strong support for the concept of immune surveillance and indicate that this process is limited by the inhibitory effect of FoxP3(+) regulatory T cells.
Assuntos
Carcinógenos , Fibrossarcoma/imunologia , Sarcoma Experimental/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoanticorpos/análise , Feminino , Fibrossarcoma/induzido quimicamente , Interferon gama/deficiência , Subunidade alfa de Receptor de Interleucina-2/imunologia , Depleção Linfocítica , Metilcolantreno , Camundongos , Camundongos Knockout , Sarcoma Experimental/induzido quimicamenteRESUMO
OBJECTIVES: To investigate whether parents' expectations of their child's fear, distress or pain during a micturating cystourethrogram (MCU) are realized. METHODOLOGY: Prospective study in which parents were asked to fill out two questionnaires using a visual analogue scale, one before (pre) and the other after the MCU procedure (post), was conducted at a tertiary level paediatric hospital in Sydney, Australia. The questionnaires were designed to compare the parents' anticipated and experienced anxiety about their child's procedure and their perception of fear, distress and pain in their child during and after the procedure. The parents' satisfaction with information provided to them on the procedure was also recorded. Twenty-five parents participated in the study. RESULTS: There were significant differences between anticipated and experienced parental anxiety. Parents' reporting of fear, distress and pain in their child during the MCU and after the procedure was lower than they had anticipated. There was a significant correlation between the parents' anxiety and their perception of severity of their child's fear (r = 0.52, P = 0.009), distress (r = 0.48, P = 0.017) and pain (r = 0.50, P = 0.01) during the procedure, but less so with the child's distress after the procedure (r = 0.39, P = 0.059). The parents were satisfied with the information given to them regarding the MCU procedure. CONCLUSIONS: Parents' perception of their child's fear, distress and pain during the MCU, as well as distress following the MCU, was not as severe as they had anticipated. Parental anxiety is an important factor in the perception of fear, distress and pain in children during and after the procedure.
Assuntos
Ansiedade/etiologia , Medo , Dor/psicologia , Pais/psicologia , Percepção , Uretra/diagnóstico por imagem , Bexiga Urinária/diagnóstico por imagem , Micção/fisiologia , Urografia/psicologia , Ansiedade/diagnóstico , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Dor/etiologia , Estudos Prospectivos , Psicologia da Criança , Inquéritos e Questionários , Urografia/efeitos adversosRESUMO
The extent to which a bacterial cocktail containing equal numbers of Pseudomonas fragi NCTC 10689, Listeria monocytogenes BL5/2, Salmonella Typhimurium LT2, and Escherichia coli JM 109 attached to loin surface cuts (7 by 5 cm) derived from steam-pasteurized beef carcasses has been evaluated. The extent of attachment was categorized as loosely attached (removed by rinsing), firmly attached (released by stomaching), and irreversibly bound. No significant difference (P > 0.10) in the attachment of bacteria to steam-pasteurized carcasses was found compared with control loin samples that had received no treatment. No significant difference (P > 0.05) was also found in the attachment strength between the different bacterial species tested. Most bacteria inoculated onto the loin cuts were reversibly bound, since they had been removed by rinsing and stomaching. The irreversible attachment of bacteria to loin cuts was found to vary significantly (P < 0.01) among the different carcass sets used but was independent of whether the carcass had undergone steam pasteurization treatment. Use of a bioluminescent strain of E. coli showed that cells bound preferentially to cut edges and convoluted areas on the loin surface and could not be removed by rinsing. The possible mechanisms of bacterial attachment and the suitability of steam pasteurization to remove contamination incurred during slaughter are discussed.
Assuntos
Aderência Bacteriana , Carne/microbiologia , Vapor , Animais , Bovinos , Escherichia coli/isolamento & purificação , Escherichia coli/fisiologia , Microbiologia de Alimentos , Listeria monocytogenes/isolamento & purificação , Listeria monocytogenes/fisiologia , Pseudomonas/isolamento & purificação , Pseudomonas/fisiologia , Salmonella typhimurium/isolamento & purificação , Salmonella typhimurium/fisiologia , Esterilização/métodosRESUMO
The phase-noise characteristics of a harmonically mode-locked fiber laser are investigated with a new measurement technique called phase-encoded optical sampling. A polarization-maintaining ring laser is mode locked by use of the short-pulse electrical output of a resonant-tunneling diode oscillator, enabling it to produce 30-ps pulses at a 208-MHz repetition rate. The interferometric phase-encoded sampling technique provides 60-dB suppression of amplitude-jitter noise and allows supermode phase noise to be observed and quantified. The white-noise pulse-to-pulse timing jitter and the rms supermode timing jitter of the laser are measured to be less than 50 and 70 fs, respectively.
RESUMO
Unilateral sternocleidomastoid muscle vibration was applied to 21 normal and six unilateral vestibular deafferented (uVD) human subjects at head erect and during 30 degrees left and right whole body roll-tilt. In normal subjects, neck vibration had no effect upon the settings of a visual bar to subjective visual horizontal (SVH) in any roll-tilt condition. In uVD subjects settings to SVH were significantly altered by neck vibration, with ipsilesional neck vibration increasing the SVH bias at head erect. Further, during contralesional roll-tilt, ipsilesional neck vibration in uVD subjects significantly increased the E-effect. These results suggest that compensation after vestibular loss allows cervical signals to influence visual perception of roll-tilt.
Assuntos
Músculos do Pescoço/fisiologia , Propriocepção/fisiologia , Nervo Vestibular/fisiologia , Percepção Visual/fisiologia , Adulto , Denervação , Feminino , Humanos , Masculino , Estimulação Luminosa/métodos , Postura/fisiologia , Valores de Referência , Software , VibraçãoRESUMO
To establish a link between otolith anatomy and function it is necessary to know the regions of the utricular and saccular maculae, which are stimulated by any arbitrary linear acceleration stimulus. That requires accurate information about the location and orientation of the spatially extended maculae in head-fixed coordinates and referred to head-fixed landmarks (such as Reid's line). New data showing the location of the otolithic maculae in the guinea pig with respect to head-fixed stereotaxic coordinates are presented. Guinea pigs were perfused with Karnovsky's fixative and the maculae were exposed while the head was held in a guinea pig stereotaxic device. An electrolytically sharpened fine wire held in a calibrated micromanipulator was touched to points all over the surface of each macula under visual observation with the aid of a high-power operating microscope. The x, y, z coordinates of these points were plotted using a three-dimensional plotting program. Both maculae have pronounced curvature so that dorsoventral shear forces will stimulate regions of both the utricular and saccular maculae.
Assuntos
Máculas Acústicas/anatomia & histologia , Cobaias/anatomia & histologia , Animais , Cabeça/anatomia & histologia , Técnicas EstereotáxicasRESUMO
To test a hypothesis about how otoliths resolve roll-tilts from translations, we measured human ocular torsion position [ocular counterrolling (OCR)] to maintained linear acceleration stimuli. All subjects (n = 8) were tested in two conditions where the same magnitude of shear along an interaural axis was generated in one of two ways: either by roll-tilt on a tilt-chair in a 1-g environment, or by centripetal linear acceleration during constant velocity rotation 1 m from the axis of rotation on a fixed-chair human centrifuge. The interaural shear to the otoliths was the same for these two conditions, but the dorsoventral shear was different and for all eight subjects the OCR on the centrifuge was significantly greater than the torsion on the tilt-chair, although the resultant angle was in fact smaller on the centrifuge than on the tilt-chair. The results confirm that dorsoventral shear is important for determining OCR. The otoliths may resolve potential stimulus ambiguities between tilts and translations by virtue of the different patterns of interaural and dorsoventral shear that these stimuli generate.
Assuntos
Centrifugação , Movimentos Oculares/fisiologia , Postura/fisiologia , Aceleração , Adulto , Humanos , Pessoa de Meia-Idade , Membrana dos Otólitos/fisiologia , Estimulação Física , Estresse MecânicoRESUMO
The authors examined the difference in errors made by eight subjects in setting a bar of light in an otherwise darkened room to either visually perceived vertical (VPV) or visually perceived horizontal (VPH) during maintained roll-tilted positions around the naso-occipital axis. Two viewing distances were examined, 25 and 60 cm. Subjects were tested at roll-tilt angles of 10 degrees intervals from upright to body horizontal (both left ear down (LED) and right ear down (RED)) in a randomized fashion. Settings were made only after a 1 min delay at each tilt angle to allow for decay of the semicircular canal signal. Chair rotation speed was 2 degrees/s with subjects being re-tested using 1/2 degree/s (at 25 cm) to determine the effect of rotation speed. Average errors for vertical versus horizontal were significantly different from each other (P < 0.01) at both the 25 and 60 cm viewing distances. The errors follow a complex function, with VPH showing smaller errors than VPV for large roll-tilts, while the opposite was true for medium-sized roll-tilts. This was true at both chair velocities. That is, VPV and VPH are not orthogonal to one another under the conditions examined. There are large differences between individuals but each individual showed a repeatable pattern. The average extent of non-orthogonality was found to be as high as 7 degrees at some large roll-tilt angles. These findings raise questions about the appropriateness of comparing the results of studies using the different tasks VPV and VPH. Factors that might contribute to this effect are discussed, including somatosensory input and ocular counterrolling (OCR).
Assuntos
Percepção Visual/fisiologia , Adulto , Escuridão , Gravitação , Humanos , Pessoa de Meia-Idade , Rotação , Fatores de TempoRESUMO
Static roll-tilt of normal healthy subjects causes the ocular tilt reaction (OTR) one component of which is disconjugate vertical eye position (skew deviation). In this study the magnitude of skew was measured subjectively by the use of a computerized Hess test at three static roll-tilt angles (head erect, left ear down and right ear down) and two viewing distances (20 cm and 60 cm). The results showed that during static roll-tilt there was a small skew deviation, the magnitude of which was increased at close viewing distances.
Assuntos
Movimentos Oculares/fisiologia , Orientação/fisiologia , Equilíbrio Postural/fisiologia , Testes de Função Vestibular , Vias Aferentes/fisiologia , Convergência Ocular/fisiologia , Lateralidade Funcional/fisiologia , Humanos , Reconhecimento Visual de Modelos/fisiologia , Postura/fisiologia , Desempenho Psicomotor/fisiologia , Valores de Referência , Nervo Vestibular/fisiologiaRESUMO
The cellular concentration of enzymes of some major metabolic pathways, such as glycolysis, can approach millimolarity. This concentration of enzyme can catalyze in vitro rates which are 100-fold higher than maximum pathway flux. In an attempt to understand the need for such high enzyme concentration, an artificial metabolic pathway of five enzymes (apropos the central enzymes of glycolysis) has been modeled. Numerical methods were then used to determine the effect of enzyme concentration on: (1) the change in total free metabolite concentration as the pathway changes from low flux to high flux, (2) the time lag (transient time) in the rate of final product formation upon the transition from low flux to high flux. Both the changes in metabolite pool size and the transient time decreased with increased enzyme concentrations. When all enzymatic reactions were assigned Keq of unity, a concentration for each enzyme of 25 microM is sufficient to provide a transient time of 1 sec. When Keq different from unity are introduced, more enzyme is required to provide comparably short transient times. Under the latter condition, a pathway of sufficiently low transient time would require all the enzyme available in mammalian muscle. It is shown that there is little scope for further increases in either enzyme concentration or of catalytic efficiency of independent enzymes. Therefore, an alternative method of increasing efficiency is considered in which enzyme-bound metabolites can serve directly as substrates for subsequent enzymes in a metabolic pathway.
Assuntos
Células/enzimologia , Enzimas/metabolismo , Animais , Glicólise , Modelos Biológicos , Músculos/enzimologiaAssuntos
Serviços de Saúde da Criança/estatística & dados numéricos , Centros Comunitários de Saúde/estatística & dados numéricos , Pobreza , Adulto , Criança , Serviços de Saúde da Criança/organização & administração , Centros Comunitários de Saúde/organização & administração , Acessibilidade aos Serviços de Saúde , Necessidades e Demandas de Serviços de Saúde , Humanos , Londres , Cooperação do PacienteRESUMO
Following the criticism by Chock and Gutfreund [Chock, P.B. & Gutfreund, H. (1988) Proc. Natl. Acad. Sci. USA 85, 8870-8874], that our proposal of direct transfer of NADH between glycerol-3-phosphate dehydrogenase (alpha-glycerol phosphate dehydrogenase, alpha-GDH; EC 1.1.1.8) and L-lactate dehydrogenase (LDH; EC 1.1.1.27) was based on a misinterpretation of the kinetic data, we have reinvestigated the transfer mechanism between this enzyme pair. By using the "enzyme buffering" steady-state kinetic technique [Srivastava, D.K. & Bernhard, S.A. (1984) Biochemistry 23, 4538-4545], we examined the mechanism (random diffusion vs. direct transfer) of transfer of NADH between rabbit muscle alpha-GDH and pig heart LDH. The steady-state data reveal that the LDH-NADH complex and the alpha-GDH-NADH complex can serve as substrate for the alpha-GDH-catalyzed reaction and the LDH-catalyzed reaction, respectively. This is consistent with the direct-transfer mechanism and inconsistent with a mechanism in which free NADH is the only competent substrate for either enzyme-catalyzed reaction. The discrepancy between this conclusion and that of Chock and Gutfreund comes from (i) their incorrect measurement of the Km for NADH in the alpha-GDH-catalyzed reaction, (ii) inadequate design and range of the steady-state kinetic experiments, and (iii) their qualitative assessment of the prediction of the direct-transfer mechanism. Our transient kinetic measurements for the transfer of NADH from alpha-GDH to LDH and from LDH to alpha-GDH show that both are slower than predicted on the basis of free equilibration of NADH through the aqueous environment. The decrease in the rate of equilibration of NADH between alpha-GDH and LDH provides no support for the random-diffusion mechanism; rather, it suggests a direct interaction between enzymes that modulates the transfer rate of NADH. Thus, contrary to Chock and Gutfreund's conclusion, all our experimental data compel us to propose, once again, that NADH is transferred directly between the sites of alpha-GDH and LDH.