Informing patient choice and service planning in surgical voice restoration: valve usage over three years in a UK head and neck cancer unit.

OBJECTIVE: This study aimed to determine the number, reasons and costs of surgical voice restoration related tracheoesophageal valve attendances over 36 months at a head and neck oncology unit. METHOD: Demographic, medical and valve related details from all patient contacts were recorded, including self-change information, urgent appointment information, modifications required and costs of prostheses. RESULTS: Over 3 years, 99 patients underwent 970 valve changes. The main reasons for changes were central leakage, prophylactic change and self-change at home. Changes were significantly more frequent in the first 12 months (mean, 42 days) compared with longstanding patients (mean, 109.96). Intervals between changes were unpredictable; no predictive factors reached statistical significance. Mean expenditure on valves was £966.63 per week (including value added tax and in-house customisation). CONCLUSION: Valve lifespan is comparable with outcomes in similar units despite more pre-emptive and patient-led changes and more comprehensive data inclusion. Investigation into how patient satisfaction and costs relate to valve selection and units' service delivery models is needed.

Prevalence and characteristics of adults with fetal alcohol spectrum disorder in corrections: a Canadian case ascertainment study.

BACKGROUND: Individuals with fetal alcohol spectrum disorder (FASD) experience a range of cognitive, affective, and physical deficits following prenatal alcohol exposure. They are thought to be overrepresented in criminal justice settings. However, limited evidence is available to inform prevalence. We sought to estimate the prevalence of FASD in a Northern Canadian correctional population. METHODS: Using an active case ascertainment approach we recruited a representative sample of 80 justice-involved adults (ages 18-40, 85% male) over an 18-month period from 2013 to 2015. Participants completed interdisciplinary clinical assessments comprising medical and psychological evaluations that adhered to the 2005 Canadian FASD Diagnostic Guidelines. RESULTS: We identified a high rate of FASD (17.5, 95% CI [9.2, 25.8%]) in this sample, and this rate could have been as high as 31.2% with confirmation of prenatal alcohol exposure. Most participants in this study presented with significant neurodevelopmental and cognitive deficits in at least two domains of functioning, irrespective of diagnosis, with only five of 80 participants (6.3%) demonstrating no cognitive impairment. CONCLUSIONS: Findings showed disproportionately high estimated FASD prevalence in this representative sample compared to general population estimates in both Canada and the U.S. (2-5%), underscoring the need for improved FASD screening and diagnosis in correctional settings, and education for clinicians working in the justice context. Strengthened health prevention and intervention efforts to support the needs of individuals with FASD outside the criminal justice context are needed.

Recognition by family members that relatives with neurodegenerative disease are likely to die within a year: a meta-ethnography.

OBJECTIVE: To synthesize evidence of family members recognizing that their relative is likely to die within the year, and identifying the need for palliative care. DESIGN: A meta-ethnography of studies of family members in multiple sclerosis (MS), Parkinson's disease (PD) and motor neuron disease (MND). REVIEW METHODS: Systematic search in electronic databases; thematic synthesis guided by the principles of meta-ethnography, which is a method for thematic synthesis of qualitative studies. RESULTS: Nine articles were included. The results of the synthesis identified two key themes. First, family members are intimately aware of changes in their relative's health and well-being. Sub-themes include family member awareness of different and progressive stages of the disease, noticing deterioration, noticing decline in functional abilities and recognizing that their relative will die. The second key theme is dilemmas of being involved in prognostication. Sub-themes include family member ambivalence toward hearing about prognostication, health professionals not being knowledgeable of the disease and family reluctance to receive palliative care. CONCLUSIONS: Family members monitor and recognize changes in their relative with PD, MND and MS and in themselves. Thus, drawing on the expertise of family members may be a useful tool for prognostication.

Impaired non-esterified fatty acid suppression to intravenous glucose during late pregnancy persists postpartum in gestational diabetes: a dominant role for decreased insulin secretion rather than insulin resistance.

AIMS/HYPOTHESIS: Non-esterified fatty acids are implicated in the pathogenesis of gestational (GDM) and type 2 diabetes. We examined the relationship between NEFA dynamics, insulin resistance and beta cell dysfunction in women with GDM in late pregnancy and postpartum. METHODS: A total of 19 Caucasian women with GDM and 19 healthy pregnant women matched for BMI and age underwent an IVGTT in the third trimester and 4 months postpartum, deriving values for insulin sensitivity (SI), insulin secretion (AIRg) and disposition index (DI). NEFA levels were measured serially. RESULTS: In pregnancy, the GDM women had similar SI but reduced AIRg and DI compared with control subjects. The GDM group demonstrated significantly slower NEFA suppression, which was attributable to the GDM women who required insulin during pregnancy (n=7) and who had markedly reduced AIRg and K(NEFA) (NEFA disappearance constant) compared with their matched controls. In contrast, GDM subjects not requiring insulin (n=12) had similar NEFA suppression curves and AIRg to control subjects. Postpartum, GDM subjects demonstrated reduced SI and DI. The impaired suppression of NEFA persisted postpartum, but again only in the subgroup of GDM subjects who had required insulin during pregnancy. Furthermore, K(NEFA) correlated with AIRg and DI in both states, but not with SI. CONCLUSIONS/INTERPRETATION: Impaired NEFA suppression occurs in GDM subjects both in late pregnancy and postpartum in response to IVGTT-induced endogenous insulin secretion. The impaired NEFA suppression is present in GDM women with the most severe beta cell dysfunction (who had required insulin during pregnancy) and is related to their insulin secretory dysfunction rather than their reduced SI.

The impact of acute elevation of non-esterified fatty acids on insulin sensitivity and secretion in women with former gestational diabetes.

OBJECTIVES: Elevations in non-esterified fatty acids (NEFA) have been shown to decrease insulin action and secretion, and are a risk factor for the development of Type 2 diabetes. As women who have had gestational diabetes (GDM) are at increased risk of diabetes, we examined the effect of an acute elevation of NEFA on insulin secretion and action in these women. PATIENTS AND DESIGN: Nineteen women with recent former GDM and 19 age- and BMI-matched postpartum healthy control subjects underwent a 40-min intravenous glucose tolerance test, with and without a preceding 2-h infusion of 20% Intralipid. Insulin action was assessed by glucose disappearance (Kg) and insulin sensitivity (SI); insulin secretion by first phase insulin release (FPIR) and disposition index (DI). RESULTS: NEFA levels were similarly elevated in both groups by the Intralipid infusion (up to 1.140 +/- 0.03 mm). As expected, the lipid infusion significantly reduced Kg (2.15 +/- 0.13 vs. 1.69 +/- 0.09/min, P < 0.001) and SI (3.14 +/- 0.28 vs. 2.13 +/- 0.17/min/mUl/min, P < 0.001) in all subjects, and these were significant within the GDM and control subgroups. FPIR was elevated in the Intralipid study in the total group of women (4.50 +/- 0.50 vs. 5.02 +/- 0.53, P = 0.02), but DI was significantly reduced (12.13 +/- 1.1 vs. 8.83 +/- 0.7, P < 0.001). There was no significant difference, however, in the absolute or percentage change in Kg, SI or FPIR with lipid infusion between the GDM and control groups. GDM status was not a predictor of the response of Kg, SI or FPIR to lipid infusion, rather, adiposity (% fat), average fasting NEFA levels and basal disposition index were associated. CONCLUSION: These data suggest that women with former gestational diabetes, in contrast to other prediabetic states, are not more susceptible to the deleterious effects of an acute elevation in nonesterified fatty acids than matched control subjects.

Human masticatory muscle forces during static biting.

Muscle forces determine joint loads, but the objectives governing the mix of muscle forces involved are unknown. This study tested the hypothesis that masticatory muscle forces exerted during static biting are consistent with objectives of minimization of joint loads (MJL) or muscle effort (MME). To do this, we compared numerical model predictions with data measured from six subjects. Biting tasks which produced moments on molar and incisor teeth were modeled based on MJL or MME. The slope of predicted vs. electromyographic (EMG) data for an individual was compared with a perfect match slope of 1.00. Predictions based on MME matched best with EMG activity for molar biting (slopes, 0.89-1.16). Predictions from either or both models matched EMG results for incisor biting (best-match slopes, 0.95-1.07). Muscle forces during isometric biting appear to be consistent with objectives of MJL or MME, depending on the individual, biting location, and moment.

Reduced utilization of Man5GlcNAc2-P-P-lipid in a Lec9 mutant of Chinese hamster ovary cells: analysis of the steps in oligosaccharide-lipid assembly.

Recently we reported that CHB11-1-3, a Chinese hamster ovary cell mutant defective in glycosylation of asparagine-linked proteins, is defective in the synthesis of dolichol [Quellhorst et al., 343:19-26, 1997: Arch Biochem Biophys]. CHB11-1-3 was found to be in the Lec9 complementation group, which synthesizes polyprenol rather than dolichol. In this paper, levels of various polyprenyl derivatives in CHB11-1-3 are compared to levels of the corresponding dolichyl derivatives in parental cells. CHB11-1-3 was found to maintain near normal levels of Man5GlcNAc2-P-P-polyprenol and mannosylphosphorylpolyprenol, despite reduced rates of synthesis, by utilizing those intermediates at a reduced rate. The Man5GlcNAc2 oligosaccharide attached to prenol in CHB11-1-3 cells and to dolichol in parental cells is the same structure, as determined by acetolysis. Man5GlcNAc2-P-P-polyprenol and Man5GlcNAc5-P-P-dolichol both appeared to be translocated efficiently in an in vitro reaction. Glycosylation of G protein was compared in vesicular stomatitus virus (VSV)-infected parent and mutant; although a portion of G protein was compared in vesicular stomatitus virus (VSV)-infected parent and mutant; although a portion of G protein was normally glycosylated in CHB11-1-3 cells, a large portion of G was underglycosylated, resulting in the addition of either one or no oligosaccharide to G. Addition of a single oligosaccharide occurred randomly rather than preferentially at one of the two sites.

Canine retraction with rare earth magnets: an investigation into the validity of the constant force hypothesis.

The objective of this study was to test the hypothesis that a prolonged constant force provides more effective tooth movement than an impulsive force of short duration. Six human subjects were selected, the main criterion being a need for extraction of their upper first premolars. Canine retraction on these subjects was executed on one side with the application of a force rapidly declining in magnitude, produced by a vertical loop, and on the other side with the application of a relatively constant force. This type of force was achieved by a similar vertical loop which was constantly activated by three parylene-coated neodymium-iron-boron (Nd2Fe14P) block magnets. The vertical loop on the control side was reactivated 6 weeks after the initial activation. No reactivation was necessary on the experimental side for the duration of the experiment. The rate of tooth movement on the two sides was compared over a period of 3 months, on the basis of maxillary impressions taken at frequent intervals during the course of the study. The canines retracted with a constant force moved statistically significantly more than the control canines (p < 0.05) during the experimental period. The average differences in the mean rates of tooth movement between the two sides were in the order of 2:1 in favor of the experimental side. There were no statistically significant differences in the changes of angulation (tipping) or rotation about the y axis between the two sides. The duration of force application seems to be a critical factor in regulating rate of tooth movement. Conversely, magnitude of the applied force did not appear to be of primary significance.

Modelling of forces in the human masticatory system with optimization of the angulations of the joint loads.

Numerical models of the human masticatory system were constructed using algorithms which minimized non-linear functions of the muscle forces or the joint loads. However, the predicted solutions for isometric biting were critically dependent upon the modelled angular freedom of the joint loads. The most complete mathematical minimization of any objective function occurs when the joint load angles are predicted. However, the predictions have to be sensible in relation to the actual morphology of the joints. Therefore, the models were tested in terms of the angles of joint load predicted for a dry skull, using muscle vectors reconstructed from the geometry of the skull. The minimizations of muscle force were intrinsically incapable of predicting the angles of joint load. Such models must rely on constrained angles and this produces a restricted minimization and also an indeterminacy. In contrast, the minimizations of joint load predicted angles of joint load which varied appropriately with condylar position. The condylar movement was achieved with a positioning model which adjusted the angulation of the muscle vectors as the jaw was positioned. This model also generated the optimal sagittal shape of the articular eminence. Muscle predictions from the various models were not examined in detail, but the general nature of the predicted muscle force patterns was shown to be reasonable in some of the models and unreasonable in others. The results supported the hypothesis that the temporomandibular joint develops functionally to allow an approximate minimization of the joint loads during isomeric biting. This does not necessarily imply that the neurophysiological control is actually based on a minimization of joint load.

Three enzymes involved in oligosaccharide-lipid assembly in Chinese hamster ovary cells differ in lipid substrate preference.

Initial steps in N-linked glycosylation involve formation of a large oligosaccharide structure on a lipid carrier, dolichyl phosphate. We have previously characterized Chinese hamster ovary (CHO) glycosylation mutants (Lec9 cells) that utilize the polyisoprenoid lipid polyprenyl phosphate rather than dolichyl phosphate in these glycosylation reactions. Polyprenyl phosphate differs from dolichyl phosphate only in the degree of saturation of its terminal isoprenyl unit. Our goal was to determine whether the glycosylation defect of Lec9 cells could be explained simply by knowing lipid substrate preferences of the enzymes involved in the assembly of oligosaccharide-lipid (OSL) intermediates. In this study, we have used in vitro assay systems to compare the ability of dolichyl phosphate and polyprenyl phosphate to act as substrates for three glycosyl transferase enzymes involved in OSL assembly. In order to insure that we were only examining lipid substrate preferences of the enzymes and not other potential defects present in Lec9 cells, we used membranes prepared from wild-type cells in these in vitro reactions. Our results indicate that one of the enzymes, mannosylphosphoryldolichol (MPD) synthase, exhibited a significant preference for the dolichol substrate. Glucosylphosphoryldolichol (GPD) synthase, on the other hand, showed no binding specificity for the dolichol substrate, although the enzyme used the dolichol substrate at a twofold higher rate. N,N'-diacetyl-chitobiosylpyrophosphoryldolichol (CPD) synthase was able to use either lipid substrate with equal efficiency. These results suggest that not all glycosyl transferases in this pathway show a preference for dolichol derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro measurement of the stress-distribution properties of the pig temporomandibular joint disc.

An in vitro experimental technique was developed to measure the stress-distribution properties of this disc. Discs were tested for conditions of increasing load and decreasing congruity between loading surfaces. Peak stresses and pressure gradients increased linearly as load on the disc increased. For a given load, as congruity of the surfaces decreased, pressure gradients increased. The results demonstrate that the disc has only a limited capacity for stress distribution. Disc thickness was a critical factor determining the peak stresses measured under the disc.

An analysis of surface congruity in the growing human temporomandibular joint.

The influence of condylar position on congruity of the surfaces of the temporomandibular joint (TMJ) was determined. The degree of congruity between the loading surfaces of the condyle and the eminence varied depending on condylar position. Better congruity of surfaces was found in condylar positions consistent with molar biting. Incongruity between surfaces occurred more frequently at the crest of the TMJ eminence and was related to the degree of eminence development. The evidence supports an hypothesis that growth of the TMJ eminence creates incongruities between loading surfaces that predispose to stress concentrations in the anterior regions of the articular surfaces. The findings may help to explain why degenerative lesions commonly occur at the crest of the eminence.

In vitro measurement of the frictional properties of the temporomandibular joint disc.

The integrity of the articulating surfaces of the temporomandibular joint (TMJ) is likely to be promoted by the control of stresses due to frictional forces between moving joint surfaces. Using a pendulum designed to measure the friction on the surface of the pig TMJ disc, factors such as duration of loading and degree of hydration of the disc were found to influence the amount of friction and the time-dependent changes in friction on the disc surface. The tests provide evidence in support of the hypothesis of 'weeping lubrication' on the surface of the TMJ disc.

Mammalian glycosyltransferases prefer glycosyl phosphoryl dolichols rather than glycosyl phosphoryl polyprenols as substrates for oligosaccharyl synthesis.

We have studied the effectiveness of polyprenyl-P-mannose and polyprenol-P-glucose as donor substrates for the dolichyl-P-mannose:Man5(GlcNAc)2-PP-dolichol mannosyltransferase and the dolichyl-P-glucose:Man9(GlcNAc)2-PP-dolichol glucosyltransferase, respectively. The polyprenol moiety differs from dolichol only in the unsaturation of the terminal isoprene unit of the molecule. Based on the kinetics of the reactions, we have found that both glycosyltransferases have higher apparent Kms and lower apparent Vmaxs using polyprenyl-P-monosaccharides as substrates rather than the dolichyl-P-monosaccharides. The products formed with the polyprenyl-P-sugars were the same as those formed by the dolichol-linked sugars, indicating that the polyprenol substrates could be utilized by the glycosyltransferases in vitro. The results also indicate that the dolichyl-P-sugars and the polyprenyl-P-sugars compete for the same binding site on the enzyme. These findings are significant in terms of understanding the glycosylation phenotypes of Chinese hamster ovary cell mutants of the Lec9 complementation group, which lack the ability to convert polyprenol into dolichol.

Mutants in dolichol synthesis: conversion of polyprenol to dolichol appears to be a rate-limiting step in dolichol synthesis.

Chinese hamster ovary (CHO) cells of the Lec9 recessive complementation group display a distinctive profile of resistance to a variety of toxic lectins. In addition, they accumulate cis-alpha-unsaturated polyprenol and use mainly polyprenol rather than dolichol to synthesize the glycosylated lipids used in asparagine-linked glycosylation of proteins. The primary defect in these cells is thought to result from a deficiency in polyprenol reductase activity. Three new mutants were isolated and determined to have qualitatively, although not quantitatively, similar lectin resistance profiles to Lec9 cells. Two of these mutants (AbrR and RicR) also contained polyprenol rather than dolichol. The lectin resistance profile of an independent mutant which accumulates polyprenol, F2A8, was also found to be qualitatively similar to the Lec9 pattern. The relationship among these mutants was analysed in more detail by construction of cell-cell hybrids. Lectin resistance profiles of the hybrids demonstrated that AbrR, RicR and F2A8 fell into the Lec9 complementation group. Analysis of prenols in the hybrids also showed that F2A8 was a member of the Lec9 group. Surprisingly, a significant fraction of the prenols found in Lec9 x Parent hybrids was polyprenol (up to 30% of the neutral fraction), whereas the prenols found in Parent x Parent hybrids were nearly exclusively dolichol (97% of the neutral lipid fraction). Therefore, reduction of polyprenol to dolichol appears to be a rate-limiting step in the synthesis of dolichol since hybrids with differing numbers of wild-type alleles can be biochemically distinguished.

Substrate specificity of N-acetylglucosamine 1-phosphate transferase activity in Chinese hamster ovary cells.

The assembly pathway of the oligosaccharide chains of asparagine-linked glycoproteins in mammalian cells begins with the formation of GlcNAc-PP-dolichol in a reaction catalysed by the enzyme N-acetylglucosamine 1-phosphate transferase. We have investigated the efficiency of two lipid substrates for the transferase activity in an in vitro assay using Chinese hamster ovary (CHO) cell membranes as an enzyme source. Experiments were carried out with varying concentrations of dolichyl phosphate or its precursor, polyprenyl phosphate. We determined that enzyme activity was optimal at pH 9, where the enzyme exhibited a 3-fold higher Vmax and a 2-fold lower Km for the dolichol substrate. At pH 7.4, the Km and Vmax differences between the two lipids were 10-fold. Under all assay conditions tested, we found that GlcNAc-PP-lipid was the only product formed. We conclude from these results that dolichyl phosphate rather than polyprenyl phosphate is the preferred substrate for the transferase enzyme in CHO cells. This observation is significant in light of the fact that we have previously isolated CHO glycosylation mutants which fail to convert polyprenol into dolichol, and hence utilize polyprenyl derivatives for glycosylation reactions. Thus, these results contribute to our understanding of the glycosylation defects in the mutant cell lines.

The effect of an applied potential on the activity of carbonic anhydrase immobilized on graphite rods.

The effect of both a positive and a negative applied potential on the p-NPA hydrolysis activity of bovine carbonic anhydrase (BCA) immobilized on graphite rods has been investigated. Background experiments show that the pH-activity profile for BCA free in solution is not affected by either a negative or a positive potential applied to graphite rods placed in the same solution. However, the activity of BCA immobilized by covalent attachment to a graphite rod is influenced by a potential externally applied to the graphite rod. An overall increase in activity (as determined by the initial rate of the p-NPA hydrolysis reaction) is observed in the presence of a -0.2 V (Ag/AgCl) applied potential, while decreased activity is evident at +0.6 V (Ag/AgCl). This is indicative of an electrolyte anion effect rather than a local pH effect. In the presence of the specific anion inhibitors Cl(-) and SCN(-), the relative BCA activity increases at -0.2 V (Ag/AgCl) and decreases at +0.6 V (Ag/AgCl) are consistent with the different BCA inhibition constants for Cl(-) and SCN(-). Accelerated loss of immobilized BCA activity also accompanies the application of the external potentials, particularly at +0.6 V (Ag/AgCl). Results described here represent an early example of potentiostatic control of nonredox enzyme activity. Several possible mechanisms are discussed including specific anion inhibition, enzyme surface charge/charged support material interactions, and charged product inhibition. It is likely that a combination of such mechanisms is operational in this system. The implications of external potentials affecting the activity of immobilized enzymes in the design of stable immobilized enzyme electrodes are also discussed.