Use of Hyaluronic Acid Filler in Patients with Secondary Cleft Lip Deformity.

METHODS: Retrospective case note review was undertaken of all patients treated in the clinic over a two-year period. RESULTS: 20 patients underwent HA filler injections to the upper lip 26 times. Most were female (F:M = 3:1) and patients were aged 18-58 years. Most patients had a unilateral cleft lip +/- palate (n = 13, 65%). The most common indication was to address upper lip volume (n = 13, 65%). Other indications included vermillion notch (n = 5, 25%), cupid bow peak height asymmetry (n = 4, 20%), scar asymmetry (n = 1, 5%) and nasal sill flattening (n = 1, 5%). Small volumes of filler were used with an average of 0.34 ml (range 0.05-1.2 ml). There were no complications and one patient reported pruritis post procedure. CONCLUSIONS: HA filler is a safe and reliable treatment for certain aspects of asymmetry following cleft lip repair. It can be used to address volume deficiency and asymmetry, cupid bow peak height discrepancies and a vermillion notch for patients who do not want surgery. Injection of HA to the lips can be performed easily, with appropriate training, in the outpatient setting.

Socioeconomic influence on orofacial cleft patient care.

BACKGROUND: Cleft lip and palate is the most common craniofacial birth defect in the UK. Orofacial clefts have functional and aesthetic implications requiring intensive multi-disciplinary follow-up to optimise development. Failure to attend follow-up is likely to have a negative impact on patient outcomes. The aim of this retrospective audit is to establish if socioeconomic status influences attendance, DNA and cancellation rates in cleft patients. METHODS AND RESULTS: A retrospective audit of 74 orofacial cleft patients born and operated on at the Royal Hospital for Sick Children Glasgow between 2006 and 2007. There was higher rate of DNA in more deprived social groups-21% (SIMD 1) against 10% (SIMD 5). A higher rate of DNA in cleft lip and palate patients was noted. This group of patients showed a marked difference in attendance between SIMD 1 (38%) and SIMD 5 (78%). CONCLUSION: More deprived areas have a higher outpatient DNA rate for cleft patients resulting in suboptimal follow-up. Ultimately, causation of poorer outcomes in this group is likely to be multi-factorial but the financial implication of travelling to multiple clinics should be considered and it may be that resource reallocation is the answer to address the current inequality of health care provision.

Tetrodotoxin blocks a graded sensory response in the eye of Limulus.

The generalization that tetrodotoxin selectively blocks all-or none electrical activity of nerve and muscle but has negligible effect upon graded responses of sensory systeins does not appear to be valid for the Limulus eye. Tetrodotoxin reversibly blocks the graded transient component of this visual response, while the steady state component of the response is rela tively unaffected by the drug.

The ectodomain of HA2 of influenza virus promotes rapid pH dependent membrane fusion.

To better understand the roles of different regions of influenza hemagglutinin in membrane fusion, we have studied the fusion properties of large unilamellar vesicles in the presence of constructs comprising the 127 amino acid ectodomain of the HA2 fragment (FHA2) as well as mutated forms of FHA2 containing single amino acid substitutions, the 95 amino acid truncated form of FHA2 lacking the N-terminal fusion peptide (SHA2), the 20 amino acid N-terminal fusion peptide and the ten amino acid peptide corresponding to the kinked loop region of FHA2. The 100 nm liposomes were made from dioleoylphosphatidylethanolamine, dioleoylphosphatidylcholine and cholesterol in equimolar ratio. At pH 5 a high rate of lipid mixing was observed with FHA2 present, even at very low molar concentrations, whereas much lower rates were observed using the shorter constructs: SHA2, the fusion peptide, and the loop peptide. Concentrations of FHA2 which promoted extensive lipid mixing also induced leakage of aqueous contents. Marked effects of FHA2 were also observed with liposomes of egg phosphatidylcholine. All of the changes observed with the liposomes were highly pH-dependent, with only negligible changes occurring at pH 7. The results demonstrate the potent action of FHA2 in promoting lipid mixing and demonstrate the contribution of other regions of the ectodomain of FHA2, in addition to the fusion peptide, to the mechanism of acceleration of membrane fusion. The results also indicate that the pH dependence of fusion is not due solely to changes in the interactions between the HA1 and HA2 subunits. Thus, the "spring loaded energy" is not required to bring about the apposition of the two membranes, considering that FHA2 is already in its thermostable conformation. The acidic amino acid residues in the kinked loop region appear to play a particularly important role in the pH-dependent fusion process as demonstrated by the marked loss of lipid mixing activity of mutant forms of FHA2.

Effects on exercise tachycardia during forty-eight hours of a series of doses of atenolol, sotalol, and metoprolol.

Beta adrenoceptor blockers differ mainly in their plasma elimination half-lives (t 1/2 s). It has been assumed that drugs with longer t 1/2 will have a longer duration of effect on exercise tachycardia. Several factors may influence the duration of action of beta blockers; we have investigated the contribution of plasma elimination t 1/2 and dose by comparing the effects on an exercise tachycardia in healthy subjects of placebo, 25, 50, 100, and 200 mg of atenolol and of sotalol, and 50, 100, 200, and 400 mg metoprolol. Subjects exercised before and at 2, 3, 6, 8, 24, 33, and 48 hr after oral doses of each drug. Plasma samples for measurement of drug concentration were drawn before each exercise period. Twenty-four hours after 50, 100, and 200 mg atenolol and 50, 100, 200, and 400 mg sotalol there were reductions in an exercise tachycardia; at this time reductions were greater after the larger doses. The plasma elimination t 1/2s of atenolol were between 7.2 +/0 1.0 hr. Although 50, 100, and 200 mg metoprolol induced the same reductions in an exercise tachycardia 2 hr after drug as 25, 50, and 100 mg atenolol and 50, 100, and 200 mg sotalol, these doses were without effect at 24 hr. Metoprolol 400 mg reduced exercise tachycardia at 24 hr but the effect was less than that of the three largest doses of atenolol and sotalol. The plasma elimination t 1/2 for metoprolol was between 3.6 +/- 0.6 and 5.0 +/- 1.8 hr. These results show that duration of cardiac beta blocking of cardiac beta blocking activity of atenolol, sotalol, and metoprolol is determined by the elimination t 1/2 and dose.

Termination of electroreceptor and mechanical lateral line afferents in the mormyrid acousticolateral area.

The projection regions of electroreceptor and mechanical lateral line afferents in electric fish of the mormyridae family are described. Electroreceptor afferents from the posterior dorsal skin run in the dorsal branch of the posterior lateral line nerve. Electroreceptor afferents from ventral skin and mechanical lateral line afferents and efferents run in the ventral branch of the nerve. Horseradish peroxidase (HRP) injections into each branch resulted in filling of its central terminals with the marker enzyme. The method yields a Golgi-like staining of afferent terminals, allowing some aspects of their morphology to be described. Comparison of results from dorsal and ventral branch injections shows the separate medullary regions to which electroreceptor and mechanical afferents project, and also demonstrates four separate somatotopic maps within the electroreceptor region. Mechanical afferents end predominantly ipsilaterally in nucleus anterior and eminentia granularis as has been suggested by others. Ipsilateral endings in nucleus octavius are also seen. Electroreceptor afferents end exclusively in the cortex and nucleus of posterior lateral line lobe (PLLL). Within the cortex there are three distinct maps of the skin surface which are separated from each other by discontinuities in the cellular layers. Somatotopic mapping is also present in the nucleus of PLLL though it is less precise than in the cortical zones. Large club endings of the cells of this nucleus are filled with HRP. Labeled cells are seen within a small midline nucleus located at the level of the eighth nerve just above the medial longitudinal fasciculus. These are probably the cell bodies of lateral line efferents.

Effect of electric organ discharge on ampullary receptors in a mormyrid.

(1) Afferents from ampullary receptors were shown to be strongly affected by the electric organ discharge (EOD) in the mormyrid Gnathonemus petersii. (2) Over a broad range of resistivities (4-60 komegacm) the response to the EOD was similar to the response to a brief (50-200 microsec) outside positive pulse, i.e. an initial acceleration of the discharge rate followed by a deceleration. (3) Brief biphasic positive-negative or negative-positive pulses where both phases were of equal amplitude and duration had no effect on ampullary afferents. Each phase had an effect, however, when given in isolation. These results suggest that a DC component in the EOD may cause the response in the ampullary afferent. (4) The response of ampullary afferents decreased sharply as resistivity was lowered below 10komegacm. Responses to the EOD in mormyromast afferents also decreased. These effects were probably due to loading of the EOD at low resistivities and to a more rapid spatial decay of EOD voltage. (5) Responses of ampullary afferents to the EOD were much less affected by external non-conducting objects than were the responses of mormyromasts. These observations plus other considerations indicate that mormyromasts must still be held to play the major role in active electrolocation. Unresponsiveness of ampullary afferents to the EOD can not be taken as a reason for this, however.

A longitudinal study of top-level executive performance.

Competency ratings were obtained from a hybrid selection system on 98 top-level executives in a predictive validity design. Hierarchical linear modeling results indicated that "resource problem-solving-oriented" competency ratings predicted initial performance. "People-oriented" competency ratings predicted subsequent performance trends. Utility estimates suggested that the system generated an additional $3 million in annual profit per candidate selected. Groups of executives with similar performance trends were identified who had encountered qualitatively different situational circumstances. Findings imply that a model of executive performance must contain main effects for person (competencies) and situation (economic-industrial) characteristics on both subsequent performance and performance trends. Future research needs to examine which situational circumstances moderate relationships between executive competencies and initial performance or subsequent performance trends.

Moderated regression analysis and Likert scales: too coarse for comfort.

One of the most commonly accepted models of relationships among three variables in applied industrial and organizational psychology is the simple moderator effect. However, many authors have expressed concern over the general lack of empirical support for interaction effects reported in the literature. We demonstrate in the current sample that use of a continuous, dependent-response scale instead of a discrete, Likert-type scale, causes moderated regression analysis effect sizes to increase an average of 93%. We suggest that use of relatively coarse Likert scales to measure fine dependent responses causes information loss that, although varying widely across subjects, greatly reduces the probability of detecting true interaction effects. Specific recommendations for alternate research strategies are made.

Neuronal responses to electrosensory input in mormyrid valvula cerebelli.

1. We have examined a large portion of the valvula cerebelli of the mormyrid fish Gnathonemus petersii for responses related to the three known classes of electroreceptors. Evoked potential and extracellular single-unit records from curarized and non-curarized preparations show that a separate area of the valvula is related to each of the different electrosensory modalities. 2. The area related to ampullary receptors is also strongly affected by mechanical stimulation to the skin. In the mormyromast and Knollenorgan regions, responses to sensory stimuli depend on when they are given in relation to the command to fire the electric organ. In the Knollenorgan region the interaction is quite simple. Responses are completely blocked if the stimulus is given during a brief period when the electric organ discharge occurs. A greater variety of interactions is seen in the mormyromast region. 3. Large areas of the valvula do not appear to be clearly and strongly retated to any of the three electrosensory modalities, suggesting the possibility that much of the structure is not devoted to electrosensory processing.

Electrosensory pathways to the valvula cerebelli in mormyrid fish.

The valvula cerebelli of mormyrid fish has been implicated in the electroreceptive capabilities of these animals. This study uses peroxidase and tritiated amino acid tracing techniques to examine the pathways by which electroreceptive information gains access to the valvula. Ampullary and mormyromast receptor information reaches the medial and ventrolateral portions of the valvula by means of a large, direct projection from n. lateralis, part of the midbrain electrosensory area. In addition, smaller indirect n. lateralis-valvular projections travel via a pretectal nucleus and the so-called postventral thalamic nucleus, Knollenorgan receptor information ends in the dorsolateral portion of the valvula. A small, relatively direct pathway runs via n. medialis ventralis, but most Knollenorgan information appears to travel via an indirect system involving n. extrolateralis pars posterior and n. isthmi. The lateral line processing areas of the valvula project back onto many of the midbrain electrosensory nuclei. These results indicate that much of the cerebellum of this family is devoted to sensory processing rather than motor functions.

Central connections of the posterior lateral line lobe in mormyrid fish.

Primary electroreceptor afferents terminate in the posterior lateral line lobe (PLLL) in electroreceptive teleosts. This paper examines the central connections of PLLL in fish of the family Mormyridae using horseradish peroxidase and tritiated amino acid tracing techniques. Some connections of the closely related lobus caudalis of the cerebellum are also examined. There are three zones on each side of the mormyrid PLLL cortex. Two receive input from mormyromast receptors, and one from ampullary receptors. An intrazonal projection system, intrinsic to PLLL, connects neighboring points within each zone. It also joins corresponding zones on the two sides of the body via commissural fibers. An interzonal system connects the two mormyromast zones on the same side of the midline. Central structures which project to PLLL include lobus caudalis, nucleus paratrigeminalis lateralis, and nucleus praeeminentialis. Nucleus praeeminentialis projects bilaterally and somatotopically to the lower molecular layer of PLLL. PLLL cortex projects bilaterally and somatotopically to two major mesencephalic sites: n. praeeminentialis, and n. lateralis. Somatotopically corresponding points in each zone of PLLL cortex project to the same small region of n. lateralis. Nucleus lateralis has a large and somatotopically organized projection to n. praeeminentialis. The afferent and efferent connections of lobus caudalis are similar to those of PLLL, indicating its close association with the electrosensory system. The anatomical results show that there is ample opportunity for electrosensory information arising on left and right sides of the body to interact centrally. One can suggest that comparison of afferent input from the two sides would reduce the non-significant variability which affects both of them equally. The results also show the presence of several somatotopically organized feedback lops which return the results of higher order processing of electrosensory information to earlier stages.

Fusion protein of the paramyxovirus SV5: destabilizing and stabilizing mutants of fusion activation.

The fusion (F) protein of the paramyxovirus SV5 strain W3A causes syncytium formation without coexpression of the SV5 hemagglutinin-neuraminidase (HN) glycoprotein, whereas the F protein of the SV5 strain WR requires coexpression of HN for fusion activity. SV5 strains W3A and WR differ by three amino acid residues at positions 22, 443, and 516. The W3A F protein residues P22, S443, and V516 were changed to amino acids found in the WR F protein (L22, P443, and A516, respectively). Three single-mutants, three double-mutants, and the triple-mutant were constructed, expressed, and assayed for fusion using three different assays. Mutant P22L did not cause fusion under physiological conditions, but fusion was activated at elevated temperatures. Compared with the W3A F protein, mutant S443P enhanced the fusion kinetics with a faster rate and greater extent, and had a lower activation temperature. Mutant V516A had little effect on F protein-mediated fusion. The double-mutant P22L,S443P was capable of causing fusion, suggesting that the two mutations have opposing effects on fusion activation. The WR F protein requires coexpression of HN to cause fusion at 37 degrees C, and does not cause fusion at 37 degrees C when coexpressed with influenza virus hemagglutinin (HA); however, at elevated temperatures coexpression of WR F protein with HA resulted in fusion activation. In the crystal structure of the core trimer of the SV5 F protein (Baker, K. A., Dutch, R. E., Lamb, R.A., and Jardetzky, T. S. (1999). Mol. Cell 3, 309-319), S443 is the last residue (with interpretable electron density) in an extended chain region and the temperature factor for S443 is high, suggesting conformational flexibility at this point. Thus, the presence of prolines at residues 22 and 443 may destabilize the F protein and thereby decrease the energy required to trigger the presumptive conformational change to the fusion-active state.

The membrane affinities of the aliphatic amino acid side chains in an alpha-helical context are independent of membrane immersion depth.

Understanding, predicting, and designing the binding of peptides and proteins to bilayers require quantifying the intrinsic propensities of individual amino acid residues to bind membranes as a function of structural context and bilayer depth. A host-guest study was performed using the peptide host named helix5 in order to determine the membrane affinities of the aliphatic side chains both in an alpha-helical context and as a function of bilayer depth. Use of the alpha-helical host with a constrained geometry allowed the placement of guest sites at three different depths in bilayers and minimized secondary structural changes due to guest substitutions. Circular dichroism and electron paramagnetic resonance (EPR) were used to characterize the aqueous and bilayer-bound structures of the peptide variants. EPR was also used to measure the bilayer-water partition constants of the peptide variants, and the Delta DeltaGtr values (relative to Gly) of the aliphatic amino acid side chains were subsequently calculated. Surprisingly, the DeltaDeltaGtr values did not significantly vary as a function of the guest site depth in bilayers. In addition, the Delta DeltaGtr values determined in an alpha-helical context are reduced to approximately two-thirds of Delta DeltaGtr values determined in other studies for the bilayer-water and octanol-water partitioning of amino acid side chains in extended and unstructured hosts. Both the relative reduction in Delta DeltaGtr values in the context of an alpha-helical host and the invariance of Delta DeltaGtr values with respect to bilayer depth are consistent with the membrane affinities of the aliphatic residues being largely determined by the classical hydrophobic effect.

Temperature dependence of polypeptide partitioning between water and phospholipid bilayers.

Various thermodynamic forces (e.g., the hydrophobic effect, electrostatic interactions, peptide immobilization, peptide conformational changes, "bilayer effects," and van der Waals dispersion forces) can participate in the transfer of polypeptides from aqueous solution into lipid bilayers. To investigate the contributions of these forces to peptide-membrane thermodynamics, we have studied the temperature dependence of the water-bilayer partitioning of 4 polypeptides derived from the first 25 amino acid residues in the presequence of subunit IV of yeast cytochrome c oxidase (Cox IVp) using electron paramagnetic resonance spectroscopy. The partitioning of the Cox IVp peptides into phospholipid bilayers increases as the temperature is increased from 3 to 40 degrees C. The contribution of bilayer surface expansion to the temperature-dependent partitioning is estimated to be relatively small and to contribute minimally to the increased bilayer binding of the peptides with increasing temperature. Thermodynamic analysis of the data shows that the transfer of the peptides from water into bilayers at 298 K is driven by the entropic term (-T delta Str) with values ranging from -6.7 to -10 kcal mol-1, opposed by the enthalpic term (delta Htr) by approximately 4 kcal mol-1, and accompanied by a change in heat capacity (delta Cp) ranging from -117 to -208 cal K-1 mol-1. Our results indicate that while a variety of forces do, in fact, contribute to the transfer free energies (delta Gtr), the major driving force for the water-to-bilayer transfer is the hydrophobic effect.

Membrane fusion machines of paramyxoviruses: capture of intermediates of fusion.

Peptides derived from heptad repeat regions adjacent to the fusion peptide and transmembrane domains of many viral fusion proteins form stable helical bundles and inhibit fusion specifically. Paramyxovirus SV5 fusion (F) protein-mediated fusion and its inhibition by the peptides N-1 and C-1 were analyzed. The temperature dependence of fusion by F suggests that thermal energy, destabilizing proline residues and receptor binding by the hemagglutinin-neuraminidase (HN) protein collectively contribute to F activation from a metastable native state. F-mediated fusion was reversibly arrested by low temperature or membrane-incorporated lipids, and the resulting F intermediates were characterized. N-1 inhibited an earlier F intermediate than C-1. Co-expression of HN with F lowered the temperature required to attain the N-1-inhibited intermediate, consistent with HN binding to its receptor stimulating a conformational change in F. C-1 bound and inhibited an intermediate of F that could be detected until a point directly preceding membrane merger. The data are consistent with C-1 binding a pre-hairpin intermediate of F and with helical bundle formation being coupled directly to membrane fusion.

Direct determination of the membrane affinities of individual amino acids.

Amino acids have distinct lipid bilayer affinities which influence the insertion and topology of membrane-bound polypeptides and proteins. To measure membrane affinities, 14 uncharged amino acids were introduced individually at a guest site in a 25-residue peptide derived from the membrane-binding presequence of yeast cytochrome c oxidase, and the peptides were labeled with a nitroxide spin-label. The free energies of transfer from phospholipid bilayers to water (delta delta Gbilayer) were determined directly by examination of partitioning into phospholipid bilayers using electron paramagnetic resonance. The delta delta Gbilayer values are in agreement with hydrophobicities assessed from 1-octanol-water partitioning of N-acetyl amino acid amides [Fauchere, J.-L., & Pliska, V. (1983) Eur. J. Med. Chem. 18, 369-375; Eisenberg, D., & McLachlan, A. (1986) Nature 319, 199-203] and quantitatively demonstrate the role of the hydrophobic effect in membrane-protein interactions.

Mobile coronary care and community mortality from myocardial infarction.

Over a 15-month period all episodes of suspected myocardial infarction were documented in two similar communities in Northern Ireland. The hospital coronary-care facilities were similar but only one area had a mobile coronary-care service. The incidence of myocardial infarction was similar in the two areas but the community mortality at 28 days was lower in all age-groups in the area served by the mobile unit. The difference in mortality was more pronounced in younger age-groups. Among those aged less than 65 the mortality rates in the two areas were 55% and 34%. The treatment in the two areas differed only in that it was provided about 2 h earlier where mobile care was available. The results suggest that the impact of early pre-hospital coronary-care on community mortality has been seriously underestimated.

Automatic postural responses in the cat: responses to headward and tailward translation.

EMG responses, vertical and A-P shear forces and kinematics of "automatic postural responses" to unexpected translational perturbations in the headward and tailward directions were studied in cats. Muscles acting on the major joints of the forelimbs and hindlimbs were studied. Movement of the animals in response to perturbation were highly stereotyped and consisted of two phases: (1) motion of the feet during platform movement while the trunk remained relatively stationary followed by (2) active correction of posture by movement of the trunk in the direction of perturbation. Vertical force changes occurred after the perturbation was well underway (latency 65 ms) and were related to the displacement of the center of mass and active correction of trunk position. Shear forces showed both passive (inertial) and active components and suggested that the majority of the torque necessary for postural correction was generated by the hindlimb. EMG responses in forelimb and shoulder muscles were most correlated with increase in vertical force, showing a generalized co-contraction in tailward translation (when these limbs were loaded) and little activity when the forelimbs were unloaded. EMG responses in hindlimb showed reciprocal activation of agonists and antagonists during perturbation with strong synergies of thigh and foot flexors in tailward translation and thigh and foot extensors in headward translation. The forelimb EMG patterns were most consistent with the conclusion that the forelimb is used primarily for vertical support during perturbation. It was concluded that hindlimb EMG responses were appropriate for both vertical support and performance of the postural correction. The hindlimb muscle synergies observed during translation are the "mirror image" of those observed in humans by other workers.