Use of pre-operative calcium and vitamin D supplementation to prevent post-operative hypocalcaemia in patients undergoing thyroidectomy: a systematic review.

OBJECTIVE: This systematic review aimed to establish the evidence behind the use of pre-operative calcium, vitamin D or both calcium and vitamin D to prevent post-operative hypocalcaemia in patients undergoing thyroidectomy. METHOD: This review included prospective clinical trials on adult human patients that were published in English and which studied the effects of pre-operative supplementation with calcium, vitamin D or both calcium and vitamin D on the rate of post-operative hypocalcaemia following total thyroidectomy. RESULTS: Seven out of the nine trials included reported statistically significantly reduced rates of post-operative laboratory hypocalcaemia (absolute risk reduction, 13-59 per cent) and symptomatic hypocalcaemia (absolute reduction, 11-40 per cent) following pre-operative supplementation. CONCLUSION: Pre-operative treatment with calcium, vitamin D or both calcium and vitamin D reduces the risk of post-operative hypocalcaemia and should be considered in patients undergoing total thyroidectomy.

Do patients benefit from physiotherapy for shoulder dysfunction following neck dissection? A systematic review.

OBJECTIVE: Accessory nerve palsy affects a proportion of patients following neck dissection, and results in shoulder dysfunction and regional pain. This project aimed to establish the evidence supporting post-operative physiotherapy for the shoulder following neck dissection. METHOD: A systematic review was conducted of prospective trials investigating the efficacy of rehabilitation for shoulder or upper limb dysfunction and pain following any type of neck dissection. RESULTS: A total of 820 papers were identified; through a staged review process, 7 trials were found that fulfilled the inclusion criteria. These included three randomised, controlled trials and four non-randomised studies. Five out of the seven trials demonstrated a statistically significant benefit of physiotherapy. CONCLUSION: Current evidence shows a benefit from physiotherapy in patients with shoulder dysfunction following neck dissection. Some evidence suggests progressive resistance is superior to other types of physiotherapy. Long-term benefit and cost efficacy have not been studied.

Beta spectrin bestows protein 4.1 sensitivity on spectrin-actin interactions.

The ability of protein 4.1 to stimulate the binding of spectrin to F-actin has been compared by cosedimentation analysis for three avian (erythrocyte, brain, and brush border) and two mammalian (erythrocyte and brain) spectrin isoforms. Human erythroid protein 4.1 stimulated actin binding of all spectrins except the brush border isoform (TW 260/240). These results suggested that the beta subunit determined the protein 4.1 sensitivity of the heterodimer, since all avian alpha subunits are encoded by a single gene. Tissue-specific posttranslational modification of the alpha subunit was excluded by examining the properties of hybrid spectrins composed of the purified alpha subunit from avian erythrocyte or brush border spectrin and the beta subunit of human erythrocyte spectrin. A hybrid composed of avian brush border alpha and human erythroid beta spectrin ran on nondenaturing gels as a discrete band, migrating near human erythroid spectrin tetramers. The actin-binding activity of this hybrid was stimulated by protein 4.1, while either chain alone was devoid of activity. Therefore, although both subunits were required for actin binding, the sensitivity of the spectrin-actin interaction to protein 4.1 is a property uniquely bestowed on the heterodimer by the beta subunit. The singular insensitivity of brush border spectrin to stimulation by erythroid protein 4.1 was also consistent with the absence of proteins in avian intestinal epithelial cells which were immunoreactive with polyclonal antisera sensitive to all of the known avian and human erythroid 4.1 isoforms.

Ten years of deep neck space abscesses.

BACKGROUND: The incidence of deep neck space abscesses, which can result in significant morbidity and mortality, is rising. The aetiology is thought to be dental. However, this study suggests a reduction in tonsillectomies may be associated with the rise. METHOD: In a retrospective cohort study, patients were identified by a clinical code within one hospital over 10 years. Evidence of preceding infection source, management, lifestyle risks, comorbidities and demographics were extracted. RESULTS: Fifty-two patients were included: 23 (44 per cent) had concurrent or recent tonsillitis; 11 (21 per cent) had poor dental hygiene; 22 (42 per cent) were smokers; and 9 (17 per cent) had diabetes. The incidence of deep neck space abscess cases increased from 1 in 2006, to 15 in 2015 (correlation value 0.9; p = 0.00019). CONCLUSION: The incidence of deep neck space abscess cases is increasing. Risk factors include tonsillitis, smoking and dental infection. This paper adds to the growing evidence that deep neck space abscesses are increasingly related to tonsillitis, and questions whether the threshold for tonsillectomy has been raised too high.

Do patients with p16-positive oropharyngeal squamous cell carcinoma get more bone metastasis than p16-negative patients?

BACKGROUND: Oropharyngeal squamous cell carcinoma is thought to rarely metastasise to bone. This study hypothesised that in p16-positive disease there is a significant incidence of bony metastasis. METHODS: This was an ambispective cohort review. All patients with oropharyngeal squamous cell carcinoma diagnosed and treated at one centre were included. RESULTS: A total of 180 consecutive patients were identified over 5 years. Fifteen patients were excluded because of lack of p16 status, none of whom had bony metastasis. The final analysis included 165 patients: 48 (29.09 per cent) in the p16-negative group and 117 (70.91 per cent) in the p16-positive group. Ten patients (8.55 per cent) in the p16-positive group developed bony metastasis, compared with zero in the p16-negative group; this difference was statistically significant (p = 0.036). CONCLUSION: Expression of p16 was associated with an increased incidence in bony metastasis in this cohort. This is the first study to explore this specific question.

Hypocalcaemia following laryngectomy: prevalence and risk factors.

OBJECTIVES: To establish the prevalence of hypocalcaemia following laryngectomy and demonstrate that total thyroidectomy is a risk factor. METHODS: A retrospective cohort study was conducted that included all patients who underwent total laryngectomy from 1st January 2006 to 1st August 2017. Exclusion criteria were: pre-operative calcium derangement, previous thyroid or parathyroid surgery, concurrent glossectomy, pharyngectomy, or oesophagectomy. RESULTS: Ninety patients were included. Sixteen patients had early hypocalcaemia (18 per cent), seven had protracted hypocalcaemia (8 per cent) and six had permanent hypocalcaemia (10 per cent). Exact logistic regression values for hypocalcaemia following total thyroidectomy compared to other patients were: early hypocalcaemia, odds ratio = 15.5 (95 per cent confidence interval = 2.2-181.9; model p = 0.002); protracted hypocalcaemia, odds ratio = 13.3 (95 per cent confidence interval = 1.5-117.1; model p = 0.01); and permanent hypocalcaemia, odds ratio = 22.7 (95 per cent confidence interval = 1.9-376.5; model p = 0.005). CONCLUSION: This is the largest study to investigate the prevalence of hypocalcaemia following laryngectomy and the first to include follow up of longer than three months. Total thyroidectomy significantly increased the risk of hypocalcaemia at all time frames and independent of other variables.

Comparison of nonerythroid alpha-spectrin genes reveals strict homology among diverse species.

The spectrins are a family of widely distributed filamentous proteins. In association with actin, spectrins form a supporting and organizing scaffold for cell membranes. Using antibodies specific for human brain alpha-spectrin (alpha-fodrin), we have cloned a rat brain alpha-spectrin cDNA from an expression library. Several closely related human clones were also isolated by hybridization. Comparison of sequences of these and other overlapping nonerythroid and erythroid alpha-spectrin genes demonstrated that the nonerythroid genes are strictly conserved across species, while the mammalian erythroid genes have diverged rapidly. Peptide sequences deduced from these cDNAs revealed that the nonerythroid alpha-spectrin chain, like the erythroid spectrin, is composed of multiple 106-amino-acid repeating units, with the characteristic invariant tryptophan as well as other charged and hydrophobic residues in conserved locations. However, the carboxy-terminal sequence varies markedly from this internal repeat pattern and may represent a specialized functional site. The nonerythroid alpha-spectrin gene was mapped to human chromosome 9, in contrast to the erythroid alpha-spectrin gene, which has previously been assigned to a locus on chromosome 1.

Serious tonsil infections versus tonsillectomy rates in Wales: A 15-year analysis.

INTRODUCTION Sore throat and tonsillitis place a significant burden on the National Health Service. National guideline criteria for gauging the severity of sore throat and tonsillitis have reduced the number of tonsillectomies performed, which is thought to have increased the rate of tonsil-related infections. METHODS Data was extracted from the prospective Patient Episode Database of Wales and analysed to determine the annual number of tonsillectomies for recurrent tonsillitis, adjusted for population changes. Admissions to acute hospitals for tonsillitis, peritonsillar abscess and deep neck space abscesses were also examined. RESULTS Between 1999 and 2014, hospital admissions for tonsillitis rose three-fold (r=0.968), while admissions for peritonsillar abscess rose by 48% (r=0.857) and retro or parapharyngeal abscess admissions also increased (r=0.709). In contrast, the number of tonsillectomies per 100,000 population gradually decreased (r=-0.16). There was a positive correlation between the incidence of tonsillitis and admissions for peritonsillar abscess (adjusted r2 0.631; p=0.015) and retropharyngeal abscess (adjusted r2 0.442; p=0.00254). There was a statistically significant negative correlation between the incidence of tonsillitis and the number of tonsillectomies performed (adjusted r2=-0.07; p=0.0235). CONCLUSIONS The significant rise in tonsillitis in Wales raises the question as to whether we should revisit the criteria for tonsillectomy. The perceived cost saving from limiting certain procedures should not prevent healthcare policymakers from considering all other evidence. The rise in peritonsillar, retropharyngeal and parapharyngeal abscess is alarming, as they are associated with significant morbidity and mortality.

Why are ototopical aminoglycosides still first-line therapy for chronic suppurative otitis media? A systematic review and discussion of aminoglycosides versus quinolones.

OBJECTIVE: This systematic review aimed to establish that quinolones are as effective as aminoglycosides when used to treat chronic suppurative otitis media. METHOD: The review included good quality, randomised, controlled trials on human subjects, published in English, that compared topical aminoglycosides with topical quinolones for the treatment of chronic suppurative otitis media. RESULTS: Nine trials met the criteria. Two studies showed a higher clinical cure rate in the quinolone group (93 per cent vs 71 per cent, p = 0.04, and 76 per cent vs 52 per cent, p = 0.009). Four studies showed no statistically significant difference in clinical outcome. A significant difference in microbiological clearance in favour of quinolones was shown in two studies (88 per cent vs 30 per cent, p < 0.001, and 88 per cent vs 30 per cent, p < 0.001). CONCLUSION: Topical quinolones do not carry the same risk of ototoxicity as aminoglycosides. Furthermore, they are equal or more effective in treating chronic suppurative otitis media and when used as prophylaxis post-myringotomy. Topical quinolones should be considered a first-line treatment for these patients.

Mechanism of cytoskeletal regulation (I): functional differences correlate with antigenic dissimilarity in human brain and erythrocyte spectrin.

Human erythrocyte and brain spectrin (fodrin, calspectin) have been compared quantitatively with respect to the extent and sites of antigenic and functional similarity. Brain spectrin cross-reacts strongly with approx. 1% of the epitopes in erythrocyte spectrin, but weakly with at least 50%. The distribution of shared determinants is not uniform. Brain spectrin is most deficient in epitopes characteristic of the 80 kDa and 52 kDa domains of the alpha-subunit (alpha-I and alpha-III) and of terminal portions of the 28 kDa and 74 kDa domains of the beta-subunit (beta-I and beta-IV). The functions associated with these domains also differ between the two proteins. Brain spectrin does not undergo extensive polymerization and binds calmodulin at a different site. The unique ability of erythrocyte spectrin to oligomerize beyond the tetramer reflects its role in the membrane skeleton. Non-erythroid spectrins probably function as specific linkers between membrane receptors and the filamentous cytoskeleton. In this sense, they may act as regulated transducers of information flow between the membrane and the cytoplasmic matrix.

Litigation in English rhinology.

OBJECTIVE: Litigation is a rising financial burden on the National Health Service. This study aims to show if litigation is increasing in rhinology and which procedures lead to the most claims. METHODS: Ten years of data were obtained from the National Health Service Litigation Authority. Rhinology claims were examined for cost, injury, diagnosis and operation type. RESULTS: Of the 123 rhinology claims identified, 52 per cent were successful. There was a 56 per cent increase in the average annual number of claims between the first half of the study period and the second (p = 0.0451). The commonest reasons for a claim were poor cosmesis (15.6 per cent) and lack of informed consent (14 per cent). CONCLUSION: The number of claims in rhinology increased over the study period. Most claims resulted from poor cosmetic outcome, lack of consent or recognised complications. It is suggested that enhanced communication and management of patient expectations could reduce litigation and improve patient satisfaction.

The effect of desmopressin on reducing blood loss in cardiac surgery--a meta-analysis of double-blind, placebo-controlled trials.

The effect of desmopressin (DDAVP) on reducing postoperative blood loss after cardiac surgery has been studied in several randomized clinical trials with conflicting outcomes. Since most trials had insufficient statistical power to detect true differences in blood loss, we performed a meta-analysis of data from relevant studies. Seventeen randomized, double-blind, placebo-controlled trials were analyzed, which included 1171 patients undergoing cardiac surgery for various indications; 579 of them were treated with desmopressin and 592 with placebo. Efficacy parameters were blood loss volumes and transfusion requirements. Desmopressin significantly reduced postoperative blood loss by 9%, but had no statistically significant effect on transfusion requirements. A subanalysis revealed that desmopressin had no protective effects in trials in which the mean blood loss in placebo-treated patients fell in the lower and middle thirds of distribution of blood losses (687-1108 ml/24 h). In contrast, in trials in which the mean blood loss in placebo-treated patients fell in the upper third of distribution (> 1109 ml/24 h), desmopressin significantly decreased postoperative blood loss by 34%. Insufficient data were available to perform a sub-analysis on transfusion requirements. Therefore, desmopressin significantly reduces blood loss only in cardiac operations which induce excessive blood loss. Further studies are called to validate the results of this meta-analysis and to identify predictors of excessive blood loss after cardiac surgery.

Intranasal and intravenous administration of desmopressin: effect on F VIII/vWF, pharmacokinetics and reproducibility.

A comparison was made of intranasal administration of 300 micrograms desmopressin (DDAVP) by spray, with intravenous administration of 0.2, 0.3 and 0.4 microgram DDAVP/kg in 10 healthy volunteers. The effect of DDAVP was measured on F VIII/vWF complex and on plasminogen activator release. In addition, plasma levels of DDAVP were determined using a specific and sensitive radioimmunoassay. Moreover, the reproducibility of the spray effect in 10 healthy volunteers was tested after administration of 300 micrograms DDAVP intranasally by spray on 5 different occasions. Plasma levels of DDAVP showed a clear dose-response with the maximum levels at 0.4 microgram/kg i.v. The effect of the spray approximated the 0.2 microgram/kg response. However, the maximum response in both F VIII/vWF complex and plasminogen activator release was obtained after 0.3 microgram/kg i.v. The response to 0.4 microgram/kg i.v. was not significantly different from the response to 0.3 microgram/kg indicating that maximum stimulation was reached with 0.3 micrograms/kg. There was no correlation between plasma levels of F VIII/vWF and DDAVP indicating that the biological response to DDAVP is subjected to saturation kinetics. The reproducibility of the effect of the spray dose on VIII:C was 21% (c.v.) and 27% for the intra-individual and inter-individual variation, respectively, and compared favorably with intravenous administration. Intranasal DDAVP (300 micrograms) is as effective as 0.2 micrograms/kg intravenously and provides an accurate, reproducible and convenient alternative to parenteral administration.

Intravenous and subcutaneous administration of desmopressin (DDAVP) to hemophiliacs: pharmacokinetics and factor VIII responses.

When desmopressin (DDAVP) is given to mild and moderate hemophiliacs intravenously (i.v.) or subcutaneously (s.c.), there is a very large between-patient variability for peak levels of factor VIII coagulant activity (VIII:C). To evaluate whether or not between-patient variability is related to DDAVP levels achieved in plasma, we measured drug levels in 14 hemophilic volunteers (VIII:C 2 to 31 U/dL) who were randomly given 0.3 micrograms/Kg of i.v. or s.c. DDAVP and crossed-over to the other treatment after an interval of 15-30 days. Peak DDAVP levels (Cmax) were higher for i.v. DDAVP (p less than 0.02), times to peak levels (tmax) were shorter for i.v. DDAVP (p less than 0.001). There was no difference between the i.v. and s.c. routes for plasma DDAVP time curve (AUC) and half-life (t 1/2), but there was much larger variability for pharmacokinetic parameters with i.v. than with s.c. DDAVP. Post-DDAVP VIII:C increased 3.4 +/- 1.6 fold (i.v.) and 3.3 +/- 1.3 fold (s.c.) over baseline levels, with no significant correlation between peak VIII:C and DDAVP levels for either route of administration. These findings establish the s.c. route of DDAVP administration to be bioequivalent in effect to the i.v. route, albeit with less variability. At the DDAVP dosage used in this study and currently recommended for therapy, the VIII:C response is neither a function of the rate of absorption of the compound nor of the magnitude of its plasma concentration.

Review: clinical opportunities provided by the nasal administration of peptides.

Peptides are rapidly being developed as potential new therapeutic agents and the nasal route is being evaluated as a means of achieving systemic absorption. Current research in man is being directed at a number of polypeptides, including calcitonin, growth hormone releasing hormones (GHRH), insulin, gonadotropin hormone releasing hormones (GnRH) and vasopressin analogues. The underlying protective functions of the nose provide anatomical, temporal and enzymatic barriers to absorption of peptides. The nasal route is relatively unsuccessful when used for high molecular weight polypeptides. Penetration enhancers improve bioavailability but are poorly tolerated. Reproducibility of effect is highly variable, major contributing factors including the site of deposition and type of delivery system as well as changes in the mucous secretion and mucociliary clearance, compounded by the presence of allergy, hay fever and the common cold in treated subjects. The future potential for this route lies in development of effective and well tolerated formulations in highly accurate delivery systems for the chronic administration of peptides, enabling the replacement of impractical and invasive intravenous injections in patients on lifelong substitution treatment for various deficiency states.

Intranasal administration of peptides: nasal deposition, biological response, and absorption of desmopressin.

The nasal administration of desmopressin [1-(3-mercaptopropionic acid)-8-D-arginine-vasopressin] in humans was investigated. Desmopressin solutions containing 99mTc-labeled human serum albumin were administered intranasally as a spray, using two metered-dose pumps, or as drops, using a rhinyle catheter or a single-dose pipet. Images of the sites of deposition and rates of clearance were monitored quantitatively by gamma scintigraphy. Plasma levels of desmopressin were measured using a highly sensitive and specific radioimmunoassay. The biological response was determined by measuring circulating levels of F VIII, the antihemophilia factor. The sprays were deposited mainly anteriorly, from which small portions were cleared slowly into the nasal pharynx. In contrast, the drops were deposited mostly posteriorly and cleared very rapidly in large portions; some were swallowed immediately. Plasma levels showed that desmopressin was absorbed to a greater extent after administration of the spray with a 2 to 3-fold increase in the relative bioavailability compared with the drops. The biological response was clearly enhanced after spray administration and produced similar increases in F VIII activity. A linear correlation was observed between maximum plasma desmopressin levels and maximum F VIII activity. The use of an intranasal spray device can deposit well-controlled doses within the nasal cavity, which remain there sufficiently long to provide a clear enhancement in absorption and bioavailability.

Effects of concentration and volume on nasal bioavailability and biological response to desmopressin.

The effects of concentration and dose volume on the nasal bioavailability and biological response to desmopressin [DDAVP; 1-(3-mercaptoproprionic acid)-8-D-arginine vasopressin] were investigated in humans. A nasal formulation of 300 micrograms of desmopressin was administered using a premetered spray device in doses of either 1 x 50-, 2 x 50-, or 1 x 100- microL actuations to both nostrils. Intravenous administration of 0.2 micrograms/kg was also given as a reference for bioavailability calculations. Plasma levels of desmopressin were measured by radioimmunoassay. The biological response was determined by measuring circulating levels of Factor VIII (F VIII), the antihemophilia factor. Peak plasma levels of desmopressin were greatest after the 2 x 50-microL dose, followed by the 1 x 50- and 1 x 100-microL doses. The bioavailability of desmopressin from the 2 x 50-microL dose was 20%, which was significantly greater than the 11% after the 1 x 50-microL (p less than 0.01) and 9% after the 1 x 100-microL (p less than 0.001) doses. The biological response was clearly enhanced after the 2 x 50-microL dose compared with the 1 x 50- and 1 x 100-microL doses. The interindividual response in F VIII levels to nasal desmopressin ranged from 20 (CV) to 30%, which compared favorably with the 36% variation after intravenous administration. This study confirms the premetered spray device as the preferred intranasal drug delivery system, and shows that by optimizing concentration, volume, and technique of administration, a significant enhancement can be obtained in bioavailability and clinical efficacy.

Preparation, characterization, and stability of new prostaglandin E2 gel for local administration.

A new gel delivery system for the local application of prostaglandin E2 consists of drug incorporated in the matrix of a cross-linked starch polymer. The properties of the starch powder provide a stabilizing milieu for the labile prostaglandin E2 and, by addition of saline, a ready-to-use gel for immediate local administration. The gel offers advantages over existing preparations in terms of chemical and microbiological stability, homogeneity, and dosage safety. This report outlines the pharmaceutical aspects involved in the development of the delivery system.

Effect of viscosity on particle size, deposition, and clearance of nasal delivery systems containing desmopressin.

The effect of methylcellulose on the particle size distribution and dosing accuracy of pre-metered spray pump devices containing the peptide desmopressin (DDAVP) was investigated. Using gamma scintigraphy, the influence of methylcellulose on the in vivo deposition and clearance of nasal solutions administered as drops or spray was studied. Nasal formulations containing 0, 0.25, and 0.50% methylcellulose produced a dose-related increase in average particle size from 51 micron for 0% to 81 and 200 micron for 0.25 and 0.50% methylcellulose, respectively. However, no effect was observed on the dosing accuracy of the spray pumps. The addition of methylcellulose gave a more localized in vivo deposition in the anterior region of the nasal vestibule. However, the net effect on clearance followed a biphasic pattern which showed an increase in retention time for the 0.25% solution, followed by a decrease in retention time and faster clearance time for the 0.50% solution. The spray delivers well-controlled doses to the nasal cavity. These findings show that viscosity, particle size, and nasal clearance are important parameters in the design of nasal delivery systems.

Effect of viscosity on the pharmacokinetics and biological response to intranasal desmopressin.

The effect of viscosity on the nasal absorption and biological response to desmopressin was studied in humans. Nasal solutions of desmopressin with and without the addition of 0.25% (w/v) methylcellulose were administered by a precompression nasal spray pump to 10 volunteers. Plasma levels of desmopressin were assayed by radioimmunoassay and the biological response was measured by determination of the antihemophilia factors (Factor VIII and von Willebrand factor). The results showed that the addition of methylcellulose produced a more sustained and slower absorption, with a longer time to maximum plasma concentration (tmax). However, the areas under the plasma concentration-time curve were not different, indicating a similar total bioavailability. The biological response showed a similar effect. Peak Factor VIII activity was not different, but the presence of methylcellulose produced a slower onset of activity. These findings indicate that although the addition of a viscous agent to nasal formulations may produce a more sustained effect, it delays the onset of activity and no enhancement is achieved in the total bioavailability.