Delivery of macromolecules across oral mucosa from polymeric hydrogels is enhanced by electrophoresis (iontophoresis)

Objective

To develop polymeric hydrogel delivery systems for iontophorseis transfer of large molecules across buccal (porcine) mucosa.

Methods

Three hydrogels (PVA, HPMC and PVA/HPMC) were prepared as stable gels (7 mm diameter/1.5 mm thick). Quantitative (8 and 36 h) assessment of porcine buccal mucosa and the three hydrogel delivery systems, using a diffusion cell in vitro model, was carried out by UV/vis spectroscopy with three model agents (3 and 10 kDa dextrans and 12 kDa parvalbumin). Passive and iontophoresis parameters were obtained. Experimental and theoretical data were compared.

Results

Iontophoresis (30 min, 1–8 h) significantly enhanced the delivery of all model agents across four single systems (hydrogels and buccal mucosa) and three sandwich systems (hydrogels on top of buccal mucosa), as confirmed by time lag factor/enhancement ratio (TLF/ER) data. The diffusion coefficients of model agents across buccal mucosa (×10⁻¹³ m² s⁻¹) were ∼100 times lower than across single hydrogels (2.97–4.80 × 10⁻¹¹ m² s⁻¹). Solubility values of all agents across hydrogels were similar, but lower across buccal mucosa. Permeability of parvalbumin was highest across PVA, and for both dextrans across PVA/HPMC. In sandwich systems TLFs were similar for all hydrogels, but significantly lower, and ERs significantly higher, than tissue alone. Experimental and theoretical TLF data were in reasonable agreement.

Significance

The in vitro data show that iontophoresis enhanced the delivery of large molecules across polymeric hydrogel systems and buccal mucosa. This creates the opportunity of new approaches to drug delivery and opens pathways to further research for delivering therapeutic agents topically and systemically.     

Botulinum injection for the management of myofascial pain in the masticatory muscles. A prospective outcome study

We prospectively analysed the outcome after botulinum injection in patients who did not recover after conservative measures to manage masticatory myofascial pain, and who were not willing to take low dose tricyclic antidepressants as a muscle relaxant. We prospectively 62 patients were assessed with visual analogue scores (VAS) for pain on the affected side before, and 6 weeks after botulinum injection(s) (50 units Dysport^® in up to 3 sites), and measured mouth opening in mm. Of those treated 49 (79%) showed at least some improvement (pain reduced by more than 25%). Patients reported more than a 90% reduction in the VAS for 25 (30%) of the 84 sides of the face treated. Only 22 of the 62 patients had more than one course of treatment to the same side. Interincisal distance improved by a mean/median of 0.9 mm (p < 0.03) after treatment. Side effects included 3 cases of temporary weakness of a facial muscle. Ranking the VAS pain scores using the Wilcoxon test before and after injection showed a significant reduction in pain (median change −29.5, interquartile range −53 to −16, p < 0.0001). The treatment significantly improved patients’ pain scores and the overall mean/median reduction in pain was 57%. Botulinum injection does not guarantee complete resolution of myofascial pain, but it usually has some beneficial effect in improving the symptoms, and should be considered as an alternate treatment for masticatory myofascial pain if conservative methods have failed.     

Deflections in Mandibular Major Connectors: A FEM Study

The major connector is the most vital component critically subjected to maximal stress concentration due to various forces acting on it. The main requirement of a major connector is its resistance to deformation by occlusal stresses. This resistance to deformation is a direct consequence of the rigidity of the major connector. Thus rigidity of the major connector is paramount to resist flexing and torquing forces that could be transmitted to the abutment teeth and other structures as destructive forces. The commonly used major connectors for the mandibular arch are lingual bar and lingual plate. In the present study, the deflection of various major connector designs due to occlusal load is assessed by finite element method. They have been analyzed through finite element models. The differences in the deflection behaviour of mandibular major connector used in Kennedy’s Class I, Class II, Class III, and Class IV edentulous situations have been compared. A CT scan of human edentulous mandible was taken and each section from symphysis to condylar region was projected on a graph paper and three-dimensional volumes were created from connected successive profiles to define the final solid geometry of cortical bone. Six framework models with different mandibular major connectors, lingual bar and lingual plate for Kennedy’s Class I, Class II, Class III, and Class IV situations were created. The three dimensional finite element models corresponding to the geometric model were generated using Ansys’s pre-processor. The model was assigned material properties. A vertical biting force of 20 N was applied. The results showed that the maximum deflection was seen in the saddle area when compared to other areas, i.e., major connector and the occlusal rest regions. The lingual bar in Kennedy’s Class III situation and lingual plate in Kennedy’s Class IV situation showed the least deflection when compared to Class I and Class II (distal extensions) situations. Lingual plate is more rigid major connector than lingual bar.     

Variations in clinicopathologic characteristics of thyroid cancer among racial ethnic groups: analysis of a large public city hospital and the SEER database

Background

Clinicopathologic variables influence the treatment and prognosis of patients with thyroid cancer.

Methods

A retrospective analysis of public hospital thyroid cancer database and the Surveillance, Epidemiology and End Results 17 database was conducted. Demographic, clinical, and pathologic data were compared across ethnic groups.

Results

Within the public hospital database, Hispanics versus non-Hispanic whites were younger and had more lymph node involvement (34% vs 17%, P < .001). Median tumor size was not statistically different across ethnic groups. Similar findings were demonstrated within the Surveillance, Epidemiology and End Results database. African Americans aged <45 years had the largest tumors but were least likely to have lymph node involvement. Asians had the most stage IV disease despite having no differences in tumor size, lymph node involvement, and capsular invasion.

Conclusions

There is considerable variability in the clinical presentation of thyroid cancer across ethnic groups. Such disparities persist within an equal-access health care system. These findings suggest that factors beyond socioeconomics may contribute to such differences.     

Implementing the National Hip Fracture Database: An audit of care

Background

Hip fractures are common injuries in the elderly, with significant associated morbidity and mortality rates. The National Hip Fracture Database (NHFD) was implemented to audit care according to national standards thus improving its clinical and cost-effectiveness.

Patients and methods

We retrospectively examined the care pathway for all hip fractures after its introduction at our centre over 1 year, with an audit of care according to the BOA-BGS ‘Blue Book’ guidelines. Data between the first (period 1: initial audit) and second (period 2: re-audit) six months of the study period were compared.

Results

There were 372 patients (28% male, 72% female) in total with 190 in period 1 and 182 in period 2. For all patients, the median age was 85 years (range 33–101) and the median time to surgery was 24.5 h (1–519.3), with 251 (67.5%) within 36 h. Surgical delay was mainly due to lack of theatre space (37.6%) and medical reasons (54.7%). The median length of stay was 11 days (2–92) and the inpatient mortality rate was 6.2% (23). When comparing the two study periods, there were significantly more patients undergoing falls (p < 0.01) and bone protection (p < 0.01) assessments in period 2. Lack of theatre space was a significantly less common (p < 0.01), with a significantly shorter median time to surgery (p = 0.01) and length of stay (p < 0.01) in period 2. More patients were discharged to rehabilitation units and the mortality rate was non-significantly lower in period 2 (7.4% vs. 5%). The best practice tariff was met in 45.3% and 70.3% (p < 0.001) of patients in periods 1 and 2 respectively providing a total income of £95230.00 (GBP).

Conclusions

Implementing the NHFD has led to an improvement the quality of hip fracture care according to national guidelines. More patients were assessed by an orthogeriatrician, with a shorter time to surgery and length of stay following re-audit. There is potential for an improvement in mortality rates as well as significant financial income for hospitals.     

Postoperative pain management in pediatric patients undergoing minimally invasive repair of pectus excavatum: The role of intercostal block

Purpose

There are no published data regarding value of intercostal block following pectus excavatum repair. Our aim was to evaluate the efficacy of intercostal block in children following minimally invasive repair of pectus excavatum (MIRPE).

Methods

Forty-five patients given patient-controlled analgesia (PCA) with morphine postoperatively were studied. Twenty-six patients were given bilateral intercostal blocks after induction of anesthesia (PCA-IB group), and nineteen patients were retrospective controls without regional blockade (PCA group). All patients were followed up 24 h postoperatively.

Results

A loading dose of morphine (0,1 ± 0,49 mg/kg) before starting PCA was used in seventeen patients in PCA group vs. no patient in PCA-IB group. Cumulative used morphine doses were lower up to 12 h after surgery in PCA-IB group (0,29 ± 0,08 μg/kg) than in the PCA group (0,46 ± 0,18 μg/kg), p < 0,01. There were no differences in pain scores, oxygen saturation values, sedation scores, and the incidence of pulmonary adverse events between the two groups. There was a tendency towards less morphine-related adverse effects in PCA-IB group compared to PCA group (p < 0,05). No complications related to the intercostal blocks were observed.

Conclusion

Bilateral intercostal blocks following MIRPE are safe and easy to perform and can diminish postoperative opioid requirement. Double-blind randomized study is required to confirm the potential to diminish opioid related side effects.     

Ovarian torsion in children: Management and outcomes

Background

The purpose of this study is to evaluate the clinical symptoms, diagnosis, management, and outcomes in children with ovarian torsion.

Methods

The charts of 50 patients with 53 cases of ovarian torsion treated between January 1989 and March 2012 were reviewed retrospectively. Long term follow up was available for 20 girls who had their ovaries left in the abdominal cavity after detorsion.

Results

In 22 cases ovaries were removed, and in 31 cases the torsion was relieved and the ovaries left in the abdominal cavity. Twenty-five of the salvaged ovaries were black-bluish and 10 bluish in color. Since 2005, after a change in preferred treatment, all ovaries treated by detorsion were left in the abdominal cavity. The long term results were observed clinically and by ultrasound in 20 girls. Multifollicular ovaries were found in 17 girls. One girl had a normal size paucifollicular ovary, a one-year-old girl had a normal size ovary with microfollicles, and one girl had no ovarian material detectable by ultrasound.

Conclusions

Long term analysis of the treatment of ovarian torsion revealed that ovaries treated by detorsion and left in the abdominal cavity preserved their normal anatomy and function. Conservative surgical treatment proved to be safe. None of the girls had thromboembolism or peritonitis, and no malignant tumors were found in the operated ovaries.     

Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans: The Candidate Gene Association Resource Plus Study

Type 2 diabetes (T2D) disproportionally affects African Americans (AfA) but, to date, genetic variants identified from genome-wide association studies (GWAS) are primarily from European and Asian populations. We examined the single nucleotide polymorphism (SNP) and locus transferability of 40 reported T2D loci in six AfA GWAS consisting of 2,806 T2D case subjects with or without end-stage renal disease and 4,265 control subjects from the Candidate Gene Association Resource Plus Study. Our results revealed that seven index SNPs at the TCF7L2, KLF14, KCNQ1, ADCY5, CDKAL1, JAZF1, and GCKR loci were significantly associated with T2D (P < 0.05). The strongest association was observed at TCF7L2 rs7903146 (odds ratio [OR] 1.30; P = 6.86 × 10⁻⁸). Locus-wide analysis demonstrated significant associations (P_emp < 0.05) at regional best SNPs in the TCF7L2, KLF14, and HMGA2 loci as well as suggestive signals in KCNQ1 after correction for the effective number of SNPs at each locus. Of these loci, the regional best SNPs were in differential linkage disequilibrium (LD) with the index and adjacent SNPs. Our findings suggest that some loci discovered in prior reports affect T2D susceptibility in AfA with similar effect sizes. The reduced and differential LD pattern in AfA compared with European and Asian populations may facilitate fine mapping of causal variants at loci shared across populations.Type 2 diabetes (T2D) is a major public health problem affecting 25.8 million people in the U.S. (1). Marked racial differences in its prevalence have been observed, with African American (AfA) adults >40 years of age having nearly twofold higher prevalence than European Americans (27.1 and 15.5%, respectively) (2). In addition to socioeconomic and behavioral risk factors, genetic factors are likely contributors to T2D risk in AfA (3).Genome-wide association studies (GWAS) for T2D and related traits have successfully identified >50 loci with common genetic variants associated with T2D risk in primarily European-descent populations (4–14) and more recently in East and South Asians (15–21). The reported index single nucleotide polymorphisms (SNPs) at these loci have been replicated in multiple populations (22–24) but less successfully in AfA (25–27). Although differences in environment and lack of study power may partly account for the lack of transferability across ethnicities, differences in linkage disequilibrium (LD) patterns, effect sizes, and risk allele frequency also likely impact the replication of index SNPs. Although the long-range LD in European populations allows for the identification of T2D loci using less dense markers, causal variants are not distinguishable from other nearby SNPs in high LD. This issue prompts the need to examine T2D loci in other populations with different allelic and LD architecture, which may help fine mapping of the underlying functional variants (28).We performed a comprehensive evaluation of the LD region of T2D loci reported in European and Asian GWAS in a meta-analysis of six AfA GWAS. By testing the index and nearby SNPs, we evaluated the transferability of the previously reported loci for T2D association in AfA. We demonstrated that the reduced and differential LD structure in AfA facilitated fine mapping of regions potentially harboring causal variants at some T2D loci.