Ovine forestomach matrix biomaterial is a broad spectrum inhibitor of matrix metalloproteinases and neutrophil elastase

Proteases play a critical role in the ordered remodelling of extracellular matrix (ECM) components during wound healing and tissue regeneration. However, the usually ordered proteolysis is compromised in chronic wounds due to over‐expression and high concentrations of matrix metalloproteinase's (MMPs) and neutrophil elastase (NE). Ovine forestomach matrix (OFM) is a decellularised extracellular matrix‐based biomaterial developed for tissue regeneration applications, including the treatment of chronic wounds, and is a heterogeneous mixture of ECM proteins and proteoglycans that retains the native structural and functional characteristics of tissue ECM. Given the diverse molecular species present in OFM, we hypothesised that OFM may contain components or fragments that inhibit MMP and NE activity. An extract of OFM was shown to be a potent inhibitor of a range of tissue MMPs (IC₅₀s = 23 ± 5 to 115 ± 14 µg/ml) and NE (IC₅₀ = 157 ± 37 µg/ml), and was more potent than extracts prepared from a known protease modulating wound dressing. The broad spectrum activity of OFM against different classes of MMPs (i.e. collagenases, gelatinases and stromelysins) may provide a clinical advantage by more effectively addressing the protease imbalance seen in chronic wounds.     

Monitoring Vital Signs during Outpatient Mohs and Post-Mohs Reconstructive Surgery Performed under Local Anesthesia

BACKGROUND: Although dermatologic surgery carries a low risk of serious adverse events, concern over the safety of outpatient surgical procedures in general has led some to question whether intraoperative patient monitoring should be performed during all procedures performed in the clinic setting. OBJECTIVE: To characterize the intraoperative monitoring practices of Mohs surgeons and examine the relationship between changes in vital signs during skin surgery and the incidence of serious adverse events. METHODS: We surveyed a group of Mohs surgeons and prospectively measured blood pressure, pulse, and pulse oximetry of 100 patients undergoing repair of Mohs surgery defects under local anesthesia in the outpatient clinic setting. RESULTS: The majority of survey respondents utilize no intraoperative monitoring, and serious adverse events are rare (0.2 per 1000 procedures performed). Moderate fluctuations in our patients' vital signs occurred (<10% deviation from baseline); however, all measured variables returned to near baseline by procedure end and were not associated with any serious adverse events. CONCLUSIONS: Surgical repair of Mohs defects performed under local anesthesia in the outpatient clinic setting continues to be very safe. Intraoperative vital sign measurements did not appear to be useful in detecting or avoiding potential adverse events in our patient population.     

Intraarterial suction thrombectomy in acute stroke

Three patients with internal carotid artery thrombus and thrombolysis in myocardial infarction (TIMI) 0-1 flow were treated by using intraarterial (IA) suction thrombectomy a mean of 4.2 hours after stroke onset. After catheterization with a 7F guide-catheter, thrombus was aspirated by using a 60-mL syringe. TIMI flow improved to 3 in all patients. The median National Institutes of Health Stroke Scale score decreased from 22 (range, 12-23) to 4 (range, 2-22) at 3 months. IA suction thrombectomy may be safe and feasible in patients with acute stroke.     

Free flaps for type III complex pharyngoesophageal defects after enlarged ablative surgery for advanced cancer of larynx and hypopharynx

Free tissue transfer has become a useful technique for reconstruction of type III complex pharyngoesophageal defects after enlarged laryngectomy and partial or total pharyngoesophageal resection. We present a retrospective analysis of our experience with 36 patients who received free flaps for reconstruction of complex pharyngoesophageal defects associated with skin and soft-tissue defects. Free fasciocutaneous flaps and jejunum combined with a deltopectoral flap and musculocutaneous pectoralis major flap, gastro-omental flap, and combined latissimus dorsi musculocutaneous and cutaneous scapular flaps were used for reconstruction. Adjuvant therapy included preoperative or postoperative radiotherapy. Free flap failure occurred in 2 of 36 patients. Twenty-eight patients had good swallowing function. Better results with fewer complications in reconstruction of type III complex pharyngoesophageal defects were obtained with the use of a combined latissimus dorsi and scapular flap.     

Causes of death from the randomized CoreValve US Pivotal High-Risk Trial

Objective

Explore causes and timing of death from the CoreValve US Pivotal High-Risk Trial.

Hurthle cell neoplasm of the thyroid gland

Background: A clinicopathological analysis and long‐term follow up of 32 patients with Hurthle cell neoplasm (HCN) was undertaken to contrast the clinical and histological features between benign versus malignant HCN of thyroid and to examine the effect of treatment on the outcome. Methods: This is a retrospective study of 32 patients with HCN who were identified out of an archival clinical/pathological/imaging database of 3752 thyroid cancer patients seen between 1976 and June 2006. All patients underwent thyroid surgery. Data for the non‐surgical treatment along with follow up were also analysed. Results: Seventeen patients were classified as malignant HCN (MHCN) and 15 as benign HCN (BHCN). Among the MHCN, there were 11 women and 6 men, whereas among BHCN there were 14 women and 1 man. Three patients designated MHCN presented with metastases, one with pulmonary metastases and two others with skeletal metastases who developed lung metastases 9–19 months later. The mean tumour size was 4.43 ± 0.66 cm for MHCN, and 2.57 ± 0.32 cm for BHCN (P = 0.03). Multicentric tumour foci were evident in five cases (29%) of MHCN but none among the BHCN (P = 0.03). At neck exploration cervical lymph node dissection was carried out in nine MHCN patients with findings of tumour metastases in 33%. Postoperatively, three MHCN patients had no thyroid remnant on ultrasound and computed tomography of neck and undetectable serum thyroglobulin; these were considered to be in remission. Fourteen other MHCN patients with postoperative thyroid remnant and/or distant metastases received ¹³¹I treatment. Eight of these patients had negative whole‐body scans after ¹³¹I treatment and undetectable thyroglobulin. Accordingly, 11 MHCN patients (64.7%) showed evidence of remission and 6 patients did not respond to ¹³¹I treatment. After a mean follow up of 35 months, all BHCN patients are alive with no evidence of disease. Of the MHCN, 11 (64.7%) were in remission and 35% had evidence of persistence/recurrence. One patient who had recurrence is dead. A lack of effectiveness of ¹³¹I therapy in two patients with distant metastases is an important finding. Conclusion: Features of MHCN consisted of a large tumour size, unequivocal capsular and vascular invasion, multicentric tumour foci, metastatic lymph node deposits in one‐third of patients and presence of distant metastasis in a few. Findings of dominant Hurthle cell cytology in a fine‐needle aspiration biopsy from a thyroid nodule should prompt surgical resection of the lesion to assess malignancy.     

Association of 18 Confirmed Susceptibility Loci for Type 2 Diabetes With Indices of Insulin Release, Proinsulin Conversion, and Insulin Sensitivity in 5,327 Nondiabetic Finnish Men

OBJECTIVE

We investigated the effects of 18 confirmed type 2 diabetes risk single nucleotide polymorphisms (SNPs) on insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin.

RESEARCH DESIGN AND METHODS

A total of 5,327 nondiabetic men (age 58 ± 7 years, BMI 27.0 ± 3.8 kg/m²) from a large population-based cohort were included. Oral glucose tolerance tests and genotyping of SNPs in or near PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, LOC387761, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B were performed. HNF1B rs757210 was excluded because of failure to achieve Hardy-Weinberg equilibrium.

RESULTS

Six SNPs (TCF7L2, SLC30A8, HHEX, CDKN2B, CDKAL1, and MTNR1B) were significantly (P < 6.9 × 10⁻⁴) and two SNPs (KCNJ11 and IGF2BP2) were nominally (P < 0.05) associated with early-phase insulin release (InsAUC_0–30/GluAUC_0–30), adjusted for age, BMI, and insulin sensitivity (Matsuda ISI). Combined effects of these eight SNPs reached −32% reduction in InsAUC_0–30/GluAUC_0–30 in carriers of ≥11 vs. ≤3 weighted risk alleles. Four SNPs (SLC30A8, HHEX, CDKAL1, and TCF7L2) were significantly or nominally associated with indexes of proinsulin conversion. Three SNPs (KCNJ11, HHEX, and TSPAN8) were nominally associated with Matsuda ISI (adjusted for age and BMI). The effect of HHEX on Matsuda ISI became significant after additional adjustment for InsAUC_0–30/GluAUC_0–30. Nine SNPs did not show any associations with examined traits.

CONCLUSIONS

Eight type 2 diabetes–related loci were significantly or nominally associated with impaired early-phase insulin release. Effects of SLC30A8, HHEX, CDKAL1, and TCF7L2 on insulin release could be partially explained by impaired proinsulin conversion. HHEX might influence both insulin release and insulin sensitivity.Impaired insulin secretion and insulin resistance, two main pathophysiological mechanisms leading to type 2 diabetes, have a significant genetic component (1). Recent studies have confirmed 20 genetic loci reproducibly associated with type 2 diabetes (2–13). Three were previously known (PPARG, KCNJ11, and TCF7L2), whereas 17 loci were recently discovered either by genome-wide association studies (SLC30A8, HHEX-IDE, LOC387761, CDKN2A/2B, IGF2BP2, CDKAL1, FTO, JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, THADA, ADAMTS9, NOTCH2, KCNQ1, and MTNR1B), or candidate gene approach (WFS1 and HNF1B). The mechanisms by which these genes contribute to the development of type 2 diabetes are not fully understood.PPARG is the only gene from the 20 confirmed loci previously associated with insulin sensitivity (14,15). Association with impaired β-cell function has been reported for 14 loci (KCNJ11, SLC30A8, HHEX-IDE, CDKN2A/2B, IGF2BP2, CDKAL1, TCF7L2, WFS1, HNF1B, JAZF1, CDC123/CAMK1D, TSPAN8/LGR5, KCNQ1, and MTNR1B) (6,12,13,16–38). Although associations of variants in HHEX (16–22), CDKAL1 (6,21–26), TCF7L2 (22,27–30), and MTNR1B (13,31,32) with impaired insulin secretion seem to be consistent across different studies, information concerning other genes is limited (12,18–25,27,33–38). The mechanisms by which variants in these genes affect insulin secretion are unknown. However, a few recent studies suggested that variants in TCF7L2 (22,39–42), SLC30A8 (22), CDKAL1 (22), and MTNR1B (31) might influence insulin secretion by affecting the conversion of proinsulin to insulin. Variants of FTO have been shown to confer risk for type 2 diabetes through their association with obesity (7,16) and therefore were not included in this study.Large population-based studies can help to elucidate the underlying mechanisms by which single nucleotide polymorphisms (SNPs) of different risk genes predispose to type 2 diabetes. Therefore, we investigated confirmed type 2 diabetes–related loci for their associations with insulin sensitivity, insulin secretion, and conversion of proinsulin to insulin in a population-based sample of 5,327 nondiabetic Finnish men.     

Parathyroid Autotransplantation during Total Thyroidectomy—Does the Number of Glands Transplanted Affect Outcome?

Parathyroid autotransplantation is a technique for ensuring the continued function of parathyroid tissue at the time of total thyroidectomy (TT). The aim of this study was to ascertain whether the number of parathyroids transplanted affects the incidence of temporary and permanent hypoparathyroidism. A retrospective cohort study included all patients undergoing a TT in a single unit between July 1998 and June 2003. The number of parathyroids transplanted, the final pathology, and the incidence of temporary and permanent hypoparathyroidism were documented. Fisher’s exact test was used for statistical analysis. A total of 1196 patients underwent a TT during the 5 years studied. Of these, 306 (25.6%) had no parathyroids transplanted, 650 (54.3%), 206 (17.2%), 34 (2.8%) had 1,2, or 3 glands autotransplanted, respectively. The incidence of temporary hypoparathyroidism was 9.8% for no gland transplants, 11.9%, 15.1%, and 31.4% for 1,2,and 3 gland transplants, respectively (p < 0.05). The incidence of permanent hypoparathyroidism was 0.98%, 0.77%, 0.97%, and 0%, respectively (p = NS). The incidence of temporary hypoparathyroidism was higher when surgery was performed for Graves’ disease. Temporary hypocalcemia is closely related to the number of autotransplanted parathyroids during TT. The long-term outcome is not affected by the number of parathyroids autotransplanted. A “ready selective” approach to parathyroid autotransplantation is an effective strategy for minimizing the rate of permanent hypoparathyroidism.     

Dissolution Curve Comparisons Through the F2 Parameter,a Bayesian Extension of the f2 Statistic

Dissolution (or in vitro release) studies constitute an important aspect of pharmaceutical drug development. One important use of such studies is for justifying a biowaiver for post-approval changes which requires establishing equivalence between the new and old product. We propose a statistically rigorous modeling approach for this purpose based on the estimation of what we refer to as the F₂ parameter, an extension of the commonly used f₂ statistic. A Bayesian test procedure is proposed in relation to a set of composite hypotheses that capture the similarity requirement on the absolute mean differences between test and reference dissolution profiles. Several examples are provided to illustrate the application. Results of our simulation study comparing the performance of f₂ and the proposed method show that our Bayesian approach is comparable to or in many cases superior to the f₂ statistic as a decision rule. Further useful extensions of the method, such as the use of continuous-time dissolution modeling, are considered.