Performing clinical studies involving hernia mesh devices: what every investigator should know about the FDA investigational device exemption (IDE) process.

The FDA's Center for Devices and Radiological Health (CDRH) is responsible for providing reasonable assurance of safety and effectiveness of all medical devices marketed within the US. To date, CDRH has cleared numerous hernia mesh devices for general use, but has not cleared/approved any mesh devices intended for certain specific uses, such as for infected wounds, hernia prevention, biofilm reduction, or prevention of adhesions. CDRH is requesting that manufacturers seeking specific hernia mesh device labeling claims consult with the Agency to determine the level of evidence necessary for justifying such claims.

Mucosal morbidity in patients with epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita is an acquired inflammatory and/or dermolytic subepidermal blistering disease characterized by IgG autoantibodies to type VII collagen. Four patients with documented epidermolysis bullosa acquisita were evaluated by a multidisciplinary team of care providers (4 dermatologists, an ophthalmologist, a radiologist, a voice and speech specialist, and an otolaryngologist) for 1 to 5 years to characterize mucosal involvement and its complications and response to treatment. Patients were evaluated clinically and by slitlamp examinations, endoscopies, computed tomographic scans, and videofluorographic swallowing studies. Spiral computed tomographic scans for virtual endoscopy were used for the nontraumatic evaluation of airways in 2 patients with respiratory tract compromise. OBSERVATIONS: Involvement of 5 or more mucosal sites--mouth, nose, conjunctiva, pharynx, and larynx--was documented in all patients. Complications included ankyloglossia, periodontal disease, scarring and crusting of nasal mucosa, symblepharon formation, obstruction of nasolacrimal ducts, deformation of the epiglottis, impaired phonation, dysphagia, esophageal strictures, and supraglottic stenosis requiring emergency tracheostomy. CONCLUSIONS: Epidermolysis bullosa acquisita may extensively (or predominantly) affect mucosal epithelia in a manner resembling cicatricial pemphigoid. Mucosal disease in these patients is often subclinical, can lead to serious complications, and is best managed using a multidisciplinary approach.

Grouped papules in Hurler-Scheie syndrome.

In a patient with Hurler-Scheie syndrome, a type of mucopolysaccharidosis (I H/S), an initial presentation was grouped papules on the extensor surfaces on the upper portions of the arms and legs. Other physical findings included progressive flexion contractures and mild developmental delay. The patient had deficient alpha-L-induronidase activity, and electron microscopy showed large cytoplasmic vacuoles and lysosomes, consistent with Hurler-Scheie syndrome. Findings of grouped papules have not been previously reported in patients with this syndrome.

Human androgen receptor binding to the androgen response element of prostate specific antigen.

This study examined the in vitro interaction of the human androgen receptor with a putative androgen response element (ARE) in the promoter region of the prostate specific antigen (PSA) gene. To characterize the androgen receptor's interactions with its DNA response elements we expressed the full length human androgen receptor protein in a baculovirus expression system. The receptor was shown to be 110 kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and was purified using ion-exchange column chromatography. Binding of the synthetic androgen R1881 to the unpurified recombinant receptor exhibited a kd of 7.6 nM by Scatchard analysis. In DNA gel electromobility shift assays the promoter region from PSA (a 313-bp fragment) was bound by the unpurified recombinant androgen receptor in a sequence-specific manner. An ARE-containing sequence from the promoter region of the PSA gene was synthesized as a 30-bp oligonucleotide and was shown to bind specifically to the human androgen receptor in gel electromobility shift assays by DNA competition and by antibody supershifts of the receptor-ARE complex. The specific binding of the insect cell expressed androgen receptor to its ARE was shown to occur even in the absence of androgen. Androgen receptors purified by ion-exchange chromatography were unable to bind to ARE, suggesting the presence of other factors required for DNA binding.

Irreversible opiate agonists and antagonists: V. Hydrazone and acylhydrazone derivatives of naltrexone.

We have synthesized a series of hydrazones and acylhydrazones of naltrexone. These substitutions had modest effects on competition of mu binding but many greatly enhanced the relative potency of the compounds for delta receptors. Increased delta affinity was most prominent with the acylhydrazones. Many of the derivatives elicited a wash-resistant inhibition of binding which was restricted to mu, not delta, binding sites. This wash-resistant inhibition of binding did not correlate with affinity, as determined by IC50 values, implying that the inhibition could not be explained simply by slow rate of dissociation due to increased affinity.

Upregulation of opioid receptor subtypes correlates with potency changes of morphine and DADLE.

Chronic treatment with opioid antagonists increases the potency of opioid agonists and produces an increase in brain opioid binding sites. In the present study, 8 day treatment with naltrexone blocked morphine and DADLE analgesia for the entire treatment period and increased mu 1, mu 2 and delta opioid receptor binding sites in mouse brain. mu 1 and mu 2 binding were increased by 81 and 67%, respectively, while delta binding was increased by 31%. Consistent with these binding changes, the potency of ICV morphine to produce analgesia was increased by over 3-fold, while the potency of ICV DADLE was increased by only 1.7. These findings indicate that relative increases in opioid receptor subtypes agree with pharmacodynamic studies on potency changes of opioid agonists.