The total contact cast: a method for treating neuropathic diabetic ulcers

Plantar ulcers that do not heal in patients with diabetes and peripheral sensory neuropathy have been shown to be precursors of lower extremity amputation. The total contact cast is considered by many authorities to be the most effective technique for healing of wounds in the neuropathic extremity, yet it still is not widely used in clinical practice. Use of the total contact cast allows mobilization and results in diminished edema and decreased pressure over the ulcerated area. Complete healing usually occurs in eight weeks or less. Total contact casting with careful follow-up should be considered as a useful modality for healing plantar ulcers in diabetic patients with neuropathy of the extremities.     

PORE EVOLUTION AND SOLVENT TRANSPORT DURING DRYING OF GELLED SOL-GEL COATINGS: PREDICTING 'SPR1NGBACK'*

This paper reports predictions of drying phenomena in deformable porous gel coatings (i.e. a porous solid elastic network filled with air or solvent). Initially, a gelled coating is saturated with solvent, but as it dries, liquid-vapor menisci begin to recede into larger pores and the gel becomes a partially-saturated porous medium. The tensile capillary pressure in the liquid causes a compressive deformation on the solid skeleton and a consequent reduction in thickness and pore-size of the coating. A theory coupling the large deformation of the solid skeleton to capillary pressure in the interstitial liquid is used to predict the course of drying of dip-coated porous gel coatings. The theory predicts a 'springback' effect in late stages of drying as the effects of capillary pressure diminish, which matches with experimental observations.     

Ribosome targeting of PKR is mediated by two double-stranded RNA-binding domains and facilitates in vivo phosphorylation of eukaryotic initiation factor-2

Protein kinase PKR is activated in mammalian cells during viral infection, leading to phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF-2alpha) and inhibition of protein synthesis. This antiviral response is thought to be mediated by association of double-stranded RNA (ds-RNA), a by-product of viral replication, with two ds-RNA-binding domains (DRBDs) located in the amino terminus of PKR. Recent studies have observed that expression of mammalian PKR in yeast leads to a slow growth phenotype due to hyperphosphorylation of eIF-2alpha. In this report, we observed that while DRBD sequences are required for PKR to function in the yeast model system, these sequences are not required for in vitro phosphorylation of eIF-2alpha. To explain this apparent contradiction, we proposed that these sequences are required to target the kinase to the translation machinery. Using sucrose gradient sedimentation, we found that wild-type PKR was associated with ribosomes, specifically with 40 S particles. Deletions or residue substitutions in the DRBD sequences blocked kinase interaction with ribosomes. These results indicate that in addition to mediating ds-RNA control of PKR, the DRBD sequences facilitate PKR association with ribosomes. Targeting to ribosomes may enhance in vivo phosphorylation of eIF-2alpha, by providing PKR access to its substrate.     

Stereotactic radiosurgery of angiographically occult vascular malformations: 14-year experience

OBJECTIVE: Radiosurgery is generally effective in obliterating true arteriovenous malformations, but less is known about its effects on angiographically occult vascular malformations (AOVMs). Since July 1983, 57 patients with surgically inaccessible AOVMs of the brain were treated using helium ion (47 patients) or linear accelerator (10 patients) radiosurgery. This study retrospectively evaluates the response of these AOVMs to treatment. METHODS: All patients presented with previous hemorrhage. The mean patient age was 35.6 years (range, 13-71 yr). The mean AOVM volume was 2.25 cm3 (range, 0.080-15.2 cm3), treated with a mean of 18.0 Gy equivalent (physical dose x relative biological effectiveness, which is 1.3 for helium ion Bragg peak) (range, 7.0-40 Gy equivalent). The Drake scale scores before treatment were as follows: excellent (25 patients), good (26 patients), and poor (6 patients). The mean follow-up period was 7.5 years (range, 9 mo-13.8 yr). RESULTS: Eighteen patients (32%) bled symptomatically (20 hemorrhages) after radiosurgery. Sixteen hemorrhages occurred within 36 months after radiosurgery (9.4% annual bleed rate; 16 hemorrhages/171 patient yr); 4 hemorrhages occurred more than 36 months after treatment (1.6% annual bleed rate; 4 hemorrhages/257 patient yr) (P < 0.001). Complications included symptomatic radiation edema (four patients, 7%), necrosis (one patient, 2%), and increased seizure frequency (one patient, 2%). Eight patients underwent surgical resection of their AOVMs 8 to 59 months after radiosurgery because of subsequent hemorrhage. The Drake scale scores after treatment were as follows: excellent (25 patients), good (24 patients), poor (3 patients), and dead (5 patients, 3 of whom died as a result of causes unrelated to the AOVMs or radiosurgery). CONCLUSION: Radiosurgery may be useful for AOVMs located in surgically inaccessible regions of the brain. A significant decrease in bleed rate exists more than 3 years after treatment compared with the bleed rate within 3 years of treatment. Because current neuroradiological techniques are not able to image obliterative response in these slow-flow vascular lesions, longer term clinical follow-up is required.     

Treatment considerations for posterior laboratory-fabricated composite resin restorations

A variety of techniques are currently available to restore dentition in the posterior region, and the selection of the proper modality is dependent upon evaluation and satisfaction of numerous criteria. Direct materials provide limited strength in the posterior segment, and full-coverage indirect techniques (e.g., crown restorations) often require the destruction of sound tooth structure. When proper case selection, preparation design, and clinical protocols are utilized, a laboratory-processed composite resin (belleGlass, Kerr/Sybron, Orange, CA) can provide an optimal means by which to successfully restore posterior dentition without compromising the existing tooth structure.     

Updating protections for human subjects involved in research. Project on Informed Consent, Human Research Ethics Group

For decades, all federally funded research involving human subjects has been subject to regulations that require the informed consent of the subject and oversight by the local institution. These regulations last underwent major revision in 1981 and have remained unchanged despite significant changes in the nature of clinical science, the financial sources of research support, and the institutional environment in which clinical research is conducted. In the intervening years, doubt has evolved as to whether the regulations currently in place adequately protect the welfare and rights of research subjects in today's clinical research environment and whether the costs, in terms of time, bureaucracy, and delay, are justified by the level of protection afforded. The Human Research Ethics Group, administered by the Center for Bioethics at the University of Pennsylvania Health System, extensively reviewed the status of existing human subjects protections with the aim of making recommendations to improve and reform the regulations. Here, we present recommendations constituting a consensus of the group members for reform in 3 key areas: protecting subject populations with special needs and vulnerabilities, oversight by institutional review boards, and regulatory policy.     

Renal clearance, tissue distribution, and CA-125 responses in a phase I trial of suramin

Exposure of human spermatozoa to nicotinamide adenine dinucleotide phosphate (NADPH) resulted in the dose dependent generation of reactive oxygen species (ROS) which, at a critical level of intensity, induced lipid peroxidation, DNA damage and a dramatic decline of sperm motility. This system was then used as a model for screening the ability of different antioxidants to combat oxidative stress created through the excessive intracellular generation of toxic oxygen products of metabolism. A variety of antioxidants that has previously been shown to be protective against extracellularly derived oxidants (e.g. superoxide dismutase, catalase, vitamin E, hypotaurine) were ineffective in this system. Albumin, however, could provide complete protection against NADPH induced oxidative stress via mechanisms that did not involve the suppression of the lipid peroxidation cascade but rather the inactivation of lipid peroxides generated during this process. Albumin did not protect against DNA damage induced by NADPH but was extremely effective at preventing DNA fragmentation arising from the suppression of glutathione peroxidase activity with mercaptosuccinate. These studies emphasize that the design of clinically effective antioxidant treatments will depend, critically, upon the source of the oxidative stress. For cases involving excessive intracellular ROS generation, albumin appears to be an important means of neutralizing lipid peroxide-mediated damage to the sperm plasma membrane and DNA.     

Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B

Protein kinase B (PKB) is activated in response to phosphoinositide 3-kinases and their lipid products phosphatidylinositol 3,4, 5-trisphosphate [PtdIns(3,4,5)P3] and PtdIns(3,4)P2 in the signaling pathways used by a wide variety of growth factors, antigens, and inflammatory stimuli. PKB is a direct target of these lipids, but this regulation is complex. The lipids can bind to the pleckstrin homologous domain of PKB, causing its translocation to the membrane, and also enable upstream, Thr308-directed kinases to phosphorylate and activate PKB. Four isoforms of these PKB kinases were purified from sheep brain. They bound PtdIns(3,4,5)P3 and associated with lipid vesicles containing it. These kinases contain an NH2-terminal catalytic domain and a COOH-terminal pleckstrin homologous domain, and their heterologous expression augments receptor activation of PKB, which suggests they are the primary signal transducers that enable PtdIns(3,4,5)P3 or PtdIns- (3,4)P2 to activate PKB and hence to control signaling pathways regulating cell survival, glucose uptake, and glycogen metabolism.     

Clinical factors contributing to the differential diagnosis of primary insomnia and insomnia related to mental disorders

OBJECTIVE: Primary insomnia and insomnia related to mental disorders are the two most common DSM-IV insomnia diagnoses, but distinguishing between them is difficult in clinical practice. This analysis was performed to identify clinical factors used by sleep specialists to distinguish primary insomnia from insomnia related to mental disorders. METHOD: Clinicians evaluated 216 patients referred for insomnia at five clinical sites, rated a list of clinical factors judged to contribute to each patient's presentation, and assigned diagnoses. Analysis of variance was performed, with contributing factors as the dependent variable and diagnostic group and clinic location as independent variables. RESULTS: Sleep specialists rated a psychiatric disorder as a stronger factor for insomnia related to mental disorders and rated negative conditioning and sleep hygiene as stronger factors for primary insomnia. However, a psychiatric disorder was rated as a contributing factor for 77% of patients who received a first diagnosis of primary insomnia. CONCLUSIONS: While neither sleep hygiene nor negative conditioning is a diagnostic criterion in DSM-IV, these results support the face validity of these clinical factors distinguishing between primary insomnia and insomnia related to mental disorders. The use of a psychiatric disorder as an inclusion criterion for insomnia related to mental disorders and an exclusion criterion for primary insomnia reinforces a categorical distinction between the two diagnoses, but the contribution of psychiatric symptoms in primary insomnia appears to be a clinically relevant one. These findings suggest the need for studies on the validity of negative conditioning and sleep hygiene in the etiology of primary insomnia, as well as on the significance of psychiatric disorders, especially depression, in primary insomnia.