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Insulin resistance, an important feature of type 2 diabetes, is manifested as attenuated insulin receptor (IR) signaling in response to insulin binding. A drug that promotes the initiation of IR signaling by enhancing IR autophosphorylation should, therefore, be useful for treating type 2 diabetes. This report describes the effect of a small molecule IR sensitizer, TLK16998, on IR signaling. This compound activated the tyrosine kinase domain of the IR beta-subunit at concentrations of 1 micromol/l or less but had no effect on insulin binding to the IR alpha-subunit even at much higher concentrations. TLK16998 alone had no effect on IR signaling in mouse 3T3-L1 adipocytes but, at concentrations as low as 3.2 micromol/l, enhanced the effects of insulin on the phosphorylation of the IR beta-subunit and IR substrate 1, and on the amount of phosphatidylinositol 3-kinase that coimmunoprecipitated with IRS-1. Phosphopeptide mapping revealed that the effect of TLK16998 on the IR was associated with increased tyrosine phosphorylation of the activation loop of the beta-subunit tyrosine kinase domain. TLK16998 also increased the potency of insulin in stimulating 2-deoxy-D-glucose uptake in 3T3-L1 adipocytes, with a detectable effect at 8 micromol/l and a 10-fold increase at 40 micromol/l. In contrast, only small effects were observed on IGF-1-stimulated 2-deoxy-D-glucose uptake. In diabetic mice, TLK16998, at a dose of 10 mg/kg, lowered blood glucose levels for up to 6 h. These results suggest, therefore, that small nonpeptide molecules that directly sensitize the IR may be useful for treating type 2 diabetes. [ABSTRACT FROM AUTHOR]

The article presents a serial study on the depletion of ascorbic acid in guinea pigs. The relationship between vitamin C and oral collagen metabolism is discussed. Weight gain among test subjects is compared. Results showed that guinea pigs deprived of vitamin C for 21 days acquired grossly swollen and hemorrhagic costochondral junctions.

The multicatalytic proteinase or proteasome is a highly conserved cellular structure that is responsible for the ATP-dependent proteolysis of many proteins involved in important regulatory cellular processes. We have identified a novel class of inhibitors of the chymotrypsin-like proteolytic activity of the 20S proteasome that exhibit IC50 values ranging from 0.1 to 0.5 microgram/mL (0.1 to 1 microM). In cell proliferation assays, these compounds inhibit growth with an IC50 ranging from 5 to 10 micrograms/mL (10-20 microM). A representative member of this class of inhibitors was tested in other biological assays. CVT-634 (5-methoxy-1-indanone-3-acetyl-leu-D-leu-1-indanylamide) prevented lipopolysaccharide (LPS), tumor necrosis factor (TNF)-, and phorbol ester-induced activation of nuclear factor kappa B (NF-kappa B) in vitro by preventing signal-induced degradation of I kappa B-alpha. In these studies, the I kappa B-alpha that accumulated was hyperphosphorylated, indicating that CVT-634 did not inhibit I kappa B-alpha kinase, the enzyme responsible for signal-induced phosphorylation of I kappa B-alpha. In vivo studies indicated that CVT-634 prevented LPS-induced TNF synthesis in a murine macrophage cell line. In addition, in mice pretreated with CVT-634 at 25 and 50 mg/kg and subsequently treated with LPS, serum TNF levels were significantly lower (225 +/- 59 and 83 +/- 41 pg/mL, respectively) than in those mice that were treated only with LPS (865 +/- 282 pg/mL). These studies suggest that specific inhibition of the chymotrypsin-like activity of the proteasome is sufficient to prevent signal-induced NF-kappa B activation and that the proteasome is a novel target for the identification of agents that may be useful in the treatment of diseases whose etiology is dependent upon the activation of NF-kappa B.

The effects of N-acetyl-leucinyl-leucinyl-norleucinal (ALLN), a potent inhibitor of proteolysis catalyzed by proteasomes, on the activation of NF-kappaB in vitro and in vivo have been examined. Confirming earlier observations, ALLN inhibits the activation of NF-kappaB in macrophage cultures stimulated with LPS, resulting in the intracellular accumulation of IkappaB and p105. The synthesis of TNF, a reaction dependent upon NF-kappaB activation, is blocked by ALLN. Treatment of mice with LPS results in the induction of TNF and IL-6 within 90 min followed by lethal shock at 24 hr. In mice pretreated with ALLN, serum TNF and IL-6 levels were significantly lower than those in untreated animals. These studies suggest that the proteasome is a novel target for the identification of agents that may be useful in the treatment of those diseases whose etiology is dependent on the activation of NF-kappaB.

Purpose: This article describes predictable techniques to augment contour- or height-deficient edentulous alveolar processes with autologous bone grafts for simultaneous or secondary placement of endosseous implants., Methods: Augmentation bone grafts harvested from the ilium and mandible were used to reverse alveolar atrophy of the maxilla and mandible. Endosseous implants were either placed simultaneously with the graft or 6 to 9 months after grafting. Implant success was calculated only after an implant-supported prosthesis was in function for a minimum of 12 months., Results: One hundred twenty-nine autologous bone grafts were placed in 99 patients. This included 70 grafts in the maxillary sinus, 32 onlay grafts, 14 veneer grafts, 9 saddle grafts, and 4 inlay grafts. Of these, 117 (90.7%) were successful. A total of 364 implants were placed in the grafted areas, 134 at the time of grafting and 230 6 to 9 months after grafting to allow time for osseous healing and remodeling. Three hundred twenty (87.9%) of the 364 implants placed in grafted areas were successful; 112 (83.6%) of the implants placed at the time of bone grafting and 208 (90.4%) of the implants placed secondarily in consolidated grafts. A total of 51 implants were placed in non-grafted areas in the same group of patients. Of these, 49 (96%) were successful., Conclusion: Autologous bone grafts can be used successfully to improve the ability to place endosseous implants. The successful placement of implants in autologous grafts is more predictable when the implants are placed secondarily, 6 to 9 months after bone grafting. Failure of individual implants does not imply failure of the bone graft. In most instances when implants failed to osseointegrate, enough bone graft remains to allow subsequent successful implant placement 6 to 9 months later.

Purpose: Deep vein thrombosis is a complication in surgical patients with a potential for disastrous results. This article discusses the pathogenesis, prevention, and treatment of this condition., Conclusion: Surgeons should be acutely aware of the potential development of deep vein thrombosis and should take prophylactic measures to prevent this problem as part of their surgical routine.

Pulmonary vascular leak induced in mice by interleukin 2 (IL-2) was attenuated by pretreatment with single or multiple doses of oral methotrexate. Methotrexate also attenuated pulmonary vascular leak when either larger doses of IL-2 or when lymphokine-activated killer (LAK) cells or LAK cells plus IL-2 were administered. Lymphoid infiltrates in the lungs of mice treated with IL-2 and methotrexate were significantly lower. The number of mice surviving treatment with high doses of IL-2 was also significantly increased when these mice were treated with methotrexate. Methotrexate prevented the IL-2-induced increase in the number of splenocytes that were asialo GM1+ but had no effect on Lyt 2+ or L3T4+ cell content. A marginal but significant inhibition in the generation of effector splenocytes that were cytolytic to either YAC or MCA-205 tumor targets was observed in mice treated with methotrexate and IL-2. In vivo studies indicated that methotrexate did not compromise the anti-tumor efficacy of treatment regimens that contained IL-2, LAK cells, or IL-2 and LAK cells. These results demonstrate the potential clinical utility of methotrexate in attenuating pulmonary vascular leak induced by IL-2 without compromising its efficacy. One potential mechanism of action of methotrexate is related to its ability to stimulate the release of adenosine followed by the inhibition of the adhesion of leukocytes to the IL-2-activated endothelium.

A new fluorescence assay for measuring the activity of geranylgeranyl transferase (type I) is described. It does not require the use of either radiolabeled geranylgeranyl diphosphate or the purified recombinant Ras protein substrate with the carboxy terminal sequence of CVLL. Dansyl GCVLL and unlabeled geranylgeranyl diphosphate are used as substrates. The Km for Dansyl GCVLL and for geranylgeranyl diphosphate is 5 microM and 800 nM, respectively. At equimolar concentrations, enzymatic activity is higher when Dansyl GCVLL is used as a substrate compared to Dansyl GCVII. Dansyl GCVLS, a substrate for farnesyl transferase, is inactive in this assay. CVFL is a competitive inhibitor of geranylgeranyl transferase and exhibits a Ki of 200 nM.

The need for enhanced surgical exposure for the high extracranial (Zone III) internal carotid artery is not uncommon. In certain circumstances, the posterior border and angle of the mandible may interfere with access to the distal internal carotid artery (ICA). The use of modified mandibular osteotomies has provided vascular surgeons in our institution with improved exposure of the ICA in selected cases. The intraoral sagittal split and extraoral vertical ramus osteotomies of the mandible allow manipulation of the posterior border and angle of the mandible with low morbidity and minimal postoperative complications. These procedures can be performed for both dentate and edentulous patients without the need for intermaxillary fixation. This paper introduces these modifications and discusses the benefits over previously described methods of mandibular manipulation.

The iliac crest is a common site for bone procurement in oral and maxillofacial surgery. The goal of this study was to evaluate the potential for bone regeneration in the presence of four common hemostatic agents in a manner that parallels iliac bone procurement in humans. The agents evaluated were 1) Avitene (microfibrillar collagen; Medchem Products, Inc, Woburn, MA); 2) bone wax (beeswax with isopropyl palmitate; Ethicon, Inc, Somerville, NJ); 3) Gelfoam (absorbable gelatin sponge; The Upjohn Company, Kalamazoo, MI); and 4) Surgicel (oxidized regenerated cellulose; Johnson & Johnson Products, Inc, Patient Care Division, New Brunswick, NJ). Five surgical defects in each of four dogs were created for placement of the four materials; one defect served as an empty control site. The dogs were then allowed to heal over a 2-month period. Radiographic and histologic examination showed new bone formation in the presence of Avitene, Surgicel, and Gelfoam. Residual material incorporated in bone, without foreign-body response, was noted in the Avitene and Gelfoam sites. Bone wax, however, showed an intense foreign-body reaction, characterized by giant cells, plasma cells, fibrous granulation tissue, and lack of bone reformation. On the basis of these initial findings, it was concluded that Surgicel, Avitene, and Gelfoam may be adequate hemostatic agents for use in iliac bone procurement, whereas the use of bone wax appears to be contraindicated.

The combined orthodontic, orthognathic surgical, and prosthodontic reconstruction of the previously treated bilateral cleft lip and cleft palate of a 20-year-old white man is reviewed. Maxillary arch collapse and severe malocclusion occurred after palatal closure in early childhood with alveolar bone grafting and premaxillectomy. A modified Le Fort I osteotomy, using a jackscrew with a modified posterior hinge, was employed to achieve rapid palatal expansion. In addition, mandibular subapical osteotomy was performed, in conjunction with postoperative orthodontic realignment. Fixed prosthodontic restorations were then used to achieve stability and a more esthetic appearance.

We have described our technique for general anesthesia for outpatients using a mixture of nitrous oxide, oxygen, and enflurane with spontaneous ventilation through a Bain anesthetic circuit. In our experience, surgical excision of impacted teeth, multiple extractions and alveoloplasty, enucleation of simple cysts, excision of benign tumors, and other similar operations have been done efficiently with these anesthetic techniques. More than 500 such cases have been managed without significant complication. The concepts of selection and preparation of patients, airway security and protection during surgery performed in the upper airway on an unconscious patient who is breathing spontaneously, continuous monitoring of vital functions, and rapid induction and recovery all combine to make this technique consistent with standards for excellence in anesthesia.