Absorption, distribution and excretion of radioactivity by male rats after a single intravenous or subcutaneous dose of 14C-azacitidine.

The absorption, distribution and excretion of radioactivity were investigated in male Sprague-Dawley rats after a single intravenous or subcutaneous dose of 14C-azacitidine. After subcutaneous administration, 14C-azacitidine was rapidly absorbed and the radioactivity was distributed to the tissues. The absorption of radioactivity after subcutaneous administration was 76.6% of that observed after intravenous administration. There were no marked differences in the tissue distribution of the radioactivity between administration routes. The concentrations of radioactivity in most tissues, including the spleen and bone marrow, which are sites of action of azacitidine, were higher than those in the plasma. Particularly high concentrations of radioactivity were detected in the spleen, kidney and liver. The accumulation of radioactivity in blood cells increased from 0.5 to 48 h. The binding of azacitidine to serum protein was low at <9%, and the cumulative urinary and fecal excretion of radioactivity for 168 h after intravenous or subcutaneous administration was >95% of the administered dose, indicating that radioactivity did not accumulate in the tissues. The radioactivity was mainly excreted in the urine.

Effect of tyrosine kinase inhibition by imatinib mesylate on mast cell tumors in dogs.

BACKGROUND: Imatinib mesylate is a small molecule targeted at dysregulated protein-tyrosine kinase. Mutation of c-kit exon 11, which induces constitutive phosphorylation of KIT, is one of the mechanisms for the development or progression of mast cell tumor (MCT) in dogs. The purpose of this study was to examine the therapeutic potential of imatinib mesylate in canine MCT. HYPOTHESIS: Imatinib mesylate has activity against MCT in dogs, and response to treatment can be correlated to presence of mutation within exon 11 of c-kit. ANIMALS: Twenty-one dogs with MCT with gross tumor burden and median tumor size of 7.2 cm (range, 1.0-25.3 cm) before treatment. METHODS: Tumors were analyzed for mutation of c-kit exon 11. Imatinib mesylate was administered PO to the dogs at a dose of 10 mg/kg daily for 1-9 weeks. RESULTS: Ten of 21 dogs (48%) had some beneficial response to imatinib mesylate treatment within 14 days of treatment initiation. All 5 dogs with a demonstrable c-kit mutation in exon 11 responded to the drug (1 complete remission, 4 partial remission). CONCLUSIONS AND CLINICAL IMPORTANCE: Imatinib mesylate has clinical activity against MCT in dogs. Response could not be predicted based on presence of absence of a mutation in exon 11 of c-kit.

Fate of nonylphenol and 17beta-estradiol contained in composted sewage sludge after land application.

Many environmental problems caused by endocrine disrupters (EDs) have been reported. Because little is known about the fate of EDs accumulated in sewage sludge, we carried out a study to clarify the fate of EDs in composted sludge after its application to soil. Nonylphenol (NP) and 17beta-estradiol (E2) were measured for leachate and soil. High concentrations of NP and E2 were detected in the leachate at the early stage, but they decreased rapidly. Also, the high contents of NP and E2 in soil decreased significantly within 300 days. Because the decrease of NP and E2 in the soil was much larger than that of NP and E2 in the leachate, there must have been a physicochemical or biological decomposition mechanism in the soil layer. We also tried to clarify the transfer of NPs to plants from compost. In the experimental conditions of this study, the transfer of NPs to plants from compost was not observed.

Role of women in medicine: a look at the history, the present condition and the future status of women in the surgical field, especially neurosurgery.

We have analyzed the historical background of women's progress in medicine in Japan and the role of female neurosurgeons as models for the next generation. Female neurosurgeons were asked to complete a questionnaire regarding their professional life in detail and the problems they are facing while managing their personal life after getting married and having a child. Some feel that there remain some constraints at work for being a female, due to their male colleagues who are not so understanding in nature. The younger generation is not so keen on joining the neurosurgical branch as their life career due to hard work and complete dedication demanded by neurosurgery. It is not easy for all to manage a neurosurgical career along together with a married life and children. Hence it is now time for those successful female neurosurgeons to become role models. Government can play an important role in these social reforms by coming up with programs to give social security to females and initiate programs for child care for married females pursuing such a demanding profession. Certain measures to encourage females to take up surgery are providing more time by arranging care for babies and families, flexibility in working hours, in addition to having a considerate husband and a considerate chief of department and senior staff. Departmental policies need to be completely impartial and should promote everyone based on their skills and knowledge. Women neurosurgeons need to get together and discuss all these issues so that the younger generation will not hesitate to take up this profession and become stalwarts of neurosurgery like their male counterparts.

A new implant designed to maximize contact with trabecular bone: survival to 18 months.

PROBLEM: A roughened, commercially pure titanium (CP-Ti) implant design has been developed that features a different length and pitch for each screw thread to direct functional stresses away from cortical bone and to the more resilient trabecular bone. Abutment-implant connection is made using a conical taper to provide a seal against invasion by microorganisms. PURPOSE: To assess short-term (18 months) clinical performance of this innovative implant design. METHODS: A total of 1,419 implants were placed in 313 patients to support 419 prostheses in a multidisciplinary, multicentered, prospective clinical study conducted by the Ankylos Implant Clinical Research Group (AICRG). More than 100 dentists at 32 centers in the United States, 1 in Korea, and 1 in Taiwan are involved in the study. Failure was defined as implant removal for any reason. The influence of mobility at placement, implant length and diameter, incision type, augmentation, crestal bone reduction, bone density, and the use of the operating room or dental clinic on survival were evaluated over 18 months. Crestal bone loss between placement and uncovering was also determined. RESULTS: Crestal bone loss ranged from 0.2 to 0.5 mm. The overall success rate from placement to 18 months was 96.6%. Implants mobile at placement failed more frequently (16.9%) compared with stable implants (3.1%). Wide-diameter implants and longer implants exhibited higher survival rates. Incision design and surgery location did not influence survival. Bone density was important to clinical survival.

Long-term assessment (5 to 71 months) of endosseous dental implants placed in the augmented maxillary sinus.

BACKGROUND: It is not uncommon for the placement of endosseous dental implants in the maxillary posterior jaw region to be complicated by the pneumatization of the maxillary sinus. When this occurs, the residual bone between the floor of the sinus and the crestal ridge is inadequate for the placement of implants. The sinus lift procedure provides a way to increase the amount of available bone and the placement of longer implants. METHODS: One hundred twenty (120) implants were placed in 45 augmented maxillary sinuses. Patients ranged in age from 34 to 78 years. The implant design included a limited number of non-hydroxyapatite (HA)-coated titanium screws, with the majority of the implants being HA-coated cylinders, grooved cylinders, and screws. The augmentation materials were autogenous bone, allogenic bone (demineralized freeze-dried bone allograft, DFDBA), alloplastic bone (HA), combination grafts of HA and DFDBA, and combination grafts of autogenous bone and DFDBA. All the cases were successfully restored with implant-supported, bar-retained overdentures or fixed partial dentures. The follow-up began at Stage 2 uncovering and ranged from 5 to 71 months, with a mean of 38.2 and standard deviation of 14.6 months. RESULTS: Three (2.5%) of the 120 implants failed between the period of implant placement and 36 months. Failures appeared to be associated with a history of smoking. Other complications encountered during the study are presented. Implant survival was higher in those placed in grafted sinuses (97.5%) than in those placed in the posterior maxilla without sinus grafting (90.3%). CONCLUSION: These findings support the use of implants placed in augmented sinuses to support dental prostheses.

The influence of smoking on 3-year clinical success of osseointegrated dental implants.

BACKGROUND: Health risks associated with smoking have been exhaustively documented and include increased incidence of periodontal disease, greater risk of osteitis following oral surgery, and compromised wound healing due to hypoxia. Information related directly to dental implants, although limited, points to higher rates of implant failures among smokers than non-smokers. This paper reports on long-term clinical outcomes of osseointegrated dental implants placed in smokers and non-smokers in a longitudinal clinical study of endosseous dental implants. METHODS: In 1990, the Dental Implant Clinical Research Group (DICRG) of the Department of Veterans Affairs (DVA) launched an 8-year, randomized, prospective clinical study of more than 2,900 endosseous dental implants in more than 800 patients at 32 study centers. Confounding variables, including smoking patterns, were recorded. For this report, new follow-up data were analyzed for two groups: 1) current smokers and 2) those who never smoked combined with those who quit. Most of the variables recorded for each implant were screened on a univariate basis as possible predictors associated with implant survival/failure. Those with P values less than 0.15 and those likely to be a factor of clinical importance were placed in a logistic regression equation and analyzed for a simultaneous effect on survival. A step-wise procedure was used to eliminate those variables that showed the least significance, until only those variables with a Wald chi-square of significance in the presence of others remained. The effects of clustering within patients and of unbalanced distribution within hospitals were standardized to facilitate analysis of influence of demographic variables. The GEE analysis was performed with the patient as the primary cluster. RESULTS: Current data do not support earlier findings that smoking contributes to early implant failure (placement to uncovering). A trend of greater failures in smokers appeared between the time after uncovering and before insertion of the prosthesis. Hydroxyapatite (HA)-coated implants had significantly lower failure rates. For the entire 3-year period, overall failures were significantly higher for smokers than non-smokers. CONCLUSIONS: Results suggest that increased implant failures in smokers are not the result of poor healing or osseointegration, but of exposure of peri-implant tissues to tobacco smoke. Data also suggest that detrimental effects may be reduced by: 1) cessation of smoking; 2) the use of preoperative antibiotics; and 3) the use of HA-coated implants.

Clostridium perfringens beta-toxin is sensitive to thiol-group modification but does not require a thiol group for lethal activity.

The beta-toxin gene isolated from Clostridium perfringens type B was expressed as a glutathione S-transferase (GST) fusion gene in Escherichia coli. The purified GST-beta-toxin fusion protein from the E. coli transformant cells was not lethal. The N-terminal amino acid sequence of the recombinant beta-toxin (r toxin) isolated by thrombin cleavage of the fusion protein was G-S-N-D-I-G-K-T-T-T. Biological activities and molecular mass of r toxin were indistinguishable from those of native beta-toxin (n toxin) purified from C. perfringens type C. Replacement of Cys-265 with alanine or serine by site-directed mutagenesis resulted in little loss of the activity. Treatment of C265A with N-ethylmaleimide (NEM), which inactivated lethal activity of r toxin and n toxin, led to no loss of the activity. The substitution of tyrosine or histidine for Cys-265 significantly diminished lethal activity. In addition, treatment of C265H with ethoxyformic anhydride which specifically modifies histidyl residue resulted in significant decrease in lethal activity, but that of r toxin with the agent did not. These results showed that replacement of the cysteine residue at position 265 with amino acids with large size of side chain or introduction of functional groups in the position resulted in loss of lethal activity of the toxin. Replacement of Tyr-266, Leu-268 or Trp-275 resulted in complete loss of lethal activity. Simultaneous administration of r toxin and W275A led to a decrease in lethal activity of beta-toxin. These observations suggest that the site essential for the activity is close to the cysteine residue.

Hydroxyapatite-coated implants: a case for their use.

The information on which this article is based comprises a small fraction of the large database compiled from the DICRG study. These results represent the early performance for HA implants (up to 36 months). The study has been ongoing for 6 years, and there are more than 2,000 implants with 4-year data and 1,500 with 5-year data. These data are similar to the 36-month data, and when they are eventually released, they are likely to reinforce the results reported here. Meanwhile, the evidence presented in this article, along with other corroborating studies cited in the introduction, are sufficient grounds to reach the following conclusion: The ideal implant design and material is one that is easy to use, requires average skills, involves minimal bone trauma, presents a biocompatible contact surface, and produces a high rate of survival in most patients. Based on 36-month survival in the DICRG study, HA-coated implants appeared to satisfy these basic requirements better than the other implants used in the study. HA-coated implants were placed in the most challenging bone types and jaw region, in patients with compromised medical histories, by dentists with different training, skills, and experience, under less than ideal clinical conditions, and still showed the highest survival rates of all implants at every point in the treatment up to 36 months.

Positive effect of surgical experience with implants on second-stage implant survival.

This Dental Implant Clinical Research Group study defined a learning curve for dental implant placement. Implants placed by inexperienced surgeons (< 50 implants) failed twice as often as those placed by experienced surgeons (> or = 50 implants). Implants placed during the first 6, 8, 10, 12, and 16 cases were compared with all others. The greatest difference was seen between the first nine cases and all others (P = .001), with later cases failing significantly less often. Inexperienced surgeons had more failures in the first nine cases (5.9%) than more experienced surgeons (2.4%). Surgeons with little or no previous experience must expect a definite learning curve. Previous experience may transfer and result in a shallower learning curve for subsequent systems.

The influence of preoperative antibiotics on success of endosseous implants up to and including stage II surgery: a study of 2,641 implants.

According to the American College of Surgeons, complex oral surgical procedures, including the transoral placement of endosseous implants, are of the type that may require prophylactic antibiotics. However, the routine use of prophylactic antibiotics in the field of dental implantology continues to be controversial, and their utilization varies widely. No data from a randomized prospective clinical study of the prophylactic use of antibiotics in implant surgery have been previously published. As part of the comprehensive Dental Implant Clinical Research Group clinical implant study, the preoperative or postoperative use of antibiotics, the type used, and the duration of coverage was left to the discretion of the surgeon. These data were recorded and correlated with failure of osseointegration during healing (stage I) and at stage II surgery (uncovering). The results showed that significantly fewer failures occurred when preoperative antibiotics were used.

The influence of 0.12% chlorhexidine digluconate rinses on the incidence of infectious complications and implant success.

The effect of perioperative chlorhexidine on the frequency of infectious complications through stage II was examined. Chlorhexidine was used perioperatively in 54.6% of patients (52.5% of implants) in a Dental Implant Clinical Research Group study with a database of 2,641 implants (595 patients). With chlorhexidine, there was a significant reduction in the number of infectious complications (4.1% vs 8.7%). Two percent of implants failed in the absence of an infectious complication, whereas 12% with infectious complications failed. This sixfold difference is highly significant. Chlorhexidine may reduce microbial complications when used in the immediate perioperative period.

The influence of type of incision on the success rate of implant integration at stage II uncovering surgery.

In 1991, the Dental Implant Clinical Research Group comprising 30 Department of Veterans Affairs medical centers and two dental schools initiated a long-term clinical study to investigate the clinical performance of implants within the Spectra-System (Core-Vent Corporation, Las Vegas, NV). This article focuses on a portion of the study database related to incision type, implant success rates, and response of crestal bone up to the time of surgical uncovering. The crestal incision was used for 1,705 implants (381 patients) and the remote incision for 593 implants (141 patients). No statistically significant difference (P = .092 chi-square statistic) was found in implant integration or the response of crestal bone.

Distribution of bone quality in patients receiving endosseous dental implants.

Knowledge of the distribution of bone quality in the various jaw regions assists the clinician in dental implant treatment planning. Bone quality was assessed with radiographs and tactile sensation for 2,839 implants at the time of placement into four anatomic regions of the jaw. The Lekholm-Zarb classification system was used. Overall, bone quality types 1 and 4 were found much less frequently than types 2 and 3. Although variations in density existed in each region, quality 2 bone dominated the mandible, and quality 3 bone was more prevalent in the maxilla. For both anterior and posterior jaw regions, types 2 and 3 bone predominated. The anterior mandible had the densest bone, followed by the posterior mandible, anterior maxilla, and posterior maxilla.

Bone quality and implant design-related outcomes through stage II surgical uncovering of Spectra-System root form implants.

Failure rates at second-stage surgery were reported for the ongoing Dental Implant Clinical Research Group studies of the Spectra-System (Core-Vent Corporation, Las Vegas, NV) implants. As of May 1995, 69 implants failed out of 2,633 placed and uncovered. The overall failure rate was 2.6%, with 3.6% in bone quality 1 (BQ-1), 2.4% in BQ-2, 2.5% in BQ-3, and 3.1% in BQ-4. HA-coated cylinders had the lowest number of failures and titanium alloy baskets the highest. The basket design failed more often in the posterior jaw areas; 9 of 32 clinical centers (28%) accounted for 72% of these failures.

The influence of bone quality on Periotest values of endosseous dental implants at stage II surgery.

Periotest values (Periotest, Siemens AG, Bensheim, Germany) were recorded as a baseline variable at surgical uncovering in the ongoing multicenter, prospective clinical studies of the Dental Implant Clinical Research Group, which uses implants from the Spectra-System (Core-Vent Corporation, Las Vegas, NV). For 2,212 osseointegrated implants, the mean Periotest value (PTV) of mandibular implants was -4.14 (anterior, -4.22; posterior, -4.06) versus -3.24 for maxillary implants (anterior, -2.91; posterior, -3.91). Implants in the densest bone (quality 1) had the lowest mean PTV (-4.13), followed by quality 2 (-4.00), quality 3 (-3.58), and quality 4 (-2.64).

[Hippocampal hemosiderin deposit due to large pituitary adenoma presenting temporal lobe epilepsy--a case report].

There have been reports of epilepsy associated with pituitary adenoma, but the epileptogenic zone and its histopathology have never been sufficiently described. We report a case of pituitary adenoma complicated by temporal lobe epilepsy, in which the epileptogenic focus was identified, resected, and examined histopathologically. The patient was a 38-year-old man on bromocriptine therapy for a huge pituitary adenoma (prolactin-producing) since 1985. He also had a history of temporal lobe epilepsy since 1989. CT images in 1985 revealed the tumor extending to the supra- and left para-sellar region. MR images in 1995 showed a significant decrease in the size of the tumor and a signal void area that was interpreted as a hemosiderin deposit in the left mesial temporal lobe. Ictal EEG demonstrated that seizure discharges were elicited at the left sphenoidal electrode and propagated to the both temporal lobes. Interictal SPECT revealed a local area of hypoperfusion in the left fronto-parietal lobe. An epileptogenic focus in the left mesial temporal lobe was diagnosed on the basis of the above examinations. The patient was treated by left anterior temporal lobectomy with partial hippocampectomy. Hemosiderin deposition in the hippocampus was suspected during surgery. Histopathological examination showed pyramidal cell loss and gliosis in the left hippocampus and confirmed the presence of hemosiderin in the CA1 region. The hemosiderin deposition in the hippocampus was inferred to have resulted from intratumoral hemorrhage due to bromocriptine therapy, and it may have caused the temporal lobe epilepsy in this patient. The outcome of surgery was freedom from seizures for eight months. Intra-tumoral hemorrhage in mesial temporal structures must be borne in mind as one of the epileptogenic mechanisms in pituitary adenoma, especially in cases in which hemosiderin is detected on MR images.

Periotest values of dental implants in the first 2 years after second-stage surgery: DICRG interim report no. 8. Dental Implant Clinical Research Group.

In 1991, the Dental Implant Clinical Research Group initiated a long-term clinical study in cooperation with the Department of Veterans Affairs to investigate the influence of implant design, application, and site of placement on clinical performance and crestal bone height. As part of this investigation, Periotest values for 2,212 root from implants were determined at second-stage surgery and during a 24-month follow-up period. Mean Periotest values decreased for implants placed in quality 1 and 2 bone, did not change for implants in quality 3 bone, and increased for implants in quality 4 bone. Implants in the posterior maxilla and single implants in the anterior maxilla had increasing mean Periotest values as compared with decreasing values for implants in other regions. Mean Periotest values for uncoated implants decreased gradually to approach those of hydroxyapatite-coated implants.