Bishop Flap and Sigma Flap to Repair Surgical Defects in High-Tension Anatomical Regions. / Colgajo obispo y colgajo sigma para defectos quirúrgicos en zonas anatómicas de elevada tensión.

BACKGROUND: The reconstruction of surgical defects in high-tension anatomical regions is challenging due to the ischemia and subsequent necrosis associated with tension closure. Research on new flaps capable of closing these defects exerting less tension would be a tremendous advancement in dermatological surgery. PATIENTS AND METHODS: We conducted a multicenter, retrospective study that used 2 new flaps-the bishop and the sigma ones-to repair surgical defects in high-tension regions such as the scalp, lower extremities, and the nasal pyramid. The bishop flap was used in 9 patients, 5 of whom exhibited their lesion in the nasal pyramid, 2 in the legs and another 2 in the scalp. The sigma flap was used in 6 patients, 5 of whom exhibited scalp lesions and 1 leg lesion. RESULTS: Uneventful and excellent results were obtained in all 15 patients due to infection, dehiscence, or necrosis. CONCLUSIONS: Both the bishop and the sigma flaps are a good alternative to repair surgical defects in high-tension regions such as the scalp, lower extremities, or the nasal pyramid.

Exercise training, creatine supplementation, and bone health in ovariectomized rats.

UNLABELLED: Evidence suggests that creatine may have some beneficial effects on bone. The study aimed to investigate the effects of exercise alone or combined with creatine on bone health in ovariectomized rats. Findings show that exercise, but not creatine, has an important role in improving bone health. INTRODUCTION: The aim of this study was to investigate the effects of exercise training alone or combined with creatine supplementation on bone health parameters in ovariectomized rats. METHODS: Wistar rats were randomly allocated into one of five groups: (i) sham-operated, (ii) ovariectomized non-trained placebo-supplemented, (iii) ovariectomized non-trained creatine-supplemented, (iv) ovariectomized exercise-trained placebo-supplemented, and (v) ovariectomized exercise-trained creatine-supplemented. Downhill running training and/or creatine supplementation (300 mg/kg body weight) were administered for 12 weeks. Bone mineral content (BMC), bone mineral density (BMD), and biomechanical and histomorphometric parameters were assessed. RESULTS: No interaction effects were observed for BMC and BMD at whole body, femur, and lumbar spine (p > 0.05). Importantly, a main effect of training was detected for whole body BMC and BMD (p = 0.003 and p < 0.001, respectively), femoral BMC and BMD (p = 0.005 and p < 0.001, respectively), and lumbar spine BMC and BMD (p < 0.001 and p < 0.001, respectively), suggesting that the trained animals had higher bone mass, irrespective of creatine supplementation. Main effects of training were also observed for maximal load (p < 0.001), stiffness (p < 0.001), and toughness (p = 0.046), indicating beneficial effects of exercise training on bone strength. Neither a main effect of supplementation nor an interaction effect was detected for biomechanical parameters (p > 0.05). No main or interaction effects were observed for any of the histomorphometric parameters evaluated (p > 0.05). CONCLUSIONS: Exercise training, but not creatine supplementation, attenuated ovariectomy-induced bone loss in this rat model.

Screening for undiagnosed pancreatic exocrine insufficiency (PEI) in a cohort of diabetic patients using faecal elastase testing and PEI scoring system.

INTRODUCTION: Type 1 and type 2 diabetes mellitus (DM) are often accompanied by mild forms of pancreatic exocrine insufficiency (PEI). The prevalence rates of PEI in diabetic patients are unclear and variable depending on the testing modality and the studies published. The clinical consequences of PEI in diabetics are also not well defined. AIM: We aimed to determine the prevalence of PEI in a diabetic cohort using the faecal elastase-1 (FE-1) assay as a screening test and to validate a patient-reported symptom-based scoring system, the (PEI-S) for diagnosing PEI within this patient population. METHODS: Two hundred and three diabetic patients attending diabetic and gastroenterology outpatients of a university hospital without previously known PEI were recruited for the study. Demographic parameters, PEI score (PEI-S), and glycated hemoglobin (HBA1c) were documented in standardized data sheets, and a stool sample was obtained. A FE-1 value < 200 µg/g and or a PEIS of > 0.6 was used as the screening cut-off for PEI. RESULTS: One hundred sixty-six patients returned faecal samples. The prevalence of PEI, as measured by low FE-1, was 12%. Smoking was associated with an increased risk of developing PEI in this diabetic population. No other independent risk factors were identified. The PEI-S system did not differentiate between people with diabetes having a normal and low FE1. CONCLUSION: 12% of this mixed, real-life cohort of type 1 and 2 DM patients had undiagnosed PEI, as defined by an FE-1 score of less than 200 µg/g. While this may appear low, given the rising prevalence of type 2 DM worldwide, there is likely an unrecognized burden of PEI, which has long-term health consequences for those affected. The PEI-S, a symptom-scoring system for patients with PEI, did not perform well in this patient group.

A novel vibratory stimulation-based occlusal splint for alleviation of TMD painful symptoms: a pilot study.

This pilot study introduces a novel vibratory stimulation-based occlusal splint (VibOS) for management of pain related to temporomandibular disorders (TMD). The study sample consisted of 10 patients (mean age: 40·5 ± 13·7 years, male/female: 3/7) who were using stabilisation splints for more than 2 months prior to the study onset and still complained of pain. Patients utilised the active and inactive VibOS during 15 days in a crossover designed clinical trial. The analysed variables were self-reported VAS pain levels and number of painful sites to palpation (PSP). Statistical analysis was performed with repeated measures anova. At baseline, mean VAS pain levels for group I and II were 45·6 ± 21·0 mm and 37·4 ± 16·3 mm, respectively. Comparison between these baseline values showed no statistical difference (P > 0·05, unpaired t-test). In group I, the inactive VibOS caused a slight increase in VAS pain levels, whereas the active VibOS promoted a significant decrease in VAS pain levels and PSP (P < 0·01). In group II, which received the active VibOS first, a significant decrease in VAS levels (P < 0·05) and in PSP (P < 0·01) was observed. No significant decrease in VAS pain levels or PSP (P > 0·05) was observed with the use of the inactive VibOS. In conclusion, this study demonstrated a good tendency of this novel VibOS in the alleviation of painful symptoms related to TMD after a 15-day management period compared to control VibOS.

Sexual risk behaviors for HIV infection in Spanish male sex workers: differences according to educational level, country of origin and sexual orientation.

The stigma associated with male sex workers (MSW) hinders the prevention, treatment, and care of HIV infection in this population. These factors make social and public health resources less accessible to MSW. To improve the effectiveness of prevention strategies, this study examines social factors such as educational level, country of origin, and sexual orientation. Semi-structured interviews of 100 MSW in Castellón and Valencia (Spanish cities) indicate that knowledge of HIV transmission is good; nevertheless, MSW significantly overestimate or underestimate some sexual practices. Levels of condom use are high; notably, they are higher during anal sex. Levels of condom use are lower with intimate partners than with clients. MSW do not present differences in terms of the socio-demographic variables analyzed and sexual orientation. Furthermore, regression analyses are not significant. These results offer more accurate profiles of MSW than were previously available, which will ultimately help improve the effectiveness of prevention programs.

ITER collective Thomson scattering-Preparing to diagnose fusion-born alpha particles (invited).

The ITER Collective Thomson scattering (CTS) diagnostic will measure the dynamics of fusion-born alpha particles in the burning ITER plasma by scattering a 1 MW 60 GHz gyrotron beam off fast-ion induced fluctuations in the plasma. The diagnostic will have seven measurement volumes across the ITER cross section and will resolve the alpha particle energies in the range from 300 keV to 3.5 MeV; importantly, the CTS diagnostic is the only diagnostic capable of measuring confined alpha particles for energies below ∼1.7 MeV and will also be sensitive to the other fast-ion populations. The temporal resolution is 100 ms, allowing the capture of dynamics on that timescale, and the typical spatial resolution is 10-50 cm. The development and design of the in-vessel and primary parts of the CTS diagnostic has been completed. This marks the beginning of a new phase of preparation to maximize the scientific benefit of the diagnostic, e.g., by investigating the capability to contribute to the determination of the fuel-ion ratio and the bulk ion temperature as well as integrating data analysis with other fast-ion and bulk-ion diagnostics.

[Inflammatory myxohyaline tumor of the distal extremities]. / Tumor mixohialino inflamatorio de las zonas distales de las extremidades.

Inflammatory myxohyaline tumor of the distal extremities is an extremely rare low-grade sarcoma with a tendency to produce local recurrence after surgical excision, but with a low metastatic potential. We present the case of a 49-year-old woman with a slow-growing asymptomatic tumor on the right pretibial region that was initially considered to be a lipoma. Histopathology revealed the presence of a polymorphic inflammatory infiltrate within a myxoid and hyaline matrix. Interspersed between the inflammatory cells were 3 different populations of neoplastic cells: atypical spindle-shaped cells; bizarre epithelioid cells, some of which were multinucleated and resembled the virocytes or Reed-Sternberg cells; and cells with abundant, vacuolated cytoplasm, similar to lipoblasts. These clinical-pathologic findings led to a diagnosis of inflammatory myxohyaline tumor of the distal extremities. Although the tumor was excised with wide surgical margins, local recurrence developed after 3 months and was treated with re-excision and radiotherapy.

Role of boost radiotherapy for local control of pure ductal carcinoma in situ after breast-conserving surgery: a multicenter, retrospective study of 622 patients.

PURPOSE: To evaluate the effect of boost radiotherapy on ipsilateral breast tumor recurrence (IBTR) for ductal carcinoma in situ (DCIS) after breast-conserving surgery and whole breast radiotherapy (WBRT) with or without boost. METHODS AND MATERIALS: Retrospective, multicentre study of 622 patients (624 tumors) diagnosed with pure DCIS from 1993-2011. RESULTS: Most tumors (377/624; 60.4%) received a boost. At a median follow-up of 8.8 years, IBTR occurred in 64 cases (10.3%). A higher percentage of patients with risk factors for IBTR received a boost (p < 0.05). Boost was not associated with lower rates of IBTR than WBRT alone (HR 0.75, 95% CI 0.42-1.35). On the univariate analyses, IBTR was significantly associated with tumor size (11-20 mm, HR 2.32, 95% CI 1.27-4.24; and > 20 mm, HR 2.10, 95% CI 1.14-3.88), re-excision (HR 1.76, 95% CI 1.04-2.96), and tamoxifen (HR 2.03, 95% CI 1.12-3.70). Boost dose > 16 Gy had a protective effect (HR 0.39, 95% CI 0.187-0.824). Multivariate analyses confirmed the independent associations between IBTR and 11-20 mm (p = 0.02) and > 20 mm (p = 0.009) tumours, and re-excision (p = 0.006). On the margin-stratified multivariate analysis, tamoxifen was a poor prognostic factor in the close/positive margin subgroup (HR 4.28 95% CI 1.23-14.88), while the highest boost dose ( > 16 Gy) had a significant positive effect (HR 0.34, 95% CI 0.13-0.86) in the negative margin subgroup. CONCLUSIONS: Radiotherapy boost did not improve the risk of IBTR. Boost radiotherapy was more common in patients with high-risk disease. Tumor size and re-excision were significant independent prognostic factors.

Mutations of the adenylyl cyclase gene that block RAS function in Saccharomyces cerevisiae.

The interaction between RAS proteins and adenylyl cyclase was studied by using dominant interfering mutations of adenylyl cyclase from the yeast Saccharomyces cerevisiae. RAS proteins activate adenylyl cyclase in this organism. A plasmid expressing a catalytically inactive adenylyl cyclase was found to interfere dominantly with this activation. The interfering region mapped to the leucine-rich repeat region of adenylyl cyclase, which is homologous to domains present in several other proteins and is thought to participate in protein-protein interactions.

Effect of the C-factor and dentin preparation method in the bond strength of a mild self-etch adhesive.

This study evaluated the effect of the C-factor and dentin preparation method (DPM) in the bond strength (BS) of a mild self-etch adhesive; the study also observed the SEM superficial aspects of the corresponding smear layer. For purposes of this study, 25 molars (n=5) were used in a bond strength test. The molars were divided into two parts (buccal and lingual): one part received a Class V cavity (C-factor=3) and the other received a flat surface (C-factor=0) with the same bur type (coarse diamond or carbide bur and fine diamond or carbide bur), both within the same dentin depth. Five teeth were prepared with wet 60-grit and 600-grit SiC papers. After restoration with Clearfil SE Bond, microtensile beans (0.8 mm2) were prepared and tested after 24 hours in a universal testing machine (0.5 mm/minute). An additional two teeth for each DPM were prepared for SEM evaluation of the smear layer superficial aspects. The BS values were submitted to one-way ANOVA, considering only the DPM (flat surfaces) and two-way ANOVA (C-Factor x DPM, considering only burs) with p=0.05. Although the DPM in the flat surfaces was not significant, the standard deviations of carbide bur-prepared specimens were markedly lower. The BS was significantly lower in cavities. The fine carbide bur presented the most favorable smear layer aspect. It was concluded that different dentin preparation methods could not prevent the adverse effect in bond strength of a high C-factor. A coarse cut carbide bur should be avoided prior to a mild self-etch adhesive, because it adversely affected bond strength. In contrast, a fine cut carbide bur provided the best combination: high bond strength with low variability, which suggests a more reliable bond strength performance.

Mutational mapping of RAS-responsive domains of the Saccharomyces cerevisiae adenylyl cyclase.

Large deletion and small insertion mutations in the adenylyl cyclase gene of Saccharomyces cerevisiae were used to map regions required for activation by RAS protein in vitro. The amino-terminal 605 amino acids were found to be dispensable for responsiveness to RAS protein. All other deletions in adenylyl cyclase destroyed its ability to respond to RAS. Small insertion mutations within the leucine-rich repeat region also prevented RAS responsiveness, while other insertions did not.

Two types of RAS mutants that dominantly interfere with activators of RAS.

In the fission yeast Schizosaccharomyces pombe, ras1 regulates both sexual development (conjugation and sporulation) and cellular morphology. Two types of dominant interfering mutants were isolated in a genetic screen for ras1 mutants that blocked sexual development. The first type of mutation, at Ser-22, analogous to the H-rasAsn-17 mutant (L. A. Feig and G. M. Cooper, Mol. Cell. Biol. 8:3235-3243, 1988), blocked only conjugation, whereas a second type of mutation, at Asp-62, interfered with conjugation, sporulation, and cellular morphology. Analogous mutations at position 64 of Saccharomyces cerevisiae RAS2 or position 57 of human H-ras also resulted in dominant interfering mutants that interfered specifically and more profoundly than mutants of the first type with RAS-associated pathways in both S. pombe or S. cerevisiae. Genetic evidence indicating that both types of interfering mutants function upstream of RAS is provided. Biochemical evidence showing that the mutants are altered in their interaction with the CDC25 class of exchange factors is presented. We show that both H-rasAsn-17 and H-rasTyr-57, compared with wild-type H-ras, are defective in their guanine nucleotide-dependent release from human cdc25 and that this defect is more severe for the H-rasTyr-57 mutant. Such a defect would allow the interfering mutants to remain bound to, thereby sequestering RAS exchange factors. The more severe interference phenotype of this novel interfering mutant suggests that it functions by titrating out other positive regulators of RAS besides those encoded by ste6 and CDC25.

A conserved alternative splice in the von Recklinghausen neurofibromatosis (NF1) gene produces two neurofibromin isoforms, both of which have GTPase-activating protein activity.

Sequence analysis has shown significant homology between the catalytic regions of the mammalian ras GTPase-activating protein (GAP), yeast Ira1p and Ira2p (inhibitory regulators of the RAS-cyclic AMP pathway), and neurofibromin, the protein encoded by the NF1 gene. Yeast expression experiments have confirmed that a 381-amino-acid segment of neurofibromin, dubbed the GAP-related domain (GRD), can function as a GAP. Using the RNA polymerase chain reaction with primers flanking the NF1-GRD, we have identified evidence for alternative splicing in this region of the NF1 gene. In addition to the already published sequence (type I), an alternative RNA carrying a 63-nucleotide insertion (type II) is present in all tissues examined, although the relative amounts of types I and II vary. The insertion is conserved across species but is not present in GAP, IRA1, or IRA2. GenBank searches have failed to identify significant similarity between the inserted sequence and known DNA or protein sequences, although the basic amino acid composition of the insertion shares features with nuclear targeting sequences. Expression studies in yeasts show that despite the partial disruption of the neurofibromin-IRA-GAP homology by this insertion, both forms of the NF1-GRD can complement loss of IRA function. In vivo assays designed to compare the GAP activity of the two alternatively spliced forms of the NF1-GRD show that both can increase the conversion of GTP-bound ras to its GDP-bound form, although the insertion of the 21 amino acids weakens this effect. The strong conservation of this alternative splicing suggests that both type I and II isoforms mediate important biological functions of neurofibromin.

Medulloblastoma in young adults. Must we give adjuvant chemotherapy?

Medulloblastoma is a rare entity in adult patients. All data about treatment are from children, where this disease is the most common cerebral tumour. Reports of medulloblastoma in adults are scarce but in all of them the prognosis seems similar to the prognosis of children. We present our experience in five cases of medulloblastoma in young adults, treated at the University Hospital "Germans Trias i Pujol" from June 1994 to October 2003. This has not been a good experience as more than 50% of the patients had a recurrence in spite of the standard treatment. We have reviewed the literature, concluding that we have to adapt the findings in children to our adult patients, offering them adjuvant chemotherapy after surgery.

Clinical course of high-grade glioma patients with a "biopsy-only" surgical approach: a need for individualised treatment.

INTRODUCTION: 'Biopsy-only' high-grade glioma (HGG) patients get limited benefit from post-operative treatments, and as a group, negatively impact median survival outcomes. MATERIAL AND METHODS: We retrospectively evaluated clinical characteristics, treatment and overall survival of HGG patients with a 'biopsy- only' surgical approach diagnosed between 1997 and 2005 at a University Hospital in Spain. RESULTS: In 31% of 294 suspected gliomas, only a diagnostic biopsy was undertaken. Reasons for 'biopsy-only' for all patients were either location in eloquent areas: (motor area 18.7%, language area 25,3%, basal ganglia 7.7%, visual area 4.4%) or extension of the disease (corpus callosum invasion 14.3% and multicentricity/multifocality 28.6%). Seventy-four patients (80.4%) were HGG: 26% of all grade IV and 49% of all grade III tumours. For these patients, post-operative Karnofsky Performance Status of over 70%, median age and median survival were, respectively: 64 and 70%, 60.7 and 57 years old, and 23.1 and 42.7 weeks (p=0.0006). Patients lived longer if post-operative treatment was given, in all grades (p<0.0001). Nineteen patients (25.6%) died within 42 days after surgery. Only 60% of them initiated radiotherapy and 10% of them did not complete it. However, tumour grade, radiotherapy and temozolomide- based chemotherapy were independently associated with longer survival in multivariate analysis (p<0.05). CONCLUSION: Almost one third of HGG patients can undergo only a biopsy and not debulking surgery. Although radiotherapy improves survival, only 50% of them complete the treatment. An individualised approach to these patients is needed to facilitate a correct analysis of therapy results. New therapies must be investigated in these patients.

Situación actual de la cirugía endocrina en régimen ambulatorio en España. Revisión sistemática de la literatura existente / Current situation of outpatient endocrine surgery in spain. Systematic review of the existing literature

En los últimos 20 años la cirugía en régimen ambulatorio se ha impuesto como una realidad cotidiana. Se ha convertido en un estándar para ciertas cirugías en casos seleccionados. La cirugía tiroidea y paratiroidea han sido unos de los procedimientos que se han implantado en muchas unidades de CMA, pero todavía hay reticencias a su realización y no existen muchas publicaciones al respecto en el ámbito nacional. Por ello, revisamos la literatura publicada en revistas indexadas respecto a la cirugía tiroidea y paratiroidea en régimen ambulatorio en España en los últimos 20 años (AU)

In the last 20 years ambulatory surgery has established itself as a daily reality. It has become a standard for certain surgeries in selected cases. Thyroid and parathyroid surgery have been one of the procedures that have been implemented in many units, but there is still reluctance to carry them out and there are not many publications on the matter at the national level. For this reason, we reviewed the literature published in indexed journals regarding thyroid and parathyroid surgery in outpatient settings in Spain in the last 20 years (AU)

Management of breast ductal carcinoma in situ in Catalonia, Spain: Results from the Grup Oncologic Calalà-Occità-Catalonia survey with 9-year follow up.

INTRODUCTION: Reliable data on DCIS incidence and management are not available in many countries. The present study describes the management of DCIS in Catalonia, Spain in the year 2005 and compares these findings to data obtained in France. Local recurrence and late toxicity rates from 2005 through the end of 2014 are reported. MATERIALS AND METHODS: Observational survey of patients with pure DCIS (n = 270) diagnosed during 2005. A written questionnaire, the same as used in the French survey, was completed by 14 doctors at 12 cancer centres in Catalonia, Spain. RESULTS: Median patient age was 55 years (range, 29-89). Diagnosis was mammographic in 225 cases (83.3%). Treatment approaches included: mastectomy (10.4% of cases), breast-conserving surgery (BCS) alone (3.7%), and BCS plus radiotherapy (RT) (85.5%). Sentinel node biopsy and axillary dissection were performed in 27.4% and 5.6% of patients, respectively. Hormonotherapy was prescribed in 45.2% of cases. Tumour nuclear grade was as follows: low (16.7% of cases), intermediate (23%), and high (55.6%). Excision was complete (margins ≥1 mm) in 75% of patients treated with BCS alone vs. 95.7% for BCS+RT. The treatment approach varied widely: mastectomy rates ranged from 7.1% to 26.7% of centres, BCS+RT from 55.5% to 87.8%, and hormonotherapy from 3.3% to 83.3%. At a median follow-up of 102.6 months, 14 patients (5.6%) presented ipsilateral breast tumour recurrence. CONCLUSIONS: These findings on DCIS management in Catalonia are consistent with previous international reports. The inter-centre differences observed are similar to those reported in other international surveys during the same period.

Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition.

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.

[Prognostic utility of scintigraphy with 99mTc-HMPAO labelled leukocytes in inflammatory bowel disease]. / Utilidad pronóstica de la gammagrafía con leucocitos marcados 99mTc-HMPAO en la enfermedad inflamatoria intestinal.

OBJECTIVE: The inflammatory bowel disease (EII) has a chronic evolution with a frequent relapses. There is no specific diagnosis method to detect the patients with a high risk to relapse. The aim of the work was to analyse the prognostic value of 99mTc-HMPAO leukocyte scintigraphy (LS) performed during an acute attack of EII. MATERIAL AND METHODS: 18 patients (mean age 32 +/- 10 years) admitted for an acute attack of EII has been prospectively studied (5 ulcerative colitis [UC] and 13 Cronh's disease [CD]), excluding patient with prior steroids or immunosuppressive therapy during the last year. LS were obtained in basal conditions and following 3 weeks of steroid treatment and the scintigraphic activity index (SAI) has been calculated. Colonoscopy has been done in all patients, and CDAI in CD and Truelove index in UC have been calculated. Patients were followed up for 1 year. In the evolution the therapy requirements as well as the good response to initial treatment have been evaluated. RESULTS: All patients with UC and 4 patients with CD showed a SAI decrease > 50 % and all had a good clinical evolution. Only 2 out of the 9 patients with CD showing a IAG decrease < 50 % and had a good clinical evolution, the 7 remaining required additional medical treatment (immunosuppressors or surgery). CONCLUSION: LS may be of prognostic value in the management of EII. A SAI decrease > 50 % at 3 weeks of steroid treatment indicates a good clinical evolution.

Analysis of the neurofibromatosis type 1 (NF1) GAP-related domain by site-directed mutagenesis.

The gene for von Recklinghausen neurofibromatosis type 1 (NF1) was recently identified by positional cloning and found to encode a protein with sequence similarity to a family of eucaryotic GTPase-activating proteins (GAPs). Expression of the NF1-GAP-related domain (NF1GRD) has been shown to complement yeast strains deficient in the yeast GAP homologs, IRA1 and IRA2, to interact with human RAS proteins and to accelerate the conversion of ras-GTP to ras-GDP. Further analysis of this region has revealed a number of residues that are highly conserved between members of the GAP family. Mutational analysis of a representative number of these residues produced one of three effects: (1) no change in NF1GRD function, (2) complete disruption of NF1GRD function and (3) intermediate retention of NF1GRD function. One of these mutations at residue 1423 was shown to have reduced ability to negatively regulate ras in yeast, which is interesting in light of a recent report demonstrating a similar naturally occurring mutation in human malignancies.