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PubMed1999

[The importance of the distal radioulnar joint for reconstructive procedures in malunited distal radius fracture].

Clinically most patients complain about ulnar sided wrist pain and limited forearm rotation following malunited distal radius fractures. Possible bony reasons consist of intraarticular incongruency, malalignment of the sigmoid notch of the distal radius or the ulna-plus-situation at the wrist level. A persisting luxation of the distal radioulnar joint (DRUJ) will present itself with complete loss of forearm rotation. The ligamentous or bony detachment of the triangular fibrocartilage complex (TFCC) will lead to instability of the DRUJ. Uncorrected, each of these components will lead to arthrosis of the DRUJ. The presence of arthrosis only allows salvage procedures for the DRUJ and will lead to functional loss. Reconstructive options consist of radius correction osteotomy, ulnar shortening osteotomy, reposition of a luxation and refixation of the TFCC. To chose the necessary reconstructive procedure, the individual pathological situation has to be analysed.

Fractures, Malunited↗

PubMedDate not supplied

An overview of assistive technology for persons with multiple sclerosis.

Multiple sclerosis (MS) is a progressive neurologic disease clinically characterized by episodes of focal disorder of the cranial nerves, spinal cord, and the brain. MS affects a significant number of young adults, and they most often face a future of progressive functional losses as more of their central nervous system and cranial nerves are affected. As the disease progresses, they have new impairments with accompanying limitations in activities, restrictions to their participation in life, and compromised quality of life. Assistive technology includes any item that is used to maintain or improve functional capabilities. The rehabilitation healthcare provider has many opportunities to intervene with assistive technologies to decrease activity limitations and participation restrictions. The purpose of this article is to (1) review the impairments and associated activity limitations and participations restrictions experienced by persons with MS, (2) provide an overview of high- and low-tech assistive technologies appropriate for persons with MS, (3) discuss funding opportunities for assistive technologies, (4) review current studies of assistive technology used for persons with MS and discuss future research directions, and (5) consider assistive technology as an intervention for disability prevention.

Activities of Daily Living↗

PubMed1998

Impairment of basal forebrain cholinergic neurons associated with aging and long-term loss of ovarian function.

Recent studies suggest that women are at greater risk for Alzheimer's disease than men and that estrogen replacement can help to reduce the risk and severity of Alzheimer's-related dementia in postmenopausal women. We have hypothesized that the increased risk for Alzheimer's-related dementia is due, in part, to the loss of ovarian function in postmenopausal women and to the effects that decreased levels of ovarian hormones have on basal forebrain cholinergic function. In the present study, the effects of aging and ovariectomy on cholinergic neurons in the rat basal forebrain were examined to determine (1) whether aging differentially affects cholinergic neurons in the basal forebrain of males vs females, and (2) whether long-term loss of ovarian function produces deficits in basal forebrain cholinergic function beyond those associated with aging and sex. In part I of the study, gonadally intact male and female rats were sacrificed at 13, 19, and 25 months of age and the effects of aging on cholinergic neurons in the medial septum (MS) and nucleus basalis magnocellularis (NBM) were compared. In part II of the study, female rats were ovariectomized at 13 months of age and then sacrificed 3 and 6 months later along with gonadally intact, age-matched controls. Adjacent sections through the MS and NBM were processed for either immunocytochemical detection of choline acetyltransferase (ChAT) and p75NTR-like immunoreactivity or for in situ hybridization detection and quantification of ChAT and trkA mRNA. Results from part I revealed no significant effects of age on the relative size or density of cholinergic neurons in the MS and NBM of gonadally intact animals. Likewise, no significant effects on the relative numbers of cholinergic neurons expressing p75NTR protein were detected. However, a significant decrease in trkA mRNA was detected in the MS of gonadally intact females, but not males, between 13 and 25 months of age. No significant effects of aging on ChAT mRNA were detected. Results from part II revealed significant decreases in both ChAT and trkA mRNA in the MS and NBM of female rats sacrificed 6 months, but not 3 months, following ovariectomy relative to age-matched, gonadally intact controls. Short-term estrogen replacement initiated 6 months following ovariectomy and administered for 3 days prior to sacrifice partially restored ChAT mRNA levels in the MS and trkA mRNA levels in the NBM. These findings suggest that ovarian hormones play a role in maintaining normal levels of ChAT and trkA expression in the MS and NBM. The fact that ChAT mRNA was decreased in the MS and NBM at 6 months following ovariectomy suggests that long-term loss of ovarian function produces a decrease in the functional status of basal forebrain cholinergic neurons projecting to the hippocampus and cortex. In addition, we hypothesize that the decreases in trkA mRNA detected both in the MS as a function of aging, and in the MS and NBM in response to ovariectomy, reflect decreases in the production of high affinity nerve growth factor (NGF) receptors, and a decrease in the responsiveness of the cholinergic neurons to endogenous NGF. This, in turn, may increase the susceptibility of the cholinergic neurons to the effects of aging and disease and thereby contribute to basal forebrain cholinergic decline. We conclude that long-term loss of ovarian function combined with aging has a negative impact on basal forebrain cholinergic neurons. These effects may contribute to the risk and severity of cognitive decline associated with aging and Alzheimer's disease in postmenopausal women.

Aging↗

PubMed2003

The role of TP53 in Cervical carcinogenesis.

Functional loss of the tumor suppressor p53 by alterations in its TP53 gene is a frequent event in cancers of different anatomical regions. Cervical cancer is strongly linked to infection by high-risk human papillomavirus (HPV) types. The viral oncoprotein E6 has the ability to associate with and neutralize the function of p53. E6 interacts with a 100-kDa cellular protein, termed E6 associated protein (E6AP; also called ubiquitin-protein ligase E3A or UBE3A), which functions as an ubiquitin protein ligase. The dimeric complex then binds p53 and E6AP catalyzes multi-ubiquitination and degradation of p53. The ability to promote p53 degradation is an exclusive property of E6 from the high-risk HPV types. Indeed, the low-risk E6 proteins lack this activity, although they can bind p53. Consistent with the E6 function of the high-risk HPV types, the majority of cervical cancer cells have a wild-type p53 gene, but the protein levels are strongly decreased. Several independent studies have shown that in a small percentage of cervical tumors the p53 gene is mutated. However, this event appears to be unrelated to the presence or absence of HPV infection and the nature of the tumor.

Female↗

PubMed1998

A comparison of two functional tests in quadriplegia: the quadriplegia index of function and the functional independence measure.

Individuals with spinal cord injury are evaluated according to a set of guidelines based on motor, sensory, and functional tests. The resulting scores are used to quantify the extent of neurological injury and functional loss. The purpose of the present study was to compare certain scoring systems using the same group of patients. Twenty-nine subjects with cervical spine cord injury were evaluated by the same examiner using three scales: (1) The American Spinal Cord Injury Association (ASIA) (2) The Quadriplegia Index of Function (QIF) (3) The Functional Independence Measure (FIM) Assessments were made both at admission to, and discharge from, the rehabilitation center. Positive change in motor score is widely used as an indicator of recovery after spinal cord injury. We assessed the relationship of the two functional tests, the FIM and the QIF, to ASIA scores and found strong correlations in both cases. The feeding and dressing categories of QIF showed an even stronger correlation to ASIA motor scores, though the statistical significance was the same for corresponding categories of FIM and QIF. The percent of recovery on ASIA motor scores was significantly correlated only to gain in QIF scores, not FIM. FIM lacks the category of bed activities. Some additions to the FIM may be useful, especially in the feeding and dressing categories, and a category of bed activities could be included as well, in order to improve sensitivity.

Activities of Daily Living↗

PubMed2003

Attenuated metabolic response to surgery in tumor-bearing rats.

BACKGROUND: During cancer, proteins are chronically wasted, including proteins of the gut. Surgical stress acutely increases protein breakdown of the gut. Surgery in cancer patients may thus have a double effect on the gut and lead to exhaustion and functional loss of the gut. METHODS: Female Lewis rats (+/-200 g) were studied bearing a subcutaneous tumor or after sham implantation. Hysterectomy was performed in half of the rats as a standardized operative procedure. Postoperative protein kinetics of the gut were determined using a primed constant infusion of L-[2,6-(3)H]-phenylalanine. Gut function was assessed by testing its permeability for sugar probes lactulose and L-rhamnose. Villus height and crypt depth were measured and polyamine concentrations were measured as markers for mucosal proliferation and differentiation. RESULTS: In control rats, gut protein breakdown increased from 6 +/- 3 to 32 +/- 8 nmol phenylalanine x 100 g body wt x min after hysterectomy. This was accompanied by increased amino acid membrane transport rates and metabolic shunting. In tumor-bearing rats, increased protein breakdown in response to surgery was attenuated (8 +/- 4 vs 17 +/- 4 nmol x 100 g body wt x min). Surgery increased the lactulose/L-rhamnose recovery ratio, indicating increased gut permeability. In the presence of a tumor gut permeability also increased and it increased further after surgery. No changes in villus height or polyamine levels could explain the increased permeability of the gut. CONCLUSION: The study shows that a mild surgical trauma increases protein breakdown of the gut and simultaneously increases gut permeability. In the presence of a tumor the metabolic response to surgery is attenuated. Gut barrier loss was highest in the combined presence of cancer and the surgical insult.

Animals↗

PubMed2005

The kidney, a cardiovascular risk marker, and a new target for therapy.

Both reduced filtration power and increased excretion of albumin in the urine are powerful markers for renal and cardiovascular progressive function loss. These risk markers indicate the risk above and beyond the conventional existing risk markers/factors. The risk is substantial, because both reduced filtration and microalbuminuria are highly prevalent in the general population, matching in prevalence with the most well-known risk factor, hypertension. Therapeutic interventions to preserve renal and cardiovascular function, such as with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists, are highly effective, particularly in those patients that have reduced filtration power. In addition, short-term reduction of albuminuria that follows the renin-angiotensin-aldosterone-system intervention appears to be predictive of long-term cardiovascular and renal protection. In conclusion, estimated glomerular filtration rate as well as albumin excretion in the urine are powerful predictors for cardiovascular and renal outcome and should be used as such. Intervention and prevention could be aimed at not only at reducing conventional risk markers, but also at reducing albuminuria.

Albuminuria↗

PubMed1998

Kidney transplantation: the use of living donors with renal artery lesions.

PURPOSE: A shortage of organs for transplantation has forced surgeons to optimize the use of marginal organs, such as kidneys with arterial disease. We present a retrospective study of the outcome of donors with renal artery disease and recipients of kidneys from living related and unrelated donors. MATERIALS AND METHODS: Kidneys with vascular abnormalities from healthy living donors were grafted into 11 recipients. These kidney transplants comprised 1.8% of those performed at our institution. The vascular abnormalities were aneurysms in 3 cases, atherosclerotic lesions in 4 and fibromuscular dysplasia in 4. After nephrectomy all abnormalities were corrected under hypothermic conditions during bench surgery except in 3 cases of ostial atherosclerotic plaque, which was left in the donors. The renal artery was anastomosed to the external iliac artery in 5 cases and to the internal iliac artery in 6. The ureter was reimplanted using an extravesical technique. RESULTS: All patients had immediate diuresis and no delayed post-transplant graft dysfunction was observed. One patient died of an unrelated cause and 3 had post-transplant graft function loss due to acute vasculopathy in 1, post-diarrhea with acute arterial thrombosis in 1 and recurrence of the hemolytic-uremic syndrome in 1. All remaining patients are well with median serum creatinine of 1.4 mg./dl. (normal 0.4 to 1.4). All donors are well and normotensive with normal renal function. CONCLUSIONS: The use of kidneys with arterial disease from living donors with unilateral disease is safe. Complete informed consent regarding the risks and benefits by donor and recipient is mandatory.

Adult↗

PubMed1996

Reirradiation tolerance of the rat heart.

PURPOSE: To investigate the influence of reirradiation on the tolerance of the heart after a previous irradiation treatment. METHODS AND MATERIALS: Female Wistar rats were locally irradiated to the thorax. Development of cardiac function loss was studied with the ex vivo working rat heart preparation (20). To compare the retreatment experiments, initial, and reirradiation doses were expressed as the percentage of the extrapolated tolerance dose (ETD) (1). RESULTS: Local heart irradiation with a single dose led to a dose-dependent and progressive decrease in cardiac function. The progressive nature of irradiation-induced heart disease is shown to affect the outcome of the retreatment, depending on both the time interval between subsequent doses and the size of the initial dose. The present data demonstrate that hearts are capable of repairing a large part of the initial dose of 10 Gy within the first 24 h. However, once biological damage as a result of the first treatment is fixed, the heart does not show any long-term recovery. At intervals up to 6 months between an initial treatment with 10 Gy and subsequent reirradiation, the reirradiation tolerance dose slightly decreased from 74% of the ETDref (at 24-h interval) to 68% of the ETDref (at 6-month interval). Between 6 and 9 months, reirradiation tolerance dose dropped more even to 43% of the ETDref. Treatment of the heart with an initial dose of 17.5 Gy, instead of 10 Gy, 6 months prior to reirradiation, also led to a further decrease of the reirradiation tolerance dose (< 38 vs. 68% of the ETDref). CONCLUSIONS: The outcome of the present study shows a decreased tolerance of the heart to reirradiation at long time intervals (interval > 6 months). This has clinical implications for the estimation of reirradiation tolerance in patients whose mediastinum has to be reirradiated a long time after a first irradiation course.

Animals↗

PubMed2000

Correlation between autopsy findings for chronic obstructive airways disease and in-life disability in South African gold miners.

OBJECTIVES: In South Africa chronic obstructive airway disease (COAD), which could be due to working in a dusty atmosphere in scheduled mines or works, is a compensatable disease. Miners are compensated for in-life respiratory disability and for findings at autopsy of COAD, which includes emphysema, bronchitis assessed by mucus gland hyperplasia in the main bronchus, and bronchiolitis assessed by goblet cell metaplasia. The question arises as to whether the autopsy findings correlate with in-life impairment. The objectives of the study were: (1) to determine whether autopsy COAD outcomes relate to lung function and to respiratory symptoms and signs; and (2) to quantify the individual contributions of emphysema, bronchiolitis and bronchitis to lung function impairment. METHODS: On 724 gold miners, pathological findings of COAD--emphysema, bronchitis and bronchiolitis-- were related to lung function measurements and respiratory symptoms and signs observed within 5 years prior to death. RESULTS: Emphysema diagnosed at autopsy was the main determinant of airflow impairment. The emphysema score categories 0-5, 5-35, 35-65 and > 65 were associated with decreased forced expiratory volume in 1 s, expressed as percentage predicted (FEV1%) as follows: 78.8%, 66.2%, 52.0% and 46.0%, respectively. The score was also associated with increasing frequency of dyspnoea. After adjustment for emphysema, the bronchitis and bronchiolitis were not related to significant lung function loss, and in subjects without emphysema, the presence of moderate or marked bronchitis was associated with a mild impairment only. Bronchitis at autopsy was associated with increased frequency of rhonchi, sputum and cough, whereas bronchiolitis was associated with increased sputum only. Silicosis found at autopsy was associated with some obstructive and restrictive lung function impairment. Tobacco smoking was associated with all the COAD outcomes.

Aged↗

PubMed2005

Inactivation of protease inhibitors and lysozyme by hypochlorous acid: role of side-chain oxidation and protein unfolding in loss of biological function.

Excessive or misplaced activation of leukocytes causes host tissue damage which has been implicated in diseases such as atherosclerosis and chronic inflammation. This may arise via either the generation of oxidants such as hypochlorous acid (HOCl) by the heme enzyme myeloperoxidase, the action of released enzymes including lysozyme and proteases, or a combination of these two activities. Thus, oxidant-mediated inactivation of protease inhibitors that modulate tissue proteolysis by the released enzymes may exacerbate protease-induced degradation of host tissue. The role of myeloperoxidase-derived oxidants, such as HOCl, in the inactivation of Kunitz-type inhibitors and lysozyme is not well-characterized and is the subject of the current study. Exposure of both trypsin inhibitor and lysozyme to low molar excesses of HOCl compared to protein is shown to result in loss of function. With trypsin inhibitor, this loss of activity is associated with the selective oxidation of Trp, Tyr, and His residues, which results in protein unfolding and the disruption of complex formation with active trypsin. Oxidation of Met residues, a major target for HOCl, or the active site Arg, does not appear to play a key role in this loss of activity. In contrast, with lysozyme, oxidation of Met residues to Met sulfoxide appears to be the major process resulting in loss of enzyme activity. With both proteins, inactivation occurs in a time-dependent manner, consistent with both direct oxidation by HOCl and secondary reactions of protein chloramines formed from amine groups (e.g., from Lys and His) playing a role in loss of activity.

Animals↗

PubMed2003

Visual acuity and contrast sensitivity in patients with neovascular age-related macular degeneration. Results from the Radiation Therapy for Age-Related Macular Degeneration (RAD-) Study.

BACKGROUND: Patients with advanced age-related macular degeneration (AMD) suffer not only from impairment in central visual acuity (VA), but also from reduction in contrast sensitivity (CS). We examined VA and CS changes over time in patients with subfoveal choroidal neovascularizations (CNV) as well as the correlation between the two parameters. METHODS: VA was determined according to a standardized protocol with the Early Treatment Diabetic Retinopathy (ETDRS) chart. CS was measured with Pelli-Robson charts. The angiographic characteristics of CNV and the presence of CNV in the fellow eye as well as gender and age were evaluated as possible prognostic factors of VA and CS progression. Two hundred and five patients with neovascular AMD were recruited within the Radiation Therapy for Age-Related Macular Degeneration (RAD) Study and were reviewed over 2 years. The treatment and control groups showed no significant difference for VA or for CS ( P>0.05), and both groups were considered together. RESULTS: At baseline, mean VA was 55.6+/-14.5 SD letters (EDTRS chart), and mean CS was 22.8+/-6.9 letters (Pelli-Robson chart). Spearman Correlation Coefficient ( r(s)) between VA and CS was r(s)=0.60, P=0.0001. Over 2 years the mean VA loss was 23.6+/-21.4 letters and mean CS reduction was 9.0+/-9.7 letters. Agreement between change of VA and change of CS was moderate ( r(s)=0.65, P=0.0001; kappa coefficient (grouped into VA loss < or =15, >15, >30 letters; CS loss < or =6, >6, >15 letters) kappa=0.43, 95% CI [0.32;0.54]). Proportional hazard models did not show any apparent influence of type of CNV, or CNV in the fellow eye, on change in VA and CS. CONCLUSION: The results indicate that VA and CS do not always show the same progression in visual function loss although they show a moderate correlation in eyes with neovascular AMD. Both parameters provide important information about visual disability and should be evaluated as outcome in interventional studies.

Aged↗

PubMed2005

[Surgical rehabilitation procedures of the upper limbs in tetraplegic patients].

Cervical spinal cord injuries represent about 40% of all spinal cord lesions. In addition to the complete paralysis of the lower limbs they induce a dramatic decrease of upper limb function. Surgical rehabilitation of the upper limbs, based mainly on tendon transposition procedures, was advocated by only few surgeons more than thirty years ago and has developed in recent years in view of their satisfactory results. We report a consecutive series of 69 tetraplegic patients operated during the past twelve years, amounting to 188 rehabilitation procedures on their upper limbs. Our results indicate that surgery was beneficial in all cases. There was no case of functional loss and the patients were mostly satisfied with the procedures.

Adolescent↗

PubMed1993

[Evaluation of visual field defects, motility disorders and diplopia within the scope of accident insurance law].

Visual Field: The determination of the level of compensation for loss of integrity is based on the Goldmann Perimetry. In case of concentric loss of the visual field the SUVA Tables 1989 are used. Hemi- and Quadrantanopsias are still evaluated according to the Rintelen Tables from 1954. No guidelines are available for the evaluation of central and paracentral skotomas. It is uncertain if automatic perimetry can be used routinely in the future for the evaluation of visual function. Motility Disorders and Diplopia: The evaluation of functional loss caused by diplopia is very difficult. Therefore a big variation of 5-30% has been determined. It is up to the specialist to evaluate the extent of the damage. In this study we looked for a correlation between the objective findings and the subjective complaints. Such a correlation could not be found so that an arbitrary classification depending on the extent of the diplopia must be recommended. This would create an analogy to the evaluation of the loss of visual acuity and visual field where no freedom is left to the judgement of the physician. Some reflections are given on the sense and benefit of the unique Swiss law concerning compensation for loss of integrity.

Diplopia↗

PubMed2006

Crystal structure of the HRDC domain of human Werner syndrome protein, WRN.

Werner syndrome is a human premature aging disorder characterized by chromosomal instability. The disease is caused by the functional loss of WRN, a member of the RecQ-helicase family that plays an important role in DNA metabolic pathways. WRN contains four structurally folded domains comprising an exonuclease, a helicase, a winged-helix, and a helicase-and-ribonuclease D/C-terminal (HRDC) domain. In contrast to the accumulated knowledge pertaining to the biochemical functions of the three N-terminal domains, the function of C-terminal HRDC remains unknown. In this study, the crystal structure of the human WRN HRDC domain has been determined. The domain forms a bundle of alpha-helices similar to those of Saccharomyces cerevisiae Sgs1 and Escherichia coli RecQ. Surprisingly, the extra ten residues at each of the N and C termini of the domain were found to participate in the domain architecture by forming an extended portion of the first helix alpha1, and a novel looping motif that traverses straight along the domain surface, respectively. The motifs combine to increase the domain surface of WRN HRDC, which is larger than that of Sgs1 and E. coli. In WRN HRDC, neither of the proposed DNA-binding surfaces in Sgs1 or E. coli is conserved, and the domain was shown to lack DNA-binding ability in vitro. Moreover, the domain was shown to be thermostable and resistant to protease digestion, implying independent domain evolution in WRN. Coupled with the unique long linker region in WRN, the WRN HRDC may be adapted to play a distinct function in WRN that involves protein-protein interactions.

Amino Acid Sequence↗

PubMed2003

Vaccination with dendritic cells pulsed with peptides of myelin basic protein promotes functional recovery from spinal cord injury.

Injury-induced self-destructive processes cause significant functional loss after incomplete spinal cord injury (SCI). Cellular elements of both the innate (macrophage) and the adaptive (T-cell) immune response can, if properly activated and controlled, promote post-traumatic regrowth and protection after SCI. Dendritic cells (DCs) trigger activation of effector and regulatory T-cells, providing a link between the functions of the innate and the adaptive immune systems. They also initiate and control the body's response to pathogenic agents and regulate immune responses to both foreign and self-antigens. Here we show that post-injury injection of bone marrow-derived DCs pulsed with encephalitogenic or nonencephalitogenic peptides derived from myelin basic protein, when administered (either systemically or locally by injection into the lesion site) up to 12 d after the injury, led to significant and pronounced recovery from severe incomplete SCI. No significant protection was seen in DC recipients deprived of mature T-cells. Flow cytometry, RT-PCR, and proliferation assays indicated that the DCs prepared and used here were mature and immunogenic. Taken together, the results suggest that the DC-mediated neuroprotection was achieved via the induction of a systemic T-cell-dependent immune response. Better preservation of neural tissue and diminished formation of cysts and scar tissue accompanied the improved functional recovery in DC-treated rats. The use of antigen-specific DCs may represent an effective way to obtain, via transient induction of an autoimmune response, the maximal benefit of immune-mediated repair and maintenance as well as protection against self-destructive compounds.

Animals↗

PubMed1992

Loss of normal allele of the APC gene in an adrenocortical carcinoma from a patient with familial adenomatous polyposis.

Endocrine neoplasms have been reported occasionally in patients with familial adenomatous polyposis (FAP). An adrenocorotical carcinoma was studied in a patient with a family history of FAP. Loss of heterozygosity (LOH) in the region close to the adenomatous polyposis coli (APC) gene was detected in this carcinoma, and evidence was obtained that there was a loss of the normal allele of the APC gene. This is the first demonstration of LOH at the APC locus in adrenocortical tumors. The present results and our previous data on LOH in a recurring desmoid tumor suggest that the heterozygous mutant/wild-type condition of the APC gene may give rise to benign tumors, and that functional loss of this gene leads to development of tumors not only in the colon but also in other various parts of the body in FAP patients.

Adenomatous Polyposis Coli↗

PubMed1998

A family of Arf effectors defined as suppressors of the loss of Arf function in the yeast Saccharomyces cerevisiae.

Arf proteins are ubiquitous, eukaryotic regulators of virtually every step of vesicular membrane traffic. ADP-ribosylation factors are essential in yeast and the lethality resulting from either overexpression or underexpression (deletion) of Arf genes has previously been ascribed to dysregulation of the secretory process. We have identified a family of four genes (Suppressors of Arf ts, SAT) as high copy suppressors of a loss of function allele of ARF1 (arf1-3). Those proteins with SAT activity were found to contain a minimal consensus motif, including a C2C2H2 cluster with a novel and specific spacing. Genetic interactions between members of this family and with ARF1 are consistent with each sharing a common cellular pathway. Included in this family is Gcs1, a protein previously described (Poon, P. P., Wang, X., Rotman, M., Huber, I., Cukierman, E., Cassel, D., Singer, R. A., and Johnston, G. C. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 10074-10077) to possess Arf GTPase-activating protein (GAP) activity, demonstrating a direct interaction between Arf and at least one of these suppressors. The suppression of the loss of Arf function by overexpression of Gcs1 and demonstration of direct, preferential binding of Gcs1 to the activated form of Arf (Arf.GTP) lead us to conclude that the biological role of Gcs1 is as an effector of the essential function of Arf in mitotic growth, rather than a down-regulator as implied by the biochemical (Arf GAP) activity. Suppression of the growth defect of arf1(-3) cells was observed under conditions that did not alter the secretory defect associated with arf1(-) mutation, indicating that the essential role of Arf in eukaryotes can be distinguished from role(s) in the secretory pathway and appear to employ distinct pathways and effectors.

ADP-Ribosylation Factor 1↗