Peripheral nerves are pathologically small in cerebellar ataxia neuropathy vestibular areflexia syndrome: a controlled ultrasound study.

BACKGROUND AND PURPOSE: Sensory neuronopathy is a cardinal feature of cerebellar ataxia neuropathy vestibular areflexia syndrome (CANVAS). Having observed that two patients with CANVAS had small median and ulnar nerves on ultrasound, we set out to examine this finding systematically in a cohort of patients with CANVAS, and compare them with both healthy controls and a cohort of patients with axonal neuropathy. We have previously reported preliminary findings in seven of these patients with CANVAS and seven healthy controls. METHODS: We compared the ultrasound cross-sectional area of median, ulnar, sural and tibial nerves of 14 patients with CANVAS with 14 healthy controls and 14 age- and gender-matched patients with acquired primarily axonal neuropathy. We also compared the individual nerve cross-sectional areas of patients with CANVAS and neuropathy with the reference values of our laboratory control population. RESULTS: The nerve cross-sectional area of patients with CANVAS was smaller than that of both the healthy controls and the neuropathy controls, with highly significant differences at most sites (P < 0.001). Conversely, the nerve cross-sectional areas in the upper limb were larger in neuropathy controls than healthy controls (P < 0.05). On individual analysis, the ultrasound abnormality was sufficiently characteristic to be detected in all but one patient with CANVAS. DISCUSSION: Small nerves in CANVAS probably reflect nerve thinning from loss of axons due to ganglion cell loss. This is distinct from the ultrasound findings in axonal neuropathy, in which nerve size was either normal or enlarged. Our findings indicate a diagnostic role for ultrasound in CANVAS sensory neuronopathy and in differentiating neuronopathy from neuropathy.

Stem cell-mediated muscle regeneration and repair in aging and neuromuscular diseases.

One of the most exciting aspirations of current medical science is the regeneration of damaged body parts. The capacity of adult tissues to regenerate in response to injury stimuli represents an important homeostatic process that until recently was thought to be limited in mammals to tissues with high turnover such as blood and skin. However, it is now generally accepted that each tissue type, even those considered post-mitotic, such as nerve or muscle, contains a reserve of undifferentiated progenitor cells, loosely termed stem cells, participating in tissue regeneration and repair. Skeletal muscle regeneration is a coordinate process in which several factors are sequentially activated to maintain and preserve muscle structure and function upon injury stimuli. In this review, we will discuss the role of stem cells in muscle regeneration and repair and the critical role of specific factors, such as IGF-1, vasopressin and TNF-alpha, in the modulation of the myogenic program and in the regulation of muscle regeneration and homeostasis.

Biosynthesis of (1-->3)-beta-D-glucan (callose) by detergent extracts of a microsomal fraction from Arabidopsis thaliana.

The aim of this work was to develop a biochemical approach to study (1-->3)-beta-D-glucan (callose) biosynthesis using suspension cultures of Arabidopsis thaliana. Optimal conditions for in vitro synthesis of callose corresponded to an assay mixture containing 50 mM Mops buffer, pH 6.8, 1 mM UDP-glucose, 8 mM Ca2+ and 20 mM cellobiose. The enzyme was Ca2+-dependent, and addition of Mg2+ to the reaction mixture did not favour cellulose biosynthesis. Enzyme kinetics suggested the existence of positive homotropic cooperativity of (1-->3)-beta-D-glucan synthase for the substrate UDP-glucose, in agreement with the hypothesis that callose synthase consists of a multimeric complex containing several catalytic subunits. Detergents belonging to different families were tested for their ability to extract and preserve membrane-bound (1-->3)-beta-D-glucan synthase activity. Cryo-transmission electron microscopy experiments showed that n-octyl-beta-D-glucopyranoside allowed the production of micelle-like structures, whereas vesicles were obtained with Chaps and Zwittergent 3-12. The morphology and size of the (1-->3)-beta-D-glucans synthesized in vitro by fractions obtained with different detergents were affected by the nature of the detergent tested. These data suggest that the general organization of the glucan synthase complexes and the properties of the in vitro products are influenced by the detergent used for protein extraction. The reaction products synthesized by different detergent extracts were characterized by infrared spectroscopy, methylation analysis, 13C-NMR spectroscopy, electron microscopy and X-ray diffraction. These products were identified as linear (1-->3)-beta-D-glucans having a degree of polymerization higher than 100, a microfibrillar structure, and a low degree of crystallinity.

Selection and genetic characterization of Streptococcus pneumoniae mutants resistant to the des-F(6) quinolone BMS-284756.

Existing quinolones are known to target the type II topoisomerases in bacteria. In order to determine which of these targets are of key importance in Streptococcus pneumoniae treated with BMS-284756 (T-3811ME), a novel des-F(6) quinolone, resistant mutants were selected in several steps of increasing resistance by plating pneumococci on a series of blood agar plates containing serial twofold-increasing concentrations of drug. After incubation, colonies that arose were selected and passaged twice on antibiotic-containing media at the selection level. Mutants generally showed increases in resistance of four- to eightfold over the prior level of susceptibility. Mutants in the next-higher level of resistance were selected from the previous round of resistant mutants. Subsequently, chromosomal DNA was prepared from parental (R6) pneumococci and from at least three clones from each of four levels of increasing antibiotic resistance. Using PCR primers, 500- to 700-bp amplicons surrounding the quinolone resistance determining regions (QRDR) of gyrA, gyrB, parC, and parE genes were prepared from each strain. Internal primers were used to sequence both DNA strands in the regions of approximately 400 bp centered on the QRDR. Mutations identified with increasing levels of resistance included changes in GyrA at Ser-81 and Glu-85 and changes in ParC at Ser-79 and Asp-83. Changes in GyrB and ParE were not observed at the levels of resistance obtained in this selection. The resistance to comparator quinolones (levofloxacin, ciprofloxacin, and moxifloxacin) also increased in four- to eightfold steps with these mutations. The intrinsically greater level of antibacterial activity and thus lower MICs of BMS-284756 observed at all resistance levels in this study may translate to coverage of these resistant pneumococcal strains in the clinic.

Intraoperative motor evoked potentials to transcranial electrical stimulation during two anaesthetic regimens.

OBJECTIVES: To study motor evoked potentials (MEPs) to multi-pulse transcranial electrical stimulation (MP-TES) during orthopaedic spinal surgery under different anaesthetic regimens. METHODS: MEPs to MP-TES were recorded from tibialis anterior and abductor hallucis bilaterally in 50 operations. Anaesthesia was maintained with propofol and nitrous oxide in 29 operations and isoflurane (0.78+/-0.17% end-tidal) and nitrous oxide in 23 (two patients received both regimens). Analgesia was provided with fentanyl or remifentanil. RESULTS: Motor stimulation caused neither EEG changes nor seizures. MEPs were obtained in 97% of patients during propofol anaesthesia. The median amplitude and coefficient of variation (CV) at baseline (across all muscles) were 198 microV and 22%, respectively. Amplitudes throughout the operation paralleled the degree of neuromuscular block and were reduced after fentanyl bolus, isoflurane or morphine. Loss of MEPs or persistent amplitude decrements were associated with neurological complications in one patient and severe blood loss in another two patients. MEPs were obtainable in 61% of patients during isoflurane anaesthesia and became inconsistent for end-tidal concentrations >0.87+/-0.08%. Amplitudes were smaller (85 microV) and baseline variability higher (coefficient of variation 29%) than in the propofol group. The decrease in the number of recordings was greater for isoflurane than propofol when the number of pulses/train decreased from 4 to 2. CONCLUSIONS: Muscle MEPs to MP-TES are a safe, sensitive and reliable method for monitoring motor pathways during propofol/nitrous oxide and fentanyl or remifentanil anaesthesia. MEPs are also obtainable in the majority of patients during isoflurane/nitrous oxide anaesthesia, but quantitative monitoring is not always possible with this regimen.

American Society of Microbiology 101st General Meeting. 20-24 May 2001, Orlando, FL, USA.

The application of sophisticated molecular biology, genetics and genomics has made possible the advanced analyses of microbial genes, the topology of DNA and chromosomes, and insight into the regulation of gene expression during all stages of the life cycle of microbes, both in vitro and in vivo. The struggle to control contagious pathogens continues world wide amidst resistance emergence to many classes of antimicrobial agents. Many hospital, research and community labs are applying themselves to a more thorough understanding of the molecular basis of this resistance. New drugs which improve on predecessor agents were presented. The following classes of antimicrobial agents were represented: quinolones, cephems, macrolides and natural products. New target opportunities against both lethal (essential) gene targets and virulence targets were presented throughout the conference. In addition, increasing attention to the involvement of microbial life forms in immune function and dysfunction were described in numerous presentations.

Working memory dysfunction in major depression: an event-related potential study.

OBJECTIVES: To study working memory function in untreated major depression using a digit probe identification and matching task. METHODS: We compared behavioural performance and event-related potentials during processing of the Sternberg working memory task in 14 depressed patients and 14 healthy matched control subjects. RESULTS: Patients made more mistakes than controls as the memory load was increased from one to 5 digits and had significantly slower reaction times at all levels of memory load. The patients' event-related potentials (ERPs) differed significantly from controls. Pathological changes were similar for auditory and visual presentation. Surface negative activity in the 157-210 ms section of the waveform was reduced for all levels of memory load, suggesting abnormal sensory/perceptual processing in the modality-specific association cortices, possibly due to a failure of selective attention mechanisms. In the 375-840 ms epoch, the patients' responses showed large amplitude sustained negative activity, maximal at Cz and a reduced late positive wave. The large prolonged negativity in the patients' ERPs suggests activation of additional neuronal assemblies than those normally participating in the task. This could reflect either compensatory mechanism or dysfunction of inhibitory systems. These changes were sensitive to memory load, suggesting that they reflect alterations of memory-related processes. CONCLUSIONS: This study provides objective evidence that major depression significantly affects working memory. The ERP changes in depression could be accounted for by dysfunction of the central executive control of working memory.

Perforated appendicitis: prospective outcome analysis for 150 children.

BACKGROUND/PURPOSE: Controversy persists in the management of perforated appendicitis with regard to antibiotic choice and duration, operative timing, drain utilization, and wound closure. For 2 decades at the authors' institution, patients were treated with ampicillin, gentamicin, and clindamycin for 10 inpatient days, with drains in the abdomen, resulting in lower complication rates than most other published series. Managed care pressures have led to less aggressive medical management regimens with length of stay and financial factors viewed as principal outcome measures with little emphasis on clinical outcomes. In addition, there are little prospective data on clinical outcomes. The authors sought to determine whether our previously documented excellent quality outcomes could be maintained when modifications aimed at decreasing cost and length of stay in our protocol were instituted. METHODS: The authors monitored prospectively clinical outcomes in patients with perforated appendicitis treated according to their clinical practice guidelines over a 43-month period. Patients received a single antibiotic, piperacillin-tazobactam, intravenously for 10 days. They were permitted to go home with a percutaneous intravenous catheter for the final 5 days if medical and social criteria were met. Other practices from our earlier protocol were continued, including immediate operation, placement of Penrose drains, and primary wound closure. RESULTS: Of 150 patients treated on our protocol, major complications included intraabdominal abscess in 5 (3.3%), cecal fistula in 2 (1.3%), phlegmon in 3 (2.0%), wound infection in 4 (2.7%), and no small bowel obstructions requiring operation. None of these complications, nor their aggregate, were significantly more common than those reported in 373 patients treated over 11 years on the authors' prior protocol (chi2, P > .05). CONCLUSIONS: Prospective outcome analysis of our protocol shows that a single broad-spectrum antibiotic (allowing portions of therapy to be delivered less expensively on an outpatient basis) effectively can treat postoperative appendicitis with very few infectious complications. These outcome data provide baseline against which future protocols can be compared. All treatment modifications aimed at decreasing costs must be analyzed to ensure quality of care is not unduly compromised.

The role of the advanced practice nurse in pediatric general surgery.

The advanced practice nurse (APN) functions in pediatric surgery in a variety of ways. In the inpatient setting, the APN can provide care to infants and children with many complex congenital and other surgical anomalies. In the outpatient office, the role includes diagnosis, management, education, and care coordination for children with both routine and complex diagnoses. This article discusses the differences in some of these roles and a few of the common diagnoses seen by the APN in a pediatric surgical practice on a routine day.

Neurological complications of anterior spinal surgery for kyphosis with normal somatosensory evoked potentials (SEPs).

We report a case of neurological complications of anterior release for correction of kyphosis. After the operation, the patient had pyramidal weakness and decreased pain sensation below T5, whereas light touch, proprioception and vibration sensation were intact. Clinical and neurophysiological findings in this patient suggested a partial lesion of the spinal cord probably due to ischaemia in the territory of the anterior spinal artery. Intraoperative and postoperative tibial nerve SEPs remained normal, which stresses the need for recording from the motor pathways.

Effects of age on working memory: an event-related potential study.

The effects of age on behavioural performance and event-related potentials recorded during a working memory task using digits presented either acoustically or visually, were studied in 37 healthy subjects with an age range from 19 to 71 years. With increasing age, psychological tests showed a progressive decline in visuo-spatial performance and both auditory and visual reaction times (RT) increased. There were multiple and varying effects of age on both early and late ERP components. For both auditory and visual responses, increasing age was associated with an increased amplitude of early positive waves (auditory P100 and visual P145) and, in the oldest subjects, significant delays of the major late positive waves. Other changes were modality-specific with a progressive shift of amplitude maxima in the early negative waves of the visual ERPs (from an N190 peak maximal at Pz in the young, to an N270 peak maximal at Cz in the older subjects) and an altered amplitude distribution of late potentials (after the P250 wave) in the auditory responses. The age at which ERP changes occurred varied-significant latency prolongations and increases in the amplitude of the major frontal positive waves occurred only in the oldest subjects, whereas a redistribution of late auditory ERPs also occurred in the intermediate age group. There was no interaction between age and increasing memory load, suggesting that there is no specific effect of age on memory scanning in this age range for these levels of task difficulty. Thus, although performance in working memory was apparently unaffected by age, as judged by behavioural parameters (apart from slowing of the reaction times), ERPs revealed significant changes in both early and late electrical brain processes associated with working memory as age increases. These changes which were not symptomatically manifest and only revealed by sensitive tests, may represent subtle dysfunction of working memory (or associated processes) which does not prevent the successful completion of our task, compensatory mechanisms (which are essential to successfully complete the task), or a combination of both age-induced dysfunction and compensatory mechanisms.

Which event-related potentials reflect memory processing in a digit-probe identification task?

Auditory and visual event-related potentials (ERPs) generated by digit-probe identification and matching in a modified Sternberg paradigm have been recorded in 37 healthy subjects with the aim of identifying the potentials which best reflect the memory processes associated with this task. We analysed the effects of memory load (one, three or five digits to memorise), probe type (probe digit present or absent from the preceding memory set) and recording site, on the ERPs. With conventional methods of determining component amplitudes and latencies, the main effects of increasing memory load on the major positive wave varied according to stimulus modality-there was an amplitude decrease for the auditory ERPs and a latency increase for the visual ERPs. However, subjective component identification methods may be prone to errors when comparing responses recorded under different stimulus conditions. Waveform changes with increasing memory load may be misinterpreted as latency (or amplitude) effects if non-analogous potentials are compared. Further, component analysis may provide only partial information, because of its relative insensitivity to sustained amplitude shifts. For these reasons, an objective computer method was used to determine the mean amplitudes for multiple '50 ms' epochs. This showed, for both auditory and visual stimuli, that the main effect of increasing memory load was a 'negative amplitude shift'. It was seen between 315 and 525 ms for auditory stimuli and between 210 and 472 ms for visual stimuli and could be distinguished from other ERP features that were sensitive to stimulus modality. These changes are either specific to the memory processes involved in carrying out this task or reflect other parallel processing which covaries with memory processing.

MRI of optic nerve and postchiasmal visual pathways and visual evoked potentials in secondary progressive multiple sclerosis.

We studied the relationship between abnormalities shown by MRI and functional disturbances in the visual pathway as assessed by the visual evoked potential (VEP) in 25 patients with established multiple sclerosis (MS); only 4 of whom had a history of acute optic neuritis. Optic nerve MRI was abnormal in 19 (76%) and is thus useful in detecting subclinical disease. Optic nerve total lesion length and area on the STIR sequence was found to correlate significantly with prolongation of the VEP latency. This may reflect a predominantly demyelinating rather than inflammatory origin for the signal change in the optic nerve.

Working memory impairment in early multiple sclerosis. Evidence from an event-related potential study of patients with clinically isolated myelopathy.

Auditory and visual event-related potentials were recorded during a short-term memory task in 24 patients who had recently presented with symptomatically and clinically isolated spinal cord syndromes suspected to be due to multiple sclerosis, and in 24 matched control subjects. Event-related potentials (ERPs) were recorded during two sequential components of the working memory task, first the temporary active memorizing of sets of digits and secondly, their subsequent manipulation, namely digit-probe recognition and matching. The patients' reaction times were slower and showed larger increments than those of the control subjects as the number of items to be memorized was increased. The patients' ERPs during both memorizing and probe matching/recognition phases differed significantly from control subjects for both auditory and visual presentations. The more marked changes were seen in a subgroup of eight patients who had the lowest levels of performance on a battery of general tests of memory and who also made significantly more errors in the working memory task as the memory load increased. In this subgroup, the abnormalities of the ERPs during recognition and matching tests occurred in the component of the response that has been shown to be sensitive to memory loading in healthy control subjects. This study provides objective evidence of subclinical working memory dysfunction in patients at an early stage of demyelinating disease, i.e. when they first present with clinically isolated spinal cord lesions and before they have developed symptoms of cognitive or memory dysfunction. The defect at this early stage is either restricted to processes involved in the formation of a memory trace or, more probably, involves both trace formation and the mechanisms that underly recognition ('retrieval') and matching of memory traces in working memory.

Working memory in temporal lobe epilepsy: an event-related potential study.

Event-related potentials (ERPs) were recorded to a digit-probe identification and matching task (modified 'Sternberg paradigm') in 29 patients with temporal lobe epilepsy (TLE) and 26 healthy subjects. Our main aim was to identify the neurophysiological correlates of abnormal short term memory function in patients with TLE. Neuropsychological tests allowed the definition and comparison of two patient groups according to the presence or absence of memory dysfunction. These two groups did not differ significantly in mean age, education years, IQ, seizure duration, seizure frequency, anti-epileptic drug (AED) regimes, or on findings on neuroimaging. ERPs recorded under different levels of memory load were analysed both by conventional component identification and by an objective computer method of determining mean amplitudes of multiple 50 ms epochs (MMA analysis). We found that some significant abnormalities were common to both groups of patients; these included slow reaction times, a reduced amplitude of the N170 wave (and the corresponding 157-210 ms epoch in the MMA analysis) and a broad late negative shift between 577 and 735 ms. Other findings, including a significantly reduced performance accuracy as the level of memory load increased, were restricted to patients with abnormal memory function. The ERP changes that were specific to these patients occurred within a latency band of 200-420 ms and included a relatively preserved, but delayed P250 component and a delayed and attenuated N290 wave. When compared with either healthy subjects or with patients with normal memory, the responses in patients with abnormal memory showed an abnormal 'positive shift' between 262 and 315 ms after probe presentation and a further positive shift between 315 and 420 ms as memory load increased. These abnormalities of 'memory scanning' ERPs in patients with TLE which paralleled neuropsychological and behavioural evidence of memory dysfunction, and which occurred in the section of the response that is sensitive to memory loading in healthy subjects, provide further objective evidence that abnormalities of short term memory processes contribute to the memory deficits of TLE.

Is "memory-scanning" time in the Sternberg paradigm reflected in the latency of event-related potentials?

The time taken to scan short term memory for a target (probe) digit in the Sternberg paradigm is thought to be reflected in the latency of a major positive wave in the associated event-related potentials. In the present study we have recorded and analysed reaction time and event-related potentials to a digit probe identification task in 37 healthy subjects. Using methods similar to those of earlier studies, we have confirmed the previously reported relationship between memory set size and the apparent latency of the major positive wave. However, analysis of the responses of individual subjects showed that increasing set size had no consistent effects on this wave. One-third of the subjects showed no latency change with increasing set size. In the other subjects, possible latency changes were invariably associated with wave form changes, suggesting that impression of latency shifts may arise from a comparison of non-analogous waves. We suggest that the most significant effect of increasing set size, in the majority of subjects, is a negative amplitude shift which overlaps and distorts a variable section of the major positive wave. In these subjects, an apparent shift in the latency of the major positive wave could be attributed to a combination of attenuation of earlier contributions and relative preservation of later subpeaks, with the result that the dominant positive waves at different levels of memory load are not analogous. By contrast, reaction time increased with set size in all subjects, irrespective of the presence or absence of associated wave form changes. Whereas the reaction time changes with increasing memory load in our study support the original concept of memory scanning, we found no consistent relationship between the latency of event-related potentials generated by this digit probe identification task and memory load. While the presence or absence of a latency shift in some subjects may be open to interpretation, our findings do not support the hypothesis that the latency of the major positive waves is an index of the time involved in memory scanning.

Evoked potentials in inherited ataxias: a multimodal electrophysiological study.

A multimodal electrophysiological study, including median nerve somatosensory evoked potentials (SSEPs), motor cortical stimulation (CS) and brainstem evoked potentials (BAEPs), was performed on 34 patients with hereditary ataxias (HAs): 15 with Friedreich's disease (FD), 10 with early onset cerebellar ataxia (EOCA), and 9 with autosomal dominant cerebellar ataxia (ADCA). A higher incidence of abnormal central motor conduction was observed in FD than in EOCA patients, but was never observed in ADCA. A relationship between central motor conduction abnormalities and disease duration and clinical impairment was found only in FD patients. All FD patients showed severe impairment of the SSEPs that was not related to disease duration. In EOCA patients, less frequent and more variable SSEP abnormalities were observed. The lowest incidence of central SSEP abnormalities was observed in ADCA. The BAEP findings in all 3 groups of patients (but particularly those with EOCA) suggest prevalent brainstem damage.

Abnormalities of early "memory-scanning" event-related potentials in patients with temporal lobe epilepsy.

We have recorded auditory event-related potentials (ERPs) evoked by the "memory-scanning" (digit-probe identification/matching) paradigm that was originally described by Sternberg (1966), in 17 patients with complex partial seizures (temporal lobe epilepsy) and in 17 matched healthy control subjects. The patients, who had all complained spontaneously of memory difficulties, had significantly reduced scores on psychological tests of memory with relatively intact digit span and cognition. Their performance of the memory-scanning task was characterized by a higher error rate, longer reaction times and an increased slope of the reaction time/set size relationship. The associated ERPs in both patients and controls showed there were significant effects of memory load on several major components, but only a reduced amplitude of the N170 and a prolonged latency of the N290 waves distinguished the patients. In addition, the N170 wave in the patients decreased further as memory load increased. The prolonged N290 latency in the patients appeared to reflect the slowed processing time. This study has shown that ERPs generated by a short-term memory task are abnormal in patients with temporal lobe epilepsy who have neuropsychologically documented cognitive and memory deficits. Some of the significant waveform alterations occur earlier than those reported in previous ERP studies and provide electrophysiological support for the hypothesis that abnormalities of the early stages of short-term memory processing may contribute to the memory difficulties experienced by patients with temporal lobe epilepsy.

Transforming growth factor-beta 1 induces transforming growth factor-alpha promoter activity and transforming growth factor-alpha secretion in the human colon adenocarcinoma cell line FET.

FET cells are well differentiated human adenocarcinoma cells whose growth is partially inhibited (50-60%) by transforming growth factor-beta 1 (TGF-beta 1). In exponentially growing cultures, TGF-beta 1 induces the expression of transforming growth factor-alpha (TGF-alpha) by 3-fold. To determine whether this induction is the result of increased TGF-alpha promoter activity, FET cells were transiently transfected with a plasmid containing 2816 base pairs of the 5'-flanking region of the TGF-alpha gene linked to luciferase. Transfected FET cells treated with growth-inhibitory concentrations of TGF-beta 1 (10 ng/ml) showed up to a 10-fold increase in luciferase activity. The increase in luciferase activity was dose dependent through the normal physiological range of TGF-beta 1 (0.5-20 ng/ml), saturating at 10 ng/ml. This effect was also TGF-alpha promoter specific, inasmuch as the Rous sarcoma virus long terminal repeat used as a control remained relatively insensitive to the effects of TGF-beta 1. By using progressively smaller portions of the TGF-alpha promoter region, the TGF-beta 1-responsive element was mapped between base pairs -77 and -201 of the 5'-flanking region. TGF-beta 1 treatment also affected epidermal growth factor receptor levels. FET cells treated with TGF-beta 1 (10 ng/ml) for 48 h showed a 20% decrease in the number of epidermal growth factor receptors and a 2-fold increase in the number of high affinity epidermal growth factor receptors on their surface. These results indicate that TGF-beta 1 acts as a positive regulator of TGF-alpha transcription, and they suggest a possible mechanism by which these cells circumvent the growth-inhibitory effects of TGF-beta 1.