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A value stream is defined as the set of all the specific actions required to bring a product through the three critical management tasks of any business: the problem-solving task, the information management task, and the physical transformation task. However, a headlong rush into adopting lean tools and techniques on the shop floor has resulted in the improvement of the information management and physical transformation tasks only, and has led many organizations towards a state of static process optimization rather than one of sustained lean growth. In this paper, we draw on practical insights from a multiple-firm action research initiative in two companies to present an alternative method for value stream mapping that also incorporates the problem-solving task. This technique has allowed the organizations to achieve not only sustainable improvement in operational performance, but also significant growth in people productivity. What emerged was a product-centric approach to cross-functional learning and improvement, which has implications for both lean theory and practice.

Ecotourism on private lands may be an incentive for conservation because of potential profits to landowners. Conservation planners in southern Africa have posited that ecotourism has higher potential in drier regions where agricultural profit is lower, and this hypothesis would seem to apply to the Great Plains of North America, which has a gradient of precipitation. Row crop agriculture is a strong competitor for land use in the eastern Great Plains. Rangelands are more common in the western Great Plains, and cattle grazing on grasslands is compatible with ecotourism. To support current interest in ecotourism in the Great Plains, we developed a spatial model to predict potential for ecotourism by overlaying a map of annual precipitation levels with a spatial tourism model developed by evaluating distance to cities and interstate highways as well as to existing ecotourism destinations. Our model suggests that northern and western portions of the Great Plains have the highest potential for ecotourism ventures that cater to short-term sightseeing visitors, while three areas in the northern and central Plains have high potential for ecotourism ventures providing long-term nature-seeking experiences in unique landscapes. The identification of an ecotourism audience is critical for success, and our spatial analysis has potential to support ecotourism and conservation of prairies and wildlife in the Great Plains.

Satellite cells (SC) are multipotential stem cells that can be induced by nutrition to alter their cellular developmental fate, which may vary depending on their fiber type origin. The objective of the current study was to determine the effect of restricting protein synthesis on inducing adipogenic transdifferentiation and apoptosis of SC originating from fibers of the fast glycolytic pectoralis major (p. major) and fast oxidative and glycolytic biceps femoris (b. femoris) muscles of the chicken. The availability of the essential sulfur amino acids Met and Cys was restricted to regulate protein synthesis during SC proliferation and differentiation. The SC were cultured and treated with 1 of 6 Met/Cys concentrations: 60/192, 30/96 (control), 7.5/24, 3/9.6, 1/3.2, or 0/0 mg/L. Reductions in Met/Cys concentrations from the control level resulted in increased lipid staining and expression of the adipogenic marker genes peroxisome proliferator-activated receptor gamma and stearoyl-CoA desaturase during differentiation in the p. major SC. Although b. femoris SC had increased lipid staining at lower Met/Cys concentrations, there was no increase in expression of either adipogenic gene. For both muscle types, SC Met/Cys, concentration above the control increased the expression of peroxisome proliferator-activated receptor gamma and stearoyl-CoA desaturase during differentiation. As Met/Cys concentration was decreased during proliferation, a dose-dependent decline in all apoptotic cells occurred except for early apoptotic cells in the p. major, which had no treatment effect (P < 0.05). During differentiation, decreasing Met/Cys concentration caused an increase in early apoptotic cells in both fiber types and no effect on late apoptotic cells except for an increase in the p. major 7.5/24 mg/L of Met/Cys treatment. In general, the viability of the SC was unaffected by the Met/Cys concentration except during proliferation in the p. major 0/0 mg/L of Met/Cys treatment, which increased SC viability. These data demonstrate the effect of nutrition on SC transdifferentiation to an adipogenic lineage and apoptosis, and the effect of fiber type on this response in an in vitro context.

Early posthatch satellite cell (SC) mitotic activity is a critical component of muscle development and growth. Satellite cells are stem cells that can be induced by nutrition to follow other cellular developmental pathways. The objective of the current study was to determine the effect of restricting protein synthesis on the proliferation and differentiation of SC, using variable concentrations of Met and Cys to modulate protein synthesis. Broiler pectoralis major SC were cultured and treated with 1 of 6 different Met/Cys concentrations: 60/192, 30/96 (control), 7.5/24, 3/9.6, 1/3.2, or 0/0 mg/L. The effect of Met/Cys concentration on SC proliferation and differentiation was measured, and myonuclear accretion was measured by counting the number of nuclei per myotube during differentiation. The 30/96 mg/L Met/Cys treatment resulted in the highest rate of proliferation compared with all other treatments by 72 h of proliferation (P < 0.05). Differentiation was measured with Met/Cys treatments only during proliferation and the cultures receiving normal differentiation medium (R/N), normal proliferation medium and differentiation medium with variable Met/Cys (N/R), or both proliferation and differentiation receiving variable Met/Cys treatments (R/R). Differentiation responded in a dose-dependent manner to Met/Cys concentration under all 3 of these treatment regimens, with a degree of recovery in the R/N regimen cells following reinstatement of the control medium. Reductions in both proliferation and differentiation were more pronounced as Met/Cys concentrations were further reduced, whereas increased differentiation was observed under the increased Met/Cys concentration treatment when applied during differentiation in the N/R and R/R regimens. The number of nuclei per myotube was significantly decreased in the severely Met/Cys restricted treatments (P < 0.05). These data demonstrate the sensitivity of pectoralis major SC to nutritional availability and the importance of optimal nutrition during both proliferation and differentiation for maximizing SC activity, which will affect subsequent muscle mass accretion.

Production planning and control (PPC) plays a vital role for the competitiveness of every company. Its application in the process industries still faces major problems and limitations. The process industries are currently facing an increasing trend in demand variability and uncertainty. Too little is known about the link between industry specific characteristics and matching PPC approaches. In this paper, we investigate the characteristics that pose critical challenges when applying PPC concepts in the semi-process industry. The results of our study show a conflict between flexibility-requiring and flexibility-limiting characteristics. Through the use of a literature review and case study we demonstrate the limitations of material requirements planning to address this new situation.

The effect of hatch time and subsequent access to feed on intramuscular adipose tissue deposition was studied in the pectoralis major muscle of male Ross 308 broiler chickens. Based on their hatch time chicks were classified as early (EH), midterm (MH), or late (LH) hatchers, with an average incubation duration of 497.7 h for EH, 508.8 h for MH, and 514.5 h for LH birds. Chicks were provided access to feed either immediately at hatch, or 24 h after the conclusion of the hatch window. Expression of the adipogenic regulatory genes peroxisome proliferator-activated receptor gamma (PPARγ), and stearoyl-CoA desaturase (SCD), were measured at the time of hatch, and zero, one, 4, 7, 28, and 40 d. Intramuscular adipocyte cell width and visualization of adipose tissue deposition was observed at 28 and 40 d. Expression of PPARγ was increased in the pectoralis major of LH birds at the time of hatch, zero, and one d. The expression of PPARγ at one and 7 d, and SCD at 7 d were increased in all birds that received delayed access to feed. At 28 d, adipocyte cell width was increased in LH birds with delayed access to feed, compared to EH and MH birds with delayed access to feed and LH birds with immediate access to feed. At 40 d, adipocyte cell width was increased in all birds that received delayed access to feed. Also at 40 d, there was a trend (P = 0.078) for more extensive intramuscular adipose tissue deposition in LH than EH birds, and in birds with delayed access to feed (P = 0.075). These data indicate delayed access to feed increases intramuscular adipose tissue deposition in the pectoralis major muscle, and suggest that hatch time influences this regulation.

The effect of hatch time and the timing of access to feed on growth rate and breast muscle development was assessed in Ross 308 broiler chickens. Chicks were removed from the incubator upon hatching, and classified as early (EH), midterm (MH), or late (LH) hatchers, based on the duration of their incubation. Feed and water were available either immediately at hatch, or 24 h after the conclusion of the hatch period. Hatchling body weight was uniform regardless of hatch time. Subsequently, bodyweight was increased in EH compared to LH birds following immediate access to feed, until 7 d in female, and 14 d in male birds. Relative breast weight was increased until 28 d in birds with immediate access to feed, and also EH and MH birds regardless of access to feed. Pectoralis major muscle morphology and expression of the myogenic regulatory factors myogenic determination factor 1 (MYOD1) and myogenin, and the proteoglycans syndecan-4, glypican-1, and decorin were measured. Myogenin and glypican-1 stimulate satellite cell (SC) differentiation. Glypican-1 expression was unaffected by treatment. A late increase in myogenin expression was observed in MH birds with delayed access to feed, and all LH birds. Syndecan-4 and MYOD1, expressed in proliferating SC, and decorin, which stimulates satellite cell proliferation and differentiation, were variably upregulated in the first wk posthatch in the same birds. These data suggest SC were activated and proliferating, but had reduced differentiation in later hatching and feed deprived birds. Conversely, EH birds with immediate access to feed had maximal myofiber width at 7 d, while fiber width was increased in birds with immediate access to feed compared to those with delayed access to feed through 40 d of age. These results demonstrate that delaying chick access to feed for 24 h upon removal from the incubator will impair muscle growth. Additionally, hatch time influences muscle development, with accelerated muscle growth in EH and MH, compared to LH birds, irrespective of access to feed.

Harvest of furbearers through trapping has been challenged by anti-trapping organizations for centuries, with organizational goals often including prohibition of all forms of trapping. Challenges to trapping may also include dissention among state wildlife agencies, pro-hunting organizations, and pro-trapping organizations. Despite recent efforts by anti-trapping organizations and occasional dissention among consumptive-use groups, national trends in snaring regulations included less restrictive regulations through time. This positive trend may offer opportunities for state wildlife agencies and pro-trapping organizations to enhance the public image of trapping, increase recruitment of trappers, and reverse the increasing trend of wildlife damage and associated costs. We offer support and suggestions to state wildlife agencies and pro-trapping organizations to help achieve these goals, with their partnership likely having a synergistic effect. Although we attempt to illuminate approaches for increasing support for trapping within the constraints of the cultural norms of the United States, we hope our approaches are useful to and promote dialogue in other jurisdictions experiencing similar problems.

The effect of feeding diets of variable methionine concentration on breast muscle development was assessed in Ross 308 broiler chicks. Four isonitrogenous and isoenergetic starter diets were formulated to contain 7.8, 5.9, 4.6, and 3.4 g methionine/kg diet, and were provided for the first 7 days post-hatch. At 7 days of age all birds were placed on an industry standard starter diet with 5.9 g methionine/kg diet until 14 days, and then provided standard broiler grower (until 28 days) and finisher (until 42 days) diets. Birds were weighed periodically throughout the study and feed intake and feed conversion ratio were determined. Ten birds per treatment were sacrificed and weighed on 0, 1, 4, 7, 14, 21, 28, 35, and 42 days. The pectoralis major (breast muscle) was then removed from the carcass and weighed. Samples of breast muscle were collected for genetic and histological analysis. Expression of the myogenic marker genes, myogenic differentiation factor 1 and myogenin, which regulate satellite cell activity, and the adipogenic marker gene, peroxisome proliferator-activated receptor gamma (PPARγ), was measured. Histological assessment of breast muscle morphology and fat deposition morphology was also performed. No effect of dietary treatment was observed on body or breast muscle weight, feed intake or feed conversion ratio. Marker gene expression was also similar in all treatment groups, except for PPARγ. Significantly higher expression of PPARγ was observed at 0 days in the 5.9 g methionine/kg diet treatment, before dietary treatments were provided. Expression of PPARγ did not differ among treatment groups on any subsequent day. Methionine dietary treatment had no effect on the morphological structure of the breast muscle, or intramuscular fat deposition. These results suggest that under the conditions of this study, satellite cell activity in the early post-hatch chick, and subsequent muscle development, were not responsive to the variable methionine manipulations tested in the pre-starter period.

Satellite cells (SC) are a multipotential stem cell population responsible for facilitating posthatch muscle fiber hypertrophy. The proliferation and differentiation of SC is sensitive to nutritional regimen, and the SC response to nutrition varies depending upon their muscle type of origin. The objective of the current study was to determine the effect of altering protein synthesis on the expression of several key genes regulating SC activity and the effect of muscle type. Satellite cells isolated from the fast glycolytic pectoralis major and the fast oxidative and glycolytic biceps femoris were studied. These genes included the myogenic regulatory factors myogenic determination factor 1 (MyoD) and myogenin, the cell-membrane associated proteoglycans syndecan-4 and glypican-1, the extracellular matrix proteoglycan decorin, and the transcription factor paired box 7. Protein synthesis potential varied by the concentration of the sulfur amino acids Met and Cys during SC proliferation and differentiation. The SC were cultured and treated with 1 of 6 Met/Cys concentrations: 60/192, 30/96 (control), 7.5/24, 3.0/9.6, 1.0/3.2, or 0/0 mg/L. A consistent pattern of gene expression emerged following Met/Cys manipulation as increasing reductions in mRNA expression for all genes were observed as Met/Cys concentration decreased, whereas increased Met/Cys concentration caused either no change or had a small negative effect on mRNA expression. Reduced paired box 7 expression would limit myogenic specification of SC, whereas decreased myogenic regulatory factor expression would affect subsequent myogenic development of the SC. Decreased levels of decorin affect SC response to growth factors like myostatin and transforming growth factor β, and extracellular matrix organization. These data highlight the importance of nutrition on the expression of genes critical for satellite cell activation, proliferation and differentiation, and growth factor signal transduction.

Single case report. Present a case of hip abscess culture positive for Aerococcus urinae in a man with paraplegia. Aerococcus species are uncommonly reported and may be misinterpreted as alpha streptococci or staphylococci. This organism can cause significant morbidity due to urinary tract infection with septicemia or endocarditis. Single case report. The patient required surgical incision and debridement. Open joint inspection was performed, which was complicated by superior dislocation. The patient later required a Girdlestone procedure. A. urinae was cultured from a hip abscess in a man with paraplegia. Bacteremia, with the bladder as the reservoir, likely led to this abscess. Aerococcus is pathogenic and should be considered when culture results reveal unusual staph or strep species.

An automated static perimeter/adaptometer is described which measures thresholds with lights of 2 wavelengths. The instrument uses light-emitting diodes to produce the stimuli and is controlled by a small computer, making it very suitable for clinical testing of large numbers of patients. The use of 2 LEDs with different peak emission wavelengths (530 and 660 nm) permits an assessment of the relative state of rod and cone mechanisms in a particular region of the retina either during dark adaptation or when the eye is fully dark adapted.

Between 1957 and 1981, 31716 cases of gastric cancer were registered in the West Midlands, UK. The age-standardized incidence has shown a decrease from 17·42 per 100000 population during the first quinquennium to 15·30 per 100000 in the last. There was an apparent increase in the proportion of proximal lesions with a decrease in the proportion of distal, antral cancers. The stage of disease at diagnosis remained constant with 79 per cent of patients having stage IV disease. Less than 1 per cent presented with stage I disease. As a result, the curative resection rate was 21 per cent. The operative mortality rates for curative partial gastrectomy and total gastrectomy were 13 and 29 per cent respectively. Surgeons undertaking more than nine total gastrectomies annually had an overall mean operative mortality rate of 22 per cent. Overall age-adjusted survival at 5 years was 5 per cent. Survival at 5 years for stage I, II and III disease was 72, 32 and 10 per cent respectively. There was a significant increase in survival time for those treated by curative resection between 1972 and 1981 compared with the previous decade. The implications for the management of gastric cancer are discussed.

An electroretinographic (ERG) technique is described in which the relationship between scotopic b wave amplitude and stimulus light intensity is determined. The relative amplitude of scotopic to photopic responses is assessed by means of red light and flicker. The method is applied to the detection of ERG abnormalities in heterozygotes for X-linked retinitis pigmentosa. These have been found in only a proportion of cases. The ERG results can be used to suggest the nature of the retinal abnormality.

We have used a pattern-reversing chequerboard (1 degree squares, or smaller: 84 per cent contrast, or less: 2 to 16 reversals/sec: field size 22 degrees x 16 degrees: mean luminance 50 cd/m2) to evoke responses from the eyes of young adults and children. ERGs were recorded with gold foil electrodes, which did not interfere with the normal optics. All patients were affected accurately. The fixation point was adjusted so that squinters received the stimulus on corresponding areas of each retina. The normal ERG obtained is 1.5 to 3 mu V in amplitude, and in thirteen normal subjects right and left eyes gave equal responses. The extreme asymmetry detected was c. 10 per cent. In all amblyopes, including children of 6 years old and upwards, satisfactory recordings were obtained. In most amblyopes, the response from the affected eye was 50 per cent or less of the response from the fellow eye. In all cases of failure to respond to treatment, the asymmetry was highly significant. In adults, occluding the screen area corresponding to the area of amblyopic suppression, reduces the ERG in the fellow eye, but does not reduce the ERG in the amblyopic eye. We conclude that amblyopic retina produces very little electrical activity that we can record. The timing, response to frequency of stimulation, and other parameters in the pattern ERG are dissimilar from those in the ERG produced by small changes of luminance. We have little evidence about the class of cell generating the response we observe, but evidently there is peripheral abnormality in the visual system even of amblyopic children.

The nature of rivalry suppression was investigated by examining the effects of changing one of the rivalling stimuli at the beginning of its phases of suppression. The stimulus was an obliquelyoriented grating whose phase, spatial frequency and contrast could be changed without altering its mean luminance. Such changes were found to disturb the course of rivalry and, more specifically, to cause the reappearance of the stimulus within 20 msec. Suppression is thus shown to be selective and not to render the subject insensitive to all classes of stimulus change.

Fifty normal eyes underwent a provocative test with pilocarpine 4 per cent. Slit-image photography before and 30 minutes after the instillation of pilocarpine 4 per cent into one eye demonstrated the range of response of the anterior segment to pilocarpine. Those eyes whose axial anterior chamber depth shallowed by greater than or equal to 0.1 mm demonstrated shallowing of the periphery of the anterior chamber, while those eyes whose axial anterior chamber depth shallowed by less than 0.1 mm showed deepening of the peripheral anterior chamber. The relevance of these findings to the development of peripheral anterior synechiae is discussed.

Image processing techniques may be classified in terms of a rather loose notion of complexity. Firstly, there are bulk transformations where the one image is translated into another by applying the same rule to each pixel in the source image. Examples of this type of process are differentiation and spatial summation. This type of process is amenable to parallel computation. At a slightly higher level is feature detection: the selection of points satisfying some criteria. Examples of this type of process are the search for and classification of edges, ends of lines, corners and forks. At the next level evaluation may concern compound structures: the spatial relation of simple features to form a new identity. The relations that may be used are to the right of, above, next to, enclosed by etc. For example a square is an edge which is closed, with four corners, and each corner is approximately 90 degrees: a tea cup in profile might be defined by a square next to a circle. Another issue is the handling of the amount of information involved in image processing. An image potentially contains a large amount of information. A picture 512 by 512 pixels with 8 bit colour definition in red, green, and blue will take 0.75 Megabytes of storage. This is roughly equivalent to the storage needed for a book. The human eye scans a picture concentrating on the dominant features and spending variable amounts of time extracting information from the various regions of a scene.

From 1957 to 1976 oesophageal resection for carcinoma was performed in 1119 patients reported to the West Midlands Cancer Registry. The operations were performed on 581 patients by 127 surgeons who averaged three or less resections per annum the ‘occasional' group’. These were compared with 538 patients (the ‘frequent’ group) whose resections were performed by four surgeons who averaged six or more resections per annum. Operative mortality was 39·4 per cent in the ‘occasional’ group and 21·6 per cent in the ‘frequent’ group (P < 0·001). The age adjusted 5-year survival was 11·1 and 15·2 per cent respectively (P < 0·05) but when the operative deaths were excluded there was no significant difference. We suggest that oesophageal resection for carcinoma should be performed only where there is an acceptably low operative mortality rate.

In "early" gastric cancer the depth of invasion by the primary tumour is confined to the submucosa of the stomach. Out of 13228 cases of gastric cancer notified to the Birmingham Cancer Registry during 1960-9, 90 (0 . 7%) were identifed as early gastric cancer. The crude five-year survival rate of these 90 patients was 57 . 8% (age-adjusted rate 70 . 4%) compared with 3 . 7% (age-adjusted rate 4 . 7%) for all cases and 14 . 6% (age-adjusted rate 17 . 4%) for the cases treated radically. Prognostic factors established for gastric cancer pertained equally to early gastric cancer. Most of the 90 patients had had symptoms related to the gastrointestinal tract, but in contrast to patients with advanced gastric cancer only 19% had lost weight on admission. These findings suggest that early investigation of dyspeptic symptoms would increase the detection of early gastric cancer, the most important prognostic group identified in gastric cancer.

Sheep oocytes were microinjected with tobacco mosaic virus RNA (TMV-RNA) and isotopically labelled with L-[35S]methionine. Total incorporation of labelled methionine was similar in TMV-RNA-injected and in carrier-injected control oocytes, whether injections were performed during the period of high protein synthesis at maturation or during the period of reduced synthesis at a time equivalent to the mid-cleavage transition (48 h after germinal vesicle breakdown). Varying the amount of TMV-RNA injected from 2.5 to 10 pg had little effect on the overall level of amino acid incorporation. Furthermore TMV-RNA appeared to be very stable in oocytes and eggs; the proportion of total polypeptide synthesis directed by TMV-RNA did not diminish during the first 48 h after injection. Synthesis of most endogenous proteins was uniformly reduced to compensate for the synthesis of TMV-polypeptides. Our results suggest, therefore, that the translational capacity of sheep oocytes is fully saturated during maturation.

MACKAY1 has made use of the phenomenon of simultaneous contrast to provide evidence for the existence in the human visual system of neural channels that are sensitive to the density of visual texture. Using the same phenomenon, we have provided comparable evidence for the existence of lateral interaction between channels sensitive to velocity. That such channels do exist is suggested by the preliminary psychophysical observations of Pantle and Sekuler2, who demonstrated a luminance threshold elevation for moving contours that is limited to a range of values around the velocity of the adapting contour.

Extended electroretinographic (ERG) testing has been carried out in a series of patients with retinitis pigmentosa, dominantly inherited. In 36 of 57 cases only cone b waves were evoked. In 20 of these, psychophysical tests showed only cones mediated vision (Massof class I), while in 16 statis scotopic perimetry demonstrated residual rod function (class II). In the remaining cases, where rod ERGs were seen, the light intensities required to evoke responses were not greatly elevated. A computer model was constructed to relate psychophysical threshold measurements to ERG data. This analysis of the results suggests that in one subgroup of patients the scotopic ERG is smaller than expected from the losses of visual field and that in another the psychophysical elevation of rod visual threshold is greater than expected from ERG measurements.

Contrast sensitivity was measured in the eyes of 200 consecutive patients attending the glaucoma family screening unit. One-third of the patients screened had an abnormal contrast sensitivity. Positive correlation (p less than 0.01) existed between this abnormal contrast sensitivity and cup : disc ratio, visual field loss, and age. No such correlation existed between contrast sensitivity and intraocular pressure.

Pattern formation in animal development requires that genes be expressed differentially according to position in the sheets of cells that make up the early embryo. The homoeobox-containing genes of Drosophila are control genes active both in the establishment of a segmentation pattern and in the specification of segment identity. In situ hybridization experiments confirm that these genes are expressed in a segmentally-restricted manner and that their expression presages morphological differentiation of segmental structures. Homoeobox genes have recently been isolated from the mouse and have been shown to be expressed during mouse development. Using in situ hybridization, we show here that expression of the mouse homoeobox gene Mo-10 (ref. 7) is spatially restricted in the developing embryo and that localization of expression is already evident within the germ layers before their morphological differentiation. These findings support the suggestion that the homoeobox genes of mammals, like those of Drosophila, may be important in pattern formation.

THE outstanding ability of o-phenylenebisdimethylarsine (diars) (I) to stabilize metals in unusual oxidation states (for example, Fe(IV)—ref. 1), co-ordination numbers (for example, tetrahedral Au(I)—ref. 2) and stereochemical arrangements (for example, dodecahedral Ti(IV)—ref. 3), has led us to investigate the preparation and co-ordinating properties of the tetrafluoro analogue (F-diars (II)).

Genetic analysis of human papillary thyroid carcinomas (PTC) has revealed unique chromosomal translocations that form oncogenic fusion proteins and promote thyroid tumorigenesis in up to 60\% of tumors examined. Although, the majority of thyroid specific translocations involve the growth factor receptor c-RET, variant rearrangements of the receptor for nerve growth factor, NTRK1 have also been described. One such translocation, TRK-T1, forms a fusion protein composed of the carboxyl terminal tyrosine kinase domain of NTRK1 and the amino terminal portion of TPR (Translocated Promoter Region). To determine if TRK-T1 expression can cause thyroid cancer in vivo, we developed transgenic mice that express the human TRK-T1 fusion protein in the thyroid. Immunohistochemical analysis of TRK-T1 transgenic mouse thyroids revealed TRK-T1 staining within the thyroid follicular epithelium. In contrast to nontransgenic littermates, 54\% of transgenic mice developed thyroid abnormalities that included follicular hyperplasia and papillary carcinoma. Furthermore, all transgenic mice examined greater than 7 months of age developed thyroid hyperplasia and/or carcinoma. These data support the conclusion that TRK-T1 is oncogenic in vivo and contributes to the neoplastic transformation of the thyroid.

Our research goal is to better understand the mechanisms controlling the initiation and progression of thyroid diseases. One such disease, papillary thyroid carcinoma (PTC), is the leading endocrine malignancy in the United States. Recently, a family of related fusion proteins, RET/PTC1-5, has been implicated in the early stages of PTC. Although all five members of this family have the c-RET proto-oncogene kinase domain in their COOH terminus, little is known about how these genes alter follicular cell biology. Consequently, to answer questions related to the mechanism of the RET/PTC fusion protein action, we have devised a molecular genetic strategy to study PTC using a mouse model of thyroid disease. A new member of this fusion oncogene family, RET/PTC3, which has been implicated in more cases of solid tumor carcinoma (79\%) than PTC1 or PTC2 and predominates (80\%) in radiation-induced thyroid cancer of children, was investigated in our study. We have generated transgenic mice expressing human RET/PTC3 exclusively in the thyroid. These mice develop thyroid hyperplasia, solid tumor variants of papillary carcinoma and metastatic cancer. This new transgenic line will be useful in deciphering the molecular and biological mechanisms that cause PTC and histological variations in humans.