Validation of the Japanese version of the Dementia Screening Questionnaire for Individuals with Intellectual Disabilities.

BACKGROUND: Dementia in people with intellectual disabilities (IDs) is difficult to detect because of preexisting cognitive deficits. An effective screening method is required. The Dementia Screening Questionnaire for Individuals with Intellectual Disabilities (DSQIID) was developed as an observer rating tool to screen dementia in people with ID. The aim of this study was to verify the screening accuracy of the DSQIID for Japanese people with ID. METHODS: Four-hundred ninety-three subjects with ID participated in this study. Caregivers who had observed the participants for more than 2 years scored the Japanese version of the DSQIID (DSQIID-J) of the participants. Three doctors examined participants directly and diagnosed dementia using the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. To identify the key screening items that predict dementia, the specificities of a single and pairs of items with 100% sensitivity were evaluated relative to the dementia diagnosis. RESULTS: Of 493 participants, 34 were people with Down syndrome (DS), and 459 were people without DS. Seventeen participants were diagnosed with dementia. The suitable cut-off score of the DSQIID-J was 10/11 (sensitivity 100% and specificity 96.8%) for screening dementia. The inter-rater reliability, test-retest reliability and internal consistency of the DSQIID-J were excellent. Regarding key items, there was no single item with 100% sensitivity, and the best two-item combination was the pair of 'Cannot dress without help' and 'Walks slower' (sensitivity 100% and specificity 93.5%). CONCLUSIONS: We identified several important question items of the DSQIID-J related to the diagnosis of dementia in people with ID. The DSQIID-J is a useful screening tool for dementia in adults with ID.

Morphological characterisation of glial and neuronal tau pathology in globular glial tauopathy (Types II and III).

AIMS: Globular glial tauopathy (GGT) is a new category within the 4-repeat tauopathies that is characterised neuropathologically by tau-positive globular glial inclusions (GGIs), namely, globular oligodendrocytic and astrocytic inclusions (GOIs and GAIs). Occurrence of tau-positive neuronal cytoplasmic inclusions (NCIs) is also a feature. GGT is classified into three pathological subtypes (Types I, II and III). We studied the tau pathology in 6 cases of GGT (Type II, n = 3; Type III, n = 3), with special reference to GAIs and NCIs. METHODS: Neuropathological examinations were conducted, along with immunohistochemistry, morphometry and three-dimensional imaging, and biochemical and genetic analysis of tau. RESULTS: The cortical GAIs in Type II and those in Type III were distinguishable from each other. In the motor cortex, GAIs were much more numerous in Type III than in Type II. Prominent occurrence of perikaryal globular structures was a feature of GAIs in Type III. By contrast, prominent occurrence of radiating process-like structures was a feature of GAIs in Type II. Overall, the GAIs were significantly smaller in Type III than in Type II. NCIs were divisible into three subgroups in terms of shape: diffuse granular, thick cord-like, and round/horseshoe-shaped structures. In all cases, NCIs were a feature of the upper and lower motor neurons. Interestingly, the round/horseshoe-shaped NCIs were observed only in Type III cases. CONCLUSIONS: These findings, which characterised GAIs and NCIs, indicated that Type II and Type III constitute two distinct pathological subtypes, and also further strengthen the concept of GGT as a distinct entity.

Incidence of respiratory depression after epidural administration of morphine for cesarean delivery: findings using a continuous respiratory rate monitoring system.

BACKGROUND: Epidural morphine is widely used for postoperative analgesia after cesarean delivery. However, respiratory depression can occur after neuraxial administration of morphine. Previous reports describing respiratory depression in obstetric patients have relied on intermittent visual counting of the respiratory rate. In this study, we estimated the incidence of respiratory depression in patients who had received epidural morphine after cesarean delivery, using a continuous respiratory rate monitoring system with a finger sensor. METHODS: One hundred patients scheduled to undergo elective cesarean delivery and receive intraoperative neuraxial morphine between April and December 2016 were recruited for this single-center, prospective observational study. Postoperatively, all patients received epidural morphine 3 mg and were equipped with the Nellcor respiratory rate monitoring system. Respiratory depression was defined as both bradypnea (respiratory rate ≤10 breaths/min) and oxygen desaturation (mild ≤95%; moderate ≤90%; severe ≤85%) for longer than one minute. The number of patients with respiratory depression between administration of morphine and first ambulation was recorded hourly. RESULTS: Complete monitoring was obtained for 89 of 100 women. The median duration of monitoring was 19.0 hours. Forty-six patients (52%) developed mild respiratory depression at least once before ambulation, but only one (1%) developed moderate respiratory depression. None required supplemental oxygen or naloxone. CONCLUSIONS: Approximately half the women experienced mild respiratory depression, but only one developed moderate respiratory depression. Continuous respiratory rate monitoring until ambulation may assist in early identification of respiratory depression after neuraxial administration of morphine.

Effects of rapid or slow body weight reduction on intramuscular protein degradation pathways during equivalent weight loss on rats.

The purpose of this study was to compare the effects of short-term fasting-induced rapid weight loss with those of slower but equivalent body weight loss induced by daily calorie restriction on muscle protein degradation pathways and muscle protein content. Male Fischer rats were subjected to either 30 % calorie restriction for 2 weeks to slowly decrease body weight (Slow) or 3-day fasting to rapidly decrease body weight by a comparable level of that of the Slow group (Rapid). The final body weights were about 15 % lower in both the Slow and Rapid groups than in the Con group (p<0.001). The total protein content and wet weight of fast-twitch plantaris muscle, but not slow-twitch soleus muscle, were significantly lower in the Rapid group compared with the control rats fed ad libitum. Substantial increases in the expression ratio of autophagosomal membrane proteins (LC3-II/-I ratio) and polyubiquitinated protein concentration, used as biomarkers of autophagy-lysosome and ubiquitin-proteasome activities, respectively, were observed in the plantaris muscle of the Rapid group. Moreover, the LC3-II/-I ratio and polyubiquitinated protein concentration were negatively correlated with the total protein content and wet weight of plantaris muscle. These results suggest that short-term fasting-induced rapid body weight loss activates autophagy-lysosome and ubiquitin-proteasome systems more strongly than calorie restriction-induced slower weight reduction, resulting in muscular atrophy in fast-twitch muscle.

Myostatin alters glucose transporter-4 (GLUT4) expression in bovine skeletal muscles and myoblasts isolated from double-muscled (DM) and normal-muscled (NM) Japanese shorthorn cattle.

The purpose of this study was to determine whether myostatin alters glucose transporter-4 (GLUT4) expression in bovine skeletal muscles and myoblasts isolated from double-muscled (DM) and normal-muscled (NM) Japanese Shorthorn cattle. Plasma concentrations of glucose were lower in DM cattle than in NM cattle (P < 0.01). The expression of GLUT4 messenger RNA (mRNA) in the skeletal muscle ex vivo and in myoblasts at 72 h after differentiation in vitro was higher in DM cattle than in NM cattle (P < 0.01). In contrast, the NM and DM cattle did not differ with respect to skeletal muscle expression of GLUT1 and myocyte enhancer factor-2c (MEF2c), a transcription factor of GLUT4. In differentiated myoblasts, the expression of GLUT1, GLUT4, and MEF2c mRNAs was greater in DM cattle than in NM cattle (P < 0.01). In the presence and absence of insulin, glucose uptake in myoblasts was increased in DM cattle relative to that of NM cattle (P < 0.01). The addition of myostatin decreased the expression of GLUT4 and MEF2c mRNAs in DM myoblasts (P < 0.05). Results of the present study suggest that myostatin inhibits the expression of GLUT4 mRNA possibly via MEF2c and that the greater ability of the DM cattle to produce muscle relative to the NM cattle may be due to their greater sensitivity to insulin and greater use of glucose.

13C-phenylalanine breath test detects altered phenylalanine kinetics in schizophrenia patients.

Phenylalanine is an essential amino acid required for the synthesis of catecholamines including dopamine. Altered levels of phenylalanine and its metabolites in blood and cerebrospinal fluid have been reported in schizophrenia patients. This study attempted to examine for the first time whether phenylalanine kinetics is altered in schizophrenia using L-[1-(13)C]phenylalanine breath test ((13)C-PBT). The subjects were 20 chronically medicated schizophrenia patients (DSM-IV) and the same number of age- and sex-matched controls. (13)C-phenylalanine (99 atom% (13)C; 100 mg) was administered orally and the breath (13)CO(2) /(12)CO(2) ratio was monitored for 120 min. The possible effect of antipsychotic medication (risperidone (RPD) or haloperidol (HPD) treatment for 21 days) on (13)C-PBT was examined in rats. Body weight (BW), age and diagnostic status were significant predictors of the area under the curve of the time course of Δ(13)CO(2) (‰) and the cumulative recovery rate (CRR) at 120 min. A repeated measures analysis of covariance controlled for age and BW revealed that the patterns of CRR change over time differed between the patients and controls and that Δ(13)CO(2) was lower in the patients than in the controls at all sampling time points during the 120 min test, with an overall significant difference between the two groups. Chronic administration of RPD or HPD had no significant effect on (13)C-PBT indices in rats. Our results suggest that (13)C-PBT is a novel laboratory test that can detect altered phenylalanine kinetics in chronic schizophrenia patients. Animal experiments suggest that the observed changes are unlikely to be attributable to antipsychotic medication.

Difference in intracortical inhibition of the motor cortex between cortical myoclonus and focal hand dystonia.

OBJECTIVE: The short interval intracortical inhibition (SICI) of the motor cortex (M1) is reduced in both cortical myoclonus and focal hand dystonia. This reduction has been attributed to the dysfunction of GABAergic system within the motor cortex. However, the precise mechanisms underlying the reduction may not be entirely identical in these two disorders, being due to primary pathological involvement in M1 or secondary to functional changes outside M1. The aim of this study was to elucidate possible differences in intracortical inhibition between these two disorders. METHODS: Subjects were 11 patients with benign myoclonus epilepsy, 7 with focal hand dystonia, and 11 normal volunteers. We studied SICI using anterior-posterior (AP) directed and posterior-anterior (PA) directed induced currents in the brain. RESULTS: In both disorders, SICI with PA-directed currents was reduced as reported previously. In contrast, SICI studied with AP currents was normal in patients with focal hand dystonia, but reduced in patients with cortical myoclonus. CONCLUSIONS: The difference between the two disorders might reflect the underlying pathological difference. In cortical myoclonus, the inhibitory interneurons of the motor cortex are affected, whereas the same interneurons are intact in dystonia. The difference in SICI induced by AP and PA directed currents in dystonia may be explained by the following possibilities: the difference in composition of I-waves contributing to EMG generation and the difference in modulation of the interneuronal activity by voluntary contraction. These changes may be secondary to dysregulation of the motor cortex by the basal ganglia or related cortices in dystonia. SIGNIFICANCE: The SICI using AP directed currents together with the conventional SICI using PA directed currents was able to demonstrate some difference in the intrinsic circuits of M1 between myoclonus and focal hand dystonia. SICI using AP directed currents can provide additional information about the motor cortical excitability changes over those obtained by the previously reported methods.

Engineering of implantable cartilaginous structures from bone marrow-derived mesenchymal stem cells.

Fabrication of implantable cartilaginous structures that could be secured in the joint defect could provide an alternative therapeutic approach to prosthetic joint replacement. Herein we explored the possibility of using biodegradable hydrogels in combination with a polyglycolic acid (PGA) scaffold to provide an environment propitious to mesenchymal stem cells (MSCs) chondrogenic differentiation. We examined the influence of type I collagen gel and alginate combined with PGA meshes on the extracellular matrix composition of tissue-engineered transplants. MSCs were isolated from young rabbits, expanded in monolayers, suspended in each hydrogel, and loaded on PGA scaffolds. All constructs (n=48) were cultured in serum-free medium containing transforming growth factor beta-1, under dynamic conditions in specially designed bioreactors for 3-6 weeks. All cell-polymer constructs had a white, shiny aspect, and retained their initial size and shape over the culture period. Their thickness increased substantially over time, and no shrinkage was observed. All specimens developed a hyalin-like extracellular matrix containing glycosaminoglycans (GAGs) and type II collagen, but significant differences were observed among the three different groups. In PGA/MSCs and collagen-PGA/MSCs constructs, the cell growth phase and the chondrogenic differentiation phase of MSCs occurred during the first 3 weeks. In alginate-PGA/MSCs constructs, cells remained round in the hydrogel and cartilage extracellular matrix deposition was delayed. However, at 6 weeks, alginate-PGA/MSCs constructs exhibited higher contents of GAGs and lower contents of type I collagen. These results suggest that the implied time for the transplantation of in vitro engineered constructs depends, among other factors, on the nature of the scaffold envisioned. In this study, we demonstrated that the use of a composite hydrogel-PGA scaffold supported the in vitro growth of implantable cartilaginous structures cultured in a bioreactor system.

[Aortic valve replacement for calcified aortic valve and annulus with ultrasonic decalcification].

UNLABELLED: We conducted ultrasonic decalcification on calcified annulus in patients with aortic stenosis (AS) using an ultrasonic operator, Sonopet (UST 2001) prior to aortic valve replacement (AVR). We studied the reliability of this method. SUBJECT AND METHOD: From January 2002 to August 2005, AVR was conducted for AS using the Sonopet in 45 patients, comprising of 18 male and 27 female subjects. The mean age was 73.3 +/- 9.7. RESULT: Artificial valves were successfully inserted at the intra-annular level in 37 patients and at the supra-annular level in 8 patients without conducting annular enlargement. In the patients with narrow annuli of less than 19 mm (23 patients), the preoperative mean annular diameter was 18.2 +/- 1.0 mm, but significantly larger artificial valves with an average diameter of 19.3 +/- 1.5 mm (p=0.003) were successfully inserted. CONCLUSION: AVR was proved to be safe and easy by previous ultrasonic decalcification of the annuls using the Sonopet. This method was very useful because it required no enlargement of aortic annulus.

Frequency of early and late-onset dementias in a Japanese memory disorders clinic.

The aim of this study was to compare the diagnostic profiles of patients with early (age<65 years) and late (age>or=65 years) onset of dementia in a memory disorders clinic in Japan. A total of 512 consecutive memory clinic patients were evaluated using clinical information and results of examinations. Diagnosis of dementia was made according to DSM-III-R, and that of subtypes according to standard diagnostic criteria. A total of 464 patients met the criteria for dementia. Amongst late-onset patients (n=430), Alzheimer's disease (AD) (48.1%) was the most frequent cause of dementia, followed by AD with cerebrovascular disease (CVD) (31.4%), vascular dementia (VaD) (9.1%), dementia with Lewy bodies (DLB) (3.7%), frontotemporal lobar degeneration (FTLD) (1.6%), and others (5.8%). On the contrary, amongst early onset patients (n=34), the most common dementia diagnosis was AD (38.2%), followed by VaD (23.5%), FTLD (14.7%), AD with CVD (5.9%), DLB (2.9%), and others (17.6%). FTLD and VaD were significantly more common in the early onset group. All patients, but one, with DLB and Parkinson's disease dementia were late-onset. The relative frequencies of AD, VaD, and DLB in our series are consistent with epidemiologic findings in several Western countries; however, the frequency of FTLD is not consistent with the previous findings presenting high frequency in late-onset patients in some Western countries.

Antimicrobial activity of isoprenoid-substituted xanthones from Cudrania cochinchinensis against vancomycin-resistant enterococci.

Ten xanthones with one or two isoprenoid groups and a prenylated benzophenone isolated from roots of Cudrania cochinchinensis (Moraceae) were tested for their antimicrobial activities against vancomycin-resistant enterococci (VRE). Among these compounds, gerontoxanthone H exhibited considerable antibacterial activity against five VRE strains (VanA, VanB and VanC) (MICs = 1.56 microg/ml). Four xanthones, 1,3,7-trihydroxy-2-prenylxanthone, gerontoxanthone I, alvaxanthone and isoalvaxanthone, showed weaker antibacterial activity against these VREs (MICs = 3.13-6.25 microg/ml). .

Effects of high-intensity intermittent swimming on PGC-1alpha protein expression in rat skeletal muscle.

AIM: The aim of the present investigation was to elucidate the effects of exercise intensity on exercise-induced expression of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) protein in rat skeletal muscle. METHODS: We measured PGC-1alpha content in the skeletal muscles of male Sprague-Dawley rats (age: 5-6 weeks old; body weight: 150-170 g) after a single session of high-intensity intermittent exercise (HIE) or low-intensity prolonged swimming exercise (LIE). During HIE, the rats swam for fourteen 20-s periods carrying a weight (14% of body weight), and the periods of swimming were separated by a 10-s pause. LIE rats swam with no load for 6 h in two 3-h sessions, separated by 45 min of rest. RESULTS: After HIE, the PGC-1alpha protein content in rat epitrochlearis muscle had increased by 126, 140 and 126% at 2, 6 and 18 h, respectively, compared with that of the age-matched sedentary control rats' muscle. Immediately, 6 and 18-h after LIE, the PGC-1alpha protein content in the muscle was significantly elevated by 84, 95 and 67% respectively. The PGC-1alpha protein content observed 6 h after HIE tended to be higher than that observed after LIE. However, there was no statistically significant difference between the two values (P = 0.12). CONCLUSION: The present investigation suggests that irrespective of the intensity of the exercise, PGC-1alpha protein content in rat skeletal muscle increases to a comparable level when stimuli induced by different protocols are saturated. Further, HIE is a potent stimulus for enhancing the expression of PGC-1alpha protein, which may induce mitochondrial biogenesis in exercise-activated skeletal muscle.

Tissue engineering of complex tooth structures on biodegradable polymer scaffolds.

Tooth loss due to periodontal disease, dental caries, trauma, or a variety of genetic disorders continues to affect most adults adversely at some time in their lives. A biological tooth substitute that could replace lost teeth would provide a vital alternative to currently available clinical treatments. To pursue this goal, we dissociated porcine third molar tooth buds into single-cell suspensions and seeded them onto biodegradable polymers. After growing in rat hosts for 20 to 30 weeks, recognizable tooth structures formed that contained dentin, odontoblasts, a well-defined pulp chamber, putative Hertwig's root sheath epithelia, putative cementoblasts, and a morphologically correct enamel organ containing fully formed enamel. Our results demonstrate the first successful generation of tooth crowns from dissociated tooth tissues that contain both dentin and enamel, and suggest the presence of epithelial and mesenchymal dental stem cells in porcine third molar tissues.

Lead content of brain tissue in diffuse neurofibrillary tangles with calcification (DNTC): the possibility of lead neurotoxicity.

Diffuse neurofibrillary tangles with calcification (DNTC) is a form of presenile dementia, characterized pathologically by fronto-temporal atrophy with neurofibrillary tangles (NFTs), neuropil threads and Fahr-type calcification, in which no senile plaques are observed. As already noted, chronic exposure to lead (Pb) might be one of the etiological factors of Fahr-type calcification. Until now, there have been no reports in which Pb concentration has been quantified in DNTC brains. We examined the concentration of Pb in fresh-frozen brain tissue and in 10% formalin-fixed brain tissue from six cases of DNTC, four cases of Alzheimer's disease, and in nine non-demented elderly controls by flameless atomic absorption spectrometry, and demonstrated a high concentration of Pb in DNTC brains. Although it remains unclear how these findings are related to the formation of NFTs, they suggest that Pb neurotoxicity may be involved in the pathogenesis of DNTC.

Determination of residual solvents in pharmaceuticals by thermal desorption-GC/MS.

A novel method for the determination of residual solvents in pharmaceuticals by thermal desorption (TD)-GC/MS has been established. A programmed temperature pyrolyzer (double shot pyrolyzer) is applied for the TD. This method does not require any sample pretreatment and allows very small amounts of the sample. Directly desorbed solvents from intact pharmaceuticals (ca. 1 mg) in the desorption cup (5 mm x 3.8 mm i.d.) were cryofocused at the head of a capillary column prior to a GC/MS analysis. The desorption temperature was set at a point about 20 degrees C higher than the melting point of each sample individually, and held for 3 min. The analytical results using 7 different pharmaceuticals were in agreement with those obtained by direct injection (DI) of the solution, followed by USP XXIII. This proposed TD-GC/MS method was demonstrated to be very useful for the identification and quantification of residual solvents. Furthermore, this method was simple, allowed rapid analysis and gave good repeatability.

Suppression of high-pressure-induced hemolysis of human erythrocytes by preincubation at 49 degrees C.

When human erythrocytes were preincubated at 37-52 degrees C under atmospheric pressure before exposure to a pressure of 200 MPa at 37 degrees C, the value of hemolysis was constant (about 43%) up to 45 degrees C but became minimal at 49 degrees C. The results from anti-spectrin antibody-entrapped red ghosts, spectrin-free vesicles, and N-(1-pyrenyl)iodoacetamide-labeled ghosts suggest that the denaturation of spectrin is associated with such behavior of hemolysis at 49 degrees C. The vesicles released at 200 MPa by 49 degrees C-preincubated erythrocytes were smaller than those released by the treatment at 49 degrees C or 200 MPa alone. The size of vesicles released at 200 MPa was independent of preincubation temperature up to 45 degrees C, and the vesicles released from 49 degrees C-preincubated erythrocytes became smaller with increasing pressure up to 200 MPa. Thus, hemolysis and vesiculation under high pressure are greatly affected by the conformation of spectrin before compression. Since spectrin remains intact up to 45 degrees C, the compression of erythrocytes at 200 MPa induces structural changes of spectrin followed by the release of large vesicles and hemolysis. On the other hand, in erythrocytes that are undergoing vesiculation due to spectrin denaturation at 49 degrees C, compression produces smaller vesicles, so that the hemolysis is suppressed.

[Successful treatment of hairy cell leukemia with pentostatin].

A 45-year-old woman was admitted to our hospital in August, 1999. Laboratory data showed a white blood cell count of 5,050/microliter with 78% abnormal lymphocytes, hemoglobin 6.8 g/dl, platelets 4.8 x 10(4)/microliter, and soluble IL-2 receptor 97,600/ml. The abnormal cells were characterized by a hairy appearance under phase contrast microscopy, and showed strong tartrate-resistant acid phosphatase activity. Immunophenotype analysis revealed that these cells were positive for CD11c, CD19 and CD25, and negative for CD5. Bone marrow biopsy showed diffuse proliferation of hairy cells with moderate myelofibrosis. We diagnosed the patient as having European-American-type hairy cell leukemia. Pentostatin was administered at a dose of 5 mg/m2 weekly. After twelve doses, the peripheral blood data returned to the normal range with no hairy cells in the blood or bone marrow, although slight splenomegaly remained. The patient underwent splenectomy in December of the same year, and we were unable to find any hairy cells by histological and immunohistochemical examination. Although most patients with hairy cell leukemia in Japan have the Japanese variant, and the European-American type is rare, pentostatin is as effective as it is for European and American patients.

Suppressive mechanisms of EPA on human T cell proliferation.

In vivo and in vitro experiments show that polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) inhibit mitogen- or antigen-stimulated proliferation of T cells in rodents and humans. However, the exact manner and mechanisms by which PUFA inhibits T cell proliferation is not clear. In the present study, we investigated the suppressive effects of EPA, an n-3 PUFA, on PHA stimulated human peripheral blood T cells. Our results showed that EPA suppresses mitogen- or antigen-stimulated human T cell proliferation by at least 2 steps; step 1) EPA suppresses T cell proliferation by inhibiting IL-2R alpha expression and IL-2 production; step 2) EPA induces cell death of blast T cells without reducing the expression of IL-2R alpha. We also showed that EPA selectively stimulates the cell death of blast T cells but not resting T cells. The suppressive effect of EPA was mediated via the production of reactive oxygen products, because EPA-stimulated H2O2 production and the suppressive effect of EPA was restored by addition of catalase or NAC. These results taken together suggest that such immunosuppressive effects of EPA may explain the apparent benefits of EPA-enriched diets for patients with inflammatory disorders.

Replacing factor-dependency with that for lysozyme: affordable culture of IL-6-dependent hybridoma by transfecting artificial cell surface receptor.

Cytokines and growth factors are indispensable for the propagation and maintenance of factor-dependent mammalian cells. However, cytokines are often so expensive that the use of factor-dependent cells for industrial applications such as protein production is often not practical. Based on our previous design of a binary hen egg lysozyme (HEL)-specific receptor composed of portions of the anti-HEL antibody and the erythropoietin receptor, a new pair of chimeric receptors having the intracellular domain of gp130 were made and transfected to an interleukin-6 (IL-6)-dependent hybridoma, 7TD1. The clone expressing the two new receptors showed clear HEL dose-dependent cell growth and monoclonal antibody production in both serum-based and serum-free media without IL-6. These results establish the feasibility of applying receptor design to tailor cells for the inexpensive induction of cell growth for the purpose of producing therapeutic products.