Biomedical subjects

D Zurakowski

Publications and source records attributed to D Zurakowski.

At least 127 records · Page 7Linked to original sources

PubMed1998

Serum leptin in children and young adults with inflammatory bowel disease.

BACKGROUND: Pediatric inflammatory bowel disease is often associated with growth failure and inadequate energy intake. Although several circulating cytokines are known to be elevated in inflammatory bowel disease, the mechanism for the related anorexia has not been described. Leptin is a newly recognized circulating protein that is an important regulator of appetite and energy metabolism; leptin levels are elevated in several animal models of inflammation. This study was conducted to determine whether serum leptin levels are elevated in young patients with inflammatory bowel disease. METHODS: One hundred twelve children and young adults with Crohn's disease or ulcerative colitis were studied prospectively. Forty-two patients with other gastrointestinal illnesses were used as control subjects. Height, weight, erythrocyte sedimentation rate, serum albumin concentration, and clinical information were collected prospectively, and leptin was measured by radioimmunoassay of stored serum. RESULTS: No significant differences in leptin levels were found among disease groups or control subjects. Body mass index and gender were the only independent predictors of serum leptin in all groups examined. Disease activity varied inversely with serum leptin in patients with Crohn's disease, but these differences were explained entirely by variations in body mass index. CONCLUSIONS: The determinants of serum leptin were the same in young patients with inflammatory bowel disease as in normal populations, indicating that alterations in leptin levels are unlikely to mediate the anorexia and growth failure associated with this disease.

Adolescent↗

PubMed1998

Sedation patterns in pediatric and general community hospital emergency departments.

BACKGROUND AND OBJECTIVES: Although pediatric sedation (PS) is widely used in emergency departments (ED), the practice of PS in general community hospital (GH) ED has not been described. We surveyed PS practice patterns in pediatric hospitals (CH) and GH and compared frequency and usage between the two groups. METHODS: All CH (n = 115) and 400 randomly selected GH were surveyed. Alcohol and drug detoxification, psychiatric, chronic care, rehabilitation, and specialty facilities were excluded. Data were collected on hospital type (pediatric or community), location (urban, suburban, rural), annual visits, academic affiliation (presence of an emergency medicine residency or pediatric emergency medicine fellowship in the hospital), and sedation agents used. RESULTS: Of 515 hospitals surveyed, 238 responded [84/115 CH (73%), 154/400 GH (39%)] yielding an overall response rate of 46%. Of the responding CH the majority were urban [57 (68%) were urban, 15 (18%) suburban, and 12 (14%) rural]. GH were more evenly distributed by location [44/153 (29%) were urban, 49/153 (32%) suburban, and 60/153 (39%) rural]. Eight (5%) GH had emergency medicine residencies, while 39 (46%) CH had pediatric emergency medicine fellowships. The mean annual pediatric volume was 38,000 for CH and 6500 for GH. For the four specified clinical scenarios, representing the most common ED procedures using sedation (laceration repair, fracture reduction, radiologic imaging), GH performed significantly fewer sedations than CH when matched for pediatric volume. PS was less frequently used among rural GH compared to suburban (P < 0.01) and urban GH (P < 0.01). Midazolam was listed as the most frequently used drug in all three geographic locations for both CH and GH. CH listed fentanyl as a second agent, while GH preferred meperidine. Fentanyl and ketamine were listed as preferred agents only in CH. For cranial computerized tomography, chloral hydrate was listed as the drug of choice by both CH and GH. Both CH and GH listed "relief of pain and anxiety" as the first and "agitation control" as the second most common reason for using sedation. CH and GH listed "the risks outweigh the benefits" as the primary reason and "ED too busy/takes too much time" as the secondary reason for not using sedation. CONCLUSIONS: GH performed fewer sedations than did CH when matched for pediatric volume in all geographic locations and for the most common ED procedures using sedation. Since 1989, sedation patterns have shifted in CH to include the short-acting agents, while GH (with the exception of midazolam) continue to prefer the long-acting agents. Midazolam is now the most frequently used sedation agent for ED procedures in both CH and GH.

Acute Disease↗

PubMed1998

Acute scrotal symptoms in boys with an indeterminate clinical presentation: comparison of color Doppler sonography and scintigraphy.

PURPOSE: To compare the performance of color Doppler ultrasonography (US) and scintigraphy in assessing testicular perfusion in boys with clinically equivocal presentations. MATERIALS AND METHODS: Forty-one boys with clinically equivocal testicular perfusion underwent color Doppler US and scintigraphy. Studies were retrospectively classified as consistent with torsion, consistent with nontorsion, or indeterminate. Sensitivity and specificity were determined with alternate positivity criteria (indeterminate studies first considered positive and then negative for torsion). RESULTS: Color Doppler US demonstrated nine of 11 cases of torsion and 23 of 30 cases of nontorsion, with one false-positive and eight indeterminate studies. Scintigraphy demonstrated 10 of 11 cases of torsion and 29 of 30 cases of nontorsion, with two indeterminate studies (both in patients with inguinal testis). When indeterminate studies were considered positive for torsion, specificity was 77% for color Doppler US versus 97% for scintigraphy (P = .05). There were no other statistically significant differences between the sensitivities and specificities. CONCLUSION: Color Doppler US and scintigraphy demonstrate no statistically significant difference in ability to demonstrate testicular torsion in boys with acute scrotal symptoms and indeterminate clinical presentations. Owing to its greater specificity, scintigraphy may help prevent unnecessary surgery when color Doppler US shows equivocal flow.

Acute Disease↗

PubMed1998

Pulmonary blood flow distribution during partial liquid ventilation.

Regional pulmonary blood flow was investigated with radiolabeled microspheres in four supine lambs during the transition from conventional mechanical ventilation (CMV) to partial liquid ventilation (PLV) and with incremental dosing of perfluorocarbon liquid to a cumulative dose of 30 ml/kg. Four lambs supported with CMV served as controls. Formalin-fixed, air-dried lungs were sectioned according to a grid; activity was quantitated with a multichannel scintillation counter, corrected for weight, and normalized to mean flow. During CMV, flow in apical and hilar regions favored dependent lung (P < 0.001), with no gradient across transverse planes from apex to diaphragm. During PLV the gradient within transverse planes found during CMV reversed, most notably in the hilar region, favoring nondependent lung (P = 0.03). Also during PLV, flow was profoundly reduced near the diaphragm (P < 0.001), and across transverse planes from apex to diaphragm a dose-augmented flow gradient developed favoring apical lung (P < 0.01). We conclude that regional flow patterns during PLV partially reverse those noted during CMV and vary dramatically within the lung from apex to diaphragm.

Animals↗

PubMed1998

Cystic fibrosis: a system for assessing and predicting progression.

OBJECTIVE: This study presents a radiography-based database scoring changes over time in a large population of patients with cystic fibrosis. The purpose of this database is to provide comparison for groups of patients undergoing experimental treatment to assess effect of the treatment. The data may also be used to compare individuals with their age-matched cohorts with cystic fibrosis. MATERIALS AND METHODS: From 230 patients, 3038 chest radiographs were scored using the Brasfield system. The scores from radiographs from all the patients were individually plotted for age, and a single age-based severity curve was created. The age-based severity curve was compared with similar curves derived from pulmonary function studies of a subset of the same patient population. RESULTS: We found high inter- and intraobserver reliability. The difference between the observers averaged 1.3 Brasfield points, the scale of which ranges up to 25 points. The age-based severity curve was presented as mean Brasfield scores versus age (birth to > 30 years) plotted with 95% confidence limits; the curve was also plotted in percentiles. The rate of decline of this curve was similar to the decline of pulmonary function studies in this patient population. CONCLUSION: The age-based curve, a structural anatomic parameter, differs from pulmonary function studies, which are functional. Thus the age-based severity curve provides an additional, independent basis for comparison between groups and individuals. It may be used for the initial assessment of lung disease and for gauging and predicting the rate of decline. The curve may be used as a long-range outcome criterion to evaluate new treatments in groups of patients with cystic fibrosis.

Adolescent↗

PubMed1998

Cystic fibrosis: predictors of accelerated decline and distribution of disease in 230 patients.

OBJECTIVE: The purpose of this study was to determine predictors of accelerated deterioration in radiographic manifestations of cystic fibrosis. The incidence and distribution of focally accentuated disease were also studied. MATERIALS AND METHODS: From 230 patients, 3038 chest radiographs were scored using the Brasfield system. Scores were plotted against age, and a single age-based severity curve was created. Specific observations (at least one episode in the first 5 years of life of air trapping, linear markings, nodular cystic lesions, or large lesions) were assessed to determine predictors of accelerated decline in scores compared with the aggregate scores plotted in the age-based severity curve. Specific observations were noted as present or absent and graded as to severity. A specific observation was counted as present if seen on at least one occasion. (The number of occasions on which the observation was made did not affect statistical analysis.) We also evaluated the distribution of lung disease by assessing the severity and nature of disease through specific lobar distribution. RESULTS: Males showed a slightly greater rate of radiologic decline. Early development of air trapping or bronchiectasis was associated with an accelerated rate of decline over time. Lobe-dominant disease occurred in one third of all images and in two thirds of the patients. It varied with age in its incidence, location, and etiology. CONCLUSION: Hyperinflation or bronchiectasis that occurs before age 5 is associated with accelerated radiographic deterioration. The incidence and location of lobe-dominant disease varied with age in these patients.

Adolescent↗

PubMed1998

Efficacy of fast screening MR in children and adolescents with suspected intracranial tumors.

PURPOSE: Our purpose was to determine the sensitivity, specificity, and receiver operator characteristic (ROC) curve of a fast screening MR protocol in children and adolescents with suspected intracranial tumors. METHODS: One hundred forty-one patients (mean age, 9.7 years; range, 2 months to 23.5 years) with suspected brain tumor were entered in a case-control study. Eighty-seven patients had intracranial tumors (31 suprasellar/hypothalamic, 27 supratentorial, 26 infratentorial, and three pineal) and 54 patients in the control group had other disorders. Two neuroradiologists reviewed blindly a detailed three-sequence conventional protocol (acquisition time, 8 minutes 27 seconds) and a two-sequence fast screening MR protocol (acquisition time, 4 minutes 44 seconds). RESULTS: Sensitivity and specificity of the fast screening protocol for intracranial tumors was 100% and 92.6%, respectively. The areas under the ROC curves were 0.966 for the fast screening and 0.980 for the conventional MR protocol. No diagnostic performance difference was found between the ROC curves using the Az index. A kappa statistic of .93 for both examinations indicated excellent interobserver agreement. Additional MR sequences and other neuroimaging studies were not deemed necessary to exclude the presence of an intracranial tumor. CONCLUSION: A fast dual-plane brain MR protocol may be adequate to screen children and adolescents thought to have an intracranial tumor. The less than 5 minute acquisition time allows a complete examination (including preparation) to be performed in 10 to 15 minutes. Future studies are recommended before this time-efficient neuroimaging examination is incorporated into clinical practice.

Adolescent↗

PubMed1998

Tectal tumors of childhood: clinical and imaging follow-up.

PURPOSE: This study was done to determine which clinical and imaging findings best correlate with outcome in children with tectal tumors. METHODS: A retrospective review was done of the medical records and imaging studies of 32 children (16 boys and 16 girls; mean age, 8 years) with tectal tumors. Eight children had CT, 11 had MR imaging, and 13 had both CT and MR studies. Findings from surgical and pathologic reports as well as from follow-up examinations (mean follow-up period, 5 years; range, 3.6 months to 17 years) were included in the review. RESULTS: All patients had hydrocephalus and all but one required CSF diversion. The tectum was the center of the tumor in all cases and the majority of the tumors appeared isodense on CT scans, isointense on T1-weighted MR images, and hyperintense on T2-weighted images. Twenty patients required no further treatment. In this group, the mean maximum tumor diameter was 1.8 cm and enhancement occurred in two cases. At follow-up, 18 patients had stable tumor size, one had an increase in tumor size with cyst formation but no worsening of symptoms, and one had a decrease in tumor size. Twelve patients required further treatment (excision and/or radiotherapy) because of progression as indicated by either increased tumor size or worsening of symptoms. In this group, the mean maximum tumor diameter was 2.5 cm and contrast enhancement occurred in nine cases. Further follow-up in this group showed decreased tumor size in eight and stable residual tumor in three. CONCLUSION: Tectal tumors in childhood have variable behavior. MR imaging assists in the clinical determination of which children need treatment beyond CSF diversion. Larger tumor size and enhancement are radiologic predictors of the need for further treatment.

Adolescent↗

PubMed1997

Cell-mediated cytotoxicity: a predictor of chronic rejection in pediatric HLA haploidentical renal transplants.

BACKGROUND: Recipient antidonor cytotoxic T-cell activity has been associated with graft loss and acute rejection in renal allograft recipients. The role of immunologic mechanisms in the development of chronic graft rejection is controversial. We analyzed all living related renal transplants performed at Children's Hospital (Boston, MA) from 1983 to 1995 to assess whether cell-mediated cytotoxicity, determined in vitro and measured before transplantation, was predictive of chronic rejection. METHODS: Eighty-three patients were studied retrospectively. Fifty-seven patients with one haplotype-matched renal transplants from living related donors were studied to determine the association between cell-mediated lympholysis (CML) level, acute rejection, chronic rejection, and graft failure. Acute rejection was defined by the decision to treat. Chronic rejection was defined by histology and/or the absolute serum creatinine value using an increasing serum creatinine level >1.0 mg/dl for children less than 3, a creatinine level >1.5 mg/dl for children between 3 and 10 years of age, and a creatinine level >2.0 mg/dl for children above 10 years of age. Return to dialysis or retransplantation was considered graft failure. RESULTS: Of the 57 haploidentical patients, there were 33 males and 24 females. The mean age at transplant was 11.1 years (SD=6.7). Twelve patients developed chronic rejection, 24 patients developed acute rejection, and 7 patients had graft failure. Pretransplant cytotoxic T lymphocyte activity was associated with chronic rejection (P=0.001) and graft failure (P=0.013) but only marginally with acute rejection (P=0.058). Controlling for age and sex, Cox's proportional hazards model revealed that CML level was predictive of time to chronic rejection (P<0.01) but not acute rejection (P=0.11). It was estimated that every 1-unit increase in CML level raises the monthly risk of chronic rejection by 7%. Ten children received HLA-identical kidneys from their siblings. There were no episodes of chronic rejection after 5 years. Two patients with high CML levels had episodes of acute rejection; both patients responded to treatment. CONCLUSION: Our data demonstrate an association between pretransplant cell-mediated cytotoxicity and the occurrence of chronic rejection in living related one-haploidentical renal transplants in pediatric patients.

Adolescent↗

PubMed1997

Survival in primary soft tissue sarcoma of the extremities and trunk.

BACKGROUND: Soft tissue sarcomas (STS) of the extremities are rare. The purpose of this study was to identify prognostic risk factors associated with survival in patients with primary extremity and truncal STS. METHODS: Patient, tumor, and pathologic data from 149 consecutive patients with localized primary STS of the extremities and trunk were analyzed using Kaplan-Meier and Cox regression techniques to identify univariate and multivariate risk factors. A subgroup analysis was performed to compare factors predictive of survival in patients who received treatment before (n = 50) and after (n = 99) treatment was standardized in 1988. RESULTS: The 5-year survival rate was 76.5% with an average follow-up of 6 years. Local recurrence occurred in 23% of all patients, 40% before 1988 and 15% after 1988 (P < 0.0001). Risk factors associated with survival included resection quality (R0 vs. R1; P < 0.0001), era of operation (P = 0.002), local recurrence (P < 0.001), UICC stage (P < 0.0001), tumor size (P < 0.001), tumor depth (P = 0.002), regional lymph nodes (P < 0.0001), and histology (P < 0.0001). Multivariate analysis revealed that tumor size, tumor depth, and resection quality were independent risk factors of survival. CONCLUSIONS: These results indicate that management of STS in a specialized institution improves overall survival. Resection quality is the most important risk factor of survival. Therefore, effort should be made during primary treatment of STS to achieve wide, tumor-free resection margins.

Adolescent↗

PubMed1997

Vesicoureteral reflux in children: incidence and severity in siblings.

PURPOSE: We attempted to determine the incidence of vesicoureteral reflux in asymptomatic siblings of children with reflux at different ages and assess the incidence of renal damage in asymptomatic siblings with reflux. MATERIALS AND METHODS: We reviewed radionuclide cystograms of 482 consecutively referred siblings of children with vesicoureteral reflux, including 295 girls and 187 boys 2 weeks to 12.8 years old (mean age 2.8 years). Ultrasonograms and renal cortical scintigrams of children with reflux were evaluated. All siblings were considered asymptomatic by the referring physicians. RESULTS: The overall incidence of vesicoureteral reflux was 36.5%, and the incidence in girls and boys was 39.3 and 32.1%, respectively. Children 24 months old or younger had the highest incidence (45.7%) and the highest risk of bilateral reflux. From ages 25 to 72 months the incidence of reflux was 33.1% and in siblings older than 72 months it was 7%. Reflux of urine to the level of the renal pelvis was detected in 28.6% of all referred siblings. Renal damage was observed on sonography or scintigraphy in 4.7% of the siblings with reflux. CONCLUSIONS: The high incidence of vesicoureteral reflux through age 72 months indicates that it is important to screen siblings of children with reflux at an early age to prevent renal damage, which can occur in the absence of symptomatic urinary tract infection.

Age Distribution↗

PubMed1997

Estimating normal bladder capacity in children.

PURPOSE: An accurate estimation of normal bladder capacity can be helpful in evaluating the patient with genitourinary disease and in interpreting urodynamic data. Prior studies have provided initial estimates. We propose 2 new equations that are practical, easy to use and more accurate than those previously published. MATERIALS AND METHODS: We retrospectively reviewed the records of more than 5,000 children undergoing radionuclide cystography at our institution. Radionuclide cystography was conducted by instilling (99m)technetium pertechnetate via gravity drip in awake children. Bladder capacity was believed to be achieved when rate of inflow diminished to a minimal rate, initiation of voiding occurred or significant discomfort was indicated. Patients with vesicoureteral reflux, infravesical obstruction, urinary tract infection, dysfunctional voiding or other lower urinary tract pathology were excluded from the study. Linear and nonlinear regression modeling established the relationship between age and bladder capacity. RESULTS: A total of 2,066 children (598 boys and 1,468 girls) had normal radionuclide cystography and were included in the analysis. Analysis of variance demonstrated that increasing age was strongly predictive of bladder capacity (p <0.0001). Because a nonlinear model was the most accurate formula for all ages (4.5 x age(0.40) = capacity [ounces]), 2 practical linear equations were determined: 2 x age (years) + 2 = capacity (ounces) for children less than 2 years old, and age (years) divided by 2 + 6 = capacity (ounces) for those 2 years old or older. Although girls had larger capacities than boys, the rate of increase was not significantly different between them. CONCLUSIONS: The relationship between normal bladder capacity and age in children follows a nonlinear curve. This nonlinear relationship can be approximated by 2 practical linear formulas that are easy to remember and are derived from a larger population than any prior study. These formulas provided accurate estimations of bladder capacity when prospectively applied to normal patients.

Adolescent↗

PubMed1997

The speaker's formant in male voices.

Spectral analysis of vowels during connected speech can be performed using the spectral intensity distribution within critical bands corresponding to a natural scale on the basilar membrane. Normalization of the spectra provides the opportunity to make objective comparisons independent from the recording level. An increasing envelope peak between 3,150 and 3,700 Hz has been confirmed statistically for a combination of seven vowels in three groups of male speakers with hoarse, normal, and professional voices. Each vowel is also analyzed individually. The local energy maximum is called "the speaker's formant" and can be found in the region of the fourth formant. The steepness of the spectral slope (i.e. the rate of decline) becomes less pronounced when the sonority or the intensity of the voice increases. The speaker's formant is connected with the sonorous quality of the voice. It increases gradually and is approximately 10 dB higher in professional male voices than in normal male voices at neutral loudness (60 dB at 0.3 min). The peak intensity becomes stronger (30 dB above normal voices) when the overall speaking loudness is increased to 80 dB. Shouting increases the spectral energy of the adjacent critical bands but not the speaker's formant itself.

Humans↗

PubMed1997

Serum basic fibroblast growth factor in pediatric Crohn's disease. Implications for wound healing.

Basic fibroblast growth factor is a heparin-binding protein known to stimulate angiogenesis and promote wound healing in tissues. Since Crohn's disease is characterized in part by submucosal vascular proliferation, we sought to determine whether serum basic fibroblast growth factor is elevated in children with Crohn's disease and whether serum levels reflect disease activity. Sera were obtained from 64 children with Crohn's disease, 44 children with ulcerative colitis, 20 children with functional abdominal pain, and 29 from children with documented inflammatory disease evaluated in our gastroenterology program. Disease activity indices and clinical data were gathered prospectively for the inflammatory bowel disease patients. Serum basic fibroblast growth factor levels were measured by enzyme-linked immunosorbent assay. Although the mean basic fibroblast growth factor level did not significantly differ between children with Crohn's disease and other conditions, there was a strong (r = 0.53, P < 0.001) correlation between basic fibroblast growth factor level and disease activity. The relationship of basic fibroblast growth factor with disease activity persisted even after adjusting for other covariates (including age, sex, hematocrit, albumin, and sedimentation rate) in a multivariate linear regression model. There was also a statistically significant, although less strong correlation (r = 0.33, P = 0.03) between basic fibroblast growth factor level and disease activity in ulcerative colitis. While basic fibroblast growth factor is not a specific marker for Crohn's disease, serum levels reflect disease activity. Therefore, basic fibroblast growth factor release may be important in mediating the angiogenesis and wound healing seen in Crohn's disease.

Adolescent↗

PubMed1997

A prospective comparison of high-resolution planar, pinhole, and triple-detector SPECT for the detection of renal cortical defects.

To compare the detection rate of renal cortical defects with Tc-99m dimercaptosuccinic acid (DMSA) using triple-detector SPECT, pinhole, and planar cortical scintigraphy, the authors prospectively studied 80 kidneys in 40 patients (26 males, 14 females) who ranged in age from 3 months to 26 years (mean: 7.5 years). They found single or multiple definite defects in 30 kidneys using SPECT, 23 using pinhole imaging, and 17 using planar imaging (McNemar's test, two-tailed, P < 0.001 and P = 0.03, respectively). SPECT was significantly better than pinhole imaging at demonstrating definite defects (P = 0.008). This study indicates that SPECT, and to a lesser extent pinhole, are superior to planar imaging for conclusively demonstrating renal cortical defects.

Adolescent↗

PubMed1997

Children with headache: clinical predictors of surgical space-occupying lesions and the role of neuroimaging.

PURPOSE: To determine clinical predictors useful in differentiation of surgical lesions from medically treated disorders and the role of neuroimaging in children with headache. MATERIALS' AND METHODS: In a 4-year retrospective study, 315 patients with headache and no known neurologic disorder underwent brain magnetic resonance (MR) imaging. Sixty-nine patients also underwent brain computed tomography (CT). Clinical data were correlated with findings from MR imaging and CT and the final diagnosis by means of logistic regression. RESULTS: Thirteen (4%) patients had surgical space-occupying lesions. Seven independent multivariate predictors of a surgical lesion were identified. Sleep-related headache and no family history of migraine were the strongest predictors. Other predictors included vomiting, absence of visual symptoms, headache of less than 6 months duration, confusion, and abnormal neurologic examination findings. A positive correlation between number of predictors and risk of surgical lesion was noted (P < .0001). No difference between MR imaging and CT was noted in detection of surgical space-occupying lesions, and there were no false-positive or false-negative surgical lesions detected with either modality on the basis of clinical follow-up. CONCLUSION: Children at high risk on the basis of these criteria usually require neuroimaging, while children at low risk may be safely followed up clinically without neuroimaging.

Adolescent↗

PubMed1997

Protein malnutrition increases plasma adrenocorticotropin and anterior pituitary proopiomelanocortin messenger ribonucleic acid in the rat.

The mechanism by which protein malnutrition increases circulating glucocorticoids is unclear. To determine whether ACTH synthesis and secretion also increase in protein malnutrition, rats were sham adrenalectomized or adrenalectomized and replaced with varying amounts of corticosterone before dietary protein deprivation. Pair-fed rats served as controls for reduced voluntary food intake in protein-deprived rats. Dietary protein deficiency, but not pair-feeding, increased resting plasma corticosterone in sham-adrenalectomized rats. Restraint-induced ACTH secretion was not inhibited by the increased basal corticosterone levels in protein-deficient rats. When increases in corticosterone were eliminated by adrenalectomy or controlled by adrenalectomy with low level corticosterone replacement, increases in resting plasma ACTH and anterior pituitary POMC messenger RNA expression occurred with protein deprivation that could be statistically discriminated by regression analysis from changes due to caloric restriction (pair-feeding) and overt glucocorticoid feedback resistance. We conclude that protein malnutrition increases pituitary-adrenocortical activity at least in part by specifically increasing the drive for ACTH synthesis and secretion.

Adrenocorticotropic Hormone↗

PubMed1997

Differentiation of engrafted multipotent neural progenitors towards replacement of missing granule neurons in meander tail cerebellum may help determine the locus of mutant gene action.

Previously we observed that stable clones of multipotent neural progenitor cells, initially isolated and propagated from the external granular layer of newborn wild-type mouse cerebellum, could participate appropriately in cerebellar development when reimplanted into the external granular layer of normal mice. Donor cells could reintegrate and differentiate into neurons (including granule cells) and/or glia consistent with their site of engraftment. These findings suggested that progenitors might be useful for cellular replacement in models of aberrant neural development or neurodegeneration. We tested this hypothesis by implanting clonally related multipotent progenitors into the external granular layer of newborn meander tail mice (gene symbol=mea). mea is an autosomal recessive mutation characterized principally by the failure of granule cells to develop in the cerebellar anterior lobe; the mechanism is unknown. We report that approximately 75% of progenitors transplanted into the granuloprival anterior lobe of neonatal mea mutants differentiated into granule cells, partially replacing or augmenting that largely absent neuronal population in the internal granular layer of the mature meander tail anterior lobe. (The ostensibly 'normal' meander tail posterior lobe also benefited from repletion of a more subtle granule cell deficiency.) Donor-derived neurons were well-integrated within the neuropil, suggesting that these progenitors' developmental programs for granule cell differentiation were unperturbed. These observations permitted several conclusions. (1) That exogenous progenitors could survive transplantation into affected regions of neonatal meander tail cerebellum and differentiate into the deficient cell type suggested that the microenvironment was not inimical to granule cell development. Rather it suggested that mea's deleterious action is intrinsic to the external granular layer cell. (Any cell-extrinsic actions--albeit unlikely--had to be restricted to readily circumventable prenatal events.) This study, therefore, offers a paradigm for using progenitors to help determine the site of action of other mutant genes or to test hypotheses regarding the pathophysiology underlying other anomalies. (2) In the regions most deficient in neurons, a neuronal phenotype was pursued in preference to other potential cell types, suggesting a 'push' of undifferentiated, multipotent progenitors towards compensation for granule cell dearth. These data suggested that progenitors with the potential for multiple fates might differentiate towards repletion of deficient cell types, a possible developmental mechanism with therapeutic implications. Neural progenitors (donor or endogenous) might enable cell replacement in some developmental or degenerative diseases--most obviously in cases where a defect is intrinsic to the diseased cell, but also, under certain circumstances, when extrinsic pathologic forces may exist.

Animals↗