Comparison of the effects of PRKAR1A and PRKAR2B depletion on signaling pathways, cell growth, and cell cycle control of adrenocortical cells.

The cyclic AMP/protein kinase A signaling cascade is one of the main pathways involved in the pathogenesis of adrenocortical tumors. The PKA R1A and R2B proteins are the most abundant regulatory subunits in endocrine tissues. Inactivating mutations of PRKAR1A are associated with Carney complex and a subset of sporadic tumors and the abundance of R2B protein is low in a subset of secreting adrenocortical adenomas. We previously showed that PRKAR1A and PRKAR2B inactivation have anti-apoptotic effects on the adrenocortical carcinoma cell line H295R. The aim of this study was to compare the effects of PRKAR1A and PRKAR2B depletion on cell proliferation, apoptosis, cell signaling pathways, and cell cycle regulation. We found that PRKAR2B depletion is compensated by an upregulation of R1A protein, whereas PRKAR1A depletion has no effect on the production of R2B. The depletion of either PRKAR1A or PRKAR2B promotes the expression of Bcl-xL and resistance to apoptosis; and is associated with a high percentage of cells in S and G2 phase, activates PKA and MEK/ERK pathways, and impairs the expression of IkB leading to activate the NF-κB pathway. However, we observed differences in the regulation of cyclins. The depletion of PRKAR1A leads to the accumulation of cyclin D1 and p27kip, whereas the depletion of PRKAR2B promotes the accumulation of cyclin A, B, cdk1, cdc2, and p21Cip. In conclusion, although the depletion of PRKAR1A and PRKAR2B in adrenocortical cells has similar effects on cell proliferation and apoptosis; loss of these PKA subunits differentially affects cyclin expression.

Protein kinase A alterations in endocrine tumors.

Various molecular and cellular alterations of the cyclic adenosine monophosphate (cAMP) pathway have been observed in endocrine tumors. Since protein kinase A (PKA) is a central key component of the cAMP pathway, studies of the alterations of PKA subunits in endocrine tumors reveal new aspects of the mechanisms of cAMP pathway alterations in human diseases. So far, most alterations have been observed for the regulatory subunits, mainly PRKAR1A and to a lower extent, PRKAR2B. One of the best examples of such alteration today is the multiple neoplasia syndrome Carney complex (CNC). The most common endocrine gland manifestations of CNC are pituitary GH-secreting adenomas, thyroid tumors, testicular tumors, and ACTH-independent Cushing's syndrome due to primary pigmented nodular adrenocortical disease (PPNAD). Heterozygous germline inactivating mutations of the PKA regulatory subunit RIα gene (PRKAR1A) are observed in about two-third of CNC patients, and also in patients with isolated PPNAD. PRKAR1A is considered as a tumor suppressor gene. Interestingly, these mutations can also be observed as somatic alterations in sporadic endocrine tumors. More than 120 different PRKAR1A mutations have been found today. Most of them lead to an unstable mutant mRNA, which will be degraded by nonsense mediated mRNA decay. In vitro and in vivo functional studies are in progress to understand the mechanisms of endocrine tumor development due to PKA regulatory subunits inactivation. PRKAR1A mutations stimulate in most models PKA activity, mimicking in some way cAMP pathway constitutive activation. Cross-talks with other signaling pathways summarized in this review have been described and might participate in endocrine tumorigenesis.

Mantle irradiation alone for selected patients with laparotomy-staged IA to IIA Hodgkin's disease: preliminary results of a prospective trial.

PURPOSE: To determine the feasibility of omitting prophylactic paraaortic irradiation in selected patients with laparotomy-staged (pathologically staged [PS]) IA to IIA Hodgkin's disease. PATIENTS AND METHODS: We initiated a prospective single-arm trial in October 1988 to study the role of mantle irradiation alone in selected PS IA to IIA patients with Hodgkin's disease. A total of 37 patients have been entered onto this trial. Entrance criteria included nodular sclerosis (NS) or lymphocyte predominance (LP) histology, absence of B symptoms, disease limited above the carina, and a negative laparotomy. Results of treatment of 23 patients in the prospective trial, monitored off treatment for > or = 1 year, are presented. Twenty-three additional PS IA to IIA patients, treated with mantle irradiation alone from 1970 to 1987, were analyzed as a comparison group. The median follow-up durations were 32 and 113 months, respectively, for the two groups. RESULTS: The 4-year actuarial rates of freedom from relapse and overall survival are 83% and 100%, respectively, for the prospective trial. The 10-year actuarial rates of freedom from relapse and overall survival are 83% and 89%, respectively, for retrospectively studied patients. There have been five recurrences among 46 patients who received mantle irradiation alone, all with a component of relapse below the diaphragm. CONCLUSION: These early results support the use of mantle irradiation alone in selected PS IA to IIA patients with NS or LP histology. Relapses, although rare, have occurred predominantly below the diaphragm. This suggests the need for continued long-term surveillance of abdominal and pelvic nodes in this group of treated patients.

Combined transcriptome studies identify AFF3 as a mediator of the oncogenic effects of ß-catenin in adrenocortical carcinoma.

Adrenocortical cancer (ACC) is a very aggressive tumor, and genomics studies demonstrate that the most frequent alterations of driver genes in these cancers activate the Wnt/ß-catenin signaling pathway. However, the adrenal-specific targets of oncogenic ß-catenin-mediating tumorigenesis have not being established. A combined transcriptomic analysis from two series of human tumors and the human ACC cell line H295R harboring a spontaneous ß-catenin activating mutation was done to identify the Wnt/ß-catenin targets. Seven genes were consistently identified in the three studies. Among these genes, we found that AFF3 mediates the oncogenic effects of ß-catenin in ACC. The Wnt response element site located at nucleotide position -1408 of the AFF3 transcriptional start sites (TSS) mediates the regulation by the Wnt/ß-catenin signaling pathway. AFF3 silencing decreases cell proliferation and increases apoptosis in the ACC cell line H295R. AFF3 is located in nuclear speckles, which play an important role in RNA splicing. AFF3 overexpression in adrenocortical cells interferes with the organization and/or biogenesis of these nuclear speckles and alters the distribution of CDK9 and cyclin T1 such that they accumulate at the sites of AFF3/speckles. We demonstrate that AFF3 is a new target of Wnt/ß-catenin pathway involved in ACC, acting on transcription and RNA splicing.

Tryptophan missense mutation in the ligand-binding domain of the vitamin D receptor causes severe resistance to 1,25-dihydroxyvitamin D.

In this study, two related young children, brother and sister, exhibited severe vitamin D-resistant rickets without alopecia. Sequence analysis of the total vitamin D receptor (VDR) cDNA from skin fibroblasts revealed a substitution of the unique tryptophan of the VDR by arginine at amino acid 286 (W286R). Cultured skin fibroblasts of the two patients expressed normal-size VDR protein (immunocytochemistry and Western blotting) and normal length VDR mRNA (Northern blotting). But, these fibroblasts, as well as COS-7 cells transfected with the W286R mutant, failed to bind 3H 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. The tryptophan substitution did not affect VDR trafficking toward the nucleus but abolished the 24-hydroxylase gene response to 1,25(OH)2D3, even at 10(-6) M concentrations. In conclusion, this case report of a new family with hereditary vitamin D-resistant rickets (HVDRR) emphasizes the crucial role of the VDR tryptophan for ligand binding and for transactivation of 1,25(OH)2D3 target genes. It clearly shows the clinical significance of this VDR amino acid for calcium homeostasis and bone mineralization. This observation suggests further that the presence of a stable VDR-bound ligand may not be obligatory for normal hair follicle development.

Cell free translation of rat epidermal calcium-binding protein (EP-12) messenger RNA.

The primary step in the biosynthesis of 12 KDa rat epidermal calcium binding protein was studied by cell-free protein synthesis. Poly(A)+ rich RNA was extracted and purified from whole newborn rat skin and translated in a lysate system in the presence of labeled methionine. Immunoprecipitation of translation products with a monospecific antibody directed against this protein, which did not react with parvalbumin yielded a product migrating as a single band of molecular weight 12 KDa on polyacrylamide gel electrophoresis. Thus, a mRNA coding for this protein is present in rat skin. The presence of this messenger RNA opens the way for further studies on the regulation of epidermal expression during epidermal cell proliferation and differentiation.

The identification of fibrous proteins in fetal rat epidermis by electrophoretic and immunologic techniques.

Two proteins have been identified in extracts of fetal rat skin which are related to the two major fibrous proteins of newborn rat stratum corneum. The relative amount of these proteins increases daily from the 16th to the 20th day (d) of gestation when judged by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and immunoelectrophoresis using antibody to the purified fibrous protein. Two-dimensional analysis by SDS-polyacrylamide gel electrophoresis and immunoelectrophoresis demonstrates that these two proteins are the only cross-reactive species in the fetal skin from 16d to 19d development. Some additional lower-molecular-weight components can be detected at 20d and 21d. In double-diffusion analysis, cross-reactive proteins in 19d fetal extracts show partial identity but have fewer antigenic sites than proteins in 20d extracts. The 20d protein shows a reaction of identity with purified newborn fibrous protein. Immunofluorescence studies on fetal skin support the prescence of cross-reacting components at 16d development related to the newborn fibrous protein. Intensity of fluorescence increases at 18d and 20d in the spinous and granular cell cytoplasm and in the keratohyaline granules. The stratum corneum, first seen at 20d, is intensely fluorescent. The cellular localization and time of appearance of the cross-reactive proteins suggest that they may be associated with tonofilaments.

Parathyroid hormone (PTH)/PTH-related protein receptor messenger ribonucleic acid expression and PTH response in a rat model of secondary hyperparathyroidism associated with vitamin D deficiency.

The aim of the present work was to characterize at the molecular level the mechanism of PTH resistance in a rat model of secondary hyperparathyroidism resulting from vitamin D deprivation. PTH/PTH-related protein (PTHrp) receptor messenger RNA (mRNA) expression, assayed by ribonuclease protection analysis, was studied in the kidney, femoral epi/metaphysis, and diaphysis. In addition, in the kidney, PTH/PTHrp receptor mRNA expression was correlated to receptor function by measuring adenyl cyclase activity in crude renal membranes after stimulation by PTH (10(-10) - 10(-6) M), forskolin (0.1 and 0.2 mM), NaF (5 and 10 mM), and isoproterenol (1 and 10 microM). Four groups of rats were studied to investigate the effects of calcium, PTH, and/or vitamin D status. The first group received a control diet (D+D+). The second group received a diet deficient in vitamin D until death (D-D-). In the two other groups that also received a vitamin D-deficient diet, the hypocalcemia and the hyperparathyroidism were later corrected, by either vitamin D supplementation (D-D+) or lactose and high calcium diet (D-Ca+), 1 week before death. The results revealed a 2-fold decrease in the PTH-induced adenyl cyclase activity of the renal membranes in the D-D- rats compared to those in the three other groups. There was no significant difference in the four groups in adenyl cyclase activity stimulated by forskolin, NaF, and isoproterenol. The decrease in PTH-induced adenyl cyclase activity was associated with an approximately 2-fold increase in PTH/PTHrp receptor mRNA expression in the kidneys of the D-D- rats compared to controls. Normalization of PTH/PTHrp receptor mRNA expression was observed after vitamin D supplementation (D-D+ rats), but not after correction of the hypocalcemia and secondary hyperparathyroidism by oral lactose and calcium supplementation. In the epi/metaphysis, an approximately 2-fold increase in PTH/PTHrp receptor mRNA was also observed in the D-D- rats compared to the controls; this increase was partially corrected upon normalization of the calcemia and PTH levels with either vitamin D (D-D+ group) or lactose/calcium (D-Ca+ group). In the diaphysis, no change in the expression of PTH/PTHrp receptor mRNA was observed in any group.(ABSTRACT TRUNCATED AT 400 WORDS)

Neuroanatomic differences between dyslexic and normal readers on magnetic resonance imaging scans.

The areas of six bilateral brain segments in the right and left hemispheres, on a horizontal brain section, and the area of subdivisions of the corpus callosum, on a midsagittal brain section, were measured on magnetic resonance images obtained from 21 dyslexic and 29 control subjects. In the entire group, the frontal half of the horizontal brain section showed asymmetry, with the right side being larger, whereas posteriorly only the occipital polar segment was asymmetrical, with the left side being larger. Dyslexic subjects exhibited asymmetry, with the right side greater than the left side, in contrast to the relatively symmetrical pattern that is normally observed in the midposterior segment that corresponds to the angular gyrus. In the corpus callosum, dyslexic subjects were found to have a larger splenium than nondyslexic subjects, and dyslexic female subjects were found to have a larger splenium than dyslexic male subjects. Because transcallosal pathways connecting the left and right angular gyrus regions traverse through the splenium of the corpus callosum, the above findings in dyslexic subjects suggest an anatomic abnormality in the angular gyrus region.

HTLV-I-associated leukemia/lymphoma in south Florida.

We report here 10 cases of adult T-cell leukemia/lymphoma (ATL) seen in South Florida between February 1988 and July 1989. All were seropositive for human T-lymphotropic virus type I (HTLV-I) and seronegative for human immunodeficiency virus type 1 (HIV-1). DNA extracted from tumor biopsies/peripheral blood lymphocytes of nine patients was shown by the polymerase chain reaction (PCR) to contain HTLV-I proviral DNA. Blot hybridization of DNA extracted from seven patients with an HTLV-I cDNA probe revealed a monoclonal pattern of proviral integration consistent with a diagnosis of ATL. Eight of the 10 patients were women. Six patients were from Haiti, three from Jamaica, and one from the Bahamas. All patients had very aggressive non-Hodgkin's lymphoma. Two patients presented with sinus and retro-orbital involvement; another had gastric lymphoma that perforated. Nine patients developed hypercalcemia. Eight patients died within 1 year of diagnosis. Two were lost to follow-up. During the course of this study, 66 new cases of non-Hodgkin's lymphoma were diagnosed at this hospital. Ten of these cases were ATL. The prevalence of HTLV-I-related lymphoma in this sample was 15%. Since tissue from all patients was not available for HTLV-I screening, however, it is possible that other cases of ATL went undetected. We conclude from this initial survey that a retroviral etiology should be considered in patients from populations known to be at risk for HTLV-I infection who present with non-Hodgkin's lymphoma.

Temporal lobe surface area measurements on MRI in normal and dyslexic readers.

In a neuroanatomical study of dyslexia, measurements were made of the superior surface of the temporal lobe (SSTL) on MRI scans in a sample of 17 dyslexics and 21 non-dyslexic subjects. Both anterior and posterior halves of the SSTL area showed significant leftward asymmetry in non-dyslexics, but showed symmetry in dyslexics. The total SSTL area showed greater leftward asymmetry in non-dyslexics than in dyslexics. The dyslexics also revealed a significant correlation (r = 0.69, P = 0.005) between Woodcock-Johnson Passage Comprehension scores and posterior SSTL asymmetry, such that those with higher scores had more leftward asymmetry. This suggests that among dyslexics the direction of SSTL asymmetry may serve as a risk factor and/or a marker for the severity of reading comprehension problems.

Protection from pathogenic SIV challenge using multigenic DNA vaccines.

To assess DNA immunization as a strategy for protecting against HIV infection in humans, we utilized SIVmne infection of Macaca fascicularis as a vaccine challenge model with moderate pathogenic potential. We compared the efficacy of DNA immunization alone and in combination with subunit protein boosts. All of the structural and regulatory genes of SIVmne clone 8 were cloned into mammalian expression vectors under the control of the CMV IE-1 promoter. Eight M. fascicularis were immunized twice with 3 mg of plasmid DNA divided between two sites; intramuscular and intradermal. Four primed macaques received a further two DNA immunizations at weeks 16-36, while the second group of four were boosted with 250 microg recombinant gp160 plus 250 microg recombinant Gag-Pol particles formulated in MF-59 adjuvant. Half of the controls received four immunizations of vector DNA; half received two vector DNA and two adjuvant immunizations. As expected, humoral immune responses were stronger in the macaques receiving subunit boosts, but responses were sustained in both groups. Significant neutralizing antibody titers to SIVmne were detected in one of the subunit-boosted animals and in none of the DNA-only animals prior to challenge. T-cell proliferative responses to gp160 and to Gag were detected in all immunized animals after three immunizations, and these responses increased after four immunizations. Cytokine profiles in PHA-stimulated PBMC taken on the day of challenge showed trends toward Thl responses in 2/4 macaques in the DNA vaccinated group and in 1/4 of the DNA plus subunit vaccinated macaques; Th2 responses in 3/4 DNA plus subunit-immunized macaques; and Th0 responses in 4/4 controls. In bulk CTL culture, SIV specific lysis was low or undetectable, even after four immunizations. However, stable SIV Gag-Pol- and env-specific T-cell clones (CD3+ CD8+) were isolated after only two DNA immunizations, and Gag-Pol- and Nef-specific CTL lines were isolated on the day of challenge. All animals were challenged at week 38 with SIVmne uncloned stock by the intrarectal route. Based on antibody anamnestic responses (western, ELISA, and neutralizing antibodies) and virus detection methods (co-culture of PBMC and LNMC, nested set PCR- of DNA from PBMC and LNMC, and plasma QC-PCR), there were major differences between the groups in the challenge outcome. Surprisingly, sustained low virus loads were observed only in the DNA group, suggesting that four immunizations with DNA only elicited more effective immune responses than two DNA primes combined with two protein boosts. Multigenic DNA vaccines such as these, bearing all structural and regulatory genes, show significant promise and may be a safe alternative to live-attenuated vaccines.

Application of ion-impact energy measurement to electrospray ionization mass spectrometry of proteins and protein mixtures.

We have used a normal metal-insulator-superconductor (NIS) microcalorimeter to measure the impact energy of protein ions produced by electrospray ionization (ESI) in a magnetic-sector mass spectrometer (MS). We have used these measurements to resolve spectral ambiguities and to analyze protein mixtures. Energy measurement may be useful for the direct MS analysis of complex biopolymer mixtures that normally would confound ESI-MS deconvolution algorithms.

Effect of vitamin D deficiency and 1,25-dihydroxycholecalciferol treatment on epidermal calcium-binding protein (ECaBP) RNA activity.

We have previously reported that the amount of epidermal calcium binding protein (ECaBP) in the skin decreases in the absence of vitamin D. Since vitamin D influences epidermal differentiation, and the synthesis of ECaBP may vary with cell differentiation, it was necessary to know whether vitamin D acts directly on the translational or post-translational level of ECaBP synthesis or indirectly by its action on epidermopoiesis. The cell-free translation technique was used to demonstrate the presence of mRNA coding for ECaBP. The activity of this mRNA has been evaluated in the skin of vitamin D-fed and in vitamin D-deficient rats with or without treatment with 1,25-dihydroxycholecalciferol (1,25(OH)2D3). Vitamin D deficiency decreased the ECaBP mRNA activity. The latter was selectively increased in animals given a single dose of 1,25(OH)2D3. These results suggest that 1,25(OH)2D3 stimulates the production of ECaBP mRNA or stabilizes this mRNA.

Reduced transverse spinal area secondary to burst fractures: is there a relationship to neurologic injury?

A retrospective case-control study was undertaken to determine the best technique to measure neural canal encroachment at each lumbar level following burst fracture and its relationship to the presence of neurologic deficit. Only patients with postinjury CT scans demonstrating a disrupted posterior body with a retropulsed bone fragment were included. Patients were divided into groups based on the level of bony injury (T12-L5) and neurologic status. Neurologic injury was classified as follows: normal (N), root (R), or cauda equina/conus/paraplegic/paraparetic (C/P). The mean transverse spinal area (TSA, cm2), spinal canal percentage patency (PP), and midsagittal diameter (MSD) were determined for each neurologic group and lumbar level. A "calculated" TSA, based on midsagittal and anterior-posterior diameters, was also derived for each patient. The data were compared level by level and correlated with the patient's neurologic status. At L1, the critical TSA was 1.0 cm2. All patients with TSAs less than this were paraplegic. At both T12 and L1, TSAs in the range of 1.0-1.25 cm2 were observed in both normal and neurologically impaired patients. A critically significant TSA was not established for levels T12, L2, L3, L4, or L5; however, the data indicated that a smaller TSA can be tolerated at successively caudal levels without neurologic deficit. No meaningful correlation between root injury and TSA was observed. The data also indicated that measurement of TSA is a more accurate method for evaluating neural canal encroachment than PP or MSD. The "calculated" TSA is a simple, objective method for obtaining this information without the aid of a computer. This study suggests that absolute TSA should be utilized in future studies evaluating decompressive treatment of thoracolumbar pathology.

1,25-Dihydroxyvitamin D3 and fetal lung maturation: immunogold detection of VDR expression in pneumocytes type II cells and effect on fructose 1,6 bisphosphatase.

Lung maturation before birth includes type II pneumocyte differentiation with progressive disappearance of glycogen content and onset of surfactant synthesis. We have shown previously that 1,25-(OH)2D3 increases surfactant synthesis and secretion by type II cells and decreases their glycogen content in fetal rat lung explants. Recently, the gene coding fructose 1,6 bisphosphatase (F1,6BP), a regulatory enzyme of gluconeogenesis, has been identified in type II cells and its promoter bears a Vitamin D response element. Present results show:The coexistence of type II cells at different stages of maturation. in rat fetal lung on day 21 of gestation (electron microscopy), and the association between maturation of type II cells and disappearance of their glycogen content. The immunogold labeling of all type II cells when using the 9A7g VDR-antibody, with significantly more abundant gold particles in cells exhibiting an intermediate glycogen content. The expression of F1,6BP mRNA in a human type II cell line (NCI-H441) and the increase of this expression after 18h incubation with 1,25-(OH)2D3 (10(-8)M). These results bring further evidence for a physiological role of 1,25-(OH)2D3 during type II pneumocyte maturation. Activation of F1,6BP may participate to the 1,25-(OH)2D3 action on surfactant synthesis via the gluconeogenesis pathway.

Extradural lymphoma presenting as an acute surgical emergency.

Extradural lymphoma can present as an acute neurosurgical emergency. The clinical presentation and radiological appearance may suggest epidural hematoma or meningioma. Lymphoma should be considered as a rare but possible diagnosis before operation. High resolution computed tomography using direct coronal imaging with and without contrast enhancement may aid in suggesting the correct preoperative diagnosis.

The measurement of proton stopping power using proton-cone-beam computed tomography.

A cone-beam computed tomography (CT) system utilizing a proton beam has been developed and tested. The cone beam is produced by scattering a 160 MeV proton beam with a modifier that results in a signal in the detector system, which decreases monotonically with depth in the medium. The detector system consists of a Gd2O2S:Tb intensifying screen viewed by a cooled CCD camera. The Feldkamp-Davis-Kress cone-beam reconstruction algorithm is applied to the projection data to obtain the CT voxel data representing proton stopping power. The system described is capable of reconstructing data over a 16 x 16 x 16 cm3 volume into 512 x 512 x 512 voxels. A spatial and contrast resolution phantom was scanned to determine the performance of the system. Spatial resolution is significantly degraded by multiple Coulomb scattering effects. Comparison of the reconstructed proton CT values with x-ray CT derived proton stopping powers shows that there may be some advantage to obtaining stopping powers directly with proton CT. The system described suggests a possible practical method of obtaining this measurement in vivo.

Odor recognition: familiarity, identifiability, and encoding consistency.

The investigation examined the association between the perceived identity of odorous stimuli and the ability to recognize the previous occurrence of them. The stimuli comprised 20 relatively familiar odorous objects such as chocolate, leather, popcorn, and soy sauce. Participants rated the familiarity of the odors and sought to identify them. At various intervals up to 7 days after initial inspection, the participants sought to recognize the odors among sets of distractor odors that included such items as soap, cloves, pipe tobacco, and so on. The recognition response entailed a confidence rating as to whether or not an item had appeared in the original set. At the time of testing, the participants also sought to identify the stimuli again. The results upheld previous findings of excellent initial recognition memory for environmentally relevant odors and slow forgetting. The results also uncovered, for the first time, a strong association between recognition memory and identifiability, rated familiarity, and the ability to use an odor label consistently at inspection and subsequent testing. Encodability seems to enhance rather than to permit recognizability. Even items identified incorrectly or inconsistently were recognized at levels above chance.

Familial dyslexia: genetic and medical findings in eleven three-generation families.

In addition to providing information on the inheritance of dyslexia, the present study of eleven three-generation families has provided a unique opportunity to compare affected and unaffected family members at all ages. The data presented here are based on pedigree information, a questionnaire administered to all participating family members in relation to sex ratio, handedness, the severity of dyslexia by sex, pre- and perinatal complications, medical complications, years of education and earning ability, and a battery of standardized tests to define the presence or absence of dyslexia. The pattern of inheritance was consistent with the postulated autosomal dominant mode of inheritance and penetrance was found to be > 90 percent. Of 73 individuals determined to have a gene leading to dyslexia, seven were classified as obligate carriers and six as compensated adults who had no current symptoms or diagnostic evidence of dyslexia. The sex ratio (1.06) was not different from the expected ratio of 1.04. Left-handedness, major pre- and perinatal complications, and autoimmune disorders and allergy were not more common in dyslexics than non-dyslexics. The number of years of education and average income were similar in affected and unaffected family members. Compensated adults and obligate carriers were similar to unaffected family members in each of these parameters.