Multipoint genome-wide linkage scan for nonword repetition in a multigenerational family further supports chromosome 13q as a locus for verbal trait disorders.

Verbal trait disorders encompass a wide range of conditions and are marked by deficits in five domains that impair a person's ability to communicate: speech, language, reading, spelling, and writing. Nonword repetition is a robust endophenotype for verbal trait disorders that is sensitive to cognitive processes critical to verbal development, including auditory processing, phonological working memory, and motor planning and programming. In the present study, we present a six-generation extended pedigree with a history of verbal trait disorders. Using genome-wide multipoint variance component linkage analysis of nonword repetition, we identified a region spanning chromosome 13q14-q21 with LOD = 4.45 between 52 and 55 cM, spanning approximately 5.5 Mb on chromosome 13. This region overlaps with SLI3, a locus implicated in reading disability in families with a history of specific language impairment. Our study of a large multigenerational family with verbal trait disorders further implicates the SLI3 region in verbal trait disorders. Future studies will further refine the specific causal genetic factors in this locus on chromosome 13q that contribute to language traits.

Cranial neuroendoscopy: novel applications and next frontiers.

Neuroendoscopy is an ever-evolving frontier in neurosurgery and its use has spanned decades with safe and efficacious treatment in a variety of cranial procedures. There are areas of technology that are broadening the cranial use of the endoscope. Here we discuss the foundations of cranial neuroendoscopy in the areas of cerebrospinal fluid diversion and tumor biopsy and discuss the recent advancements in the areas of craniosynostosis, endonasal surgery, ventriculo-cisternal approaches, brain parenchymal surgery and skull base surgery. We highlight the ongoing evolution of neuroendoscopic technology and consider the potential future applications that will help to revolutionize the current standards in endoscopy and its use inn neurosurgical practice.

Human CASK/LIN-2 binds syndecan-2 and protein 4.1 and localizes to the basolateral membrane of epithelial cells.

In Caenorhabditis elegans, mutations in the lin-2 gene inactivate the LET-23 receptor tyrosine kinase/Ras/MAP kinase pathway required for vulval cell differentiation. One function of LIN-2 is to localize LET-23 to the basal membrane domain of vulval precursor cells. LIN-2 belongs to the membrane-associated guanylate kinase family of proteins. We have cloned and characterized the human homolog of LIN-2, termed hCASK, and Northern and Western blot analyses reveal that it is ubiquitously expressed. Indirect immunofluorescence localizes CASK to distinct lateral and/or basal plasma membrane domains in different epithelial cell types. We detect in a yeast two-hybrid screen that the PDZ domain of hCASK binds to the heparan sulfate proteoglycan syndecan-2. This interaction is confirmed using in vitro binding assays and immunofluorescent colocalization. Furthermore, we demonstrate that hCASK binds the actin-binding protein 4.1. Syndecans are known to bind extracellular matrix, and to form coreceptor complexes with receptor tyrosine kinases. We speculate that CASK mediates a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with protein 4.1. Like other membrane-associated guanylate kinases, its multidomain structure enables it to act as a scaffold at the membrane, potentially recruiting multiple proteins and coordinating signal transduction.

Direct interaction of CASK/LIN-2 and syndecan heparan sulfate proteoglycan and their overlapping distribution in neuronal synapses.

CASK, the rat homolog of a gene (LIN-2) required for vulval differentiation in Caenorhabditis elegans, is expressed in mammalian brain, but its function in neurons is unknown. CASK is distributed in a punctate somatodendritic pattern in neurons. By immunogold EM, CASK protein is concentrated in synapses, but is also present at nonsynaptic membranes and in intracellular compartments. This immunolocalization is consistent with biochemical studies showing the presence of CASK in soluble and synaptosomal membrane fractions and its enrichment in postsynaptic density fractions of rat brain. By yeast two-hybrid screening, a specific interaction was identified between the PDZ domain of CASK and the COOH terminal tail of syndecan-2, a cell surface heparan sulfate proteoglycan (HSPG). The interaction was confirmed by coimmunoprecipitation from heterologous cells. In brain, syndecan-2 localizes specifically at synaptic junctions where it shows overlapping distribution with CASK, consistent with an interaction between these proteins in synapses. Cell surface HSPGs can bind to extracellular matrix proteins, and are required for the action of various heparin-binding polypeptide growth/differentiation factors. The synaptic localization of CASK and syndecan suggests a potential role for these proteins in adhesion and signaling at neuronal synapses.

Control of pain motivation by cognitive dissonance.

Responses by humans to painful electric shocks are significantly modified at subjective, behavioral, and physiological levels by verbal manipulations of degree of choice and justification for further exposure to the aversive stimuli. Pain perception, learning, and galvanic skin resistance are altered under these conditions of "cognitive dissonance," as they are by reductions in voltage intensity.

Ultrastructural analysis of a murine model of congenital hydrocephalus produced by overexpression of transforming growth factor-beta1 in the central nervous system.

The purpose of this study was to elucidate using transmission electron microscopy (TEM) the ultrastructural changes that occur within the cortical gray matter of a novel reproducible model of congenital hydrocephalus in mice created to overexpress the cytokine transforming growth factor-beta1 (TGF-beta1) in the central nervous system. Brain tissue was obtained from mice from a colony engineered to overexpress TGF-beta1 at two days postpartum and compared to a wild-type aged-matched control. This tissue was fixed using a solution containing 1.25% paraformaldehyde and 1.25% glutaraldehyde in phosphate buffer at least 3-4 h and then cut into 40-50 microm sections. Randomly selected thin sections were stained with uranyl acetate and lead citrate, and then analyzed using a JEOL-100CX or 1200EX transmission electron microscope at accelerating voltage 80 kV. Dramatic neuronal and glial pathology was observed throughout the cortical neuropil in TGF-beta1 mice. The most striking change in the hydrocephalic mice was severe edema with extracellular fluid, possibly due to cerebrospinal fluid (CSF) penetration into the cortex. In addition, severe disruption of the cytoplasmic matrix was seen throughout the cortex, with damage to cellular organelles and particularly severe damage to mitochondria. Our results suggest that congenital hydrocephalus may be associated with significant damage to cortical tissue.

Iron chelation therapy in sickle cell disease.

Iron chelation therapy with deferoxamine enhances iron excretion and removes excessive tissue iron in regularly transfused patients with sickle cell disease. Long-term studies of deferoxamine in other hemoglobinopathies demonstrate that regular chelation therapy also reduces iron-related organ damage and mortality. Careful design of chelation regimens and attention to compliance are critical elements of successful therapy. The role of new chelators in sickle cell disease is currently under Investigation.

Initial clinical experience with a new pasteurized monoclonal antibody purified factor VIIIC.

Heat treatment of lyophilized factor VIII and factor IX concentrates has been found to eliminate HIV virus infectivity in plasma-derived products. Pasteurization of factor VIII in solution has recently been used to reduce the risk of hepatitis transmission in concentrates prepared by standard fractionation methods. This report presents early experience with factor VIIIC prepared by monoclonal antibody immunoaffinity chromatography following pasteurization of the factor VIIIC/von Willebrand factor complex (Monoclate-P). Twelve patients were treated in three centers with Monoclate-P. Recovery and survival of factor VIII clotting activity were determined and patients were closely monitored for infusion safety. The mean half-life was 14.2 +/- 5.0 while recovery in predicted plasma volume was 72 +/- 12% corresponding to a response of 1.99 +/- 0.66 U/dL for every U/kg administered. These values are very similar to those found for Monoclate in previous studies indicating that pasteurized factor VIIIC purified by immunoaffinity chromatography retains satisfactory pharmacokinetic properties with an added margin of viral safety.

Small-cell undifferentiated carcinoma of the colon. A clinicopathological study of five cases and their association with colonic adenomas.

Colonic small-cell undifferentiated carcinoma (SCUC) is an extremely aggressive neoplasm. We describe five patients with colonic SCUC and review five additional, well-documented cases. The longest known duration of survival is 14 months and all patients with follow-up of this duration have died of disease. Regional lymph nodes are invariably involved at the time of diagnosis and when distant metastases were present, the liver was always affected. Four of our cases of SCUC arose in association with colonic adenomas and in two of these the SCUC component was confined to the superficial submucosa. Yet, both produced regional metastases and one had massive hepatic involvement. Ultrastructurally, colonic SCUC exhibits divergent, predominantly neuroendocrine differentiation. The ultrastructural features and association with colonic adenomas suggest an endodermal rather than neuroectodermal derivation.

Reassessment of the microcytic anemia of lead poisoning.

Hematologic abnormalities in childhood lead poisoning may be due, in part, to the presence of other disorders, such as iron deficiency or thalassemia minor. In order to reassess increased lead burden as a cause of microcytic anemia, we studied 58 children with class III or IV lead poisoning, normal iron stores, and no inherited hemoglobinopathy. Anemia occurred in 12% and microcytosis in 21% of these children. The combination of anemia and microcytosis was found in only one of 58 patients (2%). When only children with class IV lead poisoning were studied, the occurrence of microcytosis increased to 46%. However, the combination of microcytosis and anemia was found in only one of these 13 more severely affected patients. Microcytic anemia was similarly uncommon in children with either blood lead concentration greater than or equal to 50 microgram/100 ml. These data indicate that microcytosis and anemia occur much less commonly than previously reported in childhood lead poisoning uncomplicated by other hematologic disorders.

Preoperative history and coagulation screening in children undergoing tonsillectomy.

To evaluate the usefulness of preoperative screening for coagulation disorders in children, we prospectively studied laboratory and bleeding histories in 1603 children undergoing tonsillectomy. All patients had preoperative laboratory screening with a complete blood count, prothrombin time, activated partial thromboplastin time, and bleeding time. Persistent abnormalities on repeat testing 1 week later were investigated further by a standardized schema. A subset of 129 patients, including all those who bled perioperatively or had laboratory abnormalities, completed a standard historical questionnaire. Thirteen patients had persistent laboratory abnormalities diagnostic of lupus inhibitor (5), non-lupus inhibitor (6), mild hemophilia A (1), and vonWillebrand disease (1). Two patients had persistently prolonged activated partial thromboplastin times of undefined cause. Fourteen patients (10.8%) interviewed reported positive bleeding histories. Of these, five, including the patient with vonWillebrand disease, had persistent laboratory abnormalities. History alone failed to detect the patient with hemophilia A. For patients with inhibitors or prolonged activated partial thromboplastin times of unknown cause, surgery was delayed until the coagulation abnormalities resolved, and there was no perioperative bleeding. The patient with vonWillebrand disease had severe postoperative bleeding despite treatment with cryoprecipitate. In predicting perioperative bleeding, history and laboratory screening had a high specificity but a very low positive predictive value due to poor sensitivity and a low prevalence of bleeding. Some children with bleeding disorders may be identified first during routine preoperative coagulation testing, and replacement therapy or delay or cancellation of surgery may reduce or prevent perioperative hemorrhage. However, the large number of false positive laboratory tests and bleeding histories, coupled with the relative rarity of inherited and acquired coagulopathies, raises doubts about the overall value of routine screening.

The changing profile of homozygous beta-thalassemia: demography, ethnicity, and age distribution of current North American patients and changes in two decades.

BACKGROUND: The age of patients with homozygous beta-thalassemia is increasing because of better treatment and decreased births. A countering influence is immigration of ethnic groups with a high prevalence of thalassemia. METHODS: a questionnaire sent to 48 North American centers requested information about current patients with homozygous beta-thalassemia: age, clinical severity, and ethnicity. An 83% response was obtained. Twelve reference hospitals that participated in similar surveys in 1972 and 1984 were included. RESULTS: Five hundred eighteen patients with homozygous beta-thalassemia represent most North American patients. Four hundred forty-three (86%) of these had transfusion-dependent thalassemia major (TM); 75 (14%) had thalassemia intermedia (TI). Sixty-two percent were of Greek and Italian ancestry. There were approximately equal numbers of patients with TM in 5-year intervals between 0 and 25 years of age. Thereafter, the numbers of patients fell sharply. The mean age (+/- SD) of the patients with TM was 16.1 +/- 9.2 years. Striking differences were seen in Italian and Greek patients compared with those of other ancestries. Sixty-six percent of the 271 Italian and Greek patients with TM were older than 16 years of age, whereas 77% of the 172 patients of other ethnic groups with TM were younger than 15 years of age. The mean age of the 75 patients with TI was greater than that of the patients with TM. Seventy-three percent of African-American patients had TI, compared with 0% of Southeastern Asian patients. Comparisons of patients with TM from the 12 reference hospitals for two decades show increasing mean ages of TM patients (1973, 11.4 +/- 6.7 years; 1985, 14/2 +/- 7.3 years; and 1993, 16.1 +/- 9.2 years). CONCLUSIONS: There are probably only 750 to 1000 patients with homozygous beta-thalassemia in North America. Only about 15 to 20 new cases are diagnosed each year. The increasing mean age and age distribution indicate that modern therapies are effective, but immigration of non-Mediterranean ethnic groups with thalassemia has resulted in more, younger patients. TM is increasingly becoming a disease of young adults.

HemoCue system for hemoglobin measurement. Evaluation in anemic and nonanemic children.

The HemoCue system measures the hemoglobin level in undiluted capillary or venous blood after conversion of hemoglobin to azide methemoglobin. The authors have compared this system, designed primarily for office use, with the Coulter S-Plus III in a study of 200 than or equal to 105 g/L (10.5 g/dL) and 47 children with sickle cell disease. The HemoCue system yielded values similar to those of the Coulter S-Plus III for nonanemic patients (mean difference 3.5 g/L [0.35 g/dL]; limits of agreement -6.7-13.7 g/L [-0.67-1.37 g/dL]) as well as for anemic patients (mean difference 3.3 g/L [0.33 g/dL]; limits of agreement -4.7-11.3 g/L [-0.47-1.13 g/dL]) and patients with sickling disorders (mean difference 4.2 g/L [0.42 g/dL]; limits of agreement -5.6-14.0 g/L [-0.56-1.40 g/dL]). Discrepancies of more than 10 g/L (1.0 g/dL) occurred in 13 of 200 measurements (6%); the HemoCue system gave the lower reading in all instances. The HemoCue system is comparable to standard laboratory techniques for measurement of hemoglobin level in normal and anemic children and is well suited for use in the outpatient care of healthy pediatric patients as well as those with hematologic disorders.

Diversity of organ site involvement among malignant lymphomas of mucosa-associated tissues.

Fifteen cases of low-grade B-cell lymphoma involving unusual extranodal sites have been studied in comparison to cases reported or observed arising in typical mucosa-associated lymphoid tissues. In every case, histopathologic features conformed to those characteristic for lymphomas of mucosa-associated lymphoid tissues, including the production of lymphoepithelial complexes. Immunoglobulin light chain restriction was demonstrated by immunocytochemistry in 14 cases. Sites of involvement included the breast (6), skin (5), kidney (1), prostate (1), gallbladder (1), and uterine cervix (1). In three cases there was simultaneous or previous lymphoma of mucosa-associated lymphoid tissues identified in a more common mucosal site. It is concluded that the unifying concept of lymphomas of mucosa-associated lymphoid tissues applies to extranodal organs less commonly associated with mucosa-associated lymphoid tissues, as well as to those mucosal organ sites described in earlier series.

Chiari I malformations: assessment with phase-contrast velocity MR.

PURPOSE: To assess movement of the medulla, tonsils, and upper cervical cord as well as that of the posterior fossa cerebrospinal fluid pathways in both normal subjects and those with Chiari I malformations. METHODS: Nine healthy volunteers and eight patients with Chiari I malformations were examined with phase-contrast cine MR. With a region-of-interest cursor, the directions and intensities of the brain and cerebrospinal fluid were assessed and intensity-versus-time graphs generated. RESULTS: Cerebrospinal fluid flow patterns of the patients with Chiari I malformations were normal except for absence of valleculla flow. In addition, increased velocities (10 times normal) of the tonsils of all patients with Chiari I malformations together with posterior movement of the medulla (rather than the expected anterior movement seen in volunteers) occurred. CONCLUSIONS: Increased velocities of the tonsils may be the result of the carotid systolic pulse being delivered to a structure (the tonsil) without the normal surrounding cerebrospinal fluid, resulting in impact of the tonsils in the confined foramen magnum and a consequent caudocranial recoil. An alternative explanation would include the Bernoulli effect caused by the confined location of the tonsils. There may be a decrease in the peak tonsillar velocities after surgery.

The mermaid malformation: cloacal exstrophy and occult spinal dysraphism.

Five infants with cloacal exstrophy underwent neurological evaluation and radiographic examination of the caudal spine shortly after birth. Each was found to have occult spinal dysraphism. Four had terminal myelocystoceles, and one had a lipomyelomeningocele. Pathological anatomy was confirmed during surgery for the release of the tethered spinal cords. The striking association between cloacal exstrophy and occult spinal dysraphism suggests a common developmental defect in the caudal pole of the embryo. A hypothesis is offered to explain this association. Terminal myelocystocele and lipomyelomeningocele appear to be part of a continuum of lesions associated with skin-covered spina bifida.

Cowden disease and Lhermitte-Duclos disease: characterization of a new phakomatosis.

OBJECTIVE: Lhermitte-Duclos disease, or dysplastic gangliocytoma of the cerebellum, is an unusual hamartomatous lesion that can cause progressive mass effects in the posterior fossa. Cowden disease, or multiple hamartoma-neoplasia syndrome, is a rare autosomal dominant disorder characterized by mucocutaneous hamartomas and high incidences of systemic malignancies. We recently treated a patient with manifestations of both Lhermitte-Duclos disease and Cowden disease, and we were intrigued by the occurrence of these two rare disorders in the same patient. The purpose of the present study was to examine the nature of the association between Lhermitte-Duclos disease and Cowden disease. METHODS: The records for all patients who had been diagnosed at our institution as having Lhermitte-Duclos disease were reviewed, to determine whether these patients also exhibited manifestations of Cowden disease. Data were obtained from multiple sources, including patient interviews, correspondence with treating physicians, and chart reviews. RESULTS: During the past 40 years, five patients were diagnosed at Case Western Reserve University as having Lhermitte-Duclos disease. All five patients exhibited manifestations of Cowden disease. Before this review, Cowden disease had not been diagnosed for three of the patients. In our most recent case, the diagnoses of both disorders were established preoperatively. That patient was observed to have a deletion in the critical portion of Exon 5 of the PTEN gene, the gene associated with Cowden disease. CONCLUSION: Inclusion of Lhermitte-Duclos disease in the Cowden disease spectrum suggests that Cowden disease is a true phakomatosis, with hamartomas arising from cutaneous and neural ectoderm. Recent advances in molecular genetics may help to refine the current descriptive classification of the phakomatoses. The association between Lhermitte-Duclos disease and Cowden disease has been under-recognized and under-reported. Recognition of this association has direct clinical relevance, because diligent long-term follow-up monitoring of individuals with Lhermitte-Duclos disease and Cowden disease may lead to the early detection of malignancy.

Magnetic resonance imaging of Kernohan's notch.

Compression of the cerebral peduncle against the tentorial incisura contralateral to a supratentorial mass, the so-called Kernohan's notch, can be a cause of false localizing motor signs. The authors present a case of Kernohan's notch secondary to a traumatic extradural hematoma. The patient developed an oculomotor palsy and a dense motor deficit ipsilateral to the extra-axial hematoma. Magnetic resonance imaging in the postoperative period clearly showed the midbrain lesion. The motor deficit and 3rd nerve palsy subsequently resolved.

Intraspinal localization of the somatosensory evoked potential.

Somatosensory evoked potentials (SEPs) are used widely for monitoring neurophysiological function in experimental spinal injury. Yet the spinal pathways for SEP conduction remain unclear. Consequently, we sought to define specific changes in the SEP after interruption of selected spinal pathways. We activated cortical SEPs with sciatic nerve stimulation in 11 anesthetized (25 mg of pentobarbital per kg) cats after a multilevel thoracic laminectomy. The most consistent wave from component was an initial positivity (IP) at a 17- to 19-ms onset latency. We then used a Cavitron ultrasonic surgical aspirator to interrupt specific spinal pathways. A unilateral dorsal column lesion abolished the ipsilateral IP, but did not affect conduction in the contralateral column. Bilateral dorsal column lesions obliterated the IP, but sometimes left some longer latency components. Interruption of all but the ventral columns abolished the SEPs. When we interrupted all spinal pathways but the dorsal columns, an intact IP remained. In fact, a distinct IP was conducted through a single dorsal column after the division of all other spinal cord pathways. We concluded that, in the barbiturate-anesthetized cat: (a) the most consistent SEP wave form is an initial positivity at a 17- to 19-ms onset latency, (b) the integrity of the dorsal columns is both necessary and sufficient to conduct a normal-appearing IP component of the SEP, (c) the lateral columns may carry some longer latency component of the SEP, (d) the ventral columns carry no component of the SEP, and (e) bilateral recording may be useful for detecting asymmetry of injury.

Gonadotropin-secreting pineal teratoma causing precocious puberty.

A case of precocious puberty in a 7-year-old boy with a tumor of the pineal region is reported. Human chorionic gonadotropin levels were elevated in the serum and cerebrospinal fluid. Endocrinological evaluation of the hypothalamic-pituitary axis demonstrated a normal prepubertal response. The tumor was resected and proved to be an immature teratoma. Human chorionic gonadotropin levels were markedly elevated in the tumor cyst fluid. Sexual precocity regressed and human chorionic gonadotropin levels in the serum and cerebrospinal fluid fell to normal after surgery, suggesting that the precocious puberty was secondary to ectopic human chorionic gonadotropin production by the pineal teratoma.