Abnormal infant neurodevelopment predicts schizophrenia spectrum disorders.

OBJECTIVE: The aim of this study was to detect infants who carry a schizophrenic genotype and study the development of schizophrenia spectrum disorders (SZSD) from birth. INTRODUCTION: In the 1940s, Bender described uneven maturation in childhood schizophrenics and in 1952 found this in the infant histories of 6 schizophrenic children. METHODS: We tested a possible index for defective neural integration in infants termed "pandysmaturation" (PDM). This required retarded cranial growth plus retarded and erratic gross motor development on a single exam. Twelve offspring of hospitalized schizophrenic mothers and 12 infants in a "Well Baby Clinic," were examined 10 times between birth and 2 years of age. Psychiatric interviews and psychological testing were done at 10, 15, and 22 years of age, plus follow-up at 27-35 years of age. RESULTS: Six infants had PDM at 2, 6, or 13 months of age. Five individuals have been blindly diagnosed (by KSK) as having lifetime SZSD; all 5 had PDM before 8 months. Chi-square one-tailed tests confirmed the predictions: (1) PDM was related to subsequent SZSD (chi(2) = 11.43; p < 0.0005); (2) schizophrenic mothers had more infants with PDM than nonschizophrenic mothers (chi(2) = 3.28; p < 0.05); and (3) schizophrenic mothers had more SZSD offspring than nonschizophrenic mothers (chi(2) = 6.39; p < 0.0125). DISCUSSION: These first behavioral observations of aberrant neurodevelopment in pre- SZSD infants support the evidence of early neurodevelopmental disorder seen in studies of brain pathology in SZSD adults.

Longitudinal course of schizophrenia spectrum symptoms in offspring of psychiatrically hospitalized mothers.

OBJECTIVE: The aim of this study was to describe schizophrenia spectrum symptoms (SZSD) in children and adolescents with schizotypal personality disorder (SPD) as adults. INTRODUCTION: There are no descriptive studies of children who develop into adults with SPD. METHOD: Twelve offspring of psychiatrically hospitalized mothers (6 mothers with schizophrenia), were compared with 11 socioeconomic status (SES)-matched offspring of control, non-ill mothers. Offspring were evaluated clinically and psychometrically between infancy and 2, 10, 15 years of age, and adulthood. Adult Axis I and II diagnoses were made blind to infant and parent status. RESULTS: Six hospitalized mothers were diagnosed with schizophrenia, 6 with other severe psychopathology. Offspring with SZSD more likely had schizophrenic mothers, and childhood deteriorating IQs, symptoms of social isolation, constricted affect, digressive speech, suspiciousness, and excessive social anxiety. Global assessment scores in SZSD offspring were lower in childhood and adulthood than comparison offspring. DISCUSSION: Children with SZSD met currently accepted criteria for schizotypy; 3 by 10 years of age, and 2 by 19 years of age. Differential diagnosis is discussed. An appendix of case histories is presented.

Cellular pharmacology of D-d4FC, a nucleoside analogue active against drug-resistant HIV.

The backbone of effective highly active antiretroviral therapy regimens for the treatment of HIV infections currently contains at least two nucleosides. Among the features that influence the potency of each component of a regimen and the overall efficacy of the combination are the cellular uptake and bioconversion of nucleoside analogues to their active triphosphate form, and the extent of possible interactions in these steps that might occur when more than one nucleoside is used in a regimen. D-d4FC (Reverset), a new cytidine analogue with the ability to inhibit many nucleoside-resistant viral variants, was examined for these parameters. In phytohemaglutinin-stimulated human peripheral blood mononuclear cells, D-d4FC was taken up in a rapid (8 h to 50% maximal value), saturable (plateau above 10 microM parent nucleoside concentration) process, resulting in levels of D-d4FC triphosphate that should provide potent antiviral activity against a variety of virus genotypes. Based on measurement of antiviral effects in cell culture, additive and in some cases, synergistic interactions were observed with protease inhibitors, non-nucleoside reverse transcriptase inhibitors or other nucleosides, including cytidine analogues.

Prospective study of pandysmaturation and adult mental disorder in high-risk and normal-risk offspring.

More than 50 years ago, Fish postulated that a special form of early abnormal neurodevelopment, "pandysmaturation", defined a priori as constituting retarded cranial development in the first year of life, combined with delay in early motor milestone attainment, was related to genetic risk for schizophrenia, and was associated with schizophrenia-spectrum disorders in young adulthood. Fish confirmed this in a very small sample. We retested Fish's postulation in a larger prospective study. Pandysmaturation was blindly investigated through medical records and prospective researcher and maternal observations, studying 75 "high-risk" offspring of women with a history of schizophrenia or affective psychosis and 91 "normal-risk" offspring. Subjects were studied prospectively from mother's pregnancy to 22 years of age, at which time the offspring were independently assessed for schizophrenia-spectrum and affective disorders. Pandysmaturation (n = 13, with 10 "definite" and 3 "probable" degrees) was significantly related to genetic risk for schizophrenia (Odds Ratio 4.9, p = 0.02) but not to genetic risk for affective disorders (OR 1.2, p = 0.81). Pandysmaturation was significantly associated with schizophrenia-spectrum (OR 6.2, p = 0.02), but not affective (OR 0.9, p = 0.90), disorders in young adulthood. Pandysmaturation was more strongly associated than was retarded cranial development, motor milestone delay, or social/cognitive milestone delay by itself. Pandysmaturation has efficacy as an early life risk-indicator of schizophrenia-spectrum disorder in young adulthood at least in subjects at genetic risk, strengthening the evidence for a generally genetic-based neurodevelopmental model of schizophrenia-spectrum (as contrasted with affective) disorders. Pandysmaturation is a risk-indicator for future schizophrenia-spectrum disorder, for potential use in scientific studies and clinical practice.

Expression, purification, and kinetic characterization of full-length human fibroblast activation protein.

Human fibroblast activation protein (FAP), an integral membrane serine protease, was produced in insect cells as a hexa-His-tagged protein using a recombinant baculovirus expression system. Two isoforms of FAP, glycosylated and nonglycosylated, were identified by Western blotting using an anti-His-tag antibody and separated by lectin chromatography. The glycosylated FAP was purified to near homogeneity using immobilized metal affinity chromatography and was shown to have both postprolyl dipeptidyl peptidase and postgelatinase activities. In contrast, the nonglycosylated isoform demonstrated no detectable gelatinase activity by either zymography or a fluorescence-based gelatinase activity assay. The kinetic parameters of the dipeptidyl peptidase activity for glycosylated FAP were determined using dipeptide Ala-Pro-7-amino-trifluoromethyl-coumarin as the substrate. The k(cat) is 2.0 s(-1) and k(cat)/K(m) is 1.0 x 10(4) M(-1) s(-1) at pH 8.5. The pH dependence of k(cat) reveals two ionization groups with pK(a1) of 7.0 and pK(a2) of 11.0. The pH profile of k(cat)/K(m) yields similar results with pK(a1) 6.2 and pK(a2) 11.0. The neutral pK(a1) is associated with His at the active site. The basic pK(a2) might be contributed from an ionization group that is not involved directly in catalysis, instead associated with the stability of the active site structure.

Comparative studies of active site-ligand interactions among various recombinant constructs of human beta-amyloid precursor protein cleaving enzyme.

Amyloid precursor protein (APP) cleaving enzyme (BACE) is the enzyme responsible for beta-site cleavage of APP, leading to the formation of the amyloid-beta peptide that is thought to be pathogenic in Alzheimer's disease (AD). Hence, BACE is an attractive pharmacological target, and numerous research groups have begun searching for potent and selective inhibitors of this enzyme as a potential mechanism for therapeutic intervention in AD. The mature enzyme is composed of a globular catalytic domain that is N-linked glycosylated in mammalian cells, a single transmembrane helix that anchors the enzyme to an intracellular membrane, and a short C-terminal domain that extends outside the phospholipid bilayer of the membrane. Here we have compared the substrate and active site-directed inhibitor binding properties of several recombinant constructs of human BACE. The constructs studied here address the importance of catalytic domain glycosylation state, inclusion of domains other than the catalytic domain, and incorporation into a membrane bilayer on the interactions of the enzyme active site with peptidic ligands. We find no significant differences in ligand binding properties among these various constructs. These data demonstrate that the nonglycosylated, soluble catalytic domain of BACE faithfully reflects the ligand binding properties of the full-length mature enzyme in its natural membrane environment. Thus, the use of the nonglycosylated, soluble catalytic domain of BACE is appropriate for studies aimed at understanding the determinants of ligand recognition by the enzyme active site.