The mystery of the etiology of schizophrenia has been refractory to the analytical methods provided thus far by the biological and social sciences. Some 50 per cent of the beds in public mental hospitals in the USA are occupied by patients diagnosed as schizophrenics-more than a quarter of a million individuals. Empirical drug treatments now bring symptomatic relief to many of these individuals but no rational therapy founded on etiological knowledge has yet appeared with preventative or curative powers. Strong views exist about the significance of the role to be accorded genetic factors in the etiology of the disorder, ranging from minimal to sufficient. So long as we limit ourselves to a simple Mendelian framework and construe schizophrenia as a homogeneous disease entity, we do not have the "workable concept of heredity" called for by Bleulerl in 1911 when he coined the term; it has been known all along that the classical ratios are not found among the relatives of schizophrenic probands.2 Arguing by analogy with advances in mental deficiency, some subtypes, individually of rare occurrence, might fit simple models; multiple use of the latter strategy would still leave most schizophrenias unexplained, paralleling the mental retardation situation, and so far no Mendelian forms have been identified. At the risk of being labeled Procrustean, ideas about the genotypic homogeneity of the schizophrenias could be preserved by the reasonable use of the concept of incomplete manifestation.' To invoke continued mutation as the cause of a disorder with a lifetime morbid risk of eight per thousand puts a strain on current beliefs about the mutation rate for human loci of about 10-5. Evidence for the popular view that environmental hardships are sufficient to account for the etiology of schizophrenia stems from the observation4 that the prevalence of the condition is eight times higher in the lower social classes than in the upper. The direction of causality implied by the latter finding has been undermined by data in the United Kingdom5 and the USA6 showing that when schizophrenics are classified according to their fathers' social statuses, all classes are represented proportionately, thus suggesting that premorbid symptoms of schizophrenia lead to downward social drift. Further evidence against the crucial etiological importance of a poor environment comes from the fact that only some 35 per cent of the offspring of two schizophrenic parents become schizophrenic,' and Heston's8 report of a risk for schizophrenia of 16.6 per cent in children separated from their schizophrenic mothers within three days of birth. The data above together with the frequently documented excess risk for schizophrenia in the twins9 and other close relatives'0 of index cases make genetic arguments seem most plausible in accounting for the observations, but the nature of such arguments must require some form other than the traditional ones.One of the possibilities not given sufficient attention involves positing a large proportion of cases as being...

Schizophrenia research embodies a microcosm of the vexing problems that confront the behavioural sciences, but particularly those disciplines concerned with psychopathology. We are ignorant of the means to prevent schizophrenia because we continue to be ignorant about its aetiology. Despite recognizable descriptions of the syndrome in ancient Hindu treatises (c. 1400 b.c.) and 76 years after its designation as dementia praecox by Kraepelin (1896), we are still grappling with such basic issues as when and how to diagnose Eugen Bleuler's (1911) ‘group of schizophrenias' (cf. Katz, Cole, and Barton, 1968). Despite brilliant advances in molecular biology, neurochemistry, and brain-behaviour phenomena generally, we cannot pinpoint any necessary biological defect in all or most schizophrenics. Despite selfless expenditures of time and energy by gifted psychotherapists and sophisticated social science efforts, we cannot specify any necessary life experience, either at the level of the family or of a culture, common to all or most schizophrenics. While there is obvious merit in casting the problem in an interactionist framework, aetiology still defies an easy solution because we must then isolate what element(s) in the genotype interact with what element(s) in the internal and/or external environment (as well as when and how) to produce the phenotype we recognize as a schizophrenic one.

Objective To comprehensively characterize androgens and androgen precursors in classic 21-hydroxylase deficiency (21OHD) and to gain insight to the mechanisms of their formation. Design Serum samples were obtained from 38 patients (19 men) with classic 21OHD, age 3-59, and 38 sex- and age-matched controls; 3 patients with 11β-hydroxylase deficiency; 4 patients with adrenal insufficiency; and 16 patients (8 men) undergoing adrenal vein sampling. Paraffin-embedded normal (n=5) and 21OHD adrenal tissue (n=3) was used for immunohistochemical studies. Methods We measured 11 steroids in all sera using liquid chromatography-tandem mass spectrometry. Immunofluroescence localized 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) and cytochrome b5 (CYB5A) within the normal and 21OHD adrenals. Results Four 11-oxygenated 19-carbon (11oxC19) steroids were significantly higher in male and female 21OHD patients than in controls: 11β-hydroxyandrostenedione, 11-ketoandrostenedione 11β-hydroxytestosterone, and 11-ketotestosterone (3-4-fold, p< 0.0001). For 21OHD patients, testosterone and 11-ketotestosterone were positively correlated in females, but inversely correlated in males. All 11oxC19 steroids were higher in adrenal vein than in inferior vena cava samples from men and women and rose with cosyntropin stimulation. Only trace amounts of 11oxC19 steroids were found in sera from patients with 11β-hydroxylase deficiency and adrenal insufficiency, confirming their adrenal origin. HSD3B2 and CYB5A immunoreactivities were sharply segregated in the normal adrenal glands, whereas areas of overlapping expression were identified in the 21OHD adrenals. Conclusions All four 11oxC19 steroids are elevated in both men and women with classic 21OHD. Our data suggest that 11oxC19 steroids are specific biomarkers of adrenal-derived androgen excess.

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The adhesion and locomotion of mouse peripheral lymph node lymphocytes on 2-D protein-coated substrata and in 3-D matrices were compared . Lymphocytes did not adhere to, or migrate on, 2-D substrata such as serum-or fibronectin-coated glass. They did attach to and migrate in hydrated 3-D collagen lattices . When the Collagen was dehydrated to form a 2-D surface, lymphocyte attachment to it was reduced . We propose that lymphocytes, which are poorly adhesive, are able to attach to and migrate in 3-D matrices by a nonadhesive mechanism such as the extension and expansion of pseudopodia through gaps in the matrix, which could provide purchase for movement in the absence of discrete intermolecular adhesions. This was supported by studies using serum-coated micropore filters, since lymphocytes attached to and migrated into filters with pore sizes large enough (3 or 8 ,um) to allow pseudopod penetration but did not attach to filters made of an identical material (cellulose esters) but of narrow pore size (0 .22 or 0.45 Am) . Cinematographic studies of lymphocyte locomotion in collagen gels were also consistent with the above hypothesis, since lymphocytes showed a more variable morphology than is typically seen on plane surfaces, with formation of many small pseudopodia expanded to give a marked constriction between the cell and the pseudopod . These extensions often remained fixed with respect to the environment as the lymphocyte moved away from or past them . This suggests that the pseudopodia were inserted into gaps in the gel matrix and acted as anchorage points for locomotion .Though lymphocytes are motile, they adhere and move poorly on protein-coated glass or plastic under conditions in which fibroblasts, macrophages, and neutrophils adhere and move well . In consequence, generalizations about cell locomotion obtained from studies of the latter cells do not fit the more puzzling locomotor behavior of lymphocytes, a knowledge of which would help us to understand how lymphocytes recirculate, cooperate with each other and with other cell types, and infiltrate and migrate through extravascular sites .Cells moving on 2-D surfaces must make close enough contact with the substratum to provide traction for locomotion . In fibroblasts, it has been postulated that locomotion takes place because the cells form areas of contact named focal adhesions (1) where there is cross-bridging of the space between cell and substratum with an intermediate protein, fibronectin (27), which allows traction to be generated . Focal adhesions are not seen in faster-moving cells such as neutrophil leukocytes, but these cells do form rapidly shifting areas of close contact while moving on protein-coated substrata (3) .