Immunochemical studies on blood groups. XLVII. The I antigen complex--precursors in the A, B, H, Lea, and leb blood group system--hemagglutination-inhibition studies.

A partially purified blood group-like substance obtained from milk showed I activity with 2 of 21 anti-I sera. With these antisera, certain human ovarian cyst substances considered to be precursors of the A, B, H, Le(a), and Le(b) substances also showed I activity comparable to the milk material. Strong I activity could be produced by one-stage periodate oxidation and Smith degradation of human ovarian cyst A and B substances, or of hog mucin A + H substance, or by mild acid hydrolysis of human saliva or ovarian cyst blood group B substance. The two sera indicate that I specificity appears at intermediate stages in the biosynthesis of the A, B, H, Le(a), and Le(a) substances. Anti-I sera differ strikingly in their specificities, indicating substantial heterogeneity of the I determinants.

Mapping human autosomes: evidence supporting assignment of rhesus to the short arm of chromosome No. 1.

Rh-negative erythrocytes were found in the blood of an Rh-positive man suffering from myelofibrosis. Nucleated hemopoietic precursors were also circulating in his blood, and these cells had an abnormal chromosome complement from which identifiable chromosome segments had been deleted. Correlation of the serological and cytogenetic findings, combined with previous data, indicates that the Rhesus blood group locus is on the distal portion of the short arm of chromosome No. 1.

Quantitative brain magnetic resonance imaging in attention-deficit hyperactivity disorder.

BACKGROUND: Anatomic magnetic resonance imaging (MRI) studies of attention-deficit hyperactivity disorder (ADHD) have been limited by small samples or measurement of single brain regions. Since the neuropsychological deficits in ADHD implicate a network linking basal ganglia and frontal regions, 12 subcortical and cortical regions and their symmetries were measured to determine if these structures best distinguished ADHD. METHODS: Anatomic brain MRIs for 57 boys with ADHD and 55 healthy matched controls, aged 5 to 18 years, were obtained using a 1.5-T scanner with contiguous 2-mm sections. Volumetric measures of the cerebrum, caudate nucleus, putamen, globus pallidus, amygdala, hippocampus, temporal lobe, cerebellum; a measure of prefrontal cortex; and related right-left asymmetries were examined along with midsagittal area measures of the cerebellum and corpus callosum. Interrater reliabilities were .82 or greater for all MRI measures. RESULTS: Subjects with ADHD had a 4.7% smaller total cerebral volume (P = .02). Analysis of covariance for total cerebral volume demonstrated a significant loss of normal right > left asymmetry in the caudate (P = .006), smaller right globus pallidus (P = .005), smaller right anterior frontal region (P = .02), smaller cerebellum (P = .05), and reversal of normal lateral ventricular asymmetry (P = .03) in the ADHD group. The normal age-related decrease in caudate volume was not seen, and increases in lateral ventricular volumes were significantly diminished in ADHD. CONCLUSION: This first comprehensive morphometric analysis is consistent with hypothesized dysfunction of right-sided prefrontal-striatal systems in ADHD.

Summary of the clinical significance of blood group alloantibodies.

The knowledge of the potential clinical significance of alloantibodies to blood group antigens is essential for selecting appropriate red blood cell (RBC) products for transfusion. This article provides a summary of clinical and technical aspects of many alloantibodies.

Sensorimotor gating in boys with Tourette's syndrome and ADHD: preliminary results.

Deficits in sensorimotor gating, defined by prepulse inhibition (PPI), have been associated with subcortical dopaminergic overactivity in animal and clinical studies. Utilizing supraorbital nerve electrical stimulation, we produced adequate blink responses and measured decreases in amplitude resulting from electric prestimuli just above sensory threshold. Seven boys comorbid for attention-deficit hyperactivity disorder (ADHD) and a tic disorder had significantly reduced PPI, compared to 14 screened controls and seven boys with ADHD alone. If independently replicated, these results may reflect greater neurologic immaturity in these comorbid subjects. Alternatively, these findings, together with other converging lines of evidence, suggest that deficient pallidal inhibition may be etiologically related to tic and movement disorders.

Quantitative morphology of the caudate nucleus in attention deficit hyperactivity disorder.

OBJECTIVE: Because the caudate nuclei receive inputs from cortical regions implicated in executive functioning and attentional tasks, caudate and total brain volumes were examined in boys with attention deficit hyperactivity disorder (ADHD) and normal comparison subjects. To gain developmental perspective, a wide age range was sampled for both groups. METHOD: The brains of 50 male ADHD patients (aged 6-19) and 48 matched comparison subjects were scanned by magnetic resonance imaging (MRI). Volumetric measures of the head and body of the caudate nucleus were obtained from T1-weighted coronal images. Interrater reliabilities (intraclass correlations) were 0.89 or greater. RESULTS: The normal pattern of slight but significantly greater right caudate volume across all ages was not seen in ADHD. Mean right caudate volume was slightly but significantly smaller in the ADHD patients than in the comparison subjects, while there was no significant difference for the left. Together these facts accounted for the highly significant lack of normal asymmetry in caudate volume in the ADHD boys. Total brain volume was 5% smaller in the ADHD boys, and this was not accounted for by age, height, weight, or IQ. Smaller brain volume in ADHD did not account for the caudate volume or symmetry differences. For the normal boys, caudate volume decreased substantially (13%) and significantly with age, while in ADHD there was no age-related change. CONCLUSIONS: Along with previous MRI findings of low volumes in corpus callosum regions, these results support developmental abnormalities of frontal-striatal circuits in ADHD.

Brain morphometry in Tourette's syndrome: the influence of comorbid attention-deficit/hyperactivity disorder.

Three separate groups, using MRI, have reported basal ganglia abnormalities in Tourette's syndrome (TS). We found similar abnormalities in boys with attention-deficit/hyperactivity disorder (ADHD). Because TS and ADHD are frequently comorbid, we contrasted ADHD boys with and without TS along with control subjects. As expected, we found a significant loss of the normal globus pallidus asymmetry in the patients, but presence or absence of TS did not differentiate the ADHD groups. We conclude that accounting for ADHD comorbidity will be important in future TS morphometric studies.

Sydenham's chorea: magnetic resonance imaging of the basal ganglia.

Analysis of cerebral magnetic resonance images of 24 subjects with Sydenham's chorea and 48 age-, height-, weight-, gender-, and handedness-matched controls demonstrated increased sizes of the caudate, putamen, and globus pallidus in the Sydenham's chorea group. In contrast, neither total cerebral, prefrontal, or midfrontal volumes or thalamic area were increased. These results indicate the selective involvement of the basal ganglia in Sydenham's chorea.

Cerebrospinal fluid homovanillic acid predicts behavioral response to stimulants in 45 boys with attention deficit/hyperactivity disorder.

Central dopaminergic activity has been assumed to play a role in the efficacy of stimulant drugs in attention deficit/hyperactivity disorder (ADHD), although supporting evidence has been scant. This study examined baseline cerebrospinal fluid (CSF) of boys with ADHD in relation to response to three different stimulant drugs. Forty five boys with DSM-III-R-diagnosed ADHD had a lumbar puncture before double-blind trials of methylphenidate, dextroamphetamine, and placebo. Sixteen also received pemoline as part of a subsequent open trial. Stepwise linear regressions determined significant predictors of drug response. Our prior report of a positive significant correlation between CSF homovanillic acid (HVA) and ratings of hyperactivity on placebo was replicated in a new sample of 20 boys. After baseline symptom severity, CSF HVA was the best predictor of stimulant drug response, with significant independent contribution to four of the ten measures of hyperactivity that changed significantly with medication. Higher HVA predicted better drug response, and lower HVA was associated with worsening on some measures. This supports the mediating role of central dopaminergic activity in stimulant drug efficacy in childhood hyperactivity.

Chronic granulomatous disease and McLeod syndrome in a black child.

A 3-year-old black male child with X-linked chronic granulomatous disease and red cells of the rare McLeod phenotype is presented. The red cells showed acanthocytosis and did not react with anti-KL. Similarly the leukocytes were nonreactive with anti-Kx. The Xk and Xg linkage could not be investigated since all members of his family were Xg (a+).

Mapping assignment of the Rh and Duffy blood group genes to chromosome 1.

Blood group genes are inherited in a straightforward manner and their products are readily detectable. Because of this they are utilized over a wide area of scientific endeavor and provide excellent markers for use in gene mapping of the human chromosomes. Both the Rh and Duffy blood group genes have now been localized to the number 1 chromosome. Studies of a patient whose red cells exhibit mosaicism for the Rh blood group indicate that loss of the end of the short arm of chromosome number 1 is associated with loss of an Rh gene complex. The Rh gene can, therefore, be assigned with some precision to this region of the chromosome.

The Kell blood group, Kx antigen, and chronic granulomatous disease.

The Kell blood group has 18 associated red cell antigens. One, named KX, is the product of an X-linked gene and appears to be a precursor in the Kell biosynthetic pathway. Lack of KX on red cells, caused by inheritance of a variant allele at the X-linked locus, results in gross changes in Kell antigenicity, an effect called the McLeod phenotype. Such cells also show striking morphologic changes. Normal phagocytic leukocytes lack Kell antigens but have strong KX. The leukocytes of boys with X-linked chronic granulomatous disease lack KX antigen and have defective bactericidal function. The fundamental defect in chronic granulomatous disease appears to be failure to inherit the X-linked gene that determines KX synthesis. The enzymatic and functional disorders of the leukocytes, and the structural changes in the red cells, are consequences that follow.

Erythrocyte morphology in genetic defects of the Rh and Kell blood group systems.

Absence of KX antigen and of normal expression of the Kell system antigens is associated with bizarre red blood cell morphology when observed by either light or scanning electron microscopy. Numerous acanthocytes and dacryocytes have been observed in the peripheral blood smear of an apparently healthy individual with McLeod-phenotype blood, in a male patient with type II chronic granulomatous disease who had a shortened 51Cr red blood cell survival time, and in a minor population of the red blood cells of his carrier mother.

DSM-IV stereotypic movement disorder: persistence of stereotypies of infancy in intellectually normal adolescents and adults.

BACKGROUND: As part of a broader series of studies on unwanted repetitive behaviors, DSM-IV stereotypic movement disorder (SMD) was examined in an intellectually normal population. Repetitive nonfunctional behaviors, or stereotypies, are expressed during early normal development but have not been described in adults without severe psychiatric or intellectual impairment. METHOD: Lifetime and current psychiatric Axis I diagnoses were determined by structured and clinical interviews in subjects who responded to a newspaper advertisement that specifically mentioned rocking and head banging. RESULTS: Of 52 potential subjects who were screened by telephone, 32 had been previously diagnosed with an Axis I psychiatric disorder, which presumably accounted for the repetitive behavior, or were otherwise excluded. Of 20 who were interviewed in person, 12 met DSM-IV criteria for SMD; rocking or thumb sucking was present in 8 of these 12. Four of 8 rockers had a first-degree relative who had a lifetime history of a similar repetitive behavior. A lifetime history of an affective or anxiety disorder was found for 11 of 12 SMD subjects. CONCLUSION: DSM-IV stereotypic movement disorder can be diagnosed in intellectually normal individuals. Although sampling bias was probable, prominent stereotypies in individuals meeting the DSM-IV criteria for stereotypic movement disorder, which are narrower than the DSM-III-R criteria for stereotypy/habit disorder, seem likely to include rocking and thumb sucking. The likelihood of persistence of these behaviors, which are developmentally appropriate in infancy, may be enhanced by comorbidity with anxiety or affective disorders.

Comparison of glycyrrhetinic acid isoforms and carbenoxolone as inhibitors of EDHF-type relaxations mediated via gap junctions.

The vascular actions of the lipophilic gap junction inhibitors 18alpha-glycyrrhetinic acid (18alpha-GA), 18beta-glycyrrhetinic acid (18beta-GA) and the water-soluble hemisuccinate derivative of 18beta-GA, carbenoxolone, were investigated in preconstricted rings of rabbit superior mesenteric artery. EDHF-type relaxations to acetylcholine (ACh), observed in the presence of 300 microM NG-nitro-L-arginine methyl ester (L-NAME) and 10 microM indomethacin, were attenuated by preincubation with 18alpha-GA (to 100 microM), 18A-GA (to 10 microM) or carbenoxolone (to 300 microM) in a concentration-dependent fashion. By contrast, none of these agents affected responses to sodium nitroprusside, an exogeneous source of NO, and relaxations evoked by ACh in the absence of L-NAME were attenuated by only approximately 20%. 18alpha-GA exerted no direct effect on vessel tone, whereas 18beta-GA and carbenoxolone caused relaxations which were maximal at approximately 1 and approximately 10 mM, respectively. Relaxations to carbenoxolone were attenuated by endothelial denudation and by incubation with L-NAME, whereas those to 18beta-GA were unaffected. In conclusion, all three agents inhibit EDHF-type relaxations evoked by ACh, providing further evidence for the involvement of gap junctions in such responses. Unlike 18alpha-GA, carbenoxolone and 18beta-GA possess intrinsic vasorelaxant activity which in the case of carbenoxolone involves functional enhancement of NO activity in addition to direct effects on vascular smooth muscle.

To freeze or not to freeze. A comparison of methods for the handling of breast biopsies with no palpable abnormality.

Recently there have been several editorials suggesting that breast biopsies with small or nonpalpable lesions should not be subjected to frozen section examination. In this study, the approach of routinely performing frozen sections on all breast biopsies was compared to the recommended approach of performing frozen sections only on cases with gross lesions < 1.0 cm. From July 1, 1992 through June 30, 1993, there were 444 breast biopsies submitted. Nearly all of these (98%) had frozen sections performed. Among these cases, there were 14 false-negative frozen section diagnoses equating to a frozen section sensitivity of 84%, and a frozen section false-negative rate of 3.3%. From July 1, 1994 through June 30, 1995, there were 601 breast biopsies submitted. Of these cases, 310 contained a gross lesion > 1.0 cm and were subjected to frozen section examination. The remaining 291 cases contained either no distinct lesion or a gross lesion < 1.0 cm. These cases were not frozen. Among the 310 cases that were frozen, there were 3 false-negative frozen section diagnoses equating to a frozen section sensitivity of 96%, and a frozen section false-negative rate of 1.0%. These findings indicate that careful gross examination combined with selective freezing of only cases containing a gross lesion > 1.0 cm improves frozen section accuracy. This study provides statistical support for previous recommendations that frozen section examination should be limited to cases with distinct gross lesions > 1.0 cm.

Free erythrocyte protoporphyrin (FEP) I. Normal values for adults and evaluation of the hematofluorometer.

Since the early 1970s, measurement of free erythrocyte protoporphyrin (FEP) (by microextraction or by hematofluorometer) has been widely used to screen for lead poisoning and to evaluate microcytic red blood cell (RBC) disorders in children. However, published information on normal values for FEP, performance of the hematofluorometer, and usefulness of FEP in classifying microcytic RBC disorders in adults is scant. In an adult population with normal hematocrit and MCV and normal values for serum ferritin, blood lead level, and serum bilirubin, we obtained normal hematofluorometer FEP levels of less than 30 micrograms/dL for men, and less than 40 micrograms/dL levels for women. We have evaluated a hematofluorometer against a standard microextraction procedure and feel that the hematofluorometer is superior for clinical laboratories if elevated FEPs are confirmed by retesting with washed RBC. In the second part of this paper we demonstrate the usefulness of the FEP in classifying microcytic RBC disorders in adults.

Free erythrocyte protoporphyrin (FEP) II. The FEP test is clinically useful in classifying microcytic RBC disorders in adults.

Microcytic red blood cells (RBC) are commonly encountered in clinical medicine and are caused by disorders of heme synthesis [usually iron deficiency anemia (IDA) or anemia of chronic disease (ACD)] or disorders of globin synthesis (usually thalassemia syndromes or HbE). Using the clinical history and standard laboratory tests (hematocrit, per cent saturation of transferrin (% sat), serum ferritin, Hb electrophoresis, HBA2, and HbF) we classified 198 adults with microcytic RBC as follows: 48 IDA, 11 probable IDA, 11 iron-deficient erythropoiesis without anemia, 13 ACD, 42 alpha-thalassemia trait, 35 probable alpha-thalassemia trait, 20 beta-thalassemia trait, and 15 unclassified. In addition, we demonstrated that the FEP test reliably (83-90% of the time, depending on FEP methodology) classifies microcytic RBC states into disorders of heme synthesis vs. disorders of globin synthesis. Because of reliability and ease of measurement, we recommend the hematofluorometer FEP as the first step in the clinical laboratory evaluation of microcytic RBC disorders in both adults and children.

A half a node or a whole node: a comparison of methods for submitting lymph nodes.

For many neoplasms, the status of regional lymph nodes is a critical prognostic factor with direct therapeutic implications. Despite the importance of lymph node status, there is no consensus on whether lymph nodes from node dissections should be submitted in their entirety. To study this issue, for a 4-month period, all lymph nodes from node dissections were submitted in their entirety. The larger nodes were submitted systematically to determine whether the additional tissue blocks contained metastases that were not identified in the initial tissue block. We also analyzed the cost of submitting, processing, and interpreting these extra blocks. During the study period, 149 patients underwent lymph node dissections, yielding a total of 2,915 lymph nodes. Submitting the larger nodes in their entirety resulted in processing 808 additional tissue blocks that demonstrated a total of 9 additional metastases in 7 patients. In 2 of these patients, the additional metastases changed the stage of the neoplasm and may have contributed to an alteration in therapy. By using median salary figures, the estimated cost for submitting, processing, and interpreting the additional blocks was $5,935.62. Whether the additional positive nodes justify this cost should be determined by individual pathology practices.

Hematologic evaluation of employees with leukopenia. Naval Weapons Center, China Lake, California.

Evaluation of 86 employees with a history of leukopenia at the Naval Weapons Center (NWC), China Lake, California, was done by exposure questionnaires, medical histories, physical examinations, peripheral blood smear, and bone marrow evaluations, including morphologic examination, stem cell culture, and cytogenetics. Forty-eight subjects were found to be leukopenic at the time of the study, and two subjects were found to have hairy cell leukemia. All subjects had positive exposure histories and were healthy at the time of the study. Review of peripheral smears identified the patients with marrow abnormalities. Bone marrow cultures revealed several patients with possible marrow suppression. Chromosome studies were not diagnostic. Five-year follow-up health questionnaires revealed no significant health problems; the two workers with hairy cell leukemia are alive and fully functional. Leukopenia in itself does not appear to be a risk factor for poor health, and it is unknown whether or not it may be a useful screening tool to identify workers at risk in toxic environments. Careful evaluation of blood cell counts and peripheral smears should be sufficient to identify people with potential marrow abnormalities.