Single-item migraine screening tests, self-reported bothersome headache or stripe pattern hypersensitivity?

BACKGROUND: A simple screening tool may potentially help the migraine diagnosis in a primary care setting. The use of single-item tests, such as stripe pattern hypersensitivity test and self-reported bothersome headache (HA) question, as migraine screening tools have not been fully explored. METHODS: Two hundred and fifty-four subjects (patients and companions) were randomly enrolled from an OB/GYN clinic (men 82, women 172; age 38 ± 14). They were instructed to rate the stripe sensitivity level (0-4) and to report any bothersome HA (yes/no). A brief structured HA interview was conducted to describe the HA characteristics and for migraine diagnosis based on the ICHD-IIIß criteria. RESULTS: In a multivariate model, bothersome HA question and stripe pattern hypersensitivity test were both significantly associated with EM+PM+CM (odds ratio: 24.0, P < 0.01 vs 2.6, P = 0.01) or EM (odds ratio: 16.2, P < 0.01 vs 3.0, P < 0.01). Bothersome HA question had a greater screening power than stripe pattern hypersensitivity for screening EM+PM+CM (area under the ROC curve: 0.84 [95% CI 0.78-0.89] vs 0.62 [95% CI 0.55-0.69]) or EM (area under the ROC curve: 0.80 [95% CI 0.73-0.86] vs 0.64 [95% CI 0.56-0.72]). CONCLUSION: When performed in an OB/GYN clinic, self-reported bothersome HA question seemed more powerful than visual stripe pattern test in screening migraine thus could potentially be used as a single-item screening test.

Graft-versus-host disease after double-unit cord blood transplantation has unique features and an association with engrafting unit-to-recipient HLA match.

Manifestations of and risk factors for graft-versus-host disease (GVHD) after double-unit cord blood transplantation (DCBT) are not firmly established. We evaluated 115 DCBT recipients (median age, 37 years) who underwent transplantation for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor/mycophenolate mofetil immunosuppression. Incidence of day 180 grades II to IV and III to IV acute GVHD (aGVHD) were 53% (95% confidence interval, 44 to 62) and 23% (95% confidence interval, 15 to 31), respectively, with a median onset of 40 days (range, 14 to 169). Eighty percent of patients with grades II to IV aGVHD had gut involvement, and 79% and 85% had day 28 treatment responses to systemic corticosteroids or budesonide, respectively. Of 89 engrafted patients cancer-free at day 100, 54% subsequently had active GVHD, with 79% of those affected having persistent or recurrent aGVHD or overlap syndrome. Late GVHD in the form of classic chronic GVHD was uncommon. Notably, grades III to IV aGVHD incidence was lower if the engrafting unit human leukocyte antigen (HLA)-A, -B, -DRB1 allele match was >4/6 to the recipient (hazard ratio, 0.385; P = .031), whereas engrafting unit infused nucleated cell dose and unit-to-unit HLA match were not significant. GVHD after DCBT was common in our study, predominantly affected the gut, and had a high therapy response, and late GVHD frequently had acute features. Our findings support the consideration of HLA- A,-B,-DRB1 allele donor-recipient (but not unit-unit) HLA match in unit selection, a practice change in the field. Moreover, new prophylaxis strategies that target the gastrointestinal tract are needed.

Prenatal diagnosis of sickle cell anaemia and thalassaemia by analysis of fetal cells in maternal blood.

Currently, amniocentesis, chorionic villus sampling (CVS) and fetal blood sampling are used to obtain fetal cells for genetic diagnosis. These invasive procedures pose a small but not negligible risk for the fetus. Efforts have been directed towards the enrichment of fetal cells, such as erythroblasts, from maternal blood and progress has been made in the diagnosis of some chromosomal disorders and in sex determinations. We now report the detection of point mutations in single gene disorders using this method of prenatal diagnosis by enriching fetal cells from maternal blood by magnetic cell sorting followed by isolation of pure fetal cells by microdissection. In two pregnancies at risk for sickle cell anaemia and beta-thalassaemia, we successfully identified the fetal genotypes. Thus, prenatal diagnosis of single gene disorders by recovering fetal cells from maternal circulation appears to be a feasible approach.

Intravoxel incoherent motion imaging of tumor microenvironment in locally advanced breast cancer.

Diffusion-weighted imaging plays important roles in cancer diagnosis, monitoring, and treatment. Although most applications measure restricted diffusion by tumor cellularity, diffusion-weighted imaging is also sensitive to vascularity through the intravoxel incoherent motion effect. Hypervascularity can confound apparent diffusion coefficient measurements in breast cancer. We acquired multiple b-value diffusion-weighted imaging at 3 T in a cohort of breast cancer patients and performed biexponential intravoxel incoherent motion analysis to extract tissue diffusivity (D(t)), perfusion fraction (f(p)), and pseudodiffusivity (D(p)). Results indicated significant differences between normal fibroglandular tissue and malignant lesions in apparent diffusion coefficient mean (±standard deviation) values (2.44 ± 0.30 vs. 1.34 ± 0.39 µm(2)/msec, P < 0.01) and D(t) (2.36 ± 0.38 vs. 1.15 ± 0.35 µm(2)/msec, P < 0.01). Lesion diffusion-weighted imaging signals demonstrated biexponential character in comparison to monoexponential normal tissue. There is some differentiation of lesion subtypes (invasive ductal carcinoma vs. other malignant lesions) with f(p) (10.5 ± 5.0% vs. 6.9 ± 2.9%, P = 0.06), but less so with D(t) (1.14 ± 0.32 µm(2)/msec vs. 1.18 ± 0.52 µm(2)/msec, P = 0.88) and D(p) (14.9 ± 11.4 µm(2)/msec vs. 16.1 ± 5.7 µm(2)/msec, P = 0.75). Comparison of intravoxel incoherent motion biomarkers with contrast enhancement suggests moderate correlations. These results suggest the potential of intravoxel incoherent motion vascular and cellular biomarkers for initial grading, progression monitoring, or treatment assessment of breast tumors.

Switch from fetal to adult hemoglobin is associated with a change in progenitor cell population.

To examine the switch from fetal to adult hemoglobin at the cellular level, erythroid progenitor cells from newborn infants and adults were cultured in methyl cellulose with erythropoietin. Individual erythroid colonies were labeled with [3H]leucine at various times, and globin synthesis patterns examined by gel electrophoresis and fluorography. The percent gamma- or beta-globin synthesis was determined from the total of gamma + beta, and the percent G gamma from the total of G gamma + A gamma. The nonparametric correlation coefficients of percent G gamma with percent gamma or beta were obtained. Each group of colonies at each time point was examined separately. In colonies from adult blood, the proportion of G gamma-synthesis did not correlate with the proportion of gamma-synthesis. Colonies from newborn blood fell into two groups. Those that developed from relatively mature progenitor cells, and were seen on day 14, showed a strong negative correlation of G gamma with beta-globin synthesis. However, those newborn colonies that developed from immature progenitors, and were seen later in culture (days 17 and 21), showed no correlation of G gamma with beta-synthesis. These findings are compatible with a clonal model for hemoglobin switching. Fetal progenitors, in which G gamma- and beta-syntheses are negatively correlated, are gradually replaced during ontogeny by adult progenitors. The adult progenitors produce more beta (less gamma), and the proportions of G gamma- and gamma- or beta-synthesis are not correlated.

Crystal structure of a NAD-dependent D-glycerate dehydrogenase at 2.4 A resolution.

D-Glycerate dehydrogenase (GDH) catalyzes the NADH-linked reduction of hydroxypyruvate to D-glycerate. GDH is a member of a family of NAD-dependent dehydrogenases that is characterized by a specificity for the D-isomer of the hydroxyacid substrate. The crystal structure of the apoenzyme form of GDH from Hyphomicrobium methylovorum has been determined by the method of isomorphous replacement and refined at 2.4 A resolution using a restrained least-squares method. The crystallographic R-factor is 19.4% for all 24,553 measured reflections between 10.0 and 2.4 A resolution. The GDH molecule is a symmetrical dimer composed of subunits of molecular mass 38,000, and shares significant structural homology with another NAD-dependent enzyme, formate dehydrogenase. The GDH subunit consists of two structurally similar domains that are approximately related to each other by 2-fold symmetry. The domains are separated by a deep cleft that forms the putative NAD and substrate binding sites. One of the domains has been identified as the NAD-binding domain based on its close structural similarity to the NAD-binding domains of other NAD-dependent dehydrogenases. The topology of the second domain is different from that found in the various catalytic domains of other dehydrogenases. A model of a ternary complex of GDH has been built in which putative catalytic residues are identified based on sequence homology between the D-isomer specific dehydrogenases. A structural comparison between GDH and L-lactate dehydrogenase indicates a convergence of active site residues and geometries for these two enzymes. The reactions catalyzed are chemically equivalent but of opposing stereospecificity. A hypothesis is presented to explain how the two enzymes may exploit the same coenzyme stereochemistry and a similar spatial arrangement of catalytic residues to carry out reactions that proceed to opposite enantiomers.

Crystallization and preliminary diffraction studies of hydroxypyruvate reductase (D-glycerate dehydrogenase) from Hyphomicrobium methylovorum.

Two crystal forms of hydroxypyruvate reductase (D-glycerate dehydrogenase) from the methylotrophic bacterium Hyphomicrobium methylovorum have been grown from ammonium sulphate solutions. One crystal form is triclinic, with unit cell parameters a = 60.4 A, b = 60.5 A, c = 66.3 A, alpha = 102.3 degrees, beta = 113.7 degrees and gamma = 102.7 degrees, suggesting that a dimer (monomer M(r) 38,000) occupies the unit cell. This crystal form diffracts to beyond 2.4 A resolution and is suitable for crystallographic structure analysis.

The use of cimetidine for the treatment of pruritus in polycythemia vera.

Thirty-four patients with polycythemia vera complicated by pruritus were treated with 900 mg of cimetidine daily for 30 days and their responses to treatment were evaluated. The conditions of 15 (44%) were improved, with 12 patients stating that pruritus completely disappeared. Nineteen patients either showed no improvement or had increasing symptoms. No toxic effects were reported. The positive responses seen are encouraging and suggest that controlled studies are indicated to further evaluate the effectiveness of H2 antagonists.

A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide.

BACKGROUND: The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide. METHODS: A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial. RESULTS: The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo. CONCLUSIONS: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.

Safety of voriconazole and sirolimus coadministration after allogeneic hematopoietic SCT.

Antifungal prophylaxis with azoles is considered standard in allogeneic hematopoietic SCT (allo-HSCT). Although sirolimus is being used increasingly for the prevention of GVHD, it is a substrate of CYP3A4, which is inhibited by voriconazole, and concurrent administration can lead to significantly increased exposure to sirolimus. We identified 67 patients with hematologic malignancies who underwent allo-HSCT with sirolimus, tacrolimus and low-dose MTX and received concomitant voriconazole prophylaxis from April 2008 to June 2011. All patients underwent a non-myeloablative or reduced-intensity conditioned allo-HSCT. Patients received sirolimus and voriconazole concurrently for a median of 113 days. The median daily dose reduction of sirolimus at the start of coadministration was 90%. The median serum sirolimus trough levels before and at steady state of coadministration were 5.8 ng/mL (range: 0-47.6) and 6.1 ng/mL (range: 1-14.2) (P=0.45), respectively. One patient with an average sirolimus level of 6 ng/mL developed sirolimus-related thrombotic microangiopathy that resolved after sirolimus discontinuation. No sinusoidal obstructive syndrome was reported. Seventeen patients (25%) prematurely discontinued voriconazole because of the adverse events. Only two patients (3%) presented with possible invasive fungal infections at day 100. We demonstrate that sirolimus and voriconazole coadministration with an empiric 90% sirolimus dose reduction and close monitoring of sirolimus trough levels is safe and well tolerated.

Comparison of outcomes at two institutions of patients with ALL receiving ex vivo T-cell-depleted or unmodified allografts.

We compared outcomes of adult patients receiving T-cell-depleted (TCD) hematopoietic SCT (HCT) without additional GVHD prophylaxis at Memorial Sloan Kettering Cancer Center (MSKCC, N=52), with those of patients receiving conventional grafts at MD Anderson Cancer Center (MDACC, N=115) for ALL in CR1 or CR2. Patients received myeloablative conditioning. Thirty-nine patients received anti-thymocyte globulin at MSKCC and 29 at MDACC. Cumulative incidence of grades 2-4 acute (P=0.001, 17.3% vs 42.6% at 100 days) and chronic GVHD (P=0.006, 13.5% vs 33.4% at 3 years) were significantly lower in the TCD group. The non-relapse mortality at day 100, 1 and 3 years was 15.4, 25.0 and 35.9% in the TCD group and 9.6, 23.6 and 28.6% in the unmodified group (P=0.368). There was no difference in relapse (P=0.107, 21.3% vs 35.5% at 3 years), OS (P=0.854, 42.6% vs 43.0% at 3 years) or RFS (P=0.653, 42.8% vs 35.9% at 3 years). In an adjusted model, age >50, cytogenetics and CR status were associated with inferior RFS (hazard ratio (HR)=2.16, P=0.003, HR=1.77, P=0.022, HR=2.47, P<0.001), whereas graft type was NS (HR=0.90, P=0.635). OS and RFS rates are similar in patients undergoing TCD or conventional HCT, but TCD effectively reduces the rate of GVHD.

Antenatal diagnosis of recessive dystrophic epidermolysis bullosa: collagenase expression in cultured fibroblasts as a biochemical marker.

We performed fetoscopy and skin biopsy on a 19-week fetus at risk for recessive dystrophic epidermolysis bullosa (RDEB). Ultrastructural analysis of the tissue revealed dermolytic blister formation in the skin characteristic of the disease. To develop a biochemical test for use in antenatal diagnosis of RDEB, we established skin fibroblast cultures from the 20-week aborted fetus. The collagenase production by fetal RDEB fibroblast cultures was greater than seen in normal fetal fibroblast cultures. The concentration in culture medium from fetal RDEB cultures was 5.42 +/- 0.74 micrograms/ml (mean +/- SE) compared with 2.24 +/- 1.11 micrograms/ml in normal adult control cultures and 2.05 +/- 0.61 micrograms/ml in cultures from patients with other genetic forms of epidermolysis bullosa (p less than 0.025). In contrast, the concentration of collagenase in the fetal RDEB culture medium was not different from that seen in cell cultures from known patients with RDEB (5.34 +/- 1.12 micrograms/ml). Collagenase activity of the fetal RDEB medium was also increased approximately 3.5-fold. These data indicate that enhanced expression of collagenase by fetal RDEB skin fibroblasts can serve as a biochemical adjunct, and possibly an alternative, to morphologic examination of tissue for antenatal diagnosis.

Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols.

The PVSG was organized in 1967 to establish effective diagnostic criteria for polycythemia vera, to study the natural history of the disease and to define the optimal treatment. Although polycythemia vera and the other myeloproliferative diseases are relatively uncommon, the PVSG was able to accumulate well over 1,000 patients with these various disorders and to study them according to a total of 15 different protocols. PVSG-01, a long-term randomized controlled study of phlebotomy alone compared with the myelosuppressive agents, 32P or chlorambucil supplemented by phlebotomy, continues to receive follow-up data on 93% of surviving patients 18 years after initiation of the study. During its lifetime, PVSG has developed a widely accepted and highly effective set of criteria for the specific diagnosis of polycythemia vera as well as useful criteria for the diagnosis of essential thrombocythemia. It has gathered an enormous volume of data on the natural history of the myeloproliferative diseases and in particular on the nature of the prevalent complications, such as thrombotic events and hematologic and nonhematologic malignancies. With respect to the final question, the optimal treatment for polycythemia vera, it is apparent that the expectation of a single optimal therapy that would apply to all patients at all ages and stages of the disease was naive. Nevertheless considerable progress has been made. Moreover, the group has defined more precisely than ever before the nature of the complications of the disease and the association of the risks of specific complications with specific forms of therapy. It thus has made it possible to pose the next series of therapeutic questions that must be addressed in this disorder with a greater degree of sophistication than was previously possible.

Role of opsonins in clinical response to granulocyte transfusion in granulocytopenic patients.

Fifty febrile severely granulocytopenic patients were given four daily transfusions of 2.2 X 10(10) normal donor granulocytes. Twenty-three (46 percent) responded clinically, although both responders and nonresponders were similar in clinical characteristics at the outset. This study examines the relation between serum opsonic activity before initiation of granulocyte administration and clinical response. Opsonic activity to three test organisms (Escherichia coli 286 and ON 2, and Staphylococcus aureus) and to 15 blood stream isolates from 14 patients was measured as serum-dependent uptake of heat-killed 14C-labeled bacteria by normal donor leukopheresis granulocytes in an in vitro assay and compared with results obtained with a standard normal serum in each assay. At a concentration of 8 percent serum, all patient groups were equivalent to standard (90 to 102 percent) for the three test organisms. When rate-limiting concentrations of serum (1 to 2 percent) were employed, opsonic activity remained similar to standard for S. aureus in all patient groups and for the two E. coli strains in responders (82 to 98 percent). In contrast, opsonins for E. coli decreased to 41 to 50 percent of standard in nonresponders (p less than 0.01). When patients with proved infection were separately analyzed, opsonin activity for E. coli 286 and ON 2 was significantly greater in responders than nonresponders (73.6 versus 34.9 percent and 124.8 versus 58.1 percent, respectively for the two strains) (p less than 0.01). Patients with opsonin activity of 50 percent or greater of standard had a greater response rate (73 versus 19 percent and 45 versus 0 percent for the two E. coli strains) (p less than 0.005 and p = 0.08, respectively). Eight of 10 patients with 75 percent or greater of standard for opsonic activity against their own blood stream isolates also responded, whereas zero of four with opsonins less than 75 percent of standard had a favorable outcome. These results indicate that serum opsonic activity may be a determinant of clinical response to granulocyte transfusion in infected granulocytopenic patients and may be predictive of outcome. We conclude that opsonic activity should be assessed in such patients before granulocyte administration and suggest a trial of plasma infusion in opsonin-deficient patients.

Repeated 1 hour electrocardiographic monitoring of survivors of myocardial infarction at 6 month intervals: arrhythmia detection and relation to prognosis.

In a study of the relation between ventricular premature beats and sudden death among 1,739 male of myocardial infarction enrolled in the Health Insurance Plan of Greater New York (HIP), patients underwent 1 hour of electrocardiographic monitoring at a baseline examination. During follow-up periods of up to 5 1/2 years, survivors underwent repeated monitoring at 6 month intervals for a maximum of four monitorings. At each monitoring a constant proportion of the men--25 percent--showed complex ventricular premature beats (runs of two or more, R on T phenomenon, bigeminal or multiform beats) during the hour. In comparison with men free of such arrhythmia, those demonstrating these complex forms in a given hour were three times as likely to show such beats in a subsequent monitoring hour. The mortality risk over 3 1/2 years after each of the four monitoring observations was in all cases elevated among men with complex ventricular premature beats. The risk of sudden death over this period was 6 percent for men without and 13 to 17 percent for men with such complexes. A study of the 1,445 men who underwent monitoring both at baseline examination and 6 months later identified the presence of runs of ventricular premature betas in either observation as a particularly important harbinger of sudden death.

Current assessment of fetal losses as a direct consequence of chorionic villus sampling.

Chorionic villus sampling has been developed as a method of first trimester prenatal diagnosis. In order to evaluate this new approach, accurate risk figures for the procedure must be obtained. This has been difficult for a number of reasons, including establishment of baseline fetal loss rates in the first trimester, procedural "learning curves," and reporting biases. This review will discuss these problems and use data from the chorionic villus sampling program at the University of California, San Francisco, to illustrate difficulties in data interpretation.

Selective termination of multiple gestations.

Twenty-two selective terminations in multiple gestations were performed by a number of different methods. In 17 dichorionic pregnancies there was a successful delivery in surviving singletons or twins. In five monochorionic pregnancies undergoing selective termination there was a successful delivery in only one and a pregnancy loss in the other four. Six of the 18 delivered pregnancies were complicated by premature labor and delivery. Among the several methods used for selective termination, intracardiac potassium chloride injection appears to be the procedure of choice in dichorionic pregnancies.

PIP: Physicians selectively terminated 22 fetuses of multiple gestations between November 1983-August 1987. In the case of same sex twins, after initially identifying 1 fetus by amniocentesis as chromosomally abnormal, fetal blood samples were drawn for karyotyping 48-72 hours before selective termination to identify the affected fetus. These samples were repeated at time of termination to confirm termination of that fetus. Practitioners used ultrasound to perform all procedures, except hysterotomy, and to confirm asystole in the affected fetus and normal heart activity in the remaining fetus (es). 18 patients delivered normal infants, 6 of whom delivered at a gestational age of 37 weeks. Only 1 infant of the 5 monochorionic pregnancies lived. In this case, termination of the sibling fetus occurred via hysterotomy and the physician prescribed oral tocolytics for the mother. Procedures used and their results for dichorionic pregnancies follow. Potassium chloride injections into the heart or into the pericardial region of the chest resulted in a reduced premature labor rate (20%) than did cardiac puncture with air embolization (33.3%). This may be due to decreased intrauterine manipulation and decreased procedure time required to administer the potassium chloride injections. 1 exsanguination was to be performed, but the affected fetus died in the interim between fetal blood sampling and the scheduled day of confirmation. As this study confirmed, poor outcome of remaining normal fetuses is based on premature labor and monochorionic placentation. New techniques add to the many social and ethical considerations of selective termination, especially in those cases where the aborted fetuses are normal.

True trisomy 2 mosaicism in amniocytes and newborn liver associated with multiple system abnormalities.

Among 58,000 amniocenteses completed, our laboratories found one case of true cytogenetic trisomy 2 mosaicism in a fetus with multiple abnormalities. In contrast, 11 fetuses phenotypically normal at birth were found to have true trisomy 2 mosaicism in their chorionic villus cells among the 10,500 fetuses tested by chorionic villus sampling (CVS). In our single abnormal case, amniocentesis performed at 19 weeks after finding an elevated maternal serum AFP found two independent cultures with trisomy 2 karyotypes in 8 of 25 and 7 of 31 amniocytes, respectively. Although oligohydramnios was noted by ultrasound, the mother elected to continue the pregnancy. At 26 weeks the fetus had intrauterine growth retardation (IUGR), hydronephrosis, and cardiac abnormalities. When delivered by Cesarean section at 30 weeks, the infant had multiple anomalies and developed necrotizing enterocolitis and severe cholestasis. At 5 months coronal magnetic resonance imaging (MRI) displayed delayed myelination and abnormal brain morphology. The patient also exhibited significant growth failure and developmental delay. Although chromosomes were normal in blood, skin fibroblasts, and ascites fluid cells, 4 of 100 hepatic biopsy fibroblasts were 47,XY,+2. Molecular analysis excluded uniparental disomy (UPD) of chromosome 2 in the 46,XY cell line. This and other reports of rare phenotypically abnormal trisomy 2 mosaic fetuses identified by karyotyping amniocytes emphasizes the substantially higher fetal risk of abnormal development than when trisomy 2 is found only in chorionic villus cells.

Minute supernumerary marker chromosomes identified in two patients with a related, larger pseudodicentric chromosome.

We describe two cases in which a minute supernumerary marker chromosome (SMC) was identified in addition to a larger pseudodicentric chromosome. Case 1, a phenotypically normal male, had mosaicism for a psu dic(15;15)(q11.2;q11.2) chromosome and a minute SMC. Fluorescence in situ hybridization (FISH) showed that the minute SMC was D15Z1 positive, indicating a chromosome 15 origin. Case 2 was a 22-week fetus with mosaicism for a normal and two abnormal cell lines: one had a psu dic (22;22)(q11.2;q11.2) chromosome containing euchromatin, usually associated with cat eye syndrome; the other a minute SMC. The minute SMC was positive with the D14Z1/D22Z1 alpha-satellite probe, indicating a chromosome 14 or chromosome 22 origin. Deletion of centromeric material was proposed as one mechanism of centromere inactivation in dicentric chromosomes. The origin of these two minute SMC suggests that they were derived from one of the centromeres of the larger pseudodicentric chromosome. These stable minute SMC may be the by-product of a deletion event inactivating one centromere of a dicentric chromosome to generate a pseudodicentric chromosome. Alternatively, the minute SMC may originate from further rearrangement of the larger pseudodicentric chromosome. These cases suggest possible mechanisms for the origin of minute SMC.

Carcinoma of the breast: interrelationships among histopathologic features, estrogen receptor activity, and age of the patient.

Of 398 cases of breast cancer, 350 included data for all of the following: patient age, tumor size, histologic type, presence or absence of lymph node metastasis, nuclear grade of the cancer cells, extent of lymphocytic infiltration around these cells, and estrogen receptor status of the neoplastic tissue. This series is representative of and comparable with those reported in other studies of breast carcinoma. Initial evaluation suggested a relationship of cytologic differentiation and lymphocytic infiltration to estrogen receptor activity. More extensive statistical analyses, however, demonstrated that three factor interrelationships best explain the data concerning nuclear grade, lymphocytic infiltration, and estrogen receptor activity of the tumors in this study. Thus, the results of this investigation serve to warn against inferential judgments based on limited data or restricted evaluation. In addition, the analyses call attention to a significant association between age and lymphocytic infiltration around the tumor cells.