Improvement of coronary artery endothelial dysfunction with lipid-lowering therapy: heterogeneity of segmental response and correlation with plasma-oxidized low density lipoprotein.

OBJECTIVES: This study assessed coronary artery endothelial function in patients with hypercholesterolemia before and after lipid lowering, using quantitative angiography to examine the acetylcholine (Ach) response along the entire analyzable vessel. BACKGROUND: Lipid lowering reverses endothelial dysfunction, but whether improvement occurs only in some segments and not others has not been established. Statistical correlation of improvement with specific lipid moieties remains undefined. METHODS: Quantitative angiography was performed after Ach (10(-6), 10(-5), 10(-4) M) in 29 patients with coronary atherosclerosis before and 18 +/- 5.2 months after lipid-lowering treatment (statins, bile sequestrant resins). Standard lipid moieties and markers of oxidized low density lipoprotein (LDL) (immunoglobulin G and M autoantibody titers to malondialdehyde-LDL, E06 epitope) were measured serially. RESULTS: Pre-treatment of the vessel diameters at control and with 10(-6)M, 10(-5) M and 10(-4) M Ach were 2.108 +/- 0.085, 2.086 +/- 0.087, 2.069 +/- 0.084 and 1.963 +/- 0.097 mm (M +/- SE), respectively, and increased at follow-up to 2.139 +/- 0.094, 2.119 +/- 0.086, 2.127 +/- 0.084 and 2.080 +/- 0.085 mm (p < 0.0001). Improvement in the most constricted and modest declination in the more dilated segments were observed. Change in the E06 and Apolipoprotein A-1 titers correlated with improved vasomotion (p = 0.027 and 0.005, respectively). The pre- and post-treatment levels of the E06 epitope, as well as the post-treatment IgM autoantibody titer to MDA-low density lipoprotein, also correlated (p < 0.028, < 0.001 and p < 0.004, respectively). CONCLUSIONS: Drug treatment reverses endothelial dysfunction, but the effect is heterogeneous. Most coronary segments show enhancement, while others show declination of dilation, underscoring the importance of assessing the entire analyzable artery. Improvement in vasomotion correlates most significantly with markers of plasma-oxidized low-density lipoprotein.

Doxycycline prophylaxis for shigellosis.

The efficacy of oral doxycycline, 100 mg/d for 14 days, in reducing the incidence of shigellosis in newcomers to an area hyperendemic for the disease was examined in a double-blind, placebo-controlled trial. Of 107 entrants, 100 completed the study; 50 received the drug and 50 received a placebo. Diarrheal disease and associated symptoms were monitored for 8 weeks. Starting on the 3rd day of the trial, an outbreak was observed, and Shigella flexneri type 2a was isolated from 6 subjects. Eight of the subjects in the treatment group had diarrhea (16%) compared with 37 in the placebo group (74%), providing a 79% protection rate. There was no significant difference in the occurrence of accompanying symptoms between the subjects suffering from diarrhea in both groups, but the duration of disease was shorter in the treatment group. Serologic study of the outbreak showed no significant difference in antibody response to S flexneri between the treatment (14 of 43) and placebo (18 of 39) groups. Doxycycline prophylaxis apparently is effective and probably does not prevent subclinical infection.

Regulation of myocardial contractility: Insights from transgenic mice.

Myocardial contraction occurs when calcium (Ca(2+)) is released from the sarcoplasmic reticulum, binding troponin C and allowing actin and myosin to cross link. Ca(2+) release and uptake is closely regulated by G protein-coupled ß-adrenergic receptors through the action of the second messenger cAMP. An increase in cAMP level leads to phosphorylation of key regulatory proteins affecting intracellular Ca(2+) homeostasis. The ß-adrenergic receptors themselves are regulated by a set of specific kinases, termed the G-protein-coupled receptor kinases (GRKs). The study of this complex system in vivo has recently been advanced by the development of transgenic and gene-targeted (knockout) mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac hemodynamics is an extremely powerful approach to the study of myocardial contractility and its regulation. This review focuses on several recent transgenic mouse models that have increased our understanding of the regulation of cardiac contractility.

Autoimmune diseases other than lupus share common anti-DNA idiotypes.

We examined the sera of 170 patients with various autoimmune diseases other than systemic lupus erythematosus (SLE) for the presence of an anti-DNA antibody idiotype termed 16/6 and known to occur with high frequency in sera of patients with SLE. The idiotype was found in 6/15 sera from patients with polymyositis (49%), 3/18 with multiple sclerosis (17%), 3/18 with primary Sjögren's syndrome (18%), 9/40 with autoimmune thyroid diseases (23%), 2/35 with myasthenia gravis (6%), and 3/42 patients with rheumatoid arthritis (7%). The idiotype was not detected among 12 patients with scleroderma or 77 normal controls. The presence of the 16/6 idiotype was associated with the presence of another anti-DNA idiotype termed 134-Id. Serum samples were also tested for activity against DNA, various synthetic polynucleotides, and cardiolipin. The serum activity against these antigens was found to be polyspecific, though overlap in reaction against the various polynucleotides was not absolute. The 16/6 idiotype is thought to be coded by a germline gene. The presence of this idiotype in various autoimmune diseases points to a pathophysiologic link between the diseases.

Loss of Y chromosome. An age-related event or a cytogenetic marker of a malignant clone?

Cytogenetic analysis of bone marrow cells performed at the time of diagnosis of ALL in an 80-year-old male patient revealed two unrelated abnormal clones. One included the 9;22 translocation (Philadelphia chromosome) as the sole aberration and the second was missing the Y chromosome. The significance of this finding in the light of the role of -Y clone in malignancy is discussed.

Therapy-related myelodysplastic syndrome. Two cytogenetically unrelated abnormal clones in a patient with multiple myeloma.

A multiple myeloma patient presented for cytogenetic analysis at diagnosis of secondary MDS, which followed cytotoxic treatment including melphalan. Two abnormal unrelated clones were detected, one of them had 5q-, 7q- with clonal evolution of an additional aberration, t(12;13); in the second clone there was a translocation between the two homologues of chromosome 1 as the only aberration. We suggest that the clone with 5q- and 7q- represented the secondary MDS cells, whereas the abnormal clone with t(1;1) represented the plasmablasts of the multiple myeloma.

Predominant 45,X,--Y karyotype in donor cells after allogeneic BMT: cytogenetic and molecular analysis.

We describe two women; one (patient 1) with the diagnosis of acute myeloblastic leukemia (AML), the second (patient 2) with myelodysplastic syndrome (MDS). Both patients underwent allogeneic bone marrow transplantation (BMT), from their HLA-matched brothers. Cytogenetic analysis after the BMT revealed a chromosomal mosaicism in both patients, with the karyotype 46,XX/45,X with no sign of the Y chromosome. The origin of the clone with monosomy X was determined using cytogenetic analysis including heteromorphism and segregation of DNA polymorphic markers. The results led us to the conclusion that in both patients the origin of the 45,X clone was that of the donors. Patient 1 had MDS-like syndrome after the BMT and was stabilized in the chimeric state; to date she is doing well. Patient II also had MDS. However, in her case, it was her primary disease. The graft in patient II was rejected and she died 6 months after BMT.

dup(10q) lacking alpha-satellite DNA in bone marrow cells of a patient with acute myeloid leukemia.

A marker chromosome was identified in leukemic cells on an AML patient. The G-banding pattern resembled on i(10q), but its centromeric position was not clear; in some cells it had a telocentric shape, in others a metacentric or acentric shape. The origin of the marker chromosome was confirmed by FISH, using chromosome-10-specific painting. To determine the centromeric position, C-banding and alpha-satellite probes were applied in FISH, and none of them gave a positive signal. Despite the absence of the centromeric alpha-satellite sequences and the constricted feature of the centromere, the essential centromeric activity was retained in this chromosome, namely, the separation of sister chromatids in anaphase.

Reversed BCR/ABL rearrangement detected by FISH in Philadelphia negative chronic myelocytic leukemia.

We investigated leukemic cells from a patient with chronic myelocytic leukemia (CML) and a normal 46,XX karyotype. Molecular studies revealed rearrangement of the M-bcr region and formation of BCR/ABL fusion mRNA with b3a2 configuration. Fluorescence in situ hybridization (FISH) using the abl probe showed signal on both chromosomes 9 band q34, while the bcr probe hybridized to one chromosome 22 and to one chromosome 9. In this case, as in three other cases recently described (Hagemeijer et al. and Nachava et al.), the bcr/abl rearrangement is shown to be on 9q34, instead of the usual location on 22q11.

Clinical implications of fluorescence in situ hybridization analysis in 13 chronic myeloid leukemia cases: Ph-negative and variant Ph-positive.

Thirteen chronic myeloid leukemia (CML) patients, 10 with variant Philadelphia (Ph) translocations and 3 Ph negative cases, were analyzed by fluorescence in situ hybridization (FISH) with the use of BCR and ABL cosmid probes and a chromosome 22 painting probe. In the variant Ph translocations, the BCR-ABL fusion gene was located on the Ph chromosome; in 1 CML Ph-negative patient, the BCR-ABL fusion gene was located on the Ph chromosome; and, in 2 patients, it was located on chromosome 9. The chromosome 22 painting probe was detected on the third-party chromosome of the variant translocation, and in none of the variant translocations was there any detectable signal on chromosome 9. In CML patients with clonal evolution of a simple Ph, a signal of the chromosome 22 painting probe was detected on the der(9) of the Ph translocation. It was concluded that the variant Ph translocations evolved simultaneously in a three-way rearrangement. The clinical parameters of the 13 patients were similar to those of a large group of CML patients with a simple Ph translocation. It is suggested that, to determine the prognosis of CML patients with a complex karyotype, FISH analysis with a chromosome 22 painting probe be performed.

A novel translocation (1;2)(p34;p21-22) in acute myelomonoblastic leukemia.

A novel and as yet unrecorded translocation, (1;2)(p34;p21-22), detected in a patient with acute myeloid leukemia (AML) is reported. The leukemia--in this case, AML-M4--showed a rapidly progressive fatal course despite an early transient response to aggressive chemotherapy. In this patient, the leukemic cells showed a novel balanced translocation, (1;2)(p34;p21-22), in most of the metaphases at the time of diagnosis and during subsequent relapse. Interferon-inducible double-stranded RNA-dependent protein kinase (ds RNA-PK) is located in the chromosome region, 2p21-22, that was involved in the translocation in this case. The possible role of ds RNA-PK in leukemogenesis is briefly mentioned.

De novo acute myeloid leukemia with near-pentaploidy: diploid karyotype and lymphoblastic phenotype at relapse.

Hyperploidy is a rare finding in leukemias, with isolated cases of tetraploidy reported in acute myeloblastic and acute lymphblastic leukemias. We report the first case of acute myeloid leukemia with near-pentaploidy (5 n+/-) which was present in 100% of metaphases at diagnosis. By light microscopy, the leukemic blasts were exceptionally large and coarsely granulated. Following one cycle of induction chemotherapy, complete morphologic and cytogenetic remission was documented. Four weeks later relapse occured, at which time the karyotype was diploid and the morphological and immunophenotypic characteristics were those of a lymphoid leukemia. However, the presence of three aberrant chromosomes (5q+, 6q+ and 20q+) confirmed that this was clonal evolution of the original myeloid leukemia. To the best of our knowledge, this case represents the first report of near-pentaloidy in de novo, pretreatment human leukemia.

Multiple chromosomal abnormalities in fulminant anaplastic myeloma.

We describe a 58-year-old woman with anaplastic multiple myeloma and multiple chromosomal abnormalities. Her karyotype showed extreme hyperploidy with 77 chromosomes. Some of the aberrations were typical of multiple myeloma (+3, +5, +15, +19, +21, t(11;14)(q13;q32)), others were characteristic of the aggressive anaplastic myeloma (+8), t(11;14)(q13;q32), while three chromosomal abnormalities (t(11;20)(p11;q13); t(4;7)(q31;q11); and t(14;20)(q24;q13)) have not been, to the best of our knowledge, described previously in the literature. The fulminant course of the disease confirms the poor prognosis of multiple karyotypic abnormalities in myeloma.

Study of a family with Cerebrotendinous Xanthomatosis. No HLA linkage, but an informative recombination between HLA-B and Bf.

A large family with three children affected with the autosomal recessive disease of Cerebrotendinous Xanthomatosis (CTX) was studied for class I (HLA-A,B,C) and class II antigens (HLA-DR,D,SB), properdin factor B and glyoxalase. The extensive typing revealed an informative cross-over between HLA-B and Bf, indicating that Bf is located centromeric to the HLA-B locus and segregated in this family with HLA-D/DR. The parents in this family were first cousins and their parents were also first cousins. Three of their four haplotypes share B14, BfS, DR1, Dx and SB4 and may be identical by descent. The three affected children carried among them all four parental haplotypes, indicating that close linkage of the CTX locus to HLA is unlikely.

Donor lymphocyte infusions to displace residual host hematopoietic cells after allogeneic bone marrow transplantation for beta-thalassemia major.

PURPOSE: Donor lymphocyte infusion (DLI) was used to reverse relapse after allogeneic bone marrow transplantation (BMT) in a patient with beta-thalassemia major. PATIENTS AND METHODS: The patient with unstable mixed chimerism after BMT was treated with graded increments of donor lymphocytes (10(5) T cells/kg to 5 x 10(7) T cells/kg) to displace residual hematopoietic host cells. RESULTS: DLI resulted in complete donor-derived reconstitution of the hematopoietic compartment. The patient developed mild graft-versus-host disease (GVHD) that could be controlled by steroid treatment. CONCLUSIONS: This case report shows that DLI can effectively eradicate host stem cells in mixed chimeras after BMT in nonmalignant hematopoietic diseases.

Does hysteroscopy improve upon the sensitivity of dilatation and curettage in the diagnosis of endometrial hyperplasia or carcinoma?

OBJECTIVE: The objective of this study was to determine whether hysteroscopy improved upon the diagnostic sensitivity of dilatation and curettage (D+C) in the detection of endometrial hyperplasia and carcinoma. METHODS: A retrospective chart review was conducted of all patients undergoing hysteroscopy/D+C for abnormal uterine bleeding between 1991 and 1995. Hysteroscopic impressions and D+C diagnoses were compared. RESULTS: Three hundred seventy-three patients were included in the study. Of the 61 patients with D+C demonstrating hyperplasia, the hysteroscopic impression was hyperplasia in 32 (52%). Of the 10 patients with D+C demonstrating carcinoma, the hysteroscopic impression was hyperplasia in 8 (80%) and carcinoma in 2 (20%). Two additional cases of carcinoma were diagnosed within 6 months of hysteroscopy/D+C, and both had been missed on both hysteroscopy and D+C. Of 204 patients with a normal hysteroscopic impression, 23 (11%) had hyperplasia on D+C. CONCLUSIONS: Hysteroscopy did not improve upon the sensitivity of D+C in the detection of endometrial hyperplasia or carcinoma.