Acute erythroleukemia: evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and prognosis

We evaluated 48 archival cases of acute erythroleukemia and divided them into 3 groups: M6a, corresponding to the traditional French-American-British M6 category; M6b, which is pure erythroleukemia; and M6c, in which myeloblasts and pronormoblasts each account for more than 30% of cells by the French-American-British exclusion criteria. No significant differences were noted among the subtypes for ratio of males to females; age; or exposure to toxins, alcohol, or both. However, compared with the patients in the M6a group, patients in the M6b and M6c groups demonstrated a statistically significant increase in cytogenetic aberrations, proliferation markers (proliferating cell nuclear antigen and Ki67), and ringed (type III) sideroblasts. Marked survival differences were noted between the M6a (30.1 +/- 29.5 months) and M6b (3.15 +/- 4.2 months) groups, with patients in the M6c group demonstrating an intermediate prognosis (10.5 +/- 12.7 months). Chemotherapeutic regimens induced remission in all treated patients in the M6a and M6c groups but did not appear to affect the M6b group. However, the patients in the M6c group remained in remission for a significantly shorter period of time than did patients in the M6a group. Overall, survival appeared to depend on the ratio of pronormoblasts to myeloblasts at diagnosis and demonstrated a rapid decline with increasing pronormoblast and decreasing myeloblast counts. We must, therefore, devise chemotherapeutic regimens that target both blastic components of this disease.     

Effects of annealing at high pressure on structure and mechanical properties of Al87Ni7Gd6 metallic glass

The effects of annealing and annealing with a superimposed pressure of 940 MPa on the primary crystallization behaviour of α-Al and the resulting micro-hardness have been studied for as-quenched Al₈₇Ni₇Gd₆ metallic glass. Isothermal annealing experiments were conducted for 30 min at 188 °C, 191 °C, and 205 °C in silicone oil maintained either at atmospheric pressure (i.e. 0.1 MPa) or at 940 MPa. XRD analyses detected the evolution of structure with annealing at 0.1 MPa, while specimens annealed with 940 MPa pressure exhibited sharper diffraction peaks than those annealed at 0.1 MPa. DSC measurements were conducted on the as-received amorphous ribbons as well as ribbons annealed at different temperatures at either 0.1. MPa or with 940 MPa superimposed pressure. Specimens annealed with 940 MPa pressure exhibited higher onset temperatures (i.e. T_x1) and temperatures for the first exothermic peak (i.e. T_p1) for primary crystallization. TEM measurements revealed an increase in the volume fraction of α-Al with increases in annealing temperature, while micro-hardness measurements revealed an increase in hardness with increasing amounts of α-Al. Specimens annealed with 940 MPa pressure exhibited further increases in both the volume fraction of α-Al and resulting micro-hardness.     

Mosaic organization of DNA nucleotides

Long-range power-law correlations have been reported recently for DNA sequences containing noncoding regions. We address the question of whether such correlations may be a trivial consequence of the known mosaic structure ("patchiness") of DNA. We analyze two classes of controls consisting of patchy nucleotide sequences generated by different algorithms--one without and one with long-range power-law correlations. Although both types of sequences are highly heterogenous, they are quantitatively distinguishable by an alternative fluctuation analysis method that differentiates local patchiness from long-range correlations. Application of this analysis to selected DNA sequences demonstrates that patchiness is not sufficient to account for long-range correlation properties.     

Operative management of Haglund's deformity in the nonathlete: a retrospective study

Haglund's deformity, or "pump bump," is a common cause of posterior heel pain. Management of the condition usually consists of nonoperative therapy. This study presents a retrospective study of 65 cases (53 patients), with symptomatic Haglund's deformity in nonathletes (13 male and 40 female), who presented during a 4-year period (1989-1994). Sixty-five percent (39 heels) of these patients failed to respond to nonoperative therapy for an average of 62 weeks, (range, 4-260 weeks). This group of patients went on to operative treatment. Surgical management consisted of excision of the posterior calcaneal tuberosity through a medial longitudinal incision with debridement, reattachment of the Achilles tendon using bone anchors, and 4 weeks of postoperative immobilization. Thirty-nine patients (74%) were contacted for follow-up. The average follow-up period for these patients was 155 weeks, (range, 92-335 weeks). There were 50% excellent results, 47% good results, 3% fair results (1 patient), and no poor results. The Maryland Foot Score for operated heels was an average of 67/100 preoperative and an average of 92/100 postoperative. On unoperated heels the score was an average of 81/100 at first evaluation and an average of 86/100 at final evaluation. Complications included one recurrence of painful prominence, one wound infection, and one incisional neuroma. The outcome of these cases demonstrated that in those patients who fail nonoperative treatment, surgical treatment of Haglund's deformity produces a predictably good surgical result when performed using the technique described.     

Acute vasoconstriction after subarachnoid hemorrhage

OBJECTIVE: Decreased cerebral blood flow (CBF) and cerebral ischemia occurring immediately after subarachnoid hemorrhage (SAH) may be caused by acute microvascular constriction. However, CBF can also be influenced by changes in intracranial pressure (ICP) and cerebral perfusion pressure (CPP). The goal of these experiments was to assess the significance of acute vasoconstriction after SAH and its relationship to changes in CBF, ICP, CPP, and extracellular glutamate concentrations. METHODS: Three experiments were performed using the endovascular filament technique to produce SAH. In the first experiment, CBF, ICP, and CPP were measured for 60 minutes after SAH (n = 21) and were correlated with the 24-hour mortality rate. In the second experiment, rats undergoing SAH (n = 23) or a sham procedure (n = 7) were perfused 60 minutes after SAH for measurement of the circumference and wall thickness of the internal carotid and anterior cerebral arteries and correlation with CBF, ICP, and CPP. In the third experiment (n = 11), extracellular glutamate concentrations determined by hippocampal and cortical microdialysis and high performance liquid chromatography were correlated with physiological changes. RESULTS: CBF reductions to less than 40% of baseline for 60 minutes after SAH predicted 24-hour mortality with 100% accuracy and were used to define "lethal" SAH. In contrast, ICP and CPP 60 minutes after SAH were not correlated with the mortality rate. The vascular circumference was significantly smaller in lethal than in sublethal SAH or sham-operated rats (P < 0.001). Vessel measurements were correlated with both CBF and hemorrhage size (P < 0.01). Extracellular glutamate concentration increased to 600% of baseline after lethal SAH in both hippocampus and cortex and was inversely correlated with CBF (r = 0.9, P < 0.001) but did not increase after sublethal SAH. CONCLUSION: Acute vasoconstriction after SAH occurs independently of changes in ICP and CPP and is associated with decreased CBF, larger hemorrhage size, persistent elevations of extracellular glutamate, and poor outcome. Acute vasoconstriction seems to contribute directly to ischemic brain injury after SAH. Further evaluations of pharmacological agents with the potential to reverse acute vasoconstriction may increase CBF and improve outcome.     

Adrenal chromaffin cells on microcarriers exhibit enhanced long-term functional effects when implanted into the mammalian brain

Rat adrenal chromaffin cells attached to either collagen-coated dextran (Cytodex 3) or glass bead microcarriers, both of 90-200 microns diameter, were used as dopamine-secreting implants in the caudate-putamen of rats with 6-hydroxydopamine-induced unilateral lesions of the substantia nigra. As controls, beads without cells and cells in suspension alone were implanted. Chromaffin cells adhered to microcarriers reduced apomorphine-induced rotation by 75% in lesioned animals. Animals that were lesioned but not receiving cell implants or receiving beads alone showed no reduction. Animals implanted with cells not attached to beads also showed a reduction in rotation but this effect lasted less than three months. Microcarrier-attached cells, however, maintained their effect in reducing rotation for at least eight months (rotations were reduced from a control mean of 10.9 +/- 1.4 to 3.6 +/- 1.1 turns/min) without any "drop-off" of the effect. Histological examination showed that eight months post-implant the cells pre-adhered to beads were still present and could be stained by anti-tyrosine hydroxylase antibody. Sections stained with hematoxylin-eosin showed no signs of an inflammatory response. In contrast to beads implanted into the striatum, Cytodex bead implants injected into the lateral ventricle induced a histopathological response appearing to involve the ependyma and choroid plexus. Results suggest that the striatal parenchyma but not the ventricle is amenable to studies using the microcarrier approach to transplantation.     

Isolation, characterization, and partial purification of a novel ubiquitin-protein ligase, E3. Targeting of protein substrates via multiple and distinct recognition signals and conjugating enzymes

Degradation of a protein via the ubiquitin system involves two discrete steps, conjugation of ubiquitin to the substrate and degradation of the adduct. Conjugation follows a three-step mechanism. First, ubiquitin is activated by the ubiquitin-activating enzyme, E1. Following activation, one of several E2 enzymes (ubiquitin-carrier proteins or ubiquitin-conjugating enzymes, UBCs) transfers ubiquitin from E1 to the protein substrate that is bound to one of several ubiquitin-protein ligases, E3s. These enzymes catalyze the last step in the process, covalent attachment of ubiquitin to the protein substrate. The binding of the substrate to E3 is specific and implies that E3s play a major role in recognition and selection of proteins for conjugation and subsequent degradation. So far, only a few ligases have been identified, and it is clear that many more have not been discovered yet. Here, we describe a novel ligase that is involved in the conjugation and degradation of non "N-end rule" protein substrates such as actin, troponin T, and MyoD. This substrate specificity suggests that the enzyme may be involved in degradation of muscle proteins. The ligase acts in concert with E2-F1, a previously described non N-end rule UBC. Interestingly, it is also involved in targeting lysozyme, a bona fide N-end substrate that is recognized by E3 alpha and E2-14 kDa. The novel ligase recognizes lysozyme via a signal(s) that is distinct from the N-terminal residue of the protein. Thus, it appears that certain proteins can be targeted via multiple recognition motifs and distinct pairs of conjugating enzymes. We have purified the ligase approximately 200-fold and demonstrated that it is different from other known E3s, including E3 alpha/UBR1, E3 beta, and E6-AP. The native enzyme has an apparent molecular mass of approximately 550 kDa and appears to be a homodimer. Because of its unusual size, we designated this novel ligase E3L (large). E3L contains an -SH group that is essential for its activity. Like several recently described E3 enzymes, including E6-AP and the ligase involved in the processing of p105, the NF-kappa B precursor, the novel ligase is found in mammalian tissues but not in wheat germ.     

Helicobacter pylori does not migrate from the antrum to the corpus in response to omeprazole

BACKGROUND: Omeprazole is known to have an effect on Helicobacter pylori in vivo. One opinion is that H. pylori "migrates" from the antrum to the corpus in response to omeprazole therapy. METHODS: To determine whether H. pylori migrates in response to omeprazole, we assessed the presence of H. pylori in the antrum and corpus in duodenal ulcer patients receiving omeprazole for 4 wk. Culture and histological examination of antral biopsies (Genta stain) were performed before patients received omeprazole, at the end of therapy, and 4-6 wk later. The end points were presence or absence of H. pylori and the number of H. pylori colonies per biopsy. RESULTS: Seventy-two patients had H. pylori in both the antrum and corpus at entry and 4-6 wk after ending therapy. Three general patterns were prevalent at the end of omeprazole therapy: antrum- and corpus-positive (54%), antrum-negative and corpus-positive (24%), both antrum- and corpus-negative (21%), and one patient had antrum-positive with corpus-negative (1%). Evaluation of the number of colonies per biopsy in those who remained H. pylori-positive in both the antrum and corpus throughout showed that the number of H. pylori decreased in both the antrum and corpus during therapy (507 +/- 60 vs. 225 +/- 51, p < 0.01 and 415 +/- 58 vs. 290 +/- 46 0.1) for antrum and corpus, respectively, and tended to return to pre-therapy levels 4-6 wk later. The number of H. pylori in the corpus also decreased in the antrum-negative and corpus-positive group during therapy with omeprazole (433 +/- 87 vs. 185 +/- 61, p < 0.05). In most of the patients studied, the number of H. pylori in the corpus was less posttreatment than it was pretreatment. The decrease in H. pylori load was also reflected in the development of false-negative urea breath tests. CONCLUSIONS: Omeprazole is detrimental to H. pylori in both the antrum and the corpus; migration from the antrum to the corpus in response to omeprazole is a myth.