2-Chlorodeoxyadenosine therapy in advanced chronic lymphocytic leukaemia

The therapeutic potential of 2-chlorodeoxyadenosine (CdA) in patients with advanced chronic lymphocytic leukaemia (CLL) remains controversial with response rates in clinical trials ranging from 44 to 67%. This report describes our experience with CdA in 22 CLL patients having already undergone previous treatment. CdA was given by continuous intravenous infusion at a dose of 4 mg/m2/day for 7 days (4 patients) or as 2-h intravenous infusions at a dose of 5.6 mg/m2/day for 5 days (18 patients). Partial (n = 5) or complete (n = 2) response was obtained in 7 cases. As compared to unresponsive patients, responding subjects received CdA earlier in the course of their disease (mean interval between diagnosis and CdA therapy 58 vs 102 months), were less thrombocytopenic at initiation of CdA (mean platelet count 165 x 10(9)/L vs 81 x 10(9)/L) and experienced less severe neutropenia during the first course of therapy (mean minimal neutrophil count 1.55 x 10(9)/L vs 0.43 x 10(9)/L). None of 6 patients with CLL refractory to fludarabine responded to CdA. An evaluation of haematological toxicity during the first course of treatment showed grade 4 neutropenia (< 0.5 x 10(9)/L) in 7 cases and grade 4 thrombocytopenia (< 25 x 10(9)/L) in one of 19 cases where the platelet count was greater than 25 x 10(9)/L at initiation of CdA. In comparison with earlier reports, the present series of patients had received relatively heavy prior therapy, experienced more severe haematological toxicity and demonstrated a lower total response rate.     

Evidence for the effect of antibodies to TSH receptors on the thyroid ultrasonographic volume in patients with Graves' disease

OBJECTIVE: It has been demonstrated that antibodies (Ab) to thyroid-stimulating hormone receptors (R), which stimulate the thyroid gland, induce hyperthyroidism in patients with Graves' disease. Furthermore, it has been shown in thyroid cells in culture that thyroid-stimulating hormone receptor Ab acts through the adenosine 3', 5'-monophosphate pathway which stimulates both thyroid hormonogenesis and growth. We investigated the relations between thyroid autoimmunity expression and thyroid ultrasonographic parameters or thyroid hormonal status in patients with Graves' disease. PATIENTS: A prospective study of 53 consecutive patients referred with untreated Graves' disease. MEASUREMENTS: Measurements were made of serum TSH-R, peroxidase (TPO) and thyroglobulin (Tg) Ab and basal plasma free T4 (FT4), free T3 (FT3) and TSH. Thyroid morphological characteristics (number and total volume of nodule(s), total volume of lobes and total thyroid volume) were determined by ultrasonography. RESULTS: There were significant correlations (P < 0.001) between TSH-RAb levels and FT4 values (r = 0.48) or FT3 levels (r = 0.46). Likewise, significant correlations were found between TSH-RAb levels and total lobe volume values (r = 0.56, P < 0.001), total nodular volume values (r = 0.59, P < 0.01) or total thyroid volume values (r = 0.63, P < 0.001). By contrast, no correlation was found between TSH-RAb levels and the number of nodules or between any of the ultrasonographic parameters and TPOAb levels or TgAB values. CONCLUSIONS: This study demonstrates, in vivo, that TSH receptor antibodies modulate the thyroid ultrasonographic extranodular and nodular volumes in patients with Graves' disease.     

Transmembrane domain inversion blocks ER release and insulin receptor signaling

Activation of the insulin receptor, like other tyrosine kinase receptors, appears to require dimerization. We have shown previously that, even in the absence of insulin, full receptor activation can be induced by changes in the receptor transmembrane domain (TMD), suggesting that TMD dimerization is sufficient for receptor activation. To further understand the importance of the TMD in insulin receptor activation, we have inverted the entire TMD sequence including flanking basic amino acids, residue-for-residue. This mutation was predicted to alter the ability of a TMD alpha-helix to form homodimers and higher level aggregates. Despite apparently normal protein folding on either side of the membrane, this mutation caused ER retention and, for those receptors that reached the cell surface, blockade of insulin-stimulated kinase signal transmission. However, the signaling blockade could be overcome by proteolytic activation with trypsin. In contrast, shifting only the basic cytoplasmic residues to the opposite side of the TMD or mutation to neutral residues had no detectable effect on assembly, biosynthesis, topology, or signaling. These findings extend our previous observations to suggest that TMD interactions within the membrane are not only sufficient for receptor activation, but may be required. TMD interactions also appear to be necessary for oligomeric assembly and biosynthetic maturation of the insulin receptor.     

Velocity of peristaltic propagation in distal esophageal segments

Recent studies of the peristaltic pressure wave have suggested the presence of two sequential but overlapping contraction segments in the distal esophageal body. In this report, propagation velocity of esophageal peristalsis was determined in these segments in normal subjects (N = 35) and in patients with high-amplitude peristalsis (nutcracker esophagus, N = 25) to see if intersegment differences were present in the normal or abnormal setting. Velocity measurements were made from conventional manometric tracings in two 4-cm regions representing the distal smooth-muscle segments. A novel method of velocity measurement was employed that used regression lines established from contraction onset times. In normal subjects, propagation velocity decreased significantly from the proximal to distal segment (4.9 +/- 0.5 cm/sec, vs 3.2 +/- 0.2 cm/sec, P < 0.01). Velocity also decreased across segments in nutcracker-esophagus patients (5.3 +/- 0.6 cm/sec, vs 3.6 +/- 0.7 cm/sec, P = 0.06), but the difference reached statistical significance only when the subset with highest amplitudes (> or = 180 mm Hg) was analyzed separately. Greater variance in velocity in the distal smooth-muscle segment of nutcracker-esophagus patients (P < 0.01) was, in part, responsible for this statistical observation. We conclude that normal propagation velocity decreases across regions corresponding to the smooth-muscle contraction segments defined by recent studies of peristalsis, supporting the assumption that they represent separate neuromuscular units. The mechanisms responsible for contraction wave abnormalities in the nutcracker esophagus have a minimal effect on propagation velocity, an effect that is restricted to the distal smooth-muscle segment of the esophageal body.