Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

A novel role for MNTB neuron dendrites in regulating action potential amplitude and cell excitability during repetitive firing

Principal cells of the medial nucleus of the trapezoid body (MNTB) are simple round neurons that receive a large excitatory synapse (the calyx of Held) and many small inhibitory synapses on the soma. Strangely, these neurons also possess one or two short tufted dendrites, whose function is unknown. Here we assess the role of these MNTB cell dendrites using patch-clamp recordings, imaging and immunohistochemistry techniques. Using outside-out patches and immunohistochemistry, we demonstrate the presence of dendritic Na⁺ channels. Current-clamp recordings show that tetrodotoxin applied onto dendrites impairs action potential (AP) firing. Using Na⁺ imaging, we show that the dendrite may serve to maintain AP amplitudes during high-frequency firing, as Na⁺ clearance in dendritic compartments is faster than axonal compartments. Prolonged high-frequency firing can diminish Na⁺ gradients in the axon while the dendritic gradient remains closer to resting conditions; therefore, the dendrite can provide additional inward current during prolonged firing. Using electron microscopy, we demonstrate that there are small excitatory synaptic boutons on dendrites. Multi-compartment MNTB cell simulations show that, with an active dendrite, dendritic excitatory postsynaptic currents (EPSCs) elicit delayed APs compared with calyceal EPSCs. Together with high- and low-threshold voltage-gated K⁺ currents, we suggest that the function of the MNTB dendrite is to improve high-fidelity firing, and our modelling results indicate that an active dendrite could contribute to a 'dual' firing mode for MNTB cells (an instantaneous response to calyceal inputs and a delayed response to non-calyceal dendritic excitatory postsynaptic potentials).     

Odyssey of hope: a physician’s guide to communicating with brain tumor patients across the continuum of care

The optimal treatment of a patient with a malignant brain tumor requires attention to the physical and emotional well-being of the affected individual and the family. We review the concept of hope as a critical support modality throughout the continuum of care for brain tumor patients and families. We offer suggestions based on our own observations over 17 years as well as the lessons taught to us by our patients and their families over that time and through a structured interview process. Just as despair can come to one another only from other human beings, hope, too, can be given to one only by other human beings —Elie Wiesel     

Laparoscopic cautery in the treatment of endometriosis-related infertility

Life table analysis and the two-parameter exponential method have been applied to pregnancy rates in 72 patients undergoing laparoscopic cautery exclusively. Patients with male factor infertility were excluded. Estimated cure rates for patients with stage I and II disease were 98.2% and 76.6%, respectively (not significantly different). No significant difference was seen when anovulation complicated the endometriosis (68.6%). When greater than one infertility factor was present, a significant difference was observed (50.6%). Patients with stage I disease had an average fecundity of 10.30% with decreasing values observed in stage II (7.59%), anovulation (6.67%), and more than one infertility factor (3.33%). We conclude that laparoscopic cauterization is an effective mode of therapy for the treatment of stage I and II endometriosis associated with infertility.     

Endometriosis: pathophysiology, diagnosis, and treatment

Endometriosis remains a poorly understood disease. Multiple factors are likely to be responsible for the relative infertility in patients with endometriosis. All therapeutic options should be presented to the patient. Treatment of a patient with endometriosis should be individualized based on symptoms (i.e., pain and/or infertility), extent of disease, age and associated pelvic pathology. Diagnosis continues to require visual documentation with histologic confirmation if possible.     

Neosalpingostomy for distal tubal obstruction: prognostic factors and impact of surgical technique

We reviewed the clinical records of all women who underwent microsurgical terminal neosalpingostomy for distal tubal obstruction between January 1983 and June 1988. We identified 95 women whose preoperative evaluation revealed no other contributory factors for infertility and analyzed their pregnancy outcome after this procedure. Pregnancy success was inversely related to the extent of tubal distortion (dilation, rugal integrity, and status of the fimbria) and degree of adnexal adhesions. Using our classification system for distal tubal obstruction, patients with mild disease had an 80% pregnancy rate, whereas patients with moderate and severe disease had a 31% and 16% success rate, respectively. We found no statistically significant difference in pregnancy outcome when we compared this series with our previous group, reported in 1978, where contemporary microsurgical technique was not used. Although we feel that optimal surgical technique is important to maximize success, we conclude that the most important prognostic factor in pregnancy outcome after neosalpingostomy for distal tubal disease is the anatomical and functional integrity of the tube.     

Evaluation of a simple immunodiffusion technique for quantitation of platelet-associated immunoglobulin G in childhood immune thrombocytopenias

Platelet-associated IgG (PAIgG) was quantitated in 33 children with immune thrombocytopenia and platelet counts less than 100 X 10(9)/liter using a simple radial immunodiffusion (RID) assay. Elevated PAIgG levels were found in 76% (16/21) of children with acute idiopathic thrombocytopenic purpura (ITP), 88% (7/8) of children with chronic ITP, and all four children studied with systemic lupus erythematosus and thrombocytopenia. Normal PAIgG values were found in children with the following disorders: malignancy and chemotherapy-related thrombocytopenia; ITP in remission (platelet counts greater than 150 X 10(9)/liter); various nonimmune hematologic disorders and juvenile rheumatoid arthritis, these children having normal platelet counts. In children with acute ITP, elevated PAIgG values at initial presentation fell to within the normal range when clinical remission occurred. The RID assay can be easily established in most hematology laboratories and has the advantage that solubilized "test" platelets used in the assay can be stored frozen prior to analysis. We conclude that this simple technique is of value in the evaluation of childhood thrombocytopenic states and yields results comparable to those reported using more complex antiplatelet antibody assays.