Conventional and experimental drug therapy in myelofibrosis with myeloid metaplasia

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (ie, BCR-ABL-negative) myeloproliferative disorder characterized by anemia, multiorgan extramedullary hematopoiesis, constitutional symptoms, and premature death from either leukemic transformation or other disease complications. Stem cell transplantation can be curative, but many patients either are not appropriate candidates or do not choose to accept the significant risks associated with transplantation. Current pharmacologic therapy has been beneficial mainly in terms of palliating disease-associated cytopenias, constitutional symptoms, splenomegaly, and other organ damage from excess myeloproliferation. Novel treatment strategies are under investigation, including targeted inhibition of JAK2^V617F, the activating tyrosine kinase point mutation present in about half of patients with MMM. In this article, we review both the old and new pharmacologic options for MMM.     

Hyper-IgM syndrome with CHARGE association

A girl with coloboma of the iris, sensorineural deafness, growth delay, distinctive face, and cranial nerve dysfunction was diagnosed of CHARGE association in the first year of life. She presented with repeated otitis. At 3 yr of age, the patient suffered a septicemia ( Streptococcus pneumoniae , Corynebacterium sp.). The immunoglobulin G (IgG) and IgA serum levels were decreased, IgM increased and cellular immunity parameters were normal, supporting the diagnosis of hyper-IgM (HIM) syndrome. The sequence of CD40 ligand and cytidine deaminase genes were normal. From then on, she was receiving immunoglobulin intravenously with an excellent outcome . Here, we report the first case of CHARGE association and HIM syndrome in the same patient. Although the cause could not be identified, a non-random link is likely.     

Astroglial alterations in rat hippocampus during chronic lead exposure.

The present study was performed in order to follow the response of astroglial cells in the rat hippocampus to chronic low-level lead exposure. The experiments combined immunohistochemistry using anti-glial fibrillary acidic protein (GFAP) antibody and conventional transmission electron microscopy (EM). Chronic administration with drinking water [1 g% w/v (subclinical dose) of lead acetate dissolved in distilled water] was started through the mother's milk when pups were 7 days old. Following weaning, experimental offspring were treated for 3 months with the same concentration of adulterated water. The group of intoxicated animals and their controls were sacrificed by perfusion-fixation at 30, 60, and 90 days of exposure. After 60 days of lead treatment, staining of GFAP-positive cells demonstrated an astroglial transformation from the quiescent to the reactive state, characterized by an increase in GFAP. In control rats no changes in GFAP immunostaining were observed. The intensity of the astroglial response was enhanced after 90 days of lead intoxication, showing an increment of GFAP immunoreactivity. Quantification of these changes was made by computerized image analysis, confirming that the sectional areas of the astroglia in lead-exposed animals were larger than those in controls. These results are consistent with the ultrastructural alterations. Simultaneously with the increment in gliofilaments, intranuclear inclusions were seen in some astrocytes. The mechanisms by which lead affects astrocytes are unknown. Probably the astroglial changes induced by lead intoxication produce microenvironmental modifications that may disturb the neuronal function.     

Congestive gastropathy

15 patients with congestive gastropathy were reported including clinical and pathological characteristics of the disease. Every patient had alcoholic liver cirrhosis and portal hypertension. 6 patient's stomach was resected while in 2 further cases the disease was found at autopsy. In additional 7 cases the characteristic microvascular changes were observed in endoscopic biopsy specimens from the gastric mucosa. The authors presume that this disease has an acute and a chronic stage. In the acute stage dilated capillaries are present under the surface, not related to the inflammation of gastric mucosa. This phenomenon was described in the literature. In the chronic stage there are dilated and tortuous vessels in the submucosal layer surrounded by collagenous connective tissue. The authors suppose that the thick and fibrotic submucosal layer causes microcirculatory disturbances in the gastric mucosa. The impaired microcirculation may cause extensive ulcers with profuse and sometimes lethal bleeding.     

Sensitization to Zygophyllum fabago pollen. A clinical and immunologic study

Zygophyllum fahago is a herbaceous plant found widely in the Mediterranean area. There are no previous reports of its allergenicity. An aerobiologic and clinical survey was conducted in Murcia, southern Spain, to determine the quantity of airborne pollen and establish the possible role of this pollen as a cause of allergic symptoms. With a Hirst volumetric trap, we determined the atmospheric concentrations of this pollen in 1993, 1994,1995, and 1996. Of 1180 patients tested, 181 (15,34%) had a positive skin test. To determine its allergenicity, we divided 47 patients into three groups: in group 1, all the patients had symptoms of rhinoconjunctivitis plus asthma; in groups 2 and 3, rhinoconjunctivitis. In group 1, we performed a bronchial provocation test (BPT): in groups 2 and 3, we performed nasal provocation (NPT) and conjunctival provocation (CPT) tests, respectively, SDS-PAGE was used to characterize the antigenic fractions and RAST inhibition to determine cross-reactivity with other pollens. The pollen dispersion period is from May to September (445 grains/m³), BPT was positive in 13 of 15 patients, NPT in 14 of 16 patients, and CPT in 13 of 16 patients. RAST inhibition revealed cross-reactivity with Mercurialis, Ricinus, Olea. and Betula. SDS-PAGE identified 25 IgE antibody-binding components, five of which (60, 65, 41, 38, and 15.5/14,7 kDa) were recognized by 40% of the sera. By SDS-PAGE immunoblotting with sunflower antiprofilin rabbit serum and affinity chromatography we established that the Z. fahago extract has profilin. This study shows that this pollen becomes airborne and elicits an IgE response which triggers respiratory symptoms in allergic subjects.