Response to Ozone in Volunteers with Chronic Obstructive Pulmonary Disease

Twenty-eight volunteers with chronic obstructive pulmonary disease were exposed to 0.0, 0.18, and 0.25 ppm ozone in purified air for 1-hr periods with light intermittent exercise, with exposure conditions presented in random order at 1-month intervals. No statistically significant changes attributable to ozone were found in forced expiratory performance or percent oxyhemoglobin (measured near the beginning and end of each exposure). No ozone-related changes in clinical status were found by interviews that included the time for 1 wk before to 1 wk after each exposure, except that a moderate increase in lower respiratory symptoms was reported by nonsmokers in 0.18 ppm exposures only. Thus, a slight decrement in hemoglobin saturation with ozone exposure (reported in two previous studies of chronic obstructive pulmonary disease subjects) may not be a common occurrence under typical ambient exposure conditions.     

An amino acid substitution in the putative second extracellular loop of RBC band 3 accounts for the Froese blood group polymorphism

BACKGROUND: The low incidence RBC antigen Fr(a) has been excluded from 17 of the 25 established blood group systems. Previous genetic analysis assigned the gene controlling Fr(a) expression to the same chromosomal region as the solute carrier family 4, anion exchanger member 1 gene (SLC4A1). Because SLC4A1 encodes RBC band 3 and controls the expression of Diego blood group system antigens, the possible relationship of Fr(a) to the Diego blood group system was investigated by molecular analysis of SLC4A1. STUDY DESIGN AND METHODS: Blood samples were obtained from the members of two unrelated Mennonite kindreds segregating for Fr(a). DNA was extracted, amplified by PCR using intronic primer sets flanking exons 11-20 of SLC4A1, and screened by single-strand conformation polymorphism (SSCP) analysis. Those exons displaying SSCPs were subjected to DNA sequence analysis. RESULTS: An exon 13 SSCP mobility shift was observed in the DNA from all Fr(a+) persons that was not seen in the DNA from Fr(a-) family members or control subjects. Linkage between the exon 13 SSCP and FR:(a) was established, with peak lods = 3.62 at theta = 0.00 for combined paternal and maternal meioses. DNA sequencing revealed a GAG --> AAG mutation that underlies a Glu480Lys substitution in RBC band 3. CONCLUSIONS: A point mutation in exon 13 of SLC4A1 accounting for a Glu480Lys substitution in band 3 controls Fr(a) expression. On the basis of these our results, the International Society of Blood Transfusion Working Party on Terminology for Red Cell Surface Antigens has assigned Fr(a) to the Diego blood group system, with the designation DI20.     

Bendamustine,lenalidomide, and dexamethasone (BRD) is highly effective with durable responses in relapsed multiple myeloma

Bendamustine is a multifunctional alkylating agent with single agent activity in myeloma. We designed the current phase 1/2 trial to determine the maximum tolerated doses (MTD) of bendamustine that can be safely combined with lenalidomide and dexamethasone and to assess the safety and efficacy of the combination. Patients with relapsed MM following at least 1 prior therapy, but no more than four lines of prior therapy and with measurable disease were enrolled. Bendamustine 75 mg/m² given on days 1 and 2, lenalidomide 25 mg given days 1–21 and dexamethasone 40 mg on days 1, 8, 15, and 22, was the recommended Phase 2 dose. Seventy‐one patients were accrued: 21 on Phase 1 and 50 on Phase 2. The median age was 62.3 years; patients had a median of three prior lines of therapy (range 1–4), with over 70% of the patients having received prior lenalidomide, bortezomib, and/or peripheral blood stem cell transplant. Thirty‐four of 70 (49%) patients had a confirmed partial response or better, including 20 patients (29%) with a very good partial response or better. An additional 4 patients had a minor response, translating to an overall 55% clinical benefit rate. Grade 3 or higher toxicity was seen in 96% of patients, with ≥grade 3 hematologic in 94% and nonhematologic in 50%. The median progression free survival was 11.8 months and the median duration of response was 23 months. The combination of bendamustine, lenalidomide, and dexamethasone is very effective in relapsed multiple myeloma with high response rates and durable responses Am. J. Hematol. 90:1106–1110, 2015. © 2015 Wiley Periodicals, Inc.     

Time course of exercise-induced bronchoconstriction in asthmatics exposed to sulfur dioxide

Young adult asthmatic volunteers (N = 17) were exposed to 0.75 ppm sulfur dioxide (SO₂) for 3-hr periods, exercising vigorously for the first 10 min and resting thereafter. Specific airway resistance (SR_aw) and symptoms were recorded preexposure, immediately postexercise, and after 1, 2, and 3 hr of exposure. Symptoms and SR_aw were significantly increased after exercise, relative to preexposure measurements. Group mean SR_aw and symptom increases were no longer significant at 1 hr. In a few individuals, effects may have persisted for 2 hr or more. On separate occasions, comparable exposures were conducted, and forced expiratory spirometry was performed preexposure and postexercise, in addition to the other tests. Inclusion of spirometry did not significantly affect the other results. Spirometry and SR_aw showed nearly equal significance in changes postexercise. Thus, in general, asthmatics' bronchoconstriction induced by exercise in SO₂ seems to reverse quickly with rest, even if SO₂ exposure continues. Spirometry may be useful for studying pollution-induced bronchoconstriction when SR_aw measurements are impractical.     

SOCS1 and SOCS3 are the main negative modulators of the somatotrophic axis in liver of homozygous GH-transgenic zebrafish (Danio rerio)

Homozygote individuals (HO) of the GH-transgenic zebrafish lineage (F0104), despite expressing double the amount of growth hormone (GH) in relation to the hemizygote (HE) individuals, presented smaller growth in relation to the last, and similar to the non-transgenic (NT) group. Through the analysis of the expression of genes of the somatotrophic axis in the livers of HO and NT individuals, it was verified that GHR, JAK2 and STAT5.1 did not present significant differences among the analyzed genotypes (NT and HO). However, in the IGF-I gene expression, an accentuated decrease was observed in group HO (p < 0.01), suggesting a resistance effect to excess GH. This resistance could be related to the insufficient amount of energy for supporting the accelerated metabolic demand caused by excess circulating GH. Analysis of the genes involved in the regulation of GH signalization by dephosphorylation (PTP-H1 and PTP-1B) did not show any significant alteration when comparing groups HO and NT. However, the analysis of the SOCS1 and SOCS3 genes showed an induction in homozygotes of 2.5 times (p < 0.01) and 4.3 times (p < 0.05), respectively, in relation to non-transgenics. The results of the present work demonstrate that, in homozygotes, GH signaling is reduced by the action of the SOCS1 and SOCS3 proteins.     

Early-onset colorectal cancer: A sporadic or inherited disease?

Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a “sporadic” subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the “sporadic” subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this “sporadic” early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.