Hemoglobin M equon beta 41 (C7) phenylalanine leads to tyrosine

A severe hemolytic crisis was observed in a 34-yr-old female of English- Irish extraction following a viral illness treated with acetaminophen. Heinz bodies and heat instability were present only during a transient hemolytic event. A challenge dose of acetaminophen caused no detectable hematologic abnormality. Structural studies of the hemoglobin during hemolysis and again after complete recovery localized the abnormality to tryptic peptide beta Tp-5, and automated sequencing of I 125-labeled beta chains indicated a replacement of phenylalanine (C7) beta 41 by tyrosine. Substitution of the next residue, phenylalanine (CD1) beta 42 by serine (Hb Hammersmith), has resulted in chronic severe Heinz body hemolytic anemia. The lack of chronic anemia in the present disorder may reflect the different relationships of beta41 and beta 42 and/or the similarities in volume and hydrophobicity of tyrosine and phenylalanine. It is suggested that substitution of tyrosine for phenylalanine in Hb Mequon may disturb the critical environment around the heme group and render it susceptible to oxidative denaturation in the presence of infections and/or drugs.     

Recombinant human interleukin-3 and granulocyte-macrophage colony- stimulating factor show common biological effects and binding characteristics on human monocytes

Two human hemopoietic growth factors involved in monocytopoiesis, interleukin-3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were studied for their ability to stimulate blood monocytes and to bind to the monocyte membrane. Both cytokines maintained monocyte/macrophage numbers during long-term culture and increased cell size as compared with controls. Effects on cell numbers were present at low cytokine concentrations (6 to 20 pmol/L), whereas enhanced 3H-thymidine incorporation was observed only at higher concentrations (greater than or equal to 60 pmol/L). Autoradiographic studies showed only 1% to 3% of stimulated monocytes with nuclear grains. These results suggest that the primary mechanism for IL-3 and GM-CSF-induced maintenance of monocyte/macrophage numbers in humans is through an effect on cell survival. Surface receptors for both IL-3 and GM-CSF were studied by using 125I-labeled recombinant human (rh) cytokines and performing Scatchard analyses. Both cytokines showed curvilinear Scatchard plots, and computer analyses favored a two-site binding model. High-affinity binding data for 125I rhIL-3 (Kd 7.7 to 38.2 pmol/L; receptor number/cell 95 to 580) and for 125I rhGM-CSF (Kd 4.7 to 38.9 pmol/L; receptor number/cell 8 to 67) show similar binding affinities for the two cytokines but a lower receptor number/cell for 125I rhGM-CSF. Low-affinity binding characteristics for 125I rhIL-3 (Kd 513 to 939 pmol/L; receptor number/cell 179 to 5,274) and for 125I rhGM- CSF (Kd 576 to 1,120 pmol/L; receptor number/cell 130 to 657) show a similar pattern for the two cytokines. Specificity of 125I rhIL-3 and 125I rhGM-CSF binding to monocytes was established by the ability of the homologous cytokine to inhibit binding and the inability of a range of other cytokines to compete at 100-fold excess molar concentration. It is important, however, that binding of 125I rhIL-3 was partially inhibited by rhGM-CSF and that rhIL-3 partially inhibited binding of 125I rhGM-CSF to the monocyte membrane under conditions shown to prevent receptor internalization. The degree of inhibition varied between 25% and 80% in different experiments, and quantitative inhibition experiments showed that 1,000-fold excess concentrations of competitor failed to inhibit binding of the heterologous ligand completely. These results demonstrate that human IL-3 and GM-CSF have similar effects on growth and survival of human monocytes in vitro and suggest that these and other common biological effects may be mediated either through a common receptor or through distinct receptors associated on the monocyte membrane.     

Outcomes of Stable Multiple Sclerosis Patients Staying on Initial Interferon Beta Therapy Versus Switching to Another Interferon Beta Therapy: A US Claims Database Study

Introduction

This study was designed to assess real-world outcomes of patients with multiple sclerosis (MS) who were stable on interferon (IFN) beta therapy in the year prior to switching to another IFN beta therapy versus those who continued on the initial treatment.

Methods

This study used administrative claims from MarketScan Commercial Claims and Encounters Database, from January 1, 2010, to March 31, 2015, to identify MS patients aged 18–64 years who remained relapse free for at least 1 year while continuously treated with an IFN beta therapy. Stable patients remaining on their initial IFN beta therapy (no-switch patients) were matched with stable patients who switched IFN beta therapy (switch patients) using propensity score matching (first claim?=?index date). Outcome measures included annualized relapse rate (ARR), the percentage of patients who relapsed, medication possession ratio, and the proportion of days covered and were measured during the year following the index date.

Results

This study identified 531 patients in the no-switch group and 177 patients in the switch group, with subsets of 270 patients in the no-switch group and 90 patients in the switch group stable on intramuscular (IM) IFN beta-1a therapy. All outcomes during the follow-up year were significantly better in the no-switch group than in the switch group. For all patients, ARR in the switch group was more than twice that in the no-switch group (P?=?0.002). For patients stable on IM IFN beta-1a at baseline, ARR was twice as high in the switch group as in the no-switch group (P?=?0.012).

Conclusion

Among all patients stable on IFN beta therapy and the subset stable on IM IFN beta therapy in particular, those who remained on therapy had significantly better outcomes than those who switched to another IFN beta therapy.

Funding

Biogen (Cambridge, MA, USA).

     

Silibinin prevents amyloid β peptide-induced memory impairment and oxidative stress in mice

Background and purpose:

Accumulated evidence suggests that oxidative stress is involved in amyloid β (Aβ)-induced cognitive dysfunction. Silibinin (silybin), a flavonoid derived from the herb milk thistle (Silybum marianum), has been shown to have antioxidative properties; however, it remains unclear whether silibinin improves Aβ-induced neurotoxicity. In the present study, we examined the effect of silibinin on the memory impairment and accumulation of oxidative stress induced by Aβ_25–35 in mice.

Experimental approach:

Aggregated Aβ_25–35 (3 nmol) was intracerebroventricularly administered to mice. Treatment with silibinin (2, 20 and 200 mg·kg⁻¹, once a day, p.o.) was started immediately after the injection of Aβ_25–35. Locomotor activity was evaluated 6 days after the Aβ_25–35 treatment, and cognitive function was evaluated in a Y-maze and novel object recognition tests 6–11 days after the Aβ_25–35 treatment. The levels of lipid peroxidation (malondialdehyde) and antioxidant (glutathione) in the hippocampus were measured 7 days after the Aβ_25–35 injection.

Key results:

Silibinin prevented the memory impairment induced by Aβ_25–35 in the Y-maze and novel object recognition tests. Repeated treatment with silibinin attenuated the Aβ_25–35-induced accumulation of malondialdehyde and depletion of glutathione in the hippocampus.

Conclusions and implications:

Silibinin prevents memory impairment and oxidative damage induced by Aβ_25–35 and may be a potential therapeutic agent for Alzheimer''s disease.     

Validation studies of the human movement analysis panel for hand/arm performance

The human movement analysis panel (HMAP) measures separable components of arm motion and simple and complex finger coordination. HMAP testing takes 30min to administer. In separate experiments we have validated the HMAP against the standard grooved pegboard and measures of gait speed, and demonstrated important learning effects over both short durations of days, and longer intervals of months to years in normal subjects of different ages. Stepwise regression demonstrated the strongest correlation between the HMAP complex motor times and pegboard both-hand removal (R(2)=0.52, p=0.002 for dominant and R(2)=0.33, p=0.02 for non-dominant hands). The most consistent and sensitive measure of HMAP motor performance overall was the complex motor time. The HMAP is a short-duration, easily administered, objective quantitative test of motor function, with potential applications in aging, and in Parkinson's Disease and related motor disorders. The HMAP has a smaller version used in primates, so that measurements made in primate models of disease and its treatment are directly comparable to analogous clinical measurements made in the corresponding human disease.     

Outcome of Colonoscopy in Elderly African-American Patients

Background  

Average-risk individuals should be offered a screening colonoscopy beginning at 50 years of age. However, there is no clear consensus on an age at which patients should no longer be offered a screening colonoscopy. The purpose of this study was to analyze the outcome of colonoscopy in elderly individuals based on the preprocedure indication.