Acquired platelet GPVI receptor dysfunction in critically ill patients with sepsis.

Glycoprotein VI (GPVI), the platelet immunoreceptor tyrosine activating motif (ITAM) receptor for collagen, plays a striking role on vascular integrity in animal models of inflammation and sepsis. Understanding ITAM-receptor signaling defects in humans suffering from sepsis may improve our understanding of the pathophysiology, especially during disease onset. In a pilot study, platelets from 15 patients with sepsis were assessed consecutively at day of admission, day 5 to 7, and the day of intensive care unit (ICU) discharge and subjected to comprehensive analyses by flow cytometry, aggregometry, and immunoblotting. Platelet function was markedly reduced in all patients. The defect was most prominent after GPVI stimulation with collagen-related peptide. In 14 of 15 patients, GPVI dysfunction was already present at time of ICU admission, considerably before the critical drop in platelet counts. Sepsis platelets failed to transduce the GPVI-mediated signal to trigger tyrosine phosphorylation of Syk kinase or LAT. GPVI deficiency was partially inducible in platelets of healthy donors through coincubation in whole blood, but not in plasma from patients with sepsis. Platelet aggregation upon GPVI stimulation increased only in those patients whose condition ameliorated. As blunted GPVI signaling occurred early at sepsis onset, this defect could be exploited as an indicator for early sepsis diagnosis, which needs to be confirmed in prospective studies.

Alzheimer's Treatment: Real-World Physician Behavior Across Countries.

OBJECTIVE: Timely initiation of Alzheimer's disease (AD)-specific treatment may postpone cognitive deterioration and preserve patient independence. We explored real-world physician behavior in the treatment of AD. METHODS: Online questionnaires and patient record forms (PRFs) were completed by participating physicians. The physicians included general practitioners, neurologists, geriatricians and psychiatrists, recruited from France, Germany, Japan, the UK and the USA. Physicians completed an online interview and two to three PRFs based on selected records of their patients with AD. Data on treatment algorithms and key drivers for therapy were captured. RESULTS: A total of 3346 PRFs were submitted and 1086 physicians interviewed. Overall, 44% of patients with mild cognitive impairment/prodromal AD, 71% of patients with mild disease and 76% of patients with moderate disease had already received therapy. The most common reasons for not prescribing therapy were patient refusal (35%) and early disease stage (26%). Except in the USA, the majority of physicians preferred to prescribe monotherapy. Almost 30% of patients at any stage of the disease did not receive AD-specific pharmacotherapy immediately after diagnosis. CONCLUSIONS: Physicians' attitudes toward AD treatment could be driven by limited awareness regarding the benefits of early intervention and the modest efficacy of currently available therapies. Efficacious therapies for AD, especially early AD, which could be used alone or in combination with current medications to maximize treatment benefit, are still needed. The availability of more efficacious therapies may improve time to treatment initiation, treatment rates and acceptance of treatment by patients, caregivers and physicians.

Alzheimer's Diagnosis: Real-World Physician Behavior Across Countries.

INTRODUCTION: Appropriate management of patients with Alzheimer's disease (AD) helps preserve their independence and time at home. We explored physician behavior in the management of AD, focusing on diagnosis. METHODS: Online questionnaires and patient record forms (PRFs) were created by an independent market research agency and completed by participating physicians. Physicians were recruited from France, Germany, Japan, the UK, and the USA. A sample of 1086 physicians was recruited, including general practitioners, geriatricians, neurologists, and psychiatrists. Physicians completed an online interview and 2-3 PRFs based on randomly selected records of their patients with AD. Data on triggers and timing of diagnosis were captured. Data were assessed for all countries combined (global) and within each country and physician specialty. RESULTS: A total of 3346 PRFs were submitted. Approximately half of patients received diagnosis within 6 months. There were large country differences. In France, only 35% of patients were diagnosed within 6 months compared to 65% in Japan. Physicians in France also reported diagnoses taking > 9 months for a substantial number of patients (39%) compared with other countries (16-29%). Caregivers were the main driver toward diagnosis. Physician suspicion of AD was a trigger for diagnosis in only 20% of cases, globally. Overall, referral rates were low (14-23%). CONCLUSION: This study suggests that detection and timely diagnosis of AD remains suboptimal. This highlights the importance of fostering awareness of early symptoms and education on the benefits of timely diagnosis, a critical step in initiating treatment as early as possible.

Hsp90 inhibition ameliorates CD4+ T cell-mediated acute Graft versus Host disease in mice.

INTRODUCTION: For many patients with leukemia only allogeneic bone marrow transplantion provides a chance of cure. Co-transplanted mature donor T cells mediate the desired Graft versus Tumor (GvT) effect required to destroy residual leukemic cells. The donor T cells very often, however, also attack healthy tissue of the patient inducing acute Graft versus Host Disease (aGvHD)-a potentially life-threatening complication. METHODS: Therefore, we used the well established C57BL/6 into BALB/c mouse aGvHD model to evaluate whether pharmacological inhibition of heat shock protein 90 (Hsp90) would protect the mice from aGvHD. RESULTS: Treatment of the BALB/c recipient mice from day 0 to +2 after allogeneic CD4+ T cell transplantation with the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG) partially protected the mice from aGvHD. DMAG treatment was, however, insufficient to prolong overall survival of leukemia-bearing mice after transplantation of allogeneic CD4+ and CD8+ T cells. Ex vivo analyses and in vitro experiments revealed that DMAG primarily inhibits conventional CD4+ T cells with a relative resistance of CD4+ regulatory and CD8+ T cells toward Hsp90 inhibition. CONCLUSIONS: Our data, thus, suggest that Hsp90 inhibition might constitute a novel approach to reduce aGvHD in patients without abrogating the desired GvT effect.

Combined PI3K/Akt and Hsp90 targeting synergistically suppresses essential functions of alloreactive T cells and increases Tregs.

Acute graft-versus-host disease is still a major cause of transplant-related mortality after allogeneic stem cell transplantation. It requires immunosuppressive treatments that broadly abrogate T cell responses, including beneficial ones directed against tumor cells or infective pathogens. Inhibition of the heat shock protein of 90 kDa has been demonstrated to eliminate tumor cells, as well as alloreactive T cells while preserving antiviral T cell immunity. Here, we show that the suppressive effects of heat shock protein of 90 kDa inhibition on alloreactive T cells were synergistically enhanced by concomitant inhibition of the PI3K/Akt signaling pathway, which is also strongly activated upon allogeneic stimulation. Molecular analyses revealed that this antiproliferative effect was mainly mediated by induction of cell-cycle arrest and apoptosis. In addition, we observed an increased proportion of activated regulatory T cells, which critically contribute to acute graft-versus-host disease control, upon combined heat shock protein of 90 kDa/Akt isoforms 1 and 2 or heat shock protein of 90 kDa/PI3K/p110δ isoform inhibition. Moreover, antiviral T cell immunity was functionally preserved after combined heat shock protein of 90 kDa/Akt isoforms 1 and 2 inhibition. Taken together, our data suggest that the combined heat shock protein of 90 kDa/PI3K/Akt inhibition approach represents a reasonable dual strategy to suppress residual tumor growth and efficiently deplete alloreactive T cells and thus, provide a rationale to prevent and treat acute graft-versus-host disease selectively without impairing pathogen-specific T cell immunity.