Competitive engraftment of hematopoietic stem cells genetically modified with a truncated erythropoietin receptor

Transplantation of genetically modified hematopoietic stem cells (HSCs) has therapeutic potential for a variety of blood genetic disorders. Engraftment of HSCs, however, requires toxic myeloablative treatments, which render this approach questionable for non-life-threatening disorders. A potential alternative is the use of transgenes, which allows positive selection of HSCs in vivo. We used retroviral vectors to express a truncated derivative of the erythropoietin receptor (tEpoR) in murine and human hematopoietic cells. Murine HSCs expressing tEpoR at different levels (1500 to 13,000 receptors/cell) acquire a competitive repopulation capacity in vivo upon transplantation into fully or partially myeloablated co-isogenic mouse recipients. Long-term analysis of transplanted mice showed that expression of tEpoR at paraphysiological levels (approximately 1500 receptors/cell) has no effect on steady-state hematopoiesis and induces no further expansion of transduced cells after the engraftment period. Human cord blood-derived CD34+ stem/progenitor cells transduced with a lentiviral vector expressing tEpoR expand their clonogenic capacity in vitro, and significantly increase their marrow repopulation capacity upon xenotransplantation into sublethally irradiated NOD-SCID mice, with no alteration in their phenotype, survival, and differentiation properties. These data indicate that expression of tEpoR is an effective strategy to promote selective engraftment of genetically modified HSCs upon transplantation in both myeloablative and nonmyeloablative conditions, without the use of toxic drugs for selection.     

Wegener’s granulomatosis presenting with life-threatening lung hemorrhage in a 7-year-old child

Wegener’s granulomatosis (WG) is an idiopathic systemic disease that usually onsets in adolescence and is rare in young children. Its diagnosis is usually based on the presence of fever with arthralgia and weight loss, associated with symptoms of upper and/or lower respiratory tract involvement and renal disorders. We describe the appearance of a life-threatening lung hemorrhage in the absence of hemoptysis in a 7-year-old girl with a completely negative previous clinical history, who was subsequently diagnosed as having WG. The teaching message is that immediate bronchoscopy with bronchoalveolar lavage seems to be advisable in the presence of severe respiratory distress and bilateral lung as well as renal involvement. When a diffuse alveolar hemorrhage syndrome is demonstrated, WG should be considered among the main etiologies even in a relatively young child without a clinically suggestive history.     

Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome

The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploinsufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.     

Changes in healthy elderly women's physical performance: a 3-year follow-up

Background

Inflammatory states, hypovitaminosis D and secondary hyperparathyroidism may have a role in the age-related loss of muscle mass, and physical performance in healthy old people. The aim of this study is to investigate changes in muscle mass, strength and physical performance in healthy, active elderly females over a 3-year follow-up, correlating them with any inflammatory states and PTH and 25-hydroxyvitamin D (25-OHD) levels.

Methods

One hundred healthy females over 65 years of age routinely attending a twice-weekly mild fitness program were eligible for the study. Clinical history, serum parameters, body composition by DEXA, handgrip strength, knee extensor isometric/isotonic strength and functional performance measured using the Short Physical Performance Battery (SPPB) were evaluated at the baseline and after 3 years.

Results

After 3 years, the women had a significant decrease in weight (?:−0.8 ± 3.1 kg; p < 0.05) and height (?:−0.4 ± 0,6 cm; p < 0.001), while their BMI and body composition parameters did not change. Only IL-6 (?: 0.6 ± 2.0; p < 0.01) and PTH (?: 30.7 ± 29.2 ng/L; p < 0.001) increased significantly, while there were no changes in 25-OHD levels. There was a significant decrease in all the SPPB results and in muscle strength. ? PTH only correlated with the variation in 4-meter walking speed (r: 0.41; p < 0.01).

Conclusions

With advancing age, physical performance declines even in healthy, active females despite a spare of muscle mass. The increase in PTH seems to have a role in this decline, that could be clarified by further investigations.     

High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy

Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (MCD) is a lymphoproliferative disorder most commonly observed in HIV-infected patients. It is characterized by KSHV-infected plasmablasts that frequently express lytic genes. Patients manifest inflammatory symptoms attributed to overproduction of KSHV viral IL-6, human IL-6, and human IL-6. There is no standard therapy and no established response criteria. We investigated an approach targeting 2 KSHV lytic genes, ORF36 and ORF21, the protein of which, respectively, phosphorylate ganciclovir and zidovudine to toxic moieties. In a pilot study, 14 HIV-infected patients with symptomatic KSHV-MCD received high-dose zidovudine (600 mg orally every 6 hours) and the oral prodrug, valganciclovir (900 mg orally every 12 hours). Responses were evaluated using new response criteria. A total of 86% of patients attained major clinical responses and 50% attained major biochemical responses. Median progression-free survival was 6 months. With 43 months of median follow-up, overall survival was 86% at 12 months and beyond. At the time of best response, the patients showed significant improvements in C-reactive protein, albumin, platelets, human IL-6, IL-10, and KSHV viral load. The most common toxicities were hematologic. These observations provide evidence that therapy designed to target cells with lytic KSHV replication has activity in KSHV-MCD. This trial was registered at www.clinicaltrials.gov as #NCT00099073.     

Potentially Inappropriate Medications and Functional Decline in Elderly Hospitalized Patients

OBJECTIVES: To verify whether the use of potentially inappropriate medications (PIMs) is associated with loss of independence in elderly in-patients by promoting adverse drug reactions (ADRs).
DESIGN: Prospective observational study.
PARTICIPANTS: Five hundred six patients aged 65 and older admitted to 11 acute care medical wards.
MEASUREMENTS: In-hospital loss of one or more activities of daily living (ADLs) and three or more ADLs. PIMs were identified according to diagnosis-independent Beers criteria and ascertained by study physicians based on daily review of medical and nurse records. The relationship between risk factors and outcomes was assessed using logistic regression.
RESULTS: Overall, 104 patients (20.6%) were taking at least one PIM at the time of admission (baseline users), and 49 (9.7%) were newly prescribed at least one PIM during their hospital stay. The loss of one or more ADLs occurred in 9.6% of baseline users, 16.3% of new users, and 8.5% of nonusers ( P =.21) and that of three or more ADLs in 7.7% of baseline users, 12.2% of new users, and 4.8% of nonusers ( P =.10). The lack of association was confirmed after correction for potential confounders, including ADRs. The occurrence of ADRs was strongly associated with both outcomes (odds ratio (OR)=7.80, 95% confidence interval (CI)=3.53–17.3 for the loss of ≥1 ADLs; OR=3.98, 95% CI=1.50–10.5 for the loss of ≥3 ADLs), but PIMs caused only six of 106 ADRs.
CONCLUSIONS: ADRs to any drugs more than the use of PIMs might be associated with functional decline in elderly hospitalized patients, but because the power of this study was too limited to definitively exclude a direct relationship between PIMs and functional decline, this merits further investigation.     

A nutraceutical combination improves insulin sensitivity in patients with metabolic syndrome

AIM:To test the efficacy of a proprietary nutraceutical combination in reducing insulin resistance associated with the metabolic syndrome(MetS).METHODS:Sixty-four patients with MetS followed at a tertiary outpatient clinic were randomly assigned to receive either placebo or a proprietary nutraceutical combination(AP)consisting of berberine,policosanol and red yeast rice,in a prospective,double-blind,placebo-controlled study.Evaluations were performed at baseline and after 18 wk of treatment.The homeostasis model assessment of insulin resistance(HOMAIR)index was the primary outcome measure.Secondary endpoints included lipid panel,blood glucose and insulin fasting,after a standard mixed meal and after an oral glucose tolerance test(OGTT),ow-mediated dilation(FMD),and waist circumference.RESULTS:Fifty nine patients completed the study,2 withdrew because of adverse effects.After 18 wk there was a signif icant reduction in the HOMA-IR index in the AP group compared with placebo(ΔHOMA respectively-0.6 ± 1.2 vs 0.4 ± 1.9;P < 0.05).Total and low density lipoprotein cholesterol also significantly decreased in the treatment arm compared with placebo(Δlow density lipoprotein cholesterol-0.82 ± 0.68 vs-0.13 ± 0.55 mmol/L;P < 0.001),while triglycerides,high density lipoprotein cholesterol,and the OGTT were not affected.In addition,there were significant reductions in blood glucose and insulin after the standard mixed meal,as well as an increase in FMD(ΔFMD 1.9 ± 4.2 vs 0 ± 1.9 %;P < 0.05)and a significant reduction in arterial systolic blood pressure in the AP arm.CONCLUSION:This short-term study shows that AP has relevant beneficial effects on insulin resistance and many other components of MetS.     

In situ mantle cell lymphoma: clinical implications of an incidental finding with indolent clinical behavior

Background

Cyclin D1-positive B cells are occasionally found in the mantle zones of reactive lymphoid follicles, a condition that has been called “in situ mantle cell lymphoma”. The clinical significance of this lesion remains uncertain.

Design and Methods

The clinical and pathological characteristics, including SOX11 expression, of 23 cases initially diagnosed as in situ mantle cell lymphoma were studied.

Results

Seventeen of the 23 cases fulfilled the criteria for in situ mantle cell lymphoma. In most cases, the lesions were incidental findings in reactive lymph nodes. The t(11;14) was detected in all eight cases examined. SOX11 was positive in seven of 16 cases (44%). Five cases were associated with other small B-cell lymphomas. In two cases, both SOX11-positive, the in situ mantle cell lymphoma lesions were discovered after the diagnosis of overt lymphoma; one 4 years earlier, and one 3 years later. Twelve of the remaining 15 patients had a follow-up of at least 1 year (median 2 years; range, 1–19.5), of whom 11 showed no evidence of progression, including seven who were not treated. Only one of 12 patients with an in situ mantle cell lymphoma lesion and no diagnosis of mantle cell lymphoma at the time developed an overt lymphoma, 4 years later; this case was also SOX11-positive. The six remaining cases were diagnosed as mantle cell lymphoma with a mantle zone pattern. Five were SOX11-positive and four of them were associated with lymphoma without a mantle zone pattern.

Conclusions

In situ mantle cell lymphoma lesions are usually an incidental finding with a very indolent behavior. These cases must be distinguished from mantle cell lymphoma with a mantle zone pattern and overt mantle cell lymphoma because they may not require therapeutic intervention.     

Classifying Adults with Binge Eating Disorder Based on Severity Levels

The clinical utility of the severity criterion for binge eating disorder (BED), introduced in the DSM‐5 as a means of addressing heterogeneity and variability in the severity of this disorder, was evaluated in 189 treatment‐seeking adults with (DSM‐5) BED. Participants classified with mild, moderate, severe and extreme severity of BED, based on their weekly frequency of binge eating episodes, differed significantly from each other in body mass index (BMI), eating disorder features, putative factors involved in the maintenance process of the disorder, comorbid mood, anxiety and personality disorders, psychological distress, social maladjustment and illness‐specific functional impairment (medium‐to‐large effect sizes). They were also statistically distinguishable in metabolic syndrome prevalence, even after adjusting for BMI (large effect size), suggesting the possibility of non‐BMI‐mediated mechanisms. The implications of the findings, providing support for the utility of the binge frequency as a severity criterion for BED, and directions for future research are outlined. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association