Transient Neonatal Zinc Deficiency Caused by a Novel Mutation in the SLC30A2 Gene

This is a case report of a 4‐month‐old full‐term, fully breastfed boy who presented with a persistent periorificial and groin rash associated with poor weight gain and irritability. His serum zinc level was low. The mother's breast milk zinc level was found to be low despite her serum zinc levels being normal, confirming the diagnosis of transient neonatal zinc deficiency. Mutational analysis revealed a novel mutation in the mother's SLC30A2 gene, which encodes a zinc transporter expressed in mammary gland epithelial cells.     

Cytogenetic and histologic correlations in malignant lymphoma

Although a number of studies have indicated correlations between histologic subtypes of tumors and certain nonrandom chromosome changes, cytogenetic studies of lymphoma are in an early stage compared to those of leukemia. No comprehensive analysis of available data has so far been attempted in the literature either. Here we present an analysis of chromosome changes and their correlation with subtypes of lymphoma studied by conventional histology and cell surface markers, as observed in two sets of data: a group of 65 karyotypically abnormal tumors sequentially ascertained and studied by us during the period January 1, 1984 to April 30, 1985, and a larger data set derived by combining our data with those from two published series from the University of Minnesota that are comparable to our data. These combined data, which comprise the largest data set on the cytogenetics of lymphomas assembled so far, enabled a comprehensive analysis of correlation between chromosome change and tumor histology and the patterns of chromosome instability in these tumors. We found several significant associations, some previously described and others now recognized, between nonrandom chromosome gains, breaks, translocations, and deletions and histologic subtypes of tumors that characterize lymphomas. The data indicate that finding of chromosome breaks at certain sites (eg, 8q24, 14q32, 18q21) is of diagnostic value in dealing with cases of unusual lymphoma. Furthermore, nonrandom chromosome breakage exhibited three distinct patterns that reflected three levels of etiologically relevant genetic change.     

“Experience Keeps a Dear School”: the Effects of Ethnicity and Caregiving Experience on Hiring a Healthcare Advocate

In the present study, ethnic differences in evaluating the severity and associated needs of medical complications experienced by an elderly man and the likelihood of seeking professional assistance (i.e., hire a healthcare advocate [HCA]) to care for him, and for one’s own family or parent should they become ill, as a function of previous caregiving experience, were investigated. The 974 participants were White, Black, Hispanic, or Asian/Pacific Islander. They read a hypothetical vignette about a 75-year-old man, Daryl, who was experiencing health problems. Participants were instructed to imagine that they were James, Daryl’s son, and asked to indicate how severe his condition(s) were, how much medical assistance he would require, and how likely they would be to hire an HCA to assist him. They were also asked to report whether they previously had assisted a parent with activities of daily living (Assistance) and whether they would be likely to hire an HCA in the future if 1) a family member or 2) a parent, specifically, became ill. Two, 2 (Assistance) × 4 (Ethnicity) multivariate analyses of covariance (MANCOVA) were performed to assess differential responses among individuals of different ethnicities as a function of previous caregiver experience. A priori interaction contrasts were examined to determine whether Black, Hispanic, or Asian/Pacific Islander participants differed on the outcomes from White participants as a function of previous caregiver experience. There were no significant differences between Black or Asian/Pacific Islander and White participants, but Hispanic participants assigned significantly higher severity and need for medical assistance ratings and were significantly more likely to indicate that they would seek assistance from an HCA with respect to the vignette and for their own parents in the future if they had provided caregiving to a parent in the past, whereas White participants were less likely to seek assistance from an HCA if they had provided caregiving in the past to a parent. Although ethnic differences in evaluations of Daryl’s condition and in the reported likelihoods of hiring an HCA in various contexts as a function of previous caregiving experience were limited, there are important inter-cultural differences to recognize. It may be important in future research to assess ethnic differences in the expectations and experiences of caregiving.     

Shortened Telomere Length in Sputum Cells of Bronchiectasis Patients is Associated with Dysfunctional Inflammatory Pathways

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta?=????1.167, P_Adj?=?2.75?×?10^?4). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients.

     

A 10-Year Trend in Statin Use Among Older Adults in Australia: an Analysis Using National Pharmacy Claims Data

Background

Statins have become standard of care in the prevention and treatment of atherosclerotic cardiovascular disease. The objective of this study was to examine the trends in statin use among Australians aged ≥?65 years for the period 2007–2016.

Methods

Data from the Pharmaceutical Benefits Scheme covering a 10% random sample of the Australian population were analysed. The 1-year prevalence and incidence of statin use were determined for each year, as were the percentage of statin dispensations according to statin type or intensity and the percentage of new users prescribed each statin type or intensity. To describe relative changes, age-sex adjusted rate ratios (RRs) and 95% confidence intervals (CIs) were determined via Poisson regression modelling using 2007 as the reference year.

Results

The 1-year prevalence of statin use increased consistently each year from 34.2% in 2007 to 44.1% in 2016 (RR 1.29, 95% CI 1.28–1.31). The 1-year incidence was 68.5 per 1000 in 2007 and 59.0 per 1000 in 2016 (RR 0.87, 95% CI 0.84–0.90). Women were 18% (age-adjusted rate ratio [aRR] 0.82, 95% CI 0.79–0.83) less likely than men to initiate statins across all years. The incidence of statin use was also highest among individuals aged 65–74 years, who were about 15% (sex-adjusted rate ratio [sRR] 1.15, 95% CI 1.13–1.16) and 45% (sRR 1.45, 95% CI 1.44–1.47) more likely to initiate statins than those aged 75–84 and ≥ 85 years, respectively. Atorvastatin was the most commonly dispensed statin across all years. The proportion of new users dispensed high-intensity statins increased year-on-year from 23.6% in 2007 to 30.5% in 2016 (RR 1.26, 95% CI 1.21–1.31).

Conclusion

The proportion of older adults in Australia using statins has increased over the last decade, although the incidence has declined. Atorvastatin is the most commonly dispensed statin and the use of high intensity statin has increased.

     

Quantitative evaluation of liver-specific promoters from retroviral vectors after in vivo transduction of hepatocytes

Hepatic gene therapy could be used to treat a number of inherited blood diseases such as hemophilia or thrombophilia. Although liver-directed retroviral transduction can result in long-term gene expression in vivo, the low level of protein production has limited its clinical application. We reasoned that the insertion of liver-specific promoters into retroviral vectors would increase gene expression in vivo. The 347- bp human alpha 1-antitrypsin (hAAT), the 810-bp murine albumin (mAIb), the 490-bp rat phosphoenolpyruvate carboxykinase (rPECK), and the 596- bp rat liver fatty acid binding protein promoters were inserted into a Moloney murine leukemia retroviral backbone containing the hAAT reporter gene. Vectors that produced appropriately sized RNA and hAAT protein in vitro were tested in vivo by transducing regenerating rat livers. Long-term serum expression of the hAAT reporter gene was normalized to retroviral transduction efficiency as determined by using a polymerase chain reaction-based assay of genomic DNA from transduced rat livers. The hAAT, mAIb, and rPEPCK promoters were, respectively, 35- , 8-, and 0.02-fold as strong as the previously studied constitutive Pol-II promoter. We conclude that the hAAT promoter resulted in the highest expression from a retroviral vector and may result in therapeutically significant expression of other clinically significant blood proteins.     

Molecular basis of altered red blood cell membrane properties in Southeast Asian ovalocytosis: role of the mutant band 3 protein in band 3 oligomerization and retention by the membrane skeleton

Southeast Asian ovalocytosis (SAO) is an asymptomatic trait characterized by rigid, poorly deformable red cells that resist invasion by several strains of malaria parasites. The underlying molecular genetic defect involves simple heterozygous state for a mutant band 3 protein, which contains a deletion of amino acids 400 through 408, linked with a Lys 56-to-Glu substitution (band 3-Memphis polymorphism). To elucidate the contribution of the mutant SAO band 3 protein to increased SAO red blood cell (RBC) rigidity, we examined the participation of the mutant SAO band 3 protein in increased band 3 attachment to the skeleton and band 3 oligomerization. We found first that SAO RBC skeletons retained more band 3 than normal cells and that this increased retention preferentially involved the mutant SAO band 3 protein. Second, SAO RBCs contained a higher percentage of band 3 oligomer-ankyrin complexes than normal cells, and these oligomers were preferentially enriched by the mutant SAO protein. At the ultrastructural level, the increased oligomer formation of SAO RBCs was reflected by stacking of band 3-containing intramembrane particles (IMP) into longitudinal strands. The IMP stacking was not reversed by treating SAO RBCs in alkaline pH (pH 11), which is known to weaken ankyrin-band 3 interactions, or by removing the cytoplasmic domain of band 3 from SAO membranes with trypsin. Finally, we found that band 3 protein in intact SAO RBCs exhibited a markedly decreased rotational mobility, presumably reflecting the increased oligomerization and the membrane skeletal association of the SAO band 3 protein. We propose that the mutant SAO band 3 has an increased propensity to form oligomers, which appear as longitudinal strands of IMP and exhibit increased association with membrane skeleton. This band 3 oligomerization underlies the increase in membrane rigidity by precluding membrane skeletal extension, which is necessary for membrane deformation.     

Effects of interleukin-11 on the proliferation and cell cycle status of myeloid leukemic cells

Interleukin-11 (IL-11) is a pleiotropic cytokine with effects on many different targets. Within the hematopoietic system, the effects of IL- 11 are largely manifest only through combination with other cytokines, including IL-3 and Steel factor (SF). In the present study, we addressed the question of IL-11 responsiveness within the different types of human leukemic cells, as well as the mechanism of action of IL- 11 at the cellular level. Analysis of a panel of samples from different patients with acute myeloblastic leukemia (AML) and myeloid leukemic cell lines indicated that IL-11 alone was ineffective in supporting myeloid leukemic cell growth but frequently enhanced growth supported by IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), or SF. In contrast, three acute pre-B lymphocytic leukemia (pre-B-ALL) and two acute T lymphocytic leukemia (T-ALL) lines failed to respond to IL- 11 alone or when combined with other cytokines. The growth enhancement of IL-11 among the AML patient samples was dose dependent and remarkably constant with half-efficient concentrations in the range of 0.3 to 0.4 ng/mL. The thymidine suicide studies with the patient samples revealed that 40% to 50% of the blast cells were in S-phase when exposed for 16 hours to IL-3 and this level was increased to 70% to 90% in response to either IL-11 or IL-6. Our data suggest that the latter two interleukins act synergistically with the direct mitogenic factor, IL-3, in triggering AML blast-cell proliferation. Detailed analysis with several patient samples further revealed that SF and IL- 11 both enhance IL-3-supported clonogenic growth of AML blasts and the combination of all three growth factors yields optimal growth. In contrast, IL-6 does not further enhance the effect of IL-11. These results indicate that SF and IL-11 enhance IL-3-dependent clonogenic growth through two distinct pathways, whereas IL-6 and IL-11 may trigger the same pathway.     

Advanced musculoskeletal physiotherapists in post arthroplasty review clinics: a state wide implementation program evaluation

Objective

To evaluate outcomes following a state-wide implementation of post arthroplasty review (PAR) clinics for patients following total hip and knee arthroplasty, led by advanced musculoskeletal physiotherapists in collaboration with orthopaedic specialists.