The CD11b promoter directs high-level expression of reporter genes in macrophages in transgenic mice [published erratum appears in Blood 1995 Apr 1;85(7):1983]

CD11b is the alpha chain of the Mac-1 integrin and is preferentially expressed in myeloid cells (neutrophils, monocytes, and macrophages). We have previously shown that the CD11b promoter directs cell-type- specific expression in myeloid lines using transient transfection assays. To confirm that these promoter sequences contain the proper regulatory elements for correct myeloid expression of CD11b in vivo, we have used the -1.7-kb human CD11b promoter to direct reporter gene expression in transgenic mice. Stable founder lines were generated with two different reporter genes, a Thy 1.1 surface marker and the Escherichia coli lacZ (beta-galactosidase) gene. Analysis of founders generated with each reporter demonstrated that the CD11b promoter was capable of driving high levels of transgene expression in murine macrophages for the lifetime of the animals. Similar to the endogenous gene, transgene expression was preferentially found in mature monocytes, macrophages, and neutrophils and not in myeloid precursors. These experiments indicate that the -1.7 CD11b promoter contains the regulatory elements sufficient for high-level macrophage expression. This promoter should be useful for targeting heterologous gene expression to mature myeloid cells.     

Interleukin-2 induction of lymphokine-activated killer (LAK) activity in the peripheral blood and bone marrow of acute leukemia patients: II. Feasibility of LAK generation in children with active disease and in remission

Activation and expansion in culture with rIL-2 of peripheral blood (PB) and/or bone marrow (BM) specimens derived from children with ALL and ANLL, with active disease (AP) and in remission were studied (RP). Baseline NK cytolytic activity from AP was found to be depressed, whereas RP-derived cells had normal NK activity, as assayed against K562 targets. Culture in rIL-2 significantly enhanced the NK activity of both AP- and RP-derived cells and generated LAK activity, as assayed by 4-hour 51Cr release, against NK-resistant Raji cell line and against fresh, allogeneic, and autologous tumor cells. Lytic activity against fresh, cryopreserved leukemia blasts was of lower than that found against cell lines. In three patients higher lytic activity against autologous than against allogeneic blasts was demonstrated. Expansion in culture with rIL-2 varied from twofold to 120-fold. rIL-2 activation and expansion was better in RP than in AP. The predominant phenotype of activated cells, as determined by flow cytometry, was [mean % (SD)]: CD3- = 54 (12), CD8+ = 55 (17), and NKH1+ = 26 (7). The consistently high level of CD8+ cells was accompanied by very low levels of CD4+ cells: mean = 11% (14). Double-marker analysis showed mean of 33% (10) for CD3+/NKH1+ cells and mean = 32 (11) for CD8+/NKH1+ cells, implying that these populations were overlapping. Kinetics of expression of cell surface markers during 2 to 3 weeks in culture showed that CD8+ and NKH1+ enrichment occurred during the first week and lasted for up to 4 weeks, whereas CD4+ expression decreased after the second week. A significant decrease in the expression of IL-2 receptors (CD25) was observed from the second week of culture. This study shows the feasibility of in vitro generation of killer cells from PB and BM of pediatric leukemia patients.     

Changes in individual plasma amino acids following experimentally induced and fly fever virus infection

Fasting concentrations of 21 individual plasma amino acids were determined in daily (7:30 a.m.) serial samples from eight volunteers infected with sand fly fever virus and compared to values obtained in six separate daily preexposure baseline measurements in each volunteer, as well as to serial measurements in three unexposed control subjects. By 47 hr after inoculation and before the onset of fever or other clinical indications of infection, most individual plasma amino acids were significantly depressed below preexposure values. These changes began before the marked decrement in protein intake during the illness. Such changes in plasma amino acids did not occur in control subjects. Reduction in amino acid concentrations persisted until after the lysis of fever and did not coincide in timing with alterations in white blood counts or serum Zn and Fe values. Urinary total nitrogen, urea, and alpha amino nitrogen were not altered during the course of sand fly fever in these subjects. Although food intake was reduced during sand fly fever, the magnitude of the amino acid depression was far greater than that reported during starvation or protein deprivation in non-infected subjects, and the sequence of changes in plasma valine, alanine, and glycine followed patterns different from those reported during starvation. It may be postulated that unusually large quantities of certain plasma amino acids were taken up by the cells of the liver and other visceral tissues during this infection. Plasma phenylalanine responded in a manner different from that of the other amino acids. It was decreased on day 2 after exposure to the virus but by day 4 and 5 was significantly increased above preinfection values. This resulted in a significant increase in the phenylalaninetyrosine ratio during the febrile phase of sand fly fever.     

The beneficial effect of alcohol consumption on the prevalence and extent of centrilobular emphysema. A retrospective autopsy analysis

A collection of 204 inflation-fixed autopsy lungs was divided into three groups: normal, 93; centrilobular emphysema (CLE), 88; and "other," 23; the last includes lungs with other chronic processes. Clinical hospital records were reviewed to ascertain smoking history (no smoking, 31; smoking, 173) and alcohol use (none, 73; slight-to-moderate (Sli-Mod) drinkers, 66; heavy drinkers, 65). Lungs were subjected to morphometric determination of the extent of CLE, mucous gland hyperplasia in large airways, and goblet cell metaplasia in bronchioles. Prevalence of CLE diminished progressively as alcohol use increased. A logistic analysis showed that alcohol use was significantly associated (p less than 0.008) with reduced extent of CLE even after allowing for age and smoking effects. This apparent prophylactic effect of alcohol against CLE probably results from inhibition of inflammatory cells. It suggests that a drug with similar effects but without the deleterious side effects of alcohol might provide a meaningful degree of protection against emphysema in smokers.     

Insight into patient dissatisfaction with asthma treatment

BACKGROUND: Measures of patient satisfaction or dissatisfaction with treatment are increasingly being used as indicators of quality of care. As these measures become more widely used, it is important to know if patient dissatisfaction is associated with important processes or outcomes of medical care. METHODS: Survey of patient-reported asthma management issues using the Asthma Therapy Assessment Questionnaire in a large health maintenance organization in the Pacific Northwest. Associations between patient dissatisfaction with asthma treatment and patient-reported measures of asthma control, patient-provider communication, and belief in asthma medications (self-efficacy) were examined. RESULTS: Of the 5181 adult members with asthma enrolled in the health maintenance organization, 30% indicated dissatisfaction with current treatment. Dissatisfaction was higher among patients with a higher number of asthma control problems, patient-provider communication problems, or belief in medication problems (eg, failure to believe their medications are useful and inability to take asthma medications as directed). The odds of dissatisfaction with treatment were 2.8 (95% confidence interval [CI], 2.4-3.3; P<.001) for asthma control problems, 2.0 (95% CI, 1.6-2.6; P<.001) for communication problems, and 8.0 (95% CI, 6.7-9.5; P<.001) for belief in medication problems compared with patients without these perceived problems. CONCLUSION: Patient dissatisfaction with treatment may be related to important asthma disease management issues.     

Respiratory symptoms and obstructive pulmonary disease in a population aged over 70 years

STUDY QUESTION: What is the prevalence of respiratory symptoms and obstructive pulmonary disease by age, sex, and smoking history in a population aged 70 years and older? What is the association between selected comorbidities and obstructive pulmonary disease? PATIENTS AND METHODS: A questionnaire on respiratory symptoms and disease, selected comorbidities, and smoking history was mailed to a cross-sectional, sex- and age-stratified, random sample of the population 70 years and older of Bergen, Norway. RESULTS: About 11% of these elderly persons reported having at least one current obstructive pulmonary disease, 8% reported daily wheezing, and 12% reported significant dyspnea. The only respiratory symptom or disorder to show any clear age-related pattern was dyspnea, which increased through age 89 before declining. Dyspnea, current asthma, and current chronic bronchitis were about half as likely in males as females, after adjusting for smoking pack-years. Persons with obstructive pulmonary disease reported problems with walking, heart disease, and muscle/joint disease more frequently than those without. CONCLUSIONS: The prevalence of respiratory symptoms and obstructive pulmonary disease has been estimated. Only dyspnea was associated with age in this elderly population. Female sex was a predictor of dyspnea, current asthma, and current chronic bronchitis.     

Comparative Effectiveness of Usual Care With or Without Chiropractic Care in Patients with Recurrent Musculoskeletal Back and Neck Pain

Background

Chiropractic care is a popular alternative for back and neck pain, with efficacy comparable to usual care in randomized trials. However, the effectiveness of chiropractic care as delivered through conventional care settings remains largely unexplored.

Objective

To evaluate the comparative effectiveness of usual care with or without chiropractic care for patients with chronic recurrent musculoskeletal back and neck pain.

Study design

Prospective cohort study using propensity score-matched controls.

Participants

Using retrospective electronic health record data, we developed a propensity score model predicting likelihood of chiropractic referral. Eligible patients with back or neck pain were then contacted upon referral for chiropractic care and enrolled in a prospective study. For each referred patient, two propensity score-matched non-referred patients were contacted and enrolled. We followed the participants prospectively for 6 months.

Main measures

Main outcomes included pain severity, interference, and symptom bothersomeness. Secondary outcomes included expenditures for pain-related health care.

Key results

Both groups’ (N?=?70 referred, 139 non-referred) pain scores improved significantly over the first 3 months, with less change between months 3 and 6. No significant between-group difference was observed. (severity ??0.10 (95% CI ??0.30, 0.10), interference ??0.07 (??0.31, 0.16), bothersomeness ??0.1 (??0.39, 0.19)). After controlling for variances in baseline costs, total costs during the 6-month post-enrollment follow-up were significantly higher on average in the non-referred versus referred group ($1996 [SD?=?3874] vs $1086 [SD?=?1212], p?=?.034). Adjusting for differences in age, gender, and Charlson comorbidity index attenuated this finding, which was no longer statistically significant (p?=?.072).

Conclusions

We found no statistically significant difference between the two groups in either patient-reported or economic outcomes. As clinical outcomes were similar, and the provision of chiropractic care did not increase costs, making chiropractic services available provided an additional viable option for patients who prefer this type of care, at no additional expense.

     

Type 2 Diabetes and COVID-19–Related Mortality in the Critical Care Setting: A National Cohort Study in England,March–July 2020

OBJECTIVETo describe the relationship between type 2 diabetes and all-cause mortality among adults with coronavirus disease 2019 (COVID-19) in the critical care setting.RESEARCH DESIGN AND METHODSThis was a nationwide retrospective cohort study in people admitted to hospital in England with COVID-19 requiring admission to a high dependency unit (HDU) or intensive care unit (ICU) between 1 March 2020 and 27 July 2020. Cox proportional hazards models were used to estimate 30-day in-hospital all-cause mortality associated with type 2 diabetes, with adjustment for age, sex, ethnicity, obesity, and other major comorbidities (chronic respiratory disease, asthma, chronic heart disease, hypertension, immunosuppression, chronic neurological disease, chronic renal disease, and chronic liver disease).RESULTSA total of 19,256 COVID-19–related HDU and ICU admissions were included in the primary analysis, including 13,809 HDU (mean age 70 years) and 5,447 ICU (mean age 58 years) admissions. Of those admitted, 3,524 (18.3%) had type 2 diabetes and 5,077 (26.4%) died during the study period. Patients with type 2 diabetes were at increased risk of death (adjusted hazard ratio [aHR] 1.23 [95% CI 1.14, 1.32]), and this result was consistent in HDU and ICU subsets. The relative mortality risk associated with type 2 diabetes decreased with higher age (age 18–49 years aHR 1.50 [95% CI 1.05, 2.15], age 50–64 years 1.29 [1.10, 1.51], and age ≥65 years 1.18 [1.09, 1.29]; P value for age–type 2 diabetes interaction = 0.002).CONCLUSIONSType 2 diabetes may be an independent prognostic factor for survival in people with severe COVID-19 requiring critical care treatment, and in this setting the risk increase associated with type 2 diabetes is greatest in younger people.     

Deletion of the D domain of the human parainfluenza virus type 3 (HPIV3) PD protein results in decreased viral RNA synthesis and beta interferon (IFN-β) expression

Parvoviridae is a family of small non-enveloped viruses and divided into two subfamilies. The family members infect a wide range of organisms from insects to humans and some of the members (e.g., nonpathogenic adeno-associated viruses) are effective gene therapy delivery vectors. We detailed the synonymous codon usage pattern of Parvoviridae family from the available 58 sequenced genomes through multivariate statistical methods. Our results revealed that nine viruses showed some degree of strong codon bias, and the others possessed a general weak trend of codon bias. ENc-plot and neutrality plot results showed that selective pressure dominated over mutation in shapes coding sequence’s composition. The overall GC content and GC content at the third synonymous codon position were the principal determinants behind the variations within the codon usage patterns, as they both significantly correlated with the first axis of correspondence analysis. In addition, gene length had no direct influence on the codon usage pattern. Densovirinae subfamily and Parvovirinae subfamily possessed nine identical preferred codons, though most of the two subfamilies codon usage frequencies were significantly different. The result of cluster analysis based on synonymous codon usage was discordant with that of taxonomic classification. Adeno-associated viruses formed a separated clade far from other Parvoviridae members in the dendrogram. Thus, we concluded that natural selection rather than mutation pressure accounts for the main factor that affects the codon bias in Parvoviridae family.