Immunohistological demonstration of respiratory syncytial virus antigens in Paget disease of bone.

Respiratory syncytial virus antisera have been found to produce a positive immunohistologic response in osteoclasts in bone sections or in cells cultured from Paget disease lesions in 12 out of 12 patients tested. These experiments were carefully controlled by several means. Use of experimentally infected cells served as positive controls. Adsorption of antisera on human bone powder and KB cells did not remove the specific immunologic stain, but adsorption of the antisera by the virus did. Negative results were also obtained in osteoclasts of patients with primary or secondary hyperparathyroidism. In addition, negative results in specimens of Paget disease were found with antisera to measles; parainfluenza 1, 2, and 3; influenza A, B and C; rubella; and herpes simplex. These results are consistent with the hypothesis that the nuclear and cytoplasmic inclusions in the osteoclasts of Paget disease are a result of viral activity.     

Arm exercise-thallium imaging testing for the detection of coronary artery disease

Patients with lower limb impairment are often unable to undergo a standard bicycle or treadmill test for the evaluation of coronary artery disease. To establish an alternative method of testing, 50 subjects (aged 56 +/- 10 years) performed arm ergometry testing in conjunction with myocardial thallium scintigraphy. All underwent coronary angiography; significant coronary artery disease (greater than or equal to 70% stenosis) in at least one vessel was present in 41 (82%) of the 50 patients. Thallium scintigraphy was found to have an 83% sensitivity and 78% specificity for detecting coronary disease, compared with a sensitivity and specificity of 54% (p less than 0.01) and 67% (p = NS), respectively, for exercise electrocardiography. In the subgroup of 23 patients who had no prior myocardial infarction or left bundle branch block and were not taking digitalis, thallium scintigraphy had a sensitivity of 80% versus 50% for exercise electrocardiography. Scintigraphy yielded a sensitivity of 84, 74 and 90% for one, two and three vessel disease, respectively. Noninvasive arm ergometry exercise-thallium imaging testing appears to be reliable and useful and should be considered in the evaluation of coronary artery disease in patients with lower limb impairment.     

Respiratory dyskinesias: extrapyramidal dysfunction and dyspnea

Four patients had acute dyspnea and chest pain due to primary neurologic disease, not to cardiac or pulmonary disorders. They suffered from severe, involuntary respiratory dyskinesias, which resulted in an irregular respiratory rate, shortness of breath, and chest discomfort. These respiratory dyskinesias occurred as one aspect of more generalized choreiform movement disorders. Three patients had neuroleptic-induced tardive dyskinesias, and one had levodopa-induced dyskinesias. As a result of their ages and the nature of their complaints, some of these patients were originally thought to have cardiac and pulmonary disorders. Respiratory dyskinesias should be considered as a possible cause of respiratory distress in patients with extrapyramidal dysfunction.     

Prevalence and prognostic significance of silent and symptomatic ischemia after coronary bypass surgery: a report from the Coronary Artery Surgery Study (CASS) randomized population

The prevalence and prognostic significance of postoperative myocardial ischemia, as detected by exercise testing, were prospectively assessed in 174 patients from the Coronary Artery Surgery Study (CASS) randomized surgical population who had exercise testing before and 6 months after coronary artery bypass graft surgery. Whereas the prevalence of symptomatic ischemia significantly decreased postoperatively (52% vs. 6%, p less than 0.001), the frequency of silent myocardial ischemia did not change (30% vs. 29%). Survival at 12 years after bypass surgery based on the 6-month postoperative exercise test results was significantly better for the 112 patients with no ischemia (80%) than for the 51 patients with silent ischemia (68%) or the 11 patients with symptomatic ischemia (45%). These data show that coronary artery bypass graft surgery diminishes the overall prevalence of symptomatic but not silent ischemia and that both silent and symptomatic ischemia adversely affect the postoperative prognosis of these patients.     

Further insights into digoxin-quinidine interaction: Lack of correlation between serum digoxin concentration and inotropic state of the heart

The digoxin-quinidine interaction was studied in nine healthy human subjects aged 26 to 31 years. A single oral dose (400 mg) of quinidine sulfate administered to subjects taking digoxin resulted in a mean (± standard error of the mean) increase within 1 to 6 hours in the serum digoxin concentration of 0.12 ± 0.01 ng/ml (p <0.0001), an increase of 21 percent. Continued quinidine administration for 24 hours resulted in a 59 percent increase in the mean serum digoxin concentration from 0.68 ± 0.04 to 1.04 ± 0.06 ng/ml (alpha = 0.05). At the same time, however, systolic time intervals demonstrated a lengthening of the mean left ventricular ejection time index from 406 ± 4 to 419 ± 2 ms (alpha = 0.05) and the mean Q?S₂ Index from 524 ± 6 to 532 ± 7 ms (difference not significant [NS]). When compared with the shortening of these intervals predicted from the digoxin dose-response curve if digoxin were the only variable, the lengthening actually observed for both intervals was highly significant. The negative inotropic effect of quinidine administration alone was assessed with systolic time intervals in four subjects. The left ventricular ejection time index lengthened from 419 ± 3 to 425 ± 6 ms (NS) and the Q?S₂ index from 541 ± 6 to 550 ± 7 ms (NS). Therefore, the lengthening of these intervals in subjects taking digitalis after the addition of quinidine represents more than just the negative inotropic effect of quinidine, and occurs despite the increase in serum digoxin concentration.The results of this study support the view that quinidine displaces digoxin from tissue-binding sites as a major mechanism of the interaction. Furthermore, it appears that quinidine may specifically displace digoxin from cardiac-binding sites. These results raise important questions concerning the recommendation to reduce the maintenance digoxin dose when concomitant quinidine therapy is initiated.     

Pernicious anemia in Latin Americans is not a disease of the elderly

Pernicious anemia is widely regarded as a disease of the elderly. However, it is expressed differently in black women, among the most striking differences being their younger age at presentation of the disease compared with whites. We now compared 92 Latin-American patients with 115 white and 100 black patients to see if similar age differences occur in other racial groups. Latin-American men and women were both significantly younger than white men and women, and were similar in age to blacks. Only 21% of Latin-American patients were 70 years of age or older, compared with 49% of whites. It is apparent that pernicious anemia is indeed predominantly a disease of the elderly in whites but that this is not the case in other racial groups.     

Antibody responses to endemic coronaviruses modulate COVID-19 convalescent plasma functionality

SARS-CoV-2 (CoV2) antibody therapies, including COVID-19 convalescent plasma (CCP), monoclonal antibodies, and hyperimmune globulin, are among the leading treatments for individuals with early COVID-19 infection. The functionality of convalescent plasma varies greatly, but the association of antibody epitope specificities with plasma functionality remains uncharacterized. We assessed antibody functionality and reactivities to peptides across the CoV2 and the 4 endemic human coronavirus (HCoV) genomes in 126 CCP donations. We found strong correlation between plasma functionality and polyclonal antibody targeting of CoV2 spike protein peptides. Antibody reactivity to many HCoV spike peptides also displayed strong correlation with plasma functionality, including pan-coronavirus cross-reactive epitopes located in a conserved region of the fusion peptide. After accounting for antibody cross-reactivity, we identified an association between greater alphacoronavirus NL63 antibody responses and development of highly neutralizing antibodies against CoV2. We also found that plasma preferentially reactive to the CoV2 spike receptor binding domain (RBD), versus the betacoronavirus HKU1 RBD, had higher neutralizing titer. Finally, we developed a 2-peptide serosignature that identifies plasma donations with high anti-spike titer, but that suffer from low neutralizing activity. These results suggest that analysis of coronavirus antibody fine specificities may be useful for selecting desired therapeutics and understanding the complex immune responses elicited by CoV2 infection.     

Effects of APOE ɛ4 on brain amyloid,lacunar infarcts,and white matter lesions: a study among patients with subcortical vascular cognitive impairment

The relationship between the apolipoprotein E ?4 allele (APOE4) and factors associated with vascular cognitive impairment (VCI) is unclear. We aimed to examine the effects of APOE4 on brain amyloid beta using Pittsburg compound B (PiB) and subcortical cerebrovascular disease, as assessed by lacunes and white matter hyperintensities (WMH) in subcortical VCI (SVCI) patients. We recruited 230 subjects with normal cognition, 111 subjects with cognitive impairment due to clinically defined Alzheimer’s disease (ADCI), and 134 subjects with clinically defined SVCI. A PiB retention ratio greater than 1.5 was considered to be PiB positive. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each cognitive impairment group. Multiple linear regression analysis was performed to investigate whether APOE4 was associated with brain amyloid beta, lacunes, and WMH. APOE4 did not increase the risk of PiB(−) SVCI (odds ratio [OR], 1.50; 95% confidence interval [CI], 0.79–2.84), whereas APOE4 increased the risk of PiB(+) SVCI (OR, 4.52; 95% CI, 1.70–11.97) and PiB(+) ADCI (odds ratio, 4.84; 95% CI, 2.54–7.91). In SVCI patients, APOE4 was positively associated with PiB retention ratio, whereas APOE4 was not associated with the number of lacunes or with WMH volume. Our results suggest that amyloid beta burden can occur in patients with and without subcortical cerebrovascular disease, and that it is associated with APOE4. However APOE4 might be independent of subcortical cerebrovascular disease.     

Inducing Humoral and Cellular Responses to Multiple Sporozoite and Liver-Stage Malaria Antigens Using Exogenous Plasmid DNA

A vaccine candidate that elicits humoral and cellular responses to multiple sporozoite and liver-stage antigens may be able to confer protection against Plasmodium falciparum malaria; however, a technology for formulating and delivering such a vaccine has remained elusive. Here, we report the preclinical assessment of an optimized DNA vaccine approach that targets four P. falciparum antigens: circumsporozoite protein (CSP), liver stage antigen 1 (LSA1), thrombospondin-related anonymous protein (TRAP), and cell-traversal protein for ookinetes and sporozoites (CelTOS). Synthetic DNA sequences were designed for each antigen with modifications to improve expression and were delivered using in vivo electroporation (EP). Immunogenicity was evaluated in mice and nonhuman primates (NHPs) and assessed by enzyme-linked immunosorbent assay (ELISA), gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay, and flow cytometry. In mice, DNA with EP delivery induced antigen-specific IFN-γ production, as measured by ELISpot assay and IgG seroconversion against all antigens. Sustained production of IFN-γ, interleukin-2, and tumor necrosis factor alpha was elicited in both the CD4⁺ and CD8⁺ T cell compartments. Furthermore, hepatic CD8⁺ lymphocytes produced LSA1-specific IFN-γ. The immune responses conferred to mice by this approach translated to the NHP model, which showed cellular responses by ELISpot assay and intracellular cytokine staining. Notably, antigen-specific CD8⁺ granzyme B⁺ T cells were observed in NHPs. Collectively, the data demonstrate that delivery of gene sequences by DNA/EP encoding malaria parasite antigens is immunogenic in animal models and can harness both the humoral and cellular arms of the immune system.     

Development of an instrument for the identification of frail older people as a target population for integrated care

Background

Primary care is increasingly interested in the identification of frailty, as it selects the target population for integrated care. However, instruments for the identification of frailty specifically validated for use in primary care are scarce. This study developed the Easycare Two-step Older persons Screening (Easycare-TOS), which provides a valid, efficient, and pragmatic screening procedure to identify frail older people.

Aim

This paper aims to describe the development of the Easycare-TOS and the data from the pilot studies.

Design and setting

Observational pilot study in seven academic GP practices in and around Nijmegen, The Netherlands.

Method

The Easycare-TOS was developed in a cyclic process with the input of stakeholders. In every cycle, the requirements were first defined, then translated into a prototype that was tested in a pilot study. The Easycare-TOS makes optimal use of prior knowledge of the GP, and the professionals’ appraisal is decisive in the frailty decision, instead of a cut-off score. Further, it considers aspects of frailty, as well as aspects of the care context of the patient.

Results

The pilot data have shown that after step 1, two-thirds of the patients do not need further assessment, because they are judged as not frail, based on prior knowledge of the GP. The overall prevalence of frailty in this pilot study is 24%. Most professionals who participated in the pilot studies considered the time investment acceptable and the method to be of added value.

Conclusion

The Easycare-TOS instrument meets the predefined efficiency, flexibility, and acceptability requirements for use as an identification instrument for frailty in primary care.