Familial chylomicronemia syndrome. A sixty year follow-up in two siblings and their kindreds. Nosological and clinical considerations.

Familial chylomicronemia syndrome (FCS) is a rare and severe genetic disorder, characterized by marked elevation of plasma triglycerides, often diagnosed in infancy. We describe the long-term follow-up (almost 60 years), the diagnostic assessment and the management of two siblings with severe hypertriglyceridemia and a history of pancreatitis who also developed cardiovascular complications later in life. We recently disclosed that the surviving index case was homozygous for a pathogenic LPL gene variant (c.984 G>T, p.M328I). The same variant was also found in two apparently unrelated siblings with FCS living in the same geographical area as the index case.

PPARγ Pro12Ala and ACE ID polymorphisms are associated with BMI and fat distribution, but not metabolic syndrome.

BACKGROUND: Metabolic Syndrome (MetS) results from the combined effect of environmental and genetic factors. We investigated the possible association of peroxisome proliferator-activated receptor-γ2 (PPARγ2) Pro12Ala and Angiotensin Converting Enzyme (ACE) I/D polymorphisms with MetS and interaction between these genetic variants. METHODS: Three hundred sixty four unrelated Caucasian subjects were enrolled. Waist circumference, blood pressure, and body mass index (BMI) were recorded. Body composition was estimated by impedance analysis; MetS was diagnosed by the NCEP-ATPIII criteria. A fasting blood sample was obtained for glucose, insulin, lipid profile determination, and DNA isolation for genotyping. RESULTS: The prevalence of MetS did not differ across PPARγ2 or ACE polymorphisms. Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but lower systolic blood pressure compared with Pro/Pro homozygotes. A significant PPARγ2 gene-gender interaction was observed in the modulation of BMI, fat mass, and blood pressure, with significant associations found in women only. A PPARγ2-ACE risk genotype combination for BMI and fat mass was found, with ACE DD/PPARγ2 Ala subjects having a higher BMI (p = 0.002) and Fat Mass (p = 0.002). Pro12Ala was independently associated with waist circumference independent of BMI and gender. CONCLUSIONS: Carriers of PPARγ2 Ala allele had higher BMI and fat-mass but not a worse metabolic profile, possibly because of a more favorable adipose tissue distribution. A gene interaction exists between Pro12Ala and ACE I/D on BMI and fat mass. Further studies are needed to assess the contribution of Pro12Ala polymorphism in adiposity distribution.

Activation of microglia by amyloid {beta} requires P2X7 receptor expression.

Extracellular ATP is a mediator of intercellular communication and a danger signal. Release of this and other nucleotides modulates microglia responses via P2Y and P2X receptors, among which the P2X(7) subtype stands out for its proinflammatory activity and for up-regulation in a transgenic model of Alzheimer disease and in brains from Alzheimer disease patients. Here we show that amyloid beta (Abeta) triggered increases in intracellular Ca(2+) ([Ca(2+)](i)), ATP release, IL-1beta secretion, and plasma membrane permeabilization in microglia from wild-type but not from P2X(7)-deleted mice. Likewise, intra-hippocampal injection of Abeta caused a large accumulation of IL-1beta in wild-type but not in P2X(7)(-/-) mice. These observations suggest that Abeta activates a purinergic autocrine/paracrine stimulatory loop of which the P2X(7) receptor is an obligate component. Identification of the P2X(7) receptor as a non-dispensable factor of Abeta-mediated microglia stimulation may open new avenues for the treatment of Alzheimer disease.

A Modern Case Sheds Light on a Classical Enigma: Beethoven's Deafness.

Two hundred and fifty years have passed since the birth of Ludwig van Beethoven, and the enigma about his hearing loss and overall health status seems to be not completely solved. However, the admission to the hospital of a 64-year-old woman in 2018 with symptoms extremely similar to those experienced by the great composer may add further evidence to a theory previously underestimated. The health issues of the modern patient were found to be due to chronic lead intoxication. The lead was released during daily cooking using a ceramic-coated frying pan with worn surface that poisoned her breakfast most probably for years. Abdominal pain, asthenia, and hearing loss affecting the high frequencies with a many impact on speech intelligibility tormented the patient, as they had Beethoven. An extensive review of the music and medical literature was performed, as well as re-examination of manuscripts, correspondence, and autopsy reports of the famous composer; and great similarities have been found. The soundness of the most-cited classical theories about Beethoven's hearing loss will be discussed. After close scrutiny of the theories, our analysis points toward a progressive sensorineural hearing loss due to lead intoxication as the most probable cause of not only Beethoven's hypoacusis but his overall health status as well. Laryngoscope, 131:179-185, 2021.

The benefit and risk of testosterone replacement therapy in older men: effects on lipid metabolism.

Over the last decades, testosterone replacement therapy for middle-aged and older men has been gaining increasing and widespread attention and popularity. Although several benefits of testosterone replacement therapy are well established, including but not limited to improvement in libido, body composition, and bone density, concerns for multiple potential adverse effects remain. In particular, concerns are frequently raised regarding the possibility that testosterone replacement therapy may increase the risks of prostate cancer and cardiovascular disease as consequence of a potential detrimental effect of testosterone on cardiovascular risk factors. This mini-review will present and discuss the current knowledge on the relationship between testosterone replacement therapy and change in lipid fractions in older men.

Performance-based functional assessment in older hospitalized patients: feasibility and clinical correlates.

BACKGROUND: Functional evaluation is a cornerstone of multidimensional geriatric assessment; however, little is known of the clinical value of standardized performance-based assessment in the acute care setting. The aim of this study was to evaluate the clinical correlates and short-term predictive value of the Short Physical Performance Battery (SPPB) in older patients admitted to the hospital for an acute medical event. METHODS: We enrolled 92 women and men 65 years old or older who were able to walk, who had a Mini-Mental State Examination (MMSE) score > or =18, and who were admitted to the hospital with a clinical diagnosis of congestive heart failure, pneumonia, chronic obstructive pulmonary disease (COPD), or minor stroke. The SPPB was assessed at hospital admission and discharge. Self-report functional assessment included basic activities of daily living (ADL) and instrumental activities of daily living (IADL). Spearman's rank correlation coefficients and multivariable linear regression analyses were used to study the association of SPPB score and functional and clinical characteristics, including length of hospital stay. RESULTS: The mean age was 77.7 years (range 65-94 years), 49% were female, 64.1% had congestive heart failure, 16% COPD, 13.1% pneumonia, and 6.5% minor stroke. At hospital admission the mean SPPB score was 6.0 +/- 2.7. SPPB scores were inversely correlated with age, the severity of the index disease, and IADL and ADL difficulty 2 weeks before hospital admission (p <.01), and were directly correlated with MMSE score (p =.002). On average, SPPB score increased 1 point (+0.97, standard error of the mean = 0.2; p for paired t test <.001) from baseline to hospital discharge assessment. After adjustment for potential confounders, baseline SPPB score was significantly associated with the length of hospital stay (p <.007). CONCLUSION: In older acute care inpatients, SPPB is a valid indicator of functional and clinical status. SPPB score at hospital admission is an independent predictor of the length of hospital stay.

Autosomal Recessive Hypercholesterolemia: Long-Term Cardiovascular Outcomes.

BACKGROUND: Autosomal recessive hypercholesterolemia (ARH) is a rare lipid disorder characterized by premature atherosclerotic cardiovascular disease (ASCVD). There are sparse data for clinical management and cardiovascular outcomes in ARH. OBJECTIVES: Evaluation of changes in lipid management, achievement of low-density lipoprotein cholesterol (LDL-C) goals and cardiovascular outcomes in ARH. METHODS: Published ARH cases were identified by electronic search. All corresponding authors and physicians known to treat these patients were asked to provide follow-up information, using a standardized protocol. RESULTS: We collected data for 52 patients (28 females, 24 males; 31.1 ± 17.1 years of age; baseline LDL-C: 571.9 ± 171.7 mg/dl). During a mean follow-up of 14.1 ± 7.3 years, there was a significant increase in the use of high-intensity statin and ezetimibe in combination with lipoprotein apheresis; in 6 patients, lomitapide was also added. Mean LDL-C achieved at nadir was 164.0 ± 85.1 mg/dl (-69.6% from baseline), with a better response in patients taking lomitapide (-88.3%). Overall, 23.1% of ARH patients reached LDL-C of <100 mg/dl. During follow-up, 26.9% of patients had incident ASCVD, and 11.5% had a new diagnosis of aortic valve stenosis (absolute risk per year of 1.9% and 0.8%, respectively). No incident stroke was observed. Age (≥30 years) and the presence of coronary artery disease at diagnosis were the major predictors of incident ASCVD. CONCLUSIONS: Despite intensive treatment, LDL-C in ARH patients remains far from targets, and this translates into a poor long-term cardiovascular prognosis. Our data highlight the importance of an early diagnosis and treatment and confirm the fact that an effective treatment protocol for ARH is still lacking.

High interleukin-6 plasma levels are associated with low HDL-C levels in community-dwelling older adults: the InChianti study.

BACKGROUND: Low levels of high density lipoprotein cholesterol (HDL-C) are associated with increased incidence of coronary heart disease (CHD). A better understanding of the mechanisms leading to low HDL-C and CHD is essential for planning treatment strategies. Clinical studies have demonstrated that cytokines might affect both concentration and composition of plasma lipoproteins, including HDLs. METHODS: We investigated the possible association between low HDL-C levels, defined as < or =10th gender specific percentile, and circulating markers of inflammation (IL-1beta, TNF-alpha, IL-6, IL-10, IL-18, and CRP) in a population of 1044 community dwelling older Italian subjects from the InChianti study. RESULTS: Using logistic regression analysis we demonstrated that IL-6 levels (III versus I tertile, OR: 2.10; 1.10-3.75), TG (III versus I tertile OR: 27.45; 8.47-88.93), fasting insulin (III versus I tertile OR: 2.84; 1.50-5.42), and age (OR: 1.038; 1.002-1.075) were associated with low HDL-C independent of smoking, BMI, waist circumference, hypertension, diabetes, physical activity, alcohol intake, oral hypoglycaemics, CRP, IL-18, and TNF-alpha levels. The adjusted attributable risk of low HDL-C in the exposed group (III tertile of IL-6) was 54%. CONCLUSIONS: The present study provides the epidemiological evidence that besides triglycerides, fasting insulin, and age, IL-6 is one of the main correlates of low HDL-C levels in older individuals.

Characteristics of nondisabled older patients developing new disability associated with medical illnesses and hospitalization.

OBJECTIVE: To identify demographic, clinical, and biological characteristics of older nondisabled patients who develop new disability in basic activities of daily living (BADL) during medical illnesses requiring hospitalization. DESIGN: Longitudinal observational study. SETTING: Geriatric and Internal Medicine acute care units. PARTICIPANTS: Data are from 1,686 patients aged 65 and older who independent in BADL 2 weeks before hospital admission, enrolled in the 1998 survey of the Italian Group of Pharmacoepidemiology in the Elderly Study. MEASUREMENTS: Study outcome was new BADL disability at time of hospital discharge. Sociodemographic, functional status, and clinical characteristics were collected at hospital admission; acute and chronic conditions were classified according to the International Classification of Disease, ninth revision; fasting blood samples were obtained and processed with standard methods. RESULTS: At the time of hospital discharge 113 patients (6.7%) presented new BADL disability. Functional decline was strongly related to patients' age and preadmission instrumental activities of daily living status. In a multivariate analysis, older age, nursing home residency, low body mass index, elevated erythrocyte sedimentation rate, acute stroke, high level of comorbidity expressed as Cumulative Illness Rating Scale score, polypharmacotherapy, cognitive decline, and history of fall in the previous year were independent and significant predictors of BADL disability. CONCLUSION: Several factors might contribute to loss of physical independence in hospitalized older persons. Preexisting conditions associated with the frailty syndrome, including physical and cognitive function, comorbidity, body composition, and inflammatory markers, characterize patients at high risk of functional decline.

Anemia, physical disability, and survival in older patients with heart failure.

BACKGROUND: Anemia is common in congestive heart failure, and it has been associated with poor prognosis. The effect of anemia on functional ability in heart failure has not been described. We evaluated the relationship of anemia, physical disability, and survival in patients with heart failure. METHODS AND RESULTS: One-year longitudinal study of 567 non-disabled, hospitalized heart failure patients, age > or = 65 years, enrolled in the Italian Group of Pharmacoepidemiology in the Elderly Study. Anemia was defined according to the World Health Organization criteria. Physical disability was defined as dependence in performing at least 2 basic activities of daily living. After adjustment for disease severity and health-related variables, anemia was associated with higher risk of disability (odds ratio = 2.17; 95% confidence interval [CI] = 1.12-4.24). After stratification according to gender, a strong relationship of anemia and risk of disability persisted in women, but it was reduced in men. Anemic women were significantly more likely to die during the follow-up, even after adjustment for potential confounders (hazard ratio = 2.33; CI = 1.02-5.30). CONCLUSION: Anemia is a predictor of physical disability in older heart failure patients, and in women anemia is associated with increased mortality.

Anemia and recovery from disability in activities of daily living in hospitalized older persons.

OBJECTIVES: To evaluate the predictive value of hemoglobin levels upon hospital admission on recovery from activity of daily living (ADL) disability during hospital stay in older patients. DESIGN: Longitudinal observational study. SETTING: Geriatric and internal medicine acute care units. PARTICIPANTS: Data are from 5,675 patients aged 65 and older enrolled in the Italian Group of Pharmacoepidemiology in the Elderly Study with ADL disability upon hospital admission. MEASUREMENTS: ADL disability was defined as inability to perform or need for assistance in performing one or more ADLs. Recovery from ADL disability was defined as independence in ADLs upon hospital discharge. Anemia was defined according to the World Health Organization criteria. Sociodemographic and clinical characteristics were considered as potential confounders. RESULTS: Mean age was 80.5 years; 57.7% of subjects were female. Prevalence of anemia was 46.8%. A total of 536 (9.4%) participants regained independence in all six ADLs at hospital discharge. Patients with anemia had a lower rate of recovery from ADL disability than those with normal hemoglobin levels (7.0% vs 11.6%; P<.001). Adjusted analyses confirmed that anemia was inversely associated with the likelihood of ADL recovery (odds ratio=0.71, 95% confidence interval=0.57-0.88). The probability of ADL recovery in anemic patients was higher at higher hemoglobin concentrations. CONCLUSION: In older hospitalized patients, anemia is inversely associated with the likelihood of regaining ADL independence during a hospital stay.

Total serum cholesterol and recovery from disability among hospitalized older adults.

BACKGROUND: The association between total serum cholesterol and health outcomes among older adults is controversial. The objective of the present study was to determine within a cohort of acutely hospitalized disabled elderly patients whether total cholesterol predicts recovery from disability in basic activities of daily living (ADL). METHODS: Patients (3150) 65 years old or older admitted to 81 acute care units in Italy and presenting with ADL disability at hospital admission were included in this study. ADL disability was defined as need of assistance or total dependence in one or more ADLs (eating, dressing, personal hygiene, transferring, and toilet use). Recovery was defined as no disability at hospital discharge in any of the five ADLs considered. RESULTS: Mean age of study participants was 80.5 +/- 7.2 years, and 1305 (41.1%) were men. The rate of recovery from ADL disability was 14.5% for participants with total cholesterol < 200 mg/dL (n = 306/2108), 20.2% for those with total cholesterol between 200 and 239 mg/dL (n = 144/713), and 23.1% for those with total cholesterol > or = 240 mg/dL (n = 76/329). After adjustment for potential confounders, relative to that of patients with cholesterol < 200 mg/dL, risk ratios for recovery were 1.31 for participants with cholesterol between 200 and 239 mg/dL (95% confidence interval [CI], 1.07-1.62) and 1.36 (95% CI, 1.04-1.79) for those with cholesterol > or = 240 mg/dL. After exclusion of 769 patients with total cholesterol < 145 mg/dL, the risk ratios (compared with those for participants with cholesterol < 200 mg/dL) for recovery were 1.33 (95% CI, 1.07-1.66) for participants with cholesterol between 200 and 239 mg/dL and 1.41 (95% CI, 1.06-1.88) for patients with cholesterol > or = 240 mg/dL. CONCLUSIONS: Among hospitalized disabled older adults, elevated levels of cholesterol are associated with increased rate of recovery from ADL disability.

Relationship of alcohol intake with inflammatory markers and plasminogen activator inhibitor-1 in well-functioning older adults: the Health, Aging, and Body Composition study.

BACKGROUND: Increased levels of acute-phase reactants predict the onset of poor health outcomes. A U-shaped association has been reported between alcohol intake and health outcomes, which suggests that alcohol intake may modify levels of acute-phase reactants. We investigated the relationship between weekly alcohol intake and interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and plasminogen activator inhibitor-1 (PAI-1). METHODS AND RESULTS: Data are from year 1 of the Health, Aging, and Body Composition study, a biracial cohort of 3075 well-functioning men and women aged 70 to 79 years, living in Memphis, Tenn, and Pittsburgh, Pa. The analysis included 2574 persons (51.2% women; 40.1% black) with complete data. After adjustment for age, race, smoking status, history of diabetes, history of cardiovascular disease, physical activity, high-density lipoprotein cholesterol, antiinflammatory medications, statins, and total fat mass, alcohol intake showed a J-shaped relationship with mean IL-6 (P for quadratic term <0.001) and CRP (P=0.014) levels. The association was consistent in both men and women. Compared with subjects who consumed 1 to 7 drinks per week, those who never drank had an increased likelihood of having high levels of both IL-6 and CRP, as did those who drank 8 or more drinks per week. We found no relationship between alcohol intake and levels of TNF-alpha and PAI-1 (P=0.137 and 0.08, respectively). CONCLUSIONS: In well-functioning older persons, light alcohol consumption is associated with lower levels of IL-6 and CRP. These results might suggest an additional biological explanation to the epidemiological link between moderate alcohol consumption and cardiovascular events.

Executive function correlates with walking speed in older persons: the InCHIANTI study.

OBJECTIVES: To study the association between performance on psychological tests of executive function and performance on lower extremity tasks with different attentional demands in a large sample of nondemented, older adults. DESIGN: Cross-sectional study. SETTING: Community-based. PARTICIPANTS: Nine hundred twenty-six persons aged 65 and older, without dementia, stroke, parkinsonism, visual impairment, or current treatment with neuroleptics, enrolled in a large epidemiological study. MEASUREMENTS: Trail Making Test (TMT) parts A and B and two performance-based measures of lower extremity function that require different executive/attentional-demanding skills: walking speed on a 4-m course at usual pace and walking speed on a 7-m obstacle course at fast pace. A difference score (Delta TMT), obtained by subtracting time to perform part A from time to perform part B of the TMT, was used as an indicator of executive function. Based on Delta TMT, subjects were divided into poor performance, intermediate performance, and good performance. RESULTS: After adjustment, no association between Delta TMT and 4-m course usual-pace walking speed was found. Participants with poor Delta TMT and with intermediate Delta TMT performance were more likely to be in the lowest tertile for 7-m obstacle course walking speed. CONCLUSION: In nondemented older persons, executive function is independently associated with tasks of lower extremity function that require high attentional demand.

Treatment with angiotensin-converting enzyme inhibitors is associated with a reduction in short-term mortality in older patients with acute ischemic stroke.

BACKGROUND: Stroke is the third cause of death in older people living in Western countries. We tested the hypothesis that angiotensin-converting enzyme inhibitors (A-I) might affect short-term (30 day) mortality in older persons with severe acute ischemic stroke. METHODS: We analyzed data from a retrospective study including 475 consecutive older patients hospitalized for acute ischemic stroke. Mean age was 78.4 +/- 9.2 years; 58.2% were female. Stroke type was classified according to the Oxford Community Stroke Project (OCSP). RESULTS: Mortality rate was 28%. Thirty-two percent of patients were treated with A-I; mortality was 16.5% in patients treated compared with 33.3% in those not treated (chi(2) p =.001). The odds ratio for mortality in treated patients was: 0.47 (0.25-0.89) after full adjustment (age, sex, mean diastolic and systolic blood pressure, previous stroke and/or transient ischemic attack, congestive heart failure, atrial fibrillation, diabetes, hypertension, coronary heart disease, and previous treatment with A-I); 0.29 (0.09-0.89) in patients with altered level of consciousness after full adjustment; 0.60 (0.33-1.12) after adjustment for OCSP classification, age, and sex; and 0.30 (0.08-0.97) in total anterior circulation infarction stroke type after full adjustment. CONCLUSIONS: Our data suggest that treatment with A-I might reduce short-term mortality in older patients with acute ischemic stroke. Randomized clinical trials should confirm this possible specific effect of A-I.

Progression of lower-extremity disability in older women with diabetes: the Women's Health and Aging Study.

OBJECTIVE: Older patients with diabetes are more likely to have a higher prevalence of multiple risk factors for physical disability, as a result of diabetic complications. We evaluated the pace of decline in lower-extremity function and the risk for progression of disability in older women with diabetes. RESEARCH DESIGN AND METHODS: We conducted a 3-year longitudinal cohort study of a random sample of 729 physically impaired older women (age > or =65 years) living in the community (Baltimore, MD). Diabetes was ascertained by standard criteria. Self-reported functional status and objective performance measures were assessed at baseline and over six semiannual follow-up visits. RESULTS: The baseline prevalence of diabetes was 14.4%. After adjustment for age and compared with women without diabetes, those with diabetes had an RR of 1.8 (95% CI 1.3-2.5) for incident mobility disability and 1.6 (1.2-2.1) for incident activity of daily living disability. The increased incidence of new disability associated with diabetes was paralleled by a greater decline in objective measures of lower-extremity function. Adjustment for multiple risk factors for disability did not significantly attenuate the risk for disability associated with diabetes. CONCLUSIONS: In older patients, impaired lower-extremity function is a long-term diabetic complication. Comprehensive assessment of older diabetic patients should include a standardized evaluation of lower-extremity performance.