The triad of varus malalignment, meniscectomy, and chondral damage: a biomechanical explanation for joint degeneration

This biomechanical study evaluates the effect of varus malalalignment on knees with a chondral defect, both pre- and post-medial meniscectomy. Eight fresh-frozen cadaveric knees were first loaded physiologically. The knees were next loaded in increasing increments of varus. This loading cycle then was repeated after a chondral defect had been created, both pre- and post-medial meniscectomy. We found that a relatively small degree of varus malalignment caused a dramatic alteration in articular surface contact pressure and medial compartment loading, especially in the presence of chondral damage and/or medial meniscectomy. These findings may have important implications relating to the treatment of younger individuals with varus knees who have sustained meniscal and/or chondral damage.     

Cholecalciferol Supplementation Alters Calcitriol-Responsive Monocyte Proteins and Decreases Inflammatory Cytokines in ESRD

In vitro, monocyte 1α-hydroxylase converts 25-hydroxyvitamin D [25(OH)D] to 1,25-dihydroxyvitamin D to regulate local innate immune responses, but whether 25(OH)D repletion affects vitamin D–responsive monocyte pathways in vivo is unknown. Here, we identified seven patients who had 25(OH)D insufficiency and were undergoing long-term hemodialysis and assessed changes after cholecalciferol and paricalcitol therapies in both vitamin D–responsive proteins in circulating monocytes and serum levels of inflammatory cytokines. Cholecalciferol therapy increased serum 25(OH)D levels four-fold, monocyte vitamin D receptor expression three-fold, and 24-hydroxylase expression; therapy decreased monocyte 1α-hydroxylase levels. The CD16⁺ “inflammatory” monocyte subset responded to 25(OH)D repletion the most, demonstrating the greatest increase in vitamin D receptor expression after cholecalciferol. Cholecalciferol therapy reduced circulating levels of inflammatory cytokines, including IL-8, IL-6, and TNF. These data suggest that nutritional vitamin D therapy has a biologic effect on circulating monocytes and associated inflammatory markers in patients with ESRD.There are two sources of vitamin D in humans: Dietary sources, including ergocalciferol (D₂) and cholecalciferol (D₃), and endogenous production by the skin in response to sunlight (D₃ only). To become active, vitamin D (D₂ and D₃) must undergo hydroxylation in the liver to form 25-hydroxyvitamin D [25(OH)D], a prehormone that is further hydroxylated via the 1α-hydroxylase (CYP27B1) enzyme in the kidney to generate 1,25-dihydroxyvitamin D [1,25(OH)₂D], the active form of this hormone.¹ A separate enzyme, 24-hydroxylase (CYP24), is a deactivating enzyme that forms an inactive metabolite of this hormone that is excreted in the bile.¹ As patients with chronic kidney disease (CKD) progress to ESRD, renal CYP27B1 activity decreases and the formation of 1,25(OH)₂D becomes impaired, resulting in hypocalcemia and secondary hyperparathyroidism in many of these patients. Previous attempts to counteract these changes in mineral metabolism with nutritional vitamin D therapy have been unsuccessful,^2–4 because these patients are expected to lack sufficient residual renal CYP27B1 activity to support circulating serum 1,25(OH)₂D levels. For this reason, therapeutic approaches to treat vitamin D deficiency in patients with ESRD have shifted away from the use of nutritional vitamin D forms to favor the use of calcitriol or its associated analogues.Although calcitriol and its analogues have proved to be important therapies for the treatment of disordered mineral metabolism in patients with ESRD, the sole use of these compounds for the correction of vitamin D deficiency in this setting has the potential for adverse effects and may be a fundamentally flawed treatment strategy.⁵ It is well established that vitamin D has both “classical” actions to affect mineral metabolism and “nonclassical” actions at various other tissues unrelated to mineral metabolism, including the heart, prostate, and monocytes, among others.^6,7 The existence of nonclassical actions of vitamin D is supported by the presence of vitamin D regulatory enzymes, such as CYP27B1 and CYP24, within these nonclassical tissues, where it is hypothesized that circulating 25(OH)D serves as a necessary substrate for the local generation of 1,25(OH)₂D and the regulation of tissue-specific, biologic pathways. It is believed that the local production of 1,25(OH)₂D in these nonclassical tissues forms a microenvironment for the regulation of vitamin D–responsive pathways at the cellular level, ultimately leading to biologic effects that are independent of circulating 1,25(OH)₂D. Existing associations between vitamin D deficiency and various disease processes, including cancer, diabetes, infection, and cardiovascular health, have provided evidence for nonclassical actions of 1,25(OH)₂D.^8–15An overwhelming amount of data supporting nonclassical actions of 1,25(OH)₂D exists, but it remains unclear whether these actions are related to the local production of this hormone or from circulating 1,25(OH)₂D produced by the kidneys. Despite an overwhelming amount of ex vivo data suggesting the importance of local vitamin D production by cells not involved in mineral metabolism, in vivo assessments of the autocrine and paracrine functions of these cells have been difficult and are confounded by the concurrent systemic generation of 1,25(OH)₂D by the kidneys with nutritional vitamin D therapy. This controversy of local versus systemic regulation of the nonclassical actions of vitamin D has the potential for profound consequences in patients who have chronic kidney disease (CKD) and are treated with calcitriol analogues, because these patients often have a deficiency of both 25(OH)D and 1,25(OH)₂D. Although this scenario poses a difficult problem for clinicians developing treatment strategies for these patients, it affords a unique opportunity to study the effects of extrarenal production of calcitriol in the setting of minimal renal CYP27B1 activity.Thus, there is a gap in our knowledge about the effects of nutritional vitamin D (D₂ or D₃) supplementation on cellular functions in peripheral tissues unrelated to mineral metabolism, and it remains unclear whether this supplementation has any measurable physiologic effects in the setting of ESRD. To address this question, we set out to investigate the physiologic impact of nutritional vitamin D repletion on monocyte protein expression and monocyte-derived inflammatory cytokine levels in patients who have ESRD and are on hemodialysis. Our findings demonstrate that the administration of nutritional vitamin D in the form of cholecalciferol to patients with nonfunctioning kidneys does indeed have biologic effects on circulating monocytes and decreases circulating levels of multiple inflammatory cytokines that have been linked to increased morbidity and mortality in this population. Our findings may serve as early evidence for in vivo, nonclassical effects of cholecalciferol therapy in patients with ESRD and suggest a potential benefit of 25(OH)D repletion in this patient population.     

Dose form modification - a common but potentially hazardous practice. A literature review and study of medication administration to older psychiatric inpatients

BACKGROUND: Many older patients have difficulty in swallowing their tablets and capsules. Dose form modification, by crushing tablets or opening capsules, is often used by nurses to administer such medication. METHODS: Electronic searches of five literature databases on tablet crushing and capsule opening were carried out. A review of medication incident reports involving tablet crushing from the U.K. National Reporting and Learning System (NRLS) was also undertaken. An observational study of medication administration on two long-stay wards for older mentally ill inpatients was carried out in a large psychiatric hospital. RESULTS: Only 17 incidents involving tablet crushing were reported to NRLS in 13 months. In the observational study, the administration of 1257 oral doses of medication at 36 medication rounds was observed. Tablets were crushed or capsules opened for 25.5% (266/1045) of solid oral doses. For 44.0% (117/266) of these doses the tablet crushing had not been authorized by the prescriber. For 4.5% (12/266) of doses crushing was specifically contra-indicated by the manufacturer. In 57.5% (153/266) of doses, tablet crushing was avoidable by the correct use of more suitable preparations. Crushing caused contamination, spillage and hygiene problems. CONCLUSIONS: Although tablet crushing and capsule opening are common practices, they are rarely reported as causing patient harm. Tablet crushing can often be avoided by the use of more suitable preparations. Crushing tablets and opening capsules are contra-indicated for some preparations. Older patients' medication may benefit from review by a pharmacist in order to optimize safe medication administration. Where tablet crushing is unavoidable, attention to cleanliness, contamination and spillage are necessary.     

Effect of increasing hemoglobin cutoff in male donors and increasing interdonation interval in whole blood donors at a hospital-based blood donor center

BACKGROUND: The NHANES‐III survey found hemoglobin (Hb) concentrations of more than 13.5 g/dL and more than 12.0 g/dL in normal Caucasian males and females. In the United States, a Hb of least 12.5 g/dL is required for blood donation, which allows “anemic” males to donate while excluding “normal” females. Low Hb is the major cause of deferral in donors and deferrals are associated with decreased donor return rates. Additionally, frequent blood donations are associated with depletion of body iron stores. Analysis of the effect of various Hb cutoffs and interdonation intervals on our center's blood supply is presented. STUDY DESIGN AND METHODS: Whole blood donor data for a 12‐month period were studied. Potential effects on the blood supply by increasing male Hb eligibility levels and/or increasing the interdonation interval were analyzed. RESULTS: A total of 13,519 individuals (females, 56%) donated 30,678 units (mean frequency, male 2.7 and females 2.1) with the majority (42%) donating once. Increasing the male Hb eligibility to at least 13.5 g/dL will decrease collections by 1457 (5%) units. In addition, decreasing the female Hb eligibility to at least 12.0 g/dL will result in total gain of 307 (1%) units. Considering 12‐week interdonation interval and Hb eligibility of at least 13.5 g/dL (male) and at least 12.5 g/dL (female) results in decrease of 11% (3352) units. CONCLUSIONS: Increasing the Hb cutoff for male donors and/or interdonation interval for all donors will decrease available blood, some of which may be reduced by decreasing the Hb cutoff for females to at least 12.0 g/dL. As a majority of the donors donate only once with mean donation frequency being 2.4, it may be possible to overcome this shortfall by targeted recruitment of donors donating once.     

Human leukocyte antigen class I (A, B, C) and II (DRB1) diversity in the black and Caucasian South African population

A cross-section of black and Caucasian South Africans (N = 302) were genotyped at high resolution (class I HLA-A, -B, -C and class II HLA-DRB1). Five new class I alleles (A*30:01:02, A*30:02:02, A*68:27, B*42:06, and B*45:07) and one new confirmatory allele (A*29:11) were identified in the black population. Alleles and haplotypes showed expected differences between the black and Caucasian populations, with the black population, on average, showing a broader spectrum of allele representation (less single allele dominance). The most prevalent alleles at the four loci in the black population were A*30:01, B*58:02, C*06:02, and DRB1*13:01 and in the Caucasian population were A*02:01:01, B*07:02:01, C*07:01, and DRB1*03:01. HLA-B, and HLA-C loci showed the strongest overall linkage disequilibrium (LD) and HLA-B/HLA-C two locus haplotypes also showed the strongest LD (D'_ij) in both population groups. Bw allotype representation was similar between the two populations; however C allotypes differed significantly (C1 higher representation in Caucasians; C2 higher representation in blacks). HLA-A Supertype family phenotypic frequencies did not differ between the two populations, but four (B08, B27, B58, and B62) HLA-B Supertype families differed significantly. However, vaccine coverage estimation came close to 100% in both population groups, with inclusion of only four Supertype families (A1, A2, B7, B58).     

Posterior cingulum white matter disruption and its associations with verbal memory and stroke risk in mild cognitive impairment

Medial temporal lobe and temporoparietal brain regions are among the earliest neocortical sites to undergo pathophysiologic alterations in Alzheimer's disease (AD), although the underlying white matter changes in these regions is less well known. We employed diffusion tensor imaging to evaluate early alterations in regional white matter integrity in participants diagnosed with mild cognitive impairment (MCI). The following regions of interests (ROIs) were examined: 1) anterior cingulum (AC); 2) posterior cingulum (PC); 3) genu of the corpus callosum; 4) splenium of the corpus callosum; and 5) as a control site for comparison, posterior limb of the internal capsule. Forty nondemented participants were divided into demographically-similar groups based on cognitive status (MCI: n = 20; normal control: n = 20), and fractional anisotropy (FA) estimates of each ROI were obtained. MCI participants showed greater posterior white matter (i.e., PC, splenium) but not anterior white matter (i.e., AC, genu) changes, after adjusting for age, stroke risk, and whole brain volume. FA differences of the posterior white matter were best accounted for by changes in radial but not axial diffusivity. PC FA was also significantly positively correlated with hippocampal volume as well as with performance on tests of verbal memory, whereas stroke risk was significantly correlated with genu FA and was unrelated to PC FA. When investigating subtypes of our MCI population, amnestic MCI participants showed lower PC white matter integrity relative to those with non-amnestic MCI. Findings implicate involvement of posterior microstructural white matter degeneration in the development of MCI-related cognitive changes and suggest that reduced FA of the PC may be a candidate neuroimaging marker of AD risk.     

Attention-Deficit/Hyperactivity Disorder in Older Adults: Prevalence and Possible Connections to Mild Cognitive Impairment

Attentional deficits are frequently seen in isolation as the presenting sign and symptom of neurodegenerative disease, manifest as mild cognitive impairment (MCI). Persistent ADHD in the geriatric population could well be misconstrued as MCI, leading to the incorrect assumption that such persons are succumbing to a neurodegenerative disease process. Alternatively, the molecular, neuroanatomic, or neurochemical abnormalities seen in ADHD may contribute to the development of de novo late life neurodegenerative disease. The present review examines the issue of causality vs confound regarding the association of ADHD with MCI, suggesting that both are tenable hypotheses.