One Week of Hospitalization Following Elective Hip Surgery Induces Substantial Muscle Atrophy in Older Patients

Objectives

Short successive periods of skeletal muscle disuse have been suggested to substantially contribute to the observed loss of skeletal muscle mass over the life span. Hospitalization of older individuals due to acute illness, injury, or major surgery generally results in a mean hospital stay of 5 to 7 days, during which the level of physical activity is strongly reduced. We hypothesized that hospitalization following elective total hip arthroplasty is accompanied by substantial leg muscle atrophy in older men and women.

Supratentorial ischemic stroke: more than an upper motor neuron disorder.

The primary goal of this study was to identify secondary functional changes in the peripheral motor units of the paretic upper extremity (UE) in patients with severe ischemic stroke and to determine how these changes develop during the first weeks after stroke. An inception cohort of 27 consecutive patients with an acute ischemic supratentorial stroke and an initial UE paralysis was compared with 10 healthy control subjects. The ulnar nerve was electrically stimulated proximal to the wrist and electromyographic recordings were obtained from the abductor digiti minimi muscle. Hemiparetic side mean values of the compound muscle action potential (CMAP) 1 and 3 weeks after stroke were compared with the nonparetic side and with CMAP values obtained from healthy control subjects. The mean CMAP amplitude in patients was significantly lower on the paretic side compared with the nonparetic side and with control subjects. Decrease in CMAP amplitude was observed in more than half of the stroke patients, sometimes as early as 4 days after stroke, and persisted in most cases. Whenever present, it was accompanied by absence of motor recovery at that specific time after stroke. Decreased CMAP amplitude in the abductor digiti minimi muscle can be seen already in the very acute phases after stroke unrelated to peripheral neuropathy, radiculopathy, or plexopathy, and it is accompanied by absence of UMN recovery. This knowledge is important for interpreting electrophysiological data in stroke patients.     

Reflex sympathetic dystrophy of the left hand and motor impairments of the unaffected right hand: impaired central motor processing?

OBJECTIVE: To test whether central motor processing can be impaired in chronic reflex sympathetic dystrophy (RSD). DESIGN: Experimental 2-group analysis. SETTING: Tertiary care center in the Netherlands. PARTICIPANTS: Five patients with stage 3 RSD of the left forearm, free of symptoms and complaints in the right forearm; and 10 healthy control subjects. INTERVENTION: On a digitizer, RSD patients and controls had to draw 3 sequences of graphemes of different complexity with their (unaffected) dominant right hand. The drawing tracks were segmented in time periods between points of velocity minima of the pen tip. MAIN OUTCOME MEASURES: Mean velocity, coefficients of variation of both length and movement time per segment, and mean intersegmental pausing time were calculated for each sequence. RESULTS: A repeated-measures analysis of variance by using the multivariate method yielded a 35% lower mean velocity (F(1,13) = 5.83, P =.031), a 110% larger segment length variability (F(1,13) = 9.72, P =.008) and a 60% larger variability of movement time per segment (F(1,13) = 5.78, P =.032) in RSD patients. No group difference was found for intersegmental pausing time or any interaction effect with the type of task. CONCLUSION: Patients with chronic RSD have a normal ability to preprogram sequential movements of their unaffected hand; but with impaired temporospatial coding and movement execution. We concluded that cortical mechanisms may be involved in motor impairments in patients with chronic RSD.     

Assessment of bioequivalence after subcutaneous and intramuscular administration of urinary gonadotrophins

The objective was to demonstrate bioequivalence between s.c. and i.m. administration of Humegon (FSH/LH ratio 1:1) and Normegon (FSH/LH ratio 3:1). In two randomized, single-centre, cross-over studies, 18 healthy volunteers on each formulation were assigned to one of the two administration sequences. Subjects were given single doses of one of the above gonadotrophins after endogenous gonadotrophin production had first been suppressed using high-dose oral contraceptive. Subsequently, rate (Cmax, tmax) and extent (AUC) of absorption of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined for 14 days. For Cmax and AUC, analysis of variance (ANOVA) was performed on log-transformed data and for tmax ANOVA was performed on ranks. Intramuscular and s.c. injections of Humegon were bioequivalent with respect to the main pharmacokinetic parameters, being AUC and Cmax of FSH absorption. Intramuscular and s.c. injections of Normegon were bioequivalent with respect to the AUC of FSH and not bioequivalent with respect to the Cmax of FSH. For tmax of FSH as well as for most LH variables of both preparations, bioequivalence could not be proven due to the high intra- and interindividual variability and/or concentrations being close to the detection limit. Thus, the main pharmacokinetic FSH variables after i.m. and s.c. administration of Humegon and Normegon were bioequivalent.      

Is postural control associated with mental functioning in the persistent postconcussion syndrome?

OBJECTIVE: To investigate whether balance is associated with mental functioning after mild traumatic brain injury (MTBI). DESIGN: Experimental two-group design. SETTING: Outpatient rehabilitation department. PATIENTS AND OTHER PARTICIPANTS: From a consecutive sample of referred MTBI patients, 15 subjects who complained of imbalance were included (8 men and 7 women, age 35.9+/-8.6yrs). Subjects with detectable neurologic impairments were excluded. Twenty healthy control subjects of the same age group also were tested. MAIN OUTCOME MEASURES: In both groups, a force platform recorded center-of-pressure (CP) fluctuations during standing and weight shifting in different conditions. For the patients, attention and mental speed were assessed with the Symbol-Digit Substitution Test of the Wechsler Adult Intelligence Scale (Dutch version), verbal learning and memory were assessed with the 15-Words Test, and emotional distress was assessed with the Symptom Checklist-90. RESULTS: Compared with controls, patients showed an overall increase of 60% in CP velocity and an overall weight-shifting speed 25% slower (p < .005), indicating static and dynamic postural instability. Only performance on the Symbol-Digit Substitution Test was associated with both static and dynamic balance (p < .02), giving an explained variance of over 40%. CONCLUSION: The results indicate a possible association of balance with cognitive performance but not with emotional well-being after MTBI, suggesting an organic rather than a functional cause of postural instability. Further research is needed to assess the possible clinical implications.     

Antecedents and consequences of work-home interference among medical residents

A cross-sectional field study is reported in which a comprehensive model of work-home interference (WHI) was developed and tested among 166 medical residents of an academic hospital in the Netherlands. It was hypothesized that WHI functions as a critical mediating pathway in the relationship between work and home characteristics on the one hand, and work-related and general psychological health indicators on the other. The results revealed that one home characteristic and three work characteristics put pressure on the interface between the work and home life, that is, (1) having a spouse who works overtime frequently, (2) an unfavorable worktime schedule, (3) a high quantitative workload and (4) a problematic dependency on the superior. The results further showed that WHI was positively associated with emotional exhaustion and depersonalization (i.e. work-related health indicators), as well as with psychosomatic health complaints and sleep deprivation (i.e. general health indicators). More importantly, the results strongly supported our basic hypothesis that WHI mediates the impact of some work and home characteristics on psychological health indicators. This seems to be particularly true for the general health indicators: none of the home and work characteristics just mentioned, had a direct impact on these general indicators, independent of WHI. With respect to the work-related health indicators, particularly depersonalization, the mediating role of WHI was also strong, though less consistent. The theoretical and practical implications of the findings are discussed.     

Nile Red fluorescence spectroscopy reports early physicochemical changes in myelin with high sensitivity

The molecular composition of myelin membranes determines their structure and function. Even minute changes to the biochemical balance can have profound consequences for axonal conduction and the synchronicity of neural networks. Hypothesizing that the earliest indication of myelin injury involves changes in the composition and/or polarity of its constituent lipids, we developed a sensitive spectroscopic technique for defining the chemical polarity of myelin lipids in fixed frozen tissue sections from rodent and human. The method uses a simple staining procedure involving the lipophilic dye Nile Red, whose fluorescence spectrum varies according to the chemical polarity of the microenvironment into which the dye embeds. Nile Red spectroscopy identified histologically intact yet biochemically altered myelin in prelesioned tissues, including mouse white matter following subdemyelinating cuprizone intoxication, as well as normal-appearing white matter in multiple sclerosis brain. Nile Red spectroscopy offers a relatively simple yet highly sensitive technique for detecting subtle myelin changes.

Myelin is a highly ordered, lipid-rich extension of glial cell membrane that facilitates rapid and efficient saltatory conduction of action potentials along axons in the central and peripheral nervous systems. The stability of myelin membranes critically depends on its molecular composition (1–3). Although myelin is maintained roughly at a ratio of 70:30% lipid to protein (4), lipid membranes are highly fluid; changes in lipid composition are defining characteristics of myelin development (5), homeostasis in the adult, and aging in rodents (6, 7), as well as primates (8). Shifts in lipid composition also occur in inflammatory demyelinating disorders like multiple sclerosis (MS) (9, 10). Lipids are even theorized to be targets of immune attacks in autoimmune disorders, a role previously ascribed to proteins (11). Key roles for lipids notwithstanding, tools to interrogate biochemical changes to myelin lipids have largely been restricted to in vitro systems.Once thought to be inert, myelin is now known to be a chemically and structurally dynamic element (12). Specific combinations of proteins and lipids induce formation and compaction of multilamellar vesicles that resemble myelin (13), underscoring the importance of correct chemical composition for assembly. Conversely, alterations in these molecular proportions promote decompaction and myelin vesiculation (3, 14). The polarity of lipid species in cell membranes influences their packing properties and therefore stability (15). Governed by competing thermodynamic forces of lipid curling and hydrocarbon packing (16), myelin sheaths lie at the critical edge of bilayer stability and thus are susceptible to factors in the environment. Indeed, the myelin integrity theory of MS rests on the outsized influence of environmental forces on myelin stability and function (17). Therefore, methods for detecting physicochemical changes in myelin lipid composition in situ would greatly enhance our understanding of early events in myelin development, as well as myelin damage in disease states, with important implications for therapies designed to prevent myelin loss in MS and other demyelinating disorders.The study of myelin lipid biochemistry poses unique challenges (18). Traditional analytical methods, such as thin-layer chromatography and high-performance liquid chromatography (19), depend on tissue homogenization that eliminates informative spatial relationships. Imaging lipid mass spectrometry (20) preserves spatial relationships, but submicron resolution has yet to be realized, and reproducibility at the level of sample preparation remains problematic (21). Coherent anti–Stokes Raman scattering microscopy provides high-resolution, label-free imaging of lipids in histological samples (22), but this method lacks sensitivity and requires expertise in nonlinear optics as well as highly specialized hardware. Finally, fluorescent lipophilic dyes, though widely available and easy to use, have traditionally been employed to detect lipid-rich structures in only a qualitative manner. Conventional fluorescence microscopy is therefore unable to detect subtle shifts in lipid biochemistry. By contrast, Nile Red (NR) is a fluorescent dye that is well situated to report changes in the chemical polarity of cell membranes and myelin, being both lipophilic (23, 24) and differentially fluorescent depending on solvent environment (i.e., exhibits solvatochromism) (25). The current study uses NR fluorescence spectroscopy to identify polarity shifts as an early manifestation of myelin disease prior to overt demyelination. We show that this technique reports subtle biochemical changes in myelin, resulting in a method that is a very sensitive marker of incipient myelin injury.     

Mutation of Plekha7 attenuates salt-sensitive hypertension in the rat

PLEKHA7 (pleckstrin homology domain containing family A member 7) has been found in multiple studies as a candidate gene for human hypertension, yet functional data supporting this association are lacking. We investigated the contribution of this gene to the pathogenesis of salt-sensitive hypertension by mutating Plekha7 in the Dahl salt-sensitive (SS/JrHsdMcwi) rat using zinc-finger nuclease technology. After four weeks on an 8% NaCl diet, homozygous mutant rats had lower mean arterial (149 ± 9 mmHg vs. 178 ± 7 mmHg; P < 0.05) and systolic (180 ± 7 mmHg vs. 213 ± 8 mmHg; P < 0.05) blood pressure compared with WT littermates. Albumin and protein excretion rates were also significantly lower in mutant rats, demonstrating a renoprotective effect of the mutation. Total peripheral resistance and perivascular fibrosis in the heart and kidney were significantly reduced in Plekha7 mutant animals, suggesting a potential role of the vasculature in the attenuation of hypertension. Indeed, both flow-mediated dilation and endothelium-dependent vasodilation in response to acetylcholine were improved in isolated mesenteric resistance arteries of Plekha7 mutant rats compared with WT. These vascular improvements were correlated with changes in intracellular calcium handling, resulting in increased nitric oxide bioavailability in mutant vessels. Collectively, these data provide the first functional evidence that Plekha7 may contribute to blood pressure regulation and cardiovascular function through its effects on the vasculature.Hypertension is a complex disease that is characterized by increased blood pressure, renal damage, and vascular dysfunction which collectively increase risk of atherosclerosis, stroke, heart disease, and renal failure in one-quarter of all adults worldwide (1–3). Because there is strong evidence of heritability in hypertension (2, 4, 5), considerable effort has been put toward identifying novel candidate genes and their molecular mechanisms. Genome-wide association studies (GWAS) have identified many potential hypertension loci, which shed light on the genetic complexity of this disease (5–8) but have provided little mechanistic insight. As such, validation and elucidation of the functional roles and disease mechanisms for these gene candidates are the next important challenges (4).Because hypertension is a complex disease (i.e., multiple variants of small effect sizes contributing to disease risk), we hypothesized candidate gene targeting on a genetically sensitized background would reveal functional role(s) of genetic disease modifiers. The Dahl salt-sensitive (SS) rat is an inbred genetic model of salt-sensitive hypertension that displays hypertension-induced renal damage, cardiac hypertrophy and vascular dysfunction (9–11). These phenotypes are induced by exposing SS rats to a high-salt diet, which results in rapid induction of hypertensive phenotypes that closely resemble salt-induced hypertension seen in humans (12–15). Knockout of specific genes in this disease model using zinc-finger nuclease (ZFN) technology have revealed the importance of key mechanisms contributing to hypertension risk, such as the protection from salt-induced hypertension and renal injury by selective ablation of adaptive immune cells in the SS-Rag1^em1Mcwi and SS-Cd247^em1Mcwi knockout rats (16, 17) and reduced hypertension and renal injury in the SS-Ncf2^em1Mcwi (p67phox) null model exhibiting reduced medullary oxidative stress (18). Additionally, we have recently demonstrated multiple genes at a single hypertension GWAS-nominated locus (Agtrap-Plod1 locus) can have additive or subtractive effects on blood pressure and renal function when mutated in the SS rat (19). These previous studies highlight the utility of this model system for testing the roles of GWAS candidate human disease genes by disrupting their specific rat orthologs using ZFN technology (20).A single-nucleotide polymorphism (SNP) (rs381815, minor allele frequency 0.26) in intron 1 of the pleckstrin homology domain containing family A member 7 (PLEKHA7) gene, was identified by five independent GWAS to be associated with elevated systolic blood pressure and hypertension in multiple populations (5, 6, 8, 21, 22). The associated locus contains only the PLEKHA7 gene (5); however, the genetic mechanism(s) underlying this locus have not yet been functionally characterized. PLEKHA7 is highly expressed in the kidney and heart, where it may be involved in formation and maintenance of the apical junction complex of epithelial cells (23). However, limited data on PLEKHA7 function are available to extrapolate its potential role(s) in the pathogenesis of hypertension. Here we used ZFN mutagenesis to obtain the first evidence to our knowledge in any model system that Plekha7 has a functional role in several hypertension-associated phenotypes in the rat. We found that mutation of Plekha7 in the SS rat attenuated salt-induced hypertension, reduced renal damage, and improved cardiac function. We also show that Plekha7 modulates calcium handling and nitric oxide (NO) bioavailability, both of which are required for normal vascular health. Collectively, these studies provide significant mechanistic insight to the role of Plekha7 in salt-sensitive hypertension.