Can an Intervention with Testosterone and Nutritional Supplement Improve the Frailty Level of Under-Nourished Older People?

OBJECTIVE: To examine whether a testosterone and a high calorie nutritional supplement intervention can reduce frailty scores in undernourished older people using multiple frailty tools. DESIGN: Randomized controlled trial. SETTING/PARTICIPANTS: 53 community-dwelling, undernourished men and women aged >65 years from South Australia, Victoria and New South Wales. INTERVENTION: Intervention group received oral testosterone undecanoate and a high calorie supplement (2108-2416 kJ/day) whereas the control group received placebo testosterone and low calorie supplement (142-191 kJ/day). MEASUREMENTS: Frailty was operationalized using three frailty indices (FI-lab, FI-self-report, FI-combined) and the frailty phenotype. RESULTS: There were no significant differences in changes in frailty scores at either 6 or 12 months follow up between the two treatment groups for all scales. Participants at the intervention group were 4.8 times more likely to improve their FI-combined score at both time points compared to the placebo group. CONCLUSION: A testosterone and a high calorie nutritional supplement intervention did not improve the frailty levels of under-nourished older people. Even so, when frailty was measured using a frailty index combining self-reported and lab data we found that participants who received the intervention were more likely to show persistent improvement in their frailty scores.

The Randomized Control Trial of the Effects of Testosterone and a Nutritional Supplement On Hospital Admissions in Undernourished, Community Dwelling, Older People.

OBJECTIVE: In a pilot single centre study we found that treatment of undernourished older, community dwelling people for one year with oral testosterone (placebo-controlled) and a nutritional supplement (no control) was associated with a significant reduction in hospitalizations. A larger, multicentre study was conducted to investigate further this potentially important finding. DESIGN: One year, randomized, placebo-controlled, multi-centre, double-blind, trial. SETTING: Community. PARTICIPANTS: 53 undernourished men and women aged 65 years and older. INTERVENTION: Oral testosterone undecanoate (40 mg/day women, 160 mg/day men) and high energy oral nutritional supplement (2108-2416 kJ/day) or placebo medication and low energy (142-191 kJ/day) "placebo" oral nutritional supplementation. MEASUREMENTS: Hospital admissions, falls and other variables were assessed. RESULTS: 53 subjects were recruited (64% male and mean age 77 years), which was substantially less than planned. Sixteen subjects (30%) were admitted to hospital at least once, with a total of 29 admissions. Eight subjects (32%) in the placebo arm were admitted to hospital, whilst in the intervention group also there were eight (29%) subjects admitted to hospital during the study period. There was no difference in the number of hospitalisations (P = 0.842), length of hospitalization (P=0.645) or quality of life [mental health P=0.195 and physical health P=0.451) between the treatment arms. CONCLUSIONS: In undernourished older people, treatment with testosterone and a nutritional supplementation did not reduce the number and length of hospitalisations or improve quality of life.

Use of the Mini Nutritional Assessment to detect frailty in hospitalised older people.

OBJECTIVES: The aims of this study were to: (1) determine the prevalence of undernutrition and frailty in hospitalised elderly patients and (2) evaluate the efficacy of both the Mini-Nutritional Assessment (MNA) screening tool and the MNA short form (MNA-SF) in identifying frailty. SETTING AND PARTICIPANTS: A convenient sample of 100 consecutive patients (75.0 % female) admitted to the Geriatric Evaluation and Management Unit (GEMU) at The Queen Elizabeth Hospital in South Australia. MEASUREMENTS: Frailty status was determined using Fried's frailty criteria and nutritional status by the MNA and MNA-SF. Optimal cut-off scores to predict frailty were determined by Youden's Index, Receiver Operator Curves (ROC) and area under curve (AUC). RESULTS: Undernutrition was common. Using the MNA, 40.0% of patients were malnourished and 44.0% were at risk of malnutrition. By Fried's classification, 66.0 % were frail, 30.0 % were pre-frail and 4.0 % robust. The MNA had a specificity of 0.912 and a sensitivity of 0.516 in predicting frailty using the recommended cut-off for malnourishment (< 17). The optimal MNA cut-off for frailty screening was <17.5 with a specificity of 0.912 and sensitivity of 0.591. The MNA-SF predicted frailty with specificity and sensitivity values of 0.794 and 0.636 respectively, using the standard cut-off of < 8. The optimal MNA-SF cut-off score for frailty was < 9, with specificity and sensitivity values of 0.765 and 0.803 respectively and was better than the optimum MNA cut-off in predicting frailty (Youden Index 0.568 vs. 0.503). CONCLUSION: The quickly and easily administered MNA-SF appears to be a good tool for predicting both under-nutrition and frailty in elderly hospitalised people. Further studies would show whether the MNA-SF could also detect frailty in other populations of older people.

Dual-energy micro-CT of the rodent lung.

The purpose of this work is to investigate the use of dual-energy micro-computed tomography (CT) for the estimation of vascular, tissue, and air fractions in rodent lungs using a postreconstruction three material decomposition method. Using simulations, we have estimated the accuracy limits of the decomposition for realistic micro-CT noise levels. Next, we performed experiments involving ex vivo lung imaging in which intact rat lungs were carefully removed from the thorax, injected with an iodine-based contrast agent, and then inflated with different volumes of air (n = 2). Finally, we performed in vivo imaging studies in C57BL/6 mice (n = 5) using fast prospective respiratory gating in end inspiration and end expiration for three different levels of positive end expiratory pressure (PEEP). Before imaging, mice were injected with a liposomal blood pool contrast agent. The three-dimensional air, tissue, and blood fraction maps were computed and analyzed. The results indicate that separation and volume estimation of the three material components of the lungs are possible. The mean accuracy values for air, blood, and tissue were 93, 93, and 90%, respectively. The absolute accuracy in determining all fraction materials was 91.6%. The coefficient of variation was small (2.5%) indicating good repeatability. The minimum difference that we could detect in material fractions was 15%. As expected, an increase in PEEP levels for the living mouse resulted in statistically significant increases in air fractions at end expiration but no significant changes at end inspiration. Our method has applicability in preclinical pulmonary studies where changes in lung structure and gas volume as a result of lung injury, environmental exposures, or drug bioactivity would have important physiological implications.

Lung imaging in rodents using dual energy micro-CT.

Dual energy CT imaging is expected to play a major role in the diagnostic arena as it provides material decomposition on an elemental basis. The purpose of this work is to investigate the use of dual energy micro-CT for the estimation of vascular, tissue, and air fractions in rodent lungs using a post-reconstruction three-material decomposition method. We have tested our method using both simulations and experimental work. Using simulations, we have estimated the accuracy limits of the decomposition for realistic micro-CT noise levels. Next, we performed experiments involving ex vivo lung imaging in which intact lungs were carefully removed from the thorax, were injected with an iodine-based contrast agent and inflated with air at different volume levels. Finally, we performed in vivo imaging studies in (n=5) C57BL/6 mice using fast prospective respiratory gating in end-inspiration and end-expiration for three different levels of positive end-expiratory pressure (PEEP). Prior to imaging, mice were injected with a liposomal blood pool contrast agent. The mean accuracy values were for Air (95.5%), Blood (96%), and Tissue (92.4%). The absolute accuracy in determining all fraction materials was 94.6%. The minimum difference that we could detect in material fractions was 15%. As expected, an increase in PEEP levels for the living mouse resulted in statistically significant increases in air fractions at end-expiration, but no significant changes in end-inspiration. Our method has applicability in preclinical pulmonary studies where various physiological changes can occur as a result of genetic changes, lung disease, or drug effects.

Effects of a low-energy diet on sexual function and lower urinary tract symptoms in obese men.

OBJECTIVE: Abdominal obesity and type 2 diabetes mellitus are associated with erectile and urinary dysfunction in men. The extent to which sexual function and lower urinary tract symptoms (LUTSs) are improved by weight loss remains unclear. SUBJECTS: We compared the effects of 8 weeks of a low-calorie diet using meal replacements (Kicstart) on insulin sensitivity, plasma testosterone levels, erectile function (measured by the five-item version of the International Index of Erectile Function, IIEF-5), sexual desire (measured by the Sexual Desire Inventory, SDI) and LUTS (measured by the International Prostate Symptom Score, IPSS), in abdominally obese (body mass index >or=30 kg m(-2), waist circumference (WC) >or=102 cm) men (mean age 49.7 years) with uncomplicated diet or oral hypoglycemic-treated type 2 diabetes mellitus (n = 19) or without type 2 diabetes mellitus (n=25), with a control group of nondiabetic men (n = 26) with similar body mass index and WC. RESULTS: Weight loss of ∼ 10% was significantly associated with increased insulin sensitivity, plasma testosterone levels, IIEF-5 and SDI scores, as well as reduced WC and IPSS scores, in diabetic as well as nondiabetic men. The degree of weight loss was significantly associated with improvements in plasma testosterone levels (r = -0.34), erectile function (r = -0.26) and LUTS (r=0.65). Reduction in LUTS was significantly associated with increased plasma testosterone (r = -0.35), erectile function (r = -0.42) and sexual desire (r = -0.40). CONCLUSIONS: Diet-induced weight loss significantly and rapidly improves sexual function, and reduces LUTS, in obese middle-aged men with or without diabetes.

Underutilization of echocardiography for patent foramen ovale in divers with serious decompression sickness.

The presence of a patent foramen ovale (PFO) in compressed gas diving has been considered a risk factor for serious decompression illness (DCS) for more than 20 years. We conducted a ten year retrospective chart review aimed at determining if physicians treating DCS in a university medical center setting used echocardiography to assess PFO in patients with severe DCS, and if so whether PFO is over-represented in that population. Over the ten-year period, 113 divers underwent recompression therapy for decompression sickness. Of these patients, 48 had serious DCS defined by at least one objective neurological finding. We reviewed medical records for the presence of agitated saline contrast echocardiogram testing and whether or not PFO was present. Only 12 of 48 patients with serious DCS underwent transthoracic agitated saline contrast echocardiogram testing. Of these 12 patients, 6 (50%) had a resting PFO. Binomial proportion testing yielded 95% confidence limits of 21% and 79%. Given 27% PFO prevalence in the general population, PFO may be over-represented in our group of most seriously injured DCS patients yet 75% of patients with objective neurological signs did not undergo echocardiography.

Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series.

PURPOSE: Bisphosphonate (BP)-associated osteonecrosis of the jaw (ONJ) is an emerging problem with few therapeutic options. Our pilot study of BP-ONJ investigated a possible role for hyperbaric oxygen (HBO(2)) therapy. PATIENTS AND METHODS: A total of 16 patients, ranging in age from 43 to 78 years, with BP-ONJ were treated with adjunctive HBO(2) between July 2003 and April 2006. Staging was based on the size and number of oral lesions. Clinical response after treatment and at distant follow-up; the odds of remission, stabilization, or relapse; and time to failure analysis were calculated. RESULTS: The median time on BP therapy before appearance of ONJ symptoms was 18 months, and that from symptom onset to HBO(2) therapy was 12 months. Fourteen of 16 patients (87.5%) improved in stage. The size and number of ONJ lesions were decreased after HBO(2) therapy (P < .001 and P = .008, respectively; Wilcoxon signed-rank test). Immediately after HBO(2) therapy, 7 of 16 patients (44%) were in remission and 8 (50%) had stabilized; however, stabilization without remission was sustained in only 2 patients. At follow-up, 10 of the patients (62.5%) were still in remission or had stabilized. The 7 patients who continued on BP treatment during HBO(2) therapy had a shorter time to failure (8.5 months; 95% confidence interval [CI] = 7.1 to 9.8) than those who discontinued the drug (20.1 months; 95% CI = 17.5 to 23.9; P = .006 by the log-rank test). Clinical response was not associated with cancer type or malignancy remission status. CONCLUSIONS: Adjunctive HBO(2) therapy may benefit patients with BP-ONJ; however, the outcome is improved with cessation of BP administration.

Protecting the permeability pore and mitochondrial biogenesis.

Recent evidence links the pathogenesis of multiple organ dysfunction syndrome (MODS) in sepsis to mitochondrial damage. Our hypothesis is that cellular mechanisms maintaining mitochondrial function must be protected in order to prevent MODS. Recent animal experiments indicate that host defences which target and kill microbes, in part via reactive oxygen and nitrogen production, also injure mitochondria, thus activating mitochondrial cell death pathways. To limit such collateral damage, the cell up-regulates and imports into mitochondria several nuclear-encoded proteins for antioxidant defence and mitochondrial DNA (mtDNA) replication. Fully integrated responses lead to mitochondrial biogenesis, which may alter cellular phenotype to avoid mitochondrial permeability transition, apoptosis, or energy failure. Key to the cell's vulnerability to oxidant generation by the innate immune response is the mtDNA content. MtDNA depletion is opposed by oxidation reduction (redox) signals that communicate the extent of mitochondrial damage to the nucleus. Molecular studies suggest that redox mechanisms activate two biogenic transcription factors, nuclear respiratory factors 1 and 2, which forestall a deterioration of oxidative phosphorylation during infection. Biogenic failure or an intrinsic biogenic arrest could hasten degradation of mitochondrial function and drive the cell to apoptosis or necrosis. By implication, novel protective strategies for biogenesis hold promise for the prevention of MODS.

Metabolic capacity regulates iron homeostasis in endothelial cells.

The sensitivity of endothelial cells to oxidative stress and the high concentrations of iron in mitochondria led us to test the hypotheses that (1) changes in respiratory capacity alter iron homeostasis, and (2) lack of aerobic metabolism decreases labile iron stores and attenuates oxidative stress. Two respiration-deficient (rho(o)) endothelial cell lines with selective deletion of mitochondrial DNA (mtDNA) were created by exposing a parent endothelial cell line (EA) to ethidium bromide. Surviving cells were cloned and mtDNA-deficient cell lines were demonstrated to have diminished oxygen consumption. Total cellular and mitochondrial iron levels were measured, and iron uptake and compartmentalization were measured by inductively coupled plasma atomic emission spectroscopy. Iron transport and storage protein expression were analyzed by real-time polymerase chain reaction and Western blot or ELISA, and total and mitochondrial reactive oxygen species (ROS) generation was measured. Mitochondrial iron content was the same in all three cell lines, but both rho(o) lines had lower iron uptake and total cellular iron. Protein and mRNA expressions of major cytosolic iron transport constituents were down-regulated in rho(o) cells, including transferrin receptor, divalent metal transporter-1 (-IRE isoform), and ferritin. The mitochondrial iron-handling protein, frataxin, was also decreased in respiration-deficient cells. The rho(o) cell lines generated less mitochondrial ROS but released more extracellular H(2)O(2), and demonstrated significantly lower levels of lipid aldehyde formation than control cells. In summary, rho(o) cells with a minimal aerobic capacity had decreased iron uptake and storage. This work demonstrates that mitochondria regulate iron homeostasis in endothelial cells.

Nitric oxide amplifies the excitatory to inhibitory neurotransmitter imbalance accelerating oxygen seizures.

CNS O2 toxicity is manifested most profoundly by generalized motor convulsions. The hypothesis was tested that HBO2 triggers seizures by an excitatory to inhibitory neurotransmitter imbalance produced by neuronal nitric oxide (NO) activity. Anesthetized rats were exposed to 5 ATA HBO2 for 75 min with or without prior inhibition of nNOS. Interstitial NO and amino acids: aspartate (Asp), glutamate (Glu) and gamma-aminobutyric acid (GABA) were determined in the striatum by microdialysis coupled with HPLC. Blood flow and EEG in the same striatal region were measured simultaneously. Rats treated with 7-NI showed no EEG spikes of O2 toxicity, while seizure latency for untreated rats was 63 +/- 7 min. Significant increases in NO metabolites and blood flow were observed in control rats before seizures. HBO2 did not change Glu significantly and increased Asp slightly whereas GABA decreased progressively by 37 +/- 7%. Pretreatment with 7-NI led to a significantly smaller decline in GABA. Overall, the simplified excitotoxicity index Glu/GABA increased significantly after 60 min of HBO2 in control but fell in rats treated with 7-NI. We conclude that HBO2-stimulated neuronal NO production promotes an imbalance between glutamatergic and GABAergic synaptic function implicated in the genesis of oxygen-induced seizures.

Oxygen-induced mitochondrial biogenesis in the rat hippocampus.

The hypothesis that damage to mitochondrial DNA by reactive oxygen species increases the activity of nuclear and mitochondrial transcription factors for mitochondrial DNA replication was tested in the in vivo rat brain. Mitochondrial reactive oxygen species generation was stimulated using pre-convulsive doses of hyperbaric oxygen and hippocampal mitochondrial DNA content and neuronal and mitochondrial morphology and cell proliferation were evaluated at 1, 5 and 10 days. Gene expression was subsequently evaluated to assess nuclear and mitochondrial-encoded respiratory genes, mitochondrial transcription factor A, and nuclear respiratory transcription factors-1 and -2. After 1 day, a mitochondrial DNA deletion emerged involving Complex I and IV subunit-encoding regions that was independent of overt neurological or cytological O(2) toxicity, and resolved before the onset of cell proliferation. This damage was attenuated by blockade of neuronal nitric oxide synthase. Compensatory responses were found in nuclear gene expression for manganese superoxide dismutase, mitochondrial transcription factor A, and nuclear respiratory transcription factor-2. Enhanced nuclear respiratory transcription factor-2 binding activity in hippocampus was accompanied by a nearly three-fold boost in mitochondrial DNA content over 5 days. The finding that O(2) activates regional mitochondrial DNA transcription, replication, and mitochondrial biogenesis in the hippocampus may have important implications for maintaining neuronal viability after brain injury.

Superoxide dismutase responds to hyperoxia in rat hippocampus.

The brain's anti-oxidant response to highly elevated oxygen (O2) partial pressures is poorly understood. In this study we hypothesized that hyperbaric O2 (HBO2) would stimulate superoxide dismutase (SOD) transcription in the oxidative stress-sensitive rat hippocampus and measured the time course and extent of the changes in hippocampal mRNA for all three SOD isoforms and total SOD enzyme activity. Comparisons were made between exposures to 2 hours of 1 atmosphere pressure normobaric oxygen (NBO); 2 hours of 3 atmospheres HBO2; and room air. Hyperoxia (HBO2 > NBO) was associated with statistically significant increases in transcript levels of the antioxidant enzymes SOD2 (MnSOD) and SOD3 (EC-SOD) at 6 and 18 hours but not SOD1 (Cu, Zn SOD) respectively. Hyperoxia, however, did not affect total hippocampal SOD activity measured at 6 and 24 hours, indicating that the mRNA responses were necessary to maintain the anti-oxidant enzyme activity after oxidative stress.

Reduced inspiratory flow attenuates IL-8 release and MAPK activation of lung overstretch.

Lung overstretch involves mechanical factors, including large tidal volumes (VT), which induce inflammatory responses. The current authors hypothesised that inspiratory flow contributes to ventilator-induced inflammation. Buffer-perfused rabbit lungs were ventilated for 2 h with 21%, O2+5%, CO2, positive end-expiratory pressure of 2-3 cmH2O and randomly assigned to either: 1) normal VT (6 mL x kg(-1)) at respiratory rate (RR) 30, inspiration:expiration time ratio (I:E) 1:1, low inspiratory flow 6 mL x kg(-1) x s(-1); 2) large VT (12 mL x kg(-1)) at RR 30, I:E 1:1, high inspiratory flow 12 mL x kg(-1) x s(-1) (HRHF); 3) large VT at RR 15, I:E 1:1, low inspiratory flow 6 mL x kg(-1) x s(-1) (LRLF); or 4) large VT at RR 15, I:E 1:2.3, high inspiratory flow 10 mL x kg(-1) x s(-1) (LRHF). Physiological parameters, tumour necrosis factor (TNF)-alpha, interleukin (IL)-8 and activation of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK)1/2, p38 and stress-activated protein kinase (SAPK)/ c-Jun N-terminal kinase (JNK)) were measured. HRHF increased weight gain, perfusate IL-8 and phosphorylation of ERK1/2, p38 and SAPK/JNK. These responses were absent during LRLF but present during LRHF. Changes in TNF-alpha were small. Tissue IL-8 and phospho-ERK1/2 staining was localised primarily to smooth muscle, adventitia and bronchial epithelium within larger bronchioles and arterioles. These results indicate that mild overstretch of perfused lungs during high inspiratory flow enhances inflammatory signalling by cells in lung regions most affected by strong turbulent airflow.

Contributions of endothelial and neuronal nitric oxide synthases to cerebrovascular responses to hyperoxia.

Hyperoxia causes a transient decrease in CBF, followed by a later rise. The mediators of these effects are not known. We used mice lacking endothelial or neuronal nitric oxide synthase (NOS) isoforms (eNOS-/- and nNOS-/- mice) to study the roles of the NOS isoforms in mediating changes in cerebral vascular tone in response to hyperoxia. Resting regional cerebral blood flow (rCBF) did not differ between wild type (WT), eNOS-/- mice, and nNOS-/- mice. eNOS-/- mice showed decreased cerebrovascular reactivities to NG-nitro-L-arginine methyl ester (L-NAME), PAPA NONOate, acetylcholine (Ach), and SOD1. In response to hyperbaric oxygen (HBO2) at 5 ATA, WT and nNOS-/- mice showed decreases in rCBF over 30 minutes, but eNOS-/- mice did not. After 60 minutes HBO2, rCBF increased more in WT mice than in eNOS-/- or nNOS-/- mice. Brain NO-metabolites (NOx) decreased in WT and eNOS-/- mice within 30 minutes of HBO2, but after 45 minutes, NOx rose above control levels, whereas they did not change in nNOS-/- mice. Brain 3NT increased during HBO2 in WT and eNOS-/- but did not change in nNOS-/- mice. These results suggest that modulation of eNOS-derived NO by HBO2 is responsible for the early vasoconstriction responses, whereas late HBO2-induced vasodilation depends upon both eNOS and nNOS.

Internal carotid artery dissection in stroke from SCUBA diving: a case report.

Although diving with compressed air is generally safe, neurological problems resulting from infarction in SCUBA diving are well known, including arterial gas embolism and decompression sickness (caisson's disease, bends) involving the brain and spinal cord. While air gas embolism forms the overwhelming majority of causes for stroke in divers, internal carotid artery (ICA) dissection is another potential mechanism for central nervous system infarction in the setting of SCUBA diving. A 38 year-old female, who presented with complaints of headache, nausea, vomiting, and left sided hemiparesis after rapid ascent to the surface from a depth of 120 feet of seawater was initially treated for decompression illness in a hyperbaric chamber. Further neurological workup revealed a right ICA dissection. This case demonstrates the dangers of ICA dissection following rapid ascent to the surface from underwater and emphasizes an interesting presentation of stroke associated with SCUBA diving.

Tissue factor in experimental acute lung injury.

Acute lung injury (ALI) is characterized by fibrin deposition in the tissue and vascular spaces. Coagulation is activated after exposure to endotoxin or bacteria, and a procoagulant environment rapidly develops in the vascular, interstitial, and alveolar spaces of the lung. These changes are tissue factor (TF)-dependent and associated with increases in inflammatory cytokines. Procoagulant changes also occur in the lungs of patients with the acute respiratory distress syndrome (ARDS), suggesting that epithelial inflammation activates the extrinsic pathway. Many inflammatory mediators have specific effects on coagulation; however, the role of TF in regulation of pulmonary inflammatory responses is less clear. Here we report initial data on blockade of TF-initiated coagulation in baboons with Escherichia coli sepsis-induced ALI, using active site-inactivated FVIIa (FVIIai ASIS). Treatment with FVIIai prevented plasma fibrinogen depletion and attenuated fibrin deposition in the tissues. The drug also decreased systemic cytokine responses and inflammatory changes in the lung, including neutrophil infiltration, and decreased edema. Coagulation blockade with FVIIai improved lung function by preserving gas exchange and compliance, decreased pulmonary hypertension, and enhanced renal function. These results show that TF-FVIIa complex is an important regulatory site for the pathologic response of the lung to sepsis.