Tricuspid annular plane systolic excursion-to-aortic ratio provides a bodyweight-independent measure of right ventricular systolic function in dogs.

OBJECTIVES: To evaluate whether tricuspid annular plane systolic excursion (TAPSE) can be normalized to aortic valve (Ao) measurements in dogs. To determine TAPSE:Ao reference intervals for healthy dogs and examine diagnostic performance of TAPSE:Ao in dogs with pulmonary hypertension (PH). ANIMALS: One hundred and thirty-seven healthy adult dogs; 115 dogs with myxomatous mitral valve disease (MMVD) but no PH; 91 dogs with PH. METHODS: A combined prospective and retrospective study. Full echocardiographic evaluations were performed on all dogs; TAPSE was indexed to Ao to produce a unitless TAPSE:Ao. Reference intervals for TAPSE:Ao were generated, and TAPSE:Ao was regressed on tricuspid regurgitant jet velocity in dogs with PH and on LA:Ao in dogs with MMVD without PH. Diagnostic test analysis was used to examine the ability of TAPSE:Ao to identify severe PH. An adjusted TAPSE:Ao (TAPSE:Ao(adj)) was derived to account for MMVD in dogs with PH. RESULTS: The ratio, TAPSE:Ao, removed the effect of bodyweight from TAPSE measurements. Healthy dogs had TAPSE:Ao > 0.65. The ratio, TAPSE:Ao, showed a linear negative relationship with tricuspid regurgitation velocity and positive relationship with LA:Ao. The adjusted ratio, TAPSE:Ao(adj), increased the sensitivity of diagnosis of PH in dogs with moderate-severe MMVD without affecting the diagnosis of PH in dogs with PH and with no or mild MMVD. CONCLUSIONS: The ratios, TAPSE:Ao and TAPSE:Ao(adj), are a bodyweight-independent means of assessing right ventricular systolic function in dogs and for identifying severe PH in dogs with or without MMVD.

Mortality benefit of statin use in traumatic spinal cord injury: a retrospective analysis.

STUDY DESIGN: An observational study based on retrospective review of the medical charts and death records of 163 individuals with traumatic spinal cord injuries (SCI). OBJECTIVES: To determine whether HMG coA Reductase Inhibitor ('statin') use in a cohort of patients with traumatic SCI reduced overall and cause-specific mortality. SETTING: An outpatient clinic designated for veterans with SCI at the Oklahoma City Veterans Administration Hospital. METHODS: Review and analysis of the medical records of 163 veterans with traumatic SCI cared for between the years 2000 and 2014. Data collected included statin use, duration of statin use and intensity of statin therapy, as well as cause-specific mortality. RESULTS: Seventy five participants had taken statins for an average of 5.7 ± 3.7 years, and had greater cardiovascular risk burdens than those who had not taken statins (n = 88). Statin use was associated with a reduced risk of death. The mortality rate for those patients on statins was 33.8-49.9 per 1000 person-years, depending on assumptions made regarding residual effects of statin use. Under most assumptions this was significantly lower than the mortality rate seen in those not on statins (47.4-66.8 deaths per 1000 person-years). Within the statin group, neither duration nor average intensity of statin therapy affected mortality. CONCLUSION: Statin use among a cohort of veterans with traumatic SCI reduced all-cause mortality. This retrospective study ought to spur further investigations into the potential benefits of statin use among people with chronic SCI, and begin a discussion as to whether individuals with injuries should routinely be offered statin therapy.

Whites and African-Americans in headache specialty clinics respond equally well to treatment.

This study sought to determine if Whites and African-Americans respond similarly to headache treatment administered in 'real-world' headache specialty treatment clinics. Using a naturalistic, longitudinal design, 284 patients receiving treatment for headache disorders completed 30-day daily diaries that assessed headache frequency and severity at pretreatment and 6-month follow-up and also provided data on their headache disability and quality of life at pretreatment and 1-, 2- and 6-month follow-up. Controlling for socioeconomic status and psychiatric comorbidity, hierarchical linear models found that African-Americans and Whites reported significant reductions in headache frequency and disability and improvements in life quality over the 6-month treatment period. African-Americans, unlike Whites, also reported significant decreases in headache severity. Nevertheless, Africans-Americans had significantly more frequent and disabling headaches and lower quality of life after treatment relative to Whites. Although Whites and African Americans responded favourably to headache treatments, more efficacious treatments are needed given the elevated level of headache frequency that remained in both racial groups following treatment.

Reverse engineering of dynamic networks.

We consider the problem of reverse-engineering dynamic models of biochemical networks from experimental data using polynomial dynamic systems. In earlier work, we developed an algorithm to identify minimal wiring diagrams, that is, directed graphs that represent the causal relationships between network variables. Here we extend this algorithm to identify a most likely dynamic model from the set of all possible dynamic models that fit the data over a fixed wiring diagram. To illustrate its performance, the method is applied to simulated time-course data from a published gene regulatory network in the fruitfly Drosophila melanogaster.

Appropriate use of NSAIDs: considering cardiovascular risk in the elderly.

In the first of this two-part article, we reviewed essential gastrointestinal (GI) data necessary for choosing selective COX-2 inhibitors (coxibs) versus nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other NSAID-related GI issues. Although GI considerations are critical to appropriate NSAID selection, the worldwide withdrawal of rofecoxib because of adverse cardiovascular (CV) events has changed the focus of appropriate NSAID selection. In part 2, we discuss relevant CV adverse effects related to NSAID use. Based upon data reviewed, we believe there are differences between coxibs and that all NSAIDs, including nonselective agents, have some degree of CV risk. Their use should be based upon patient's risks and benefits. Our clinical use pathway or algorithm will continue to frame the ongoing discussion and guide clinicians along what has become a difficult decision in daily practice.

Choosing nonselective NSAIDs and selective COX-2 inhibitors in the elderly. A clinical use pathway.

The literature has well established that nonsteroidal anti-inflammatory drugs (NSAIDS) are very effective in treating pain and inflammation, but these drugs are associated with significant gastrointestinal (GI) toxicity. This is especially true in the elderly patient population. Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) were developed to decrease the incidence of GI adverse events. Nevertheless, recent concerns regarding coxibs and their association with adverse cardiovascular events have led physicians to re-examine the appropriate use of all NSAIDs. Part 1 of this two-part article reviews essential data related to adverse GI events to help physicians select appropriate patients to receive nonselective NSAIDs or coxibs. Other considerations, such as the benefits of proton pump inhibitors (PPIs) and the mitigating effects of concurrent aspirin use, are also discussed. Our clinical use pathway or algorithm will frame the discussion and guide clinicians through what has become a difficult decision in daily practice.

Circular dichroism, kinetic and mass spectrometric studies of copper(I) and mercury(II) binding to metallothionein.

The metalloprotein metallothionein (MT) is remarkable in its metal binding properties: for the mammalian protein, well-characterized species exist for metal to sulfur ratios of M7S20, M12S20, and M18S20, where M = Cd(II), Zn(II), Hg(II), Ag(I), Au(I), and Cu(I). Optical spectra in general, and circular dichroism (CD) and luminescence spectra in particular, provide rich detail of a complicated metal binding chemistry when metals are added directly to the metal-free or zinc-containing protein. CD spectral data unambiguously identify key metal to protein stoichiometric ratios that result in well-defined structures. Electrospray ionization-mass spectrometry data are reported for reactions in which Hg(II) binds to apo-MT 2A as previously described from CD data. Emission spectra in the 450-750 nm region have been reported for metallothioneins containing Ag(I), Au(I), and Cu(I). The luminescence of Cu-MT can also be detected directly from mammalian and yeast cells. We report both steady-state and new dynamic data for titrations of Zn-MT with Cu(I). Analysis of kinetic data for the addition of the first two Cu(I) atoms to Zn-MT indicates a first-order mechanism over a concentration range of 5-50 microM. Three-dimensional modeling was carried out using the results of the CD and EXAFS studies, model calculations for Zn7-MT, Hg7-MT, and Cu12-MT are described.

The bedside confusion scale: development of a portable bedside test for confusion and its application to the palliative medicine population.

BACKGROUND: Clinical tests for confusion in medically ill patients are frequently burdensome and difficult to use. Available tests lack portability and tend to be shunned in clinical practice by physicians. OBJECTIVE: To develop a simple, sensitive bedside test for confusion. DESIGN: Prospective comparison study. SETTING: An in-patient palliative medicine unit in a large urban hospital. PATIENTS: Thirty-one consecutive patients admitted to the unit. INTERVENTION: None. MEASUREMENTS: A 2-minute screening test, the Bedside Confusion Scale (BCS), which utilizes an observation of level of consciousness at the time of clinical interaction, followed by a timed task of attention, was administered to 31 consecutively admitted patients. The results were compared to a previously validated test, the Confusion Assessment Method (CAM). The BCS and the CAM were scored in standardized fashion and results of the two populations compared. Demographic and clinical characteristics of the patient population, along with the Karnofsky performance scores (KPS) and neurological findings were registered. RESULTS: Using the CAM as the reference standard, the sensitivity of the BCS was 100%. Worsening KPS and more abnormalities on neurological examination were seen across normal (BCS = 0), borderline (BCS = 1), and abnormal (BCS >/= 2) groups (p > 0.01, trend test). CONCLUSIONS: In an in-patient palliative medicine population, the BCS correlates with the previously validated CAM and exhibits high sensitivity, an essential quality of a useful screening test.

Implementing guidelines for cancer pain management: results of a randomized controlled clinical trial.

PURPOSE: Pain and symptom management is an integral part of the clinical practice of oncology. A number of guidelines have been developed to assist the clinician in optimizing comfort care. We implemented clinical guidelines for cancer pain management in the community setting and evaluated whether these guidelines improved care. PATIENTS AND METHODS: Eighty-one cancer patients, aged 37 to 76 years, were enrolled onto a prospective, longitudinal, randomized controlled study from the outpatient clinic settings of 26 western Washington-area medical oncologists. A multilevel treatment algorithm based on the Agency for Health Care Policy and Research Guidelines for Cancer Pain Management was compared with standard-practice (control) pain and symptom management therapies used by community oncologists. The primary outcome of interest was pain (Brief Pain Inventory); secondary outcomes of interest were all other symptoms (Memorial Symptom Assessment Scale) and quality of life (Functional Assessment of Cancer Therapy Scale). RESULTS: Patients randomized to the pain algorithm group achieved a statistically significant reduction in usual pain intensity, measured as slope scores, when compared with standard community practice (P < .02). Concurrent chemotherapy and patient adherence to treatment were significant mediators of worst pain. There were no significant differences in other symptoms or quality of life between the two treatment groups. CONCLUSION: This guideline implementation study supports the use of algorithmic decision making in the management of cancer pain. These findings suggest that comprehensive pain assessment and evidence-based analgesic decision-making processes do enhance usual pain outcomes.

Differences in physician access patterns to hospice care.

Few issues in health care have recently generated as much discussion as the two seemingly unrelated topics of out-of-hospital health care financing and compassionate care of patients at the end of life. These two topics meet where health care costs cross paths with the economic viability of hospice and palliative medicine. In this study, we evaluated 101 admissions to a large Medicare-certified hospice in the last quarter of 1995 to assess factors associated with timing of referral to hospice. Mean length of stay in hospice was 55 days; median was 23 days. The majority of patients had cancer diagnoses (74%). Contrary to our hypothesis, there was no statistically significant difference in mean patient lengths of stay between oncologist-referred and nononcologist-referred patients. However, when we compared patient lengths of stay lasting less than--versus longer than--30 days, more patients referred by nononcologists were in hospice longer than 30 days (chi 2 = 3.92, P < 0.05). With further evaluation, this difference was attributable to longer stays by patients covered by the Medicine hospice benefit, by those with noncancer diagnoses, and by those who were older. More of these patients were referred by nononcologists. The difference in referral patterns between oncologists and nononcologists disappeared when only cancer patients were considered. Consistent with initial hypotheses, caregivers of patients with shorter lengths of stay were significantly less satisfied with hospice care (t = -4.06, P < 0.001). These results suggest that health care benefits and other patient-specific issues influence timing of hospice referral rather than simply preferences by types of physicians. The impact on Medicare expenditures and hospice viability is discussed.

Spectroscopic studies of copper and silver binding to metallothioneins.

MAMMALIAN METALLOTHIONEIN IS REMARKABLE IN ITS METAL BINDING PROPERTIES: well-characterized species exist for metal to sulfur ratios of M(7)S(20), M(12)S(20), and M(18)S(20), where M = Cd(ll), Zn(ll), Hg(ll), Ag(I), Au(I), and Cu(I). Circular dichroism and luminescence spectra provide rich details of a complicated metal binding chemistry when metals are added directly to the metal free- or zinc-containing protein. CD spectral data unambiguously identify key metal to protein stoichiometric ratios that result in well-defined structures. Emission spectra in the 450-750 nm region have been reported for metallothioneins containing Ag(I), Au(I), and Cu(I). The luminescence of Cu-MT can also be detected directly from mammalian and yeast cells. Qualitative and quantitative interpretations show that the final structure adopted by Ag-MT is not the same as that formed by Cu(I) ions in Cu-MT. XAFS structural data are reported for a number of metallothioneins, including Ag(12)-MT and Ag(17)-MT. Electrospray ionization mass spectrometry provides details on the species formed when Ag(I) binds to metallothionein. Mass spectral data are reported for metal-free MT 2A and Ag(n)-MT (n = 14-18).

Spatial memory under acute cold and restraint stress.

This study examined spatial memory as measured by radial arm maze (RAM) performance after exposure to two stress conditions and a normothermic-unrestrained control condition. Male Fischer 344 rats were trained on the win-shift RAM procedure for 7 days, by which time they achieved asymptotic performance. The next day, rats in the two stress groups were exposed to 15 min of restraint in either 37 degrees C water (normothermic-restraint) or in 20 degrees C water (cold-restraint). Rats were then allowed 40 min in a dry cage before being tested in the RAM. Performance was measured using the following dependent variables: number of correct out of the first eight choices, total number of choices, and time per choice. There were statistically significant effects of stress on all these variables; performance decrements were observed in both stress conditions relative to the normothermic-unrestrained condition. Normothermic-restrained rats displayed less impairment than cold-restrained rats on the stress day. Performance of normothermic-restrained rats returned to baseline levels the day after stress, whereas performance for the cold-restrained rats typically did not. This study demonstrates that: 1) restraint and cold stress impair performance on a memory task; and 2) impairment extent is related to stress severity. One of the mechanisms responsible for the observed behavioral deficits under cold stress may involve altered cholinergic function, because we previously demonstrated that hippocampal acetylcholine levels also decrease in relation to the severity of cold stress.

Narcolepsy. Signs, symptoms, differential diagnosis, and management.

Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness and cataplexy and less often by hypnagogic hallucinations and sleep paralysis. While patients report excessive daytime sleepiness and cataplexy as the more frequent symptoms of this condition, excessive daytime sleepiness is generally believed to be the most debilitating. Narcolepsy often is undiagnosed or misdiagnosed for a variety of reasons. Although confirmation of an initial diagnosis requires monitoring of physiologic variables conducted at a sleep center by specialists, the primary care physician has a critical role in the identification and management of this incurable affliction. This article provides recommendations for the diagnosis and management of narcolepsy. The cataplexy associated with narcolepsy can be managed with tricyclic antidepressants. The excessive sleepiness is managed with stimulants but newer agents, such as modafinil, which will be marketed as Provigil, and selegiline hydrochloride, with fewer adverse effects and less abuse potential, may offer means of promoting daytime wakefulness. Groups such as the National Sleep Foundation, Washington, DC, and the Narcolepsy Network, Cincinnati, Ohio, can provide patients with needed support and information.

Incorporation of copper into the yeast Saccharomyces cerevisiae. Identification of Cu(I)--metallothionein in intact yeast cells.

Copper is an essential metal ion to many living organisms, including mammals, as it mediates a wide variety of important biochemical processes. At elevated concentrations, copper is extremely toxic to host cells. This paradoxical nature of copper has necessitated a highly regulated procedure for its cellular accumulation, transport, and excretion. One important group of proteins involved in eukaryotic copper speciation is the protein metallothionein. Luminescence microscopy data, emission, and circular dichroism spectral data are reported as copper is incorporated into metallothionein by the yeast Saccharomyces cerevisiae. These techniques provide information on the mechanism of copper uptake by S. cerevisiae. A two-stage kinetic mechanism for the uptake of copper from the growth medium by the yeast cells is observed. The first stage displays an uptake rate that is dependent on the initial copper concentration of the growth medium, and lasts for approximately 6 h. The second stage has a slower rate of copper uptake than the first, but the kinetics are independent of the initial copper concentration. Emission spectra recorded directly from the intact yeast cells (at 77 K) show that the cellular incorporation of copper proceeds via several species, eventually leading to storage of the copper in the form of Cu-metallothionein. The photomicrographs of yeast cells grown in a copper-containing medium clearly show an orange luminescence, indicating the formation of a Cu(I)-thiolate species. The identification of this species as copper-metallothionein was confirmed by measurement of the circular dichroism and emission properties following excretion and isolation of the copper-containing protein from the yeast cells. Analysis of the emission spectrum from S. cerevisiae Cu-metallothionein at 77 K reveals two emission bands, centered at 570 and 700 nm. The high-energy emission band exhibits a two-component decay, with excited state lifetimes of 4.70 and 48.5 microseconds. The low-energy emission exhibits one major decay component with a lifetime of 1.13 microseconds. A high-molecular-weight, copper-containing species is also isolated from the yeast cells and is characterized spectroscopically.

Minocycline-related lupus erythematosus with associated liver disease.

A young woman developed minocycline-related lupus erythematosus with associated autoimmune hepatitis. All clinical and laboratory abnormalities returned to normal when the drug was stopped. The symptoms worsened dramatically upon rechallenge, strongly suggesting the reaction was related to the minocycline.

Comparison of the structures of the metal-thiolate binding site in Zn(II)-, Cd(II)-, and Hg(II)-metallothioneins using molecular modeling techniques.

The first fully energy-minimized structures for a series of structurally related metal complexes of the important mammalian metal binding protein metallothionein are described. The structures were calculated based on structural information obtained from existing spectroscopic and crystallographic data, and minimized using molecular mechanics (MM2) techniques. A two domain structure, with stoichiometries of M(II)3-(Scys)9 and M(II)4-(Scys)11 where M = zinc(II), cadmium(II), and mercury(II), was assembled and minimized. The resultant three-dimensional structure closely resembled that of rat liver Cd5Zn2-MT 1 obtained by analysis of x-ray diffraction data [A. H. Robbins, D.E. McRee, M. Williamson, S. A. Collett, N. H. Xuong, W. F. Furey, B. C. Wang and C. D. Stout, J. Mol. Biol. 221, 1269-1293 (1991)]. Minimized structures for Zn7-MT, Cd7-MT, and Hg7-MT are reported. Deep crevices that expose the metal-thiolate clusters are seen in each structure. However, for the mercury-containing protein, much of the mercury-thiolate structure is visible and it is proposed that this provides access for extensive interaction between solvent water molecules and the mercury(II), resulting in the observed distortion away from tetrahedral geometry for Hg7-MT. Volume calculations are reported for the protein metallated with 7 Zn(II), Cd(II), or Hg(II). A series of structural changes calculated for the step-wise isomorphous replacement of Zn(II) by Cd(II) and Hg(II) in the Zn4S11 alpha domain are shown.

The role of exercise in rehabilitation for patients with end-stage renal disease.

End-stage renal disease (ESRD) is a major health problem in the United States. Many patients with ESRD experience a decline in physical functioning as a result of the disease process and its associated sequelae. Cardiovascular changes, anemia, and skeletal muscle weakness contribute significantly to this decreased capacity, leading, in many instances, to a primarily sedentary lifestyle. Studies conducted on the effectiveness of exercise training for patients with ESRD reveal numerous physiological and psychological benefits, particularly when training is continued for several months. However, the number of structured exercise programs available as part of a rehabilitation program for ESRD patients is limited. This article provides an overview of the role of exercise for patients with renal disease, and a case study illustrates how nurses, in collaboration with the interdisciplinary team, can be effective in preventing continued deconditioning and in maintaining a more positive outlook in patients with ESRD.

Tyrosine administration prevents hypoxia-induced decrements in learning and memory.

Exposure to hypobaric hypoxia rapidly produces decrements in learning and memory. Tyrosine, a neurotransmitter precursor, has beneficial behavioral effects when administered to animals and humans exposed to various acute stressors. To determine whether tyrosine would protect rats from the adverse effects of hypobaric hypoxia on spatial reference and working memory, it was administered to 27 male Fischer 344 rats tested in the Morris water maze. Rats were tested starting at 2 and 6 h of an 8 h exposure to a simulated altitude of 5950 m (19,500 ft) or sea level. Tyrosine or placebo was administered 1/2 h prior to each testing session (400 mg/kg, IP). Altitude exposure significantly increased working memory escape latency; treatment with tyrosine reversed this decrement. There was no effect of altitude or tyrosine on reference memory. There were also no treatment-related differences in performance when animals were tested the next day at sea level. The beneficial effects of tyrosine on working memory performance may be due to a direct effect of tyrosine on memory, alleviation of a hypoxia-induced retardation of learning, or to other central or peripheral effects of this dietary catecholamine precursor.

Morphological alterations in the hippocampus following hypobaric hypoxia.

1. The morphological consequences of hypobaric hypoxia, exposure to reduced pressure atmospheres, were examined in the hippocampus of male Fischer 344 rats. Severe chronic hypoxia can produce permanent neuronal damage with hippocampal structures being especially vulnerable. 2. Hippocampal morphology was studied using histological observations after a 4 day exposure to sea level, 3500 m, or 6400 m. Two groups tested at 6400 m were sacrificed at different intervals following exposure, 72 and 144 h, to examine the effect of post-exposure time on neuronal damage. 3. Histological damage was observed in rats' brains following exposure to altitude, with cell degeneration and death increasing as altitude increased. In addition, it was found that the longer the time following exposure before sacrifice, the more noticeable the damage, suggesting delayed neurotoxicity. Increases in the number of damaged cells following altitude were significant for the CA3 region of one 6400 m group; however, other differences did not reach statistical significance. Rats exposed to altitude for 4 days ate less and lost significantly more weight than did animals at sea level. 4. It appears that 4 days of exposure to altitudes less than or equal to 6400 m does produce changes in the CA3 subfield, but the damage is different than that seen with other models of non-transient ischemia.