Colistin-associated nephrotoxicity among patients in intensive care units (ICU) of hospitals in Selangor.

INTRODUCTION: The increasing trend of extensively drugresistant gram negative bacteria responsible for nosocomial infections has prompted resurgence colistin usage. Colistin-induced nephrotoxicity is a concern with disparity in the reported rates between previous studies. This study aims to evaluate colistin-induced nephrotoxicity among Malaysian population. METHODS: The medical records of ICU patients receiving colistin therapy in Hospital Serdang and Hospital Sungai Buloh from 2010 to 2012 were retrospectively reviewed. Demographics data, treatment characteristic as well as culture result and creatinine level were documented. Nephrotoxicity was determined based on RIFLE criteria. RESULTS: A total of 100 patients were included. Median daily dose, cumulative dose and duration of colistin therapy were 3.0 MIU (IQR: 4, range 1-12), 17.8 MIU (IQR: 31.5, range 2-180) and seven days (IQR: 4, range 1-30). Nephrotoxicity was found in 23% of the study population. All cases were reversible but marginally associated with higher mortality. No statistical association exist between age, gender and race as well as administration routes with nephrotoxicity by univariable analysis. The association of dose and duration with nephrotoxicity was also not significant by univariable analysis. After adjustment for confounders, statistical association between the independent variables and dependent variable remains not significant. CONCLUSION: Lower dose and shorter duration in local settings contribute to lack of association between colistin therapy and nephrotoxicity in this study. Higher dosing regimen with loading dose application has been introduced in the latest National Antibiotic Guideline. Further evaluation of colistin-induced nephrotoxicity and potential risk factors is therefore warranted.

Opening of ATP-sensitive potassium channel by insulin in the brain-induced insulin secretion in Wistar rats.

Cerebral insulin can regulate glucose homeostasis via activation of the parasympathetic nervous system, which results in the reduction of hepatic glucose output. However, the precise mechanism(s) through which cerebral insulin directly exerts an effect on insulin secretion remains unclear. In the present study, we found that cerebral administration of insulin caused an increase of plasma insulin concentration and a concomitant decrease in plasma glucose levels within one hour. These effects were blocked by vagotomy or intraperitoneal injection of 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide, a specific M (3) antagonist. The mediating influence of parasympathetic activation can thus be considered. The adenosine triphosphate-sensitive potassium (K-ATP) channel is a key mediator of the cerebral action of insulin. The plasma glucose-lowering action of insulin was abolished by cerebral administration of glibenclamide or repaglinide at concentrations sufficient to block K-ATP channels. In conclusion, our findings suggest that cerebral insulin may induce insulin release by stimulating the opening of K-ATP channels, which in turn activate parasympathetic tone in pancreatic tissue.

Early detection of radiographic knee osteoarthritis using computer-aided analysis.

OBJECTIVE: To determine whether computer-based analysis can detect features predictive of osteoarthritis (OA) development in radiographically normal knees. METHOD: A systematic computer-aided image analysis method weighted neighbor distances using a compound hierarchy of algorithms representing morphology (WND-CHARM) was used to analyze pairs of weight-bearing knee X-rays. Initial X-rays were all scored as normal Kellgren-Lawrence (KL) grade 0, and on follow-up approximately 20 years later either developed OA (defined as KL grade=2) or remained normal. RESULTS: The computer-aided method predicted whether a knee would change from KL grade 0 to grade 3 with 72% accuracy (P<0.00001), and to grade 2 with 62% accuracy (P<0.01). Although a large part of the predictive signal comes from the image tiles that contained the joint, the region adjacent to the tibial spines provided the strongest predictive signal. CONCLUSION: Radiographic features detectable using a computer-aided image analysis method can predict the future development of radiographic knee OA.

Serum protein signatures detect early radiographic osteoarthritis.

OBJECTIVE: To test the hypothesis that early knee and hand osteoarthritis (OA) development is characterized by detectable changes in serum proteins relevant to inflammation, cell growth, activation, and metabolism several years before OA becomes radiographically evident. METHODS: Using microarray platforms that simultaneously test 169 proteins relevant to inflammation, cell growth, activation and metabolism, we conducted a case-control study nested within the Baltimore Longitudinal Study of Aging (BLSA). Subjects included 22 incident cases of OA and 66 age-, sex- and body mass index (BMI)-matched controls. Serum samples tested were obtained at the time of radiographic classification as either case or control, and up to 10 years earlier at a time when all participants were free of radiographic OA. Proteins with mean signal intensities fourfold higher than background were compared between cases and controls using multivariate techniques. RESULTS: Sixteen proteins were different between OA cases compared to controls. Four of these proteins [matrix metalloproteinase (MMP)-7, interleukin (IL)-15, plasminogen activator inhibitor (PAI)-1 and soluble vascular adhesion protein (sVAP)-1] were already different in samples obtained 10 years before radiographic classification and remained different at the time of diagnosis. Six additional proteins were only associated with subsequent OA development and not with established OA. CONCLUSIONS: Changes in serum proteins implicated in matrix degradation, cell activation, inflammation and bone collagen degradation products accompany early OA development and can precede radiographic detection by several years.

Physical and cognitive performance and burden of anticholinergics, sedatives, and ACE inhibitors in older women.

Polypharmacy, common in older people, confers both risk of adverse outcomes and benefits. We assessed the relationship of commonly prescribed medications with anticholinergic and sedative effects to physical and cognitive performance in older individuals. The study population comprised 932 moderately to severely disabled community-resident women aged 65 years or older who were participants in the Women's Health and Aging Study I. A scale based on pharmacodynamic principles was developed and utilized as a measure of drug burden. This was related to measures of physical and cognitive function. After adjusting for demographics and comorbidities, anticholinergic drug burden was independently associated with greater difficulty in four physical function domains with adjusted odds ratios (95% confidence interval (CI)) of 4.9 (2.0-12.0) for balance difficulty; 3.2 (1.5-6.9) for mobility difficulty; 3.6 (1.6-8.0) for slow gait; 4.2 (2.0-8.7) for chair stands difficulty; 2.4 (1.1-5.3) for weak grip strength; 2.7 (1.3-5.4) for upper extremity limitations; 3.4 (1.7-6.9) for difficulty in activities of daily living; and 2.4 (95% CI, 1.1-5.1) for poor performance on the Mini-Mental State Examination. Sedative burden was associated only with impaired grip strength (3.3 (1.5-7.3)) and mobility difficulty (2.4 (1.1-5.3)). The burden of multiple drugs can be quantified by incorporating the recommended dose regimen and the actual dose and frequency of drug taken. Anticholinergic drug burden is strongly associated with limitations in physical and cognitive function. Sedative burden is associated with impaired functioning in more limited domains. The risk associated with exposure of vulnerable older women to drugs with anticholinergic properties, and to a lesser extent those with sedative properties, implies that such drugs should not be used in this patient group without compelling clinical indication.

Electromyographic patterns suggest changes in motor unit physiology associated with early osteoarthritis of the knee.

OBJECTIVE: To assess characteristics of active motor units (MUs) during volitional vastus medialis (VM) activation in adults with symptomatic knee osteoarthritis (OA) across the spectrum of radiographic severity and age-comparable healthy control volunteers. METHODS: We evaluated 39 participants (age 65+/-3 years) in whom weight-bearing knee X-rays were assigned a Kellgren & Lawrence (KL) grade (18 with KL grade=0; four each with KL grades=1, 2 and 4; nine with grade 3). Electromyography (EMG) signals were simultaneously acquired using surface [surface EMG (S-EMG)] and intramuscular needle electrodes, and analyzed by decomposition-enhanced spike-triggered averaging to obtain estimates of size [surface-represented MU action potentials (S-MUAP) area], number [MU recruitment index (MURI)] and firing rates [MU firing rates (mFR)] of active MUs at 10%, 20%, 30% and 50% effort relative to maximum voluntary force [maximal voluntary isometric contraction (MVIC)] during isometric knee extension. RESULTS: Knee extensor MVIC was lower in OA participants, especially at higher KL grades (P=0.05). Taking the observed force differences into account, OA was also associated with activation of larger MUs (S-MUAP area/MVICx%effort; P<0.0001). In contrast, the estimated number of active units (MURI/MVICx%effort) changed differently as effort increased from 10% to 50% and was higher with advanced OA (KL=3, 4) than controls (P=0.0002). CONCLUSION: VM activation changes at the level of the MU with symptomatic knee OA, and this change is influenced by radiographic severity. Poor muscle quality may explain the pattern observed with higher KL grades, but alternative factors (e.g., nerve or joint injury, physical inactivity or muscle composition changes) should be examined in early OA.

Effects of knee injection on skeletal muscle metabolism and contractile force in rats.

OBJECTIVE: We tested the hypothesis that intrusion of the knee joint capsule alters quadriceps muscle metabolism and function independently from the damage induced to knee cartilage. METHODS: Adult rats were separated into four groups: intraarticular injections of saline (SAL; n=9); intraarticular injections of papain, a model for osteoarthritis (PIA; n=7); sham injections (SHAM; n=8); and controls (CTL; n=5). 31P magnetic resonance spectroscopy (31P-MRS) was performed after 2 weeks. Spectra were obtained from the left quadriceps: two at baseline, eight during electrical stimulation with simultaneous measurement of contractile force, and 15 during recovery. 31P-MRS data were presented as the ratio of inorganic phosphate (Pi) to phosphocreatine (PCr), concentrations of PCr [PCr], intramuscular pH, and the rates and time constants of PCr breakdown during stimulation and PCr recovery. Intramuscular cytokine concentrations were measured within the quadriceps. Histologic slides of the knees were scored for severity of cartilage damage. RESULTS: The interventional groups produced values of Pi/PCr ratio, [PCr], contractile force and pH that were significantly different from CTL. These changes in muscle function were accompanied by higher concentrations of interleukin-1 observed with PIA and SAL. We did not observe any effect of cartilage damage on muscle function or metabolism. CONCLUSIONS: Knee joint intrusion alters quadriceps muscle metabolism with accelerated depletion of energy stores and fatigue during stimulation. This study demonstrates that needle intrusion into the knee joint results in muscle dysfunction, independently from the extent of cartilage damage.

Arterial stiffness and hand osteoarthritis: a novel relationship?

OBJECTIVE: Osteoarthritis (OA) and vascular stiffening may share elements of common pathogenesis, but their potential relatedness has been the focus of little prior inquiry. We tested the hypothesis that these two aging-associated conditions are related to each other. METHOD: We analyzed cross-sectional data from 256 participants of the Baltimore Longitudinal Study of Aging (BLSA), a study of normative aging. All underwent measurement of arterial pulse wave velocity (PWV), an index of vascular stiffness, as well as hand radiographs that were graded for evidence of OA. Twenty total joints across three joint groups (distal interphalangeal [DIP], proximal interphalangeal [PIP], carpal-metacarpal [CMC]) were each assigned a Kellgren-Lawrence grade (K-L) of 0 (normal) through 4 (severe), with K-L grades >or=2 considered evidence of definite OA. Radiographic hand OA was defined as definite OA changes in at least two of the three anatomic hand sites (DIP, PIP, CMC). OA burden was represented by the total number of affected OA joints, and a cumulative K-L grade was aggregated across all hand joint groups. The relationship of PWV with these three measures of hand OA was assessed by linear regression. RESULTS: Upon univariate analysis, the presence of radiographic hand OA (beta=218.1, P<0.01), the total number of OA joints (beta=32.9, P<0.01), and the cumulative K-L grade across all joint groups (beta=12.2, P<0.01) were each associated with increased PWV. These associations, however, were no longer significant in age-adjusted models. CONCLUSION: Although significant individual relationships between PWV and several measures of hand OA were observed, these associations were largely attributable to the confounding effect of age.

The relationship between testosterone and molecular markers of inflammation in older men.

Aging is accompanied by a pro-inflammatory state expressed by the increasing levels of inflammatory cytokines, including interleukin-6 (IL- 6), tumor necrosis factor alpha (TNF-alpha) and interleukin- 1beta (IL-1beta). At the same time, aging is associated with a decrease in serum testosterone (T) levels. There is evidence from many experimental studies that IL-6, TNF-alpha and IL-1beta inhibit T secretion by their influence on the central (hypothalamic-pituitary) and peripheral (testicular) components of the gonadal axis. On the other hand, observational and interventional studies suggest that T supplementation reduces inflammatory markers in both young and old hypogonadal men. Preliminary data from 473 older male participants of the InCHIANTI population showed a significant inverse relationship between T and soluble IL-6 receptor (sIL-6r) levels (a soluble portion of the IL-6 receptor that may enhance the biological activity of IL-6) but not with other markers of inflammation. This study, together with previous observations, suggests that a close relationship exists between the development of a pro-inflammatory state and the decline in T levels, two trends that are often observed in aging men. In the context of this paradigm, we discuss androgen deprivation therapy, a treatment used in men with metastatic prostate cancer as an ideal model to improve our understanding of the relationship between T and inflammatory markers. We advocate the notion that changes in inflammatory markers and T in aging men are causally linked. However, longitudinal and interventional studies are needed to confirm that T can be used therapeutically, based on its anti-inflammatory properties.

[The preparation of Ag/AgCl nanoparticle and its resonance scattering spectroscopic study].

Putting the AgCl nanoparticle as crystal nucleus and in the condition of the existence of tri-sodium citrate, the Ag+, which covers the surface of AgCl nanoparticle, photochemically reduces to Ag and thus Ag/AgCl composite nanoparticle is obtained. The spectroscopic characters of Ag/AgCl nanoparticle in aqueous solution have been studied. There are two resonance scattering peaks at 310 and 590 nm, and an absorption peak at 400 nm.

Osteoarthritis: no cure, but many options for symptom relief.

Because curative disease-modifying medications for osteoarthritis are still not available, medical management strategies focus on pain relief. Other goals are to identify functional deficits early and to start restorative, if not preventive, rehabilitation. We review recent developments and summarize the clinical features and treatments currently available.

The accuracy of self-report of physician diagnosed rheumatoid arthritis in moderately to severely disabled older women. Women's Health and Aging Collaborative Research Group.

OBJECTIVE: To determine the accuracy of self-report of physician diagnosed rheumatoid arthritis (RA) in moderately to severely disabled older women. METHODS: A total of 1002 participants in the Women's Health and Aging Study were included. These women were > or =65 years old, had an average of 4 chronic illnesses, and represented the one-third most disabled women living in the community. Self-report of a physician's diagnosis of RA was compared to cases of "definite" RA that were adjudicated using an algorithm modeled on the American College of Rheumatology criteria for RA. RESULTS: The sensitivity of self-report of physician diagnosed RA was 77%, with 90.6% specificity and 99% negative predictive value, kappa = 0.46. The positive predictive value was 34% and likely reflected the low prevalence of RA in this sample (3.1%). Five of the 6 women who did not correctly report RA were under the care of a rheumatologist. CONCLUSION: The accuracy of self-report of a physician's diagnosis of RA in this sample of disabled women with multiple chronic illnesses matched that observed in the general adult population of previous studies. Accuracy was enhanced by including report of receiving care by a rheumatologist.

Comparison of pain assessment instruments in cognitively intact and cognitively impaired nursing home residents.

This study was conducted to determine which pain severity and location instruments were most useful in the nursing home setting. Pain severity and location were assessed monthly for 1 year in 37 participants enrolled in a restorative rehabilitation program. Pain location was determined by the residents' indications on a diagram, a doll, and their body. Pain severity was determined by resident response to verbal, visual analog, faces, and word scales. Cognitively impaired residents had greater difficulty using all instruments. The McGill Word Scale was used most to determine pain severity. Pointing to themselves most frequently determined pain location among residents. New strategies are needed for pain assessment in the elderly, especially the cognitively impaired elderly, and a combination of instruments to assess pain in the latter group may be necessary.

The patterns and prevalence of hand osteoarthritis in a population of disabled older women: The Women's Health and Aging Study.

OBJECTIVE: To describe the prevalence of hand osteoarthritis (OA) by joint site, joint count and severity in a representative population of older disabled women. METHODS: 1,002 moderately to severely disabled women aged > or = 65 years were selected from a representative population of community-dwelling women. Hand OA was established using a reproducible algorithm based on self-reported pain, standardized physical examinations, hand photographs, and physician questionnaire responses. OA was categorized as either symptomatic disease, intermittently symptomatic/ asymptomatic disease, possible disease, or no disease. RESULTS: Symptomatic OA, requiring the presence of hand pain on most days for at least 1 month, occurred in approximately 23% of disabled older women in each age group, and most reported pain in the moderate to severe range. The prevalence of intermittently symptomatic/ asymptomatic OA was higher with increasing age. Finally, the most commonly affected hand OA sites were the distal interphalangeal (DIP) and the first carpometacarpal (CMC1) joint groups. CONCLUSION: These findings demonstrate the very high prevalence of clinical hand OA in disabled older women and show that a large proportion of hand OA results in substantial symptoms.

Prevalence of significant knee pain among older Americans: results from the Third National Health and Nutrition Examination Survey.

OBJECTIVE: To assess the prevalence of persistent knee pain among older adults in the US. DESIGN: A nationally representative cross-sectional survey with an in-person interview and medical examination SETTING AND PARTICIPANTS: Between 1988 and 1994, 6596 adults aged 60 to 90+ years were examined as part of the National Health and Nutrition Examination Survey III. Mexican Americans and non-Hispanic blacks were over-sampled to produce reliable estimates for these groups. MAIN OUTCOME MEASUREMENTS: Participants were asked to report whether they had experienced knee pain on most days for the 6 weeks preceding their medical exam. RESULTS: Overall, 18.1% of US men and 23.5% of US women aged 60 years and older reported knee pain. Sixty- to ninety-year-old men reported knee pain less frequently than their age-matched female counterparts. There was a trend for reports of knee pain to increase steadily as these adults aged from 60 to 85 years. The highest prevalence of knee pain was reported among 85- to 90-year-old men (23.7%) and women (30.0%). Among non-Hispanic white adults older than age 60, 18.4% of men and 22.0% of women reported knee pain. Reports of knee pain among non-Hispanic black men and Mexican American men were similar to those of their non-Hispanic white counterparts. In contrast, 26.4% of Mexican American women and 32.8% of non-Hispanic black women reported knee pain. We also found that difficulty in performing physical functioning activities was associated with a higher prevalence of knee pain. CONCLUSIONS: Many US adults older than age 60 years report knee pain, and the prevalence is higher in older adults. Reports of knee pain are highest among non-Hispanic black women and the oldest Americans. Intervention strategies are needed to prevent and better manage knee pain among older US adults to stem the adverse health consequences and diminished quality of life associated with this common problem.

Raynaud's phenomenon in older adults: diagnostic considerations and management.

Raynaud's phenomenon (RP) is characterised by sensitivity to cold temperatures associated with either biphasic or uniphasic change in colour of the digits. Since few studies are available which include older adults, the prevalence of RP in the older adult population is estimated from surveys or studies of the general population. The causes of RP in older adults may differ significantly from those in young adults and, therefore, so would the evaluation of RP. Because of comorbitis that accompany advancing age, the management of RP in older adult patients must take into consideration toxicity and adverse reactions that may develop, especially in the frail individual. Although nonpharmacological therapy is preferable, slow-release calcium antagonists provide a relatively well tolerated and effective treatment for moderate to severe RP in older adult patients. Aggressive treatment including hospitalisation is appropriate for older adult patients during periods of critical digital ischaemia associated with RP.

Gamma knife radiosurgery for large volume brain tumors: an analysis of acute and chronic toxicity.

Gamma Knife radiosurgery is often used to treat intracranial tumors <4 cm (approximately 13.5 cm3) in mean diameter. Larger lesions are rarely treated because of the expectation that increasing target volume will increase toxicity. We retrospectively analyzed 35 patients with primary or metastatic brain tumors of more than 13.5 cm3 treated with the Gamma Knife. Only 3 (8.5%) patients developed acute clinical toxicity. Nine (25%) patients developed post-Gamma Knife radionecrosis based on imaging studies, with only 3 of these patients (9% of the study population) having clinical progression of symptoms. Necrosis was not found to be related to prescribed dose, treatment volume or number of treated isocenters. We found no undue toxicity from the treatment of large brain tumors with the Gamma Knife.

Osteoarthritis in older adults.

OBJECTIVE: This review highlights the clinical and pathophysiologic features of osteoarthritis (OA) of the peripheral joints and discusses the current and future management options for this common but potentially disabling disease. This article also addresses the contribution of osteoarthritis to falls and functional impairment in older people. DESIGN: A critical assessment of current data regarding the pathogenesis of osteoarthritis, current and future therapies, and the potential role of OA in falls and functional impairment in older people. CONCLUSIONS: Osteoarthritis is the most prevalent articular disease in older adults. Disease markers that will detect early disease and allow early intervention with pharmacologic agents that modify, if not halt, disease progression are much needed, but they are presently unavailable. Current management should include safe and adequate pain relief using systemic and local therapies and should also include medical and rehabilitative interventions to prevent, or at least compensate for, functional deficits. Although OA can result in impaired mobility and lower extremity function, its contribution as a cause of recurrent falls or impaired self-care, relative to other comorbid conditions, remains ill-defined. Further analysis of the determinants of disability, loss of mobility and falls in older patients with OA is needed.

Local control after the use of adjuvant electron beam intraoperative radiotherapy in patients with high-risk head and neck cancer: the UCSF experience.

PURPOSE: We assess the effect of electron beam intraoperative radiotherapy (EB-IORT) on local-regional control and any associated complications in patients with locally advanced or recurrent head and neck cancer. MATERIALS AND METHODS: The records of 30 patients with head and neck cancer who received EB-IORT from March 1991 to December 1994 were retrospectively reviewed. The indications for EB-IORT in 25 patients were recurrent or persistent disease despite previous treatment with full-course external-beam radiotherapy and/or one or more resections. In five other cases the indication was extensive primary disease with multiple high-risk factors for local recurrence, including extension into the base of the skull, advanced extensive disease, and perineural or bony invasion. All patients had a Karnofsky performance score > or = 70 prior to EB-IORT. Median age was 65 years. Final pathology revealed positive or close surgical margins in all patients. The areas treated were generally inaccessible to catheter placement for brachytherapy. The most common histology was squamous cell carcinoma. EB-IORT was given as a single fraction of 1500 cGy to the 90% isodose with 6 or 9 Mev electrons using cone sizes ranging from 2.5 to 7 cm in diameter. Data were analyzed to determine the local-regional control rate, survival, and complications after EB-IORT. RESULTS: With a median follow-up time of 30 months, nine patients (27%) had only local recurrence. Of these, only one recurrence was inside the EB-IORT field and eight were outside the EB-IORT field. Two patients (7%) developed distant metastases only and one patient (3%) had both local recurrence and distant metastasis. Seven patients died, five with disease. Twenty-two patients are known to be alive, 15 (68%) of whom have no evidence of disease. One patient was lost to follow-up after 12 months; when last examined he was free of disease. Five patients (16%) have had mild-to-moderate transient complications probably related to EB-IORT. The 3-year actuarial local-regional control rate was 60%. CONCLUSIONS: Our data suggest that EB-IORT may play an important role in decreasing local recurrence in patients with multiple high-risk factors. Despite previous full-course external beam radiotherapy and extensive resections, EB-IORT did not confer significant additional long-term morbidity. Although results are encouraging, randomized studies are required to definitively establish the role of EB-IORT in the management of advanced or recurrent head and neck cancer.