Pain and functional trajectories in symptomatic knee osteoarthritis over up to 12 weeks of exercise exposure.

OBJECTIVE: Exercise is the recommended treatment for knee osteoarthritis (OA). However, heterogeneous patterns in treatment response are poorly understood. Our purpose was to identify pain and functional trajectories from exercise interventions in knee OA, and to determine their association with baseline factors. METHODS: Prospective cohort of 171 participants (mean age 61 years; BMI 32 kg/m2, 71% female; 57% white) with symptomatic knee OA from a randomized trial comparing 12-week Tai Chi and Physical Therapy. We analyzed weekly Western Ontario and McMaster Osteoarthritis Index (WOMAC) pain (0-500) and function (0-1700) scores using group-based trajectory models. Associations between baseline factors and trajectories were examined using multinomial logistic regression. RESULTS: We identified four pain trajectories: Lower-Early Improvement (43%), Moderate-Early Improvement (32%), Higher-Delayed Improvement (15%), and Higher-No Improvement (10%). We found similar trajectories for function, except that the lower function trajectories diverged into gradual (12%) or delayed-improvement (15%). Compared with the Lower-Early Improvement pain trajectory, moderate and higher trajectories were associated with poorer physical and psychosocial health. A similar pattern of associations were found among the function trajectories. CONCLUSIONS: We found four distinct trajectories for pain and function over up to 12-weeks of exercise interventions. While most participants experienced improvements over a short-term exposure, subgroups with greater baseline pain/physical disability had either gradual, delayed, or no improvements. These findings help disentangle the heterogeneity of treatment response and may advance patient-centered care in knee OA.

Mindfulness is associated with psychological health and moderates pain in knee osteoarthritis.

OBJECTIVE: Previous studies suggest that higher mindfulness is associated with less pain and depression. However, the role of mindfulness has never been studied in knee osteoarthritis (OA). We evaluate the relationships between mindfulness and pain, psychological symptoms, and quality of life in knee OA. METHOD: We performed a secondary analysis of baseline data from our randomized comparative trial in participants with knee OA. Mindfulness was assessed using the Five Facet Mindfulness Questionnaire (FFMQ). We measured pain, physical function, quality of life, depression, stress, and self-efficacy with commonly-used patient-reported measures. Simple and multivariable regression models were utilized to assess associations between mindfulness and health outcomes. We further tested whether mindfulness moderated the pain-psychological outcome associations. RESULTS: Eighty patients were enrolled (60.3 ± 10.3 years; 76.3% female, body mass index: 33.0 ± 7.1 kg/m2). Total mindfulness score was associated with mental (beta = 1.31, 95% CI: 0.68, 1.95) and physical (beta = 0.69, 95% CI:0.06, 1.31) component quality of life, self-efficacy (beta = 0.22, 95% CI:0.07, 0.37), depression (beta = -1.15, 95% CI:-1.77, -0.54), and stress (beta = -1.07, 95% CI:-1.53, -0.60). Of the five facets, the Describing, Acting-with-Awareness, and Non-judging mindfulness facets had the most associations with psychological health. No significant association was found between mindfulness and pain or function (P = 0.08-0.24). However, we found that mindfulness moderated the effect of pain on stress (P = 0.02). CONCLUSION: Mindfulness is associated with depression, stress, self-efficacy, and quality of life among knee OA patients. Mindfulness also moderates the influence of pain on stress, which suggests that mindfulness may alter the way one copes with pain. Future studies examining the benefits of mind-body therapy, designed to increase mindfulness, for patients with OA are warranted.

Translational development of splice-modifying antisense oligomers.

INTRODUCTION: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention. Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints. Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.

Do Results of Surveillance Cultures Impact the Choice of Empirical Antibiotics Among Patients with Carbapenem-Resistant Acinetobacter baumannii Infections?

We aimed to determine whether the results of surveillance cultures were associated with use of appropriate empirical antibiotic therapy among patients with carbapenem-resistant Acinetobacter baumannii infections. We found that surveillance status was not associated with appropriate empirical antibiotic therapy (P=.36). There were significant delays to concordant therapy among surveillance-positive patients (P=.03).

Cross-sectional DXA and MR measures of tibial periarticular bone associate with radiographic knee osteoarthritis severity.

OBJECTIVE: We evaluated the relationship of medial proximal tibial periarticular areal bone mineral density (paBMD) and trabecular morphometry and determined whether these bone measures differed across radiographic medial joint space narrowing (JSN) scores. METHODS: 482 participants of the Osteoarthritis Initiative (OAI) Bone Ancillary Study had knee dual X-ray absorptiometry (DXA) and trabecular bone 3T magnetic resonance imaging (MRI) exams assessed at the same visit. Medial proximal tibial paBMD was measured on DXA and apparent trabecular bone volume fraction (aBV/TV), thickness (aTb.Th), number (aTb.N), and spacing (aTb.Sp) were determined from MR images. Radiographs were assessed for medial JSN scores (0-3). We evaluated associations between medial paBMD and trabecular morphometry. Whisker plots with notches of these measures versus medial JSN scores were generated and presented. RESULTS: Mean age was 63.9 (9.2) years, BMI 29.6 (4.8) kg/m(2), and 53% were male. The Spearman correlation coefficients between DXA-measured medial paBMD and aBV/TV was 0.61 [95% confidence interval (CI) 0.55-0.66]; between paBMD and aTb.Th was 0.38 (95%CI 0.30-0.46); paBMD and aTb.N was 0.65 (95%CI 0.60-0.70); paBMD and aTb.Sp was -0.65 (95%CI -0.70 to -0.59). paBMD and the trabecular metrics were associated with medial JSN scores. CONCLUSION: The moderate associations between periarticular trabecular bone density and morphometry and their relationship with greater severity of knee OA support hypotheses of remodeling and/or microscopic compression fractures in the natural history of OA. Longitudinal studies are needed to assess whether knee DXA will be a predictor of OA progression. Further characterization of the periarticular bone in OA utilizing complementary imaging modalities will help clarify OA pathophysiology.

Efficacy of ertapenem for treatment of bloodstream infections caused by extended-spectrum-ß-lactamase-producing Enterobacteriaceae.

Ertapenem is active against extended-spectrum-ß-lactamase (ESBL)-producing Enterobacteriaceae organisms but inactive against Pseudomonas aeruginosa and Acinetobacter baumannii. Due to a lack of therapeutic data for ertapenem in the treatment of ESBL bloodstream infections (BSIs), group 2 carbapenems (e.g., imipenem or meropenem) are often preferred for treatment of ESBL-producing Enterobacteriaceae, although their antipseudomonal activity is unnecessary. From 2005 to 2010, 261 patients with ESBL BSIs were analyzed. Outcomes were equivalent between patients treated with ertapenem and those treated with group 2 carbapenems (mortality rates of 6% and 18%, respectively; P = 0.18).

Successful eradication of a monoclonal strain of Klebsiella pneumoniae during a K. pneumoniae carbapenemase-producing K. pneumoniae outbreak in a surgical intensive care unit in Miami, Florida.

We describe the investigation and control of a Klebsiella pneumoniae carbapenemase-producing K. pneumoniae outbreak in a 20-bed surgical intensive care unit during the period from January 1, 2009 through January 1, 2010. Nine patients were either colonized or infected with a monoclonal strain of K. pneumoniae. The implementation of a bundle of interventions on July 2009 successfully controlled the further horizontal spread of this organism.

Vagus nerve stimulation for depression: rationale, anatomical and physiological basis of efficacy and future prospects.

Treatment-resistant depression (TRD) is a major public health concern due to its high costs to society. One of the novel approaches for the treatment of depression is the vagus nerve stimulation (VNS). Therapeutic brain stimulation through delivery of pulsed electrical impulses to the left cervical vagus nerve now has established safety and efficacy as an adjunct treatment for medication-resistant epilepsy and has recently been approved as an adjunct long-term treatment for chronic or recurrent depression. There is considerable evidence from both animal and human neurochemical and neuroimaging studies, that the vagus nerve and its stimulation influence limbic and higher cortical brain regions implicated in mood disorders, providing a rationale for its possible role in the treatment of psychiatric disorders. Clinical studies (open-label and comparator with treatment in naturalistic setting) in patients with TRD have produced promising results, especially when the response rates at longer-term (one- and two-year) follow-up time points are considered. Ongoing research efforts will help determine the place of VNS in the armament of therapeutic modalities available for major depression.

Gonococcal ophthalmia treated with ciprofloxacin.

Neisseria gonorrhoeae infection in the eye and its treatment with ciprofloxacin is presented.

Effects of excess vitamin A on development of cranial neural crest-derived structures: a neonatal and embryologic study.

BACKGROUND: Vitamin A and its metabolites have been shown to be teratogenic in animals and humans producing defects of neural crest derived structures that include abnormalities of the craniofacial skeleton, heart, and thymus. Our prior studies with retinoic acid have established that gestational day (gd) 9 is a sensitive embryonic age in the mouse for inducing craniofacial and thymic defects. METHODS: We exposed pregnant mice to variable doses of vitamin A (retinyl acetate) on gd 9 and embryos were evaluated for changes in developing pharyngeal arch and pouch morphology, neural crest cell migration and marker gene expression. Additionally, we investigated whether a single organ system was more sensitive to low doses of vitamin A and could potentially be used as an indicator of vitamin A exposure during early gestation. RESULTS: High (100 mg/kg) and moderate (50 and 25 mg/kg) doses of vitamin A resulted in significant craniofacial, cardiac outflow tract and thymic abnormalities. Low doses of vitamin A (10 mg/kg) produced craniofacial and thymic abnormalities that were mild and of low penetrance. Exposed embryos showed morphologic changes in the 2nd and 3rd pharyngeal arches and pouches, changes in neural crest migration, abnormalities in cranial ganglia, and altered expression of Hoxa3. CONCLUSIONS: These animal studies, along with recent epidemiologic reports on human teratogenicity with vitamin A, raise concerns about the potential for induction of defects (perhaps subtle) in offspring of women ingesting even moderate to low amounts of supplemental vitamin A during the early gestational period.

Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse.

BACKGROUND: Short-term depletion of plasma tryptophan has been shown to result in depressive relapse in patients with remission of major depression. Positron emission tomography and single photon emission computed tomography studies implicated the dorsolateral prefrontal cortex, orbitofrontal cortex, thalamus, and caudate nucleus in the pathogenesis of depression. The purpose of this study was to measure cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. METHODS: Patients diagnosed as having major depression (N = 21) who clinically improved with serotonin reuptake inhibitors underwent 2 test days involving tryptophan depletion or placebo, followed 6 hours later by positron emission tomography scanning with fludeoxy-glucose F18. Brain metabolism was compared in patients with (n = 7) and without (n = 14) a tryptophan depletion-induced depressive relapse. RESULTS: Tryptophan depletion resulted in a decrease in brain metabolism in the middle frontal gyrus (dorsolateral prefrontal cortex), thalamus, and orbitofrontal cortex in patients with a depletion-induced depressive relapse (but not in patients without depletion-induced relapse). Decreased brain metabolism in these regions correlated with increased depressive symptoms. Baseline metabolism was increased in prefrontal and limbic regions in relapse-prone patients. CONCLUSION: Specific brain regions, including the middle frontal gyrus, thalamus, and orbitofrontal cortex, may mediate the symptoms of patients with major depression.

ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae.

A K+ channel gene has been cloned from Drosophila melanogaster by complementation in Saccharomyces cerevisiae cells defective for K+ uptake. Naturally expressed in the neuromuscular tissues of adult flies, this gene confers K+ transport capacity on yeast cells when heterologously expressed. In Xenopus laevis oocytes, expression yields an ungated K(+)-selective current whose attributes resemble the "leak" conductance thought to mediate the resting potential of vertebrate myelinated neurons but whose molecular nature has long remained elusive. The predicted protein has two pore (P) domains and four membrane-spanning helices and is a member of a newly recognized K+ channel family. Expression of the channel in flies and yeast cells makes feasible studies of structure and in vivo function using genetic approaches that are not possible in higher animals.

Opiate dependence and withdrawal: preliminary assessment using single photon emission computerized tomography (SPECT).

Naloxone (0.8 mg, s.c.) effects on opiate withdrawal signs and symptoms and regional brain function were assessed in 10 methadone-maintained patients and 10 healthy subjects in a double-blind, placebo-controlled study. Regional brain function was assessed using single photon emission computerized tomography (SPECT) by evaluating the uptake of [99mTc]d,l-hexamethylpropyleneamine oxime (HMPAO) in the brain, a process related to regional cerebral perfusion. Comparisons of patients and healthy subjects after saline infusion suggested that chronic opiate dependence was associated with lower corrected activity ratios (regional count density/whole brain count density) in frontal and parietal cortices and greater activity ratios in the thalamus. Opiate-dependent patients, but not healthy subjects, developed opiate withdrawal signs and symptoms after naloxone administration. Following naloxone administration, patients undergoing opiate withdrawal exhibited lower whole brain count density than healthy subjects. They also had lower activity ratios in frontal and parietal cortices and increased thalamic activity ratios relative to healthy subjects receiving naloxone. Naloxone administration in healthy subjects, but not opiate withdrawal in patients, was associated with decreased right parietal cortex and increased right temporal cortex and left basal ganglia activity ratios. Relative to naloxone effects in healthy subjects, opiate withdrawal was associated with decreased whole brain count density and a reduced right temporal cortex activity ratio. This preliminary study reports an initial evaluation of HMPAO-SPECT imaging for assessing regional alterations in brain function during opiate dependence and withdrawal. While group differences were reported, the small magnitude of regional alterations in patients undergoing opiate withdrawal raised concern that HMPAO-SPECT methods employed were inadequate for assessing human regional brain function during phases of opiate addiction. Other emerging functional brain imaging technologies should be evaluated relative to improved HMPAO-SPECT methods for this purpose.

Tryptophan depletion in patients with obsessive-compulsive disorder who respond to serotonin reuptake inhibitors.

METHODS: The effects of short-term tryptophan depletion were examined in 15 patients with DSM-III-R obsessive-compulsive disorder who had demonstrated symptom reduction following treatment with serotonin reuptake inhibitors. Patients received a 24-hour, low-tryptophan (160-mg/d) diet followed the next morning by a drink of 15 amino acids. A double-blind, placebo-controlled cross-over design was used. RESULTS: The diet and the amino acid drink reduced free plasma tryptophan levels by a mean of 84% 5 hours later. Short-term tryptophan depletion did not significantly change mean ratings of obsessions and compulsions. In contrast, mean depression ratings were significantly increased with tryptophan depletion compared with the control (tryptophan-supplemented) testing. CONCLUSION: Maintenance of serotonin reuptake inhibitor-induced improvement of obsessive and compulsive symptoms, unlike remission of depressive symptoms, may not depend on ongoing short-term availability of serotonin.

The role of central oxytocin in obsessive compulsive disorder and related normal behavior.

Oxytocin (OT) is a neurosecretory nonapeptide synthesized in hypothalamic cells, which project to widely distributed sites in the CNS as well as the neurohypophysis. Central OT affects a variety of cognitive, grooming, affiliative, sexual, and reproductive behaviors in animals. Obsessive Compulsive Disorder (OCD) includes a range of cognitive and behavioral symptoms that bear some relationship to dimensions of behavior associated with OT. Anecdotal data and a recently completed cerebrospinal fluid (CSF) study provide evidence that some forms of OCD are related to OT dysfunction. Based on these findings, we hypothesize: 1) that some forms of OCD are at the extreme end of a range of normal behaviors that are mediated by OT and related systems; and that 2) some normal cognitive, affiliative, and sexual behaviors contain elements that are similar to features of OCD. Alternative hypotheses are considered, and a series of predictions are presented concerning the relationship between central OT and the onset, course, treatment response, and response to challenge procedures seen in this form of OCD.

Biological approaches to treatment-resistant obsessive compulsive disorder.

Biological approaches to the patient with treatment-resistant obsessive compulsive disorder are briefly reviewed. The most commonly employed strategy involves combining a potent serotonin reuptake inhibitor (SRI) (e.g., clomipramine or fluvoxamine) with another medication that may exert effects on the brain serotonin system. Open-label reports regarding the addition of tryptophan, fenfluramine, lithium, or buspirone to ongoing SRI therapy of obsessive compulsive disorder are encouraging. However, the anti-obsessive compulsive efficacy of SRI-lithium and SRI-buspirone combination therapy has not been confirmed in recent controlled trials. Preliminary evidence suggests that addition of neuroleptic may benefit SRI-refractory obsessive compulsive disorder patients who have a comorbid chronic tic disorder. Other biological approaches (e.g., electroconvulsive therapy and psychosurgery) are considered in terms of their narrowly defined roles in the treatment of patients with SRI-resistant obsessive compulsive disorder. Finally, an algorithm is proposed for those patients with obsessive compulsive disorder who fail to respond to an adequate trial with a potent SRI.

A model of cooperation between complementary and allopathic medicine in a primary care setting.

This paper describes an acupuncture and osteopathy service offered free of charge to patients at a National Health Service general practice. The background to the setting up of this service, its organization, funding, aims and philosophy, and the ethical and legal implications for the general practitioners whose patients are treated by complementary therapists are discussed. This service provides a model of cooperation between allopathic and complementary medicine in a primary care setting and could be copied elsewhere.

Temporal summation of repetitive click stimuli.

Monaural loudness balances were performed by eight normal-hearing subjects to determine the effect of click repetition rate on loudness sensation. Click trains of 500 msec duration were matched in loudness to a standard 500 msec 1000 Hz tone burst presented at three reference loudness levels (70, 80, and 90 phons). Click trains were presented at repetition rates of 11, 31, 51, and 91 clicks per sec. It was found that click trains at faster repetition rates required lower intensities for judgments of equal loudness sensation. This finding was attributed to the process of temporal loudness summation. The magnitude and nature of the temporal summation process as well as the influence of the reference loudness level are discussed.

Giant and symptomatic inflammatory polyps of the colon in idiopathic inflammatory bowel disease.

Four cases of giant inflammatory polyps were found in a series of 86 consecutive colectomies for inflammatory bowel disease. Two presented a distinctive clinical syndrome of abdominal pain and chronic iron-deficiency anemia due to blood loss. Secondary ulceration of the heads of the polyps accounted for the bleeding and anemia, and the size of the polyps accounted for the abdominal pain. In both cases unusually long portions of colon were involved by the giant polyps. The third and fourth cases had rare complications--reactivation of an enterocutaneous fistula and perforation of an acquired diverticulum. These cases demonstrate that giant inflammatory polyps may produce symptoms independently of the underlying inflammatory bowel disease. In reported cases of giant inflammatory polyps, approximately two-thirds had Crohn's disease and one-third had ulcerative colitis. The transverse colon was the commonest location, pain was the commonest symptom, and the polyps were localized to a short segment of colon in the majority of cases. More than 50% of cases mimicked neoplasm on barium enema. Giant inflammatory polyps may produce a variety of distinctive signs and symptoms and deserve independent recognition.

Infection control programs in twelve North Carolina extended care facilities.

To assess the scope of infection control programs in extended care facilities, 1-day surveys were conducted in 12 North Carolina facilities over an 8-month period using a standardized questionnaire. All 12 facilities had a designated infection control practitioner (ICP), although none had attended an infection control education course. Eleven had an Infection Control Committee of which 8 (73%) met regularly. The Director of Nurses generally (58%) was the ICP and spent about 2 hr/wk on infection control. Ten (83%) facilities conducted infection surveillance among residents but did not accurately compute nosocomial infection rates. Eleven (92%) facilities had employee health programs that included preemployment and annual tuberculosis screening. None had a comprehensive resident health program. Infection control aspects of patient care practices often varied from facility to facility. Nosocomial infection surveillance among 336 residents in 9 facilities using modified CDC criteria revealed an overall prevalence rate of 5.4%. Additional infections were suspected but not included because of limitations of laboratory data and chart documentation.