Cerebrospinal Fluid Interleukin-6 in Central Nervous System Inflammatory Diseases

Background

Interleukin (IL)-6 is recognised as an important cytokine involved in inflammatory diseases of the central nervous system (CNS).

Objective

To perform a large retrospective study designed to test cerebrospinal fluid (CSF) IL-6 levels in the context of neurological diseases, and evaluate its usefulness as a biomarker to help discriminate multiple sclerosis (MS) from other inflammatory neurological diseases (OIND).

Patients and Methods

We analyzed 374 CSF samples for IL-6 using a quantitative enzyme-linked immunosorbent assay. Groups tested were composed of demyelinating diseases of the CNS (DD, n = 117), including relapsing-remitting MS (RRMS, n = 65), primary progressive MS (PPMS, n = 11), clinically isolated syndrome (CIS, n = 11), optic neuritis (ON, n = 30); idiopathic transverse myelitis (ITM, n = 10); other inflammatory neurological diseases (OIND, n = 35); and non-inflammatory neurological diseases (NIND, n = 212). Differences between groups were analysed using Kruskal−Wallis test and Mann−Whitney U-test.

Results

CSF IL-6 levels exceeded the positivity cut-off of 10 pg/ml in 18 (51.4%) of the 35 OIND samples, but in only three (3.9%) of the 76 MS samples collected. CSF IL-6 was negative for all NIND samples tested (0/212). IL-6 cut-off of 10 pg/ml offers 96% sensitivity to exclude MS.

Conclusion

CSF IL-6 may help to differentiate MS from its major differential diagnosis group, OIND.     

Increased Expression of AQP 1 and AQP 5 in Rat Lungs Ventilated with Low Tidal Volume is Time Dependent

Background and Goals

Mechanical ventilation (MV) can induce or worsen pulmonary oedema. Aquaporins (AQPs) facilitate the selective and rapid bi-directional movement of water. Their role in the development and resolution of pulmonary oedema is controversial. Our objectives are to determine if prolonged MV causes lung oedema and changes in the expression of AQP 1 and AQP 5 in rats.

Methods

25 male Wistar rats were subjected to MV with a tidal volume of 10 ml/kg, during 2 hours (n = 12) and 4 hours (n = 13). Degree of oedema was compared with a group of non-ventilated rats (n = 5). The expression of AQP 1 and AQP 5 were determined by western immunoblotting, measuring the amount of mRNA (previously amplified by RT-PCR) and immunohistochemical staining of AQPs 1 and 5 in lung samples from all groups.

Results

Lung oedema and alveolar-capillary membrane permeability did not change during MV. AQP-5 steady state levels in the western blot were increased (p<0.01) at 2 h and 4 h of MV. But in AQP-1 expression these differences were not found. However, the amount of mRNA for AQP-1 was increased at 2 h and 4 h of MV; and for AQP 5 at 4 h of MV. These findings were corroborated by representative immunohistochemical lung samples.

Conclusion

In lungs from rats ventilated with a low tidal volume the expression of AQP 5 increases gradually with MV duration, but does not cause pulmonary oedema or changes in lung permeability. AQPs may have a protective effect against the oedema induced by MV.     

Computational Modeling Reveals Distinct Effects of HIV and History of Drug Use on Decision-Making Processes in Women

Objective

Drug users and HIV-seropositive individuals often show deficits in decision-making; however the nature of these deficits is not well understood. Recent studies have employed computational modeling approaches to disentangle the psychological processes involved in decision-making. Although such approaches have been used successfully with a number of clinical groups including drug users, no study to date has used computational modeling to examine the effects of HIV on decision-making. In this study, we use this approach to investigate the effects of HIV and drug use on decision-making processes in women, who remain a relatively understudied population.

Method

Fifty-seven women enrolled in the Women''s Interagency HIV Study (WIHS) were classified into one of four groups based on their HIV status and history of crack cocaine and/or heroin drug use (DU): HIV+/DU+ (n = 14); HIV+/DU− (n = 17); HIV−/DU+ (n = 14); and HIV−/DU− (n = 12). We measured decision-making with the Iowa Gambling Task (IGT) and examined behavioral performance and model parameters derived from the best-fitting computational model of the IGT.

Results

Although groups showed similar behavioral performance, HIV and DU exhibited differential relationship to model parameters. Specifically, DU was associated with compromised learning/memory and reduced loss aversion, whereas HIV was associated with reduced loss aversion, but was not related to other model parameters.

Conclusions

Results reveal that HIV and DU have differential associations with distinct decision-making processes in women. This study contributes to a growing line of literature which shows that different psychological processes may underlie similar behavioral performance in various clinical groups and may be associated with distinct functional outcomes.     

Antidepressant and Neurocognitive Effects of Isoflurane Anesthesia versus Electroconvulsive Therapy in Refractory Depression

Background

Many patients have serious depression that is nonresponsive to medications, but refuse electroconvulsive therapy (ECT). Early research suggested that isoflurane anesthesia may be an effective alternative to ECT. Subsequent studies altered drug, dose or number of treatments, and failed to replicate this success, halting research on isoflurane''s antidepressant effects for a decade. Our aim was to re-examine whether isoflurane has antidepressant effects comparable to ECT, with less adverse effects on cognition.

Method

Patients with medication-refractory depression received an average of 10 treatments of bifrontal ECT (n = 20) or isoflurane (n = 8) over 3 weeks. Depression severity (Hamilton Rating Scale for Depression-24) and neurocognitive responses (anterograde and retrograde memory, processing speed and verbal fluency) were assessed at Pretreatment, Post all treatments and 4-week Follow-up.

Results

Both treatments produced significant reductions in depression scores at Post-treatment and 4-week Follow-up; however, ECT had modestly better antidepressant effect at follow-up in severity-matched patients. Immediately Post-treatment, ECT (but not isoflurane) patients showed declines in memory, fluency, and processing speed. At Follow-up, only autobiographical memory remained below Pretreatment level for ECT patients, but isoflurane patients had greater test-retest neurocognitive score improvement.

Conclusions

Our data reconfirm that isoflurane has an antidepressant effect approaching ECT with less adverse neurocognitive effects, and reinforce the need for a larger clinical trial.     

Perinatal Supplementation with Omega-3 Polyunsaturated Fatty Acids Improves Sevoflurane-Induced Neurodegeneration and Memory Impairment in Neonatal Rats

Objectives

To investigate if perinatal Omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplementation can improve sevoflurane-induced neurotoxicity and cognitive impairment in neonatal rats.

Methods

Female Sprague-Dawley rats (n = 3 each group) were treated with or without an n-3 PUFAs (fish oil) enriched diet from the second day of pregnancy to 14 days after parturition. The offspring rats (P7) were treated with six hours sevoflurane administration (one group without sevoflurane/prenatal n-3 PUFAs supplement as control). The 5-bromodeoxyuridine (Brdu) was injected intraperitoneally during and after sevoflurane anesthesia to assess dentate gyrus (DG) progenitor proliferation. Brain tissues were harvested and subjected to Western blot and immunohistochemistry respectively. Morris water maze spatial reference memory, fear conditioning, and Morris water maze memory consolidation were tested at P35, P63 and P70 (n = 9), respectively.

Results

Six hours 3% sevoflurane administration increased the cleaved caspase-3 in the thalamus, parietal cortex but not hippocampus of neonatal rat brain. Sevoflurane anesthesia also decreased the neuronal precursor proliferation of DG in rat hippocampus. However, perinatal n-3 PUFAs supplement could decrease the cleaved caspase-3 in the cerebral cortex of neonatal rats, and mitigate the decrease in neuronal proliferation in their hippocampus. In neurobehavioral studies, compared with control and n-3 PUFAs supplement groups, we did not find significant spatial cognitive deficit and early long-term memory impairment in sevoflurane anesthetized neonatal rats at their adulthood. However, sevoflurane could impair the immediate fear response and working memory and short-term memory. And n-3 PUFAs could improve neurocognitive function in later life after neonatal sevoflurane exposure.

Conclusion

Our study demonstrated that neonatal exposure to prolonged sevoflurane could impair the immediate fear response, working memory and short-term memory of rats at their adulthood, which may through inducing neuronal apoptosis and decreasing neurogenesis. However, these sevoflurane-induced unfavorable neuronal effects can be mitigated by perinatal n-3 PUFAs supplementation.     

Cranialization of the Frontal Sinus for Secondary Mucocele Prevention following Open Surgery for Benign Frontal Lesions

Objective

To compare frontal sinus cranialization to obliteration for future prevention of secondary mucocele formation following open surgery for benign lesions of the frontal sinus.

Study Design

Retrospective case series.

Setting

Tertiary academic medical center.

Patients

Sixty-nine patients operated for benign frontal sinus pathology between 1994 and 2011.

Interventions

Open excision of benign frontal sinus pathology followed by either frontal obliteration (n = 41, 59%) or frontal cranialization (n = 28, 41%).

Main Outcome Measures

The prevalence of post-surgical complications and secondary mucocele formation were compiled.

Results

Pathologies included osteoma (n = 34, 49%), mucocele (n = 27, 39%), fibrous dysplasia (n = 6, 9%), and encephalocele (n = 2, 3%). Complications included skin infections (n = 6), postoperative cutaneous fistula (n = 1), telecanthus (n = 4), diplopia (n = 3), nasal deformity (n = 2) and epiphora (n = 1). None of the patients suffered from postoperative CSF leak, meningitis or pneumocephalus. Six patients, all of whom had previously undergone frontal sinus obliteration, required revision surgery due to secondary mucocele formation. Statistical analysis using non-inferiority test reveal that cranialization of the frontal sinus is non-inferior to obliteration for preventing secondary mucocele formation (P<0.0001).

Conclusion

Cranialization of the frontal sinus appears to be a good option for prevention of secondary mucocele development after open excision of benign frontal sinus lesions.     

Should Prior FIT Results Be Incorporated as an Additional Variable to Estimate Risk of Colorectal Neoplasia? A Prospective Study of 5,813 Screening Colonoscopies

Background

Recent studies showed that previous negative results from faecal immunochemical tests (FITs) for colorectal cancer (CRC) screening was associated with lower risk of advanced neoplasia (AN). We evaluated whether prior FIT results should be included to estimate the risk of AN in 2008–2012.

Methods

A community-based screening practice recruited 5,813 asymptomatic residents aged 50 to 70 years in Hong Kong for CRC screening. We included study participants who had (1). positive FIT with subsequent colonoscopy workup (FIT+ group; n = 356); (2). negative FIT in three consecutive years and received a colonoscopy (FIT- group; n = 857); (3). received colonoscopy without FIT (colonoscopy group; n = 473); and (4). received both colonoscopy and FIT at the same time (combined group; n = 4,127). One binary logistic regression model evaluated whether prior FIT results were associated with colonoscopy findings of AN.

Results

The proportion of participants having AN/CRC was 18.0% (FIT+), 5.5% (FIT-), 8.0% (colonoscopy group), and 4.3% (combined group), respectively. When compared with the colonoscopy group, those in the FIT- group were not significantly more or less likely to have AN/CRC (AOR  = 0.77, 95% C.I. = 0.51 to 1.18, p  = 0.230). Having one (AOR = 0.73, 95% C.I. 0.48–1.12, p = 0.151) or three consecutive negative FIT result (AOR = 0.98, 95% C.I. 0.60–1.62, p = 0.944) were not associated with lower risks of AN/CRC. Subjects in the FIT+ group was 3.32-fold (95% C.I. 2.07 to 5.32, p<0.001) more likely to have AN/CRC.

Conclusions

These findings indicated that subjects with negative FIT findings could be risk stratified similarly as those who had not previously received FIT.     

Organ Dysfunction among Piglets Treated with Inhaled Nitric Oxide and Intravenous Hydrocortisone during Prolonged Endotoxin Infusion

Objective

It has previously been shown that a combination of inhaled nitric oxide (iNO) and intravenous (IV) steroid attenuates endotoxin-induced organ damage in a 6-hour porcine endotoxemia model. We aimed to further explore these effects in a 30-hour model with attention to clinically important variables.

Design

Randomized controlled trial.

Setting

University animal laboratory.

Subjects

Domestic piglets (n = 30).

Interventions

Animals were randomized into 5 groups (n = 6 each): 1) Controls, 2) LPS-only (endotoxin/lipopolysaccharide (LPS) infusion), 3) LPS + iNO, 4) LPS + IV steroid, 5) LPS + iNO + IV steroid.

Measurements and Main Results

Exposure to LPS temporarily increased pulmonary artery mean pressure and impeded renal function with elevated serum creatinine and acidosis compared to a control group over the 30-hour study period. Double treatment with both iNO and IV steroid tended to blunt the deterioration in renal function, although the only significant effect was on Base Excess (p = 0.045). None of the LPS + iNO + IV steroid treated animals died during the study period, whereas one animal died in each of the other LPS-infused groups.

Conclusions

This study suggests that combined early therapy with iNO and IV steroid is associated with partial protection of kidney function after 30 hours of experimental LPS infusion.     

Pattern Recognition Analysis of Proton Nuclear Magnetic Resonance Spectra of Brain Tissue Extracts from Rats Anesthetized with Propofol or Isoflurane

Background

General anesthesia is routinely used as a surgical procedure and its safety has been endorsed by clinical outcomes; however, its effects at the molecular level have not been elucidated. General anesthetics influence glucose metabolism in the brain. However, the effects of anesthetics on brain metabolites other than those related to glucose have not been well characterized. We used a pattern recognition analysis of proton nuclear magnetic resonance spectra to visualize the changes in holistic brain metabolic phenotypes in response to the widely used intravenous anesthetic propofol and the volatile anesthetic isoflurane.

Methodology/Principal Findings

Rats were randomized into five groups (n = 7 each group). Propofol and isoflurane were administered to two groups each, for 2 or 6 h. The control group received no anesthesia. Brains were removed directly after anesthesia. Hydrophilic compounds were extracted from excised whole brains and measured by proton nuclear magnetic resonance spectroscopy. All spectral data were processed and analyzed by principal component analysis for comparison of the metabolite profiles. Data were visualized by plotting principal component (PC) scores. In the plots, each point represents an individual sample. The propofol and isoflurane groups were clustered separately on the plots, and this separation was especially pronounced when comparing the 6-h groups. The PC scores of the propofol group were clearly distinct from those of the control group, particularly in the 6-h group, whereas the difference in PC scores was more subtle in the isoflurane group and control groups.

Conclusions/Significance

The results of the present study showed that propofol and isoflurane exerted differential effects on holistic brain metabolism under anesthesia.     

A High Degree of LINE-1 Hypomethylation Is a Unique Feature of Early-Onset Colorectal Cancer

Objective

Early-onset colorectal cancer (CRC) represents a clinically distinct form of CRC that is often associated with a poor prognosis. Methylation levels of genomic repeats such as LINE-1 elements have been recognized as independent factors for increased cancer-related mortality. The methylation status of LINE-1 elements in early-onset CRC has not been analyzed previously.

Design

We analyzed 343 CRC tissues and 32 normal colonic mucosa samples, including 2 independent cohorts of CRC diagnosed ≤50 years old (n = 188), a group of sporadic CRC >50 years (MSS n = 89; MSI n = 46), and a group of Lynch syndrome CRCs (n = 20). Tumor mismatch repair protein expression, microsatellite instability status, LINE-1 and MLH1 methylation, somatic BRAF V600E mutation, and germline MUTYH mutations were evaluated.

Results

Mean LINE-1 methylation levels (±SD) in the five study groups were early-onset CRC, 56.6% (8.6); sporadic MSI, 67.1% (5.5); sporadic MSS, 65.1% (6.3); Lynch syndrome, 66.3% (4.5) and normal mucosa, 76.5% (1.5). Early-onset CRC had significantly lower LINE-1 methylation than any other group (p<0.0001). Compared to patients with <65% LINE-1 methylation in tumors, those with ≥65% LINE-1 methylation had significantly better overall survival (p = 0.026, log rank test).

Conclusions

LINE-1 hypomethylation constitutes a potentially important feature of early-onset CRC, and suggests a distinct molecular subtype. Further studies are needed to assess the potential of LINE-1 methylation status as a prognostic biomarker for young people with CRC.     

Interventions to Reduce and Prevent Obesity in Pre-Conceptual and Pregnant Women: A Systematic Review and Meta-Analysis

Background

The increasing prevalence of obesity in pregnant women is associated with adverse maternal and neonatal outcomes, and increased costs to healthcare, the economy and broader society.

Objectives

To assess the efficacy of behavioural interventions for managing gestational weight gain (GWG) in the pre-conceptual and pregnancy period in overweight, obese and morbidly obese women.

Search Methods

A search was performed for published studies in the English language, from date? 2000–31 December 2012 in five electronic databases; PubMed, Scopus, Cochrane Library, CINAHL and PsycINFO.

Selection criteria

Studies were included if they compared the efficacy or effectiveness of a particular behavioural intervention in pregnant or pre-conceptual women with standard maternity care. Studies that included women with co-morbid conditions such as diabetes mellitus and polycystic ovarian syndrome were excluded to help isolate the effect of the intervention.

Results

Fifteen studies involving 3,426 participants were included. One study (n = 692) focused on the pre-conceptual period and the remaining 14 (n = 2,734) in the pregnancy period. Pooled mean difference for GWG indicated a lower GWG in the intervention groups when compared to standard maternity care groups (n = 1771, mean difference (MD) −1.66 kg, 95% CI −3.12 to −0.21 kg). With respect to the types of participants, considerable heterogeneity between studies was shown in the obese subgroup [Tau² = 15.61; Chi² = 40.80, df = 3 (P<0.00001); I² = 93%].

Conclusions

Behavioural interventions in pregnancy may be effective in reducing GWG in obese women without comorbid conditions, but not overweight or morbidly obese women. Behavioural interventions had no effect on postpartum weight loss or retention, gestation week of delivery and infant birth weight in overweight, obese and morbidly obese women.     

Viral Load,Integration and Methylation of E2BS3 and 4 in Human Papilloma Virus (HPV) 16-Positive Vaginal and Vulvar Carcinomas

Objective

To investigate if viral load, integration and methylation of E2BS3 and 4 represent different ways of tumor transformation in vaginal and vulvar carcinoma and to elucidate its clinical impact.

Methods

Fifty-seven samples, positive for HPV16, were selected for the study. Detection of viral load was made with realtime-PCR using copy numbers of E6 and integration was calculated from comparing E2 to E6-copies. Methylation of E2BS3 and 4 was analysed using bisulphite treatment of tumor DNA, followed by PCR and pyrosequencing.

Results

Vaginal tumors were found to have a higher viral load (p = 0.024) compared to vulvar tumors but a high copy number (> median value, 15 000) as well as high methylation (>50%) was significantly (p = 0.010 and p = 0.045) associated with a worse cancer-specific survival rate in vulvar carcinoma, but not in vaginal carcinoma. Four groups could be defined for the complete series using a Cluster Two step analysis; (1) tumors holding episomal viral DNA, viral load below 150 000 copies not highly methylated (n = 25, 46.3%); (2) tumors harboring episomal viral DNA and being highly methylated (>50%; n = 6, 11.1%); (3) tumors with viral DNA fully integrated (n = 11, 20.4%), and (4) tumors harboring episomal viral DNA and being medium- or unmethylated (<50%) and having a high viral load (> total mean value 150 000; n = 12, 22.2%). The completely integrated tumors were found to be distinct group, whilst some overlap between the groups with high methylation and high viral load was observed.

Conclusion

HPV16- related integration, methylation in E2BS3 and 4 and viral load may represent different viral characteristics driving vaginal and vulvar carcinogenesis. HPV16- related parameters were found to be of clinical importance in the vulvar series only.     

Translating Evidence for Low Back Pain Management into a Consumer-Focussed Resource for Use in Community Pharmacies: A Cluster-Randomised Controlled Trial

Background

This cluster-randomised controlled trial determined the effectiveness of an evidence-based, pamphlet intervention in improving low back pain (LBP)-related beliefs among pharmacy consumers.

Methods

Thirty five community pharmacies were randomised to three groups: pamphlet+education intervention [n = 11]; pamphlet only intervention [n = 11]; control: usual care [n = 13]. Eligibility requirements for clusters included: community-based pharmacies and proprietor participation consent. Pharmacy consumers (N = 317) aged 18–65 years currently experiencing LBP participated. Intervention group allocation depended on the pharmacy attended. Individual-level outcomes were measured at pre-intervention (T0), at two (T1) and eight (T2) weeks post-intervention and included beliefs about LBP [Back Pain Beliefs Questionnaire (BBQ); Fear Avoidance Beliefs Questionnaire (FABQ)]. Secondary outcomes included pain severity, activity impairment and pamphlet perceived usefulness. Blinding to group allocation included primary investigators, outcome assessors and the statistician. Pharmacy staff and consumers were un-blinded.

Results

Of 35 pharmacies recruited (317 consumers), no clusters were lost to follow-up. Follow-up was available for n = 24 at 2 weeks only; n = 38 at 8 weeks only; n = 148 at both time points, with n = 148+24+38 = 210 analysed (107 excluded: no follow up). Adjusting for baseline scores demonstrated no significant differences in beliefs (2 or at 8 weeks) between pamphlet (with or without education) versus control, or between ‘pamphlet with’ versus ‘without’ education. Work-related fear (FABQ) was significantly lower in consumers receiving pamphlet (with or without education) versus control (difference −2.3, 95%CI: −4.4 to −0.2). There was no significant difference between “pamphlet with” versus “pamphlet without” groups. Consumers receiving the “pamphlet with” reported greater perceived usefulness than consumers receiving the “pamphlet without” (difference 0.9 (95%CI: 0.0 to 1.8)).

Conclusion

Community pharmacies provided a feasible primary care portal for implementing evidence-based information. The associated improvement in work-related LBP-beliefs for consumers receiving the pamphlet suggests this simple intervention may be a useful component of care.

Trial Registration

ACTR.org.au ACTRN12611000053921     

Economic Evaluation of Multisystemic Therapy for Young People at Risk for Continuing Criminal Activity in the UK

Objective

To evaluate whether multisystemic therapy (MST) is more cost-effective than statutory interventions that are currently available for young offenders in England.

Method

A cost-offset evaluation of MST based on data from a randomised controlled trial conducted in North London, England, comparing MST with usual services provided by two youth offending teams (YOT). Service costs were compared to cost savings in terms of rates of criminal re-offending.

Results

108 adolescents, aged 11–17 years, were randomly allocated to MST+YOT (n = 56) or YOT alone (n = 52). Reductions in offending were evident in both groups, but were higher in the MST+YOT group. At 18-month follow-up, the MST+YOT group cost less in terms of criminal activity (£9,425 versus £11,715, p = 0.456). The MST+YOT group were significantly cheaper in terms of YOT services than the YOT group (£3,402 versus £4,619, p = 0.006), but more expensive including the cost of MST, although not significantly so (£5,687 versus £4,619, p = 0.195). The net benefit per young person for the 18-month follow-up was estimated to be £1,222 (95% CI −£5,838 to £8,283).

Conclusions

The results reported in this study support the finding that MST+YOT has scope for cost-savings when compared to YOT alone. However, the limitations of the study in terms of method of economic evaluation, outcome measures used and data quality support the need for further research.     

Influence of Body Mass Index (BMI) on Functional Improvements at 3 Years Following Total Knee Replacement: A Retrospective Cohort Study

Background

The number of patients presenting for total knee replacement who are classified as obese is increasing. The functional benefits of performing TKR in these patients are unclear.

Aim

To assess the influence pre-operative body mass index has upon knee specific function, general health status and patient satisfaction at 3 years following total knee replacement.

Design

Retrospective comparative cohort study using prospectively collected data from an institutional arthroplasty register.

Methods

1367 patients were assessed using the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) and Medical Outcomes Trust Short Form-36 (SF-36) scores supplemented by a validated measure of satisfaction pre-operatively and subsequently at 1,2 and 3 year post-operatively. Comparisons were made by dividing the cohort into 4 groups based on body mass index (BMI) 18.5–25.0 kg/m² (n = 253);>25.0–30.0 kg/m² (n = 559);>30.0−35.0 kg/m² (n = 373);>35.0 kg/m² (n = 182).

Results

Despite lower pre-operative, 1 and 3 year WOMAC and SF-36 scores patients with the highest BMIs >35.0 kg/m² experienced similar improvements to patients with a ‘normal‘ BMI (18.5–25.0 kg/m²) at 1 year (Difference in WOMAC improvement = 0.0 (95%CI −5.2 to 5.2), p = 1.00) and this improvement was sustained at up to 3 years (Difference in 1 year to 3 year improvement = 2.2 (95%CI: −2.1 to 6.5), p = 1.00). This effect was also observed for the SF-36 mental and physical component scores. Despite equivalent functional improvements levels of satisfaction in the >35.0 kg/m² group were lower than for any other BMI group (>35.0 kg/m² = 84.6% satisfied versus 18.5–5.0 kg/m² = 93.3% satisfied,p = 0.01) as was the proportion of patients who stated they would have the operation again (>35.0 kg/m² = 69.6% versus 18.5–25.0 kg/m² = 82.2%,p = 0.01).

Conclusion

Obese and morbidly obese patients gain as much functional benefit from total knee replacement as patients with lesser body mass indexes. This benefit is maintained for up to 3 years following surgery. However, these patients are less satisfied with their knee replacement and almost a third would not have the operation again.     

RASopathic Skin Eruptions during Vemurafenib Therapy

Purpose

Vemurafenib is a potent inhibitor of V600 mutant BRAF with significant impact on progression-free and overall survival in advanced melanoma. Cutaneous side effects are frequent. This single-center observational study investigates clinical and histological features of these class-specific cutaneous adverse reactions.

Patients and Methods

Patients were all treated with Vemurafenib 960 mg b.i.d. within local ethic committees approved clinical trials. All skin reactions were collected and documented prospectively. Cutaneous reactions were classified by reaction pattern as phototoxic and inflammatory, hair and nail changes, keratinocytic proliferations and melanocytic disorders.

Results

Vemurafenib was well tolerated, only in two patients the dose had to be reduced to 720 mg due to arthralgia. 26/28 patients (93%) experienced cutaneous side effects. Observed side effects included UVA dependent photosensitivity (n = 16), maculopapular exanthema (n = 14), pruritus (n = 8), folliculitis (n = 5), burning feet (n = 3), hair thinning (mild alopecia) (n = 8), curly hair (n = 2) and nail changes (n = 2). Keratosis pilaris and acanthopapilloma were common skin reactions (n = 12/n = 13), as well as plantar hyperkeratosis (n = 4), keratoacanthoma (n = 5) and invasive squamous cell carcinoma (n = 4). One patient developed a second primary melanoma after more than 4 months of therapy (BRAF and RAS wild type).

Conclusion

Vemurafenib has a broad and peculiar cutaneous side effect profile involving epidermis and adnexa overlapping with the cutaneous manifestations of genetic diseases characterized by activating germ line mutations of RAS (RASopathy). They must be distinguished from allergic drug reaction. Regular skin examination and management by experienced dermatologists as well as continuous prophylactic photo protection including an UVA optimized sun screen is mandatory.     

Serum Retinol-Binding Protein 4 as a Marker for Cardiovascular Disease in Women

Background

Elevated serum level of retinol-binding protein 4 (RBP4) has been associated with obesity-related co-morbidities including insulin resistance, dyslipidemia and hypertension.

Objectives

The present study examined the relationship between serum level of RBP4 and various risk factors related to cardiovascular disease (CVD) in men and women.

Methods

284 subjects (139 males, 145 females), grouped into healthy (n = 60), obese diabetes (n = 60), non-obese diabetes (n = 60), obese non-diabetes (n = 60) and patients with CVD (n = 44), were assessed for anthropometric and biochemical parameters related to obesity, diabetes and CVD. In addition, serum levels of several adipokines, including fatty acid binding protein 4 (FABP4) and lipocalin 2 (LCN2) and RBP4 were measured using specific immunoassays.

Results

Serum RBP4 level correlated significantly with principal component derived from known risk factors of CVD (β = 0.20±0.06, P = 0.002). Significance of this correlation was limited to women (β = 0.20±0.06, P = 0.002) and it persisted even after adjusting for BMI (β = 0.19±0.06, P = 0.002). Overall (n = 284) serum RBP4 values significantly correlated with FABP4 (R = 0.19, p = 0.001). Serum FABP4 level of CVD subjects was significantly higher than healthy control (P = 0.001) and non-obese diabetes (P = 0.04) groups, but this difference was attributable to differences in BMI. Serum LCN2 level correlated well with RBP4 (R = 0.15, P = 0.008) and FABP4 (R = 0.36, P<0.001), but did not differ significantly between CVD and other groups.

Conclusions

Results of this study indicate a significant correlation between serum RBP4 and various established risk factors for CVD and suggest RBP4 may serve as an independent predictor of CVD in women.     

Recovery of Diaphragm Function following Mechanical Ventilation in a Rodent Model

Background

Mechanical ventilation (MV) induces diaphragmatic muscle fiber atrophy and contractile dysfunction (ventilator induced diaphragmatic dysfunction, VIDD). It is unknown how rapidly diaphragm muscle recovers from VIDD once spontaneous breathing is restored. We hypothesized that following extubation, the return to voluntary breathing would restore diaphragm muscle fiber size and contractile function using an established rodent model.

Methods

Following 12 hours of MV, animals were either euthanized or, after full wake up, extubated and returned to voluntary breathing for 12 hours or 24 hours. Acutely euthanized animals served as controls (each n = 8/group). Diaphragmatic contractility, fiber size, protease activation, and biomarkers of oxidative damage in the diaphragm were assessed.

Results

12 hours of MV induced VIDD. Compared to controls diaphragm contractility remained significantly depressed at 12 h after extubation but rebounded at 24 h to near control levels. Diaphragmatic levels of oxidized proteins were significantly elevated after MV (p = 0.002) and normalized at 24 hours after extubation.

Conclusions

These findings indicate that diaphragm recovery from VIDD, as indexed by fiber size and contractile properties, returns to near control levels within 24 hours after returning to spontaneous breathing. Besides the down-regulation of proteolytic pathways and oxidative stress at 24 hours after extubation further repairing mechanisms have to be determined.     

Does Increased Exercise or Physical Activity Alter Ad-Libitum Daily Energy Intake or Macronutrient Composition in Healthy Adults? A Systematic Review

Background

The magnitude of the negative energy balance induced by exercise may be reduced due to compensatory increases in energy intake.

Objective

To address the question: Does increased exercise or physical activity alter ad-libitum daily energy intake or macronutrient composition in healthy adults?

Data Sources

PubMed and Embase were searched (January 1990–January 2013) for studies that presented data on energy and/or macronutrient intake by level of exercise, physical activity or change in response to exercise. Ninety-nine articles (103 studies) were included.

Study Eligibility Criteria

Primary source articles published in English in peer-reviewed journals. Articles that presented data on energy and/or macronutrient intake by level of exercise or physical activity or changes in energy or macronutrient intake in response to acute exercise or exercise training in healthy (non-athlete) adults (mean age 18–64 years).

Study Appraisal and Synthesis Methods

Articles were grouped by study design: cross-sectional, acute/short term, non-randomized, and randomized trials. Considerable heterogeneity existed within study groups for several important study parameters, therefore a meta-analysis was considered inappropriate. Results were synthesized and presented by study design.

Results

No effect of physical activity, exercise or exercise training on energy intake was shown in 59% of cross-sectional studies (n = 17), 69% of acute (n = 40), 50% of short-term (n = 10), 92% of non-randomized (n = 12) and 75% of randomized trials (n = 24). Ninety-four percent of acute, 57% of short-term, 100% of non-randomized and 74% of randomized trials found no effect of exercise on macronutrient intake. Forty-six percent of cross-sectional trials found lower fat intake with increased physical activity.

Limitations

The literature is limited by the lack of adequately powered trials of sufficient duration, which have prescribed and measured exercise energy expenditure, or employed adequate assessment methods for energy and macronutrient intake.

Conclusions

We found no consistent evidence that increased physical activity or exercise effects energy or macronutrient intake.