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Aims Antibiotic-loaded bone cements (ALBCs) may offer early protection against the formation of bacterial biofilm after joint arthroplasty. Use in hip arthroplasty is widely accepted, but there is a lack of evidence in total knee arthroplasty (TKA). The objective of this study was to evaluate the use of ALBC in a large population of TKA patients. Materials and Methods Data from the National Joint Registry (NJR) of England and Wales were obtained for all primary cemented TKAs between March 2003 and July 2016. Patient, implant, and surgical variables were analyzed. Cox proportional hazards models were used to assess the influence of ALBC on risk of revision. Body mass index (BMI) data were available in a subset of patients. Results Of 731 214 TKAs, 15 295 (2.1%) were implanted with plain cement and 715 919 (97.9%) with ALBC. There were 13 391 revisions; 2391 were performed for infection. After adjusting for other variables, ALBC had a significantly lower risk of revision for any cause (hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77 to 0.93; p < 0.001). ALBC was associated with a lower risk of revision for all aseptic causes (HR 0.85, 95% CI 0.77 to 0.95; p < 0.001) and revisions for infection (HR 0.84, 95% CI 0.67 to 1.01; p = 0.06). The results were similar when BMI was added into the model, and in a subanalysis where surgeons using only ALBC over the entire study period were excluded. Prosthesis survival at ten years for TKAs implanted with ALBC was 96.3% (95% CI 96.3 to 96.4) compared with 95.5% (95% CI 95.0 to 95.9) in those implanted with plain cement. On a population level, where 100 000 TKAs are performed annually, this difference represents 870 fewer revisions at ten years in the ALBC group. Conclusion After adjusting for a range of variables, ALBC was associated with a significantly lower risk of revision in this registry-based study of an entire nation of primary cemented knee arthroplasties. Using ALBC does not appear to increase midterm implant failure rates. Cite this article: Bone Joint J 2019;101-B:1331–1347.

This report discusses an unusual case of a 23-year-old woman with a painful bipartite medial cuneiform and severe arthritic and cystic changes at the partition with no history of trauma. Magnetic resonance imaging confirmed a large cyst with subchondral erosions at the dorsal and plantar segments with significant bone marrow edema. Definitive treatment consisted of arthrodesis on the dorsal to plantar segments using one lag screw, demineralized bone matrix grafting, and a bone stimulator.

Breast cancer is the leading cause of cancer death among women worldwide. Blocking a single signaling pathway is often an ineffective therapy, especially in the case of aggressive or drug-resistant tumors. Since we have previously described the mechanism involved in the crosstalk between Retinoic Acid system and protein kinase C (PKC) pathway, the rationale of our study was to evaluate the effect of combining all-trans-retinoic acid (ATRA) with a classical PCK inhibitor (Gö6976) in preclinical settings. Employing hormone-independent mammary cancer models, Gö6976 and ATRA combined treatment induced a synergistic reduction in proliferative potential that correlated with an increased apoptosis and RARs modulation towards an anti-oncogenic profile. Combined treatment also impairs growth, self-renewal and clonogenicity potential of cancer stem cells and reduced tumor growth, metastatic spread and cancer stem cells frequency in vivo. An in-silico analysis of “Kaplan–Meier plotter” database indicated that low PKCα together with high RARα mRNA expression is a favorable prognosis factor for hormone-independent breast cancer patients. Here we demonstrate that a classical PKC inhibitor potentiates ATRA antitumor effects also targeting cancer stem cells growth, self-renewal and frequency.

Background:\ud \ud Colonoscopy is currently the gold standard for detection of colorectal lesions, but may be limited in anatomically localising lesions. This audit aimed to determine the accuracy of colonoscopy lesion localisation, any subsequent changes in surgical management and any potentially influencing factors.\ud \ud Methods:\ud \ud Patients undergoing colonoscopy prior to elective curative surgery for colorectal lesion/s were included from 8 registered U.K. sites (2012–2014). Three sets of data were recorded: patient factors (age, sex, BMI, screener vs. symptomatic, previous abdominal surgery); colonoscopy factors (caecal intubation, scope guide used, colonoscopist accreditation) and imaging modality. Lesion localisation was standardised with intra-operative location taken as the gold standard. Changes to surgical management were recorded.\ud \ud Results:\ud \ud 364 cases were included; majority of lesions were colonic, solitary, malignant and in symptomatic referrals. 82% patients had their lesion/s correctly located at colonoscopy. Pre-operative CT visualised lesion/s in only 73% of cases with a reduction in screening patients (64 vs. 77%; p = 0.008). 5.2% incorrectly located cases at colonoscopy underwent altered surgical management, including conversion to open. Univariate analysis found colonoscopy accreditation, scope guide use, incomplete colonoscopy and previous abdominal surgery significantly influenced lesion localisation. On multi-variate analysis, caecal intubation and scope guide use remained significant (HR 0.35, 0.20–0.60 95% CI and 0.47; 0.25–0.88, respectively).\ud \ud Conclusion:\ud \ud Lesion localisation at colonoscopy is incorrect in 18% of cases leading to potentially significant surgical management alterations. As part of accreditation, colonoscopists need lesion localisation training and awareness of when inaccuracies can occur.

Objective To examine associations between faecal haemoglobin concentrations below the cut-off used in colorectal cancer screening and outcomes in the next screening round. Methods In the Scottish Bowel Screening Programme, faecal haemoglobin concentrations and diagnostic outcomes were investigated for participants with a negative result (faecal haemoglobin concentrations Results Of 37,780 participants with negative results, at the next screening round, 556 (1.5%) screened positive and 30,293 (80.2%) negative. Initial median faecal haemoglobin concentrations (2.1 µg Hb/g faeces, IQR: 0.0–13.2) were higher in those with subsequent positive results than those with subsequent negative results (0.0 µg Hb/g faeces, IQR: 0.0–1.4; p Conclusions A higher proportion of participants with faecal haemoglobin concentrations of ≥ 20 µg Hb/g faeces had advanced neoplasia detected at the next round than participants with lower faecal haemoglobin concentrations. Although most relevant when using high faecal haemoglobin concentrations cut-offs, studies of faecal haemoglobin concentrations and outcomes over screening rounds may provide strategies to direct available colonoscopy towards those at highest risk.

Background and aims: The Scottish Bowel Screening Programme aims to detect cancer in asymptomatic individuals. We aimed to measure the prevalence of lower gastrointestinal symptoms in faecal occult blood (FOB) screen-positive patients, to correlate the symptoms with neoplasia and to compare the predictive value of FOB screening with urgent symptomatic referrals in Ayrshire and Arran. Methods: Data were collected prospectively on FOB screen-positive patients undergoing colonoscopy. Patients completed a symptom questionnaire. Positive predictive values (PPVs) for detecting neoplasia were calculated and a chi-square test was performed to determine any influence of symptoms in diagnosing neoplasia. Symptomatic patients undergoing colonoscopy via a general practice fast-track system were compared. Results: A total of 378 FOB screen-positive patients were included. In all, 198 (52%) had colorectal symptoms. Overall, 32 were diagnosed with colorectal cancer and 93 had polyps . FOB positivity and symptoms gave a PPV of 34% for neoplasia. FOB positivity without symptoms gave a PPV of 32% for neoplasia. Urgent referral of symptomatic patients had a lower PPV of 21% for neoplasia ( p Conclusion: Half the FOB screen-positive patients had bowel symptoms. Symptoms in these patients had no correlation with an increased rate of neoplasia. The PPV for neoplasia is superior in symptomatic and asymptomatic screen-positive patients when compared to conventional urgent symptom-based referral.

AimsGuaiac faecal occult blood tests are being replaced by faecal immunochemical tests (FIT). We investigated whether faecal haemoglobin concentration (f-Hb) was related to stage in progression of colorectal neoplasia, studying cancer and adenoma characteristics in an evaluation of quantitative FIT as a first-line screening test.MethodsWe invited 66 225 individuals aged 50–74 years to provide one sample of faeces. f-Hb was measured on samples from 38 720 responders. Colonoscopy findings and pathology data were collected on the 943 with f-Hb≥400 ng Hb/ml (80 µg Hb/g faeces).ResultsOf the 814 participants with outcome data (median age: 63 years, range 50–75, 56.4% male), 39 had cancer, 190 high-risk adenoma (HRA, defined as ≥3 or any ≥10 mm) and 119 low-risk adenoma (LRA). 74.4% of those with cancer had f-Hb>1000 ng Hb/ml compared with 58.4% with HRA, and 44.1% with no pathology. Median f-Hb concentration was higher in those with cancer than those with no (p10 mm) compared with small adenoma (pConclusionsf-Hb is related to severity of colorectal neoplastic disease. This has ramifications for the selection of the appropriate cut-off concentration adopted for bowel screening programmes.

Objective: The aim of the present study was to obtain information about deaths due to sepsis in São Paulo from 2004 to 2009 and their relationship with geographical distribution. Methods: Causes of death, both main and secondary, were defined according to the codes of the International Classification of Disease version 10 (ICD-10) contained in the database. Sepsis, septic shock, multiple organ failure, pneumonia, urinary tract infection, peritonitis and other intraabdominal infections, skin and soft tissue infections (including surgical wound infection) and meningitis were considered as immediate cause of death or as the condition leading to the immediate cause of death related or associated to sepsis. Results: In the analyzed period, there was a 15.3% increase in the absolute number of deaths from sepsis in São Paulo. The mean number of deaths during this period was 28,472 ± 1566. Most deaths due to sepsis and sepsis-related diseases over the studied period occurred in a hospital or health care facility, showing that most of the patients received medical care during the event that led to death. We observed a significant concentration of deaths in the most populous regions, tending more toward the center of the city. Conclusions: Georeferencing data from death certificates or other sources can be a powerful tool to uncover regional epidemiological differences between populations. Our study revealed an even distribution of sepsis all over the inhabited areas of São Paulo. Keywords: Sepsis, Mortality, Infection, Georeferencing

Lung cancer (LC) remains the leading cause of cancer mortality worldwide, and non-small cell LC (NSCLC) represents 80% of all LC. Oxidative stress and inflammation, autophagy, ubiquitin-proteasome system, nuclear factor (NF)-KB, and mitogen activated protein kinases (MAPK) participate in LC pathophysiology. Currently available treatment for LC is limited and in vivo models are lacking. We hypothesized that antioxidants and NF-KB, MAPK, and proteasome inhibitors may exert an antitumoral response through attenuation of several key biological mechanisms that promote tumorigenesis and cancer cell growth. Body and tumor weights, oxidative stress, antioxidants, inflammation, NF-KB p65 expression, fibulins, apoptosis, autophagy, tumor and stroma histology were evaluated in the subcutaneous tumor of LC (LP07) adenocarcinoma) BALB/c mice, with and without concomitant treatment with NF-KB (sulfasalazine), MEK (U0126), and proteasome (bortezomib) inhibitors, and N-acetyl cysteine (NAC). Compared to LC control mice, in subcutaneous tumors, the four pharmacological agents reduced oxidative stress markers and tumor proliferation (ki-67). Inflammation and NF-KB p65 expression were attenuated by NF-KB and MAPK inhibitors, and the latter also enhanced apoptotic markers. Catalase was induced by the three inhibitors, while bortezomib also promoted superoxide dismutase expression. NF-KB and MEK inhibitors significantly reduced tumor burden through several biological mechanisms that favored tumor degradation and attenuated tumor proliferation. These two pharmacological agents may enhance the anti-tumor activity of selectively targeted therapeutic strategies for LC. Proteasomal inhibition using bortezomib rather promotes tumor degradation, while treatment with antioxidants cannot be recommended. This experimental model supports the use of adjuvant drugs for the improvement of LC treatment. Fil: Mateu-Jimenez, Mercè. Barcelona Biomedical Research Park; España Fil: Fermoselle, Clara. Barcelona Biomedical Research Park; España Fil: Rojo, Federico. Fundación Jiménez Díaz; España Fil: Mateu, Javier. Hospital del Mar; España Fil: Peña, Raúl. Hospital del Mar; España Fil: Urtreger, Alejandro Jorge. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Diament, Miriam. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Bal, Elisa Dora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Pijuan, Lara. Hospital del Mar; España Fil: Herreros, Antonio. Hospital del Mar; España Fil: Barreiro, Esther. Barcelona Biomedical Research Park; España

Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor that was related to cancer development and metastasis dissemination on several types of tumors. However, it is not known the effect of SLPI on mammary and colon tumors. The aim of this study was to examine the effect of SLPI on mammary and colon tumor growth. The effect of SLPI was tested on in vitro cell apoptosis and in vivo tumor growth experiments. SLPI over-expressing human and murine mammary and colon tumor cells were generated by gene transfection. The administration of murine mammary tumor cells over-expressing high levels of SLPI did not develop tumors in mice. On the contrary, the administration of murine colon tumor cells over-expressing SLPI, developed faster tumors than control cells. Intratumoral, but not intraperitoneal administration of SLPI, delayed the growth of tumors and increased the survival of mammary but not colon tumor bearing mice. In vitro culture of mammary tumor cell lines treated with SLPI, and SLPI producer clones were more prone to apoptosis than control cells, mainly under serum deprivation culture conditions. Herein we demonstrated that SLPI induces the apoptosis of mammary tumor cells in vitro and decreases the mammary but not colon tumor growth in vivo. Therefore, SLPI may be a new potential therapeutic tool for certain tumors, such as mammary tumors.

Background Meta-analyses have indicated that preoperative mechanical bowel preparation (MBP) confers no clear benefit and may indeed be harmful for patients with colorectal cancer. The effects of bowel preparation on longer-term outcomes have not been reported. The aim was to compare long-term survival and surgical complications in patients who did or did not receive MBP before surgery for colonic cancer. Methods This was a retrospective cohort study of all patients undergoing potentially curative surgery for colonic cancer after routine hospital admission in the West of Scotland between January 2000 and December 2005. Clinical audit data were linked to cancer registrations and death certificates. Kaplan–Meier and Cox proportional hazards models were used to explore determinants of survival. Results A total of 1730 patients underwent potentially curative surgery for colonic cancer, of whom 886 (51·2 per cent) were men. The mean(s.d.) age was 69·7(10·6) years. Some 1460 patients (84·4 per cent) received MBP. Median follow-up was 3·5 (range 0·1–6·7) years. There were no statistically significant differences in 30-day postoperative complication rates between groups. The unadjusted hazard ratio (HR) for death from all causes for patients treated with MBP (versus no MBP) was 0·72 (95 per cent confidence interval 0·57 to 0·91). Multivariable analysis with adjustment for age, sex, socioeconomic circumstances, disease stage and presentation for surgery showed that MBP had no independent effect on all-cause mortality (HR 0·85, 0·67 to 1·10). Conclusion Neither postoperative complications nor long-term survival are improved by MBP before colonic cancer surgery.

We report a case of liver damage in an elderly patient after the use of herbal products of Hypericum perforatum and copaiba (Copaifera langsdorffii Desf). Hepatotoxicity related to Hypericum perforatum is anecdotally known, but for copaiba, widely used as anti-inflammatory, there is just experimental data in the national literature. This report aimed to draw attention to the possible toxic effects of this association as well as to the clinical recovery of the patient after discontinuing their use. There is a tendency to suspect of the action of drugs to justify a non-viral acute liver injury, because of the large number of drugs responsible for hepatotoxicity. There are experiments and clinical reports in the literature describing some herbal products, including Hypericum perforatum, as the causative agents of this aggression, and are considered innocuous and used with no restrictions. We must remember that adverse reactions also occur with these substances; hence, they should be investigated when collecting the patient´s history, for leading to severe liver failure.

Myeloid-derived suppressor cells (MDSCs) are key regulatory cells that control inflammation and promote tumor-immune escape. To date, no specific immunomodulatory drug has proven efficacy in targeting the expansion and/or function of these cells in different pathophysiologic settings. In this study, we identified a context-dependent effect of the nonsteroidal anti-inflammatory drug indomethacin (IND) on MDSCs, depending on whether they were derived from tumor microenvironments (TME) or from tumor-free microenvironments (TFME). Treatment of mice bearing the LP07 lung adenocarcinoma with IND inhibited the suppressive activity of splenic MDSCs, which restrained tumor growth through mechanisms involving CD8(+) T cells. The same effect was observed when MDSCs were treated with IND and conditioned media from LP07 tumor cells in vitro. However, in the absence of a tumor context, IND enhanced the intrinsic suppressive function of MDSCs and amplified their protumoral activity. In a model of autoimmune neuroinflammation, IND-treated MDSCs differentiated in TFME attenuated inflammation, whereas IND-treated MDSCs differentiated in TME aggravated clinical symptoms and delayed resolution of the disease. Mechanistically, IND reduced arginase activity as well as NO and reactive oxygen species production in MDSCs differentiated in TME but not in TFME. Moreover, expression of the C/EBP-â transcription factor isoforms correlated with the suppressive activity of IND-treated MDSCs. Our study unveils the dual and context-dependent action of IND, a drug that serves both as an anti-inflammatory and anticancer agent, which differentially affects MDSC activity whether these cells are derived from TME or TFME. These results have broad clinical implication in cancer, chronic inflammation and autoimmunity Fil: Blidner, Ada Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Salatino, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Mascanfroni, Ivan Darío. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina Fil: Diament, Miriam. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Bal, Elisa Dora. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Maria A. Jasnis. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Slobodanka M. Klein. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología "Ángel H. Roffo"; Argentina Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Mycoplasma pneumoniae (MP) and Chlamydophila pneumoniae (CP) antigens are encountered in complicated atheromas and may be implicated in the diversity of atherosclerotic lesions. Mycoplasma can downregulate the immune system, altering levels of inflammation, which may favor the proliferation of other co-infectious agents. In the present study we analyze whether initially stable human atheromas exhibit different ratios of MP/CP antigens compared to ongoing atheromatous lesions. Two groups were examined for the presence of inflammatory cells, macrophages, growth factors and infectious agents: Group I (GI), n=16, early stable atheromas,4 CD68(+) macrophages/400 x field, showing a normal distribution and a fibrous cap; Group II (GII), n=14, growing atheromas,or =4 CD68+ cells/400 x field, lacking a fibrous cap, showing a non-normal macrophage distribution. The amounts of CP (but not MP) antigens and lymphocytes in GI were significantly lower than in GII. MP/CP ratios were higher in GI. MP correlated with CP and PDGFB in GI (r=0.79 and r=0.83, p0.001), but not in GII (r=-0.4 and r=-0.08, p=0.81). MP and CP antigens are already present in early atheromas, and a higher MP/CP ratio correlates with increased growth factors, lower inflammation and plaque stability.

Mice bearing LP07 lung adenocarcinoma present some characteristics similar to those shown in patients with several malignant diseases. LP07 tumor bearers develop paraneoplastic syndromes such as cachexia, leukocytosis, and hypercalcemia, partly due to a systemic inflammatory response. We analyzed some of the mechanisms involved in the effectiveness of the association of the appetite-stimulant medroxiprogesterone acetate (MPA) and the nonselective cyclooxigenase (COX) inhibitor indomethacin (INDO) in LP07 tumor bearing mice. INDO and INDO plus MPA treatments significantly inhibited tumor growth, which was not inhibited by MPA. The number of lung metastatic nodules was decreased with all treatments, being most effective INDO alone and INDO plus MPA. A significant decrease of plasmatic levels of the matrix metalloproteinases MMP-9 and MMP-2 correlated with these results. Paraneoplastic syndromes, leukocytosis, and cachexia were abolished by all treatments. We determined effects of the treatments on circulating cytokines shown to regulate cachexia and inflammation. Both treatments alone, and INDO plus MPA, reduced circulating IL-6 throughout tumor evolution. A pronounced increase in serum IL-1ss levels was detected in untreated tumor bearers. These levels decreased and were closer to normal serum values when LP07 mice were treated with INDO plus MPA. The combination of a nonsteroidal antiinflammatory drug as INDO and MPA showed to be effective in inhibiting tumor and metastatic growth and diminishing paraneoplastic symptoms and SIR. A variety of specific molecules are implicated as playing a role in cancer-induced cachexia and hematological alterations.

Objective: Our purpose was to test the hypothesis that progress of labor slows as parity exceeds 4 by comparing labor curves of grand multiparous women (para 5 and over) (GMs) with those of nulliparous and lower-parity multiparous women. Study Design: Retrospective cohorts of spontaneously laboring, vertex-presenting, term GMs who were admitted to two medical centers during the period from January 1990 through June 1995 were randomly computer-matched to a nulliparous and a lower-parity multiparous control subject, matched for age, hospital, and year of delivery. Cervical examination data were graphed retrospectively from the time of full dilatation. Curves were compared by pairwise likelihood ratio tests, by using a random effects model to adjust for obstetric interventions, with significance set at P Results: Pregnancies in 1095 GMs, 1174 lower-parity multiparous women, and 908 nulliparous women were studied. GMs exhibit a longer initial phase of labor than either nulliparous women or lower-parity multiparous women, begin to dilate rapidly at a greater dilatation than nulliparous women, and experience acceleration of labor at a rate no faster than lower-parity multiparous women. The average labor curve of GMs resembles that of nulliparous women before dilatation of 4 cm is attained, then transitions to the typical curve of the lower-parity multiparous women until dilatation of 6 cm is attained and thereafter is indistinguishable from that of the lower-parity multiparous women ( P Conclusions: Once parity exceeds 4, progress of labor slows. “Poor progress” beyond dilatation of 4 cm should not be considered abnormal for a GM, because she is likely still in the latent phase until dilatation of 6 cm is attained. Nor should she be expected to progress through her active phase any faster than lower-parity multiparous women. (Am J Obstet Gynecol 2002;186:1331-8.)

Infection with the hepatitis C virus (HCV) is a major cause of chronic liver diseases and hepatocellular carcinoma worldwide, and thus represents a significant public health problem. The type I interferon (IFN), IFNα, has been successful in treating HCV-infected patients, but current IFN-based treatment regimens for HCV have suboptimal efficacy, and relatively little is known about why IFN therapy eliminates the virus in some patients but not in others. Therefore, it is critical to understand the basic mechanisms that underlie the therapeutic resistance to IFN action in HCV-infected individuals, and there is an urgent need to identify those patients most likely to respond to IFN therapy for HCV. To characterize the response of HCV-infected patients to treatment with IFNα, the expression of an IFN-response gene signature comprised of IFN-stimulated genes and genes that play an important role in the innate immune response was examined in liver biopsies from HCV-infected patients enrolled in a clinical trial. In the present study we found that the expression of a subset of IFN-response genes was dysregulated in liver biopsy samples from nonresponsive hepatitis C patients as compared with virologic responders. Based on these findings, a statistical model was developed to help predict the response of patients to IFN therapy, and compared to results obtained to the IL28 mutation model, which is highly predictive of the response to IFN-based therapy in HCV-infected patients. We found that a model incorporating gene expression data can improve predictions of IFN responsiveness compared to IL28 mutation status alone.

Objectives To describe diet, alcohol, physical activity and tobacco use prospectively, that is, before and 10 months after colonoscopy for patients and their partners.\ud \ud Design Prospective cohort study of health behaviour change in patients and partners. Comparison groups are patients receiving a normal result notification (NRN) versus patients receiving an abnormal result notification (ARN). Patients and partners (controls) are also compared.\ud \ud Setting 5 Scottish hospitals.\ud \ud Participants Of 5798 colonoscopy registrations, 2577 (44%) patients met the eligibility criteria of whom 565 (22%) were recruited; 460 partners were also recruited.\ud \ud Measures International Physical Activity Questionnaire, Scottish Collaborative Group Food Frequency Questionnaire (includes alcohol), smoking status, sociodemographic characteristics, body mass index, medical conditions, colonoscopy result, Multidimensional Health Locus of Control Scale, behaviour-specific self-efficacy scales.\ud \ud Results 57% of patients were men, with a mean age of 60.8 years (SE 0.5) and 43% were from more affluent areas. 72% (n=387) of patients received an ARN and 28% (n=149) received an NRN. Response rate of the second questionnaire was 68.9%. Overall, 27% of patients consumed \ud \ud Conclusions Colonoscopy is associated with marginal beneficial changes in some behaviours but not others. Further work is needed to explore how services can optimise increases in beneficial behaviours and mitigate increases in harmful ones.

Genetic polymorphisms at the apolipoprotein B (apo B) have been associated with elevated plasma concentrations of low-density lipoprotein (LDL) cholesterol, atherosclerosis and increased risk for coronary artery disease (CAD). In the present study, four apo B gene polymorphisms (MspI, XbaI, Ins/Del and 3'HVR) have been investigated to determine their frequencies and influence on the lipid profile of 177 hypercholesterolemic white Brazilian subjects (HG) and 100 control individuals (CG). The genotype distribution and allele frequency of MspI, XbaI and Ins/Del polymorphisms of apo B gene were similar between HG and CG groups. The frequency of the alleles smaller than 43 repeats (or =43) of 3'HVR polymorphism in the HG group was higher when compared to controls (16.4 vs. 8.5%, P0.05). Moreover, these alleles were associated with higher total cholesterol concentrations in serum of hypercholesterolemic individuals (P0.05). In addition, an association between Ins/Del and 3'HVR polymorphism was observed. The allelesor =43 and Del were more frequent in the HG when compared to the CG individuals (P0.05). We concluded that 3'HVR polymorphism at the apo B gene may be an important genetic marker to evaluate atherosclerotic disease risk.

The possible association of genetic markers at the apolipoprotein E (HhaI polymorphism), apolipoprotein B (XbaI, EcoRI and Ins/Del polymorphisms), and low-density lipoprotein receptor (LDLR) (AvaII, HincII and PvuII polymorphisms) with coronary artery disease (CAD) was evaluated in 50 Brazilian women with CAD diagnosed by angiography and in 100 healthy women (controls). The frequency of E3/E4 genotype for HhaI polymorphism at the Apo E gene was significantly higher in CAD patients than in controls (40% vs. 14%, respectively, P

Familial hypercholesterolemia is characterized by high serum levels of total cholesterol and LDL-cholesterol. It may be homozygous or heterozygous. In homozygous patients, LDL-cholesterol levels range from 500 to 1000 mg/dL and coronary artery disease is precocious, usually manifesting itself between the 2nd and 3rd decades of life. The diagnosis is often made by the presence of xanthoma tuberosum and tendinous xanthomas that appear between the 1st and 2nd decades of life. The use of high doses of statins or even unusual procedures (apheresis, partial ileal bypass surgery, liver transplantation, gene therapy), or both, is necessary for increasing survival and improving quality of life, because a reduction in cholesterol levels is essential for stabilizing the coronary artery disease and reducing xanthomas. We report our experience with 3 patients with xanthomatous familial hypercholesterolemia and coronary artery disease, who underwent partial ileal bypass surgery. Their follow-up over the years (approximately 8 years) showed a mean 30% reduction in total cholesterol, with a significant reduction in the xanthomas and stabilization of the coronary artery disease.

BACKGROUND Little is known about genes that affect childhood body weight. OBJECTIVE The objective of this study was to examine the association between alleles of the mitochondrial uncoupling protein 2 (UCP2) gene and obesity because UCP2 may influence energy expenditure. DESIGN We related UCP2 genotype to body composition and resting energy expenditure in 105 children aged 6-10 y. Overweight children and nonoverweight children of overweight parents were genotyped for a 45-base pair deletion/insertion (del/ins) in 3'-untranslated region of exon 8 and for an exon 4 C to T transition. RESULTS Eighty-nine children were genotyped for the exon 8 allele: 50 children had del/del, 33 had del/ins, and 6 had ins/ins. Mean (+/-SD) body mass index (BMI; in kg/m(2)) was greater for children with del/ins (24.1 +/- 5.9) than for children with del/del (20.4 +/- 4.8; P < 0.001). BMI of ins/ins children (23.7 +/- 7.8) was not significantly different from that of del/ins children. A greater BMI in del/ins children was independent of race and sex. Body composition was also different according to UCP2 genotype. All body circumferences and skinfold thicknesses examined were significantly greater in del/ins than in del/del children. Body fat mass as determined by dual-energy X-ray absorptiometry was also greater in del/ins than in del/del children (P < 0.005). For 104 children genotyped at exon 4, no significant differences in BMI or body composition were found among the 3 exon 4 genotypes. Neither resting energy expenditure nor respiratory quotient were different according to UCP2 exon 4 or exon 8 genotype. CONCLUSIONS The exon 8 ins/del polymorphism of UCP2 appears to be associated with childhood-onset obesity. The UCP2/UCP3 genetic locus may play a role in childhood body weight.

A heterogeneous group of patients with congenital muscular dystrophy associated with clinical or radiologic central nervous system involvement other than the severe classic form with merosin deficiency, muscle-eye-brain disease, and Walker-Warburg syndrome is described. A probable hereditary or familial occurrence could be suggested in all patients. One merosin-positive patient presented severe motor incapacity and cerebral atrophy without any clinical manifestation of central nervous system involvement. A second patient, also merosin-positive, had moderate motor and mental handicap, and epilepsy with no changes in neuroimaging. A third patient, found to have partial merosin deficiency by muscle biopsy, manifested severe psychomotor retardation and cerebral atrophy with foci of abnormal white-matter signal on magnetic resonance imaging. Finally, two merosin-positive siblings with microcephaly, mental retardation, and an incapacitating progressive neuromuscular course, exhibited cataracts without defects of neuronal migration or brain malformation. This report emphasizes the broad clinical spectrum and heterogeneity of merosin-positive congenital muscular dystrophy with associated central nervous system involvement, and illustrates the importance of further studies on clinical, immunohistochemical, and genetic grounds for identifying new subsets of congenital muscular dystrophy. (J Child Neurol 2000;15:172-178).

We report on two siblings that have been followed for 14 years, with merosin-positive congenital muscular dystrophy (CMD), cataract, retinitis pigmentosa, dysversion of the optic disc, but no cerebral anomalies, except for microcephaly and slight mental retardation (MR). The younger child had three generalized seizures easily controlled by anticonvulsant therapy. Both children presented hypotonia from birth, delayed psychomotor development, generalized muscular weakness, and atrophy and joint contractures of knees and ankles. The course of the disease, apparently static during the first 10 years of life, became progressive during the second decade with loss of deambulation by the age of 13. Creatine kinase was increased in both children. Bilateral cataract was diagnosed at 6-months of age. In spite of the occurrence of microcephaly, MR was slight and the siblings acquired reading and writing skills after the aged 10. Head magnetic resonance imaging showed normal results in both siblings. The classification of these cases within the broad spectrum of CMD is difficult since most of the known muscle-eye-brain syndromes generally show severe MR and brain anomalies. We consider these cases as corresponding to the rarer syndromes of merosin-positive CMD with associated features such as cataract and MR that were particularly emphasized during the 50th ENMC International Workshop on CMD [Dubowitz V. Workshop report: 50th ENMC International workshop on congenital muscular dystrophy. Neuromusc Disord 1997;7:539-547]. Further genetic, pathological, neuroradiological, and immunocytochemical studies will be necessary for better elucidation of the classification and pathogenesis of CMD.

Subacute sclerosing panencephalitis (SSPE) is an inflammatory neurodegenerative disease related to the persistence of measles virus. Although its frequency is declining because of measles eradication, we still have some cases being diagnosed. With the aim to describe epidemiological aspects of SSPE in Brazil, we sent a protocol to Child Neurologists around the country, 48 patients were registered, 27 (56 %) were from the southeast region, 34 (71%) were male and 35 (73%) white, 27 (56%) had measles, 9 (19%) had measles and were also immunized, 7 (14%) received only immunization, 1 patient had a probable neonatal form. Mean time between first symptoms and diagnosis was 12 months (22 started with myoclonus or tonic-clonic seizures, 7 (14%) with behavioral disturbances); 36 patients (75%) had EEG with pseudoperiodic complexes. Follow up performed in 28 (58 %) patients showed: 12 died, 2 had complete remission and the others had variable neurological disability Our data shows endemic regions in the country, a high incidence of post-immunization SSPE and a delay between first symptom and diagnosis.

Paraneoplastic syndromes are rarely described in animal models. It may be useful to have a suitable experimental model to study the mechanisms by which they are produced. In this study, we describe a murine lung adenocarcinoma, P07, which presents hypercalcemia, leukocytosis and cachexia. We determined the presence of PTHrP in plasma as well as GM-CSF produced by P07 cells. TNF-alpha, which is responsible for cachexia, could neither be detected in serum nor in P07 cell supernatants. We conclude that this model, which shows paraneoplastic syndromes similar to those of lung tumor patients, should be useful to study the pathways and significance of these signs.

Coronary heart disease (CHD) has presented high prevalence in the Brazilian population. Nevertheless, studies of genetic risk factors for CHD in our country are insufficiently carried out. We have investigated the effects of Ava II (exon 13) and Hinc II (exon 12) polymorphisms at the low‐density lipoprotein receptor (LDLR) gene on circulating lipids of 170 white unrelated individuals presenting a lipid profile with high risk for CHD (HRG) and 130 controls (CG) from São Paulo City, Brazil. Ava II and Hinc II polymorphic regions at the LDLR gene were amplified by PCR and analyzed by enzymatic isotyping. The frequency of the genotypes A+A+ (Ava II) and H+H+ (Hinc II) was greater in HRG group compared to that of the controls (32 vs. 16% and 32 vs. 18%, respectively). Moreover, in the HRG group, A+A+ and H+H+ genotypes were associated with high concentrations of total cholesterol and LDL‐C in serum (P = 0.0001). Our results indicate that Ava II and Hinc II polymorphisms at the LDLR locus contribute to the variability of total cholesterol and LDL‐C levels in HRG individuals. These data suggest that the LDLR polymorphism remains a useful genetic marker for predicting CHD risk. J. Clin. Lab. Anal. 13:251–258, 1999. © 1999 Wiley‐Liss, Inc.

Summary A total of 211 selected paediatricians were invited to participate in a national survey designed to evaluate the age of attainment of developmental milestones in children aged 0–5 years. Following a pilot study and a cascade training design, 61.1% of the paediatricians successfully completed the data collection on 139 developmental items. In the pilot study, there were more missing (not performed) items in children over one year of age, thus confirming the impression that paediatricians are more familiar with evaluating development in infants. However, in the age range 1–5 years, there were significantly fewer missing items in the gross motor area than in the other areas. Following a training programme and data editing and cleaning, a final sample of 3573 healthy, normal children was obtained. The impact of the training process was significant, in the sense that 3.5% of the items in children older than one year were not performed by the paediatricians before training, but this percentage was reduced to 1.9% after training (P < 0.01). The sample formed 0.11% of the national population less than 6 years of age and included a sex ratio of 1.01 compared with a national ratio of 1.02. There were no significant differences in the geographical distribution of the sample in comparison with that of the national population. The social composition, assessed by maternal education level, was biased towards a better education level than the national population. Mean Z-scores for height and weight were not significantly different from zero, when calculated on the basis of the national growth standards. In addition to successfully obtaining a representative sample for the analysis of the age of attainment of developmental milestones in Argentinian children, the survey also accomplished an educational objective in the training of paediatricians in developmental paediatrics.

Although the term "homelessness" is a routine word in the vocabulary of Americans, it is difficult for most people to determine exactly who is and who is not "homeless." There are the obvious, visible homeless people who are found on urban America's park benches. But there are many other people whose homelessness is "out of sight, and out of mind" (Vissing, 1996). Homeless teenagers may be the most invisible group of all. Contrary to conventional norms, many teenagers do not live at home with their parents. Many live with relatives, with friends, or by themselves in accommodations that are customarily unacceptable for people their age (Kufeldt, 1991; Kufeldt & Nimmo, 1987; Matchan, 1993; McCarthy & Hagan, 1992; Mihaly, 1991; Morrissette & McIntyre, 1989; Shaffer & Caton, 1984; Wright, 1987). There is no word that adequately explains the range of housing situations experienced by teenagers. They may not be homeless like urban skid row single adults, for they are still children who may not qualify for aid or independent status. Not counted as adults, yet not living with their families, some teenagers flounder in housing situations that are less than ideal. The word "homeless" is not a useful term to explain the population of teenagers who experience housing problems; it does not portray a recognizable population, nor does it explain the nature of their housing problems. As a result of conceptual, definitional, and methodological issues that have guided traditional research about homelessness (Adams, Gullotta, & Clancy, 1985; Boxill, 1990; Finkelhor, Hotaling, & Sedlack, 1990; Kryder-Coe, Salamon, & Molnar, 1991), not enough is known about who these marginally housed teenagers are, what their experiences with housing distress are like, or how many are affected. These are important questions to address, because many national child advocacy organizations indicate that child and youth family problems and homelessness may increase (Children's Defense Fund, 1992; National Commission on Children, 1991). Given predicted future scenarios, housing distress and homelessness are likely to increasingly affect youths (Rescorla, Parker, & Stolley, 1991). This exploratory study addressed two of the most basic questions pertaining to teenage housing problems: (1) How many teenagers live in distressing housing arrangements? and (2) What housing alternatives are being used by teenagers? Information on the numbers of teenagers who do not live in traditional settings and those who spend time in other homes over the course of the year is an indication of home disruption that places teenagers at risk of becoming homeless (Bassuk & Rosenberg, 1988; Caton, 1986; Edelman & Ladner, 1991; Hewlett, 1991; Hopper & Hamberg, 1985; Johnson, Miranda, Sherman, & Weill, 1991; Jones, Levine, & Rosenberg, 1991). How Many Teenagers Have Housing Problems? The national sources typically used to identify housing conditions, such as the U.S. census, simply do not address the phenomenon of teenage homelessness and housing distress. The census, as designed, does not provide a clear understanding of the relationship between people in a given housing unit. When the U.S. Bureau of the Census attempted to count people who were homeless, they failed miserably in producing an accurate count (Burt, 1992; Hudson, 1996; National Coalition for the Homeless, 1991). Methodological flaws abounded in their count of the homeless population, because enumerators looked only in certain locations for those without housing, leaving rural areas untouched and families and children grossly undercounted. Although the U.S. Conference of Mayors (1987) found that each year there is a 20 percent increase in the number of people who are homeless, they did not specify how many were single adults, families, youths, or children. The report pointed out that if current rates of homelessness remain unchanged, over 18. …

We report clinical and pathological findings in 9 children affected by congenital muscular dystrophy with normal or borderline intelligence and hypodensity of cerebral white matter (CMD-HWM), also frequently called 'occidental or western form of cerebro-muscular dystrophy' (OCMD). Our patients have uniform, distinct, clinical presentation that includes: normal or subnormal intelligence, severe, slowly progressive motor disability, high rate of facial involvement and dysmorphic aspect, increased creatine kinase levels and variable degrees of abnormal, radiographic, cerebral white matter pattern. By comparing our cases with previous reports we suggest that this subtype of CMD is not uncommon in Brazil and it is represented by a particularly severe and homogeneous clinical picture with important motor disability. The immunohistochemical staining for merosin, performed on the muscle biopsy of 6 among 9 patients, showed that all are merosin negative.

We present clinical data from 14 multiple sclerosis (MS) patients who have been admitted to our hospital between January 1980 and May 1992, whose age of onset ranged from 2–15 years. Our patients could be classified as having a clinically definite form of the disease. Initial symptoms varied from minor, such as motor or sensory impairment, bladder dysfunction, to the worst clinical presentation, suggesting diffuse encephalopathy. All the patients had a relapsing-remitting course. We report the paraclinical and laboratory examinations that were done in these patients. Over the period 1980 to 1992 these patients had 39 attacks. CSF analysis was performed in the phase of activity of the disease on 23 occasions and was normal in 12. At least one brain CT scan was performed in 9 patients and showed white matter abnormalities in 6. Cranial magnetic resonance imaging was done in 6 patients and were abnormal in 5. Visual evoked potential (EP) was abnormal in 7 of 8 patients; brainstem acoustic EP was abnormal in 4 of 8 patients and somatosensory EP in 4 of 8. MS is not so rare in childhood and although its diagnosis is essentially a clinical one, paraclinical investigations are of great value in the identification of demyelinating disorders in childhood.

Bowel screening aims to reduce colorectal-cancer mortality by the detection and treatment of early-stage asymptomatic disease and the removal of precancerous adenomas. Bowel screening started in Ayrshire and Arran in September 2007. We report the impact of this screening on the diagnosis and stage of colorectal cancer and characterize screen-detected cancers in comparison with those diagnosed through other pathways.Diagnoses were identified from an audit database. Referrals were grouped into screen detected, routine, urgent and emergency presentations.Between January 2001 and December 2010, 2289 diagnoses of colorectal cancer were made. From 2001 to 2006, the mean (range) number of new colorectal-cancer diagnoses per year was 210 (198-220). Between 2007 and 2010, the mean (range) number of diagnoses per year was 256 (239-274), a significant (P = 0.008) increase. Since September 2007, 877 colorectal cancers have been diagnosed: 17% were screen detected; 11% were detected as a result of routine GP referral; 51% were detected after urgent GP referral; and 21% were emergency presentations. TNM stage increased with urgency of referral. Approximately two-thirds (66%) of screen-detected colorectal cancers were node negative vs 25% of emergency presentations (P0.001). Most screen-detected cancers were distal to the splenic flexure (75%). Screened cancers had favourable pathology; lower T and N stages (both P0.001), less venous invasion (P0.001) and better differentiation (P0.05). Similar results were seen after stratification for TNM stage. Screening has not yet resulted in a significant shift towards early-stage disease since 2007.Screening has been associated with an increase in the numbers of both new and early-stage colorectal cancers. Screen-detected cancers are predominantly early-stage disease with favourable pathology. At present, it remains to be seen whether screening will ultimately translate into an overall reduction in advanced-stage disease.

To assess variability in the proportions of types of major resection for rectal cancer throughout the west of Scotland (WoS) and ascertain factors explaining the variability.Retrospective cohort study of a regional population clinical audit database. This was linked to cancer registrations and death certificates in order that outcome analyses could be derived. Univariate and multivariate binary logistic regression analyses were used to explore determinants of survival.A total of 1574 patients met the inclusion criteria. The age range was from 22 to 97 years. The mean age was 67, median age 68 and the standard deviation was 11.5. The majority of patients (61%) were male. Unlike previous series, male patients and those with poorer socioeconomic circumstances (SEC) were no more likely to receive an abdominoperineal excision (APE) procedure for rectal cancer.Variation exists in the west of Scotland regarding surgical treatment for rectal cancer. We found no difference in the type of procedure offered according to sex, intent of operation or socioeconomic circumstances with reference to APE and anterior resection (AR) for rectal cancer. We conclude therefore that our region provides an equitable service on grounds of sex and SEC. This demonstrates that an equitable surgical service has been provided for those suffering from rectal cancer. Circumferential margin positivity was four times more likely in an APE than an AR for rectal cancer. This is not explained by age, stage, sex, socioeconomic circumstances (SEC), volume of surgery, intent of operation, type of admission or year of incidence.

Subclinical hypothyroidism (SCH) has been associated with atherosclerosis, but the abnormalities in plasma lipids that can contribute to atherogenesis are not prominent. The aim of this study was to test the hypothesis that patients with normocholesterolemic, normotriglyceridemic SCH display abnormalities in plasma lipid metabolism not detected in routine laboratory tests including abnormalities in the intravascular metabolism of triglyceride-rich lipoproteins, lipid transfers to high-density lipoprotein (HDL), and paraoxonase 1 activity. The impact of levothyroxine (LT4) treatment and euthyroidism in these parameters was also tested.The study included 12 SCH women and 10 matched controls. Plasma kinetics of an artificial triglyceride-rich emulsion labeled with radioactive triglycerides and cholesteryl esters as well as in vitro transfer of four lipids from an artificial donor nanoemulsion to HDL were determined at baseline in both groups and after 4 months of euthyroidism in the SCH group.Fractional clearance rates of triglycerides (SCH 0.035 ± 0.016 min⁻¹, controls 0.029 ± 0.013 min⁻¹, p = 0.336) and cholesteryl esters (SCH 0.009 ± 0.007 min⁻¹, controls 0.009 ± 0.009 min⁻¹, p = 0.906) were equal in SCH and controls and were unchanged by LT4 treatment and euthyroidism in patients with SCH, suggesting that lipolysis and remnant removal of triglyceride-rich lipoproteins were normal. Transfer of triglycerides to HDL (SCH 3.6 ± 0.48%, controls 4.7 ± 0.63%, p = 0.001) and phospholipids (SCH 16.2 ± 3.58%, controls 21.2 ± 3.32%, p = 0.004) was reduced when compared with controls. After LT4 treatment, transfers increased and achieved normal values. Transfer of free and esterified cholesterol to HDL, HDL particle size, and paraoxonase 1 activity were similar to controls and were unchanged by treatment.Although intravascular metabolism of triglyceride-rich lipoproteins was normal, patients with SCH showed abnormalities in HDL metabolism that were reversed by LT4 treatment and achievement of euthyroidism

OBJECTIVE: To verify whether the capacity of high-density lipoprotein (HDL) to simultaneously receive non-esterified cholesterol, triglycerides, cholesteryl esters, and phospholipids changes with aging and the presence of coronary artery disease. DESIGN: Cross-sectional study with biochemical analyses. SUBJECTS: Eleven elderly patients with coronary artery disease (74±5 years) were compared with the following groups of non-coronary artery disease subjects (referred to as “healthy”): 25 young (25±5 years), 25 middle-aged (42±6 years), and 25 elderly subjects (75±8 years). METHODS: Plasma samples were incubated with a nanoemulsion labeled with radioactive lipids; the transfer of the lipids from the nanoemulsion to the HDL was measured in chemically precipitated HDL. HDL size and paraoxonase-1 activity were also determined. RESULTS: The transfer of cholesteryl esters and phospholipids to high-density lipoprotein was significantly greater (p

Background Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition. Methods 30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood. Results A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p

We report on a girl with apparent hypomelanosis of Ito(ITO); cytogenetic studies disclosed the karyotype 46,X,t(X;10)(p11;q11)mat. We present further evidence that at least one of the genetic forms of ITO is located at Xp11; reviewing the clinical characteristics of patients with incontinentia pigmenti type 1 (IP1) and ITO with X-autosome translocations, we suggest that IP1 and ITO represent allelic forms or a contiguous gene syndrome. Thus, different genetic alterations in this region (Xp11) give rise to ITO or IP1 or borderline phenotypes. We also suggest that all patients with ITO, due to Xp11 mutation, have functional or genetic mosaicisms. © 1993 Wiley-Liss, Inc.

Background Two prognostic scoring systems have been proposed in colorectal cancer: the pathologically based positive lymph node ratio (pLNR) and the inflammation-based modified Glasgow Prognostic Score (mGPS). This study compared these two scores with the tumour node metastasis (TNM) staging system in terms of cancer survival. Methods Between 2003 and 2005, 206 patients, of mean(s.d.) age 69·9(10·6) (range 40–95) years, underwent curative resection for colorectal cancer in two centres. Age, sex, primary tumour site and whether radio/chemotherapy was given were recorded in addition to the three scores (TNM stage, pLNR and mGPS). Univariable and multivariable analyses of overall survival were performed. Results Age, rectal cancer, TNM stage, pLNR and mGPS were significant factors in univariable analysis. On multivariable analysis, N category and tumour stage (I–III) were removed from the model, leaving pLNR and mGPS as independent predictors of overall survival: hazard ratio 1·51 (95 per cent confidence interval 1·24 to 1·84; P < 0·001) and 1·56 (1·18 to 2·08; P = 0·020) respectively. C-statistic analysis, used to compare pLNR and mGPS directly, found only pLNR to be significant (P < 0·001) Conclusion This study found pLNR to be the superior prognostic scoring system in determining long-term survival in patients undergoing resection for colorectal cancer.

Hereditary multiple exostosis (HME) is an autosomal dominant disorder characterized by multiple osteochondromas. We describe a case of acute cervical spinal cord compression arising from an exostosis at the lamina of C7 and T1 in a 4-year-old Mexican-American boy with HME. His affected sibling also displayed spinal cord compression because of a bony exostosis. Acute cervical spinal cord compression resulting from osteochondroma is a serious complication of HME. (c) 2010 Wiley-Liss, Inc.

Summary: We studied 70 children who had experienced at least two seizures before age 12 years, excluding febrile seizures, neonatal seizures, or seizures occurring during a metabolic, or infectious insult to the central nervous system (CNS) and who had been seizure free for at least 2 years. Twenty children (28.5%) experienced a recurrence, 75% during antiepileptic (AED) drug discontinuation or 10 seizures before seizure control, an abnormal EEG in the year before AED discontinuation, presence of focal neurologic signs and/or mental retardation, and presence of a mixed seizure pattern. Fourteen children (70%) with recurrence had two or more risk factors, whereas 36 (72%) without recurrence had no risk factor or only one. We conclude that a selected group of epileptic children who remain seizure-free for a period of at least 2 years can have AEDs discontinued based on presence or absence of risk factors. RESUME Les auteurs ont etudia 70 enfants qui avaient presente au moins 2 crises avant l'age de 12 ans, a l'exclusion de convulsions febriles, de crises neonatales, ou de crises survenant lors d'un phenomene aigu metabolique ou infectiux. Ces enfants n'avaient plus presente de crises pendant au moins 2 ans. Vingt enfants (28.5%) ont presente une recidive, (75%) pendant ou moins de 6 mois apres l'arret du traitement antiepileptique. Les facteurs de risques statistiquement lies a la recidive des crises etaient: plus de 10 crises avant le controle des crises, un EEG anormal pendant l'annee precedant l'arret des medicaments, la presence de signes neurologiques focaux et d'un retard mental et la presence de plusieurs types de crises associes. Quatorze enfants (70%) ayant recidive avaient deux facteurs de risques ou plus, 36 (72%) des enfants qui n'ont pas recidive presentaient aucun ou un selu facteur de risques. Les auteurs concluent qu'une proportion selective d'enfants epileptiques, qui n'ont plus presente de crises pendant au moins 2 ans, peuvent beneficier d'un arret du traitement, en fonction de la presence ou de l'absence de facteurs de risques. RESUMEN Los autores estudian 70 ninos que habian experimentado, al menos 2 ataques, antes de la edad 12 anos excluyendo los ataques febriles, los ataques neonatales o los ataques que ocurrian durante afecciones metabolicas o infecciosas con participacion del sistema nervioso central y que habian estado, al menos 2 anos, sin episdodios. Veinte ni˜oacute;s (28.5%) experimentaron una recurrencia, el 75% durante la interrupcion de la medicacion antiepileptica (AED) o tambien en los primeros 6 meses despues de esta interrupcion. Los factores de riesgo que se relacionaron estadisticamente con la recurrencia de ataques fueron: mas de 10 ataques antes del control de los mismos, un EEG anormal en el ano previo a la interrupcion de la AED, presencia de signos neurologicos focales y/o retraso mental y la presencia de un patron mixto de ataques. Catorce ninos (70%) con recurrencias tenian 2 o mas factores de risgo mientras que en 36 (72%) sin recurrencias no tenian uno o ningun factor de riesgo. Los autores concluyen que en un grupo seleccionado de ninos epilepticos que permanezcan sin ataques durante al menos 2 anos, se pueden interrumpir las AEDs segun la presencia de ausencia de factores de riesgo. ZUSAMMENFASSUNG Wir untersuchten 70 Kinder die wenigstens zwei Anfalle vor dem 12. Lebensjahr hatten und mindestens 2 Jahre anfallsfrei waren. Ausgeschlossen wurden Kinder mit Fieberkrampfen, Neugeborenenkrampfen oder Gelegenheitskrampfen. Nach Absetzen der Medikation erlitten 20 Kinder (28.5%) ein Anfallsrezidiv, und zwar 75% in den ersten 6 Monaten nach Absetzen. Statistisch berechnete Risikofaktoren waren: mehr als 10 Anfalle vor Eintreten der Anfallsfreiheit. Abnormes EEG im Jahr vor dem Absetzen der Medikation. Fokale neurologische Symptome und oder mentale Retardierung und Auftreten gemischter Anfallstypen. 14 Kinder (70%) mit einem Rezidiv hatten zwei oder mehr Risikofaktoren, wahrend 36 (72%) ohne Anfallsrezidiv nur einen Risikofaktor aufwiesen. Daraus schlieβen wir, daβ wine ausgewahlte Gruppe anfallskranker Kinder, mit wenigstens zwei jahrelanger Anfallsfreiheit abgesetzt werden kann, ja nach Vorliegen oder Fehlen von Risikofaktoren.

Eighteen macrocephalic children with enlargement of the subarachnoid space (ESAS), with or without mild ventricular dilatation, were followed prospectively to a mean age of 56 months. All were born at term, with uneventful neonatal period and negative tests for congenital infections. There were 17 boys and 1 girl and the mean follow-up period was 46 months (8-58 months). The initial neurologic evaluation, between ages of 2 to 33 months, disclosed abnormalities in 2 cases. At the follow-up one was still abnormal and the other had a normal neurological examination. Another child, who had a normal neurological examination at the age of 5 months, at the age of 7 years and 7 months had an IQ of 77. Thus the abnormality rate at follow-up was 11%. The OFC returned to the normal range in 45% of the children at the follow-up period. There were no cases of intracranial hypertension. One infant had subdural taps performed at the age of 13 months that disclosed a fluid with the same characteristics as the CSF. All the children had a CT-scan performed at the beginning of the study that revealed a large subarachnoid space; in 77% it was associated with mild ventricular dilatation. Eleven had CT-scans repeated, during the study period, which showed resolution of the process in 3 cases, improvement in 2, and unchanged in 6. We conclude that enlargement of the subarachnoid space in macrocephalic children is often a benign entity. ESAS and macrocephaly will still be present in the majority of children in the long-term follow-up.

The anorexigenic neuromodulator alpha-melanocyte-stimulating hormone (alpha-MSH; referred to here as alpha-MSH1-13) undergoes extensive posttranslational processing, and its in vivo activity is short lived due to rapid inactivation. The enzymatic control of alpha-MSH1-13 maturation and inactivation is incompletely understood. Here we have provided insight into alpha-MSH1-13 inactivation through the generation and analysis of a subcongenic mouse strain with reduced body fat compared with controls. Using positional cloning, we identified a maximum of 6 coding genes, including that encoding prolylcarboxypeptidase (PRCP), in the donor region. Real-time PCR revealed a marked genotype effect on Prcp mRNA expression in brain tissue. Biochemical studies using recombinant PRCP demonstrated that PRCP removes the C-terminal amino acid of alpha-MSH1-13, producing alpha-MSH1-12, which is not neuroactive. We found that Prcp was expressed in the hypothalamus in neuronal populations that send efferents to areas where alpha-MSH1-13 is released from axon terminals. The inhibition of PRCP activity by small molecule protease inhibitors administered peripherally or centrally decreased food intake in both wild-type and obese mice. Furthermore, Prcp-null mice had elevated levels of alpha-MSH1-13 in the hypothalamus and were leaner and shorter than the wild-type controls on a regular chow diet; they were also resistant to high-fat diet-induced obesity. Our results suggest that PRCP is an important component of melanocortin signaling and weight maintenance via control of active alpha-MSH1-13 levels.

Current British Society of Gastroenterology guidelines use adenomatous polyp size as one of the key factors in determining polyp follow-up. This study aimed to compare polyp size assessment by colonoscopists and pathologists before and after fixation to determine the optimal method for measurement.Thirty-five colorectal polyps were found during pre-arranged colonoscopies in one centre. Polyp size was measured to the nearest 1 mm by three different methods: 1. by the endoscopist at colonoscopy; 2. by the pathologist fresh, following removal; 3. by the pathologist fixed, following fixation. The endoscopist and the pathologist were blinded to each other's measurements.Seventeen men, eighteen women with mean age of 66.2 years (SD: 9.4, range: 38.7-85.5) underwent polypectomy/s with all polyps removed intact. Polypectomies were performed by consultants (43%), nurse specialists (34%) and specialist registrars (23%). The median size (mm) of polyps measured were endoscopically, 6.5 (2-25 mm); fresh specimen 7.0 (4-28 mm) and fixed 7.0 (4-28 mm). Endoscopic measurements were significantly lower than that of fresh and fixed sizes (P0.001 and P = 0.003 respectively), with poor correlation [correlation of variance (CV): 21.0% and intraclass correlation coefficient (ICCC): 0.841 for endoscopic and fresh measurements; CV: 21.1% and ICCC: 0.838 for endoscopic and fixed measurements]. There was no statistical difference between fresh and fixed specimen measurements (P0.05; CV: 4.2%, ICCC: 0.974). In three patients, the endoscopic measurement was1 cm in polyps that were found to beor= 1 cm on pathological measurement.Endoscopists consistently underestimated polyp size. Fixation had no effect on polyp size. Pathologists' measurement of polyp size on fixed specimens should determine the need for further colonoscopic follow-up.

Alternative lymph node (LN) parameters have been proposed to improve staging in colorectal cancer. This study compared these alternative parameters with conventional TNM staging in predicting long-term survival in patients undergoing curative resection. A total of 295 consecutive patients (mean age 70 years; range 39–95; s.d. 10.4) underwent resection for colorectal cancer from 2001 to 2004. Age, sex, primary tumour site, TNM stage and chemotherapy/radiotherapy were recorded. Patients with colon and rectal cancers were analysed separately for LN parameters: LN total; adequate LN retrieval (⩾12) and inadequate (0.05). On multivariate analysis, only pLNR was an independent predictor of overall survival in both colon and rectal cancers (HR 11.65, 95% CI 5.00–27.15, P

OBJECTIVE The waveform of the first derivative of thoracic electrical bioimpedance was used to calculate systolic time intervals of the cardiac cycle, preejection period/left ventricular ejection time ratio, and diastolic time intervals, isovolumic relaxation period/filling time ratio. DESIGN Prospective clinical study. Waveforms were examined from 913 normal and abnormal tracings from a thoracic electrical bioimpedance monitor. This monitor was coupled to a two-channel strip-chart recorder that identified preejection period/LV ejection time and isovolumic relaxation period/filling time in 86% of the tracings. SETTING Two university-affiliated hospitals and one community hospital. PATIENTS We assessed 100 subjects (ranging in age from 17 to 93 yrs) under various conditions. MEASUREMENTS AND MAIN RESULTS Data from 15 normal subjects were used as a reference series to define normative values. Preejection period/left ventricular ejection time ratio was 0.35 +/- 0.1 (SD) and was consistent with data from systolic time intervals derived from simultaneous study of the ECG recording, carotid artery tracing, and phonocardiography. The diastolic time ratio (isovolumic relaxation period/filling time) was 0.4 +/- 0.2, in agreement with normal values derived by echocardiography and angiography. In a subgroup of 17 critically ill patients, a correlative study of simultaneously measured thoracic electrical bioimpedance, nuclear stethoscope, and radionuclide ventriculography was conducted. Systolic functions were compared by the ejection fraction derived by preejection period/left ventricular ejection time ratio displayed on the thoracic electrical bioimpedance monitor and by the radionuclide technique, and were found to be 57 +/- 13.8% and 58 +/- 8.6%, respectively (r2 = .49; y = 4.06x + 0.94; p less than .02; n = 17). Increased diastolic time ratios with normal or near-normal systolic time intervals were documented in nine (53%) of 17 critically ill patients with low systolic index. CONCLUSION Both systolic and diastolic time intervals can be investigated noninvasively at the bedside by the thoracic electrical bioimpedance technique to provide a better understanding of left heart function.

Variants in leptin gene (LEP) have been implicated in the pathogenesis of obesity. The relationship between LEP G-2548A polymorphism and obesity-related traits was evaluated in a sample of Brazilian women (n = 228) who were randomly selected from two clinical centers in Sao Paulo city. Blood samples were collected for DNA extraction, plasma leptin and serum lipids measurements. LEP G-2548A genotypes were identified by a PCR- RFLP strategy using the endonuclease Alw44I. LEP G-2548A was associated with obesity after adjustment for covariates (age, hypertension, coronary artery disease, smoking and physical activity). Women carrying G allele had a four times higher risk of obesity than the A allele carriers (OR: 4.11, CI95%: 1.06-15.90, p = 0.041). G allele was also related to increased plasma leptin (p = 0.024) and body mass index (p = 0.027). Hypertension, hyperglycemia, dyslipidemia and coronary artery disease were associated with obesity. However LEP G-2548A polymorphism was not related to these variables. All together these data suggest that LEP G-2548A polymorphism has an important role in regulating plasma leptin levels and body mass index in women.

Recombinant human α-l-iduronidase (Aldurazyme ® , laronidase) was approved as an enzyme replacement therapy for patients with the lysosomal storage disorder, mucopolysaccharidosis I (MPS I). In order to assess the long-term safety and efficacy of laronidase therapy, 5 of 10 patients in the original laronidase Phase 1/2 clinical trial were re-evaluated after 6 years of treatment. Lysosomal storage was further improved at 6 years (urinary glycosaminoglycans (GAG) excretion decreased 76%; mean liver size at 1.84% of body weight). Shoulder maximum range of motion was maintained or further increased and reached a mean 33.2 (R) and 25.0 (L) degrees gained in flexion and 34.0 (R) and 27.3 (L) degrees gained in extension. Sleep apnea was decreased in four of five patients and the airway size index improved. Cardiac disease evaluations showed no progression to heart failure or cor pulmonale but pre-existing significant valve disease did progress in some patients. Substantial growth was observed for the pre-pubertal patients, with a gain of 33cm (27%) in height and a gain of 31kg in weight (105%). In general, the evaluated patients reported an improved ability to perform normal activities of daily living. Overall these data represent the first evidence that laronidase can stabilize or reverse many aspects of MPS I disease during long-term therapy and that early treatment prior to the development of substantial cardiac and skeletal disease may lead to better outcomes.

To evaluate the effectiveness of and tolerability to sustained-release bupropion, in smokers with cardiovascular diseases treated in a smoking cessation service, as well as to investigate variables predictive of success or failure in smoking cessation.Sustained-release bupropion was prescribed to 100 current smokers with cardiovascular disease for 12 weeks. Patients were followed for 52 week. The variables studied were gender, age, number of cigarettes, exhaled carbon monoxide, nicotine dependence (Fagerstrom Tolerance Questionnaire), depression (Beck Depression Inventory), anxiety (State-Trait Anxiety Inventory), alcohol consumption (Alcohol Use Disorders Identification Test), number of diagnoses other than smoking, adverse events, and use of medications concomitantly with sustained-release bupropion.Abstinence rate was 50% at week 12 and 25% at week 52. The logistic regression analysis showed that ageing was positively associated with success, whereas the worsening of the condition, as verified by the presence of a higher number of other health conditions associated with smoking, was negatively associated with success.We conclude that the prescription of bupropion for smokers with cardiovascular diseases proved to be safe and effective, especially during the treatment period (week 12).

Advanced complicated atherosclerotic lesions have been related to many factors, including inflammation, infectious agents, and growth factors. Mycoplasma pneumoniae (MP) and Chlamydia pneumoniae (CP), inflammation, and growth factors have been associated with severe atherosclerotic lesions in necropsy material in recent work at our lab. The present study intends to clarify the pathogenesis of atherosclerosis, analyzing which of these elements (macrophages, MP, CP, lymphocytes, and growth factors) are associated with initial development of atherosclerotic lesions, discriminating elements related to stabilization of the plaque versus those related to subendothelial active accumulation of macrophages in living patients. Surgical ascending aorta fragments presenting mild atherosclerotic lesions from 30 coronary atherosclerotic patients were immunohistochemically quantified regarding CP, MP, T cells (CD4, CD8), B cells (CD20), macrophages (CD68), and growth factors [platelet-derived growth factor A (PDGF-A), PDGF-B, transforming growth factor-beta (TGF-beta), granulocyte-macrophage colony-stimulating factor (GM-CSF)]. Cases were grouped according to the presence or not of active accumulation of macrophages at the subendothelium that indicates atheroma in development: group I (GI) fragments with4 CD68+ cells/x400 field, in normal distribution (mean 1.8 +/- 1) representing stable atherosclerotic mild lesion, and GII fragments presentingor=4 CD68+ cells/x400 field, in a non-normal distribution, mean (8.9 +/- 4.8, atheromas in progress), which was followed by increased number of lymphocytes. The median number in GI was significantly lower than that in GII: CD4 T (2.5 vs. 7.7), CD8 T (1.0 vs. 5.5), and CD20 B (1.5 vs. 5.5) cells/x400 field, p0.001. Percentage area positive for CP antigens was significantly lower in GI than in GII: 1.0 vs. 9.2, p0.001. There was a higher percentage area occupied by MP than CP in both GI and GII (7.8 vs. 13.8). There was no difference regarding mean number of growth factor-positive cells/x400 field: PDGF-A, 1.4 vs. 3.9; PDGF-B, 3.4 vs. 5.7; TGF-beta, 0.9 vs. 2.2; and GM-CSF, 2.0 vs. 2.2. Considering all cases, a positive correlation was seen between inflammatory cells and CP+ cells (r0.5 and p0.01). Growth factors did not correlate with inflammatory cells, CP, or MP and were usually seen in smooth muscle cell and fibrotic areas. Study of initial atherosclerotic lesions showed that MP is present in both kinds of lesion: stable and active subendothelial accumulation of macrophages. Stabilization was related to proportional increase of both infectious agents, which were also related to increased amount of PDGF-A and PDGF-B. Active macrophage accumulation lesions were related to higher elevation in CP concentration at subendothelial regions, in association with B cells, but not of MP and growth factors. MP and CP, inflammation, and growth factors, which were already described in severe atherosclerotic lesions in necropsy material, are also present in mild lesions in living patients, strongly favoring a pathogenetic role for these bacteria in the pathogenesis of atherosclerosis. Predominance of CP in relation to MP may favor progression of the plaque, which is associated with increased B-cell proliferation. PDGF-A and PDGF-B are associated with plaque stability, at least in arterial segments not prone for development of complicated lesions.