Lack of MMP-9 expression is a marker for poor prognosis in Dukes’ B colorectal cancer

Background

Matrix metalloproteinases (MMPs) play a role in cancer progression by degrading extracellular matrix and basement membranes, assisting in tumour neovascularization and in supporting immune response in cancer.

Methods

We studied the prognostic value of immunohistochemical expression of MMP-2, MMP-8, and MMP-9 in a series of 619 colorectal cancer patients using tissue microarray specimens.

Results

Of the samples, 56% were positive for MMP-2, 78% for MMP-8, and 60% for MMP-9. MMP-9 associated with low WHO grade (p?<?0.001). In univariate analysis of Dukes’ B tumours, MMP-9 negativity associated with poor survival (p?=?0.018), and MMP-9 positivity was an independent prognostic marker in multivariate analysis of these tumours (p?=?0.034).

Conclusion

Negative MMP-9 expression can predict poor prognosis in Dukes’ B colorectal tumours and may prove useful for identifying patients, who should be offered adjuvant treatment.

     

Alexithymia is common among adolescents with severe disruptive behavior

This study aimed to examine alexithymic features and associations between alexithymia and psychiatric symptoms among adolescents living in a closed institution because of severe behavioral problems. Forty-seven adolescents (29 boys and 18 girls) aged 15 to 18 years completed the 20-item Toronto Alexithymia Scale (TAS-20) Questionnaire and the Youth Self-Report, whereas their foster parents completed the Child Behavior Checklist. The TAS-20 scores of the participants were compared with those of an extensive population sample (N = 6000) matched by age and birth year. Reform school adolescents are significantly more alexithymic than the control group, and the TAS-20 scores are correlated with numerous psychiatric problems, mainly in the internalizing spectrum, but also with thought problems and self-reported aggression. Promoting abilities in identifying and describing feelings is important when treating delinquent adolescents.     

Morphologic and functional correlates of synaptic pathology in the cathepsin D knockout mouse model of congenital neuronal ceroid lipofuscinosis

Mutations in the cathepsin D (CTSD) gene cause an aggressive neurodegenerative disease (congenital neuronal ceroid lipofuscinosis) that leads to early death. Recent evidence suggests that presynaptic abnormalities play a major role in the pathogenesis of CTSD deficiencies. To identify the early events that lead to synaptic alterations, we investigated synaptic ultrastructure and function in presymptomatic CTSD knockout (Ctsd) mice. Electron microscopy revealed that there were significantly greater numbers of readily releasable synaptic vesicles present in Ctsd mice than in wild-type control mice as early as postnatal day 16. The size of this synaptic vesicle pool continued to increase with disease progression in the hippocampus and thalamus of the Ctsd mice. Electrophysiology revealed a markedly decreased frequency of miniature excitatory postsynaptic currents (mEPSCs) with no effect on paired-pulse modulation of the evoked excitatory post synaptic potentials in the hippocampus of Ctsd mice. The reduced mEPSCs frequency was observed before the appearance of epilepsy or any morphologic sign of synaptic degeneration. Taken together, these data indicate that CTSD is required for normal synaptic function and that a failure in synaptic trafficking or recycling may bean early and important pathologic mechanism in Ctsd mice; these presynaptic abnormalities may initiate synaptic degeneration in advance of subsequent neuronal loss.     

Bacterial endotoxin activity in human serum is associated with dyslipidemia, insulin resistance, obesity, and chronic inflammation

OBJECTIVE

To investigate whether bacterial lipopolysaccharide (LPS) activity in human serum is associated with the components of the metabolic syndrome (MetS) in type 1 diabetic patients with various degrees of kidney disease and patients with IgA glomerulonephritis (IgAGN).

RESEARCH DESIGN AND METHODS

Serum LPS activity was determined with the Limulus Amoebocyte Lysate chromogenic end point assay in type 1 diabetic patients with a normal albumin excretion rate (n = 587), microalbuminuria (n = 144), macroalbuminuria (n = 173); patients with IgAGN (n = 98); and in nondiabetic control subjects (n = 345). The relationships of the LPS/HDL ratio and MetS-associated variables were evaluated with Pearson correlation.

RESULTS

The MetS was more prevalent in type 1 diabetic patients (48%) than in patients with IgAGN (15%). Diabetic patients with macroalbuminuria had a significantly higher serum LPS/HDL ratio than patients with IgAGN. In the normoalbuminuric type 1 diabetic group, patients in the highest LPS/HDL quartile were diagnosed as having the MetS three times more frequently than patients in the lowest quartile (69 vs. 22%; P < 0.001). High LPS activity was associated with higher serum triglyceride concentration, earlier onset of diabetes, increased diastolic blood pressure, and elevated urinary excretion of monocyte chemoattractant protein-1.

CONCLUSIONS

High serum LPS activity is strongly associated with the components of the MetS. Diabetic patients with kidney disease seem to be more susceptible to metabolic endotoxemia than patients with IgAGN. Bacterial endotoxins may thus play an important role in the development of the metabolic and vascular abnormalities commonly seen in obesity and diabetes-related diseases.In patients with type 1 diabetes, long duration of the disease and poor glycemic control increase the risk for micro- and macrovascular complications. A significant proportion of type 1 diabetic patients who develop these complications exhibit clinical features commonly seen in subjects with the metabolic syndrome (MetS), including dyslipidemia, insulin resistance, obesity, hypertension, and chronic inflammation (1,2). Vascular diseases are also common in patients with IgA glomerulonephritis (IgAGN), and those with a progressive form of the disease run a significantly elevated risk of developing different cardiovascular sequela (3). Whether the MetS is independently associated with the progression of IgAGN is currently unclear, but at least several related factors, including hyperuricemia, hypertriglyceridemia, weight, insulin resistance, and inflammation, seem to associate with the development of kidney dysfunction in IgAGN (4,5).Many of these clinical subphenotypes likely emerge from the complex interactions between a genetic background, lifestyle, and environmental factors. Recent studies have highlighted the role of the innate immune system in the developmental process of these metabolic abnormalities (6). Our living environment is inhabited with commensal and pathogenic bacteria, which have both beneficial and detrimental effects on human health. If the immune defense functions properly, these microorganisms rarely cause any serious infections in healthy individuals. The situation is different in immunocompromised patients—local infections, use of antibiotics, and even diet may lead to the colonization of opportunistic bacteria in various sites of the body. In diabetic patients, long duration of the disease and poor glycemic control increase the risk for urinary tract, pulmonary, oral, and skin infections (6,7).Lipopolysaccharides (LPS) are unique glycolipids in the cell wall of gram-negative bacteria. LPS molecules, also known as bacterial endotoxins, may trigger acute and chronic inflammation, leading to immune cell activation and cytokine release. HDL cholesterol is one of the most important factors involved in the elimination of LPS molecules from circulation. In healthy subjects, LPS is mainly bound to HDL, whereas in patients with sepsis, LPS is redistributed toward LDL and VLDL lipoproteins (8). High LPS activity combined with low HDL levels increases the risk for cardiovascular disease (9).LPS infusion in mammals leads to the appearance of factors known to be associated with the MetS: elevated levels of proinflammatory markers, dyslipidemia, fasting hyperglycemia, insulin resistance, and obesity (10–12). In some research applications, bacterial endotoxins have been used to induce acute kidney injury in animals. Monocyte chemoattractant protein-1 (MCP1) is a potential marker for progressive renal disease because its expression and excretion are also regulated by bacterial endotoxins (13,14).We have recently shown that high serum levels of LPS activity are associated with the development and progression of kidney disease in Finnish type 1 diabetic patients. Most of the patients with high serum LPS activity exhibited features of dyslipidemia and insulin resistance (15). These metabolic abnormalities are frequently observed in diabetic patients with micro- or macrovascular complications (2). To our knowledge, no previous studies have explored the potential links between bacterial endotoxins and the MetS in subjects with impaired kidney function. Therefore, we wanted to investigate whether serum LPS activity is associated with metabolic risk factors in three distinct study populations: type 1 diabetic patients with various degrees of kidney disease, patients with IgAGN, and nondiabetic subjects.     

Predictive value of health-related fitness tests for self-reported mobility difficulties among high-functioning elderly men and women

BACKGROUND AND AIMS: The functional independence of elderly populations deteriorates with age. Several tests of physical performance have been developed for screening elderly persons who are at risk of losing their functional independence. The purpose of the present study was to investigate whether several components of health-related fitness (HRF) are valid in predicting the occurrence of self-reported mobility difficulties (MD) among high-functioning older adults. METHODS: Subjects were community-dwelling men and women, born 1917-1941, who participated in the assessment of HRF [6.1-m (20-ft) walk, one-leg stand, backwards walk, trunk side-bending, dynamic back extension, one-leg squat, 1-km walk] and who were free of MD in 1996 (no difficulties in walking 2- km, n=788; no difficulties in climbing stairs, n=647). Postal questionnaires were used to assess the prevalence of MD in 1996 and the occurrence of new MD in 2002. Logistic regression analysis was used as the statistical method. RESULTS: Both inability to perform the backwards walk and a poorer result in it were associated with risk of walking difficulties in the logistic model, with all the statistically significant single test items included. Results of 1-km walk time and one-leg squat strength test were also associated with risk, although the squat was statistically significant only in two older birth cohorts. Regarding stair-climbing difficulties, poorer results in the 1-km walk, dynamic back extension and one-leg squat tests were associated with increased risk of MD. CONCLUSIONS: The backwards walk, one-leg squat, dynamic back extension and 1-km walk tests were the best predictors of MD. These tests are recommended for use in screening high-functioning older people at risk of MD, as well as to target physical activity counseling to those components of HRF that are important for functional independence.     

Association between ghrelin gene variations and blood pressure in subjects with impaired glucose tolerance

BACKGROUND: Ghrelin is a gut-brain hormone, which stimulates food intake and controls energy balance. Recently, it has been shown that ghrelin may also play a role in the regulation of blood pressure (BP) by acting at the sympathetic nervous system. In the present study we genotyped six variants of the ghrelin gene and its promoter, and tested whether these single nucleotide polymorphisms (SNPs) were associated with BP levels in participants of the Finnish Diabetes Prevention Study. METHODS: The Finnish Diabetes Prevention Study was a longitudinal study where 522 subjects with impaired glucose tolerance were randomized into either an intervention or control group. DNA was available from 507 subjects (mean body mass index [BMI] 31.2+/-4.5 kg/m2, age 55+/-7 years). All six SNPs were screened by the restriction fragment length polymorphism method. RESULTS: Subjects with the most common genotype combination of the following four SNPs, -604G/A, -501A/C, Leu72Met, and Gln90Leu, had the lowest systolic (131+/-11 v 137+/-13 mm Hg, P=.003) and diastolic BP levels (79+/-7 v 83+/-7 mm Hg, P=.004) at the baseline of the study and during 3 years of follow-up compared to all other genotypes. Adjustments for age, gender, antihypertensive medication, BMI, waist circumference, and alcohol intake did not change this association. CONCLUSIONS: Several ghrelin gene variations were associated with BP levels in subjects with impaired glucose tolerance.     

Effects of multispecies probiotic supplementation on intestinal microbiota in irritable bowel syndrome

BACKGROUND: A multispecies probiotic has shown beneficial effects in irritable bowel syndrome. In addition, certain other probiotics have demonstrated advantageous effects, but the mechanisms behind this are poorly understood. AIM: To investigate the mode of action of a multispecies probiotic consisting of Lactobacillus rhamnosus GG, Lactobacillus rhamnosus Lc705, Propionibacterium freudenreichii ssp. shermanii JS and Bifidobacterium breve Bb99 by monitoring its effects on intestinal microbiota and markers of microbial activity. METHODS: A total of 55 irritable bowel syndrome patients participated in this placebo-controlled double-blind trial. Subjects received either multispecies probiotic or placebo supplementation daily during a 6-month period. The composition of intestinal microbiota was analysed with real-time polymerase chain reaction, short-chain fatty acids with gas chromatography and enzymes with spectrophotometer. RESULTS: Each supplemented probiotic strain was detected in faecal samples. Intestinal microbiota remained stable during the trial, except for Bifidobacterium spp., which increased in the placebo group and decreased in the probiotic group (P = 0.028). No changes in short-chain fatty acids occurred. A decrease in ss-glucuronidase activity was detected in 67% of the subjects in the probiotic group vs. 38% in the placebo group (P = 0.06). CONCLUSIONS: Factors other than the microbial groups and metabolites studied herein seem responsible for the alleviation of irritable bowel syndrome symptoms by the multispecies probiotic.     

Elevated pro-inflammatory and lipotoxic mucosal lipids characterise irritable bowel syndrome

AIM: To investigate the pathophysiology of irritable bowel syndrome (IBS) by comparing the global mucosal metabolic profiles of IBS patients with those of healthy controls. METHODS: Fifteen IBS patients fulfilling the Rome Ⅱ criteria, and nine healthy volunteers were included in the study. A combined lipidomics (UPLC/MS) and metabolomics (GC × GC-TOF) approach was used to achieve global metabolic profiles of mucosal biopsies from the ascending colon. RESULTS: Overall, lipid levels were elevated in patients with IBS. The most significant upregulation was seen for pro-inflammatory lysophosphatidylcholines. Other lipid groups that were significantly upregulated in IBS patients were lipotoxic ceramides, glycosphingolipids, and di- and triacylglycerols. Among the metabolites, the cyclic ester 2(3H)-furanone was almost 14-fold upregulated in IBS patients compared to healthy subjects (P = 0.03).CONCLUSION: IBS mucosa is characterised by a distinct pro-inflammatory and lipotoxic metabolic profile.Especially, there was an increase in several lipid species such as lysophospholipids and ceramides.     

Gestational diabetes identifies women at risk for permanent type 1 and type 2 diabetes in fertile age: predictive role of autoantibodies

OBJECTIVE: Our aim was to evaluate the predictive value of gestational diabetes mellitus (GDM), diabetes-associated autoantibodies, and other factors for development of clinical diabetes later in life. RESEARCH DESIGN AND METHODS: In this case-control study the presence of autoantibodies was studied in 435 women with GDM and in healthy matched control subjects. The need for exogenous insulin during GDM was recorded. In the GDM group, the mean follow-up period was 5.7 years and in the control group 6.1 years. RESULTS: Among the subjects with GDM, 20 (4.6%) developed type 1 diabetes and 23 (5.3%) developed type 2 diabetes, whereas none of the control subjects became diabetic. Two-thirds of those who developed type 1 diabetes tested positive initially for islet cell antibodies (ICAs), whereas 56% of them had autoantibodies to GAD (GADAs) and 38% to the protein tyrosine phosphatase-related IA-2 molecule. Only 2 of the 23 women who presented later with type 2 diabetes tested positive for autoantibodies. According to multivariate analysis, initial age < or =30 years, the need for insulin treatment for GDM, and antibody positivity for ICAs and GADAs were associated with increased risk for clinical type 1 diabetes. CONCLUSIONS: Pregnancy seems to identify women who are at risk of developing diabetes later in life. About 10% of Finnish women with GDM will develop diabetes over the next 6 years; nearly half of them develop type 1 diabetes and the other half type 2 diabetes. Age < or =30 years, the need for insulin treatment during pregnancy, and positivity for ICAs and GADAs confer a high risk of subsequent progression to type 1 diabetes in women affected by GDM.     

Toll-like receptor 4 polymorphism is associated with coronary stenosis but not with the occurrence of acute or old myocardial infarctions

OBJECTIVE: Atherosclerosis is considered to be a chronic inflammatory disease. Toll-like receptor 4 (TLR-4), a key mediator in activating inflammatory cascade, has an A-to-G functional polymorphism that changes aspartic acid to glycine at position 299. TLR-4 is activated by, for example, lipopolysaccharides. The purpose of this study was to investigate the role of a common Asp299Gly polymorphism of the TLR-4 gene in atherosclerosis. MATERIAL AND METHODS: The study comprised autopsy material from 657 men (the Helsinki Sudden Death Study; mean age 53, range 33-70 years). RESULTS: Fewer G-allele carriers had 3-vessel coronary artery disease compared with AA homozygotes (OR 0.32; 95 % CI, 0.12-0.88, p = 0.027), and they also had a lower mean value for maximal coronary stenosis (p = 0.019). TLR-4 polymorphism was not significantly associated with the occurrence of acute or old myocardial infarction (MI). CONCLUSIONS: The G allele of the TLR-4 gene, which is associated with a lower inflammation response, was associated with a lower risk of coronary stenosis but not with the occurrence of MI and hence is not a major factor in the development of coronary atherosclerosis.