Lactobacillus rhamnosus GG and Streptococcus thermophilus induce suppressor of cytokine signalling 3 (SOCS3) gene expression directly and indirectly via interleukin-10 in human primary macrophages

In the present study we have characterized T helper type 2 (Th2) [interleukin (IL)-10]/Th1 (IL-12) cytokine expression balance in human primary macrophages stimulated with multiple non-pathogenic Gram-positive bacteria used in the food industry and as probiotic substances. Bacteria representing Lactobacillus, Bifidobacterium, Lactococcus, Leuconostoc, Propionibacterium and Streptococcus species induced anti-inflammatory IL-10 production, although quantitative differences between the bacteria were observed. S. thermophilus was able to induce IL-12 production, while the production of IL-12 induced by other bacteria remained at a low level. The highest anti-inflammatory potential was seen with bifidobacteria, as evidenced by high IL-10/IL-12 induction ratios. All studied non-pathogenic bacteria were able to stimulate the expression of suppressor of cytokine signalling (SOCS) 3 that controls the expression of proinflammatory cytokine genes. Lactobacillus and Streptococcus species induced SOCS3 mRNA expression directly in the absence of protein synthesis and indirectly via bacteria-induced IL-10 production, as demonstrated by experiments with cycloheximide (CHX) and anti-IL-10 antibodies, respectively. The mitogen-activated protein kinase (MAPK) p38 signalling pathway played a key role in bacteria-induced SOCS3 gene expression. Enhanced IL-10 production and SOCS3 gene expression induced by live non-pathogenic Lactobacillus and Streptococcus is also likely to contribute to their immunoregulatory effects in vivo.     

Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation

Lymphatic vessel plasticity and stability are of considerable importance when attempting to treat diseases associated with the lymphatic vasculature. Development of lymphatic vessels during embryogenesis is dependent on vascular endothelial growth factor (VEGF)-C but not VEGF-D. Using a recombinant adenovirus encoding a soluble form of their receptor VEGFR-3 (AdVEGFR-3-Ig), we studied lymphatic vessel dependency on VEGF-C and VEGF-D induced VEGFR-3 signaling in postnatal and adult mice. Transduction with AdVEGFR-3-Ig led to regression of lymphatic capillaries and medium-sized lymphatic vessels in mice under 2 weeks of age without affecting collecting lymphatic vessels or the blood vasculature. No effect was observed after this period. The lymphatic capillaries of neonatal mice also regressed partially in response to recombinant VEGFR-3-Ig or blocking antibodies against VEGFR-3, but not to adenovirus-encoded VEGFR-2-Ig. Despite sustained inhibitory VEGFR-3-Ig levels, lymphatic vessel regrowth was observed at 4 weeks of age. Interestingly, whereas transgenic expression of VEGF-C in the skin induced lymphatic hyperplasia even during embryogenesis, similar expression of VEGF-D resulted in lymphangiogenesis predominantly after birth. These results indicate considerable plasticity of lymphatic vessels during the early postnatal period but not thereafter, suggesting that anti-lymphangiogenic therapy can be safely applied in adults.     

Neurological outcome of childhood brain tumor survivors

We assessed neurological and neurocognitive outcome in childhood brain tumor survivors. Altogether, 75 out of 80 brain tumor survivors diagnosed below 17 years between 1983 and 1997; and treated in Tampere University Hospital, Finland, were invited to participate in this population-based cross-sectional study. Fifty-two (69%) participated [mean age 14.2 (3.8–28.7) years, mean follow-up 7.5 (1.5–15.1) years]. Neurological status was abnormal in 69% cases. All were ambulatory, but only 50% showed normal motor function. Twenty-nine percent showed clumsiness/mild asymmetry and 21% hemiparesis. One suffered from intractable epilepsy. According to structured interview, 87% coped normally in daily living. Median full-scale IQ was 85 (39–110) in 21 6–16 year olds (70%); in 29% IQ was <70. Thirty of the 44 school-aged subjects attended school with normal syllabus and 32% needed special education. Six of the 16 patients over 18 years of age were working. Regarding quality of life, 38% were active without disability, 33% active with mild disability, 21% were partially disabled, but capable of self-care, and 8% had severe disability, being incapable of self-care. Supratentorial/hemispheric tumor location, tumor reoperations, shunt revisions and chemotherapy were associated with neurological, cognitive and social disabilities. In conclusion, of the 52 survivors, neurological status was abnormal in 69%; 71% lived an active life with minor disabilities, 29% had major neurological, cognitive and social disabilities, and 8% of them were incapable of self-care. Predictors of these disabilities included supratentorial/hemispheric tumor location, tumor reoperations, shunt revisions and chemotherapy. Survivors need life-long, tailor-made multiprofessional support and follow-up.     

Short-term consumption of probiotic-containing cheese and its effect on dental caries risk factors

Cheese is known to contain compounds that reduce the risk of dental caries. The long-term consumption of milk containing Lactobacillus rhamnosus GG, ATCC 53103 (LGG), has been shown to reduce caries risk in children. The aim of the present study was to examine whether short-term consumption of cheese containing LGG and Lactobacillus rhamnosus LC 705 would diminish caries-associated salivary microbial counts in young adults. Altogether, 74 18-35 year-old subjects completed this double-blinded, randomised, placebo-controlled study. During the 3 week intervention, the subjects ate 5 x 15 g cheese per day. Oral examinations were made before and after the study. Stimulated salivary secretion rates, buffer capacity and counts of salivary Streptococcus mutans, yeast and lactobacilli were evaluated before and after the intervention and after a 3 week post-treatment period. The results showed no statistically significant difference between the groups in Streptococcus mutans counts after the intervention, but during the post-treatment period there was a significantly greater reduction in these counts in the intervention group compared to the control group (P=0.05). However, Streptococcus mutans counts decreased in 20% (P=0.01) and yeast counts in 27% (P=0.005) of all the subjects, regardless of the intervention group. Results from logistic regression showed a trend indicating that probiotic intervention might reduce the risk of the highest level of Streptococcus mutans (OR=0.37, 95% CI 0.08-1.75, P=0.21) and salivary yeasts (OR=0.40, 0.09-1.71, P=0.22).     

Early suppression of disease activity is essential for maintenance of work capacity in patients with recent‐onset rheumatoid arthritis: Five‐year experience from the FIN‐RACo trial

Objective

To explore the impact of an early treatment response on maintenance of work capacity in patients with early, active rheumatoid arthritis (RA).

Methods

In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent‐onset RA were randomized to receive either a combination of disease‐modifying antirheumatic drugs (DMARDs) with prednisolone or a single DMARD with or without prednisolone for 2 years. Treatment responses were evaluated according to the American College of Rheumatology (ACR) criteria. After a 5‐year followup, the cumulative number of days of sick leave and RA‐related permanent work disability was calculated for each of the 162 patients who were available for the active work force at baseline.

Results

Of the 159 patients assessed at 6 months, 29 were in clinical remission, 66 achieved an ACR50 response but not remission, 29 achieved an ACR20 response but not an ACR50 response, and 35 failed to achieve an ACR20 response. In these 4 groups, the median numbers of work disability days per patient‐year from 6 months through 60 months of followup were 0 (interquartile range [IQR] 0–3), 4 (IQR 0–131), 16 (IQR 0–170), and 352 (16–365), respectively (P < 0.001). Pairwise multiple comparisons showed a statistically significant difference between all groups except the ACR50 and ACR20 groups. At 12 months, 30 patients were in remission. None of the 44 patients in remission at 6 or 12 months became permanently work disabled over the 5‐year followup, as compared with 15 patients in the ACR50 group (23%), 6 in the ACR20 group (21%), and 19 without an ACR20 response at 6 months (56%).

Conclusion

Prompt induction of remission translates into maintenance of work capacity. At 6 months, an ACR50 response is no better than an ACR20 response with regard to future productivity, while failure to achieve an ACR20 response carries a high risk for work disability.

     

Comparison of buprenorphine with morphine in the treatment of postoperative pain in children

The safety and efficacy of buprenorphine and morphine as postoperative analgesics for children were compared in 60 boys and girls 4 to 14 years old having elective orthopedic operations on upper or lower extremities. The drugs were given in a double-blind manner initially intravenously and thereafter by sublingual buprenorphine or intramuscular morphine administered as required to relieve pain until the third postoperative morning. The IV dose needed to achieve complete initial analgesia was 5.2 +/- 2.8 micrograms/kg buprenorphine and 166 +/- 100 micrograms/kg morphine. The duration of effect was significantly longer with buprenorphine than with morphine, 248 +/- 314 and 114 +/- 109 minutes, respectively (P = 0.03). The most common side effects were nausea and vomiting (28 and 16%) and urinary retention (21 and 19%) in the buprenorphine and morphine groups, respectively. Analgesia with sublingual buprenorphine was as effective and reliable as with intramuscular morphine but a longer duration of action could not be demonstrated.     

Serum selenium concentration, glutathione peroxidase activity and lipid peroxides in a co-twin control study on multiple sclerosis

Serum selenium concentration, glutathione peroxidase activity and lipid peroxides were determined in patients with multiple sclerosis (MS). The series consisted of 13 same-sexed twin pairs derived from the Finnish Twin Cohort of 15,815 pairs. Fourteen subjects had a definite and 1 a probable MS, and their 11 co-twins showed no evidence of central nervous system disease. No statistical differences were observed, but the 3 patients with active progressive MS had a higher mean level of lipid peroxides than the rest of the patients. We suggest that serum lipid peroxidation may be involved in the activity of MS.