Probiotics in infancy induce protective immune profiles that are characteristic for chronic low-grade inflammation

Background Probiotics are widely studied both in the treatment and prevention of allergic diseases, but their mode of action is poorly known. Objective Our aim was to examine the effect of probiotic bacteria on in vivo cytokine, antibody, and inflammatory responses in allergy‐prone infants. Methods In a randomized double‐blind study, probiotic bacteria or placebo were given for 1 month before delivery to mothers and for 6 months to infants with a family history of allergy. Plasma samples were analysed for C‐reactive protein (CRP), total IgA and IgE, food‐specific IgA, IgG, and IgE, IL‐2, IL‐4, IL‐6, IL‐10, TNF‐α, and IFN‐γ. We analysed the associations of immunological and inflammatory parameters at age 6 months with probiotic treatment and allergic phenotype at 2 years. Results Infants receiving probiotic bacteria had higher plasma levels of CRP (P=0.008), total IgA (P=0.016), total IgE (P=0.047), and IL‐10 (P=0.002) than infants in the placebo group. Increased plasma CRP level at age 6 months was associated with a decreased risk of eczema [odds ratio (OR) 0.41 [95% confidence interval (CI) 0.17–0.99], P=0.046], and with a decreased risk of allergic disease [OR 0.38 (95% CI 0.16–0.87), P=0.023] at age 2 years, when adjusted with probiotic use. Conclusion The association of CRP with a decreased risk of eczema at 2 years of age in allergy‐prone children supports the view that chronic, low‐grade inflammation protects from eczema. Probiotic‐induced low‐grade inflammation was characterized by elevation of IgE, IgA, and IL‐10, the changes typically observed in helminth infection‐associated induction of regulatory mechanisms. The findings emphasize the role of chronic microbial exposure as an immune modulator protecting from allergy.     

Effect of Liposomal and Free Bisphosphonates on the IL-1β, IL-6 and TNFα Secretion from RAW 264 Cells in Vitro

Purpose. In order to evaluate the possible antiinflammatory action of bisphosphonates, the effect of the drugs on the secretion of proinflammatory cytokines (IL-l, IL-6 and TNF) from macrophages was studied. Liposomes or high concentration of extracellular calcium was used to enhance the intracellular delivery of bisphosphonates. Methods. RAW 264 cells were used as macrophage model, and they were induced with lipopolysaccharide to produce the cytokines. The cytokine concentrations in the culture supernatants were measured with time-resolved fluoroimmunoassay. Results. As a free drug, clodronate and pamidronate, but not etidronate, inhibited LPS-stimulated secretion of the cytokines from macrophage-like RAW 264 cells. Low concentrations of pamidronate, however, induced the IL-6 secretion, and the cytokine inhibitory action at the higher concentrations of pamidronate was attributed to cytotoxicity of the compound. The cytokine induction or toxic effects were not observed with clodronate or etidronate. When the drugs were encapsulated in negatively charged unilamellar liposomes, the inhibitory potency of both clodronate and etidronate enhanced by a factor of 10-20, while that of pamidronate was not increased. The complex formation of bisphosphonates with extracellular calcium, although enhancing the uptake of the compounds by macrophages, did not considerably increase their cytokine inhibitory potency. Conclusions. Bisphosphonates have inhibitory action on cytokine secretion by macrophages. The non-cytotoxic cytokine inhibition by liposome encapsulated clodronate could be beneficial in local inflammatory diseases, where the inflammation is sustained by the excessive amounts of inflammatory cytokines produced by activated macrophages.     

Dopamine transporter and D2-receptor density in late-onset alcoholism

Rationale: Late onset type 1 alcoholism has been suggested to be associated with an underlying dopaminergic defect. Therefore, it is relevant to study both postsynaptic D₂-receptor and presynaptic dopamine transporter (DAT) densities among alcoholics. Objective: We investigated DAT densities, along with striatal and extrastriatal dopamine D₂-receptor densities, in nine non-violent late-onset male alcoholics, who had no major mental disorder nor antisocial personality disorder (ASPD), and nine healthy controls. Methods: [¹²³I]PE2I and [¹²³I]epidepride were used in SPECT imaging. Results: DAT occupancy ratios (striatum/cerebellum) were significantly lower among alcoholics than in controls. Extrastriatal D₂-receptor occupancy ratios (temporal pole/cerebellum) were not significantly different between the groups. Conclusions: Striatal presynaptic DAT densities are decreased among type 1 alcoholics, and this finding is not associated with recent alcohol abuse. Received: 22 March 1999 / Final version: 25 June 1999     

Prospective randomized comparison of endonasal endoscopic dacryocystorhinostomy and external dacryocystorhinostomy

Objectives and Study Design: The advent of the rigid endonasal endoscope and the development of functional endoscopic sinus surgery (FESS) technique have awakened interest in an endonasal endoscopic dacryocystorhinostomy (EESC-DCR) in treating nasolacrimal obstruction. This prospective, randomized study compares EESC-DCR with traditional external dacryocystorhinostomy (EXT-DCR) for their success rates, surgical duration, and postoperative symptoms. Patients and Methods: Sixty-four cases in 60 patients with primary acquired nasolacrimal sac or duct obstruction were divided into two subgroups by symptoms (simple epiphora/ chronic dacryocystitis). These patients were randomized within both subgroups into two operation groups. Altogether 32 EESC-DCRs and 32 EXT-DCRs were performed. The final follow-up visit was at 1 year. The patency of the lacrimal passage was investigated by irrigation and patients were questioned about their symptoms. Results: The success rate at 1 year after surgery was 75% for EESC-DCR and 91% for EXT-DCR after primary surgery. The difference was not statistically significant (P = .18). The success rate after secondary surgery with a follow-up time of 1 year was 97% in both study groups. The average duration for EESC-DCR was 38 minutes, and 78 minutes for EXT-DCR, (P < .001). Conclusions: EXT-DCR, when compared with EESC-DCR, appears to give a higher, although not statistically significant, primary success rate, but the secondary success rates are equal, indicating that these two different DCR techniques are acceptable alternatives.     

Antibodies against copper-oxidised and malondialdehyde-modified low density lipoproteins in pre-eclamptic pregnancies

Objective To measure auto-antibodies against oxidatively modified low density lipoprotein (LDL) in pre-eclamptic pregnancies using two different techniques.
Design Clinical study comparing pre-eclamptic and normal pregnancies.
Setting Tampere University Hospital, Finland.
Population Twenty-one primigravidae with pre-eclampsia and 13 healthy, normotensive primigravidae as controls.
Methods The serum titers of antibodies against both malondialdehyde-modified and copper-oxidised LDL (MDA-LDL and copper-ox LDL) were analysed and related to parameters reflecting the severity of pre-eclampsia.
Results There was a positive correlation (   r = 0.58  ) between antibodies against MDA-LDL and copper-ox LDL in women with pre-eclampsia but not in healthy pregnant controls. The antibody levels against copper-ox LDL, but not against MDA-LDL, were higher in women with pre-eclampsia than in women with a normal pregnancy (   P < 0.01  ). While the antibody titers against copper-ox LDL did not correlate with any parameter reflecting the severity of pre-eclampsia, those against MDA-LDL showed a positive correlation with the level of diastolic blood pressure (   r = 0.54  ) and a negative correlation with platelet count (   r = 461  ) in women with pre-eclampsia.
Conclusions There are increased titers of serum autoantibodies against copper-oxidised LDL in pre-eclampsia, which may reflect enhanced lipid peroxidation involving circulating lipoproteins.     

Alpha2A-adrenoceptors are important modulators of the effects of D-amphetamine on startle reactivity and brain monoamines.

Amphetamines are commonly used to treat attention-deficit hyperactivity disorder, but are also widely abused. They are employed in schizophrenia-related animal models as they disrupt the prepulse inhibition (PPI) of the acoustic startle response. The behavioral effects of amphetamines have mainly been attributed to changes in dopamine transmission, but they also involve increases in the synaptic concentrations of norepinephrine (NE). alpha2-Adrenoceptors (alpha2-ARs) regulate the excitability and transmitter release of brain monoaminergic neurons mainly as inhibitory presynaptic auto- and heteroreceptors. Modulation of acoustic startle and its PPI by the alpha2A-AR subtype was investigated with mice lacking the alpha2A-AR (alpha2A-KO) and their wild-type (WT) controls, without drugs and after administration of the alpha2-AR agonist dexmedetomidine or the antagonist atipamezole. The interaction of D-amphetamine (D-amph) and the alpha2-AR-noradrenergic neuronal system in modulating startle reactivity and in regulating brain monoamine metabolism was assessed as the behavioral and neurochemical responses to D-amph alone, or to the combination of D-amph and dexmedetomidine or atipamezole. alpha2A-KO mice were supersensitive to both neurochemical and behavioral effects of D-amph. Brain NE stores of alpha2A-KO mice were depleted by D-amph, revealing the alpha2A-AR as essential in modulating the actions of D-amph. Also, increased startle responses and more pronounced disruption of PPI were noted in D-amph-treated alpha2A-KO mice. alpha2A-AR also appeared to be responsible for the startle-modulating effects of alpha2-AR drugs, since the startle attenuation after the alpha2-AR agonist dexmedetomidine was absent in alpha2A-KO mice, and the alpha2-AR antagonist atipamezole had opposite effects on the startle reflex in alpha2A-KO and WT mice.