Association of Serotype-Specific Antibody Concentrations and Functional Antibody Titers with Subsequent Pneumococcal Carriage in Toddlers Immunized with a 9-Valent Pneumococcal Conjugate Vaccine

Association of pneumococcal nasopharyngeal carriage with the concentration and opsonophagocytic activity (OPA) of serum serotype-specific antibodies was determined for toddlers 1 month after immunization with a 9-valent pneumococcal conjugate vaccine. Higher anti-serotype 14 and anti-serotype 19F IgG and anti-serotype 14 IgM correlated with a lowered probability of pneumococcal acquisition. Postvaccination OPA did not correlate with pneumococcal carriage.     

A putative Lynch syndrome family carrying MSH2 and MSH6 variants of uncertain significance—functional analysis reveals the pathogenic one

Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected family members complicates the risk assessment. Here, we describe a putative LS family carrying VUS in both MSH2 (c.2768T>A, p.Val923Glu) and MSH6 (c.3563G>A, p.Ser1188Asn). Two colorectal cancer (CRC) patients were studied for mutations and identified as carriers of both variants. In spite of a relatively high mean age of cancer onset (59.5 years) in the family, many CRC patients and the tumor pathological data suggested that the missense variation in MSH2, the more common susceptibility gene in LS, would be the predisposing alteration. However, MSH2 VUS was surprisingly found to be MMR proficient in an in vitro MMR assay and a tolerant alteration in silico. By supplying evidence that instead of MSH2 p.Val923Glu the MSH6 p.Ser1188Asn variant is completely MMR-deficient, the present study confirms the previous findings, and suggests that MSH6 (c.3563G>A, p.Ser1188Asn) is the pathogenic mutation in the family. Moreover, our results strongly support the strategy to functionally assess all identified VUS before predictive gene testing and genetic counseling are offered to a family.     

High blood pressure-lowering and vasoprotective effects of milk products in experimental hypertension

Milk casein-derived angiotensin-converting enzyme (ACE)-inhibitory tripeptides isoleucine-proline-proline (Ile-Pro-Pro) and valine-proline-proline (Val-Pro-Pro) have been shown to have antihypertensive effects in human subjects and to attenuate the development of hypertension in experimental models. The aim of the present study was to investigate the effect of a fermented milk product containing Ile-Pro-Pro and Val-Pro-Pro and plant sterols on already established hypertension, endothelial dysfunction and aortic gene expression. Male spontaneously hypertensive rats (SHR) with baseline systolic blood pressure (SBP) of 195 mmHg were given either active milk (tripeptides and plant sterols), milk or water ad libitum for 6 weeks. SBP was measured weekly by the tail-cuff method. The endothelial function of mesenteric arteries was investigated at the end of the study. Aortas were collected for DNA microarray study (Affymetrix Rat Gene 1.0 ST Array). The main finding was that active milk decreased SBP by 16 mmHg compared with water (178 (SEM 3) v. 195 (SEM 3) mmHg; P < 0.001). Milk also had an antihypertensive effect. Active milk improved mesenteric artery endothelial dysfunction by NO-dependent and endothelium-derived hyperpolarising factor-dependent mechanisms. Treatment with active milk caused mild changes in aortic gene expression; twenty-seven genes were up-regulated and eighty-two down-regulated. Using the criteria for fold change (fc) < 0.833 or > 1.2 and P < 0.05, the most affected (down-regulated) signalling pathways were hedgehog, chemokine and leucocyte transendothelial migration pathways. ACE expression was also slightly decreased (fc 0.86; P = 0.047). In conclusion, long-term treatment with fermented milk enriched with tripeptides and plant sterols decreases SBP, improves endothelial dysfunction and affects signalling pathways related to inflammatory responses in SHR.     

A probiotic mixture including galactooligosaccharides decreases fecal β-glucosidase activity but does not affect serum enterolactone concentration in men during a two-week intervention

A high serum concentration of enterolactone, an enterolignan produced by colonic microbiota from precursors in cereals, vegetables, and fruits, is associated with reduced risk of acute coronary events. Probiotics and prebiotics modify colonic metabolism and may affect the serum enterolactone concentration. The effects of a probiotic mixture alone and with galactooligosaccharides (GOS) on serum enterolactone concentration and fecal metabolism were investigated in 18 healthy men. Participants received 3 interventions, each for 2 wk: 1) probiotics [Lactobacillus rhamnosus strains GG (LGG) and LC705, Propionibacterium freudenreichii ssp. shermanii JS, and Bifidobacterium breve Bb99, for a total amount of 2 × 10(10) CFU/d]; 2) probiotics and GOS 3.8 g/d; 3) probiotics, GOS, and rye bread (minimum 120 g/d). Serum enterolactone and fecal dry weight, enzyme activities, pH, SCFA, lactic acid bacteria, bifidobacteria, propionibacteria, and the strains LGG and LC705 were determined. The serum enterolactone concentration (nmol/L) tended to be decreased from baseline [mean (95% CI) 18.6 (10.8-26.4)] by probiotics alone [15.2 (7.8-22.7); P = 0.095], was not significantly affected by probiotics with GOS [21.5 (13.2-29.8)], and was increased by probiotics with GOS and rye bread [24.6 (15.4-33.7); P < 0.05]. Probiotics alone did not affect fecal β-glucosidase activity and bifidobacteria, but probiotics with GOS decreased β-glucosidase activity and increased bifidobacteria compared with baseline (P < 0.05) and with probiotics alone (P < 0.01). In conclusion, this probiotic mixture with or without GOS does not significantly affect serum enterolactone concentration. Because probiotics with GOS decreased fecal β-glucosidase activity but not serum enterolactone, the reduced fecal β-glucosidase, within the range of activities measured, does not seem to limit the formation of enterolactone.     

Reduced systemic vascular resistance in healthy volunteers with presyncopal symptoms during a nitrate-stimulated tilt-table test

AIMS

The mechanism of nitrate-induced syncope remains controversial. We examined the haemodynamic changes in healthy volunteers during nitroglycerin-stimulated tilt-table test.

METHODS

Continuous radial pulse wave analysis, whole-body impedance cardiography and plethysmographic finger blood pressure were recorded in a supine position and during head-up tilt in 21 subjects with presyncopal symptoms (6 male/15 female, age 43 ± 3 years) after 0.25 mg sublingual nitroglycerin and 21 control subjects (6 male/15 female, age 43 ± 2 years). The drug was administered in the supine position and a passive head-up tilt followed 5 min later. Additionally, nitroglycerin was only administered during head-up tilt in 19 subjects and the haemodynamics were recorded.

RESULTS

Supine and upright haemodynamics were similar before nitroglycerin administration in the two groups. During the nitroglycerin-stimulated tilt test, aortic and radial mean blood pressure decreased significantly more in the presyncope group when compared with the controls (P = 0.0006 and P = 0.0004, respectively). The decreases in systemic vascular resistance (P = 0.0008) and heart rate (P = 0.002), and increase in aortic reflection time (P = 0.0002) were greater in the presyncope group, while the change in cardiac index was not different between the groups (P = 0.14). If nitroglycerin was administered during the upright tilt and not in supine position, the haemodynamic changes were quite corresponding.

CONCLUSIONS

Presyncopal symptoms during nitrate-stimulated tilt test were explained by decreased systemic vascular resistance and increased aortic reflection time, while cardiac output remained unchanged. These findings indicated reduced arterial resistance in nitroglycerin-induced presyncope.     

Monitoring lidocaine single-crystal dissolution by ultraviolet imaging

Dissolution critically affects the bioavailability of Biopharmaceutics Classification System class 2 compounds. When unexpected dissolution behaviour occurs, detailed studies using high information content technologies are warranted. In the present study, an evaluation of real-time ultraviolet (UV) imaging for conducting single-crystal dissolution studies was performed. Using lidocaine as a model compound, the aim was to develop a setup capable of monitoring and quantifying the dissolution of lidocaine into a phosphate buffer, pH 7.4, under stagnant conditions. A single crystal of lidocaine was placed in the quartz dissolution cell and UV imaging was performed at 254 nm. Spatially and temporally resolved mapping of lidocaine concentration during the dissolution process was achieved from the recorded images. UV imaging facilitated the monitoring of lidocaine concentrations in the dissolution media adjacent to the single crystals. The concentration maps revealed the effects of natural convection due to density gradients on the dissolution process of lidocaine. UV imaging has great potential for in vitro drug dissolution testing.     

Influence of Temperature on Solvent-Mediated Anhydrate-to-Hydrate Transformation Kinetics

Purpose  

To achieve an in-depth understanding of the underlying mechanism of the acceleration or deceleration effect of temperature on solvent-mediated anhydrate-to-hydrate phase transformation.