Systemic Inflammation and Multimodal Biomarkers in Amnestic Mild Cognitive Impairment and Alzheimer's Disease.

There is increasing evidence suggesting that one of the most relevant pathophysiological features of Alzheimer's disease (AD) is neuroinflammation, which plays an important role in the production and regulation of AD-related proteins (amyloid beta (Aß) and Tau) and exacerbates AD pathology. Neuroinflammation can also be induced by systemic influences (factors from outside the central nervous system). However, the role of systemic inflammation in AD pathophysiology is much less understood. Thus, our main objective in this study was to verify whether the presence of serum cytokines (IL-1ß, IL-6, IL-10, IL-12, and TNF-α) affects different AD biomarkers: Aß1-42 and Tau protein levels, hippocampal volumes (HV), and default mode network functional connectivity (DMN FC) in healthy elderly controls, amnestic mild cognitive impairment (aMCI) patients due to AD, and mild AD patients. To accomplish this, we acquired 3-T MRI, blood, and cerebrospinal fluid (CSF) samples from 42 healthy controls, 55 aMCI patients due to AD, and 33 mild AD patients. Comparing the groups, we found that the mild AD patients presented smaller HV, disrupted DMN FC, and proportionally less IL-1ß than the controls. The aMCI patients only differed from the controls in DMN FC. In intra-group comparison, aMCI and mild AD with detectable levels of cytokines (TNF-α, IL-1ß, IL-10, and IL-12) had decreased DMN FC. On the other hand, patients with detectable levels of IL-10 and IL-12 presented a more favorable AD biomarkers profile (larger HV, more CSF Aß1-42, and less p-Tau), indicating a possible protective role of these ILs. Our findings indicate a possible relationship between systemic inflammation with DMN FC disruption, hippocampal atrophy, and CSF protein levels in the subjects with mild AD and aMCI.

The role played by salts in the formation of SBA-15, an in situ small-angle X-ray scattering/diffraction study.

The influence of salts (NaCl, NaBr, and NaI) on the formation of mesoporous silica SBA-15 was studied in situ by small-angle X-ray scattering and diffraction. Pluronic P104 was used as structure director. The micellar properties and the dynamics of formation were clearly dependent on the presence of salt. It was also shown that the kinetics of mesophase formation, the initial value of the cell parameters, and the extent of long-range order were all influenced by salt additions. The observations are explained to primarily originate from the influence of the anions on the ethylene oxide part of the polymer, i.e., the corona region of the Pluronic micelles. Two effects are identified: a general ion effect causing dehydration of the ethylene oxide part and consequently inducing micellar growth, and a specific ion effect that counterbalances this. The study provides the basis for understanding the means by which addition of simple Na-salts influence the formation of mesoscopically ordered silicas synthesized using nonionic surfactants as structure directors, hence advancing the knowledge base toward a more rational design of mesoporous materials.

In-plane miscibility and mixed bilayer microstructure in mixtures of catanionic glycolipids and zwitterionic phospholipids.

SAXS/WAXS studies were performed in combination with freeze fracture electron microscopy using mixtures of a new Gemini catanionic surfactant (Gem16-12, formed by two sugar groups bound by a hydrocarbon spacer with 12 carbons and two 16-carbon chains) and the zwitterionic phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) to establish the phase diagram. Gem16-12 in water forms bilayers with the same amount of hydration water as DPPC. A frozen interdigitated phase with a low hydration number is observed below room temperature. The kinetics of the formation of this crystalline phase is very slow. Above the chain melting temperature, multilayered vesicles are formed. Mixing with DPPC produces mixed bilayers above the corresponding chain melting temperature. At room temperature, partially lamellar aggregates with local nematic order are observed. Splitting of infinite lamellae into discs is linked to immiscibility in frozen state. The ordering process is always accompanied by dehydration of the system. As a consequence, an unusual order-disorder phase transition upon cooling is observed.

Effects of undernutrition on serum and testicular testosterone levels and sexual function in adult rats.

The aim of this study was to evaluate testosterone concentrations, sexual behavior, and androgen receptor protein level in the testes of rats submitted to protein- and energy-restricted diets during 30 days. Adult male Wistar rats were assigned to one of the following groups: (C) control, diet with 23% of protein; (PR) protein-restricted, diet with 8% of protein; (ER) energy-restricted, diet with 23% of protein in restricted quantities. Mount number, ejaculation latencies and copulatory efficiency were evaluated to determine sexual behavior. At the end of the experiment, the animals were sacrificed to determine serum and testicular testosterone concentrations as well as testicular androgen receptor protein level. Compared to the C group, the ER group presented a significant decrease in body (36%), testis (20%) and epididymis (14%) weights in serum (78%) and testicular (68%) testosterone concentrations as well as in copulatory efficiency (26%). On the other hand, the ER group presented a significant increase in mount number (114%) and ejaculatory latency (62%). The androgen receptor protein levels were significantly reduced in both PR and ER groups (41% and 74%, respectively). This is the first paper to demonstrate that the effect of undernutrition on reproduction is not related to reduced protein intake but caloric restriction. Also, in caloric restriction, there is a relationship between sex behavior, androgen receptors, and testosterone concentration.

Leptin injection during lactation alters thyroid function in adult rats.

The aim of this study was to evaluate the effects of hyperleptinemia during the first ten days of life on thyroid function in adulthood. After birth, pups were separated into two groups: L8 - receiving daily injections of recombinant mouse leptin (8 microg/100 g body weight, sc) and control (C) - receiving the same volume of saline. Both groups were treated for the first 10 days of lactation. The animals were sacrificed at 150 days of age, and the blood was collected for leptin, TSH, total triiodothyronine (TT 3 ) and total thyroxin (TT 4 ) serum concentration determinations by radioimmunoassay. The thyroid gland was excised to determine thyroid iodine uptake. Leptin, TT 3 and TT 4 serum concentrations in L8 group were significantly (108 %, 47 % and 32 %; p < 0.05) higher than that of controls. There was no significant difference between the groups related to thyroid iodine uptake and TSH serum concentration. These data suggest that the first half of lactation period is important in determining thyroid function in adulthood, and that it can be programmed by serum leptin concentration.

Leptin treatment during the neonatal period is associated with higher food intake and adult body weight in rats.

For this study, we have determined the effects of neonatal leptin treatment on the evolution of body weight. Experiment 1: pups were divided into two groups: LepF - injected with leptin (8 micro g/100 g of body weight) for the first 10 days of lactation and control (C) - receiving saline. Experiment 2: pups were divided into two groups: LepL - injected with the same leptin concentration of experiment one for the last 10 days of lactation, and C, which received saline. Body weight and food intake were monitored until age 150 days, after which leptin concentrations were measured by ELISA. The LepF group had a significant increase in body weight (p < 0.05) from day 98 onward, in food intake (p < 0.05) from day 74 onward, and higher serum leptin concentration compared to the control (108 %, p < 0.05). The LepL group had a significant increase in body weight (p < 0.05) from day 113 onward, in food intake from day 121 onward (p < 0.001), and higher serum leptin concentration compared to controls (6.9 %, p < 0.05). These results suggest that both periods of lactation constituted a critical window for body weight and food intake programming, but the effects are more marked when the leptin is injected within the first ten days.

Local anesthetic-induced microscopic and mesoscopic effects in micelles. A fluorescence, spin label and SAXS study. Single angle X-ray scattering.

The interaction of the local anesthetic tetracaine (TTC) with anionic sodium lauryl sulfate (SLS) and zwitterionic 3-(N-hexadecyl-N,N-dimethylammonio)propanesulfonate (HPS) micelles was investigated by fluorescence, spin labeling EPR and small angle X-ray scattering (SAXS). Fluorescence pH titrations allowed the choice of adequate pHs for the EPR and SAXS experiments, where either charged or uncharged TTC would be present. The data also indicated that the anesthetic is located in a less polar environment than its charged counterpart in both micellar systems. EPR spectra evidenced that both anesthetic forms increased molecular organization within the SLS micelle, the cationic form exerting a more pronounced effect. The SAXS data showed that protonated TTC causes an increase in the SLS polar shell thickness, hydration number, and aggregation number, whereas the micellar features are not altered upon incorporation of the uncharged drug. The combined results suggest that the electrostatic interaction between charged TTC and SLS, and the intercalation of the drug in the micellar polar region induce a change in molecular packing with a decrease in the mean cross-sectional area, not observed when the neutral drug sinks more deeply into the micellar hydrophobic domain. In the case of HPS micelles, the EPR spectral changes were small for the charged anesthetic and the SAXS data did not evidence any change in micellar structure, suggesting that this species protrudes more into the aqueous phase due to the lack of electrostatic attractive forces in this system.

Low-protein diet changes thyroid function in lactating rats.

Lactating rats were fed with free access to an 8% protein-restricted diet (PR); the control group was fed a 23% protein diet (C). An energy-restricted (pair-fed) group was given the same food as the animals in the control group, but the amounts of food consumed by both PF and PR were about the same. The body weight and serum albumin concentration of PR and PF dams were significantly (P < 0. 05) lower than that of the controls. The PR group had a significant increase in serum-free triiodothyronine (FT3) concentration, 24-hr mammary gland and milk radioiodine (I131) uptake (67%, 278%, and 200%, respectively) as compared with the controls. On the other hand, those animals had a significantly lower serum-free thyroxine (FT4) concentration and 2- and 24-hr thyroid I131 uptake (67%, 64%, and 74%, respectively). Protein malnutrition during lactation did not alter thyroid or liver 5'-deiodinase activity significantly. However, PF dams had a significantly lower (25%) thyroid 5'-deiodinase activity. These data suggest that protein-restricted lactating dams had an adaptive change in the thyroid function, which could be important to increase the transference of iodine or triiodothyronine through the milk to their pups and prevent sequelae of neonatal hypothyroidism.

Thyroid function in post-weaning rats whose dams were fed a low-protein diet during suckling.

This study was designed to evaluate the thyroid and pituitary hormone levels in post-weaning rats whose dams were fed a low-protein diet during suckling (21 days). The dams and pups were divided into 2 groups: a control group fed a diet containing 22% protein that supplies the necessary amount of protein for the rat and is the usual content of protein in most commercial rat chow, and a diet group fed with a low-protein (8%) diet in which the protein was substituted by an isocaloric amount of starch. After weaning all dams and pups received the 22% protein diet. Two hours before sacrifice of pups aged 21, 30 and 60 days, a tracer dose (0.6 microCi) of 125I was injected (i.p.) into each animal. Blood and thyroid glands of pups were collected for the determination of serum T4, T3 and TSH and radioiodine uptake. Low protein diet caused a slight decrease in radioiodine uptake at 21 days, and a significant decrease in T3 levels (128 +/- 14 vs 74 +/- 9 ng/dl, P < 0.05), while T4 levels did not change and TSH was increased slightly. At 30 days, T3 and TSH did not change while there was a significant increase in both T4 levels (4.8 +/- 0.3 vs 6.1 +/- 0.2 micrograms/dl, P < 0.05) and in radioiodine uptake levels (0.34 +/- 0.02 vs 0.50 +/- 0.03%/mg thyroid, P < 0.05). At 60 days serum T3, T4 and TSH levels were normal, but radioiodine uptake was still significantly increased (0.33 +/- 0.02 vs 0.41 +/- 0.03%/mg thyroid, P < 0.05). Thus, it seems that protein malnutrition of the dams during suckling causes hypothyroidism in the pups at 21 days that has a compensatory mechanism increasing thyroid function after refeeding with a 22% protein diet. The radioiodine uptake still remained altered at 60 days, when all the hormonal serum levels returned to the normal values, suggesting a permanent change in the thyroid function.

Thyroid function in post-weaning rats whose dams were fed a low-protein diet during suckling

This study was designed to evaluate the thyroid and pituitary hormone levels in post-weaning rats whose dams were fed a low-protein diet during suckling (21 days). The dams and pups were divided into 2 groups:a control group fed a diet containing 22 per cent protein that supplies the necessary amount of protein for the rat and is the usual content of protein in most commercial rat chow, and a diet group fed a lowprotein (8 per cent) diet in which the protein was substituted by an isocaloric amount of starch. After weaning all dams and pups received the 22 per cent protein diet. Two hours before sacrifice of pups aged 21, 30 and 60 days, a tracer dose (0.6 mui) ofl25I was injected (ip) into each animal. Blood and thyroid glands of pups were collected for the determination of serum T4, T3 and TSH and radioiodine uptake. Low protein diet caused a slight decrease in radioiodine uptake at 21 days, and a significant decrease in T3 levels (l28 ñ 14 vs 74 ñ 9 ng/dl, P<0.05), while T4 levels did not change and TSH was increased slightly. At 30 days, T3 and TSH did not change while there was a significant increase in both T4 levels (4.8 ñ 0.3 vs 6.1 ñ 0.2 mug/dl, P<0.05) and in radioiodine uptake levels (0.34 ñ 0.02 vs 0.50 ñ 0.030 per cent/mg thyroid, P<0.05). At 60 days serum T3, T4 and TSH levels were normal, but radioiodine uptake was still significantly increased (0.33 ñ 0.02 vs 0.41 ñ 0.03 per cent/mg thyroid, P<0.05). Thus, it seems that protein malnutrition of the dams during suckling causes hypothyroidism in the pups at 21 days that has a compensatory mechanism increasing thyroid function after refeeding with a 22 per cent protein diet. The radioiodine uptake still remained altered at 60 days, when all the hormonal serum levels returned to the normal values, suggesting a permanent change in the thyroid function.