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Background/aims: Human gut microbiota harbors numerous metabolic properties essential for the host's health. Increased intestinal transit time affects a part of the population and is notably observed with human aging, which also corresponds to modifications of the gut microbiota. Thus we tested the metabolic and compositional changes of a human gut microbiota induced by an increased transit time simulated in vitro., Methods: The in vitro system, Environmental Control System for Intestinal Microbiota, was used to simulate the environmental conditions of 3 different anatomical parts of the human colon in a continuous process. The retention times of the chemostat conditions were established to correspond to a typical transit time of 48 hours next increased to 96 hours. The bacterial communities, short chain fatty acids and metabolite fingerprints were determined., Results: Increase of transit time resulted in a decrease of biomass and of diversity in the more distal compartments. Short chain fatty acid analyses and metabolite fingerprinting revealed increased activity corresponding to carbohydrate fermentation in the proximal compartments while protein fermentations were increased in the lower parts., Conclusions: This study provides the evidence that the increase of transit time, independently of other factors, affects the composition and metabolism of the gut microbiota. The transit time is one of the factors that explain some of the modifications seen in the gut microbiota of the elderly, as well as patients with slow transit time.

Photoluminescence spectroscopy is a key method to monitor defects in semiconductors from nanophotonics to solar cell systems. Paradoxically, its great sensitivity to small variations of local environment becomes a handicap for heterogeneous systems, such as are encountered in environmental, medical, ancient materials sciences and engineering. Here we demonstrate that a novel full-field photoluminescence imaging approach allows accessing the spatial distribution of crystal defect fluctuations at the crystallite level across centimetre-wide fields of view. This capacity is illustrated in archaeology and material sciences. The coexistence of two hitherto indistinguishable non-stoichiometric cuprous oxide phases is revealed in a 6,000-year-old amulet from Mehrgarh (Baluchistan, Pakistan), identified as the oldest known artefact made by lost-wax casting and providing a better understanding of this fundamental invention. Low-concentration crystal defect fluctuations are readily mapped within ZnO nanowires. High spatial dynamics-photoluminescence imaging holds great promise for the characterization of bulk heterogeneous systems across multiple disciplines.

Purpose: To evaluate the efficacy of mucoadhesive insulin-loaded whey protein (WP) /alginate (ALG) microparticles (MP) for oral insulin administration., Methods: Insulin-loaded microparticles (ins-MP) made of whey protein and alginate were prepared by a cold gelation technique and an adsorption method, without adjunction of organic solvent in order to develop a biocompatible vehicle for oral administration of insulin. In vitro characterization, evaluations of ins-MP in excised intestinal tissues and hypoglycaemic effects after intestinal administration in healthy rats were performed, Results: The release properties and swelling behaviors, investigated in different pH buffers, demonstrated a release based on diffusion mechanism following matrix swelling. Mucoadhesion studies in rabbits and insulin transport experiments with excised intestinal rat tissues revealed that encapsulation in microparticles with mucoadhesive properties promotes insulin absorption across duodenal membranes and bioactivity protection. In vivo experiments reinforced the interest of encapsulation in whey protein/alginate combination. Confocal microscopic observations associated with blood glucose levels bring to light duodenal absorption of insulin biologically active following in vivo administration., Conclusions: Insulin-loaded WP/ALG MP with high quantities of drug entrapped, in vitro matrix swelling and protective effect as well as excellent mucohadesive properties was developped. Improvement of intestinal delivery of insulin and increased in bioavailability were recorded.

To exert their health effect, phytochemicals such as carotenoids and vitamin E have to be bioavailable. We investigated the digestive stability and intestinal absorption of lycopene and alpha-tocopherol from a whole food containing red tomatoes and sunflower oil using, for the first time, the dynamic gastrointestinal system TNO gastrointestinal tract model (TIM) coupled with Caco-2 cells. Digestive samples were added to Caco-2 cells after appropriate ultracentrifugation, filtration, and dilution. alpha-Tocopherol was stable during digestion in the TIM, whereas a 25% loss was observed for lycopene. The absorption of both compounds was curvilinear, bidirectional, and concentration-dependent. The percentages of alpha-tocopherol absorbed, but not that of lycopene, were lower with digestas compared to those with pure compounds, suggesting competition for absorption with other components of the test meal. According to in vivo data, a lower bioavailability was found for lycopene compared to that for alpha-tocopherol. These results support the usefulness of this in vitro approach for estimating the bioavailability of active compounds from food.

An innovative "biodrug" concept based on oral administration of living recombinant microorganisms as a vehicle to deliver active compounds directly into the digestive tract has recently been developed. To validate this concept, we studied a recombinant Saccharomyces cerevisiae strain in order to investigate its viability and its ability to produce a protein (glutathione-S-transferase (GST)-V(5)H(6)) in the rat. Following oral administration, the recombinant yeast showed a survival rate of around 40% in the upper parts of the digestive tract, but was more sensitive to the conditions in the large intestinal, where viability dropped to 1%. Western blot analysis was able to detect the model protein throughout the digestive tract, including stomach, duodenum, jejunum (proximal, median and distal), ileum, cecum and colon. The gastrointestinal sac technique was employed to quantify GST-V(5)H(6) in all the digestive compartments. These results suggest that S. cerevisiae may represent a useful host for producing compounds of interest directly in the digestive tract.

Background & Aims: The aim of our study consisted to measure the pharmacokinetic parameters of methylprednisolone administered in a continuous infusion of a paediatric parenteral nutrition mixture for 24h in the rabbit., Methods: Fourteen rabbits were split into two groups and assigned a different administration vehicle (all-in-one or two-in-one nutrition mixture). We used USC PACK* pharmacokinetics software to compare the influence of the composition of the paediatric parenteral nutritional solutions on the values of the pharmacokinetic parameters of methylprednisolone., Results: Neither the steady-state plasma concentrations of methylprednisolone hemisuccinate nor the values of the pharmacokinetic parameters of methylprednisolone differed significantly when administered in two-in-one or all-in-one nutrition mixtures., Conclusions: The composition of the nutritional medium had no discernable effect on the bioavailability of methylprednisolone. Neither the speed at which the steady-state plasma concentration was reached, nor the values of the pharmacokinetic parameters of methylprednisolone were significantly modified.

An innovative "biodrug" concept, based on the oral administration of living recombinant microorganisms, has recently emerged for the prevention or treatment of various diseases. An engineered Saccharomyces cerevisiae strain expressing plant P450 73A1 (cinnamate-4-hydroxylase [CA4H] activity) was used, and its survival and ability to convert trans-cinnamic acid (CIN) into p-coumaric acid (COU) were investigated in vivo. In rats, the recombinant yeast was resistant to gastric and small intestinal secretions but was more sensitive to the conditions found in the large intestine. After oral administration of yeast and CIN, the CA4H activity was shown in vivo, with COU being found throughout the rat's digestive tract and in its urine. The bioconversion reaction occurred very fast, with most of the COU being produced within the first 5 min. The gastrointestinal sac technique demonstrated that the recombinant yeast was able to convert CIN into COU (conversion rate ranging from 2 to 5%) in all the organs of the rat's digestive tract: stomach, duodenum, jejunum, ileum, cecum, and colon. These results promise new opportunities for the development of drug delivery systems based on engineered yeasts catalyzing a bioconversion reaction directly in the digestive tract.

trans-Cinnamic acid (CIN) and p-coumaric acid (COU) are ingested by humans in their diet. While the metabolism and health benefits of CIN have been widely documented, little is known about its absorption sites, and there have been few studies dedicated to COU. The gastrointestinal sac technique demonstrated that CIN and COU are absorbed by all digestive organs in rats and partially transported via MCT-mediated carrier. Absorption was lowest in the stomach. Regardless of the organs that were studied, CIN was more efficiently absorbed than COU. After their individual oral administration to rats, CIN and COU were excreted in 0-24 h urine (0.3% and 23% of ingested CIN and COU, respectively). This suggests that COU was less metabolized than CIN. CIN and COU are absorbed across the digestive epithelium and subsequently interact with target tissues. Despite its lower gastrointestinal absorption, COU may have greater health benefits because it seems to be less metabolized than CIN.

Prehistoric evidence for the drilling of human teeth in vivo has so far been limited to isolated cases from less than six millennia ago. Here we describe eleven drilled molar crowns from nine adults discovered in a Neolithic graveyard in Pakistan that dates from 7,500-9,000 years ago. These findings provide evidence for a long tradition of a type of proto-dentistry in an early farming culture.

Many drugs can be administered in parenteral nutrient mixtures, but no work on the delivery of corticoids by such means is reported. We studied the influence of pediatric parenteral nutrient mixtures on the kinetic parameters of the corticoid methylprednisolone injected in an intravenous bolus in rabbits as its sodium succinate ester. Four groups of six male New Zealand rabbits were used. After extraction, the plasma drug concentrations were measured by high performance liquid chromatography. The distribution volume of the ester and the clearance rates of the two entities (ester and methylprednisolone) were lowered in the presence of a lipid emulsion. The description of these pharmacokinetic parameters provides a basis for a preclinical study of 24h administration of methylprednisolone in a parenteral nutrient mixture., (Copyright 2003 Elsevier Ltd.)

Female rats exposed to long (LD 18:6) or short (LD 6:18) photoperiods from 21 days of age were mated when they reached 55 days of age. On day 2 of gestation animals of each group were either pinealectomized or sham-operated. Lighting regimens were not changed during the course of the study. Male offspring of the four groups of dams were sacrificed on day 70 after birth. Rats that were maintained on long photoperiod had higher testicular testosterone, androstenedione, and dihydrotestosterone content than those raised on a LD 6:18 cycle. Whatever the breeding photoperiod used, maternal pinealectomy induced no modification of reproductive function. Among rats kept in short photoperiod, neonatal pinealectomy (on day 5 after birth) resulted in an enhanced testicular androgen content without any modification of plasma androgen concentration. These results indicate that (1) the previously reported effect of the mother's pineal on pubertal rat testicular function is not present in adulthood and (2) the pineal of the offspring is required to maintain normal testicular androgen content in the adult rat but exerts no influence on circulating androgens.

Female Sprague-Dawley rats, exposed to a long (18L:6D) or a short (6L:18D) photoperiod from 21 days of age, were mated when they reached 55 days of age. On Day 2 of gestation, dams were pinealectomized or sham-operated. Pre- and postnatal photoperiods were identical, and offspring were killed at 15 days of age. Maternal pinealectomy had no effect when rats were kept on 18L:6D. Rats born to sham-operated mothers and kept on 6L:18D had higher testicular testosterone and androstenedione content than offspring raised on the long photoperiod. This stimulatory effect of the short photoperiod was blocked by maternal pinealectomy and was not dependent on the offspring's own pineal since it was observed in both sham-operated and neonatally (on Day 5 after birth) pinealectomized rats. When sham-operated mothers housed on 18L:6D were treated daily during pregnancy and lactation by s.c. melatonin injection, there was an increase in the testicular testosterone content of offspring. It was concluded that when rats are maintained on a 6L:18D cycle the maternal pineal gland enhances the testicular testosterone and androstenedione content in 15-day-old offspring. This effect is probably mediated by maternally derived melatonin. At 15 days of age, the pineal of the offspring had no influence on testicular function.

Female rats were exposed to a short (6L:18D) photoperiod from 21 days of age. On day 2 of gestation, animals were pinealectomized or sham-operated. Lighting regimens were not changed during the course of the study. Male offspring of the 2 groups of rats were sacrificed on days 21 after birth. Pinealectomy of the mother induced the following modifications: a decrease in prostate and seminal vesicle weights, a decrease in testicular testosterone and androstenedione content and in plasma dihydrotestosterone levels. We conclude that when rats are maintained on a 6L:18D cycle the maternal pineal gland stimulates the testicular function in 21-day-old offspring.

Female Sprague-Dawley rats exposed to a short (6L:18D) photoperiod from 21 days of age were mated when they reached 55 days of age. On Day 2 of gestation animals were pinealectomized or sham-operated. On Day 5 after birth male pups of the two groups of dams were either pinealectomized or sham-operated. They were killed at 42 and 49 days of age. In offspring born to sham-operated dams and in those born to pinealectomized mothers, neonatal pineal ablation resulted in increased testicular testosterone and androstenedione content. In sham-operated and neonatally pinealectomized rats removal of the maternal pineal gland induced a decrease in testicular testosterone and androstenedione content. In contrast, after maternal pinealectomy there was a decrease in plasma testosterone and dihydrotestosterone values and testicular dihydrotestosterone content in sham-operated rats but not in those neonatally pinealectomized. We conclude that (1) the pineal glands of the mother and offspring are required to maintain normal testicular testosterone and androstenedione content in the rat, and (2) the pineal of the offspring influences the inhibitory effects of maternal pinealectomy on testicular dihydrotestosterone content and on plasma testosterone and dihydrotestosterone concentration in the offspring.

Male mice heterozygous for the reciprocal autosomal translocation T(7,19)145H (T145H/+) were completely sterile, Spermatogenesis was arrested at some stage during the first meiotic division. The pituitary-gonadal axes of these mice were compared with those of normal male littermates (+/+) at 63 days of age. Testis and epididymis weights were significantly lower than in normal males, but no deficiencies in circulating FSH were observed despite drastic loss of germinal cells, suggesting that spermatids were not involved in the feed-back control of FSH (T145H/+, 2155 +/- 64 ng/ml; +/+, 1830 +/- 94 ng/ml; mean +/) s.e.m.). Androgen activity in T145H/+ males seemed normal judging by weights of androgen target tissues (prostate, seminal vesicles), serum LH and testosterone levels (T145H/+ : LH = 132 +/- 19 ng/ml, testosterone = 5.5 +/- 2.8 ng/ml; +/+ : LH = 127 +/- 22 ng/ml, testosterone = 7.4 +/- 2.7 ng/ml). These results indicate that the translocation in the heterozygous state does not modify control of FSH secretion or the LH-interstitial cell axis.

The effect of bromocriptine (BR) on pituitary-testicular function has been investigated in vivo and in vitro in adult male rats. Testosterone production in vitro by collagenase- dispersed Leydig cells from 84-day-old rats was evaluated in the presence and absence of hCG and/or different doses of BR. In the presence of 1.5 X 10(-5) M BR, both basal and hCG-stimulated testosterone production were decreased whereas at lower doses BR was ineffective. In vivo 60-day-old rats were injected sc with BR (150 micrograms/rat or 750 micrograms/rat twice daily) or vehicle for 24 days. This treatment reduced the plasma level and pituitary content of prolactin, slightly increased the plasma levels of LH and FSH but did not affect pituitary gonadotrophin content. Irrespective of the dose of BR injected, plasma levels of androgen did not change, but with the large dose of BR a decrease in testicular content of testosterone (P = 0.05) was observed. In the same animals the number of LH/hCG receptors was significantly reduced, and the sensitivity of the isolated Leydig cells to hCG stimulation in vitro was reduced; however, both the basal secretion and the maximum testosterone response to hCG were unaffected. These results show impairment of pituitary-testicular function in BR-treated rats, either as a result of BR-induced hypoprolactinaemia or as a consequence of direct effects of BR on the Leydig cells.

We studied the effect of hCG, aminoglutethimide and pineal effluent on the basal testosterone secretion by superfused adult rat interstitial cells. The period used to determine the mean rates of release was 120-240 min. after the start of superfusion i.e. when basal secretory rate was stable. A 2 h administration of hCG (10 mUI/ml) induced a rapid increase in testosterone output while aminoglutethimide (100 microM) decreased it. Basal testosterone release was not modified when interstitial cells were superfused with effluent of a chamber containing 1, 2 or 4 pineal glands. These results suggest that pineal secretory products exert no direct acute action on testosterone biosynthesis by rat interstitial cells.

Six healthy subjects, aged 35.8 +/- 4.4 years, volunteered to participate in a 40-week training program on a bicycle ergometer [three 60-min sessions per week at 80%-85% of maximal oxygen uptake (VO2 max)]. Before training and at the 10th, 20th, 30th, and 40th weeks of the training program, plasma testosterone, cortisol, and androstenedione concentrations were measured at rest (t0) and at the end (t60) of a 1-h endurance exercise requiring 85%-90% of VO2 max. Training resulted in significant increases of anaerobic threshold (12.6%) and VO2 max (7.3%). The training program did not significantly alter the resting values of plasma testosterone, androstenedione, and cortisol; in contrast, the exercise responses (delta = t60-t0) of testosterone, androstenedione, and cortisol were increased. The highest amplitude of these responses was reached at the 30th week for cortisol and androstenedione and at the 40th for testosterone. These results suggest that long-term training enhances both testicular adrenal and responses to endurance exercise. The possible role of hormonal changes in the mobilization of energy substrates during exercise is discussed.

The effects of bromocriptine induced hypoprolactinemia on the testicular function were studied in adult rats. Bromocriptine treatment (1500 micrograms/day for 24 days) reduced serum and pituitary Prolactin levels, indicating a decrease in prolactin secretion and synthesis. No change in reproductive organ weights was seen in treated animals. Hypoprolactinemia had no effect on plasma testosterone or androstenedione levels and testicular androstenedione content, but decreased significantly testicular testosterone content. These findings indicated that experimental hypoprolactinemia induced a decrease in testicular testosterone content without affecting androgens levels.

A method for frequent sampling of blood and injections of fluids in undisturbed rats is described. The right external jugular vein and the left carotid artery are cannulated without completely blood stream interruption in the vessel. Injection or perfusion can be performed during several weeks. Blood was collected for at least 15 post-operative days. The technique appears suitable for pituitary kinetics studies which can be carried out several times in rats bearing indwelling catheters.

Female rats were exposed to a short (6 L: 18 D) photoperiod from 21 days of age. On day 2 of gestation, animals were pinealectomized sham-operated. Lighting regimens were not changed during the course of the study. Male offspring of the 2 groups of rats were sacrificed on days 30, 42 and 49 after birth. Pinealectomy of the mother induced the following modifications: in 30-day-old offsprings, a decrease in prostatic weight and plasma dihydrotestosterone level; in 42-day-old rats, a decrease in prostatic weight, in testicular androstenedione and dihydrotestosterone content, and in plasma testosterone and dihydrotestosterone levels; in 49-day-old animals, decreased testicular and plasma testosterone and dihydrotestosterone levels. These results indicate that rat testicular function, after exposure to a short photoperiod beginning before conception, is decreased by maternal pinealectomy. The mother's pineal gland may play a part in the control of rat testicular function.

In a previous study we showed that there were no differences in anaerobic metabolism between groups of 11-yr-old children living at high (3,700 m) and low (330 m) altitudes. The aim of this study is to investigate changes in this metabolism during pubertal development. We compare blood lactate concentration ([L]) after maximal bicycle exercise in 20 boys acclimatized to high altitude (HA, 12 yr old) and at low altitude in 14 boys (LA1, 12 yr old) and in 13 boys (LA2, 14 yr old). The subjects had the same level of physical fitness and the same nutritional and socioeconomic status. Pubertal development was identified by salivary testosterone concentration ([T]). Results (means +/- SE) showed 1) at the age of 12 years, [L] and [T] in HA were significantly higher than in LA1 ([L] was 9.2 +/- 0.5 vs. 6.8 +/- 0.5 mmol/l, [T] was 233 +/- 66 vs. 132 +/- 30 pmol/l), 2) [L] and [T] in HA were statistically the same as in LA2, and 3) a linear relationship between [L] and [T] was significant (P less than 0.05) in all HA and LA subjects. This suggests that the higher [L] in 12-yr-old boys living at HA could result in an enhanced anaerobic metabolism linked to an earlier gonadal maturation evaluated by testosterone level.

The direct effect of increasing doses of melatonin (10(-8) to 10(-5) M) on testosterone production by superfused rat interstitial cells was studied. A constant basal testosterone output was observed for approximately 3 h after the initial high release. A continuous hypothalamo-pituitary stimulation induced a rapid testosterone response reaching peak values in 40-60 min, then decreasing progressively. Basal testosterone release was not modified by 20 or 140 min melatonin infusions. Furthermore, melatonin induced no alteration of the stimulative testosterone response when directly infusing the cells. This study demonstrates that melatonin in vitro has no direct effect on testosterone production by adult rat interstitial cells. It would seem, therefore, that the well known inhibitory influence of melatonin on rat reproductive function is not produced by a direct effect on Leydig cells.

Pinealectomy was performed on rat foetuses aged 16.5 days +/- 8 h. Sham-pinealectomized animals were bred under the same conditions. Animals were killed when 50 or 64-days old. Plasma LH response to Gn-RH (100 ng via carotid artery) was studied in undisturbed adult male rats. 1. Body weight at birth was higher in pinealectomized rats than in sham-pinealectomized animals but, in 50 or 64-day-old body weights were not different. 2. In 50-day-old pinealectomized rats, absolute weights of testis and epididymis were higher than in sham-pinealectomized animals. When organ weights were compared to body weight by analysis of covariance, only the epididymis weight was enhanced by pinealectomy. 3. In 64-day-old animals, foetal pinealectomy did not increase reproductive organ weights. In contrast, prostate weight was decreased after pineal removal. 4. Plasma and pituitary gonadotropins were not modified by foetal pinealectomy. In undisturbed adult male rats, the plasma LH response to Gn-RH administration was identical in pinealectomized rats and in sham-pinealectomized animals. These findings may suggest an inhibitory effect of the pineal and foetal growth, but foetal pinealectomy exerts no gonadal stimulation in the adult male rats.

In the mouse, the autosomal reciprocal translocation T (7; 19) 145 H caused complete male sterility. The spermatogenesis was arrested at prophase or early metaphase I stages during the first meiotic division. The exocrine and endocrine testicular functions of azoospermic males (T 145 H/+) were compared with those of normal male littermates (+/+) at 63 days of age. Testis and epididymis weights in T 145 H/+ were significantly lower than those in +/+. By histological examination, the interstitial cells appeared preponderant but this was probably illusory due to the decrease in seminiferous tubular size and diminished testicular size. Moreover, androgen activity in T 145 H/+ seemed normal judging by weights of androgen target tissues (prostate, seminal vesicles), and plasma testosterone level.

Testis weight, ventral prostate weight, plasma gonadotropins and testosterone and testicular LH receptors were assessed throughout sexual maturation in the 23 to 84 day old rat. Intact, sham-operated and cryptorchid rats (operated at day 21) were studied. In the intact rats, plasma FSH rose to a peak at day 33, and fell to a plateau from day 50 throughout adult life. Plasma LH showed a sharp peak at day 42. Testis LH receptor content increased continually with age, reaching a plateau at day 49, but there was no change in the affinity constant (Ka = 2.4 +/- 0.5 X 10(10) M-1) measured at four time intervals. These observations suggested that the peak of FSH initiated an increase in testicular LH receptors, and that the LH peak enhanced it. In the cryptorchid rats, FSH showed a maximum between days 30 and 40. After day 33, FSH was higher in the cryptorchid rats than in the controls. The pattern of plasma LH was different in controls and cryptorchids; in the latter group, LH was often higher than in the controls. Testicular LH receptors increased continually between days 23 and 84, but Ka remained constant (Ka = 2.2 +/- 0.9 X 10(10) M-1) during that period. When compared with the control rats, the cryptorchid animals showed an increased concentration of testicular LH receptors at day 84, but this concentration decreased at days 35, 49 and 84; plasma testosterone also declined at days 23 and 49. These data suggested that the Leydig cell function of the cryptorchid rats was altered.