Vascular ATGL-dependent lipolysis and the activation of cPLA2-PGI2 pathway protect against postprandial endothelial dysfunction.

Adipose triglyceride lipase (ATGL) is involved in lipolysis and displays a detrimental pathophysiological role in cardio-metabolic diseases. However, the organo-protective effects of ATGL-induced lipolysis were also suggested. The aim of this work was to characterize the function of lipid droplets (LDs) and ATGL-induced lipolysis in the regulation of endothelial function. ATGL-dependent LDs hydrolysis and cytosolic phospholipase A2 (cPLA2)-derived eicosanoids production were studied in the aorta, endothelial and smooth muscle cells exposed to exogenous oleic acid (OA) or arachidonic acid (AA). Functional effects of ATGL-dependent lipolysis and subsequent activation of cPLA2/PGI2 pathway were also studied in vivo in relation to postprandial endothelial dysfunction.The formation of LDs was invariably associated with elevated production of endogenous AA-derived prostacyclin (PGI2). In the presence of the inhibitor of ATGL or the inhibitor of cytosolic phospholipase A2, the production of eicosanoids was reduced, with a concomitant increase in the number of LDs. OA administration impaired endothelial barrier integrity in vitro that was further impaired if OA was given together with ATGL inhibitor. Importantly, in vivo, olive oil induced postprandial endothelial dysfunction that was significantly deteriorated by ATGL inhibition, cPLA2 inhibition or by prostacyclin (IP) receptor blockade.In summary, vascular LDs formation induced by exogenous AA or OA was associated with ATGL- and cPLA2-dependent PGI2 production from endogenous AA. The inhibition of ATGL resulted in an impairment of endothelial barrier function in vitro. The inhibition of ATGL-cPLA2-PGI2 dependent pathway resulted in the deterioration of endothelial function upon exposure to olive oil in vivo. In conclusion, vascular ATGL-cPLA2-PGI2 dependent pathway activated by lipid overload and linked to LDs formation in endothelium and smooth muscle cells has a vasoprotective role by counterbalancing detrimental effects of lipid overload on endothelial function.

Recovery after long-term summer drought: Hydraulic measurements reveal legacy effects in trunks of Picea abies but not in Fagus sylvatica.

Climate change is expected to increase the frequency and intensity of summer droughts. Sufficient drought resistance, the ability to acclimate to and/or recover after drought, is thus crucial for forest tree species. However, studies on the hydraulics of mature trees during and after drought in natura are scarce. In this study, we analysed trunk water content (electrical resistivity: ER) and further hydraulic (water potential, sap flow density, specific hydraulic conductivity, vulnerability to embolism) as well as wood anatomical traits (tree ring width, conduit diameter, conduit wall reinforcement) of drought-stressed (artificially induced summer drought via throughfall-exclusion) and unstressed Picea abies and Fagus sylvatica trees. In P. abies, ER indicated a strong reduction in trunk water content after 5 years of summer drought, corresponding to significantly lower pre-dawn leaf water potential and xylem sap flow density. Vulnerability to embolism tended to be higher in drought-stressed trees. In F. sylvatica, only small differences between drought-stressed and control trees were observed. Re-watering led to a rapid increase in water potentials and xylem sap flow of both drought-stressed trees, and to increased growth rates in the next growing season. ER analyses revealed lower trunk water content in P. abies trees growing on throughfall-exclusion plots even 1 year after re-watering, indicating a limited capacity to restore internal water reserves. Results demonstrated that P. abies is more susceptible to recurrent summer drought than F. sylvatica, and can exhibit long-lasting and pronounced legacy effects in trunk water reserves.

Retinal layers thickness changes following epiretinal membrane surgery.

PurposeTo evaluate the time course of changes in the thickness of retinal layers after epiretinal membrane (ERM) removal surgery.MethodsA retrospective cohort study of patients following surgery for idiopathic ERM. We used new specialized image analysis software to create a thickness map of each retinal layer and analyzed changes during one year follow-up. Healthy fellow eyes were used as negative controls and the retina prior to surgery as positive control.ResultsTwenty-one patients were included with a mean age of 68±13 years. Central macular thickness decreased steadily until 6 months after surgery (25% decrease, 516±76 to 386±73 µm, P<0.001) with no further decrease between 6 and 12 months (386±73 to 390±73 µm, P=0.291). The retinal nerve fiber layer (RNFL), and the ganglion cell and inner plexiform layer (GCIPL) were most affected (57%, P<0.001 and 27%, P=0.010, respectively). The thickest region showed a more abrupt decrease of 21% at first follow-up (504±61 to 399±58 µm, P=0.001) with subsequent decrements of about 3%. Prior to surgery all retinal layers were thicker in study eyes compared with healthy control eyes (6-63%, all P<0.05).ConclusionsFollowing ERM surgery, in the course of 6 months, the macula gradually becomes thinner after which a stable state is reached. All layers appear to be affected, with the RNFL and GCIPL impacted the most. Our results provide a unique view on how the thickness of different retinal layers changes following ERM surgery.

Valence fluctuation and magnetic ordering in EuNi2(P(1-x)Ge(x))2 single crystals.

Unusual phases and phase transitions are seen at the magnetic-nonmagnetic boundary in Ce-, Eu- and Yb-based compounds. EuNi2P2 is a very unusual valence fluctuating Eu system, because at low temperatures the Eu valence stays close to 2.5 instead of approaching an integer value. The Eu valence, and thus the magnetic property in this system, can be tuned by Ge substitution in the P site as EuNi2Ge2 is known to exhibit the antiferromagnetc (AFM) ordering of divalent Eu moments with T(N)=30K. We have grown EuNi2(P(1-x)Ge(x))2 (0.0≤ x ≤0.5)) single crystals and studied their magnetic, thermodynamic and transport properties. Increasing Ge doping to x > 0.4 results in a well-defined AFM ordered state with T(N)=12K for x = 0.5. Moreover, the reduced value of magnetic entropy for x = 0.5 at T(N) suggests the presence of valance fluctuation/the Kondo effect in this compound. Interestingly, the specific heat exhibits an enhanced Sommerfeld coefficient upon Ge doping. Subsequently, electronic structure calculations lead to a non-integral valence in EuNi2P2 but a stable divalent Eu state in EuNi2Ge2, which is in good agreement with the experimental results.

Empowerment and satisfaction in a multinational study of routine clinical practice.

OBJECTIVE: Decision-making between mental health clinicians and patients is under-researched. We tested whether mental health patients are more satisfied with a decision made (i) using their preferred decision-making style and (ii) with a clinician with the same decision-making style preference. METHOD: As part of the CEDAR Study (ISRCTN75841675), a convenience sample of 445 patients with severe mental illness from six European countries were assessed for desired clinical decision-making style (rated by patients and paired clinicians), decision-specific experienced style and satisfaction. RESULTS: Patients who experienced more involvement in decision-making than they desired rated higher satisfaction (OR=2.47, P=0.005, 95% CI 1.32-4.63). Decisions made with clinicians whose decision-making style preference was for more active involvement than the patient preference were rated with higher satisfaction (OR=3.17, P=0.003, 95% CI 1.48-6.82). CONCLUSION: More active involvement in decision-making than the patient stated as desired was associated with higher satisfaction. A clinical orientation towards empowering, rather than shared, decision-making may maximise satisfaction.

ANSO study: evaluation in an indoor environment of a mobile assistance robotic grasping arm.

OBJECTIVE: To evaluate the reliability and functional acceptability of the ''Synthetic Autonomous Majordomo'' (SAM) robotic aid system (a mobile Neobotix base equipped with a semi-automatic vision interface and a Manus robotic arm). MATERIALS AND METHODS: An open, multicentre, controlled study. We included 29 tetraplegic patients (23 patients with spinal cord injuries, 3 with locked-in syndrome and 4 with other disorders; mean SD age: 37.83 13.3) and 34 control participants (mean SD age: 32.44 11.2). The reliability of the user interface was evaluated in three multi-step scenarios: selection of the room in which the object to be retrieved was located (in the presence or absence of visual control by the user), selection of the object to be retrieved, the grasping of the object itself and the robot's return to the user with the object. A questionnaire was used to assess the robot's user acceptability. RESULTS: The SAM system was stable and reliable: both patients and control participants experienced few failures when completing the various stages of the scenarios. The graphic interface was effective for selecting and grasping the object ­ even in the absence of visual control. Users and carers were generally satisfied with SAM, although only a quarter of patients said that they would consider using the robot in their activities of daily living.

Assessment of hospital disaster plans for conventional mass casualty incidents following terrorist explosions using a live exercise based upon the real data of actual patients.

PURPOSE: The National Committee for Hospital Preparedness for Conventional Mass Casualty Incidents and the Hospital Preparedness Division of the Home Front Command are in charge of preparing live exercises held yearly in public hospitals in Israel. Our experience is that live exercises are limited in their ability to test clinical decision making and its influence upon incident management. A live exercise was designed upon real patient data and tested in several public hospitals. The aim of the manuscript is to describe the impact of this new format on clinical decision making in large-scale live exercises. METHODS: A database of histories, physical examination findings, laboratory results and imaging results for 420 patients treated following terrorist explosions was created using information derived from actual patient encounters. Similar information for 100 patients treated following motor vehicle accidents was also collected. Information from the database was used to create victim profiles used during the course of exercises held in eight public hospitals with 60-800-bed capacities. RESULTS: Before implementing the new injury tags, no conclusions could be made concerning the quality of clinical decision making. Conducting the exercise using the new format helped identify deficiencies in the hospital disaster plan in triage, emergency department management and in the proper utilisation of resources such as radiology, operating rooms and the secondary transfer of patients. CONCLUSION: Previous knowledge of patient diagnoses and resource needs allow the identification and quantification of deficiencies and problems identified in clinical decision making, resource utilisation and incident management.

In search of a standardized treatment for poststernotomy mediastinitis.

Poststernotomy mediastinitis following median sternotomy procedures such as open heart surgery is a rare complication which nevertheless has a mortality rate of up to 50 %. Several treatment options are currently available; however, none of them are standardized. Based on the experience gained from open heart surgery performed at the MediClin Heart Institute Lahr/Baden, a therapeutic algorithm was developed. The treatment steps consist of repeated radical surgical debridement, sternal restabilization, vacuum-assisted closure therapy (VAC) as well as a surgical reconstruction via M. pectoralis plasty (MPP). This approach had a 30-day mortality of 0 % and a hospital mortality of 10.4 %. The approach proved to be safe and advantageous for specific patient groups operated on at the MediClin Heart Institute Lahr/Baden.

Immune-mediated encephalitis and virilization in association with a mature cystic ovarian teratoma in an adolescent girl.

BACKGROUND: Mature cystic teratomas are the most common form of ovarian tumor in children and adolescents. These tumors are mostly benign and non-secreting. Virilization from an ovarian teratoma is exceptionally rare in pediatrics. Equally rare is the association of ovarian teratomas with auto-immune encephalitis. METHODS: We describe the case of a 15-year-old girl with menstrual abnormalities and virilization, who had a past medical history of encephalitis of an unknown etiology 16 months prior to presentation. RESULTS: Endocrine evaluation revealed an elevated serum testosterone and 17-hydroxy progesterone. A large left ovarian tumor was seen on a CT scan. Surgical excision revealed a mature cystic teratoma containing 6 liters of clear fluid with high androgen levels. Antibodies to the N-methyl-D-aspartate receptor of the hippocampus were detected in pre-operatively archived serum, but undetectable 6 months postoperatively. Immunohistochemistry studies on the tumor sections revealed that the antibodies in the patient's serum reacted with areas of the tumor expressing the N-methyl-D-aspartate receptor. Postoperatively, the patient's menstrual cycles became regular and her behavioral problems resolved. Her testosterone levels fell precipitously as well. CONCLUSION: Both virilizing mature cystic teratomas and teratoma-associated encephalitis are extremely rare in the pediatric population. We report on the first instance of these 2 rare entities occurring in the same patient.

Dynamics of DNA melting.

The dynamics of loops at the DNA denaturation transition is studied. A scaling argument is used to evaluate the asymptotic behavior of the autocorrelation function of the state of complementary bases (either open or closed). The long-time asymptotic behavior of the autocorrelation function is expressed in terms of the entropy exponent, c, of a loop. The validity of the scaling argument is tested using a microscopic model of an isolated loop and a toy model of interacting loops. This suggests a method for measuring the entropy exponent using single-molecule experiments such as fluorescence correlation spectroscopy.

Nasal respiratory support in premature infants: short-term physiological effects and comfort assessment.

AIM: To evaluate the effects of nasal respiratory support on physiologic parameters and comfort of premature infants, when compared to spontaneous breathing without nasal respiratory support. METHODS: This was a prospective, randomized, controlled, cross-over clinical study. Infants were enrolled into the study when in 'stable' condition (when discontinuation of nasal respiratory support was considered appropriate). Infants were randomized to receive first 3 h of nasal respiratory support (nasal continuous positive airway pressure or nasal intermittent mandatory ventilation) or to spontaneous breathing, and then were crossed-over to the other assignment. Each infant served as his own control. RESULTS: Fifty-four infants were included in the study (birth-weight: 1528 +/- 545 g; gestational age: 30.5 +/- 2.7 weeks). Average values of systolic, diastolic and mean blood pressure and discomfort score were significantly higher while respiratory rate was significantly slower on nasal respiratory support compared to spontaneous breathing. Heart rate was comparable on both modes. CONCLUSIONS: Nasal respiratory support in 'stable' premature infants is associated with increased blood pressure and increased discomfort, despite a decreased respiratory rate. The clinical importance of these effects is modest. Medical teams should consider these effects and balance its need with its adverse effects according to the clinical condition.

Loop dynamics in DNA denaturation.

The dynamics of a loop in DNA molecules at the denaturation transition is studied by scaling arguments and numerical simulations. The autocorrelation function of the state of complementary bases (either closed or open) is calculated. The long-time decay of the autocorrelation function is expressed in terms of the loop exponent c both for homopolymers and heteropolymers. This suggests an experimental method for measuring the exponent c using florescence correlation spectroscopy.

Embryotoxicity and teratogenicity study with neohesperidin dihydrochalcone in rats.

The embryotoxicity/teratogenicity of neohesperidin dihydrochalcone (NHDC) was examined in Wistar Crl:(WI)WU BR rats. NHDC was fed at dietary concentrations of 0, 1.25, 2.5 or 5 to groups of 28 mated female rats from day 0 to 21 of gestation. At Cesarean section 25, 22, 23, and 23 rats were found to be pregnant in the control, low-, mid-, and high-dose group, respectively. The NHDC treatment was well tolerated and all animals survived till the end of the study. Body weights (bw) and body weight gains did not differ between controls and NHDC treatment groups. The intake of NHDC was 0.8-0.9, 1.6-1.7, and 3.1-3.4 g/kg bw/day for the low-, mid-, and high-dose group, respectively. Except for cecal enlargement, there were no changes observed at necropsy which could be related to the NHDC treatment. All dams had viable fetuses. The fecundity and gestation index, the number of corpora lutea, implantation sites, live and dead fetuses, early and late resorptions, pre- and post-implantation losses, and sex-ratio were not affected by the treatment. There were no differences for the mean weight of the gravid and empty uterus, ovaries, and placenta between the NHDC treatment groups and the controls. Examination of the fetuses for external, visceral, and skeletal changes did not reveal any fetotoxic, embryotoxic or teratogenic effects of NHDC. In conclusion, no adverse effects were observed at NHDC levels of up to 5% of the diet, the highest dose level tested, at which the rats consumed about 3.3g/kg body weight/day. The observed cecal enlargement is a well-known physiological, adaptive response to the ingestion of high doses of a low-digestible substance and is generally accepted to lack toxicological relevance.

Safety assessment of gamma-cyclodextrin.

Gamma-cyclodextrin (gamma-CD) is a cyclic alpha-(1,4)-linked oligosaccharide consisting of eight glucose molecules. Like other cyclodextrins, gamma-CD can form inclusion complexes with a variety of organic molecules because the inner side of the torus-like molecule is less polar than the outer side. In foods, gamma-CD may be used as a carrier for flavors, vitamins, polyunsaturated fatty acids, and other ingredients. It also has useful properties as a stabilizer in different food systems. The daily intake from all its intended uses in food at highest feasible concentrations has been estimated at 4.1g/person/day for consumers of gamma-CD containing foods. The present review summarizes the safety data of gamma-CD. The toxicity studies consist of standard genotoxicity tests, subchronic rat studies with oral and intravenous administration of gamma-CD for up to 3 months, a subchronic (3-month) toxicity study in dogs, a (1-year) oral toxicity study in rats, and embryotoxicity/teratogenicity studies in rats and rabbits. In the studies with oral administration, gamma-CD was given at dietary concentrations of up to 20%. All these studies demonstrated that gamma-CD is well tolerated and elicits no toxicological effects. Metabolic studies in rats showed that gamma-CD is rapidly and essentially completely digested by salivary and pancreatic amylase. Therefore, the metabolism of gamma-CD closely resembles that of starch and linear dextrins. A human study with ingestion of single doses of 8 g gamma-CD or 8 g maltodextrin did not reveal a difference in gastrointestinal tolerance of these two products. An interaction of ingested gamma-CD with the absorption of fat-soluble vitamins or other lipophilic nutrients is not to be expected because the formation of inclusion complexes is a reversible process, gamma-CD is readily digested in the small intestine, and studies with beta-CD, a non-digestible cyclodextrin, have shown that the bioavailability of vitamins (A, D, and E) is not impaired. On basis of these studies it is concluded that gamma-CD is generally recognized as safe (GRAS) for its intended uses in food.

Subchronic oral toxicity studies with alpha-cyclodextrin in rats.

The toxicity of alpha-cyclodextrin (alpha-CD), a cyclic polymer of six alpha-1,4-linked glucopyranosyl units with potential applications as a food ingredient, more specifically a water-soluble dietary fiber, was examined in a 4-week range finding study and a 13-week oral toxicity study in rats. In the 4-week study, the test substance was administered to groups of Bor:WISW(SPF;Cpb) rats at dietary levels of 0, 1, 5, and 15% (5 rats/sex/group). An additional group received a diet with 5% beta-CD. In the 13-week study, groups of Crl:(WI)WU Br rats received diets with 0, 1.5, 5, or 20% alpha-CD. An additional group received a diet with 20% lactose (20 rats/sex/group). Satellite groups of 10 rats/sex were attached to the control, 20% alpha-CD and 20% lactose group. Following the 13-week treatment period, these satellite groups were kept on a standard, cereal-based rodent diet for a 4-week recovery period. Parameters measured during the two studies included clinical signs, body weights, food and water intake, hematological and clinicochemical parameters, and organ weights as well as gross and histopathological observations at necropsy. In the 13-week study, ophthalmoscopic examinations as well as urine and feces analyses were also conducted. There were no treatment-related mortalities in either study. In the 4-week study, persistent diarrhea was the most prominent, treatment-related effect observed in the animals of the 15% alpha-CD group especially in the male animals. In association with this effect, food consumption and food conversion efficiency were decreased. In line with observations from studies with other low-digestible, yet fermentable carbohydrates, the weight of the full and empty cecum was increased significantly in the 5% alpha-CD, 5% beta-CD, and 15% alpha-CD group. The reduced relative liver weights (in males and females) and the significantly increased relative testes weight which were observed in the 15% alpha-CD group, were attributed to the impaired nutritional condition (due to diarrhea) and the reduced body weight of the animals of this group, respectively. Microscopic examination of the main organs did not reveal pathological alterations that could be attributed to the alpha-CD treatment. In the 13-week study, soft stool and infrequent mild diarrhea were observed only during the first 2-3 weeks in the 20% alpha-CD and 20% lactose group (mainly male animals). Accordingly, body weights were reduced in males of the 20% lactose group throughout the study and in the 20% alpha-CD group during the last week of the study. Food intakes were slightly increased in the 20% alpha-CD group and the food conversion efficiency, was significantly reduced in males, but not females, of the 20% alpha-CD and 20% lactose group. There were no treatment-related changes of hematological parameters. In line with similar observations from studies on other low-digestible carbohydrates, the urinary pH was decreased and urinary calcium levels increased in the 20% alpha-CD and 20% lactose group. Similarly, the fecal dry weight and nitrogen output was increased in these groups. At termination of the treatment, significantly in creased cecum weights (full and empty) were observed in the 5 and 20% alpha-CD groups and the 20% lactose group. The relative (not absolute) weight of the spleen was significantly increased in males of the 20% alpha-CD group. In the 20% lactose group, the relative weights of the spleen and liver (females) and the testes, brain, and adrenals (males) were significantly increased. The histopathological examination of these and all other organs and tissues did not reveal any abnormalities that could be attributed to the alpha-CD or lactose treatment. In conclusion, the ingestion of alpha-CD for 13-weeks at dietary levels of up to 20% (corresponding to intakes of 12.6 and 13.9 g/kg bodyweight/d in male and female rats, respectively) did not produce any signs of toxicity or adverse effects.

Subchronic (13-week) oral toxicity study of alpha-cyclodextrin in dogs.

The oral toxicity of alpha-cyclodextrin (alpha-CD) was examined in a 13-week feeding study in which groups of Beagle dogs received alpha-CD in the diet at concentrations of 0 (control), 5, 10, or 20% (4 dogs/sex/group). No treatment-related changes were noted in behavior or appearance of the dogs and no mortalities occurred. Diarrhea occurred in all alpha-CD groups. The incidence and severity of diarrhea increased with increasing dietary levels of alpha-CD and was more pronounced in males than females. Nonetheless, all dogs remained in good health and gained weight. Food intake was slightly increased and food efficiency was slightly decreased in the 20% alpha-CD group. However, these changes did not reach statistical significance. No treatment-related differences were observed with respect to ophthalmoscopic examinations, hematological parameters, clinicochemical analyses of the plasma, and semiquantitative urine analyses. Only the urinary pH was slightly below control levels in males (p > 0.05) and females (p < 0.05) of the 20% alpha-CD group. No abnormalities were seen at necropsy that could be attributed to the treatment. The organ weight data revealed cecal enlargement in the 10 and 20% alpha-CD groups (significant only in males). The relative weight of the colon was also slightly increased in the 10 and 20% alpha-CD groups (significant only in females of the 10% alpha-CD group). On microscopic examination, no treatment-related alterations were observed in any of the various organs and tissues. In conclusion, transient diarrhoea, enlargement of the cecum and colon and a slightly increased acidity of the urine were the only treatment-related effects. These changes are well-known physiological responses to the presence of high amounts of not digested, fermentable carbohydrates in the lower gut. They are known to be reversible on cessation of the treatment and are not associated with histological alterations of the intestinal tissues. It is concluded, therefore, that the high dose level, at which the male and female dogs consumed about 9.8 and 10.4 g alpha-CD/kg bw/d, respectively, is the NOAEL of this 13-week toxicity study.

Embryotoxicity and teratogenicity study with alpha-cyclodextrin in rats.

The embryotoxicity/teratogenicity of alpha-cyclodextrin (alpha-CD) was examined in Wistar Crl:(WI)WU BR rats. alpha-CD was fed at dietary concentrations of 0, 1.5, 5, 10, or 20% to groups of 25 pregnant female rats from day 0 to 21 of gestation. An additional group received a diet with 20% lactose. The additions to the diet of alpha-CD and lactose were made at the expense of pregelatinized potato starch. Body weight as well as food and water intake were recorded during the treatment period. The rats were killed on day 21 and examined for standard parameters of maternal reproductive performance. The fetuses were examined for external abnormalities, body weight and crown rump length. Fetuses were examined for skeletal and visceral abnormalities. Generally, alpha-CD was well tolerated and no deaths occurred in any group. Weight gain and food consumption were similar in all groups during gestation, except for a slightly yet significantly increased food intake in the 20% alpha-CD group from day 6 to 21. Water intake was similar in all alpha-CD groups; in the lactose group, it was significantly higher than in the controls. Maternal reproductive performance was not affected by the alpha-CD treatment. Examination of the fetuses for external, visceral and skeletal changes did not reveal any fetotoxic, embryotoxic, or teratogenic effects of alpha-CD. In conclusion, no adverse effects were observed at alpha-CD intakes of up to 20% of the diet, the highest dose level tested at which the rats consumed about 13 g/kg bw/day.

Embryotoxicity and teratogenicity study with alpha-cyclodextrin in rabbits.

In a standard embryotoxicity/teratogenicity study, alpha-cyclodextrin (alpha-CD) was administered to groups of sixteen, artificially inseminated New Zealand White rabbits at dietary concentrations of 0, 5, 10, or 20%. An additional group received a diet containing 20% lactose. Treatment started on day 0 of gestation and ended on day 29 when the animals were killed. Except for the occurrence of transient diarrhoea in one rabbit of the 20% alpha-CD group for a few days, the treatment was well tolerated. A reduced food intake in the 20% alpha-CD group during the first week of treatment resulted in a reduced weight gain from day 0 to 12 of the study. However, the difference to the controls was not significant and at termination of the study body weights were similar in all groups. Even at the highest dose level, which corresponds to an intake of 5.9-7.5 g/kg bw/day, no signs of maternal toxicity were observed. Maternal reproductive performance was not affected by the treatment. Uterine weight, placental weight, fetal weight, number of fetuses, sex ratio, number of implanation sites, resorptions, and corpora lutea did not differ among the groups. Visceral and skeletal examinations of the fetuses did not reveal any malformations, anomalies or variations that could be attributed to treatment. It was concluded that dietary alpha-CD is generally well tolerated by pregnant rabbits, has no adverse effect on maternal reproductive performance and is not embryotoxic, fetotoxic, or teratogenic at dietary concentrations of up to 20%, the highest dose level tested.

Disposition of 14C-alpha-cyclodextrin in germ-free and conventional rats.

The absorption, disposition, metabolism, and excretion of uniformly (14)C-labeled alpha-cyclodextrin ((14)C-alpha-CD) was examined in four separate experiments with Wistar rats. In Experiment 1, (14)C-alpha-CD (25 microCi, 50 mg/kg bw) was administered intravenously to four male and four female conventional rats. In Experiment 2, (14)C-alpha-CD (25 microCi, 200 mg/kg bw) was given by gavage to four male and four female germ-free rats. In Experiments 3 and 4, (14)C-alpha-CD was given to groups of four male and four female conventional rats by gavage at different dose levels (100 microCi, 200 mg/kg bw; 25 microCi, 200 and 100 mg/kg bw). In all experiments, (14)C was measured in respiratory CO(2), urine, and feces over periods of 24-48 h, and in the contents of the gastrointestinal tract, blood, main organs, and residual carcass at termination of the experiments. The chemical identity of the (14)C-labeled compounds was examined by HPLC in blood (Experiment 1), urine (Experiments 1-4), feces (Experiments 2-4), and samples of intestinal contents (Experiments 2 and 4). Recovered (14)C was expressed as percentage of the administered dose. Experiment 1 showed that intravenously administered alpha-CD is excreted rapidly with urine. During the first 2h after dosing, plasma (14)C levels decreased rapidly (t(1/2), 26 and 21 min in male and female rats, respectively). About 13% of the administered (14)C dose (range 4.6-30.6) was detected in the feces, respiratory CO(2), organs, and carcass at the end of the experiment, i.e., 24 h after dosing. The presence of about 1.9% in the intestinal contents and feces suggests that a certain fraction of systemic alpha-CD is eliminated with the bile or saliva. Conclusive evidence, either positive or negative, for a hydrolysis and further metabolism of a small fraction of the administered alpha-CD by the enzymes of the mammalian body could not be gained from this experiment. Upon oral administration of (14)C-alpha-CD to germ-free rats (Experiment 2), about 1.3% of the label expired as CO(2) within 24 h. In the urine collected from 0 to 8 h after dosing, (14)C-alpha-CD was the only radiolabeled compound detected. The amounts of alpha-CD detected in the urine suggest that on average about 1% of an oral dose is absorbed in rats during small-intestinal passage. In conventional rats (Experiments 3 and 4), a delayed appearance of respiratory (14)CO(2) was observed which is attributed to the non-digestibility of alpha-CD and its subsequent microbial fermentation in the cecum and colon. In the urine collected at 4 h after dosing, a small amount of unchanged (14)C-alpha-CD was detected which confirms that about 1% of the ingested alpha-CD is absorbed intact and is excreted via the kidneys. No (14)C-alpha-CD was found in the feces. It is concluded from the data that ingested (14)C-alpha-CD is not digested in the small intestine of rats but is fermented completely by the intestinal microbiota to absorbable short-chain fatty acids. Therefore, the metabolism of alpha-CD resembles closely that of resistant starch or other fermentable dietary fibers.