Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodents

We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N′,N′-dimethyl-urea), a D₃/D₂ dopamine receptor partial agonist with ∼10-fold preference for the D₃ receptor. Oral bioavailability of cariprazine at a dose of 1 mg/kg in rats was 52% with peak plasma concentrations of 91 ng/mL. Cariprazine 10 mg/kg had good blood-brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of [³H](+)-PHNO, a dopamine D₃ receptor-preferring radiotracer, in the D₃ receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED₅₀ = 0.27 mg/kg) was sustained for 8 h. Cariprazine blocked amphetamine-induced hyperactivity (ED₅₀ = 0.12 mg/kg) and conditioned avoidance response (CAR) (ED₅₀ = 0.84 mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED₅₀ = 0.049 mg/kg) and phencyclidine (ED₅₀ = 0.09 mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED₅₀ = 0.11 mg/kg) and rats (ED₅₀ = 0.18 mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED₅₀ value. Cariprazine 0.02-0.08 mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D₃ receptors versus currently marketed typical and atypical antipsychotics.     

13N as a tracer for studying glutamate metabolism

This mini-review summarizes studies my associates and I carried out that are relevant to the topic of the present volume [i.e. glutamate dehydrogenase (GDH)] using radioactive ¹³N (t_1/2 9.96 min) as a biological tracer. These studies revealed the previously unrecognized rapidity with which nitrogen is exchanged among certain metabolites in vivo. For example, our work demonstrated that (a) the t_1/2 for conversion of portal vein ammonia to urea in the rat liver is ∼10-11 s, despite the need for five enzyme-catalyzed steps and two mitochondrial transport steps, (b) the residence time for ammonia in the blood of anesthetized rats is ≤7-8 s, (c) the t_1/2 for incorporation of blood-borne ammonia into glutamine in the normal rat brain is <3 s, and (d) equilibration between glutamate and aspartate nitrogen in rat liver is extremely rapid (seconds), a reflection of the fact that the components of the hepatic aspartate aminotransferase reaction are in thermodynamic equilibrium. Our work emphasizes the importance of the GDH reaction in rat liver as a conduit for dissimilating or assimilating ammonia as needed. In contrast, our work shows that the GDH reaction in rat brain appears to operate mostly in the direction of ammonia production (dissimilation). The importance of the GDH reaction as an endogenous source of ammonia in the brain and the relation of GDH to the brain glutamine cycle is discussed. Finally, our work integrates with the increasing use of positron emission tomography (PET) and nuclear magnetic resonance (NMR) to study brain ammonia uptake and brain glutamine, respectively, in normal individuals and in patients with liver disease or other diseases associated with hyperammonemia.     

Identification of a Passiflora alata Curtis dimeric peptide showing identity with 2S albumins

Antifungal proteins and peptides, essential compounds for plant defense, have been isolated from several tissues of various plants. These proteins could be used as a natural alternative to control phytopathogenic fungi. In this report a heterodimeric antifungal protein named Pa-AFP1, showing higher identity with the 2S albumin family, was purified by using 70-100% ammonium sulfate saturation and further purification steps such as anionic exchange Q-Sepharose chromatography associated with HPLC reversed-phase C4 chromatography. Analysis by Tricine-SDS-PAGE revealed two peptidic molecular masses of approximately 4500 Da and 7000 Da, in the presence of β-mercaptoethanol, while by removing the reducing agent a single protein with molecular mass of about 11,500 Da was obtained. Moreover, dimer mass was confirmed by MALDI-TOF analyses (11,569.76 Da). The antifungal protein, named Pa-AFP1, efficiently inhibited the growth of filamentous fungi Colletotrichum gloeosporioides, and was added to a short list of 2S albumins with antimicrobial properties. Otherwise, this same peptide showed no activity toward bacteria and yeasts. In summary, this compound could be used in the future to develop biotechnological products for the control of phytopathogenic fungi.     

Inhibitory effect of oral Lactobacillus against oral pathogens

Aims: To determine the inhibitory effect of oral Lactobacillus against putative oral pathogens. Methods and Results: Total 357 strains comprising 10 species of oral Lactobacillus, Lactobacillus fermentum (195), Lactobacillus salivarius (53), Lactobacillus casei (20), Lactobacillus gasseri (18), Lactobacillus rhamnosus (14), Lactobacillus paracasei (12), Lactobacillus mucosae (12), Lactobacillus oris (12), Lactobacillus plantarum (11) and Lactobacillus vaginalis (10) were used as producer strains. Inhibitory effect against a panel of indicators, periodontitis‐ and caries‐related pathogens, was assessed. Most oral Lactobacillus was able to inhibit the growth of both periodontitis‐ and caries‐related pathogens. The strongest inhibitory activity was associated with Lact. paracasei, Lact. plantarum, Lact. rhamnosus, Lact. casei and Lact. salivarius. Lactobacillus SD1–SD6, representing the six species with the strong inhibitory effect, inhibited growth of Streptococcus mutans ATCC 25175 in the biofilm model. Also, it was demonstrated that growth of Strep. mutans was inhibited in a mixture with Lact. paracasei SD1. The inhibition was enhanced in acidic condition and 5% glucose. Conclusions: The results have shown that oral Lactobacillus SD1–SD6 showed a strong inhibitory effect against Strep. mutans and Streptococcus sobrinus, as well as, Gram‐negative periodontal pathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. Significance and Impact of the Study: The results indicated that Lactobacillus may be of benefit as probiotics for the prevention of oral diseases.     

In vivo D2O labeling to quantify static and dynamic changes in cholesterol and cholesterol esters by high resolution LC/MS

High resolution LC/MS-MS and LC/APPI-MS methods have been established for the quantitation of flux in the turnover of cholesterol and cholesterol ester. Attention was directed toward quantifying the monoisotopic mass (M0) and that of the singly deuterated labeled (M+1) isotope. A good degree of isotopic dynamic range has been achieved by LC/MS-MS ranging from 3-4 orders of magnitude. Correlation between the linearity of GC/MS and LC atmospheric pressure photoionization (APPI)-MS are complimentary (r² = 0.9409). To prove the viability of this particular approach, male C57Bl/6 mice on either a high carbohydrate (HC) or a high fat (HF) diet were treated with ²H₂O for 96 h. Gene expression analysis showed an increase in the activity of stearoyl-CoA desaturase (Scd1) in the HC diet up to 69-fold (P < 0.0008) compared with the HF diet. This result was supported by the quantitative flux measurement of the isotopic incorporation of ²H into the respective cholesterol and cholesterol ester (CE) pools. We concluded that it is possible to readily obtain static and dynamic measurement of cholesterol and CEs in vivo by coupling novel LC/MS methods with stable isotope-based protocols.     

Serum LDL- and HDL-cholesterol determined by ultracentrifugation and HPLC

Simple and precise methods for LDL-cholesterol (LDL-C) and HDL-cholesterol (HDL-C) measurements are essential for assessment of cardiovascular disease (CVD) risks and for lipid and lipoprotein studies. We report here an ultracentrifugation (UC) and HPLC method that requires substantially less specimen volume and provides the necessary reliability and throughput required by large-volume, high-quality research and clinical studies. 2-Mercaptoethanol (ME) was used to dissociate serum lipoprotein [a] (Lp[a]) into apolipoprotein [a] and Lp[a] remnant (Lp[a-]) and eliminated the contamination of Lp[a] in HDL separated by UC. Serum aliquots were centrifuged at a density of 1.006 kg/l for the separation of HDL plus LDL, and in the presence of ME at a density of 1.063 kg/l for the separation of HDL. Cholesterol concentrations of the bottom fractions were analyzed by HPLC. LDL-C and HDL-C determined using this method were equivalent to those with β-quantification and the designated comparison method of the Centers for Disease Control. The total coefficient of variations for LDL-C and HDL-C were 0.65-1.12% and 0.96-2.07%, respectively. This method requires a small amount of specimen and is easy to operate. This method may be used in research or in clinical laboratories where precise and specific lipoprotein cholesterol analysis is needed.     

Different pathways are involved in the early development of the transient oral apparatus in anuran tadpoles (Anura: Leiuperidae)

The oral apparatus of anuran tadpoles is a unique structure composed of soft and keratinized parts surrounding the mouth. Among the many variations, a common oral apparatus involves a dorsal gap in the marginal papillae, keratinized jaw sheaths, and two upper and three lower rows of labial teeth. In Leiuperidae, besides this generalized morphology, four configurations are distinguished by the arrangement of the lower marginal papillae and the number of lower tooth rows. Study of the early oral ontogeny in 12 species representing these five configurations shows variations in the development of the lower marginal papillae and the third lower labial tooth row. Similar configurations may result from similar pathways (e.g. Physalaemus cuvieri group and Pseudopaludicola falcipes) or different pathways (e.g. generalized oral discs of Pleurodema and Physalaemus). Different oral configurations may result from overlapping trajectories ending at different stages (e.g. Physalaemus riograndensis and Ph. biligonigerus) or different trajectories (e.g. Ph. henselii and Ph. gracilis). Further studies are needed to interpret the role that heterochrony has played in evolutionary change within this family. The unsuspected variation occurring in this transient structure highlights its evolutionary potential and might be insightful in studies of anuran phylogenies that are largely based on adult characters. © 2011 The Linnean Society of London, Biological Journal of the Linnean Society, 2011, 104 , 330–345.     

Factors associated with the oral health-related quality of life in elderly persons in dental clinic: validation of a Mandarin Chinese version of GOHAI

Gerodontology 2011; doi: 10.1111/j.1741‐2358.2009.00360.x
Factors associated with the oral health‐related quality of life in elderly persons in dental clinic: validation of a Mandarin Chinese version of GOHAI Objectives: To translate the original English version of Geriatric Oral Health Assessment Index (GOHAI) into Mandarin Chinese and assess its reliability and validity for use among the elderly in inland China and to explore the factors associated with oral health‐related quality of life (OHRQoL). Methods: The original English version of GOHAI was translated, back‐translated and cross‐culturally adapted. The psychometric properties of GOHAI‐M were assessed in a sample of 263 people aged 60 years and over and OHRQoL was examined in 221 subjects using GOHAI‐M. Multiple regression analysis was conducted. Results: Internal consistency of the GOHAI‐M was excellent (Cronbach’s α : 0.81). Split‐half reliability coefficient was 0.80, and item‐scale correlation coefficient ranged from 0.25 to 0.71. Self‐rated oral health was significantly associated with OHRQoL (r_s = 0.505, p < 0.01). The relation coefficient between GOHAI‐M and self‐perceived need for dental treatment and number of missing teeth were 0.231 and ?0.653, respectively (p < 0.05). Multiple regression analysis found that better OHRQoL was significantly associated with better self‐ratings of oral health (β = 0.497, p = 0.01), number of missing teeth (β = 0.187, p < 0.01) and life satisfaction (β = 0.132, p < 0.05). Conclusion: The Mandarin Chinese version of GOHAI demonstrates acceptable reliability and validity. OHRQoL is associated with self‐rated oral health, number of missing teeth and satisfaction with life.     

An oral health care guideline for institutionalised older people

Institutionalized older people are prone to oral health problems and their negative impact due to frailty, disabilities, multi-morbidity, and multiple medication use. Until recently, no evidence-based oral health care guideline for institutionalized older people has been available. For that reason, the Dutch Association of Nursing Home Physicians developed the Oral health care Guideline for Older people in Long-term care Institutions (OGOLI), meeting the requirements of the AGREE instrument for assessing a guideline's quality. This short report presents the keynotes and the content of the Oral health care Guideline. Most recommendations are based on expert opinions. Only 4 recommendations (education, pneumonia, use of an electric toothbrush, and fluoride rinsing in case of a sudden increase of oral plaque amount) are based on evidence level A2 conclusions. This emphasizes the need for further research on oral health of institutionalized older people.