Discrimination learning and attentional set formation in a mouse model of Fragile X.

Fragile X Syndrome is the most prevalent genetic cause of mental retardation. Selective deficits in executive function, including inhibitory control and attention, are core features of the disorder. In humans, Fragile X results from a trinucleotide repeat in the Fmr1 gene that renders it functionally silent and has been modeled in mice by targeted deletion of the Fmr1 gene. Fmr1 knockout (KO) mice recapitulate many features of Fragile X syndrome, but evidence for deficits in executive function is inconsistent. To address this issue, we trained wild-type and Fmr1 KO mice on an experimental paradigm that assesses attentional set-shifting. Mice learned to discriminate between stimuli differing in two of three perceptual dimensions. Successful discrimination required attending only to the relevant dimension, while ignoring irrelevant dimensions. Mice were trained on three discriminations in the same perceptual dimension, each followed by a reversal. This procedure normally results in the formation of an attentional set to the relevant dimension. Mice were then required to shift attention and discriminate based on a previously irrelevant perceptual dimension. Wild-type mice exhibited the increase in trials to criterion expected when shifting attention from one perceptual dimension to another. In contrast, the Fmr1 KO group failed to show the expected increase, suggesting impairment in forming an attentional set. Fmr1 KO mice also exhibited a general impairment in learning discriminations and reversals. This is the first demonstration that Fmr1 KO mice show a deficit in attentional set formation. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Non-surgical alternative in the treatment of skeletal Class III problems

The dental profession is not static, but dynamic. New research findings, along with medical and technological advances, necessitate constant re-examination of treatment philosophies and techniques. What were acceptable treatment techniques in the past may not necessarily be the most effective and best techniques for our patients today. Currently, many practitioners feel that the only treatment for the correction of a skeletal Class III abnormality is via orthognathic surgery in older patients. In some cases it may be the only treatment option. But in most cases today, there are more conservative, non-surgical treatment alternatives in correcting Class III problems in younger aged children. In treating facial-skeletal problems, it must be emphasized that the human face is a biological masterpiece of form and function. Its importance has been documented in arts and sciences since the beginning of modern civilization. It is important enough so that individuals who are blessed with attractive features are afforded greater opportunities in our society. Attractive faces are associated with intelligence, honesty and good work ethics. With the advent of orthognathic surgery, functional appliance, functional regulator, and myofunctional therapy, the dental profession has the capability of leveling out the playing field for many individuals in our society. It does so by being able to correct problems closely associated with the human psyche--the human face. The ability to change facial features brings tremendous prestige to our profession. Along with this prestige comes greater responsibility. Our ability to change facial features entails greater understanding of facial balance and harmony. Ricketts states that the face must conform to stringent proportions known as the "divine proportion" in order for it to be esthetically pleasing. Also, our ability to move facial-skeletal structures entails greater understanding of the biomechanics of the human face. Without this knowledge practitioners can cause iatrogenic problems, such as temporomandibular disorders. Conversely, correcting facial-skeletal abnormalities have been found to alleviate many medical problems, such as chronic headaches, neck-back-shoulder pain, respiratory disorders, auditory disorders, etc. As more and more information is gathered, it is becoming clear that the physical, emotional and psychological health of a human being is intimately related to craniomandibular anatomy. In fact, the jaw and dental structures (with the exception of the tooth enamel) is formed from the neural crest cells along with the endocrine system, while the central nervous system is formed from the neural tube. The entire nervous system, the endocrine system and the dental system are formed from common tissue origin. This can explain why many facial-skeletal corrections are often accompanied by alleviation of many medical and physiological problems. These are exciting times for our profession. However, if we wish to address the needs of our patients well into the next century, we must continue to seek greater and greater knowledge in the area of the craniomandibular anatomy relative to the rest of the human body. It has much to do with facial esthetics, physiologic and psychologic harmony, and TMJ health. This knowledge will enable our profession to have the power to change human lives in a very positive way. As doctors, there can be no greater personal and professional satisfaction than to realize that, through our professional intervention, we are able to offer our patients the possibility of achieving greater happiness and quality of life.     

Colchicine-induced Mallory body formation in the mouse

Long term griseofulvin treatment of mice results in the development of Mallory bodies (MB), Griseofulvin application apparently "primed" the liver cell for MB formation, and the hepatocytes were then able to respond almost immediately with MB to a griseofulvin challenge even after a 1-month griseofulvin-free period. Colchicine, in contrast to cytochalasin B, also induced MB under these latter experimental conditions. Since intermediate filaments increase in various types of cells in response to antitubulin agents, this observation further supports the hypothesis that MB are related to intermediate filaments.     

The arc index in evaluation of Class III malocclusion

Lateral cephalometric radiographs were obtained for 46 individuals (18 men and 28 women) aged 20 to 30 years. The sample consisted of Taiwanese with Class III malocclusions and prognathic facial profiles. A modification of the Sassouni arch analysis was used to evaluate this group. All parameters were compared with the norms for adult Taiwanese. The facial pattern of the Class III group was similar to that reported in other studies. The maxilla was in a retrusive position; the lengths of the maxilla and the mandible were significantly different from those in the normal group; the mandibular central incisor was retroinclined; and the total gonial angle, upper gonial angle, and lower gonial angle in the Class III group were significantly different from those angles in the normal group in both sexes. The arc index represented the maxillomandibular positional relationship. There was a statistically significant difference between the mean arc indexes of the Class III and the normal groups. The results indicated that the more negative the arc index, the greater the Class III tendency.     

Transgenic mouse models of lipoprotein metabolism and atherosclerosis

Lipoprotein transport genes have either been added to the germ line of mice by transgenic techniques or knocked out by homologous recombination in embryonic stem cells. The resultant over- or underexpression of these genes has resulted in new insights about how these genes function in the body and their role in lipoprotein metabolism. Either singly or in combination, these genetic modifications can be used to engineer the mouse to make it a better model for human lipoprotein disorders and atherosclerosis.     

Splint therapy for skeletal Class III malocclusion in the primary dentition

The objective of this study was to evaluate the effect of referral bias in a clinical audit of lymphoma in a university hospital. We compared demographic and clinical characteristics as well as survival for Jerusalem residents (local) and referred (distant) patients diagnosed from 1987 to 1992 and treated in our institution. Referred patients were younger (p < 0.0001), and less likely to be immigrants (p < 0.0001), than local patients. Aggressive non-Hodgkin's lymphomas (NHL) were more common in the referred population (p = 0.015). Survival for Hodgkin's disease was consistently better for local patients, but for patients with NHL the findings were reversed. In this study referred patients differed in their clinical and sociodemographic characteristics but did not consistently exhibit a worse outcome than that of local patients. The unpredictable nature of referral bias may be due to better functional status or resources among referred patients, or to selective referral for procedures such as bone marrow transplantation. While reports on the natural history of disease from tertiary institutions may be biased by referral patterns, the direction of the bias is not uniform.     

Hepatic lipase affects both HDL and ApoB-containing lipoprotein levels in the mouse

Transgenic mice were created overproducing a range of human HL (hHL) activities (4-23-fold increase) to further examine the role of hepatic lipase (HL) in lipoprotein metabolism. A 5-fold increase in heparin releasable HL activity was accompanied by moderate (approx. 20%) decreases in plasma total and high density lipoprotein (HDL) cholesterol and phospholipid (PL) but no significant change in triglyceride (TG). A 23-fold increase in HL activity caused a more significant decrease in plasma total and HDL cholesterol, PL and TG (77%, 64%, 60%, and 24% respectively), and a substantial decrease in lipoprotein lipids amongst IDL, LDL and HDL fractions. High levels of HL activity diminished the plasma concentration of apoA-I, A-II and apoE (76%, 48% and 75%, respectively). In contrast, the levels of apoA-IV-containing lipoproteins appear relatively resistant to increased titers of hHL activity. Increased hHL activity was associated with a progressive decrease in the levels and an increase in the density of LpAI and LpB48 particles. The increased rate of disappearance of 125I-labeled human HDL from the plasma of hHL transgenic mice suggests increased clearance of HDL apoproteins in the transgenic mice. The effect of increased HL activity on apoB100-containing lipoproteins was more complex. HL-deficient mice have substantially decreased apoB100-containing low density lipoproteins (LDL) compared to controls. Increased HL activity is associated with a transformation of the lipoprotein density profile from predominantly buoyant (VLDL/IDL) lipoproteins to more dense (LDL) fractions. Increased HL activity from moderate (4-fold) to higher (5-fold) levels decreased the levels of apoB100-containing particles. Thus, at normal to moderately high levels in the mouse, HL promotes the metabolism of both HDL and apoB-containing lipoproteins and thereby acts as a key determinant of plasma levels of both HDL and LDL.     

Evidence that P2X purinoceptors mediate the excitatory effects of alphabetamethylene-ADP in rat locus coeruleus neurones

Extracellular and whole-cell patch clamp recordings were used to study the excitatory responses elicited by purine nucleotides in pontine slices of the rat brain containing the locus coeruleus (LC). The P2 purinoceptor agonists, alphabeta-methyleneadenosine 5'-triphosphate (alphabetameATP) and adenosine 5'-O-(2-thiodiphosphate) (ADPalphabetaS), and a novel purinoceptor agonist, alphabeta-methyleneadenosine 5'-diphosphate (alphabetameADP), elicited concentration-dependent increases in the spontaneous firing rate over the concentration range (1-300 microM). On vagus nerve or dorsal root preparations alphabetameADP (100 microM) had no agonist activity. In the presence of both alphabetameATP (300 microM), ADPbetaS (300 microM) elicited a further and significant increase in the firing rate of the LC neurones, whilst neither alphabetameATP nor alphabetameADP (300 microM) elicited a further response. The P2 purinoceptor antagonists, suramin (100 microM) and pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 30 microM), markedly attenuated responses to all three agonists. Whole-cell recording of membrane current showed that, at - 60 mV, alphabetameATP and alphabetameADP (both 100 microM) elicited inward currents of a similar magnitude, whilst the inward currents elicited by a lower concentration of ADPbetaS (30 microM) were larger and faded in the presence of this agonist. In the presence of tetrodotoxin and a combination of other neurotransmission blockers, both alphabetameATP and alphabetameADP still produced inward currents. Based on the known selectivity of the agonists used in this study, there appear to be two distinct P2 purinoceptor types present on neurones in the LC, which correspond to the P2X and P2Y types. The responses elicited by alphabetameADP appear to be mediated through a putative P2X purinoceptor, although further work is required to determine which P2X receptor subtype(s) are involved.     

Effects of leptin adipose tissue lipoprotein lipase in the obese ob/ob mouse

OBJECTIVE: To characterize the adaptations of lipid metabolism, with special emphasis on tissue lipoprotein lipase, to negative energy balance brought by chronic treatment of obese ob/ob mice with leptin. DESIGN: According to a 2 x 2 factorial analysis, lean and obese C57BL/6J mice were subcutaneously infused with leptin (100 micrograms.kg-1.day-1) or vehicle (phosphate-buffered saline) during seven days. RESULTS: Cumulative food intake and final body weight of vehicle-infused obese mice were twofold higher than in lean controls. Leptin decreased cumulative food intake and body weight of obese, but not lean mice. Lipoprotein lipase (LPL) activity in white inguinal and epididymal and brown interscapular adipose tissues of control obese mice was at least twofold higher than in lean mice, but comparable in the vastus lateralis muscle. Leptin treatment of obese mice significantly lowered LPL activity to that of lean mice in all tissues examined. Vehicle-infused obese mice had higher liver triglyceride content and were hypertriglyceridemic compared to lean mice, and triglyceride concentrations in plasma and liver were decreased proportionally after leptin treatment. Leptin lowered glycemia and insulinemia of obese mice to lean levels and decreased plasma corticosterone. Leptin infusion had no notable effect on tissue lipoprotein lipase nor plasma variables of lean mice. CONCLUSIONS: Leptin infusion abolished hyperinsulinemia in the ob/ob mouse, an effect that was probably responsible for the concomitant normalization of adipose LPL activity. This study shows that decreased LPL activity, plasma triglyceride concentrations and hepatic triglyceride production constitute some of the adaptive peripheral adaptations of lipid metabolism, which accompany the reduction in fat mass accretion brought by leptin treatment of the obese ob/ob mouse.     

Thin-plate spline analysis of the cranial base in subjects with Class III malocclusion

The role of the cranial base in the emergence of Class III malocclusion is not fully understood. This study determines deformations that contribute to a Class III cranial base morphology, employing thin-plate spline analysis on lateral cephalographs. A total of 73 children of European-American descent aged between 5 and 11 years of age with Class III malocclusion were compared with an equivalent group of subjects with a normal, untreated, Class I molar occlusion. The cephalographs were traced, checked and subdivided into seven age- and sex-matched groups. Thirteen points on the cranial base were identified and digitized. The datasets were scaled to an equivalent size, and statistical analysis indicated significant differences between average Class I and Class III cranial base morphologies for each group. Thin-plate spline analysis indicated that both affine (uniform) and non-affine transformations contribute toward the total spline for each average cranial base morphology at each age group analysed. For non-affine transformations, Partial warps 10, 8 and 7 had high magnitudes, indicating large-scale deformations affecting Bolton point, basion, pterygo-maxillare, Ricketts' point and articulare. In contrast, high eigenvalues associated with Partial warps 1-3, indicating localized shape changes, were found at tuberculum sellae, sella, and the frontonasomaxillary suture. It is concluded that large spatial-scale deformations affect the occipital complex of the cranial base and sphenoidal region, in combination with localized distortions at the frontonasal suture. These deformations may contribute to reduced orthocephalization or deficient flattening of the cranial base antero-posteriorly that, in turn, leads to the formation of a Class III malocclusion.     

Multiple subtypes of voltage-gated calcium channel mediate transmitter release from parasympathetic neurons in the mouse bladder

Multiple subtypes of voltage-gated calcium channels are coupled to transmitter release from central neurons; however, only N-type channels have been shown to play a role in autonomic neurons. The aim of the present study was to investigate potential roles for other channel subtypes in transmitter release from parasympathetic neurons in the mouse bladder using calcium channel toxins alone and in combination. Transmitter release was measured indirectly by recording the contraction of bladder dome strips in response to electrical stimulation of the neurons by single pulses or trains of 20 pulses at 1-50 Hz. omega-Conotoxin-GVIA (GVIA) and omega-conotoxin-MVIIC (MVIIC) inhibited contractions in a concentration-dependent manner, with IC50 values of approximately 30 and 200 nM, respectively, at low stimulation frequencies. omega-Agatoxin-IVA (agatoxin) alone did not have any significant effect up to 300 nM. Cumulative addition of the toxins demonstrated that 300 nM agatoxin had a significant effect after N-type channels were blocked with 100 nM GVIA. MVIIC (3 microM) reduced the contraction amplitude further. Testing the toxins on the cholinergic or purinergic component of the contraction separately showed that acetylcholine release depends primarily on N-type channels and, to a lesser extent, on P- and Q-type channels, whereas ATP release involves predominantly P- and Q-type channels. In conclusion, parasympathetic neurons in the mouse bladder, like central neurons, use multiple calcium channel subtypes. Furthermore, the release of the two main transmitters in these neurons has differing dependencies on the calcium channel subtypes.     

cis-acting elements that mediate the negative regulation of Moloney murine leukemia virus in mouse early embryos

We have addressed the question of the nature of Moloney murine leukemia virus (MoMuLV) repression in mouse embryos by assaying for the transient expression of MoMuLV-derived constructs microinjected into early cleavage embryos. We show that the same cis-acting DNA sequences responsible for the block in MoMuLV expression in embryonal carcinoma cell lines operate in early embryos: (i) the MoMuLV long terminal repeat is nonfunctional, and (ii) the +147 to +163 repressor binding site, or negative regulatory element, negatively regulates the expression from an active promoter.     

The differences in the chronology and calcification of second molars between angle Class III and Class II occlusions in Japanese children

OBJECTIVE: To examine dietary selenium intake and indices of selenium status (plasma and red blood cell selenium and glutathione peroxidase activities) in apparently healthy Scottish individuals. DESIGN AND SUBJECTS: One hundred subjects, aged between 40 and 60 y, completed a seven day weighed food intake and provided blood samples for selenium status analysis. SETTING: Inverurie, Aberdeenshire, Scotland. RESULTS: Average reported selenium intake was low (43 micrograms/d). A significant number of subjects had reported intakes below the RNI. Low levels of plasma selenium were also found but no subject had values below 40 micrograms/1. Red blood cell selenium was within the reference range established for a healthy UK population. Smoking status had no consistent effect on selenium status. CONCLUSIONS: The results of the present study suggest that selenium status of certain Scottish individuals may be compromised and that further studies are warranted. SPONSORSHIP: BASF, Germany; The Tobacco Products Research Trust, UK; Scottish Office Agriculture Environment and Fisheries Department.     

Craniofacial adaptations induced by chincup therapy in Class III patients

The purpose of the present study is to examine the effects of an orthopedic force produced by chincup treatment in patients with Class III malocclusion. Anteroposterior maxillary and mandibular changes were examined as were changes in the vertical dimension. Further, the possibility of posterior displacement of temporomandibular joints in treated Class III subjects was evaluated. Serial lateral headfilms of 22 young females (average age, 9 years), who had received chincup therapy were compared with those of 20 skeletal Class III subjects of similar age who received no treatment during the interval studied. A computerized x-y coordinate program was applied to analyze the cephalometric landmarks and measurements. The treated group showed improvement of the skeletal Class III pattern associated with a slight increase (0.8 degrees per year) in SNA and a slight decrease (-0.7 degrees per year) in SNB and also a decreased gonial angle. The distance from the condyle to the chin (Co-Gn or effective mandibular length) increased significantly less in the treated group in comparison with controls. Increases in lower anterior facial height were not different between the treated and untreated groups. In addition, the cranial base angles N-S-Ba and N-S-Ar showed no statistical difference between groups, but these angles tended to increase with time in both groups. Basion and Articulare showed almost the same amount of backward and downward movement in both groups. The results of this study indicate that the primary effect of chincup therapy was in producing a reduction in mandibular growth increments during the period studied. Maxillary growth was not affected during treatment. Further, the results of this study fail to support the hypothesis that chincup appliance significantly induces the posterior displacement of the glenoid fossa.     

Early treatment of Class III malocclusion? Colin's case

This is the first of six simulated case reports accompanying the questionnaire detailed in the article 'How to Do It: Making Clinical Audit Work' found earlier in this issue. You will find comprehensive discussion of the problem of making a decision about the early treatment of Class III malocclusion.     

The identification of Class III malocclusions by discriminant analysis

Atrial natriuretic factor (ANF), a cardiac peptide hormone with potent natriuretic and vasodilator actions, mediates its biologic responses via increases in intracellular cyclic guanosine monophosphate (cGMP). Recognizing that phosphodiesterases degrade cGMP and that congestive heart failure (CHF) is characterized by reduced renal responses to ANF, the authors hypothesized that cGMP phosphodiesterases limit the renal actions of exogenous and endogenous ANF in the presence of experimental CHF. In anesthetized dogs with severe CHF and avid sodium retention produced by rapid ventricular pacing, the authors explored the renal actions of M&B 22,948 (Rh?ne-Poulenc, Essex, UK), an inhibitor of cGMP-specific phosphodiesterases. High-dose intrarenal cGMP phosphodiesterase inhibition (PDI), with minimal effects upon systemic hemodynamics and hormones, significantly enhanced sodium excretion. This occurred primarily by decreasing distal nephron sodium reabsorption while enhancing renal cGMP generation. In separate groups of dogs, low-dose intrarenal cGMP PDI potentiated the actions of exogenous ANF on glomerular filtration and distal nephron sodium reabsorption, leading to enhanced natriuresis in the presence or absence of severe CHF. These studies support a link between ANF and the renal actions of cGMP PDI, and indicate that cGMP phosphodiesterases may contribute to sodium retention in advanced CHF by limiting the renal actions of increased endogenous ANF.     

Finite element morphometry of the midfacial complex in subjects with Angle's Class III malocclusions

The purpose of this study was to determine whether the morphology of the midface differed in normal (Class I) and midfacially-retrognathic (Class III) prepubertal subjects, and to localize differences morphometrically. Lateral cephalographs of 133 European-American children between 5-11 years of age were traced and average geometries, scaled to an equivalent size, were generated based upon seven nodes (pterygoid point, PTS; rhinion, RO; posterior nasal spine, PNS; midpalatal point, MPP; anterior nasal spine, ANS; subspinale, A; and prosthion, Pr). The samples also were subdivided into seven age- and sex-matched groups for morphometric comparisons. Procrustes analysis indicated that the overall midfacial configurations differed statistically (P < 0.05). Therefore, a color-coded finite element (FEM) program was used to localize differences in morphology graphically. Comparing Class I and III groups for size-change, FEM revealed that negative allometry was evident in the posterior half of the midfacial configuration localized between PTS, PNS, and MPP. The anterior half was more isotropic, however, but the anterior-most aspect of the configuration between Pr and RO showed some positive allometry particularly in the premaxillary and incisor regions. For shape-change, major differences in shape over the entire midface were not as evident, with an isotropic midfacial morphology for normal and Class III subjects. It is concluded that an identifiable pattern of deformation is evident for the Class III subjects during the prepubertal growth period. Therefore, midfacial retrognathia associated with Class III malocclusions results, at least in part, from deficient anteroposterior elongation of the midfacial complex allied with deformation of the premaxillary region.