The relationship between father-absence and encopresis.
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Adolescent↗
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Results for “Reactive Attachment Disorder”
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The additivity of substrate fragments in enzyme-ligand binding.
BACKGROUND: Enzymes have evolved to recognise their target substrates with exquisite selectivity and specificity. Whether fragments of the substrate--perhaps never available to the evolving enzyme--are bound in the same manner as the parent substrate addresses the fundamental basis of specificity. An understanding of the relative contributions of individual portions of ligand molecules to the enzyme-binding interaction may offer considerable insight into the principles of substrate recognition. RESULTS: We report 12 crystal structures of Escherichia coli thymidylate synthase in complexes with available fragments of the substrate (dUMP), both with and without the presence of a cofactor analogue. The structures display considerable fidelity of binding mode and interactions. These complexes reveal several interesting features: the cofactor analogue enhances the localisation of substrate and substrate fragments near the reactive thiol; the ribose moiety reduces local disorder through additional specific enzyme-ligand interactions; the pyrimidine has multiple roles, ranging from stereospecificity to mechanistic competence; and the glycosidic linkage has an important role in the formation of a covalent attachment between substrate and enzyme. CONCLUSIONS: The requirements of ligand-protein binding can be understood in terms of the binding of separate fragments of the ligand. Fragments which are subsystems of the natural substrate for the enzyme confer specific contributions to the binding affinity, orientation or electrostatics of the enzymatic mechanism. This ligand-binding analysis provides a complementary method to the more prevalent approaches utilising site-directed mutagenesis. In addition, these observations suggest a modular approach for rational drug design utilising chemical fragments.
Crystallography, X-Ray↗
Dip-pen nanolithography of reactive alkoxysilanes on glass.
The use of organofunctional silane chemistry is a flexible and general method for immobilizing biomolecules on silicon oxide surfaces, including fabricating DNA, small-molecule, and protein microarrays. The biggest hurdle in employing dip-pen nanolithography (DPN) for extending this general approach to the nanoscopic domain is the tendency of trialkoxy- and trichlorosilanes to rapidly polymerize due to hydrolysis reactions. The control of the local water concentration between the substrate surface and the scanning AFM tip is critical, both to the physical and chemical processes involved in DPN writing and to the ability to form well-defined thin layers of reactive silanes without extensive polymerization induced disorder. We found that we could control the degree of polymerization through careful choice of the alkoxysilane used as the "ink" for DPN and through control of the relative humidity during inking and writing with the coated AFM tip. As a proof-of-principle, we demonstrate that areas patterned with an alkoxysilane on glass with DPN are functional for subsequent immobilization of fluorescently labeled streptavidin via covalent attachment of biotin. This preliminary result sets the stage for the ability to capture proteins in their fully hydrated state from buffered solution, by molecular recognition onto previously written reactive nanoscopic regions on oxidized silicon and glass.
DNA↗
Glycosyl phosphatidylinositol-linked blood group antigens and paroxysmal nocturnal hemoglobinuria.
Human erythrocyte cell surface molecules that are attached to the cell membrane by glycosyl-phosphatidylinositol (GPI) anchors include the complement regulatory proteins decay accelerating factor (DAF, CD55) and membrane inhibitor of reactive lysis (MIRL, CD59), as well as the proteins that bear the Cartwright, Dombrock, and JMH blood group antigens. The acquired hematopoietic stem cell disorder paroxysmal nocturnal hemoglobinuria (PNH) results from the absence or marked deficiency in expression of GPI-anchored proteins in affected hematopoietic cells. PNH usually if not always results from a somatic mutation of an X-linked gene called PIG-A; the product of the PIG-A gene is a glycosyl transferase necessary for construction of the GPI anchor. DAF is a ubiquitously expressed protein present in many tissues, including gastrointestinal epithelia, corneal epithelia, and serosa of urinary and reproductive organs. DAF is a 70 kD glycoprotein containing complement regulatory short consensus repeats (SCRs); its gene is located in the regulation of complement activation (RCA) gene cluster on chromosome 1 and is about 40 kb in size. The Cromer blood group antigens, which reside on DAF, include 10 currently defined antigens, of which seven are of high incidence. The molecular basis of the Cr (a-) phenotype has been determined to be a single base pair substitution in DAF SCR4 (G-->C, leading to an ala193 to pro amino acid substitution). The Tc alpha antigen appears to be determined by the amino acid sequence of SCR1, with the Tc (a-b+) phenotype arising from a base pair substitution of G55-->T, leading to an arg18 to leu amino acid substitution. The null phenotype for Cromer antigens occurs when DAF is completely absent; only one example has been completely studied on the molecular level. That individual is homozygous for a point mutation in SCR1 (G314-->A) that creates a stop codon (TGA) in place of one normally encoding trp53 (TGG) and thus prevents further translation of the mRNA. The Dr(a-) phenotype expresses reduced quantities of DAF (approximately 40% of normal levels), as well as a polymorphism of DAF. Lack of the Dr alpha antigen has been proved to result from a single point mutation in SCR3 (C-->T in codon 165) that leads to a single amino acid substitution (ser-->leu). The Cartwright (Yt) antigens reside on acetylcholinesterase (AChE). In erythroid cells, a small exon that encodes the signal for attachment of the GPI anchor is retained in a tissue-specific process.(ABSTRACT TRUNCATED AT 400 WORDS)
Acetylcholinesterase↗
A homozygous nonsense mutation in the PLEC1 gene in patients with epidermolysis bullosa simplex with muscular dystrophy.
Plectin is a widely expressed cytomatrix component involved in the attachment of the cytoskeleton to the plasma membrane. We have recently reported that the skin and muscles of three patients affected by epidermolysis bullosa simplex with muscular dystrophy (MD-EBS), a genetic disorder characterized by skin blistering associated with muscle involvement, are not reactive with antibodies specific to plectin. We demonstrated that in the skin, lack of plectin leads to failure of keratin filaments to connect to the plasma membrane via the hemidesmosomes, whereas in the muscle the deficient expression of the molecule correlates with an aberrant localization of desmin in the muscle fibers. In this study we demonstrate that in a MD-EBS kindred with two affected members, the disease results from a homozygous nonsense mutation in the plectin (PLEC1) gene leading to a premature stop codon (CGA to TGA) and decay of the aberrant plectin messenger RNA. The segregation of the mutated allele implicates the mutation in the pathology of the disorder. These results confirm the critical role of plectin in providing cell resistance to mechanical stresses both in the skin and the muscle.
Alleles↗
Changes in psychopathology of parents of NOFT (non-organic failure to thrive) infants during treatment.
This clinical case-study of 50 infants suffering from NOFT (non-organic failure to thrive) and their parents supports the idea that the feeding problem is intimately related to parental disorders. We find a high rate (70%) of parental psychopathology (axis I diagnosis applying DSM-III-R) at the time of referral and a significant reduction (to 37%) during treatment of the infants and their parents. After a year only 12% of the parents were diagnosed with psychiatric disorders. In contrast personality disorders (axis II diagnosis applying DSM-III-R) show more stability and can be regarded as a trait variable, whereas the psychiatric disorders are of a more reactive nature. These conclusions may be influenced somewhat by the strictly hospital based design of our pilot study (infants and parents contacted only after clinical referral) and by inclusion only of firstborn infants. Nevertheless, they point to the psychopathology of parents as a main cause for non-organic failure to thrive. Psychopathological traits such as severe attachment behavior problems and primary bonding difficulties may have been latent and only became manifest due to the task of nurturing an infant for the first time.
Analysis of Variance↗
Vimentin immunostaining in fibroblastic reticulum cells within human reactive and neoplastic lymphoid follicles.
We analyzed the distribution of fibroblastic reticulum cells (FRCs), stationary cells of lymphoid tissues, as visualized by the anti-vimentin (V9) monoclonal antibody in human reactive and neoplastic lymphoid follicles, by using immunoenzymatic and immunofluorescence methods on fixed and paraffin-embedded tissue sections from 37 lymphoid specimens with reactive disorders and 10 specimens with nodular/follicular non-Hodgkin's lymphomas (NHLs). The pattern of distribution of the vimentin-positive (VIM+) FRCs was compared with that of follicular dendritic reticulum cells (DRCs) as visualized by anti-S-100 protein antibody. Elongate VIM+ FRCs intimately attached to reticulum fibers were randomly distributed in the paracortical and interfollicular areas of lymph nodes, whereas they were recognized specifically in the mantle zones of the secondary follicles, mostly in the outer margins. Germinal centers were consistently devoid of VIM+ FRCs. Comparative analysis on serial sections as well as paired immunoperoxidase and double immunofluorescence studies demonstrated that there was a sharp difference between the patterns of intrafollicular distribution of VIM+ FRCs and S-100 protein-positive (S-100+) DRCs without juxtaposition, the FRCs being confined to the mantle zones. In the 10 nodular/follicular NHLs VIM+ FRCs could be observed in the thinned mantles of neoplastic nodules displaying a corona-like pattern that accentuated the boundaries of the nodules. The results of this study support the view that the intrafollicular distribution of VIM+ FRCs is specific for the mantle zone. The different microenvironmental organization within the follicles of VIM+ FRCs and S-100+ DRCs suggests that FRCs or at least VIM+ FRCs are stationary cells strictly related to the mantle zone microenvironment, where they may play a role in supposed sustentacular and immunologic functions similar to that of DRCs in the germinal center microenvironment.
Antibodies, Monoclonal↗
Muscle cross-bridges: do they rotate?
We have used electron paramagnetic resonance (EPR) spectroscopy to monitor the orientation of spin labels attached specifically to a reactive sulfhydryl on the myosin heads in glycerinated rabbit psoas skeletal muscle. Previous work has shown that the paramagnetic probes are highly ordered in rigor muscle and display a random angular distribution in relaxed muscle (Thomas and Cooke , 1980). Addition of ADP to rigor fibers caused no spectral changes, while addition of AMPPNP or PPi increased the fraction of disordered probes. We show here that the application of stress to fibers in the presence of ADP, AMPPNP or PPi causes no change in their spectra. During the generation of isometric tension approximately 80% of the probes display a random angular distribution as in relaxed muscle while the remaining 20% are highly oriented at the same angle as found in rigor muscle. In each of the above cases the spectrum consists of two components, one highly ordered as in rigor and one highly disordered. Saturation transfer EPR has shown that the ordered component is rigid while the disordered component is mobile on the microsecond time scale (Thomas, Ishiwata , Seidel and Gergely , 1980). These data lead to the conclusion that the disordered spectral component arises from myosin heads that are detached from actin while the ordered component comes from heads that are attached to actin. The observation that the ordered component displays an identical angular distribution under all conditions indicates that its orientation is not linked to force generation.
Adenosine Diphosphate↗
Evidence for cross-bridge order in contraction of glycerinated skeletal muscle.
The linear dichroism of iodoacetylrhodamine labels attached to the single reactive thiol groups of myosin heads was measured to determine the spatial orientation of myosin cross-bridges in single glycerinated skeletal muscle fibers. We have shown previously that in rigor the chromophoric labels are well ordered and assume an orientation nearly perpendicular to the fiber axis; in the presence of MgADP, a large fraction of probe remains well ordered but the probe attitude assumes a more slanted orientation; in relaxed muscle, the probe order is largely lost, implying a high degree of cross-bridge disorder. In this paper, we report that during isometric contraction a large fraction of the probe shows a high degree of order, suggesting the attachment of approximately equal to 65% of the cross-bridges to actin. These ordered cross-bridges have a probe attitude similar to that of the MgADP-induced static state and hence are in a mechanical state quite distinct from rigor.
Adenosine Diphosphate↗
Oedipal dynamics in panic disorder.
Both research and clinical work have revealed factors that can lead to the onset and persistence of panic disorder. Preoedipal conflicts intensify the danger of oedipal longings for panic patients. Competition with the same-sex parent is linked with angry preoedipal fantasies and associated fears of disruption in attachments. Fantasies or actual successes can thus trigger panic episodes. Regression to a helpless, dependent state such as panic defends against the danger of aggressive, competitive fantasies and actual achievements. However, the regressive state can also be experienced as dangerous, and can be linked with frightening homosexual fantasies. A reactive aggressive oedipal stance can sometimes result, triggering escalating turmoil. The panic episode serves a series of compromise formations in dealing with these conflicted wishes.
Adult↗
Internal motions in myosin head: effect of ADP and ATP.
Internal flexibility of myosin heads in glycerinated muscle fibres in the presence of MgADP plus orthovanadate and after addition of Ca-ATP was studied using an isothiocyanate-based spin label attached to the reactive sulfhydryl sites of myosin. The spin labels were immobilized on the microsecond time scale and exhibited significant orientational order in rigor. In AM+.ADP.V(i) state a smaller fraction of ordered population was found showing distinct orientation from rigor; the larger population of heads was in dynamically disordered state. This new ordered population of heads was detected even in contracting fibres.
Adenosine Diphosphate↗
Energetics of the actomyosin bond in the filament array of muscle fibers.
The interaction between actin and myosin in the filament array of glycerinated muscle fibers has been monitored using paramagnetic probes and mechanical measurements. Both fiber stiffness and the spectra of probes bound to a reactive sulfydral on the myosin head were measured as the actomyosin bond was weakened by addition of magnesium pyrophosphate (MgPPi) and glycerol. In the absence of MgPPi, all myosin heads are attached to actin with oriented probes. When fibers were incubated in buffers containing MgPPi, a fraction of the probes became disordered, and this effect was greater in the presence of glycerol. To determine whether the heads with disordered probes were detached from actin, spin-labeled myosin subfragment-1 (MSL-S1) was diffused into unlabeled fibers, and the fractions bound to actin and free in the medium were correlated with the oriented and disordered spectral components. These experiments showed that the label was oriented when MSL-S1 was attached to actin in a ternary complex with the ligand and that all heads with disordered probes were detached from actin. Thus the fraction of oriented labels could be used to determine the fraction of heads attached to actin in a fiber in the presence of ligand. The fraction of myosin heads attached to actin decreased with increasing [MgPPi], and in the absence of glycerol approximately 50% of the myosin heads were dissociated at 3.3 mM ligand with little change in fiber stiffness. In the presence of 37% glycerol plus ligand, up to 80% of the heads could be detached with a 50% decrease in fiber stiffness. The data indicate that there are two populations of myosin heads in the fiber. All the data could be fit with a model in which one population of myosin heads (comprising approximately 50% of the total) sees an apparent actin concentration of 0.1 mM and can be released from actin with little change in fiber stiffness. A second population of myosin heads (approximately 50%) sees a higher actin concentration (5 mM) and is only released in the presence of both glycerol and ligand.
Actins↗
Defective contact activation of platelets from dogs with basset hound hereditary thrombopathy.
Basset Hound Hereditary Thrombopathy (BHT) is an autosomally inherited disorder of platelet function characterized by a thrombasthenia-like defect in aggregation but normal clot retraction. Glycoprotein IIb-IIIa (GP IIb-IIIa) is detectable in BHT platelets but may be functionally defective. In order to further characterize this potential model for human Glanzmann's thrombasthenia, contact reactivity of BHT platelets was studied by whole mount electron microscopy. Gel filtered BHT platelets, after 30 minutes of contact activation, attached poorly to a formvar substrate. There was an 8 fold difference in the number of adherent BHT platelets and normal platelets. In addition, contact induced shape change was inhibited when compared to control dogs. Almost 95% of control platelets reached fully dendritic or spread forms after 30 minutes of contact; in contrast only 63.7% of BHT platelets reached this degree of activation. The addition of 8.2 uM ADP to BHT platelets induced nearly a 4 fold increase in the number of spread forms and a 5 fold increase in the number of adherent BHT platelets, but did not cause aggregate formation. Both the defect in adhesion and shape change and the ability of ADP to stimulate both adhesion and contact-induced shape change in BHT platelets are similar to recent observations in our laboratory in patient's with type II Glanzmann's thrombasthenia.
Adenosine Diphosphate↗
Characteristic immunohistochemical and ultrastructural findings indicate that Kindler's syndrome is an apoptotic skin disorder.
BACKGROUND: Kindler's syndrome is a rare genodermatosis mainly characterized by the onset of skin blistering in early childhood, web formation of fingers and toes, photosensitivity, and progressive poikiloderma. There is still debate whether this disease represents a distinctive entity in the spectrum of congenital bullous poikilodermas or a variant of dystrophic epidermolysis bullosa. OBJECTIVE: To evaluate the recently proposed and debated characteristic immunohistochemical and ultrastructural features of Kindler's syndrome. PATIENT/METHODS: Immunofluorescence (IF) antigen mapping and transmission electron microscopy (TEM) were performed on a skin specimen from non-sun-exposed inner aspect of the upper arm of a 49-year-old patient with characteristic clinical features of Kindler's syndrome. RESULTS: IF studies revealed focally an extensively broadened, partly reticular staining pattern in the dermoepidermal basement membrane zone (BMZ) with antibodies against laminin-5 and type IV as well as type VII collagen. Anti-alpha6 and beta4 integrin staining revealed small gaps in the linear reactivity in the BMZ. Abundant keratin bodies, as detected by anti-immunoglobulin M (IgM) staining, were focally present in the dermis, indicating prominent epidermal apoptosis. This was verified by a histochemical apoptosis stain [terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) reaction]. Transmission electron microscopic examination showed manifold reduplications of the lamina densa (with attached anchoring fibrils) as well as a keratin body surrounded by a fibroblast in the upper dermis. CONCLUSION: We present characteristic immunohistochemical and ultrastructural features of Kindler's syndrome identical to those described by Shimizu et al. and provide evidence that Kindler's syndrome might primarily be an apoptotic disorder of basal keratinocytes.
Apoptosis↗
Maternal panic disorder: infant temperament, neurophysiology, and parenting behaviors.
OBJECTIVE: To determine whether 4- and 14-month-old infants of mothers with panic disorder (PD) would be more likely to show differences in temperament, neurophysiology (salivary cortisol and sleep), and relationships with their mothers than controls. METHOD: Two cohorts were recruited: 4-month-old infants with PD mothers (n = 25) and 4-month-old controls (n = 24), and 14-month-old infants with PD mothers (n = 27) and 14-month-old controls (n = 18). Mothers completed diagnostic interviews and questionnaires concerning infant temperament, sleep, and parenting. Infant salivary cortisol samples and standard observational procedures to measure infant temperament, sleep, attachment, and parenting were also used. RESULTS: Infants with PD mothers did not show more high reactivity, behavioral inhibition, or ambivalent/resistant attachment but did demonstrate different neurophysiology (higher salivary cortisol and more disturbed sleep) than controls. PD mothers also displayed less sensitivity toward their infants and reported parenting behaviors concerning infant sleep and discipline that have been associated with child problems. CONCLUSIONS: While infants with PD mothers did not show early behavioral differences from controls, they did display neurophysiological divergences consistent with higher arousal/arousability. Such neurophysiological divergences (elevated salivary cortisol and disturbed sleep) might be important early indicators of risk. Helping PD mothers parent their more highly aroused/arousable infants could reduce the development of psychopathology.
Adult↗
For better or worse: interpersonal relationships and individual outcome.
At a time of strong biological emphasis in psychiatry, it is important to emphasize that relationships with important others may play a crucial role in individual outcome. Psychoanalytic theories in the form of object relations, self psychology, and relational psychoanalysis reflect this emphasis, and at a broader level, the interpersonal school of psychiatry focuses selectively on the role of relationships in health and illness. Ten central premises of the interpersonal school are presented, followed by brief, selective reviews of three bodies of empirical data: studies of well-functioning marriages and families, the role of adult relationships in undoing the adult consequences of destructive childhood experiences, and the relationship of marital variables to the onset and course of depressive disorders. Clinical experience and research findings suggest that clinicians treating couples and families may be helpful by using techniques designed to both increase the intensity of affective bonds and repair the inevitable disruptions of those bonds. It is also noted that recent psychophysiologic studies suggest that derivatives of intense affective bonds and their disruptions, in the form of confiding and conflict, may influence both vascular reactivity and cellular immune competence. These studies suggest that "for better or worse" may have physiologic as well as psychological implications.
Adult↗
Chance, structure, stress: the birth and development of the human mind-brain.
Recent physiological studies of the human mind-brain lend support to the theory of object relations, and in particular to the manner in which the object of the early period enters the infant's dawning psyche to elicit a perdurable pattern of both positive and negative response to stimuli. The psychoanalytic concept of reactivation, and the psychoanalytic view of language as (in part) a substitute for the absent object, are linked with specific cerebral mechanisms to disclose the bodily realities that underlie emotive disturbance.
Brain↗
HLA antigens and resistance to HIV.
The role of histocompatibility antigens in HIV infection has been investigated by several approaches. Thus the haplotype A1B8DR3 that is usually linked to autoimmune disorders seems to be associated with accelerated progression to AIDS. Cross-reactivity between MHC antigens and HIV-1 proteins is evident from alloimmunization experiments in mice and xenoimmunization of monkeys with human cells. Furthermore, recent reports suggest that some individuals with uncommon HLA antigens may be resistant to HIV infection. In addition to expressing cross-reacting antigens with HLA, HIV also exhibits substantial amounts of host beta-2 microglobulin and HLA-DR attached to its surface. Taken together, these data are stimulating new hypotheses relevant for AIDS pathogenesis. Based on alloimmunization, novel approaches have also been proposed in attempts to promote an effective immune response to HIV.
HIV Infections↗