Antithrombin III Toyama: a hereditary abnormal antithrombin III of a patient with recurrent thrombophlebitis

A familial abnormal antithrombin III (AT-III) is reported. The characteristic of the abnormality in this family is low heparin cofactor activity with normal progressive antithrombin activity and normal or rather increased level of AT-III antigen. The patient is a 23-year-old female who had suffered from recurrent thrombophlebitis involving her lower extremities. Her plasma AT-III antigen concentration was 54 mg/dl and progressive antithrombin and factor Xa inhibitory activities were of normal level. However, the heparin cofactor activity of her plasma was as low as 26% of normal control. On crossed immunoelectrophoresis (CIE) containing heparin in the first dimension agarose, patient's AT-III showed no increase in electrophoretic mobility compared to that in the absence of heparin, suggesting that the patient's AT-III has no affinity for heparin. From CIE pattern in the presence of heparin, the patient was found to be a homozygote, and parents and one of her younger sisters were heterozygotes. Thus, the mode of inheritance is proposed to be autosomal dominant.     

Development of the corticospinal tract in the mouse spinal cord: a quantitative ultrastructural analysis

The growth of corticospinal tract (CST) axons was studied quantitatively at the 7th cervical (C7) and the 4th lumbar (L4) spinal segments in the balb/cByJ mice at the ages of postnatal day (P) 0, 2, 4, 6, 8, 10, 14, and 28. The cross-sectional area of the CST increased progressively with time. Unmyelinated axons, the most prominent CST element during early development, reached maximum at C7 and L4 on P14. Two phases of increase in the number of unmyelinated axons were observed at C7, while only one surge of axonal outgrowth was found at the L4 level. Pro-myelinated axons, defined as axons surrounded by only one layer of oligodendrocytic process, were first seen at P2 and P4 in the C7 and the L4 level, respectively, followed by a dramatic increase in the number of myelinated axons from P14 onwards at both spinal levels. Myelination of the CST axons occurred topographically in a dorsal-to-ventral pattern. The number of growth cones increased rapidly at the C7 level to reach its maximum at P4, while those at L4 increased steadily to the peak at P10. Growth cones with synapse-like junctions were occasionally observed in the growing CST. Degenerating axons and growth cones partly accounted for the massive axon loss at both spinal segments during CST development. Overall, the mouse CST elements changed dynamically in numbers during postnatal development, suggesting a vigorous growing and pruning activity in the tract. The mouse CST also showed a similar growth pattern to that of the rat CST.     

Distinction of two pathologic antithrombin III molecules: Antithrombin III ‘Aalborg’ and antithrombin III ‘Budapest’

Plasma from two different thrombophilic families with functional inherited antithrombin III deficiency, i.e., with low antithrombin III activity but normal immunoreactive antithrombin III concentration, were investigated simultaneously in the same laboratory. The experiments (thrombin and Factor Xa inactivation, heparin affinity chromatography, modified two dimensional immunoelectrophoresis and gel filtration) showed a distinct difference between the two antithrombin III anomalies. The antithrombin III ‘Aalborg’ had decreased thrombininactivating activity but normal Factor Xa-inactivating activity. The heparin affinity and the molecule weight are normal. The antithrombin III ‘Budapest’ displays a more profound abnormality with pathologic thrombin and Factor Xa inactivation, decreased heparin affinity and abnormal molecular weight.     

Topiramate augmentation in patients with resistant major depressive disorder: a double-blind placebo-controlled clinical trial

Background

Despite evolution of new antidepressant treatment, clinicians still encounter challenges in the treatment of depressed patients. Looking for new medications that can potentiate the effects of current antidepressants seems to be necessary. Our objective is to survey the efficacy of topiramate augmentation in resistant major depressive disorder (MDD).

Method

This augmentation trial was designed as an 8-week randomized, placebo-controlled, double-blind study. Fifty three patients with DSM-IV diagnosis of MDD who had failed to respond to at least 8 weeks of treatment with an adequate dose of one of the SSRIs (fluoxetine, citalopram or serteraline) were included in the study. Patients were randomized to receive a flexible dose of topiramate (100-200 mg/day) or placebo beside their current antidepressant medication for a period of eight weeks. Outcome measures were Hamilton Depression Scale (HAM-D) and Clinical Global Impression (CGI).

Results

42 patients completed the study and there were 6 and 5 dropouts in topiramate and placebo groups, respectively. The topiramate group demonstrated significant improvement over the study period based on mean HAM-D score at week 8 compared to baseline (P = .000, Z = 3.699). Those receiving topiramate demonstrated to have a mean decrease of 32.0% in HAM-D score, compared to only 5.5% for those receiving placebo. Depressed mood, suicidality, insomnia (early, middle and late), agitation and anxiety symptoms were significantly improved in the topiramate group.

Conclusion

Our double-blind placebo-controlled study demonstrated that topiramate augmentation potentiate the efficacy of selective serotonin reuptake inhibitors (SSRIs) in treatment of resistant major depressive disorder. Of note is that our study is preliminary and larger double-blind studies are needed to confirm the results.     

Characterization of a small molecule PAI-1 inhibitor, ZK4044

Plasminogen activator inhibitor-1 (PAI-1) is a key negative regulator of the fibrinolytic system. In animal studies, inhibition of PAI-1 activity prevents arterial and venous thrombosis, indicating that PAI-1 inhibitors may be used as a new class of antithrombotics. In this study, we characterize a small molecule PAI-1 inhibitor, ZK4044, which was identified by high throughput screening and chemically optimized. In a chromogenic substrate-based urokinse (uPA)/PAI-1 assay and a tissue-type plasminogen activator (tPA)-mediated clot lysis assay, ZK4044 inhibited human PAI-1 activity with IC50 values of 644+/-255 and 100+/-90 nM, respectively. ZK4044 had no detectable inhibitory activity toward other serpins such as antithrombin III, alpha1-antitrypsin and alpha2-antiplasmin, indicating that ZK4044 is a specific PAI-1 inhibitor. ZK4044 was shown to bind directly to PAI-1 and prevent the binding of PAI-1 to tPA in a dose-dependent manner in surface plasmon resonance Biacore-based experiments. ZK4044 also prevented PAI-1/tPA complex formation, as analyzed by SDS/PAGE. ZK4044 had little effect on elastase-mediated cleavage of active PAI-1, indicating that the primary mode of action of ZK4044 is most likely to directly block the PAI-1/tPA interaction rather than to convert active PAI-1 to latent PAI-1. In the chromogenic substrate-based uPA/PAI-1 assay, ZK4044 was approximately 2-fold less potent against a mutant PAI-1 (14B-1), which contains four mutations at N150H, K154T, Q319L and M354I, compared with wild-type PAI-1, suggesting that the ZK4044 binding site on the surface of PAI-1 is close to these mutant residues. Together, our data show that ZK4044 represents a new class of small molecule PAI-1 inhibitors with anti-thrombotic potential.     

Heparin-induced thrombocytopenia: a stoichiometry-based model to explain the differing immunogenicities of unfractionated heparin, low-molecular-weight heparin, and fondaparinux in different clinical settings

INTRODUCTION: Heparin-induced thrombocytopenia (HIT) is caused by platelet-activating antibodies that recognize platelet factor 4 (PF4)/heparin complexes. The frequency of HIT is highly variable in different clinical settings, and is more frequent with unfractionated heparin (UFH) than with low-molecular-weight heparin (LMWH), despite the in vitro observation that HIT antibodies activate platelets similarly well with LMWH as with UFH. An important difference between UFH, LMWH, and fondaparinux is their widely differing plasma concentrations. We aimed to provide a model that included anticoagulant concentrations and PF4 availability as risk factors influencing the anti-PF4/heparin immune response. MATERIALS AND METHODS: By photon correlation spectroscopy we determined the concentrations at which UFH, LMWH, and fondaparinux form complexes optimally with PF4. Plasma concentrations of UFH and LMWH were calculated based on ex vivo pharmacokinetic data, with information on fondaparinux and PF4 concentrations taken from the literature. RESULTS AND CONCLUSIONS: The main features of our model are: optimal complex formation occurs at prophylactic-dose UFH and high PF4 levels, whereas therapeutic-dose LMWH concentrations are too high for optimal complex formation; in contrast, concentrations of fondaparinux are usually below the optimal stoichiometric range. Thus, immunization should occur more often in situations with major rather than minor platelet activation, and--for a given degree of platelet activation (PF4 availability)--as: prophylactic-dose UFH>therapeutic-dose UFH>prophylactic-dose LMWH, fondaparinux>therapeutic-dose LMWH. Our model provides a framework for explaining empirical observations that LMWH induces less anti-PF4/heparin antibodies than does UFH, and that anti-PF4/heparin antibodies are more often found in patients undergoing major surgery than in medical patients.     

Isolation and characterization of a hereditary abnormal antithrombin III 'Antithrombin III Toyama'

A hereditary abnormal antithrombin III (AT-III) 'Antithrombin III Toyama' was purified from the plasma of a patient with recurrent thrombophlebitis by a procedure involving barium chloride and ammonium sulfate fractionations, affinity chromatography on anti-AT-III-Sepharose gel, and DEAE-Sephadex chromatography. Purified abnormal AT-III was shown to be the same as normal one in the molecular size, having the same molecular weight, amino-terminal sequence and carboxy-terminal amino acid. Abnormal AT-III gave the same UV spectrum as normal AT-III and both proteins were immunologically identical. Abnormal AT-III, however, showed the different electrophoretic mobility on agarose gel electrophoresis and immunoelectrophoresis. Abnormal AT-III was more electronegative than normal one, before and after a neuraminidase digestion of both proteins. These results suggest that in antithrombin III Toyama an amino acid residue at the heparin-binding site has been replaced by less basic or more acidic one which has no ability to interact with heparin, resulting in a loss of heparin cofactor activity of this protein.     

Autoimmune Neurological Disorders with IgG4 Antibodies: a Distinct Disease Spectrum with Unique IgG4 Functions Responding to Anti-B Cell Therapies

The main IgG4 antibody–mediated neurological disorders (IgG4-ND) include MuSK myasthenia; CIDP with nodal/paranodal antibodies to Neurofascin-155, contactin-1/caspr-1, or pan-neurofascins; anti-LGI1 and CASPR2-associated limbic encephalitis, Morvan syndrome, or neuromyotonia; and several cases of the anti-IgLON5 and anti-DPPX-spectrum CNS diseases. The paper is centered on the clinical spectrum of IgG4-ND and their immunopathogenesis highlighting the unique functional effects of the IgG4 subclass compared to IgG1-3 antibody subclasses. The IgG4 antibodies exert pathogenic effects on their targeted antigens by blocking enzymatic activity or disrupting protein–protein interactions affecting signal transduction pathways, but not by activating complement, binding to inhibitory FcγRIIb receptor or engaging in cross-linking of the targeted antigen with immune complex formation as the IgG1-IgG3 antibody subclasses do. IgG4 can even inhibit the classical complement pathway by affecting the affinity of IgG1-2 subclasses to C1q binding. Because the IgG4 antibodies do not trigger inflammatory processes or complement-mediated immune responses, the conventional anti-inflammatory therapies, especially with IVIg, immunosuppressants, and plasmapheresis, are ineffective or not sufficiently effective in inducing long-term remissions. In contrast, aiming at the activated plasmablasts connected with IgG4 antibody production is a meaningful therapeutic target in IgG4-ND. Indeed, data from large series of patients with MuSK myasthenia, CIDP with nodal/paranodal antibodies, and anti-LGI1 and CASPR2-associated syndromes indicate that B cell depletion therapy with rituximab exerts long-lasting clinical remissions by targeting memory B cells and IgG4-producing CD20-positive short-lived plasma cells. Because IgG4 antibody titers seem reduced in remissions and increased in exacerbation, they may serve as potential biomarkers of treatment response supporting further the pathogenic role of self-reacting B cells. Controlled trials are needed in IgG4-ND not only with rituximab but also with the other anti-B cell agents that target CD19/20, especially those like obexelimab and obinutuzumab, that concurrently activate the inhibitory FcγRIIb receptors which have low binding affinity to IgG4, exerting a more prolonged anti-B cell action affecting also antigen presentation and cytotoxic T cells. Antibody therapies targeting FcRn, testing those anti-FcRn inhibitors that effectively catabolize the IgG4 antibody subclass, may be especially promising.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-022-01210-1.     

A Spanish experience of DSM III in a Consultation-Liaison psychiatric service

The authors applied the DSM III diagnosis to 500 patients seen at a Consultation-Liaison psychiatric service. Compared with similar American studies there was a lower frequency of adjustment and somatoform disorders and a higher proportion of drug abuse cases. Several possible reasons for these differences are mentioned. Although the use of DSM III has clear advantages in a General Hospital context, important difficulties were found: the use of some diagnostic criteria, the absence of a code to relate Axes I and III, the poor systemization of scores in social Axes IV and V and the lack of a specific category for attempted suicide are but a few of the difficulties encountered. Finally, some modifications of DSM III are suggested in order to improve its clinical usefulness.     

Temporal and spatial profiles of cell loss after spinal cord injury: Reduction by a metalloporphyrin

This study presents quantitative temporal and spatial profiles of neuronal loss and apoptosis following a contusion spinal cord injury (50 g . cm). The profiles were evaluated by counting the cresol violet-stained surviving cells and the total number of TUNEL-positive cells and of TUNEL-positive neurons in sections 0- 4 mm from the epicenter and 1, 6, 12, 24, 48, and 72 hr and 1 week postinjury. We demonstrated that neurons continue to disappear over 1 week postinjury and that neuronal loss shifts to areas longer distances from the epicenter over time. TUNEL-positive cells in both gray and white matter appeared after 6 hr, gradually increased to a peak level after 48 hr, and declined by 72 hr postinjury. TUNEL-positive neurons peaked earlier and were present for 1 week, although the total number of neurons was reduced significantly by the end of the week. The neuronal loss and apoptosis were partially prevented by a metalloporphyrin [Mn(III) tetrakis (4-benzoic acid) porphyrin (MnTBAP)]. We demonstrated that MnTBAP (10 and 50 mg/kg, given intraperitoneally) significantly reduced neuronal death in the sections 1-2.5 mm rostral and 1 mm caudal from the epicenter compared with that in the vehicle-treated group, suggesting MnTBAP is more effective in the sections rostral than in those caudal to the epicenter. MnTBAP (10 mg/kg) significantly reduced the number of TUNEL-positive neurons in the sections 1 mm caudal from the epicenter. Our profiles provide a database for pharmacological intervention, and our results on MnTBAP treatment support an important role for antioxidant therapy in spinal cord injury.     

The effects of antithrombin III, heparin and a novel heparinoid infusions on the bleeding tendency using an experimental model in the rat

The effects of selective increase of plasma AT-III concentration (to 2 U/ml and 8 U/ml) in the presence or absence of low dose commercial heparin and a novel natural heparinoid (Org 10172) on APTT, clotting factors and bleeding were investigated in an experimental model in rats.

Slight increases in the APTT were observed with: a. Org 10172, b. both AT-III doses and c. combinations hereoff. However, synergism was observed in the prolongations of the APTT when the AT-III concentrate (70 U/kg and 500 U/kg) was combined with both heparin dosages. AT-III concentrates (70 U/kg and 500 U/kg) or Org 10172 (2,5 mg/kg) separately or in combination showed no effect on bleeding. Heparin (0,125 and 0,25 mg/kg i.v.) also showed no effect on bleeding neither if they were combined with the lower dose AT-III. However, heparin (both dosages) combined with 500 U/kg of AT-III concentrates significant increased blood loss.

These observations suggest that infusion of AT-III concentrate additionally to low dose heparin therapy did not increase bleeding in the rat model used provided that extreme high AT-III plasma levels (8 U/ml) were avoided. The novel natural heparinoid Org 10172 alone or combined with either AT-III dosage induced no increased bleeding.     

Meningioma in the anterior III ventricle in a child

A case is described of meningioma in the anterior part of the III ventricle in a 14-year-old girl. The mass was successfully removed through a transcallosal approach.     

Fluorogenic substrate assay of antithrombin III: A clinical study

The fluorogenic substrate assay of antithrombin III (AT III) was compared with a thrombin inhibition (two-stage) clotting test and a radial immunodiffusion assay. Normal ranges based on a population of 25 individuals were 88–121% (fluorogenic substrate), 72–111% (clotting) and 22.5–35.3 mg/dl (RID). A clinical comparison of the methods showed a linear relationship between the fluorogenic substrate and immunologic methods (r = 0.69, p<0.005), as well as between the fluorogenic substrate and clotting methods (r = 0.75, p<0.005). The fluorogenic substrate assay reflected the highest incidence of low AT III levels in all three clinical groups included (36 patients with arteriosclerosis, 18 with fractures and 37 with thrombosis/embolism).     

Urocortin III, a brain neuropeptide of the corticotropin-releasing hormone family: modulation by stress and attenuation of some anxiety-like behaviours

Following its discovery 20 years ago, corticotropin-releasing hormone (CRH) has been postulated to mediate both hormonal and behavioural responses to stressors. Here, we characterize and describe a behavioural role for the murine gene, UcnIII, which encodes a recently discovered CRH-related neuropeptide, urocortin III. We found that mouse UcnIII is expressed predominantly in regions of the brain known to be involved in stress-related behaviours, and its expression in the hypothalamus increases following restraint. In addition, we found that intracerebroventricular administration of mUcnIII stimulates behaviours that are associated with reduced anxiety, including exploration of an open field and decreased latency to enter the lit compartment of a dark-light chamber, but has no effect on the elevated-plus maze. Finally, we found that mUcnIII does not exert any effects on the hormonal stress response. Based upon our findings, UcnIII may be an endogenous brain neuropeptide that is modulated by stress and stimulates behaviours associated with reduced anxiety. In this capacity, UcnIII may attenuate stress-related behaviours, which may be useful both to help cope with stressful situations as well as to avoid pathology associated with excessive reaction to stressors.     

Serum adipokine levels in adults with a history of childhood maltreatment

Individuals with a history of childhood maltreatment present increased rates of metabolic disturbances, but the underlying mechanisms for such phenomena are poorly understood. This study examined whether the secretion of adipokines, adipocyte-derived inflammation markers closely associated with metabolic disorders, is altered in individuals with a history of childhood maltreatment. The serum levels of inflammatory markers adiponectin and resistin were measured from 147 general population participants who had a history of adverse mental symptoms, and who also reported their experiences of childhood maltreatment. Participants with experiences of childhood maltreatment (n=30) had lowered levels of serum adiponectin (p=0.007) and resistin (p=0.028). The differences in adiponectin levels persisted in multivariate modeling with adjustments for age, gender, and body mass index (OR for each 1 standard deviation decrease in the serum adiponectin level 2.65, 95% CI 1.31-5.35, p=0.007). Additional adjustments for marital status or a diagnosis of major depressive disorder, or the exclusion of individuals using NSAIDs, oral corticosteroids, or antidepressants did not alter the results. The association between resistin levels and childhood maltreatment did not remain independent in the same models. Our findings suggest that in individuals with previously reported adverse mental symptoms, a history of childhood maltreatment is independently associated with lowered levels of the anti-inflammatory marker adiponectin. This may lead to a lowered anti-inflammatory buffer capacity, which can, in turn, increase the susceptibility to physical and psychological states characterized by pronounced pro-inflammation.     

Polymorphic variation in the dopamine D4 receptor predicts delay discounting as a function of childhood socioeconomic status: evidence for differential susceptibility

Inconsistent or null findings among studies associating behaviors on the externalizing spectrum—addictions, impulsivity, risk-taking, novelty-seeking traits—with presence of the 7-repeat allele of a common length polymorphism in the gene encoding the dopamine D4 receptor (DRD4) may stem from individuals’ variable exposures to prominent environmental moderators (gene × environment interaction). Here, we report that relative preference for immediate, smaller rewards over larger rewards delayed in time (delay discounting), a behavioral endophenotype of impulsive decision-making, varied by interaction of DRD4 genotype with childhood socioeconomic status (SES) among 546 mid-life community volunteers. Independent of age, sex, adulthood SES and IQ, participants who were both raised in families of distinctly low SES (low parental education and occupational grade) and carried the DRD4 7-repeat allele discounted future rewards more steeply than like-reared counterparts of alternate DRD4 genotype. In the absence of childhood socioeconomic disadvantage, however, participants carrying the 7-repeat allele discounted future rewards less steeply. This bidirectional association of DRD4 genotype with temporal discounting, conditioned by participants’ early life circumstances, accords with a recently proposed developmental model of gene × environment interaction (‘differential susceptibility’) that posits genetically modulated sensitivity to both adverse and salubrious environmental influences.     

Cytoplasmic body myopathy: Report on a family and review of the literature

A 15-year-old girl who was seen for scoliosis presented with cardiorespiratory failure associated with a respiratory infection. She was found to have weakness predominant in the face, sternomastoid, proximal limb, respiratory, spinal and cardiac muscles. The serum creatine kinase level was slightly elevated and the electrocardiogram was abnormal. The electromyograph was consistent with a myopathy. The course was malignant. Her 14-year-old brother had similar findings and succumbed at the age of 14 and one-half years from cardiorespiratory failure. The mother had minimal weakness of proximal limb muscles since early life. The tendon reflexes were normal as was the serum creatine kinase level. The course was benign. On light microscopy the muscle biopsy in the girl showed fibre diameter variation, centrally placed nuclei, necrosis, fibrosis and cytoplasmic bodies. The muscle biopsy in the brother and mother had similar findings except that the inclusion bodies were not seen in the mother. On electron microscopy, the girl showed typical cytoplasmic bodies, involving predominantly type 1 fibres. The mother also had these structures. The literature is reviewed and the origin, pathogenesis and aetiology of the cytoplasmic body are discussed.