Glatiramer acetate-specific antibody titres in patients with relapsing / remitting multiple sclerosis and in experimental autoimmune encephalomyelitis

Glatiramer acetate (GA) is an immunomodulatory drug approved for the treatment of clinically isolated syndrome (CIS) and relapsing/remitting multiple sclerosis (RRMS). As an antigen-based therapy, GA induces GA-specific antibodies in treated patients and animals. GA-specific antibodies do not neutralize therapeutic effects on relapses and disability. Rather, it has been suggested that GA-specific antibodies may be associated with improved clinical outcomes. We evaluated antibody responses in eight patients with RRMS treated with GA for 15 months and antibody responses in GA-treated C57BL/6 mice before and after induction of experimental autoimmune encephalomyelitis (EAE). There were no significant differences from pretreatment levels of total IgE or GA-specific IgE in patients with RRMS. Total IgG1, IgG3 and GA-specific IgG4 were significantly increased at 15 months of GA treatment. Antibody type and titre were not associated with clinical outcomes, i.e. expanded disability status scale (EDSS) score, disease burden on magnetic resonance images (MRI) or clinical relapses. In contrast, mice with EAE showed a marked increase in GA-specific IgE and GA-specific IgG1 antibody responses. GA-treated mice demonstrated improved clinical symptoms and lower mortality than untreated controls. Our results suggest that antibody responses to GA are heterogeneous among patients with RRMS, with no apparent association between antibody response and clinical outcomes. Clinical improvements in EAE-induced GA-treated mice suggest that GA-specific IgE and IgG1 may contribute to GA treatment effects in EAE.     

The collecting duct,dopamine and vasopressin‐dependent hypertension

AVP not only increases osmotic water permeability (P_f) in the rat cortical collecting duct (CCD), but also acts synergistically with aldosterone to augment sodium reabsorption (J_Na). These effects are inhibited by catecholamines via α₂ adrenergic receptors, and by dopamine. We review here studies designed to determine the mechanism and receptor involved in dopamine action. The inhibitory effect of dopamine on Na⁺ and water transport was found to be reversible, and was not produced by agonists specific to D_1A and D_1B receptors. D₂‐type (D₂, D₃ or D₄) receptors and activation of the GTP‐binding protein G_i were implicated by the observation that dopamine had no inhibitory effect when J_Na and P_f were stimulated by a cyclic AMP analogue plus isobutylmethylxanthine. The only dopaminergic antagonist that reversed the inhibitory effect of dopamine was clozapine, which is relatively D₄‐specific. We also found that dopamine or D₁‐specific agonists by themselves had no effect on cAMP production. However, dopamine inhibited the high rate of AVP‐dependent cAMP production, and this effect of dopamine was reversed by clozapine but not other antagonists or by inhibitors of protein kinase C. The D₄ receptor was observed in western blots of renal cortical proteins, and it was localized to the collecting duct by RT‐PCR and immuno‐histochemistry using a D₄‐specific antibody. These results show that at least a portion of the natriuretic effect of dopamine can be attributed to inhibition of AVP‐dependent Na⁺ reabsorption by the CCD, and they introduce another signalling system as a candidate in the aetiology of low‐renin, salt‐dependent hypertension.     

“If Everyone Else Is Having This Talk With Their Doctor,Why Am I Not Having This Talk With Mine?”: The Experiences of Sexuality and Sexual Health Education of Young Women With Spina Bifida

IntroductionWomen with spina bifida are sexually active, but most never discuss this topic with providers.AimTo determine what women with spina bifida understand about their sexual health, how they learned about it, what questions they have, and their experiences with their sexuality.MethodsFor this qualitative study, women with spina bifida ages 16 and older without marked developmental delay were individually interviewed. 25 women with spina bifida participated (mean age 27.1 years, range 16–52). Interviews were independently coded for themes by 3 reviewers, using Grounded Theory, with disagreements resolved by consensus.Main Outcome MeasuresWe identified overlapping themes regarding the women’s perception and experience of their sexuality and sexual health education.Results17 of the 25 (68%) participants had been or were currently sexually active. 5 themes emerged regarding their understanding of their sexuality and their sexual experiences: (i) being perceived as asexual, (ii) sources for sex education, (iii) need for spina bifida–specific sex education, (iv) impact of spina bifida–specific features on sexual encounters, and (v) perceived relationship between low sexual self-confidence and risk for sexual assault.Clinical ImplicationsWomen with spina bifida are sexual beings, but they are perceived as asexual by providers, which prevents them from getting adequate sexual health education and leaves them with misconceptions and unanswered questions, as well as vulnerable to sexual abuse.Strength & LimitationsThe strengths of this study include the diversity of women interviewed, including their age, severity of disability, and experiences with their sexuality, as well as the ability to reach thematic saturation. The limitation of this study is that most women received treatment at a single Midwestern tertiary referral center in the United States.ConclusionIncluding sexual health discussions in the usual care of women with spina bifida is critical to enhancing their sexual confidence and experience and preventing sexual abuse.Streur CS, Schafer CL, Garcia VP, et al. “If Everyone Else Is Having This Talk With Their Doctor, Why Am I Not Having This Talk With Mine?”: The Experiences of Sexuality and Sexual Health Education of Young Women With Spina Bifida. J Sex Med 2019;16:853–859.     

Effect of atmospheric ammonia on mortality rate of rats with barbiturate intoxication

Ammonia inhalation (0.84–1.07 mg/liter, 3 h) was accompanied by a 65% increase in ammonia concentration in mixed blood of intact rats. This treatment did not cause death of intact animals, but potentiated the lethal effect of sodium thiopental and inhibited external respiration and O₂ consumption in animals. The resistance of rats to the lethal effect of barbiturate tended to decrease under conditions of experimental hyperammonemia induced by intraperitoneal injection of ammonium acetate in a nonlethal dose (6 mmol/kg). Our results indicate that potentiation of the toxic effect of barbiturates by atmospheric ammonia is related to its resorptive effects. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 6, pp. 634–636, June, 2007     

Hyperammonemic encephalopathy in urinary diversion with urea-splitting urinary tract infection

We present two cases of hyperammonemic encephalopathy secondary to urea-splitting urinary tract infection with urinary diversion. One patient had a ureterosigmoidostomy, the other an ileal loop diversion. Neither patient had significant underlying liver disease, but both had considerable muscle atrophy that may have predisposed them to develop hyperammonemia. Medical therapy did not provide long-term control of symptoms. In both cases, hyperammonemic encephalopathy resolved after revision of their urinary diversions. The probable mechanism of the metabolic derangements produced by urea-splitting urinary tract infections is reviewed. We suggest that patients with urinary diversion who develop hyperammonemic encephalopathy secondary to a urea-splitting urinary tract infection be treated with surgical revision of the urinary system to improve drainage and decrease bowel contact time.     

Molecular cloning of mevalonate kinase and regulation of its mRNA levels in rat liver.

Mevalonate kinase [ATP:(R)-mevalonate 5-phosphotransferase, EC 2.7.1.36] may be a regulatory site in the cholesterol biosynthetic pathway, and a mutation in the gene coding for this enzyme is thought to cause the genetic disease mevalonic aciduria. To characterize this enzyme, a rat liver cDNA library was screened with a monospecific antibody, and a 1.7-kilobase cDNA clone coding for mevalonate kinase was isolated. The complete DNA sequence was determined, and the longest open reading frame coded for a protein containing 395 amino acids with a deduced molecular weight of 41,990. Identification of the cDNA clone was confirmed by expression of enzyme activity in yeast and by protein sequence data obtained from sequencing purified rat mevalonate kinase. The deduced amino acid sequence of mevalonate kinase contained a motif for the ATP-binding site found in protein kinases, and it also showed sequence homology to the yeast RAR1 protein. The size of mevalonate kinase mRNA in rat liver was approximately 2 kilobases. Treatment with diets containing cholesterol-lowering agents caused an increase in both mevalonate kinase activity and mRNA levels, whereas diets containing 5% cholesterol lowered the levels of both enzyme activity and mRNA. These data indicate that long-term regulation of enzyme activity in rat liver is controlled by changes in the levels of mevalonate kinase mRNA.     

Pulmonary histiocytosis X: comparison of radiographic and CT findings

The authors retrospectively evaluated radiographs, computed tomographic (CT) scans, and results of pulmonary function tests (when available) for 17 patients with biopsy-proved pulmonary histiocytosis X. In 11 patients, high-resolution CT was used. In 12 patients, CT demonstrated cystic air spaces, usually less than 10 mm in diameter. In three of these 12, cysts were the only abnormality, but in six others, nodules (usually less than 5 mm in diameter) were also present. Two patients had only nodules and one, only emphysema. CT showed that many lesions that appeared reticular on plain radiographs were actually cysts. CT showed no central or peripheral concentration of lesions, but it did reveal that many small nodules were distributed in the centers of secondary lobules around small airways. CT findings correlated better with the diffusing capacity (rho = -0.71) than did the plain radiographic findings (rho = -0.57). Thus, CT was better than radiography at showing the morphology and distribution of lung abnormalities.     

Comparison of digital systems and conventional dental film for the detection of approximal enamel caries

Objectives

The aims of this study were (1) to compare the accuracy of the detection of approximal enamel caries lesions using three intraoral storage phosphor plate digital systems and one conventional film-based radiographic system; and (2) to determine whether there is a correlation between the histological and radiographic measurements of enamel caries.

Methods

160 approximal surfaces were radiographed under standardized conditions using three storage phosphor stimulable systems (DenOptix and Digora FMX with white and blue plates), and one film system (Insight film). 17 observers scored the images for the presence and depth of caries using a 4-point scale. The presence of caries was validated histologically (gold standard). Two-way analysis of variance was used to test the differences in sensitivity, specificity and overall accuracy (TP + TN). The data from the radiographic and histological measurements were statistically analysed by Spearman’s rank correlation coefficient.

Results

Two-way analysis of variance and the post hoc t-test demonstrated that Digora (white plate) had higher specificity and overall accuracy values than DenOptix (P = 0.021); there was no statistically significant difference among the other imaging modalities (P > 0.05). There was no significant correlation between the histological depth measurements and the radiographic measurements from Digora (blue plate) (P = 0.43), Digora (white plate) (P = 0.15), DenOptix (P = 0.17) and Insight film (P = 0.06).

Conclusions

The results suggest that (1) the performance of the three storage phosphor image plate systems was similar to that of the Insight film for detection of approximal enamel caries, and (2) the increase in histological depth of enamel caries was not significantly correlated with radiographic measurements.     

Bleeding and thrombosis in the myeloproliferative disorders

Bleeding and thrombosis are major causes of morbidity and mortality in patients with myeloproliferative disorders. The significance of uncontrolled polycythemia as a risk factor for thrombosis in these patients has been established. However, the role of thrombocytosis in the pathogenesis of hemostatic complications remains controversial. Abnormalities of platelet function and prolongation of the bleeding time occur in a highly variable number of cases. Specific platelet defects that have been identified in the myeloproliferative defects include abnormal platelet morphology, acquired storage pool disease, platelet membrane abnormalities, and abnormal arachidonic acid metabolism. Causal relationships between any of these specific abnormalities and either bleeding or thrombosis have not been clearly established. The therapeutic efficacy of myelosuppression to reduce the platelet count in patients with thrombocytosis and the role of antiplatelet drugs in the myeloproliferative disorders are controversial issues.