Turnover in humans of β2-microglobulin: the constant chain of HLA-antigens

The turnover of beta 2-microglobulin, the common subunit of the HLA antigens, has been examined in normal subjects and in some patients with kidney disorders, multiple myeloma and rheumatoid arthritis. All patients displayed elevated serum levels of beta 2-microglobulin. The plasma disappearance curve of 125I-beta 2-microglobulin demonstrated that the protein has a rapid turnover (t 1/2 = 2.1 h; range 1.1-2.8 h) in normal persons and in patients with a normal glomerular filtration rate. In patients with kidney disorders the impaired renal filtration prolonged the turnover time and led to elevated serum levels of beta 2-microglobulin. Simultaneous measurements of 125I-beta 2-microglobulin in serum and urine allowed estimations of the beta 2-microglobulin net reabsorption in the renal tubuli. Two patients with renal disease reabsorbed 84% and 89%, respectively, of the beta 2-microglobulin filtered in the glomeruli. In normal persons the net reabsorption is close to 100%. In patients with normal kidney function increased serum levels of beta 2-microglobulin seem to be due to an increased synthetic rate of the protein as the elimination rate is normal. HLA antigen heavy chains in serum are present in smaller amounts than beta 2-microglobulin. The present data, therefore, suggest an imbalanced synthesis of the two chains.     

Pharmacological Activation of IKr Impairs Conduction in Guinea Pig Hearts

Activation of I_Kr Impairs Conduction. Introduction: The hERG (Kv11.1) potassium channel underlies cardiac I_Kr and is important for cardiac repolarization. Recently, hERG agonists have emerged as potential antiarrhythmic drugs. As modulation of outward potassium currents has been suggested to modulate cardiac conduction, we tested the hypothesis that pharmacological activation of I_Kr results in impaired cardiac conduction. Methods and Results: Cardiac conduction was assessed in Langendorff‐perfused guinea pig hearts. Application of the hERG agonist NS3623 (10 μM) prolonged the QRS rate dependently. A significant prolongation (16 ± 6%) was observed at short basic cycle length (BCL 90 ms) but not at longer cycle lengths (BCL 250 ms). The effect could be reversed by the I_Kr blocker E4031 (1 μM). While partial I_Na inhibition with flecainide (1 μM) alone prolonged the QRS (34 ± 3%, BCL 250 ms), the QRS was further prolonged by 19 ± 2% when NS3623 was added in the presence of flecainide. These data suggest that the effect of NS3623 was dependent on sodium channel availability. Surprisingly, in the presence of the voltage sensitive dye di‐4‐ANEPPS a similar potentiation of the effect of NS3623 was observed. With di‐4‐ANEPPS, NS3623 prolonged the QRS significantly (26 ± 4%, BCL 250 ms) compared to control with a corresponding decrease in conduction velocity. Conclusion: Pharmacological activation of I_Kr by the hERG agonist NS3623 impairs cardiac conduction. The effect is dependent on sodium channel availability. These findings suggest a role for I_Kr in modulating cardiac conduction and may have implications for the use of hERG agonists as antiarrhythmic drugs. (J Cardiovasc Electrophysiol, Vol. 21, pp. 923‐929, August 2010)     

Programmed cell death‐10 enhances proliferation and protects malignant T cells from apoptosis

Lauenborg B, Kopp K, Krejsgaard T, Eriksen KW, Geisler C, Dabelsteen S, Gniadecki R, Zhang Q, Wasik MA, Woetmann A, Odum N. Programmed cell death‐10 enhances proliferation and protects malignant T cells from apoptosis. APMIS 2010; 118: 719–28. The programmed cell death‐10 (PDCD10; also known as cerebral cavernous malformation‐3 or CCM3) gene encodes an evolutionarily conserved protein associated with cell apoptosis. Mutations in PDCD10 result in cerebral cavernous malformations, an important cause of cerebral hemorrhage. PDCD10 is associated with serine/threonine kinases and phosphatases and modulates the extracellular signal‐regulated kinase pathway suggesting a role in the regulation of cellular growth. Here we provide evidence of a constitutive expression of PDCD10 in malignant T cells and cell lines from peripheral blood of cutaneous T‐cell lymphoma (Sezary syndrome) patients. PDCD10 is associated with protein phosphatase‐2A, a regulator of mitogenesis and apoptosis in malignant T cells. Inhibition of oncogenic signal pathways [Jak3, Notch1, and nuclear factor‐κB (NF‐κB)] partly inhibits the constitutive PDCD10 expression, whereas an activator of Jak3 and NF‐κB, interleukin‐2 (IL‐2), enhances PDCD10 expression. Functional data show that PDCD10 depletion by small interfering RNA induces apoptosis and decreases proliferation of the sensitive cells. To our knowledge, these data provide the first functional link between PDCD10 and cancer.     

Short Communication

Heterozygous, de novo mutations in the glial fibrillary acidic protein (GFAP) gene were recently found to be associated with Alexander disease. We examined the functional effect of such mutations, and observed a decrease in GFAP dimerization. This effect behaves in a dominant fashion and points towards a potential mechanism in pathogenesis.     

Circulating Thyroid Antibodies in Congenital Hypothyroidism

ABSTRACT. The role of maternal thyroid antibodies in congenital hypotyroidism is controversial. We have analysed serum thyroid antibodies in patients and their mothers. In a bioassay, antibodies interacting with thyroid cells were analysed by measuring of TSH-stimulated CAMP production in a rat thyroid cell line, FRTLS. Serum antibodies against the TSH receptor, thyroid peroxidase and thyroglobulin were determined by radioreceptor assay and enzyme-linked immunosorbent assays. The bioassay was performed with IgG preparations from 89 mothers of children with congenital hypothyroidism. Analyses for TSH receptor antibodies and thyroid peroxidase/thyroglobulin antibodies were performed on 144 and 118 sera of newborn patients respectively. No evidence of an increased prevalence of thyroid antibodies was found on comparison with controls. One infant had transient neonatal hyperthyrotropinaemia because of TSH receptor blocking antibodies transferred from the mother. Our data indicate that, apart from transplacental transfer of TSH receptor antibodies, maternal immunoglobulins have a limited role in the aetiology of congenital thyroid dysfunction.     

Consumption of Care Among Problem Drinkers in a Small Industrial Town in Sweden

Romelsj A Consumption of care among problem drinkers in a smallindustrial town in Sweden. Family Practice 1988; 5: 271–277. A study of visits to general practitioners, district nurses,occupational health doctors, social services and inpatient careduring one year was conducted for all 282 male and 30 femaleproblem drinkers identified from various registers in a Swedishindustrial town. The 4.5% male problem drinkers aged 20 to 79years accounted for 13.8% of visits to general practitioners,15.3% of stays in somatic departments, 74.1% of stays in psychiatriccare, and over 50% of visits to the social services by malesin those ages. Care consumption by the problem drinkers wasfor both sexes highest among young people. Data about alcoholproblems at any time could be found in 42% of the records formale problem drinkers, while 21% were given a diagnosis of alcoholismby their general practitioner. The problem drinkers were givena great variety of diagnoses. The results emphasize that allpatients should be asked about alcohol habits and that educationand programmes for prevention and treatment should be organizedby primary care together with other relevant parties.     

Pattern of Sertoli cell degeneration in cryptorchid prepubertal tests

Seventy-three testicular biopsies from 54 children (aged 2 months-14 years) with undescended testes were examined by light and electron microscopy. The biopsies included abdominal, inguinally fixed, inguinally moveable, and retractile testes. Alterations in Sertoli cell morphology were found in all biopsies. The alterations included dilated elements of rough endoplasmic reticulum, vacuolization of the cytoplasm, mitochondria with poorly preserved cristae, increase in electron density of the matrix, elongation of the nuclei, and irregularities of the nuclear membrane. According to the numerical appearance of these cells and to the extent of lesions in single Sertoli cells, seven phases in the continuous process of tubular alteration were distinguished. The most severe tubular damaged (phase VII) occurred when the seminiferous epithelium consisted exclusively of necrotic cells. All phases of tubular alterations were seen regularly in each of the biopsies investigated. Germ cells occurred only in phases I-IV and were never observed in tubules in phases V-VII. Significant differences became evident between inguinal and retractile testes by morphometric evaluation. It was demonstrated that the number of germ cells per cross-sectioned tubule (S/T value) correlated negatively with the percentage of tubules in phases V-VII. In contrast to inguinal testes, a complete absence of Sertoli cells and an S/T value less than 0.1 were never found in retractile testes and the percentage of tubules in phases V-VII was reduced significantly compared with inguinal testes. Our findings indicate that (i) maldescended testis in patients between 1 and 15 years-of-age is associated with a special pattern of Sertoli cell degeneration; (ii) Sertoli cell degeneration is a continuous process, which can lead eventually to complete dissolution of the seminiferous epithelium; (iii) total degeneration is not related to age but is dependent on testicular position; (iv) a defined phase of degeneration excludes germ cell development, and therefore enhanced Sertoli cell degeneration in cryptorchid testes must also account for the reduction in germ cell number.     

Role of Gustatory and Postingestive Actions of Sweeteners in the Generation of Positive Affect as Evaluated by Place Preference Conditioning

Either an 18% sucrose or a 0·1% saccharin solution was used as reward in a conditioned place preference procedure. The respective solution was consumed immediately before the subject was confined to the non-preferred compartment of a place preference box. In this way only the affective reaction produced by the rewarding stimulus participated in place conditioning. Non-deprived rats consumed similar quantities of the two solutions, suggesting that they were equally rewarding. Yet only sucrose induced place preference. The lack of effect of saccharin may have been due to weaker positive affect or to an inability to induce an affective state that outlasted consummatory behavior. The first possibility was evaluated in the second experiment. Food-deprived rats were subjected to a discrimination learning task in a runway with plain water, sucrose or saccharin as reinforcer. Sucrose sustained running responses and produced improvement of discrimination behavior. Saccharin had a small effect at the first sessions only. It was concluded that saccharin is less rewarding than sucrose. In a final experiment, one group of rats was injected with glucose (2 g/kg) 17 min before being introduced in the non-preferred compartment of a place preference box. Another group was given the same dose of glucose just before drinking saccharin for 15 min. Immediately thereafter place conditioning was performed. Glucose alone had no effect, while a place preference was established when glucose injection was combined with saccharin drinking. These results show that the positive affect produced by sweet substances does not outlast consummatory behavior in the absence of postabsorptive actions.