Experimental cutaneous leishmaniasis. III. Effects of thymectomy on the course of infection of CBA mice with leishmania tropica

This paper describes the course of infection and the immunological response in thymus-deprived and normal CBA mice after intradermal inoculation with promastigotes of L. tropica.

Infection of normal mice resulted in the development of a cutaneous ulcer healing within 12 weeks. As the infection progressed and the draining lymph nodes increased in weight, changes in the paracortical and follicular regions were accompanied by the development of delayed hypersensitivity and the production of antibodies detectable by immunofluorescence and a parasite agglutination test.

Lesions in thymectomized irradiated mice healed more slowly and the draining lymph nodes were smaller than in normal mice. Follicular reactions were feeble and paracortical activity depressed. The most noticeable feature of these lymph nodes was a persistent and intense macrophage infiltration. Delayed hypersensitivity and antibodies detectable by immunofluorescence were correspondingly low; but parasite agglutinating antibody was not depressed. The course of infection and immunological response of a control group of sham thymectomized, irradiated mice resembled that of normal mice.

These experiments indicate that thymus-dependent cell populations play an important role in the response of mice to infection with L. tropica.

     

Is fecundability associated with month of birth? An analysis of 19th and early 20th century family reconstitution data from The Netherlands

The relationship between fecundability and month of birth was investigated in a cohort of 1526 women who married between 1802 and 1929, using only women whose first marriage occurred before the age of 35 years. On the basis of their time to pregnancy (TTP, calculated as time between wedding and first birth minus gestational length), women were categorized into two groups: fecunds (TTP up to 12 months or prenuptial conceptions, n = 1348) and subfecunds (TTP >18 months, n = 118). By use of logistic regression, cosinor functions with a period of 1 year or 6 months and variable shift and amplitude were fitted through the monthly odds of subfecunds versus fecunds. The best fitting curve was unimodal, with a zenith in September (P = 0.13 for H0: no differences). Exclusion of childless women (n = 36, minimum follow-up 5 years) from the subfecunds led to a similar curve (P < 0.01), while childless women, as compared with fecunds, showed a birth distribution that was best represented with a bimodal curve with zeniths in January and July (P = 0.06). This study provides evidence for the existence of differences in fecundability by month of birth. The cause of this relationship is unclear, but may lie in a melatonin-dependent circannual variability of the quality of the oocyte.      

Regional mapping of the gene encoding dihydroorotate dehydrogenase,an enzyme involved in UMP synthesis,electron transport,and superoxide generation,to human chromosome region 16q22

De novo UMP synthesis is a critical metabolic pathway for nucleic acid synthesis and for a variety of metabolic pathways. The pathway is a target for many widely used cancer chemotherapy agents, several of which are pyrimidine analogs. Humans and cattle have been described with mutations in UMP synthesis that lead to serious inborn errors of metabolism. Dihydroorotate dehydrogenase (EC 1.3.3.1) (DHODH) carries out the fourth committed step in the pathway and may also be important for mitochondrial electron transport and oxygen radical metabolism. We report here that the gene encoding this enzyme in humans is located in the chromosomal region 16q22. With the mapping of DHODH, the mapping of all the steps of UMP synthesis is complete. All three genes involved map to different human chromosomes. This information is important in consideration of regulation of UMP synthesis in mammals, including humans.     

A sensitive assay for detecting low-affinity interactions at the cell surface reveals no additional ligands for the adhesion pair rat CD2 and CD48

The ligand for the T cell antigen CD2 is CD48 in rodents, but CD58 in humans. The extracelluar parts of these three antigens are structurally related in that all contain two immunoglobulin superfamily (IgSF) domains. There have been reports of alternative ligands for CD2 in the human, but not so far in rodents. We describe the analysis of ligands for rat CD2 and CD48 using fluorescent beads capable of displaying a high ligand density and detecting low-affinity interactions like that of CD2 with CD48 (Kd = 60 ? 90 μM). Monovalent chimeric proteins containing the two IgSF domains of rat CD48 or CD2 and domains 3 and 4 of rat CD4 (CD4d3+4) were anchored to fluorescent covaspheres^TM via a CD4 monoclonal antibody (mAb) with the CD48 or CD2 domains available for ligand binding. Multivalent CD48-CD4d3 + 4 covaspheres^TM gave strong specific binding to rat CD2 expressed on the surface of transfected Jurkat cells. CD48-CD4d3+4 was compared with CD48-IgG and CD48-IgM as tools for detecting binding at the cell surface. Soluble divalent CD48-IgG and decavalent CD48-IgM bound to soluble CD2 with a K_off of around 10^?3 s^?1 as determined using a BIAcore^TM biosensor. However, binding to cells by CD48-IgG and CD48-IgM was only detectable when they were immobilized on covaspheres^TM and represented no increase in sensitivity over CD48-CD4 covaspheres^TM when tested for binding to cells expressing high and low levels of CD2. CD48-CD4d3 + 4 covaspheres^TM only bound to rat cells expressing CD2. In the reverse orientation, binding of CD2-CD4d3 + 4 covaspheres^TM was dependent on expression of CD48. Pre-incubation of cells with CD2 or CD48 mAb abolished all binding of CD48-CD4d3 + 4 or CD2-CD4d3 + 4, respectively. The data provide no evidence for an alternative ligand for rat CD2 or CD48.     

Perivascular Drainage of Amyloid-β Peptides from the Brain and Its Failure in Cerebral Amyloid Angiopathy and Alzheimer's Disease

Alzheimer's disease is the commonest dementia. One major characteristic of its pathology is accumulation of amyloid-β (Aβ) as insoluble deposits in brain parenchyma and in blood vessel walls [cerebral amyloid angiopathy (CAA)]. The distribution of Aβ deposits in the basement membranes of cerebral capillaries and arteries corresponds to the perivascular drainage pathways by which interstitial fluid (ISF) and solutes are eliminated from the brain—effectively the lymphatic drainage of the brain. Theoretical models suggest that vessel pulsations supply the motive force for perivascular drainage of ISF and solutes. As arteries stiffen with age, the amplitude of pulsations is reduced and insoluble Aβ is deposited in ISF drainage pathways as CAA, thus, further impeding the drainage of soluble Aβ. Failure of perivascular drainage of Aβ and deposition of Aβ in the walls of arteries has two major consequences: (i) intracerebral hemorrhage associated with rupture of Aβ-laden arteries in CAA; and (ii) Alzheimer's disease in which failure of elimination of ISF, Aβ and other soluble metabolites from the brain alters homeostasis and the neuronal environment resulting in cognitive decline and dementia. Therapeutic strategies that improve elimination of Aβ and other soluble metabolites from the brain may prevent cognitive decline in Alzheimer's disease.     

Vasopressin-elicited refractoriness of the response to vasopressin in toad urinary bladder

Incubation of the urinary bladder of Bufo marinus with high concentrations of vasopressin produces refractoriness to subsequent stimulation of water permeability by low concentrations of vasopressin. Development of refractoriness is directly dependent on concentration of vasopressin and duration of incubation with the hormone. Refractoriness develops in the absence of transepithelial water flow, is evident following a 2-h recovery period of incubation in hormone-free Ringer solution, and is reversed after prolonged incubation in hormone-free Ringer solution. Development and reversal of refractoriness is not altered by actinomycin D or cycloheximide. The steps at which refractoriness develops have been identified partially. Under different conditions, refractoriness involves: 1) reduced vasopressin-sensitive adenylate cyclase activity, 2) reduced epithelial cell cAMP accumulation in response to vasopressin the absence of demonstrable change in vasopressin-sensitive adenylate cyclase activity, cAMP phosphodiesterase activity, or loss of cAMP into the Ringer solution, and 3) refractoriness of water permeability response to exogenous cAMP.