Engagement of the CD4 receptor inhibits the interleukin-2-dependent proliferation of human T cells transformed by Herpesvirus saimiri

Infection with Herpesvirus saimiri, a tumor virus of non-human primates, transformed human CD4⁺ T cell clones to permanent interleukin (IL)-2-dependent growth without need for restimulation with antigen and accessory cells. The IL-2-dependent proliferation of these cells was dramatically inhibited by soluble anti-CD4 whole antibodies, F(ab′)₂ and Fab fragments, and also by gp 120 of human immunodeficiency virus. The inhibition was not due to cell death and could be overcome by high concentrations of exogenous IL-2. Cell surface expression of CD4, and to a lesser degree the density of the IL-2 receptor α chain, were reduced upon anti-CD4 treatment. After long lasting (>12h) incubation with anti-CD4, abundance and activity of CD4-bound p56^lck were diminished while the free fraction of p56^lck remained unchanged. Since IL-2 binding to its receptor activated only the CD4-bound fraction of p56^lck, the IL-2-induced p56^lck activity was diminished after long-term CD4 ligation. Taken together, our results suggest a cross talk between CD4- and IL-2 receptor-mediated signaling via p56^lck.     

Heterogeneity in maple syrup urine disease: Aspects of cofactor requirement and complementation in cultured fibroblasts

Fibroblast strains derived from six patients with maple syrup urine disease have been investigated for their requirements of the cofactors NAD, CoASH, Mg⁺⁺ and TPP in comparison with 10 normal control strains. The reconstitution of the decarboxylase function of branched chain α-keto acid (BCKA) dehydrogenase complex in lysed cells was studied with respect to the substrates u-keto-isocaproic acid, α-keto-isovaleric acid, and α-keto-β-methylvaleric acid (KIC, KIVA, MEVA). The enzyme activity of all normal control strains for the substrates KIC and KIVA was not reconstituted by TPP + Mg⁺⁺ alone, but CoASH + NAD could reconstitute the enzyme activity with KIC and KIVA in different degrees. Only two control strains were tested with MEVA as substrate, and these showed in contrast that TPP + Mg⁺⁺ could partly reconstitute the enzyme activity. In contrast to the relative homogeneiy in the reconstitution profiles of normal strains, the five classical and one intermittent MSUD strains showed heterogeneity in cofactor requirements.
Complementation analysis using heterokaryons prepared from fibroblasts of four patients with classical MSUD and one patient with intermittent MSUD showed, in contrast to experiments with normal controls, a partial amelioration of the defect in two combinations; it is suggested that the defect in these strains is located at different functional subunits of the multienzyme complex.     

The effect of irradiation on the fever of delayed hypersensitivity

The effect of total body irradiation on the development of delayed hypersensitivity and on the febrile response to specific antigen has been studied in guinea-pigs with the following results:

1. 200 R. whole body irradiation in guinea-pigs, while suppressing circulating antibody response, did not prevent the development of delayed hypersensitivity.

2. Irradiated and non-irradiated hypersensitive animals had an equal febrile response to systemic challenge with specific antigen.

3. Serum from antigen-challenged, irradiated, hypersensitive animals contained a pyrogenic factor of the endogenous serum type capable of producing fever in normal recipients.

These results support the conclusion that production of circulating specific antibody is not essential either for development of delayed hypersensitivity or for the febrile response of the hypersensitive animal to specific antigen.

     

Studies on the mechanism of phorbol ester-induced inhibition of intercellular junctional communication

Intercellular gap-junctional communication was measured using[¹⁴C]citrulline incorporation in co-cultures of argininosuccinatelyase-deficient human fibroblasts and argininosuccinate synthetase-deficientChinese Hamster V79 cells. As previously shown, in this systemjunctional communication is completely inhibited by the tumorpromoting phorbol ester 12-O-tetra-decanoylphorbol-13-acetate(TPA). In the absence of extracellular calcium, TPA inhibitionwas less pronounced. However, synergism with calcium ionophoreA23187 could not be demonstrated. Chlorpromazine, trifluoperazineand 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl esterpartially antagonised the effect of TPA. No antagonism was demonstrablebetween calmidazolium and TPA. Treatment of co-cultures withexogenous phospholipase C or 1-oleoyl-2-acetylglycerol (OAG)resulted in communication inhibition, suggesting that proteinkinase C activation is involved in the mechanism of phorbolester-mediated communication inhibition. However co-cultureswhich had been made refractory to TPA by prolonged exposureto high concentrations remained sensitive to inhibition by phospholipaseC and OAG. These results suggest either that diacylglycerolcan produce other effects independent of protein kinase C activation,or that refractoriness to phorbol esters is not simply due toa decrease in the amount of protein kinase C.     

Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers

The ApoE4 allele is the most well-studied genetic risk factor for Alzheimer’s disease, a condition that is increasing in prevalence and remains without a cure. Precision nutrition targeting metabolic pathways altered by ApoE4 provides a tool for the potential prevention of disease. However, no long-term human studies have been conducted to determine effective nutritional protocols for the prevention of Alzheimer’s disease in ApoE4 carriers. This may be because relatively little is yet known about the precise mechanisms by which the genetic variant confers an increased risk of dementia. Fortunately, recent research is beginning to shine a spotlight on these mechanisms. These new data open up the opportunity for speculation as to how carriers might ameliorate risk through lifestyle and nutrition. Herein, we review recent discoveries about how ApoE4 differentially impacts microglia and inflammatory pathways, astrocytes and lipid metabolism, pericytes and blood–brain barrier integrity, and insulin resistance and glucose metabolism. We use these data as a basis to speculate a precision nutrition approach for ApoE4 carriers, including a low-glycemic index diet with a ketogenic option, specific Mediterranean-style food choices, and a panel of seven nutritional supplements. Where possible, we integrate basic scientific mechanisms with human observational studies to create a more complete and convincing rationale for this precision nutrition approach. Until recent research discoveries can be translated into long-term human studies, a mechanism-informed practical clinical approach may be useful for clinicians and patients with ApoE4 to adopt a lifestyle and nutrition plan geared towards Alzheimer’s risk reduction.     

Reimbursement models to tackle market failures for antimicrobials: Approaches taken in France,Germany, Sweden,the United Kingdom,and the United States

IntroductionThe pipeline of new antibacterials remains limited. Reasons include low research investments, limited commercial prospects, and scientific challenges. To complement existing initiatives such as research grants, governments are exploring policy options for providing new market incentives to drug developers.Materials and methodsReimbursement interventions for antibacterials in France, Germany, Sweden, US, and UK were reviewed and analysed by the authors.ResultsIn France, Germany, and the US, implemented interventions centre on providing exceptions in cost-containment mechanisms to allow higher prices for certain antibacterials. In the US, also, certain antibacterials are granted additional years of protection from generic competition (exclusivity) and faster regulatory review. The UK is piloting a model that will negotiate contracts with manufacturers to pay a fixed annual fee for ongoing supply of as many units as needed. Sweden is piloting a model that will offer manufacturers of selected antibacterials contracts that would guarantee a minimum annual revenue. A similar model of guaranteed minimal annual revenues is under consideration in the US (PASTEUR Act).ConclusionsThe UK and Sweden are piloting entirely novel procurement and reimbursement models. Existing interventions in the US, France, and Germany represent important, but relatively minor interventions. More countries should explore the use of novel models and international coordination will be important for ‘pull’ incentives to be effective. If adopted, the PASTEUR legislation in the US would constitute a significant ‘pull’ incentive.     

Characterization of ompA genotypes by sequence analysis of DNA from all detected cases of Chlamydia trachomatis infections during 1 year of contact tracing in a Swedish County

In this study we aimed to characterize the ompA gene by sequencing DNA from all detected cases of Chlamydia trachomatis infection in a Swedish county during 2001, in order to improve the efficiency of contact tracing. Approximately 990 bp of the ompA gene was amplified, and sequence analysis was achieved in 678 (94%) of 725 C. trachomatis-positive cases in this unselected population. The most prevalent genotype was serotype E (39%), followed by F (21%), G (11%), D (9%), K (9%), J (7%), H (2%), B (1%), and Ia (1%). Serotype E was found in five genotype variants, with the reference sequence comprising 96% of all E cases. Serotype D was the most variable, and of seven sequence variants, three were identified as recombinants with serotype E. Altogether 29 genetic variants were detected, and mutations and recombination events are discussed. Clinical manifestations were not associated with genotypes. Sequence variation was linked to sexual networks identified by contact tracing and improved epidemiological knowledge but was of limited benefit.