TGF-Beta inhibits the in vitro induction of lymphokine-activated killing activity

Summary Employing serum-free media, human peripheral blood mononuclear cells, and purified recombinant interleukin-2 (IL-2), conditions were observed in which the development of IL-2-driven cytotoxic activity was suppressed. The cytotoxic activity of such IL-2-generated lymphokine activated killing (LAK) was tested against natural killer-resistant cultured tumor cells (Daudi, Raji, and a glioma). LAK generation was inhibited by addition of some normal sera, normal platelets, or some tumor cells. Because recent reports have indicated that transforming growth factor-beta (TGF-beta)-like factors are often secreted by tumors and the acidic alpha granules of platelets and can be present in sera, we tested the effect of purified human TGF-beta on the activation of LAK. Our results indicated that TGF-beta is very suppressive for LAK induction, and can completely prevent both the IL-2-driven proliferation and cytotoxicity at concentrations as low as 5 ng/ml. Titrations of IL-2 and of TGF-beta indicated that the suppression is dose-dependent and can be avoided by employing higher levels of IL-2. It was also found that the suppressive effect of TGF-beta can be overcome by washing suppressed cell populations and further culture in low levels of IL-2. Collectively, these data indicate that TGF-beta can be a potent inhibitor of LAK generation under standard activation conditions, but that this effect is regulated by the relative level of IL-2 and may be overcome and/or reversed in vitro.     

Radioimmunoassay of rat apolipoprotein A-IV

We have developed a specific and sensitive radioimmunoassay for rat apolipoprotein A-IV (apoA-IV). The protocol includes treatment of the samples for 1 h at 60 degrees C with 0.7% Tween 20. Under these conditions, linear logit-log plots have been obtained for apoA-IV in lymph and plasma lipoprotein fractions as well as for purified apoA-IV. The sensitivity of the assay is to 20 ng. Absolute mass values obtained with the assay were validated by comparison with values obtained with an independent method of colorimetric reading of apoA-IV separated by polyacrylamide gel electrophoresis from plasma high density lipoproteins. The concentration of apoA-IV in fasting plasma averaged 10.2 mg/dl and in the mesenteric duct lymph 15.8 and 12.6 mg/dl during the fasting and the fat absorption states, respectively.     

An Ustilago maydis Mutant Partially Blocked in P45014DM Activity Is Hypersensitive to Azole Fungicides

An Ustilago maydis ergosterol biosynthesis mutant (A14) which is partially blocked in sterol 14alpha-demethylase (P45014DM) activity is described. This mutant accumulated the abnormal 14alpha-methyl sterols, eburicol, 14alpha-methylfecosterol, and obtusifoliol, along with significant amounts of ergosterol. Although the A14 mutant grew nearly as well as the wild type, it was impaired in cell extension growth, which indicated a dysfunction in apical cell wall synthesis. The mutant was also found to be hypersensitive to the azole fungicides penconazole and tebuconazole.     

Fundholding in general practice and financial risk.

OBJECTIVE--To estimate the financial effect of random yearly variations in need for services on fundholding practices with various list sizes. DESIGN--A simulation model was derived using historical data on general practitioner referrals for the 113 surgical procedures covered by the general practitioner fund, combined with data on the hospital prices for those procedures. PATIENTS--Resident population of Central Birmingham Health Authority. MAIN OUTCOME MEASURES--Expected expenditure on the relevant surgical procedures for the whole district and for practices with list sizes of 9000, 12,000, 15,000, 18,000, 21,000, or 24,000 for each of 100 simulated years. RESULTS--By using average hospital prices for the West Midlands region the mean (SD) annual expenditure for the 179,400 residents was 4,832,471 pounds (87,149 pounds); the random variation between the 5th and 95th most expensive years was 5.7% of the mean cost. For a practice with a list size of 9000 the values were 244,891 pounds (18,349 pounds), with a variation of 27.5%. With a list size of 24,000 the values were 652,762 pounds (32,512 pounds), with a variation of 15.3%. CONCLUSIONS--Random variations in need for inpatient services will have a significant financial impact on the practice fund. The problem will be particularly great for smaller practices. Additional measures are required to ensure that the scheme is not undermined and that the potential benefits are secured.     

Inheritance of extra triradii of palmar interdigital areas II and IV.

Data obtained from 423 individuals were analyzed for mode of inheritance of extra triradii on palmar interdigital area II and IV separately, and in combination. It indicates that a single dominant allele A for extra triradius in the area II, and an allele D in the area IV, may be responsible for the presence of the patterns in the respective area, with 75 to 80 per cent penetrance. There are numbers of individuals in which extra triradii are present in both interdigital areas II and IV. The mode of inheritance has been estimated from the data obtained and was found to have co-dominant alleles A and D for the presence in their respective areas. Further analysis revealed the existence of three alleles. A and D for presence, and 0 for absence. The alleles A and D are co-dominant, if combined in the genotype AD, but either allele is dominant in heterozygous combination with 0.     

Community-directed distributors—The “foot soldiers” in the fight to control and eliminate neglected tropical diseases

The neglected tropical diseases (NTDs) affect hundreds of millions of people, predominantly in rural, often difficult-to-access areas, poorly served by national health services. Here, we review the contributions of 4.8 million community-directed distributors (CDDs) of medicines over 2 decades in 146,000 communities in 27 sub-Saharan African countries to control or eliminate onchocerciasis and lymphatic filariasis (LF). We examine their role in the control of other NTDs, malaria, HIV/AIDS interventions, immunisation campaigns, and support to overstretched health service personnel. We are of the opinion that CDDs as community selected, trained, and experienced “foot soldiers,” some of whom were involved in the Ebola outbreak responses at the community level in Liberia, if retrained, can assist community leaders and support health workers (HWs) in the ongoing Coronavirus Disease 2019 (COVID-19) crisis. The review highlights the improved treatment coverage where there are women CDDs, the benefits and lessons from the work of CDDs, their long-term engagement, and the challenges they face in healthcare delivery. It underscores the value of utilising the CDD model for strong community engagement and recommends the model, with some review, to hasten the achievement of the NTD 2030 goal and assist the health system cope with evolving epidemics and other challenges. We propose that, based on the unprecedented progress made in the control of NTDs directly linked to community engagement and contributions of CDDs “foot soldiers,” they deserve regional and global recognition. We also suggest that the World Health Organization (WHO) and other international stakeholders promote policy and guidance for countries to adapt this model for the elimination of NTDs and to strengthen national health services. This will enhance the accomplishment of some Sustainable Development Goals (SDGs) by 2030 in sub-Saharan Africa.