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The molecular phylogeny of Alu and other repeated sequences in the human genome provides clues to events during primate evolution. A subclass of human Alu's has been previously identified as dimorphic insertions within members of the medium reiteration frequency (mer) class of repeats, reflecting the complicated sequence of insertion and radiation events leading to the current human genome structure. One dimorphic Alu is located within a previously unidentified mer family member, in the first intron of the human T4 (CD4) gene. The insertion (Alu+ allele) has a frequency of approximately 70% in Europeans and Africans and is homozygous in 20 Asian samples. Polymerase chain reaction amplification, direct DNA sequencing, and Southern analysis using oligonucleotide probes revealed that the Alu- allele was derived from the Alu+ allele by loss of part of the inserted sequence. Comparison with a tightly linked marker within the human genome and studies of baboon DNA samples revealed that the original insertion was a relatively early event in primate evolution, but that the Alu sequence loss leading to the dimorphism has occurred much more recently. Loss of Alu insertions therefore represents one mechanism for the generation of human Alu dimorphisms.

The actions of tetradecanoylphorbolacetate (TPA) and 12-deoxyphorbolphenylacetate-20-acetate (DPPAA) together with a phytohaemagglutinin (PHA) have been examined on the proliferative responses of human mononuclear cells (MNC) depleted of specific cell subsets by the use of monoclonal antibodies. PHA-induced proliferation was found to be reduced when monocytes/macrophages and T-helper cells were depleted from MNC, but enhanced compared with MNC responses when T-suppressor cells were depleted. In contrast, TPA- and DPPAA-induced proliferation was unchanged or slightly enhanced following macrophage/monocyte depletion, and whereas TPA-induced proliferation was largely independent of subtype constitution, the non-tumour promoting DPPAA appeared to selectively enhance proliferation of the T8+ suppressor subset. Indomethacin increased the proliferative MNC responses of phorbol esters whilst having little effect upon the PHA response, an effect antagonized by addition of PGE2. The addition of interleukin-2 (IL-2) increased the proliferative response, as well as resistance to inhibition induced by cyclosporin A and dexamethasone and partially abolished the selective actions of DPPAA and PHA. In IL-2 dependent cultures PHA induced stimulation was more sensitive to inhibition by cyclosporin than were the phorbol esters. The results suggest that, although induction of lymphocyte proliferation by phorbol esters is not a correlate for tumour promotion itself, non-promoting phorbol esters may have a more restricted ability to induce proliferation than TPA.

Activity correlations in the phorbol ester series. The production of inflammation by phorbol esters on mammalian skin correlates on a structural basis with in vitro measurements of lymphocyte mitogenesis and mobilization of prostaglandins. All of the pro-inflammatory phorbol esters tested in our laboratory have been shown to activate the enzyme protein kinase C, and such an interaction could in large part explain the induction of an inflammatory response in vivo. Certain of these compounds additionally induce aggregation of human and rabbit blood platelets. This activity does not structurally correlate with the induction of inflammation but may correlate with the known tumour-promoting actions of phorbol derivatives. Compounds which induce platelet aggregation stimulate the secretion of a biologically active substance which we have termed ‘Factor W’. The production of Factor W occurs into human plasma following platelet stimulation by phorbol tumour-promoting agents. It is an unstable substance, distinct in its aggregating properties from phorbol esters, ADP, 5-hydroxytryptamine, thrombin, platelet aggregating factor and the products of arachidonate oxidative metabolism.

In Ghana, a close analysis of special library activities reveals the fact that the general pace of development lags far behind modern trends and techniques; this is surprising because library development in the country started with the development of special libraries.A possible reason for this slow rate of development has been given by Villars, who suggests that special libraries in Ghana have grown in isolation of each other, and in consequence, definite patterns of development have been difficult to establish.By 1970, about forty special libraries had been set up in the country. More than half of this number (twenty-three) were established between 1961-1970. After Independence in 1957, many organizations were established, such as the Volta River Authority, Bank of Ghana, National Investment Bank, Council for Scientific and Industrial Research, etc. All these organizations were set up with a motivation towards development and thus desired or needed library facilities.

An unusual case of spontaneous rupture of the esophagus is reported in which the patient survived without surgical closure or drainage procedure. The site of perforation and subsequent closure are documented radiologically.

It was not possible to desensitize human blood platelets to 12-deoxyphorbol-phenylacetate (DOPP) stimulation in a manner analogous with that to platelet aggregating factor (PAF), prostaglandin-endoperoxide analogue (U46619) or adenosine diphosphate (ADP). Platelets previously desensitized to U46619, when challenged with DOPP and ADP, showed an increased aggregation and release of 5-HT. Sub-threshold aggregating doses of U46619 also caused a potentiation of the platelet response and release reaction to DOPP. The concentration of U46619 used to pretreat platelets affected the extent of potentiation of platelet stimulation induced by DOPP. The degree of potentiation was also affected by the time interval between addition of U46619 and DOPP. U46619 did not potentiate the aggregating effects of PAF, or ionophore A23187. The stimulus potentiation of DOPP by U46619 was abolished by prostacyclin (PGI2) and an antibody to U46619, but was unaffected by indomethacin and CP/CPK.

Eight phorbol esters were studied for their ability to stimulate prostaglandin production in human rheumatoid synovial cells over the dose range 0.1 ng to 1.0 micrograms. These derivatives were based upon phorbol, 4-deoxyphorbol, and 12-deoxyphorbol nuclei. This activity was structurally dependent and, although it did not correlate with the actions of the same compounds to induce erythema in vivo, it did correlate with their ability to stimulate human lymphocyte mitogenesis. Stimulation of PGE2 production by a phorbol and a 12-deoxyphorbol analog was inhibited in this system by both indomethacin and dexamethasone.

Diester diterpenes based upon phorbol, 4-deoxyphorbol, 4 alpha-deoxyphorbol, 4-deoxy-5-hydroxyphorbol and 4,20-dideoxy-5-hydroxyphorbol were isolated from the fruit oil of Sapium indicum. Corresponding tri- and tetra-esters were produced by acetylation and mono-esters by selective hydrolysis. Twenty-six compounds were tested for production of erythema in vivo and induction of human and rabbit platelet aggregation in vitro. The flatter shape of the AB-ring trans compounds is necessary for interaction of phorbolesters at their receptor in that the cis analogues were inactive. The tertiary C-4 hydroxy group of phorbol was not necessary for activity although the 4-deoxy derivatives were less potent than the 4-hydroxy diterpenes. A primary hydroxy group at C-20 was essential for biological activity because the methyl and aldehyde derivatives of this position were inactive. The C-20 acetates were also inactive on platelets, but they did produce erythema, possibly because of the removal of the ester due to lipase activity in the skin. 5-hydroxy-analogues which undergo intramolecular hydrogen bonding had greatly reduced activities in both systems. Membrane stabilisers, phospholipase A2 and calmodulin inhibitors were antagonists for phorbol esters in platelet aggregation tests, whilst cyclo-oxygenase inhibitors and free radical scavengers had no inhibitory effects. Consequently, one electron withdrawal and free radical formation plays no part in the biological activity of these compounds.