Sulfhydryls and the in vitro polymerization of tubulin

The free sulfhydryls of brain tubulin prepared by cyclic polymerization procedures both with and without glycerol have been examined. The average free sulfhydryl titer of tubulin prepared with glycerol (7.0 sulfhydryls/55,000 mol wt) is greater than that of tubulin prepared without glycerol (4.0 sulfhydryls/55,000 mol wt). Diamide, a sulfhydryl-oxidizing agent, inhibits the polymerization of tubulin. Diamide also disperses the 20S and 30S oligomers of tubulin seen in analytical ultracentrifuge patterns of tubulin solutions and, depending on the temperature at which diamide is added, converts all or part of the oligomeric material to 6S dimers. Electron microscopy demonstrates that diamide also destroys the 450-A ring structures characteristic of tubulin solutions. All diamide effects are reversible by the addition of 10 mM dithioerythreitol, a sulfhydryl-reducing agent. That diamide interacts with sulfhydryls on tubulin is directly demonstrated by a 50% decrease in the free sulfhydryl titer of tubulin measured after diamide treatment. Concentrations of CaCl2 which inhibit polymerization also decrease the free sulfhydryl titer of tubulin.     

Early diagnosis of rheumatoid arthritis

On the basis of own observations of courses the author adopts a definite attitude to the early symptomatology of the rheumatoid arthritis. During the first weeks of the rheumatoid arthritis the following symptoms are found: articular syndromes, more frequently in form of obstinate polyarthralgias, mono-oligoarthritis, accompanied by morning rigidity and accelerated BSR as well as impairment of the general condition. In the majority of the patients only the tentative diagnosis rheumatoid arthritis may be made. After a one to three months' course of the disease the diagnosis becomes more probable. It is above all based on constancy and symmetry, characteristic localisation of the articular process, morning rigidity, radiologically paraarticular loosening of the structure and morphological symptoms of an acute and subacute synovialitis. 6 to 12 months after the beginning of the disease a clinical picture forms which allows to make the diagnosis of a certain or classical rheumatoid arthritis in accordance with the criteria of the ARA. The occurrence of a high activity of multiple affection of the joints (permanent symmetrical polyarthritis including the small joints of the hands and feet), distinctive morning rigidity, high fever and much accelerated BSR, beginning with the first weeks of the disease, speaks for the possibility of the development of an arthrovisceral form of the course of rheumatoid arthritis.     

Interleukin-1 mediates a rapid inflammatory response after injection of adenoviral vectors into the brain

Adenovirus-mediated gene transfer into the brain is associated with significant inflammation and activation of anti-vector and anti-transgene immune responses that curtail the gene delivery of adenoviruses and therapeutic efficacy. Elucidating the molecular mediators of inflammatory and immune responses to adenoviruses injected into the brain should allow us to inhibit their inflammatory actions, thereby reducing vector clearance and enhance adenoviral-mediated gene transfer into the CNS. Cytokines are primary mediators of the immune response and are released during inflammation. Here we report for the first time that injection of replication-deficient adenovirus vectors into the cerebral ventricles of rats causes a rapid increase in body temperature. This fever response precedes any vector-encoded transgene expression and occurs with vectors encoding no transgene, as well as with vectors encoding a therapeutic transgene i.e., HSV1-thymidine kinase. No fever is detected after infection of the striatum, an important brain target in studies on neurodegeneration. After infection of the brain ventricles, CSF levels of immunoreactive tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta increase significantly (up to 300-fold). In the hypothalamus, the locus of thermoregulation in the brain, only IL-1beta and IL-6 are significantly elevated. A neutralizing TNF-alpha antibody has no effect on adenovirus-induced fever. However, pretreatment with either the IL-1 receptor antagonist or the cyclooxygenase inhibitor flurbiprofen completely abolishes adenovirus-induced fever, suggesting that IL-1 and prostaglandins are direct mediators of this response. These results are the first to demonstrate that IL-1, but not TNF-alpha, is the main mediator of a very early inflammatory response to adenovirus in the brain.     

South Turkwel: a new pliocene hominid site in Kenya

New fossils discovered south of the Turkwel River in northern Kenya include an associated metacarpal, capitate, hamate, lunate, pedal phalanx, mandibular fragment, and teeth. These fossils probably date to around 3.5 m.y.a. Faunal information suggests that the environment at South Turkwel was predominantly bushland. The mandibular and dental remains are fragmentary, but the postcranial fossils are informative. Comparisons with Australopithecus, modern human, chimpanzee and gorilla hand bones suggest that the Turkwel hominid was most like Australopithecus afarensis and A. africanus. Carpometacarpal articulations are intermediate between those of modern humans and African apes, suggesting enhanced gripping capabilities compared with extant apes. The hamulus was strikingly large, similar in proportion only to Neandertals and some gorillas, suggesting the presence of powerful forearms and hands. There are no indicators of adaptations to knuckle-walking or suspensory locomotion in the hand, and the pedal phalanx suggests that this hominid was habitually bipedal.