Plasmid DNA encoding transforming growth factor-beta1 suppresses chronic disease in a streptococcal cell wall-induced arthritis model.

Transforming growth factor beta is a potent immunomodulator with both pro- and antiinflammatory activities. Based on its immunosuppressive actions, exogenous TGF-beta has been shown to inhibit autoimmune and chronic inflammatory diseases. To further explore the potential therapeutic role of TGF-beta, we administered a plasmid DNA encoding human TGF-beta1 intramuscularly to rats with streptococcal cell wall-induced arthritis. A single dose of 300 microg plasmid DNA encoding TGF-beta1, but not vector DNA, administered at the peak of the acute phase profoundly suppressed the subsequent evolution of chronic erosive disease typified by disabling joint swelling and deformity (articular index = 8.17+/-0. 17 vs. 1.25+/-0.76, n = 6, day 26, P < 0.01). Moreover, delivery of the TGF-beta1 DNA even as the chronic phase commenced virtually eliminated subsequent inflammation and arthritis. Both radiologic and histopathologic as well as molecular evidence supported the marked inhibitory effect of TGF-beta1 DNA on synovial pathology, with decreases in the inflammatory cell infiltration, pannus formation, cartilage and bone destruction, and the expression of proinflammatory cytokines that characterize this model. Increases in TGF-beta1 protein were detected in the circulation of TGF-beta1 DNA-treated animals, consistent with the observed therapeutic effects being TGF-beta1 dependent. These observations provide the first evidence that gene transfer of plasmid DNA encoding TGF-beta1 provides a mechanism to deliver this potent cytokine that effectively suppresses ongoing inflammatory pathology in arthritis.     

Encouraging Underscreened Women to Have Cervical Cancer Screening: The Effectiveness of a Computer Strategy

Background.Computers that collect data from patients and provide both patients and practitioners with printed feedback on a range of health risks are a tool for assisting general practitioners with preventive care. This study assessed the impact of computer-generated printed feedback on cervical screening among women who were underscreened for cervical cancer.Method.Female attenders at two Australian general practices were randomly allocated to Experimental or Control groups. Women in both groups completed a health risk survey on a touch screen computer prior to their consultation. Those in the Experimental group received printed pages summarizing their results, including their eligibility for cervical screening and last Pap test, for themselves and their doctor. The number and proportion of underscreened women who had a Pap test in the 6 months after completing the computer survey, as determined by pathology records, were examined.Results.Of the 679 participants, 139 were classified as underscreened on the basis of self-report (74 Experimental, 65 Control) and 272 on the basis of their pathology records (148 Experimental, 124 Control). Overall about one-third of women had a test in the 6-month period, and the differences between the groups were not significant for women overall (18–70 years) or for women 18–49 years. Among women 50–70 who were underscreened based on self-report, those receiving the printout were more likely to have a Pap test in the next 6 months (P< 0.05). This pattern was also evident, but did not reach statistical significance, for older women who were underscreened based on pathology records.Conclusions.We are unable to draw conclusions regarding the effectiveness of the computer system due to the modest proportions of women screened, the small numbers, and the fact that the computer survey may have created an intervention effect in the Control group. As the study suggests the computer system is acceptable to women and may be effective for encouraging screening among older women, further exploration of the system is desirable.     

Choristomas of the seventh and eighth cranial nerves.

Choristomas, masses of normal tissues in aberrant locations, contain smooth muscle fibers and fibrous tissues. We describe the MR imaging features of two choristomas located in the internal auditory canals and arising from the facial and vestibulocochlear nerves. Both lesions enhanced with contrast material. In one case, enhancement was seen in the geniculate ganglion and greater superficial petrosal nerve. In the other, a medial component enhanced less than the lateral component did.     

The effect of palytoxin on neuromuscular junctions in the anococcygeus muscle of the rat

Palytoxin, a highly toxic natural product isolated from zoanthids of the genus Palythoa, is accumulated by a wide range of fishes and marine invertebrates used as food in the Indo-Pacific. It is responsible for many incidents of human morbidity and mortality. The toxin is a potent smooth muscle spasmogen. The cause of the contraction of smooth muscle is unclear, but recent work strongly suggests that it is primarily initiated by the release of neurotransmitters from the motor innervation of the smooth muscle. We show here that palytoxin caused the swelling of the muscle cells and some internal organelles of the anococcygeus muscle of the rat, but no substantial structural damage to the tissue. Axons and Schwann cells were also swollen but the most dramatic feature was the depletion of synaptic vesicles from putative release sites in the axons. Some axons were physically damaged following exposure to the toxin, but this was relatively uncommon (<10% of all axons studied). In the majority of axons there was no damage to nerve terminal membranes, but there was damage to mitochondria. The depletion of vesicles involved all types – clear, dense-cored, large and small. Our observations and pharmacological data gathered elsewhere, provide a neuropathological basis for the spasmogenic activity of palytoxin.     

Wound Botulism Associated with Black Tar Heroin

The incidence of wound botulism is increasing and the epidemiology of the disease is changing. The majority of new cases are associated with injection drug use, in particular, the use of Mexican black tar heroin. This case report and discussion of wound botulism illustrate the following important points: Dysphagia, dysphonia, diplopia, and descending paralysis, in association with injection drug use, should alert the treating physician to the possibility of wound botulism. In such patients, the onset of respiratory failure may be sudden and without clinically obvious signs of respiratory weakness. For the reported patient, maximum inspiratory force measurements were the only reliable indicator of respiratory muscle weakness. This is a measurement not routinely performed in the ED, but may prove essential for patients with suspected wound botulism. To minimize the effect of the botulinum toxin and to decrease length of hospital stay, antitoxin administration and surgical wound debridement should be performed early.     

Thermodynamic stability of wild-type and mutant p53 core domain

Some 50% of human cancers are associated with mutations in the core domain of the tumor suppressor p53. Many mutations are thought just to destabilize the protein. To assess this and the possibility of rescue, we have set up a system to analyze the stability of the core domain and its mutants. The use of differential scanning calorimetry or spectroscopy to measure its melting temperature leads to irreversible denaturation and aggregation and so is useful as only a qualitative guide to stability. There are excellent two-state denaturation curves on the addition of urea that may be analyzed quantitatively. One Zn²⁺ ion remains tightly bound in the holo-form of p53 throughout the denaturation curve. The stability of wild type is 6.0 kcal (1 kcal = 4.18 kJ)/mol at 25°C and 9.8 kcal/mol at 10°C. The oncogenic mutants R175H, C242S, R248Q, R249S, and R273H are destabilized by 3.0, 2.9, 1.9, 1.9, and 0.4 kcal/mol, respectively. Under certain denaturing conditions, the wild-type domain forms an aggregate that is relatively highly fluorescent at 340 nm on excitation at 280 nm. The destabilized mutants give this fluorescence under milder denaturation conditions.