Natural outcome of idiopathic macular hole

To ascertain the natural outcome of idiopathic macular holes, we studied 186 eyes with the disorder: stages 1 (48 eyes), 2 (30 eyes), 3 (71 eyes), and 4 (37 eyes), which were followed for over twelve months. In 11 (23%) eyes with stage 1 lesions full-thickness macular hole developed during the follow-up period, and in 12 (25%) eyes visual acuity decreased two or more Snellen lines. Twenty-five (83%) and 21 (70%) eyes with stage 2 lesions, 39 (55%) and 22 (31%) eyes with stage 3 lesions, and 7 (19%) and 5 (14%) eyes with stage 4 lesions had enlarged macular holes and decreased visual acuity during the follow-up, respectively. The present results suggest that different stages of macular holes have different natural outcomes and the treatment should be based on their stages.     

Nursing or chiropody? Nurses'' attitudes to toe nail trimming

The majority of low grade non-Hodgkin's follicular lymphoma undergo clinical progression to intermediate and high grade lymphoma, but the molecular mechanisms involved in this transformation are not yet well understood. In this article, we describe the case of a 66 year old man with follicular non-Hodgkin's lymphoma (NHL), in whom a centroblastic leukaemic transformation led to death in six months, despite a transient period of remission. At the time of transformation, cytogenetic analysis revealed the original coexistence of t(14;18)(q32;q21) and t(8;22)(q24;q11). These results were confirmed by fluorescent in situ hybridization, while molecular analysis showed a BCL2-JH rearrangement but failed to detect a c-myc rearrangement or any additional p53 mutation. Our observations would therefore suggest other mechanisms to be involved in the transformation of follicular NHL.     

A human exchange factor for ARF contains Sec7- and pleckstrin-homology domains

The small G protein ARF1 is involved in the coating of vesicles that bud from the Golgi compartments. Its activation is controlled by as-yet unidentified guanine-nucleotide exchange factors. Gea1, the first ARF exchange factor to be discovered in yeast, is a large protein containing a domain of homology with Sec7, another yeast protein that is also involved in secretion. Here we characterized a smaller human protein (relative molecular mass 47K) named ARNO, which contains a central Sec7 domain that promotes guanine-nucleotide exchange on ARF1. ARNO also contains an amino-terminal coiled-coil motif and a carboxy-terminal pleckstrin-homology (PH) domain. The PH domain mediates an enhancement of ARNO exchange activity by negatively charged phospholipid vesicles supplemented with phosphatidylinositol bisphosphate. The exchange activity of ARNO is not inhibited by brefeldin A, an agent known to block vesicular transport and inhibit the exchange activity on ARF1 in cell extracts. This suggests that a regulatory component which is sensitive to brefeldin A associates with ARNO in vivo, possibly through the amino-terminal coiled-coil. We propose that other proteins with a Sec7 domain regulate different members of the ARF family.     

TANIT AIM project (A2036): Telematics for ANaesthesia and Intensive Therapy

On-going work relating to the development of advanced telematics systems for Critical Care environments is described. This work is in part sponsored by the Commission of European Communities under the AIM TANIT project. Two example departments have been selected for piloting in the project: Intensive Care and Anaesthesia. The objective of this paper is to outline the complex issues that need to be addressed when developing such systems.     

Identification of a motif associated with the lactogenic actions of human growth hormone

Human growth hormone (hGH) stimulates somatogenic and lactogenic actions through the GH and prolactin (PRL) receptors, respectively. In contrast, non-primate GHs stimulate only somatotropic action. Phe44, of the human GH sequence is present in all hormones stimulating lactogenic action and absent in all hormones stimulating only somatotropic action. We speculate that the presence of Phe44 is a feature necessary for specifying lactogenic activity. In this report, the role of Phe44 was investigated by its deletion or substitution with alanine or leucine. Deletion of Phe44 or substitution with leucine did not significantly change the structure of hGH as determined by circular dichroism, absorbance, and fluorescence spectroscopies. In contrast, substitution of alanine perturbed the structure. Deletion of Phe44 reduced binding affinity for the lactogenic receptor, resulting in a reduced activation. Substitution with either alanine or leucine partially restored lactogenic receptor binding affinity, which correlated with the hormones' activity in the Nb2 rat lymphoma cells. All the recombinant hGHs had similar somatotropic activities in FDC-P1 cells transfected with the hGH receptor. These data indicate that the hydrophobic side chain of Phe44 is required for lactogenic receptor binding and activation but is unnecessary for somatotropic action.     

A phase I study of TNP-470 administered to patients with advanced squamous cell cancer of the cervix

A Phase I study of the novel angiogenesis inhibitor TNP-470 was performed. Patients with inoperable recurring or metastatic squamous cell cancer of the cervix with evaluable disease, no coagulopathy, and adequate renal, hepatic, and hematological function were eligible. One course of treatment consisted of an i.v. infusion of TNP-470 over 60 min every other day for 28 days, followed by a 14-day rest period. The starting dose was 9.3 mg/m2. Eighteen evaluable patients were treated, with a median age of 48 years (range 27-55) and performance status Zubrod 1 (range 0-2). Grade 3 neurotoxicities consisting of weakness, nystagmus, diplopia, and ataxia were encountered in two patients receiving the 71.2 mg/m2 dose. An intermediate dose level of 60 mg/m2 was evaluated and found to be well tolerated by three patients. Only one patient experienced grade 3 nausea on the 60 mg/m2 dose level. No myelosuppression, retinal hemorrhage, weight loss, or significant alopecia were observed. One patient had a complete response, which continues for 26 months, and three patients with initially progressive disease stage had stable disease for 5, 7.7, and 19+ months. Other Phase I studies, including over 200 patients, were performed concurrently with this study. Based on this experience, the dose of TNP-470 recommended for further studies is 60 mg/m2 as a 60-min i.v. infusion every Monday, Wednesday, and Friday. Neurotoxicity was dose limiting, but appears to be reversible. Otherwise, the treatment was well tolerated. The drug may be active in squamous cell cancer of the cervix. Further studies of TNP-470 in squamous cell cancer of the cervix are warranted.     

Pathogenesis of hemorrhage induced by proteinase H from eastern diamondback rattlesnake (Crotalus adamanteus) venom

The systemic effects of a purified hemorrhagic toxin, proteinase H, from Crotalus adamanteus venom, were studied. Female, white CD-1 mice were injected intravenously with proteinase H and tissue samples were obtained at 1, 3 and 24 hr after injection. Hemorrhage was observed grossly within 1 hr in several internal organs including the stomach and small intestine, the heart and the lungs. Surface discolorations thought to be petechial hemorrhages were observed in the kidneys. The livers of treated animals were visibly swollen and darkened and lobules were accentuated. Tissue samples were taken from the stomach, duodenum, heart, lungs, liver and kidneys and prepared for observation by light and electron microscopy. Frank hemorrhage was observed by light microscopy in the walls of the stomach and duodenum, in the myocardium and in the lungs. Pulmonary hemorrhage was severe, with involvement of nearly all of the pulmonary tissue within 3 hr. A1 doses of 5 micrograms/g, hepatic degeneration was observed by 3 hr. Renal glomeruli were noticeably swollen and the lumena of the proximal convoluted tubules indistinct. Closer examination by electron microscopy revealed that the endothelial cells comprising the fenestrated glomerular capillaries remained intact but signs of degeneration (i.e. cytoplasmic swelling and mitochondrial swelling) were observed. Proteinase H induces systemic hemorrhage in the heart, lungs, stomach and small intestine, renal glomerulonephropathy and hepatic degeneration.     

Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine

OBJECTIVE: To evaluate the ability of hydroxychloroquine sulfate (HCQ) to extend the response to combination therapy with HCQ and methotrexate (MTX) and the safety of longterm HCQ maintenance therapy in patients with active rheumatoid arthritis (RA). METHODS: Two-part study consisting of an open label segment evaluating combination HCQ/MTX therapy followed by a double blind segment evaluating maintenance therapy for a total of 60 weeks. First, all patients were treated with HCQ 400 mg/day and MTX 7.5 to 15 mg/week for 24 weeks. Then, responders were randomized into 3 groups: (1) HCQ with MTX as needed for disease flare (n = 40), (2) HCQ 400 mg/day (n = 41), or (3) placebo with MTX as needed for disease flare (n = 40), each for 36 weeks. RESULTS: Clinical disease and laboratory variables improved significantly during initial combination therapy with HCQ and MTX. After MTX withdrawal, HCQ-containing maintenance regimens delayed the onset of disease flare (p = 0.023). There were no unexpected adverse events at any time or between-group differences in the distribution of adverse events during the double blind segment. CONCLUSION: Combination of HCQ and MTX appeared to be effective and well tolerated for 24 weeks. After withdrawal of MTX, HCQ extended the response seen with combination therapy and was well tolerated for 36 weeks. Initial therapy with HCQ and MTX, followed by maintenance HCQ, may be a useful alternative for the treatment of RA.