Diabetes intervention in the information age

Sustained improvement in blood glucose control is the only treatment outcome which will reduce or eliminate the long term complications of diabetes mellitus. We have designed and evaluated an electronic information system which facilitates this task. The system is voice-interactive, physician directed and affords, to remote patients, 24 h access via touch-tone telephone. Accordingly, patients access the system each day to report self-measured blood glucose levels or hypoglycaemic symptoms together with dietary changes, planned exercise, stress, illness or other lifestyle events. In turn they receive immediate advice with respect to medication dosing changes, and other pertinent feedback. Preliminary system beta-testing for safety and efficacy was performed for one year in an open study of 204 patients derived from two independent, health-care environments. Among the two testing centres, over 60,000 telephone cells were received by the computer systems during the start-up year. Safety and efficacy expectations were met. In addition, prevalence of diabetes related crises (hyperglycaemia or hypoglycaemia) fell approximately 3-fold. Glycated haemoglobin fell significantly (1.0-1.3%) in patients actively using the system. In control groups of patients not actively using the system, there were no improvements in metabolic control while body weights were stable in all groups. The new system was safe and effective in our hands and empowered our health professionals to provide improved diabetes care.     

Hypofrontality revisited: a high resolution single photon emission computed tomography study in schizophrenia

Hypofrontality or reduced activity in the prefrontal cortex, measured as reduced frontal perfusion or glucose uptake, has gained the status of an established finding in the medical literature on schizophrenia. Many relevant studies, however, have potential sources of bias, such as small subject numbers, or unreliable performance of activation tasks by the patients during the scanning procedure. Seventy patients with non-affective and non-organic psychoses were recruited--most qualifying for DSM III-R schizophrenia or schizophreniform psychosis (n = 60)--together with 20 healthy volunteers. They underwent single photon emission computed tomography with 99mTc-exametazime, carried out at rest. Tracer uptake was normalised to the occipital cortex. Group differences in tracer uptake were predicted in anterior regions of interest (prefrontal cortex and mesial frontal/cingulate cortex). Actively psychotic (including schizophrenic) patients not taking any drugs showed increased uptake in the prefrontal cortex. Reduced tracer uptake occurred in the mesial frontal cortex of schizophrenic patients, particularly if they were taking drugs. Relatively increased prefrontal tracer uptake associated with relatively decreased mesial frontal uptake characterised the patients in comparison with the controls. Generalised hypofrontality is, therefore, not a feature of schizophrenic patients at rest whether taking drugs or not.     

The Notch ligand, Jagged-1, influences the development of primitive hematopoietic precursor cells

We examined the expression of two members of the Notch family, Notch-1 and Notch-2, and one Notch ligand, Jagged-1, in hematopoietic cells. Both Notch-1 and Notch-2 were detected in murine marrow precursors (Lin-Sca-1+c-kit+). The Notch ligand, Jagged-1, was not detected in whole marrow or in precursors. However, Jagged-1 was seen in cultured primary murine fetal liver stroma, cultured primary murine bone marrow stroma, and in stromal cell lines. These results indicate a potential role for Notch-Notch ligand interactions in hematopoiesis. To further test this possibility, the effect of Jagged-1 on murine marrow precursor cells was assessed by coculturing sorted precursor cells (Lin-Sca-1+c-kit+) with a 3T3 cell layer that expressed human Jagged-1 or by incubating sorted precursors with beads coated with the purified extracellular domain of human Jagged-1 (Jagged-1(ext)). We found that Jagged-1, presented both on the cell surface and on beads, promoted a twofold to threefold increase in the formation of primitive precursor cell populations. These results suggest a potential use for Notch ligands in expanding precursor cell populations in vitro.     

Hyperactivation may assist human spermatozoa to detach from intimate association with the endosalpinx

The behaviour of human spermatozoa was observed during incubation with epithelial cells isolated from the isthmic and ampullary sections of human uterine (Fallopian) tubes. During incubation, spermatozoa were observed to bind to the epithelial cells of the tube (the endosalpinx), and individual spermatozoa attached and detached at intervals. The kinematic characteristics of spermatozoa during these behaviour patterns were determined. The results showed that detached spermatozoa typically had an increased curvilinear velocity and amplitude of lateral head displacement, accompanied by a decrease in their linearity. Significantly (P < 0.01) more of the detaching spermatozoa were hyperactivated than were spermatozoa prior to attachment for both isthmic (35.3 +/- 5.5 versus 4.0 +/- 3.3%; mean +/- SEM) and ampullary (26.0 +/- 7.0 versus 2.0 +/- 1.4%) regions. Incubation with epithelial cells from either region produced no differences in any category of sperm behaviour. Furthermore, there was no significant difference between regions in the amount of time spermatozoa spent bound (33.6 +/- 12.9 and 20.6 +/- 3.0 s for isthmic and ampullary tissue respectively). These results support the hypothesis that hyperactivation may assist spermatozoa in breaking connections with epithelial cells.     

Structural requirements for the cytotoxicity of the N-terminal region of HIV type 1 Nef

We have found that the hemolytic and cytotoxic activities of myristoylated Nef N-terminal peptides require a net positive charge in the first seven amino residues of the sequence. The activities are considerably less dependent on the secondary structure of the peptides. Film balance studies showed that both active and inactive peptides interacted with neutral phospholipid monolayers, suggesting that binding to neutral lipids was not a sufficient condition for lytic activity. It was also found that nonmyristoylated N-terminal peptide did not interact to the same extent with the monolayer, indicating that myristoylation was essential for lipid interaction. It is considered that the positively charged residues of the proximate N terminus of Nef interact with acidic lipids of biological membranes, reinforcing the weak membrane-targeting properties of the myristyl chain. Parallels are drawn between this mode of interaction with membranes and that of members of the Src family of proteins, which are also myristoylated and have positively charged residues in their proximate N termini. In particular, these proteins and Nef also have serine residues in their proximal N-terminal regions, which when phosphorylated could neutralize the positive charge and thus provide a mechanism for modulating membrane interaction.