The Veterans Affairs Implantable Insulin Pump Study: effect on cardiovascular risk factors

OBJECTIVE: To determine whether implantable insulin pump (IIP) and multiple-dose insulin (MDI) therapy have different effects on cardiovascular risk factors in insulin-requiring patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A randomized clinical trial was conducted at seven Veterans Affairs medical centers in 121 male patients with type 2 diabetes between the ages of 40 and 69 years receiving at least one injection of insulin per day and with HbA1c, levels of > or =8% at baseline. Weights, blood pressures, insulin use, and glucose monitoring data were obtained at each visit. Lipid levels were obtained at 0, 4, 8, and 12 months, and free and total insulin levels were obtained at 0, 6, and 12 months. All medications being taken were recorded at each visit. RESULTS: No difference in absolute blood pressure, neither systolic nor diastolic, was seen between patients receiving MDI or IIP therapy, but significantly more MDI patients required anti-hypertensive medications. When blood pressure was modeled against weight and time, IIP therapy was significantly better than MDI therapy for systolic blood pressure in patients with BMI <33 and for diastolic blood pressure in patients with BMI >34 kg/m2. Total cholesterol levels decreased in the overall sample, but IIP patients exhibited significantly higher levels than MDI patients. Triglyceride levels increased over time for both groups, with IIP patients having significantly higher levels than patients in the MDI group. BMI was a significant predictor of, and inversely proportional to, HDL cholesterol level. No difference in lipid-lowering drug therapy was seen between the two groups. Free insulin and insulin antibodies tended to decrease in the IIP group as compared with the MDI group. C-peptide levels decreased in both groups. CONCLUSIONS: IIP therapy in insulin-requiring patients with type 2 diabetes has advantages over MDI therapy in decreasing the requirement for antihypertensive therapy and for decreasing total and free insulin and insulin antibodies. Both therapies reduce total cholesterol and C-peptide levels.     

Life table study of Aedes aegypti (Diptera: Culicidae) in Puerto Rico fed only human blood versus blood plus sugar

Life table studies were performed in 1996 with Aedes aegypti (L.) during the low (cool/dry) and high (hot/rainy) dengue virus transmission seasons in Puerto Rico. Mated adult females from field-collected pupae were placed individually in cages and divided into 2 treatment groups: one was fed only human blood and the other human blood plus a 10% sucrose solution. Survival and number of eggs laid were recorded daily for each female. During both seasons, age specific survivorship was higher for the blood plus sugar group, groups fed only human blood had higher reproductive outputs (mx), and net replacement rates (Ro) for blood only groups were higher than for those fed blood plus sugar. Intrinsic rates of growth (r) were the same for both treatments during the low (cool/dry) transmission season, but higher for the blood-only treatment during the high (hot/rainy) transmission season. Our results indicate that feeding on only human blood provides an evolutionary advantage to Ae. aegypti females in Puerto Rico. These results are similar to those from an earlier study carried out with Ae. aegypti in Thailand; the advantage of feeding on human blood does not seem to be restricted to a particular geographic region. We also found that the benefits associated with human feeding persist through epidemiologically different times of the year. We conclude that feeding on human blood is reproductively beneficial for Ae. aegypti, which may increase their contact with human hosts, and therefore may influence their vectorial capacity for dengue viruses through frequent feeding on blood.     

Rod outer segment maintenance is enhanced in the presence of bFGF, CNTF and GDNF

We employed a morphological assay of outer segment collapse to determine if growth factors or other supplements directly affect dissociated rod photoreceptors in vitro. The morphological changes in outer segments were correlated with the light responsiveness of rods. Time-lapse video microscopy was used to observe the collapse of rod outer segments from isolated single cells and small clumps of cells. A consistent pattern of outer segment collapse into the inner segment was observed, yielding a convenient assay of the effects of neurotrophic factors on photoreceptor functional maintenance. The functional state of rods, defined as light-responsiveness, was measured with suction electrode recordings and matched with the various stages of outer segment collapse. Ciliary neurotrophic factor (CNTF) and glial cell-line-derived neurotrophic factor (GDNF) at a high concentration, yielded statistically significant improvements in rat outer segment survival times. Basic fibroblast growth factor (bFGF), which rescues photoreceptors in several rodent models of retinal degeneration, produced a significant increase in survival time in the presence of the cofactor heparin. In 4 out of 10 cases using human tisue, bFGF also yielded a significant increase in survival times. When brain-derived neurotrophic factor (BDNF) was applied to rat rods, outer segment survival times did not change. Outer segments collapsed more quickly when either pigment epithelial cell derived factor (PEDF) or sugar N-acetyl D-galactosamine (NAD-gal) were present. Our results show that rod photoreceptors can respond to bFGF, GDNF and CNTF in vitro and provide evidence for a direct effect of these neurotrophic factors on rods. The rapid collapse of isolated photoreceptors in this model provides a convenient means for testing various neurotrophic agents and the induced cellular responses.     

Adenosine monophosphate as a mediator of ATP effects at P1 purinoceptors

1. When perfused with a medium containing no added magnesium and 4-aminopyridine (4AP) (50 microM) hippocampal slices generated epileptiform bursts of an interictal nature. We have shown in a previous study that adenosine 5'-triphosphate (ATP) depressed epileptiform activity and that this effect was blocked by the adenosine A1 receptor antagonist cyclopentyltheophylline but was not affected by adenosine deaminase. This implied that ATP might act indirectly at P1 receptors or at a xanthine-sensitive P2 receptor. The aim of the present study was to investigate further the action of ATP on epileptiform activity. 2. ATP can be metabolized by ecto-nucleotidases to adenosine 5'-diphosphate (ADP), adenosine 5'-monophosphate (AMP) and adenosine, respectively. Each of these metabolites can activate receptors in its own right: P2 receptors for ADP and P1 receptors for AMP and adenosine. 3. We now show that both AMP and ATP (50 microM) significantly decrease epileptiform discharge rate in a rapid and reversible manner. 5'Adenylic acid deaminase (AMP deaminase, AMPase) (0.2 u ml(-1)), when perfused alone did not significantly alter the discharge rate over the 10 min superfusion period used for drug application. When perfused concurrently with AMP (50 microM), AMP deaminase prevented the depressant effect of AMP on discharge rate. 4. AMP deaminase, at a concentration of 0.2 u ml(-1) which annulled the effect of AMP (50 microM), prevented the inhibitory activity of ATP (50 microM). A higher concentration of ATP (200 microM) depressed the frequency of spontaneous bursts to approximately 30% control and this response was also prevented by AMP deaminase. 5. Superfusion of the slices with 5'-nucleotidase also prevented the inhibitory activity of ATP on epileptiform discharges. 6. The results suggest that AMP mediates the inhibitory effects of ATP on epileptiform activity, a conclusion which can explain the earlier finding that cyclopentyltheophylline but not adenosine deaminase inhibited the effect of ATP. A corollary to this is that, when examining the pharmacology of ATP, care must be taken to inactivate AMP with AMP deaminase, as well as adenosine with adenosine deaminase, before a direct action of ATP on P1 receptors can be postulated. Failure to do so may have led to erroneous conclusions in some previous studies of nucleotide activity on nucleotide receptors.     

Regenerating sciatic nerve does not utilize circulating cholesterol

Vascular endothelial growth factor (VEGF) is a major contributor to retinal neovascularization. The possible participation of VEGF and its high-affinity tyrosine kinase receptors, flk-1 and flt-1, in early background diabetic retinopathy was studied in the streptozotocin-induced diabetic rat model of experimental retinopathy using in situ hybridization, blotting techniques, and immunohistochemistry. Diabetic retinopathy was assessed by quantitative morphometry of retinal digest preparations. The number of acellular capillaries increased 2.7-fold in diabetic animals with diabetes' duration of 6 months compared with nondiabetic controls. VEGF expression was not detectable by in situ hybridization in nondiabetic rats but was highly increased in the ganglion cell layer and in the inner and outer nuclear layers of retinas from diabetic animals. VEGF protein was extractable only from diabetic retinas, and a strong immunolabeling was detected in vascular and perivascular structures. Increased flk-1 and flt-1 mRNA levels were also found in the ganglion cell and both nuclear layers of diabetic samples only. Dot blot and Western blot analyses confirmed the increase in flk-1 mRNA and protein in diabetic retinas. Also, flk-1 immunoreactivity was associated with vascular and nonvascular structures of the inner retinas from diabetic animals. These data obtained from a rodent model in which retinal neovascularization does not occur support the concept that the VEGF/VEGF receptor system is upregulated in early diabetic retinopathy.     

CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand

4-1BB ligand (4-1BBL) is a member of the tumor necrosis factor (TNF) family expressed on activated antigen-presenting cells. Its receptor, 4-1BB, is a member of the TNF receptor family expressed on activated CD4 and CD8 T cells. We have produced a soluble form of 4-1BBL using the baculovirus expression system. When coimmobilized on plastic with anti-CD3, soluble 4-1BBL induces interleukin (IL)-2 production by resting CD28+ or CD28- T cells, indicating that 4-1BBL can function independently of other cell surface molecules, including CD28, in costimulation of resting T cell activation. At low concentrations of anti-CD3, 4-1BBL is inferior to anti-CD28 in T cell activation. However, when 4-1BB ligand is provided together with strong TCR signals, then 4-1BBL and anti-CD28 are equally potent in stimulation of IL-2 production by resting T cells. We find that TNF receptor-associated factor (TRAF)1 or TRAF2 associate with a glutathione S-transferase-4-1BB cytoplasmic domain fusion protein in vitro. In T cells, we find that association of TRAF1 and TRAF2 with 4-1BB requires 4-1BB cross-linking. In support of a functional role for TRAF2 in 4-1BB signaling, we find that resting T cells isolated from TRAF2-deficient mice or from mice expressing a dominant negative form of TRAF2 fail to augment IL-2 production in response to soluble 4-1BBL. Thus 4-1BB, via the TRAF2 molecule, can provide CD28-independent costimulatory signals to resting T cells.     

Wild isolates of murine cytomegalovirus induce myocarditis and antibodies that cross-react with virus and cardiac myosin

The pyruvate dehydrogenase complex (PDC) plays a key role in the anaerobic metabolism of the parasitic nematode Ascaris suum. Two isoforms of the alpha-subunit of pyruvate dehydrogenase (E1) have been identified: alpha I is most abundant in anaerobic adult muscle and alpha II in aerobic larvae. Both isoforms have been expressed as alpha 2 beta 2 tetramers with a muscle-specific beta-subunit, purified to apparent homogeneity, reconstituted with E1-deficient adult A. suum muscle PDC, and assayed for PDC and E1 kinase activity. Recombinant alpha II is a poor substrate for the adult E1 kinase, but its stoichiometry of phosphorylation/inactivation is similar to that reported for the human E1. Initially, inactivation parallels the incorporation of about 1 mol 32P/mol E1 and at maximal phosphorylation about 2.4 32P/mol E1 is incorporated. In contrast, recombinant alpha I (r alpha I) is phosphorylated rapidly, and substantially more phosphorylation accompanies inactivation. To examine this altered pattern of phosphorylation, the two phosphorylation sites in each E1 alpha subunit of the r alpha I (site 1 and site 2) were changed either individually or together from Ser to Ala by site-directed mutagenesis. Site 1 was phosphorylated more rapidly than site 2, but the phosphorylation of either site resulted in inactivation, and the phosphorylation of only a single E1 alpha subunit of the tetramer was necessary for inactivation. However, both E1 alpha subunits of the tetramer were phosphorylated, based on the incorporation of about 3.5 mol 32P/mol E1 at maximal phosphorylation and the altered mobility of most of the E1 alpha subunits during SDS-PAGE. These observations suggest that the regulation of both E1 isoforms is modified to maintain PDC activity during the transition to anaerobiosis.     

Treatment of patients with psychogenic amnesia with the help of therapeutic anamnesis

Psychogenic (dissociative) amnesia is a psychiatric disorder characterised by a sudden loss of memory which is too extensive to be explained by ordinary forgetfulness, but which has no organic disease or explanation. Psychogenic amnesia is categorised among the dissociative disorders in DSM-IV and ICD-10 and begins suddenly, usually after severe psychosocial stress. The prognosis is good with complete recovery, and there is seldom relapse. This article describes a man, 45 years of age, who developed severe depression and amnesia following a very troublesome divorce. He did not talk, he communicated by signs and gestures, and he isolated himself in his mother's home. After being admitted to a psychiatric ward he became anorectic and developed erosive eoesophagitis/gastroduodenitis. Initially he was given perfenazin (Trilafon) 24 mg/day. The psychiatric treatment produced no results for the first three weeks, but the patient gradually recovered when the therapist and the patient recapitulated the conflicts associated with the divorce, using documents from the patient's lawyer as a guide. This method is called "therapeutic anamnesis" and is similar in many ways to psychiatric treatment of post-traumatic stress reactions.     

Inhibitory action of YJA20379, a new proton pump inhibitor on Helicobacter pylori growth and urease

The use of an episiotomy for vaginal delivery is a controversial topic in modern obstetrics. If one is done, however, correct technique of perineal trauma repair is important. The usual episiotomy has traditionally been closed with interrupted suture. The use of a less reactive material, e.g. polyglycolic acid (Dexon), seem to be suitable for subcutaneous skin closure and beneficial in terms of acute postpartum discomfort and healing. The comparison of healing and patient comfort parameters between interrupted and subcutis polyglycolic acid suture used for episiotomy repair after delivery was done. Patients had follow-up during hospital stay, and two months after delivery a self administered questionnaire was sent to all women who participated, enquiring about perineal pain, resumption of sexual intercourse and cosmetics of suture line. Of 52 patients who had repair with interrupted suture, 21 were lost to follow-up. Of 65 gravidas who had repair with subcutis suture, 23 were lost to follow-up. At the 3rd day postpartum examination, patients with subcutis sutures had significantly better healing. An inflammatory process was present in 2 of 52 patients with interrupted sutures comparable with 1 of 65 in the subcutis group, and a gaping wound in 0 of 52 and 1 of 65, respectively. Recovery of function, measured by resumption of sexual activity by 8 weeks, was demonstrated in 5 of 31 patients with interrupted sutures versus 24 of 42 patients who had subcutis sutures. Episiotomy repair with subcutis polyglycolic acid (Dexon) offers significant advantages over traditional interrupted suture, both in terms of wound healing and resumption of sexual activity.