Increased workload fully activates the blunted IRS-1/PI3-kinase/Akt signaling pathway in atrophied uremic muscle.

Muscle wasting in chronic renal failure is associated with increased morbidity and mortality; however, resistance exercise is effective at increasing muscle mass while improving muscle strength and function. To study the mechanism by which this occurs, we compared uremic and control rats where work overload was surgically induced unilaterally in the plantaris muscle. We found that work overload increases muscle insulin-like growth factor-1 and mechano-growth factor expression. This in addition to direct mechanical activation of signaling was likely the cause of the observed increased in the protein levels and phosphorylation of the mediators of these growth factors, the insulin receptor substrate-1/phosphoinositide 3-kinase/Akt pathway. The mechanical enhancement of signal transduction appeared to be mediated in part by increased signal protein levels and decreased SOCS2 mRNA expression (suppressor of cytokine signaling-2). Despite impaired basal signaling, the work-induced signaling response was similar to that observed in nonuremic rats and produced changes consistent with decreased muscle protein degradation, increased protein synthetic capacity, and an increased number of multinucleated muscle cells. Our studies suggest that these work-induced changes account for the improved uremic muscle mass reaching levels comparable to those seen in normal rats.

Factors influencing the handling of insulin by the isolated rat kidney.

The renal handling of immunoreactive insulin was studied in the isolated perfused normothermic rat kidney to determine (a) the relative contributions of glomerular clearance and peritubular clearance to the renal clearance of insulin under different conditions, (b) what metabolic factors influence the ability of tubular cells to remove insulin from the glomerular filtrate and the peritubular circulation, and (c) whether the same factors influence the luminal and contraluminal uptake of insulin.In control kidneys the organ clearance of insulin (OCi) was 974+/-63 mul/min (SEM), of which a maximum of 46% could theoretically be accounted for by filtration. OCi was not altered by fasting, lack of exogenous fuel (glucose), or the addition of cyanide. The glomerular filtration rate did not correlate with the OCi, but there was a significant (P < 0.001) negative correlation (r = -0.828) between the peritubular clearance and glomerular filtration rate. Both N-ethylmaleimide and cold (10 degrees C) reduced the rate of insulin removal. Fractional excretion of filtered insulin (9.7+/-1.7% in controls) was not significantly altered by fasting or perfusing without glucose. In contrast, KCN increased fractional excretion of insulin to 41.9+/-3.7% whereas cold increased fractional excretion to 69.0+/-3.3%. This study indicates that renal tubular cells remove insulin from the tubular lumen and the peritubular compartment. Furthermore, the data suggest that insulin removal by tubular cells is a temperature-sensitive process consisting of two different systems. The system associated with the luminal aspect of the cell appears to be dependent on oxidative metabolism, whereas the system associated with the contraluminal aspects of the cell appears to be independent thereof. Under several circumstances when the glomerular clearance of insulin falls thereby reducing the amount of insulin absorbed by the luminal aspect of the cell, contraluminal uptake increases, and a constant rate of insulin removal is maintained by the kidney.

Impaired JAK-STAT signal transduction contributes to growth hormone resistance in chronic uremia.

Chronic renal failure (CRF) is associated with resistance to the growth-promoting and anabolic actions of growth hormone (GH). In rats with CRF induced by partial renal ablation, 7 days of GH treatment had a diminished effect on weight gain and hepatic IGF-1 and IGFBP-1 mRNA levels, compared with sham-operated pair-fed controls. To assess whether GH resistance might be due to altered signal transduction, activation of the JAK-STAT pathway was studied 10 or 15 minutes after intravenous injection of 5 mg/kg GH or vehicle. Hepatic GH receptor (GHR) mRNA levels were significantly decreased in CRF, but GHR protein abundance and GH binding to microsomal and plasma membranes was unaltered. JAK2, STAT1, STAT3, and STAT5 protein abundance was also unchanged. However, GH-induced tyrosine phosphorylation of JAK2, STAT5, and STAT3 was 75% lower in the CRF animals. Phosphorylated STAT5 and STAT3 were also diminished in nuclear extracts. The expression of the suppressor of cytokine signaling-2 (SOCS-2) was increased twofold in GH-treated CRF animals, and SOCS-3 mRNA levels were elevated by 60% in CRF, independent of GH treatment. In conclusion, CRF causes a postreceptor defect in GH signal transduction characterized by impaired phosphorylation and nuclear translocation of GH-activated STAT proteins, which is possibly mediated, at least in part, by overexpression of SOCS proteins.

The handling of immunoreactive vasopressin by the isolated perfused rat kidney.

Using the isolated rat kidney perfused with an artificial medium containing glucose as the sole fuel, we studied the renal handling of immunoreactive arginine vasopressin (AVP) and determined the effect of various factors on the ability of the kidney to remove AVP. In control kidneys perfused with AVP at concentrations below 116 muU/ml, the organ clearance of AVP (OC(AVP)) was 1,145+/-47 (SE) mul/min, whereas glomerular filtration rate (GFR) averaged 515+/-37 mul/min. Filtration could thus account for up to 45% of the OC(AVP), the balance presumably being cleared from the peritubular circulation. Of the AVP filtered, only 38% could be recovered in the urine (urinary clearance AVP averaged 205+/-12 mul/min) suggesting that the balance was taken up by the tubular epithelium and degraded. Fractional excretion of filtered AVP rose significantly in the presence of anoxia and cold (10 degrees C) to 49 and 59%, respectively, but was not affected by ouabain or high levels of AVP (458+/-58 muU/ml). The OC(AVP) was not significantly altered by the absence of glucose in the perfusate, anoxia, or ureteral ligation, maneuvers that were associated with significant reductions in GFR. In these and the control experiments, there was a significant inverse correlation between GFR and peritubular clearance emphasizing the importance of the latter (r = -0.749; P < 0.001). Cold, ouabain, and high concentrations of AVP reduced the clearance of AVP by the kidneys. On the basis of these studies we conclude that the kidney clears AVP from the circulation via two pathways, glomerular clearance and peritubular clearance. This exposes both the luminal and contraluminal surfaces of the tubular cells to the hormone, allowing these cells to remove AVP from the filtrate and the peritubular compartment. Noteworthy is the observation that under several conditions when GFR falls reducing the glomerular clearance of AVP, peritubular clearance increases and the total clearance of AVP by the kidney remains constant.

Effect of insulin therapy on established diabetic nephropathy in rats.

The effectiveness of insulin therapy on early diabetic nephropathy has not been established. In this study we examined the influence of continuous subcutaneous insulin on the progression of established nephropathy in streptozocin-induced diabetic rats. Normal controls and diabetic rats were studied for 11 mo. During the first 6 mo, all the diabetic rats received 2 U protamine zinc insulin s.c. twice weekly. During the last 5 mo of study, diabetic rats either continued on the occasional subcutaneous insulin regimen or received regular insulin by continuous subcutaneous infusion. Six months after the initiation of the study, the diabetic rats were severely hyperglycemic, and their relative mesangial areas had increased. Continued poor glycemic control in the rats receiving occasional insulin was associated with relative increased mesangial area (25.2 +/- 1.0% of glomerular area) and significant proteinuria (148 +/- 17 mg/24 h) compared with normal controls. In contrast, the use of continuous subcutaneous insulin therapy with improved glycemic control arrested mesangial changes (19.5 +/- 1.4% of glomerular area) and prevented the excessive proteinuria (71 +/- 13 mg/24 h). Indeed, these parameters did not differ from age-matched controls. We conclude that in the rat, continuous subcutaneous insulin therapy instituted after the development of early glomerular pathology is effective in arresting the disease process.

Binding and degradation of insulin by isolated renal brush border membranes.

Filtered proteins including insulin are absorbed in the proximal tubule by means of pinocytosis. The first step in this process is binding of the protein to brush border membrane. As it is not known whether absorption exhibits specificity, we set out to determine whether specific binding sites for insulin are present in brush border membranes. Rabbit-isolated brush border membranes were incubated with 125I-insulin and varying concentrations of cold insulin or other peptide hormones. Binding and degradation of 125I-insulin occurred in a time- and temperature-dependent manner. Native insulin competitively inhibited 125I-insulin binding, but calcitonin, arginine vasopressin, glucagon, and growth hormone (10(-6) M) were relatively ineffective. Nonspecific binding averaged one-third of the total radioactivity bound. Scatchard analysis of binding data revealed two classes of insulin receptors: high affinity, low capacity receptors and low affinity, high capacity receptors. Gel filtration analysis of 125I-insulin exposed to brush border membrane revealed the formation of low-molecular-weight products similar to that produced by intact kidneys. The degrading process exhibited some specificity, for cold insulin (10(-6) M) was more effective than calcitonin, vasopressin, glucagon, or growth hormone in inhibiting degradation (32% versus less than 13% inhibition; P less than 0.01). Whether this reflects inhibition of insulin specific binding before exposure to degradation or inhibition of specific enzymes is unclear. In summary, it appears that renal brush border membranes have a major insulin-specific receptor component that could potentially mediate tubular insulin absorption. In addition, there is a smaller nonspecific component that may also have the potential to mediate insulin absorption. Finally, it appears that brush border membranes have the ability to degrade insulin to low-molecular-weight products by a process that exhibits some specificity for insulin.

Effect of bacitracin on binding and processing of insulin by established renal cell line.

The effect of bacitracin on the binding and processing of 125I-labeled insulin was studied in a proximal tubular epithelium-like opossum kidney cell line. This cultured cell line handles insulin in a manner comparable to the in vivo situation, which requires membrane binding, internalization, and intracellular degradation. The addition of bacitracin inhibited insulin degradation significantly and delayed the time of appearance of products in the medium (22 min) compared with control cells (14 min). Maximum total cell-associated radioactivity increased from 1.5 +/- 0.19% in the control cells to 2.5 +/- 0.17% in the treated cells. Separation of cell membrane from internalized radioactivity was achieved by acid washing and showed no change in membrane-bound radioactivity or rate of internalization, but a significant increase in intracellular radioactivity was noted. Gel-filtration chromatography revealed that this was due to an accumulation of chromatographically intact insulin. Accordingly, we conclude that bacitracin inhibits insulin degradation in cultured kidney cells by perturbing the intracellular processing of insulin, not by altering the binding or internalization of the hormone or by inhibiting the release of small degradation products. Because of the multiple actions of this agent, the exact site in these kidney cells at which intracellular degradation is inhibited remains to be established. However, in contrast to studies with lysosomes isolated from cells of other tissues, this study showed that when lysosomes isolated from rat renal cortex were exposed to bacitracin, insulin degradation was inhibited markedly (81%).

Effect of bacitracin on retroendocytosis and degradation of insulin in cultured kidney epithelial cell line.

In an earlier study, we described the presence of a retroendocytotic pathway for insulin in a cultured kidney epithelial cell line. Derived from the opossum kidney (OK), these cells possess many features of proximal tubule epithelium, which is the major site of kidney insulin metabolism. We studied the interaction between the retroendocytotic and the degradative pathways with bacitracin as a pharmacological probe. Monolayers of OK cells were loaded with 125I-labeled insulin over 30 min, acid washed to remove membrane-bound insulin, then incubated in fresh medium for 60 min while the release of intracellular radioactivity was monitored. In experiments carried out in the presence of bacitracin (2 mM), there was a two-thirds increase in intracellular radioactivity at the end of the loading phase. Measurements made during the subsequent release phase showed that bacitracin reduced the release of degradation products. Thus, although controls released 72.1 +/- 8.1% of the internalized radioactivity as trichloroacetic acid (TCA)-soluble products, bacitracin-treated cells released 59.2 +/- 9.4% (P less than 0.02). In contrast, release of TCA-precipitable insulin increased from 15.2 +/- 4.6% in controls to 25.8 +/- 3.7% in bacitracin-treated cells (P less than 0.01). In separate experiments analyzed by gel-exclusion chromatography, 6.4 +/- 0.6% of radioactivity released from preloaded control cells into medium over 60 min was insulin sized compared to 29.7 +/- 1.4% in bacitracin-treated cells. High-performance liquid chromatography revealed that 61.5 +/- 3.5% of this insulin-sized material released from control cells preloaded with A14-insulin eluted as intact insulin and the remainder as unidentified intermediate degradation products.(ABSTRACT TRUNCATED AT 250 WORDS)

A double-blind, placebo-controlled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms.

BACKGROUND: The goal was to evaluate the efficacy of testosterone in alleviation of hypogonadal symptoms (diminished libido, depressed mood, low energy, and depleted muscle mass) in men with symptomatic human immunodeficiency virus illness. METHODS: Seventy-four patients were enrolled in a double-blind, placebo-controlled 6-week trial with bi-weekly testosterone injections, followed by 12 weeks of open-label maintenance treatment. Major outcome measures were Clinical Global Impressions Scale ratings for libido, mood, energy, and erectile function; Hamilton Depression Rating Scale scores, and Chalder Fatigue Scale scores. Body composition changes were assessed with bioelectric impedance analysis. RESULTS: Seventy men completed the 6-week trial. Response rates, defined as much or very much improved libido, were 74% (28/38) for patients randomized to testosterone, and 19% (6/32) for placebo-treated patients (P<.001). Of the 62 completers with fatigue at baseline, 59% (20/34) receiving testosterone and 25% (7/28) receiving placebo reported improved energy (P<.01). Among the 26 completers with an Axis I depressive disorder at baseline, 58% of the testosterone-treated patients reported improved mood compared with 14% of placebo-treated patients (Fisher exact test = .08). With testosterone treatment, average increase in muscle mass over 12 weeks was 1.6 kg for the whole group, and 2.2 kg for the 14 men with wasting at baseline. Improvement on all parameters was maintained during subsequent open-label treatment for up to 18 weeks. CONCLUSION: Testosterone is well tolerated and effective in the short-term treatment of symptoms of clinical hypogonadism in men with symptomatic human immunodeficiency virus illness, restoring libido and energy, alleviating depressed mood, and increasing muscle mass.

The processing of insulin-like growth factor-I (IGF-I) by a cultured kidney cell line is altered by IGF-binding protein-3.

The proximal renal tubule is a common site of peptide hormone metabolism, including that of insulin-like growth factor-I (IGF-I). To further explore the renal uptake and processing of IGF-I, a study was carried out with the proximal-like cultured opossum kidney (OK) cell line. [125I]IGF-I associated with these cells in a specific manner. Association was competitively inhibited by IGF-I. Des(1-3)-IGF-I was equally effective, insulin had only a small effect, and the unrelated peptides, glucagon and GH, were without effect. Degradation was inhibited in similar manner. Comparisons of [125I]IGF-I with [125I]insulin revealed comparable cell association, but degradation of internalized IGF-I was several-fold slower. Furthermore, IGF-I degradation was less sensitive, by half, to the inhibitory effect of chloroquine. When OK cells were exposed to [125I]IGF-I in the presence of IGF-binding protein-3 (IGFBP-3) cell association (binding and internalization) was reduced significantly. Of note, total cell degradation was reduced (P < 0.01), but the IGF-I that was internalized was degraded more rapidly than in control cells. Gel filtration and reverse phase HPLC revealed that the products of IGF-I degradation included large IGF-I-size intermediates in addition to trichloroacetic acid-soluble material. This product profile was not altered by IGFBP-3. Thus, as previously described for insulin, cultured OK cells possess specific IGF-I receptors and degrade internalized IGF-I. However, IGF-I processing differs from that of insulin, in that degradation is slower and relatively insensitive to competition by insulin. This study also shows that IGFBP-3 inhibits the binding and uptake of [125I]IGF-I by these kidney cells. However, once IGF-I is internalized, IGFBP-3 enhances degradation. Although the mechanism of this paradoxical action requires further study, analysis of the products of degradation suggests that the same enzymes are involved in IGF-I degradation regardless of whether IGFBP-3 is present.

Degradation of insulin by isolated rat renal cortical endosomes.

It has been widely accepted that in kidney, degradation of insulin occurs in lysosomes. It is thought that after internalization into the cell, insulin dissociates from its receptor, which then recycles to the plasma membrane, while the hormone is transported in endosomes to the lysosomes, where it is degraded. However, earlier studies from this laboratory have suggested that insulin may also be degraded in an extralysosomal site, most likely endosomes. Indeed, studies in other tissues, most notably liver, have shown that insulin degradation does take place in endosomes. Since the intracellular processing of insulin differs between different tissues and cell types, and as the kidney is a major site of insulin degradation, we set out to determine directly whether endosomes degrade internalized insulin in the kidney. Rats were injected with [125I]monoiodoinsulin, labeled at either the A14 or B26 tyrosine. After killing, the kidney cortex was excised, and heavy endosomes were prepared by differential and isopycnic centrifugation. The isolated [125I]insulin-loaded endosomes were incubated for up to 60 min in intracellular medium, and degradation of [125I] insulin was estimated by means of precipitation in trichloroacetic acid. In the presence of ATP (10 mM), the percent degraded was increased over the control value (no ATP present), but under these circumstances, degradation was greater when the endosomes contained internalized 125I-labeled [B26]insulin than with A14-labeled [125I]insulin (26% vs. 13% degraded/h). In the absence of ATP, the percent degraded increased when the pH of the incubation medium was lowered. Radiolabeled material was extracted from endosomes, and Sephadex G-50 analysis revealed the presence of high mol wt, insulin-size, and low mol wt material. Reverse phase HPLC analysis of the insulin-size material revealed the presence of intact insulin and a number of degradation products. The elution profiles of some of these products were consistent with that reported to arise from the action of the insulin-degrading enzyme. Western blot analysis with the antiinsulin-degrading enzyme monoclonal antibody 9B12 confirmed the presence of the enzyme in endosomal preparations. We conclude that degradation of insulin does occur in kidney cortical endosomes, probably involves the insulin-degrading enzyme, and results in the formation of relatively large intermediate products as well as low mol wt products.

Sequential processing of insulin by cultured kidney cells.

It is now well established that in kidney, as in liver, endosomes participate in the degradation of insulin. Degradation in this compartment involves the action of the insulin-degrading enzyme or a similar enzyme with the formation of large intermediate products. The role of lysosomes is less clear, for although earlier studies suggested that they are the major or sole site of degradation, this has been increasing questioned. More recently, it has been concluded that endosomes, at least in liver, are the major site of insulin degradation and that classic lysosomes are only involved in the latter stages of degradation if at all. As intracellular insulin processing varies among cell types, we set out to examine directly the processing of insulin within cultured proximal-like opossum kidney cells. By means of analytical subcellular fractionation and reverse phase HPLC analysis of products, we established the following sequence of events. After internalization, [125I]A14-insulin is partially degraded in endosomes. The formed products together with intact insulin, which accounts for most of the radioactive material in the endosomes, are then directed to the lysosomal compartment, where degradation proceeds rapidly to completion. Bacitracin inhibited degradation in both compartments and, although not eliminating insulin trafficking, may impair the transfer of insulin from endosomes to lysosomes. This study establishes a major role for lysosomes in kidney cell insulin degradation.

Removal of immunoreactive arginine vasopressin by the perfused rat liver.

To assess the ability of the liver to remove immunoreactive arginine vasopressin (AVP) from the circulation and to determine the effect of certain metabolic factors on the process, a study was carried out with rat livers perfused at 37 C with an oxygenated albumin--electrolyte solution containing AVP (117 +/- 4.5 muU/ml). In controls, the hepatic clearance of AVP was 795 +/- 120 microliter/min (SEM). The addition of AVP in concentrations up to 9029 microU/ml, perfusion with a glucose-free medium, or perfusion without oxygen did not significantly alter the hepatic clearance of AVP. However, perfusion with cold medium (11 C) significantly altered AVP removal in that initially AVP removal increased, while later on AVP removal became completely inhibited. This phenomenon may possibly be a consequence of a cold-induced increase in hepatic AVP trapping which is rapidly saturated due to a cold-induced depression of AVP transport and degradation. Support for this thesis was provided by finding that high AVP concentrations depressed the cold-endhancing removal phase.

High performance liquid chromatographic analysis of insulin degradation products from a cultured kidney cell line.

The kidney is a major site for insulin removal and degradation, but the subcellular processes and enzymes involved have not been established. We have examined this process by analyzing insulin degradation products by HPLC. Monoiodoinsulin specifically labeled on either the A14 or B26 tyrosine residue was incubated with a cultured kidney epithelial cell line, and both intracellular and extracellular products were examined on HPLC. The products were then compared with products of known structure generated by hepatocytes and the enzyme insulin protease. Intracellular and extracellular products were different, suggesting two different degradative pathways, as previously shown in liver. The extracellular degradation products eluted from HPLC both before and after sulfitolysis similarly with hepatocyte products and products generated by insulin protease. The intracellular products also eluted identically with hepatocyte products. Based on comparisons with identified products, the kidney cell generates two fragments from the A chain of intact insulin, one with a cleavage at A13-A14 and the other at A14-A15. The B chain of intact insulin is cleaved in a number of different sites, resulting in peptides that elute identically with B chain peptides cleaved at B9-B10, B13-B14, B16-B17, B24-B25, and B25-B26. These similarities with hepatocytes and insulin protease suggest that liver and kidney have similar mechanisms for insulin degradation and that insulin protease or a very similar enzyme is involved in both tissues.

Nuclear transport of insulin-like growth factor-I and insulin-like growth factor binding protein-3 in opossum kidney cells.

When added to cultured opossum kidney cells, IGF-I is internalized and transported to distinct intracellular compartments that depend on the cell location within the monolayer. In resting cells away from the periphery of the monolayer, IGF-I is internalized by a clathrin coated pit pathway and delivered to the endosomal compartment. In contrast, cells growing at the edges of a monolayer or an experimental wound internalize IGF-I by an alternative route which rapidly delivers IGF-I to the nucleus. Similarly to IGF-I, IGFBP-3 is also internalized and accumulates in the endosomal compartment in resting cells whereas it is targeted to the nucleus in proliferating cells. IGFBP-3, which contains a putative nuclear targeting signal, may act as a carrier for IGF-I nuclear transport. The transport of IGF-I and IGFBP-3 to two different compartments may influence their biological activity.

The effect of different preparations of human growth hormone on plasma renin activity in normal males.

The effect of acute administration of 2 preparations of growth hormone (hGH) on plasma renin activity (PRA) was studied in normal volunteers. 4 IU of standard, commercially available hGH II, Kabi, Sweden) were injected im into each of four normal subjects, and the PRA was determined in the basal state and at 30, 60, 120, 180, and 240 min after injection. Free fatty acid (FFA) was determined basally and at 15 and 210 min post-injection. The study was repeated on a different day in the same group using highly purified hGH (hGH I, 4 IU) virtually free of arginine-vasopressin. Four other normal subjects received 12 IU standard hGH (hGH II, Kabi, Sweden). There was no significant difference in PRA values with 4 IU of either preparation or with 12 IU of hGH II in any of the groups, although mean PRA was elevated in two of the patients receiving 12 IU hGH II. A rise in FFA occurred in all subjects, indicating the biological activity of hGH preparations. The possible significance of these findings to the renin-angiotensin system found in acromegaly is considered.

Fluoxetine treatment for depression in patients with HIV and AIDS: a randomized, placebo-controlled trial.

OBJECTIVE: The goals of this study were to determine whether fluoxetine is superior to placebo in treating HIV-seropositive patients with major depression or dysthymia or both, whether severity of immunosuppression is associated with treatment response, and whether fluoxetine treatment is associated with change in immune status as measured by CD4 cell count. METHOD: A double-blind, randomized, placebo-controlled 8-week trial of fluoxetine was conducted in a university-affiliated research outpatient clinic. The fluoxetine-placebo randomization was 2:1. All patients were offered 4 months of additional open treatment. Main outcome measures included the Clinical Global Impression, Hamilton Depression Rating Scale, and CD4 cell count. RESULTS: Of 120 patients randomly assigned to fluoxetine or placebo, 87 completed 8 weeks of treatment. In the total group, 51% had AIDS. All but three were men, 35% were nonwhite, and 6% had intravenous drug use as a risk factor. In an intention-to-treat analysis, 57% of fluoxetine patients and 41% of placebo patients were responders. Among patients who completed the study, 74% responded to fluoxetine and 47% to placebo; this difference was statistically significant. Severity of immunosuppression was not related to antidepressant response, attrition, or side effects, and fluoxetine treatment was not associated with change in CD4 cell count. CONCLUSIONS: Fluoxetine is an effective antidepressant in the context of HIV illness. However, both placebo response and attrition were substantial, suggesting both that nonspecific factors may be more salient and that yet another medication (i.e., an antidepressant) may be less acceptable among patients with serious medical illness already requiring multiple concomitant medications.

The "Moonies": a psychological study of conversion and membership in a contemporary religious sect.

The authors undertook this study to enhance psychiatric understanding of contemporary charismatic religious sects. After a pilot study, a representative sample of members of the Unification Church (N = 237) completed a 216-item structured questionnaire. Respondents were below the mean for an age- and sex-matched group on a psychological general well-being scale, and they reported significantly greater neurotic distress before conversion. The authors discuss correlates of an improved emotional state following conversion and employ attribution theory, drawn from social psychology, to put the conversion process into a psychiatric perspective.

Effect of imipramine on mood and enumerative measures of immune status in depressed patients with HIV illness.

OBJECTIVE: The authors' first objective was to ascertain whether imipramine is superior to placebo in treating axis I depressive disorders in the context of HIV illness. Supplementary questions were whether severity of immunodeficiency is associated with antidepressant response and whether patients with greater immunodeficiency can tolerate standard doses of imipramine. Second, the authors sought to determine whether imipramine treatment is associated with changes in immune status. METHOD: A double-blind, randomized placebo-controlled trial of imipramine was conducted in a university-affiliated research outpatient clinic. After 6 weeks of treatment, responders were maintained double-blind for another 6 weeks and nonresponders were removed from the study and treated openly. All patients were offered 26 weeks of treatment. Of the 97 patients who were randomly assigned to placebo or imipramine, 80 completed the 6-week phase. Main outcome measures included the Clinical Global Impression, the Hamilton Depression Rating Scale, the Brief Symptom Inventory, and CD4 cell count. RESULTS: Among study completers, 31 (39%) had AIDS. The response rate to imipramine was 74% and the response rate to placebo was 26%. There was no difference in depression response between patients with more or less severe immunodeficiency, nor was there a difference in medication dose or side effects. Neither type nor duration of treatment influenced CD4 cell count during the course of treatment. CONCLUSIONS: Depressed patients with HIV illness respond to imipramine at the same rate as medically healthy depressed patients. Severity of immunosuppression is not associated with imipramine treatment outcome. There is no evidence that imipramine has negative effects on enumerative measures of immune status.

Insulin-like growth factor-I ameliorates delayed kidney graft function and the acute nephrotoxic effects of cyclosporine.

BACKGROUND: Delayed graft function (DGF) is a relatively common complication after cadaveric renal transplantation. The adverse effect of DGF on long-term graft survival has lead to intensive efforts to reduce ischemic graft injury. In this study we examined the effects of a new protective treatment based on insulin growth factor (IGF)-I. We evaluated the impact of the treatment on renal recovery and on the nephrotoxicity that is a common side effect of mainstream immunosuppressants. Because therapy with IGF-I or the analog des(1-3)IGF-I is effective in treating experimental ischemic renal failure, these peptides may be useful as perspective clinical treatments. METHODS: We have addressed three areas relating to the potential use of IGF-I and its analog des(1-3)IGF-I. First, because of the immunogenic properties of IGF-I, we assessed the effect of des(1-3)IGF-I on the rejection of skin allografts in Lewis rats. Next we determined whether treatment with des(1-3)IGF-I influences the early function of transplanted kidneys in a model of DGF induced by a combination of warm and cold ischemia. Finally we tested whether IGF-I protects against acute cyclosporine nephrotoxicity. RESULTS: Des(1-3)IGF-I did not accelerate the rejection of the skin grafts (P=0.57). The administration of this peptide in a model of syngenic renal transplant improved the early function of the graft. Postoperative values of creatinine and blood urea nitrogen were significantly better (P<0.05) in treated animals. IGF-I also ameliorated the nephrotoxicity of cyclosporine, with better values of creatinine and blood urea nitrogen (P<0.05). CONCLUSIONS: In evaluating this study it should be recognized that the animal models studied, although widely used, differ from the human condition. However, IGF-I and des(1-3)IGF-I exhibit properties that strongly suggest their value in preventing clinical DGF, and they deserve further studies.