OBJECTIVE

To explore the role of endothelin-<em>1</em>, a potent endothelial-derived vasoconstrictor peptide, in pulmonary hypertension, by measuring its concentration in arterial and venous plasma.

METHODS

A survey, case series study.

METHODS

University-affiliated hospitals and outpatient clinics.

METHODS

Twenty-seven patients with pulmonary hypertension: 7 with primary, and 20 with secondary pulmonary hypertension of various causes. The control groups (n = <em>1</em>6) comprised 8 healthy volunteers and 8 patients with coronary artery disease but without evidence of pulmonary hypertension.

RESULTS

Pulmonary artery pressure was markedly increased (94/43 +/- 23/<em>1</em>3 mm Hg) in the patients with pulmonary hypertension. Venous plasma immunoreactive endothelin-<em>1</em>, measured by a specific radioimmunoassay, was significantly higher in patients with pulmonary hypertension (3.5 +/- 2.5 pg/mL, P less than 0.00<em>1</em>) than in normal subjects (<em>1</em>.45 +/- 0.45 pg/mL), or patients with coronary disease (0.75 +/- 0.64 pg/mL). The arterial-to-venous ratio of immunoreactive endothelin-<em>1</em> was significantly greater than unity in primary pulmonary hypertension (2.2<em>1</em> +/- 0.72, P = 0.0<em>1</em>), whereas the patients with secondary pulmonary hypertension had a mean ratio not different from <em>1</em> (0.97 +/- 0.42). In contrast, the mean arterial-to-venous ratios were significantly less than unity in both control groups (0.59 +/- 0.35, and 0.54 +/- 0.64; P less than 0.02, for normal subjects and coronary disease patients, respectively), indicating a possible clearance of endothelin-<em>1</em> across the healthy lung.

CONCLUSIONS

Patient with pulmonary hypertension have substantial alterations in plasma immunoreactive endothelin-<em>1</em>, which may reflect changes in net release or clearance of endothelin-<em>1</em> by the lung. In patients with primary pulmonary hypertension, the high levels in arterial compared with venous plasma suggest pulmonary production of endothelin-<em>1</em>, which may contribute to elevated pulmonary vascular resistance.

BACKGROUND

To compare the efficacy and toxicity of three platinum-based combination regimens against cisplatin plus irinotecan (IP) in patients with untreated advanced non-small-cell lung cancer (NSCLC) by a non-inferiority design.

METHODS

A total of 602 patients were randomly assigned to one of four regimens: cisplatin 80 mg/m(2) on day <em>1</em> plus irinotecan 60 mg/m(2) on days <em>1</em>, 8, <em>1</em>5 every 4 weeks (IP) carboplatin AUC 6.0 min x mg/<em>mL</em> (area under the concentration-time curve) on day <em>1</em> plus paclitaxel 200 mg/m(2) on day <em>1</em> every 3 weeks (TC); cisplatin 80 mg/m(2) on day <em>1</em> plus gemcitabine <em>1</em>000 mg/m(2) on days <em>1</em>, 8 every 3 weeks (GP); and cisplatin 80 mg/m(2) on day <em>1</em> plus vinorelbine 25 mg/m(2) on days <em>1</em>, 8 every 3 weeks (NP).

RESULTS

The response rate, median survival time, and <em>1</em>-year survival rate were 3<em>1</em>.0%, <em>1</em>3.9 months, 59.2%, respectively, in IP; 32.4%, <em>1</em>2.3 months, 5<em>1</em>.0% in TC; 30.<em>1</em>%, <em>1</em>4.0 months, 59.6% in GP; and 33.<em>1</em>%, <em>1</em><em>1</em>.4 months, 48.3% in NP. No statistically significant differences were found in response rate or overall survival, but the non-inferiority of none of the experimental regimens could be confirmed. All the four regimens were well tolerated.

CONCLUSIONS

The four regimens have similar efficacy and different toxicity profiles, and they can be used to treat advanced NSCLC patients.

Cyclosporin A (CsA) is a potent immunosuppressive agent, now gaining wide application in human organ transplantation. The immunosuppressive activity of CsA is at least in part due to inhibition of lymphokine production by activated T lymphocytes. Specifically, inhibition of T-cell growth factor (TCGF; also designated interleukin 2) production appears to be an important pathway by which CsA impairs T-cell function. To define further both the specificity of CsA and the level at which it interferes with lymphokine gene expression, we have studied its effects on TCGF mRNA accumulation as well as TCGF gene transcription. These studies were performed with a cloned human leukemic T-cell line (Jurkat, subclone 32), which can be induced with phytohemagglutinin and phorbol <em>1</em>2-myristate <em>1</em>3-acetate to produce large amounts of TCGF. In these cells, high levels of TCGF mRNA were present in induced but not in uninduced Jurkat cells as judged by hybridization to a cloned human TCGF cDNA probe. CsA completely inhibited induced TCGF mRNA accumulation at concentrations of 0.3-<em>1</em>.0 microgram/<em>ml</em>, whereas low levels of appropriately sized TCGF mRNA were present at 0.0<em>1</em> microgram/<em>ml</em>. In nuclear transcription experiments, CsA inhibited the synthesis of TCGF transcripts in a dose-dependent manner with complete inhibition at a concentration of <em>1</em> microgram/<em>ml</em>. In contrast, CsA did not inhibit the expression of two other inducible genes, TCGF receptor and HT-3. Further, HLA gene expression was also less affected than TCGF in CsA-treated cells. These data suggest a relatively selective action of CsA on TCGF gene transcription.

The chimeric monoclonal antibody cAC<em>1</em>0, directed against CD30, induces growth arrest of CD30+ cell lines in vitro and has pronounced antitumor activity in severe combined immunodeficiency (SCID) mouse xenograft models of Hodgkin disease. We have significantly enhanced these activities by conjugating to cAC<em>1</em>0 the cytotoxic agent monomethyl auristatin E (MMAE) to create the antibody-drug conjugate cAC<em>1</em>0-vcMMAE. MMAE, a derivative of the cytotoxic tubulin modifier auristatin E, was covalently coupled to cAC<em>1</em>0 through a valine-citrulline peptide linker. The drug was stably attached to the antibody, showing only a 2% release of MMAE following <em>1</em>0-day incubation in human plasma, but it was readily cleaved by lysosomal proteases after receptor-mediated internalization. Release of MMAE into the cytosol induced G2/M-phase growth arrest and cell death through the induction of apoptosis. In vitro, cAC<em>1</em>0-vcMMAE was highly potent and selective against CD30+ tumor lines (IC50 less than <em>1</em>0 ng/<em>mL</em>) but was more than 300-fold less active on antigen-negative cells. In SCID mouse xenograft models of anaplastic large cell lymphoma or Hodgkin disease, cAC<em>1</em>0-vcMMAE was efficacious at doses as low as <em>1</em> mg/kg. Mice treated at 30 mg/kg cAC<em>1</em>0-vcMMAE showed no signs of toxicity. These data indicate that cAC<em>1</em>0-vcMMAE may be a highly effective and selective therapy for the treatment of CD30+ neoplasias.

OBJECTIVE

To study the systemic release and kinetics of high mobility group box-<em>1</em> protein (HMGB<em>1</em>) in relation to clinical features in a population of patients with severe sepsis or septic shock and to compare these with the kinetics of the cytokines interleukin-6, interleukin-8, interleukin-<em>1</em>0, and tumor necrosis factor-alpha.

METHODS

Prospective study of two cohorts of patients.

METHODS

Intensive care unit and infectious disease clinic at Karolinska University Hospital Huddinge.

METHODS

Twenty-six patients with severe sepsis, 33 patients with septic shock, and a reference group of five patients with sepsis.

METHODS

None.

RESULTS

Sixty-four patients were included, ten of whom died within 28 days. Cytokine levels were measured at five time points during the first week after admission and were correlated to Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores. Two HMGB<em>1</em> assays were used. Both demonstrated delayed kinetics for HMGB<em>1</em> with high levels on inclusion that remained high throughout the study period. Serum concentration at <em>1</em>44 hrs, the last sampling point, was 300 times higher, 34,000 +/- 76,000 pg/mL (mean +/- sd), than any of the other cytokines. This study, however, found no predictable correlation between serum levels of HMGB<em>1</em> and severity of infection. We did quite unexpectedly find significantly lower levels of HMGB<em>1</em> in nonsurvivors compared with survivors as measured by our main assay, but the other showed no difference between the two groups. Levels of interleukin-6, interleukin-8, interleukin-<em>1</em>0, and tumor necrosis factor-alpha correlated significantly with severity of disease, and all were significantly higher in patients with septic shock compared with those with severe sepsis. Neither of these comparisons showed significant correlations for HMGB<em>1</em>.

CONCLUSIONS

This is the first prospective study assessing the release over time of HMGB<em>1</em> in a population of patients with sepsis, severe sepsis, or septic shock. Levels remained high in the majority of patients up to <em>1</em> wk after admittance, indicating that the cytokine indeed is a downstream and late mediator of inflammation. Further studies are required to fully define the relationship of HMGB<em>1</em> to severity of disease.

OBJECTIVE

The aim of this study was to assess the results of a <em>1</em>0-year experience with a minimally invasive operation that requires neither cartilage incision nor resection for correction of pectus excavatum.

METHODS

From <em>1</em>987 to <em>1</em>996, <em>1</em>48 patients were evaluated for chest wall deformity. Fifty of <em>1</em>27 patients suffering from pectus excavatum were selected for surgical correction. Eight older patients underwent the Ravitch procedure, and 42 patients under age <em>1</em>5 were treated by the minimally invasive technique. A convex steel bar is inserted under the sternum through small bilateral thoracic incisions. The steel bar is inserted with the convexity facing posteriorly, and when it is in position, the bar is turned over, thereby correcting the deformity. After 2 years, when permanent remolding has occurred, the bar is removed in an outpatient procedure.

RESULTS

Of 42 patients who had the minimally invasive procedure, 30 have undergone bar removal. Initial excellent results were maintained in 22, good results in four, fair in two, and poor in two, with mean follow-up since surgery of 4.6 years (range, <em>1</em> to 9.2 years). Mean follow-up since bar removal is 2.8 years (range, 6 months to 7 years). Average blood loss was <em>1</em>5 <em>mL</em>. Average length of hospital stay was 4.3 days. Patients returned to full activity after <em>1</em> month. Complications were pneumothorax in four patients, requiring thoracostomy in one patient; superficial wound infection in one patient; and displacement of the steel bar requiring revision in two patients. The fair and poor results occurred early in the series because (<em>1</em>) the bar was too soft (three patients), (2) the sternum was too soft in one of the patients with Marfan's syndrome, and (3) in one patient with complex thoracic anomalies, the bar was removed too soon.

CONCLUSIONS

This minimally invasive technique, which requires neither cartilage incision nor resection, is effective. Since increasing the strength of the steel bar and inserting two bars where necessary, we have had excellent long-term results. The upper limits of age for this procedure require further evaluation.

BACKGROUND

Contrast-induced nephropathy remains a common complication of radiographic procedures. Pretreatment with sodium bicarbonate is more protective than sodium chloride in animal models of acute ischemic renal failure. Acute renal failure from both ischemia and contrast are postulated to occur from free-radical injury. However, no studies in humans or animals have evaluated the efficacy of sodium bicarbonate for prophylaxis against contrast-induced nephropathy.

OBJECTIVE

To examine the efficacy of sodium bicarbonate compared with sodium chloride for preventive hydration before and after radiographic contrast.

METHODS

A prospective, single-center, randomized trial conducted from September <em>1</em>6, 2002, to June <em>1</em>7, 2003, of <em>1</em><em>1</em>9 patients with stable serum creatinine levels of at least <em>1</em>.<em>1</em> mg/dL >> or =97.2 micromol/L) who were randomized to receive a <em>1</em>54-mEq/L infusion of either sodium chloride (n = 59) or sodium bicarbonate (n = 60) before and after iopamidol administration (370 mg iodine/<em>mL</em>). Serum creatinine levels were measured at baseline and <em>1</em> and 2 days after contrast.

METHODS

Patients received <em>1</em>54 mEq/L of either sodium chloride or sodium bicarbonate, as a bolus of 3 <em>mL</em>/kg per hour for <em>1</em> hour before iopamidol contrast, followed by an infusion of <em>1</em> <em>mL</em>/kg per hour for 6 hours after the procedure.

METHODS

Contrast-induced nephropathy, defined as an increase of 25% or more in serum creatinine within 2 days of contrast.

RESULTS

There were no significant group differences in age, sex, incidence of diabetes mellitus, ethnicity, or contrast volume. Baseline serum creatinine was slightly higher but not statistically different in patients receiving sodium bicarbonate treatment (mean [SD], <em>1</em>.7<em>1</em> [0.42] mg/dL [<em>1</em>5<em>1</em>.2 [37.<em>1</em>] micromol/L] for sodium chloride and <em>1</em>.89 [0.69] mg/dL [<em>1</em>67.<em>1</em> [6<em>1</em>.0] micromol/L] for sodium bicarbonate; P =.09). The primary end point of contrast-induced nephropathy occurred in 8 patients (<em>1</em>3.6%) infused with sodium chloride but in only <em>1</em> (<em>1</em>.7%) of those receiving sodium bicarbonate (mean difference, <em>1</em><em>1</em>.9%; 95% confidence interval [CI], 2.6%-2<em>1</em>.2%; P =.02). A follow-up registry of <em>1</em>9<em>1</em> consecutive patients receiving prophylactic sodium bicarbonate and meeting the same inclusion criteria as the study resulted in 3 cases of contrast-induced nephropathy (<em>1</em>.6%; 95% CI, 0%-3.4%).

CONCLUSIONS

Hydration with sodium bicarbonate before contrast exposure is more effective than hydration with sodium chloride for prophylaxis of contrast-induced renal failure.

A surveillance program (SENTRY) of bloodstream infections (BSI) in the United States, Canada, Latin America, and Europe from <em>1</em>997 through <em>1</em>999 detected <em>1</em>,<em>1</em>84 episodes of candidemia in 7<em>1</em> medical centers (32 in the United States, 23 in Europe, 9 in Latin America, and 7 in Canada). Overall, 55% of the yeast BSIs were due to Candida albicans, followed by Candida glabrata and Candida parapsilosis (<em>1</em>5%), Candida tropicalis (9%), and miscellaneous Candida spp. (6%). In the United States, 45% of candidemias were due to non-C. albicans species. C. glabrata (2<em>1</em>%) was the most common non-C. albicans species in the United States, and the proportion of non-C. albicans BSIs was highest in Latin America (55%). C. albicans accounted for 60% of BSI in Canada and 58% in Europe. C. parapsilosis was the most common non-C. albicans species in Latin America (25%), Canada (<em>1</em>6%), and Europe (<em>1</em>7%). Isolates of C. albicans, C. parapsilosis, and C. tropicalis were all highly susceptible to fluconazole (97 to <em>1</em>00% at < or =8 microg/<em>ml</em>). Likewise, 97 to <em>1</em>00% of these species were inhibited by < or =<em>1</em> microg/<em>ml</em> of ravuconazole (concentration at which 50% were inhibited [MIC(50)], 0.007 to 0.03 microg/<em>ml</em>) or voriconazole (MIC(50), 0.007 to 0.06 microg/<em>ml</em>). Both ravuconazole and voriconazole were significantly more active than fluconazole against C. glabrata (MIC(90)s of 0.5 to <em>1</em>.0 microg/<em>ml</em> versus <em>1</em>6 to 32 microg/<em>ml</em>, respectively). A trend of increased susceptibility of C. glabrata to fluconazole was noted over the three-year period. The percentage of C. glabrata isolates susceptible to fluconazole increased from 48% in <em>1</em>997 to 84% in <em>1</em>999, and MIC(50)s decreased from <em>1</em>6 to 4 microg/<em>ml</em>. A similar trend was documented in both the Americas (57 to 84% susceptible) and Europe (22 to 80% susceptible). Some geographic differences in susceptibility to triazole were observed with Canadian isolates generally more susceptible than isolates from the United States and Europe. These observations suggest susceptibility patterns and trends among yeast isolates from BSI and raise additional questions that can be answered only by continued surveillance and clinical investigations of the type reported here (SENTRY Program).

BACKGROUND

Despite suppressive treatment with highly active antiretroviral therapy (HAART), replication-competent virus can still be isolated from peripheral blood mononuclear cells and genital cells of many individuals receiving suppressive HAART.

OBJECTIVE

To determine whether free virion RNA can be detected in the blood plasma and/or genital tract fluids from patients receiving suppressive HAART.

METHODS

Prospective cohort study conducted from November <em>1</em>998 to May <em>1</em>999.

METHODS

Academic medical center.

METHODS

Human immunodeficiency virus <em>1</em>-infected individuals (20 men and 2 women) shown in our laboratories to have fewer than 50 copies/<em>mL</em> of HIV-<em>1</em> RNA in peripheral blood plasma while taking suppressive HAART.

METHODS

Free virion RNA levels in peripheral blood plasma and genital fluids, quantified using an ultrasensitive reverse transcriptase polymerase chain reaction able to quantify cell-free virion RNA to a lower limit of 5 copies/mL and qualitatively detect viral RNA below this level.

RESULTS

In all 22 patients, residual viral RNA could be detected in the peripheral blood plasma (mean level, <em>1</em>7 copies/<em>mL</em>). The presence of viral RNA suggests that ongoing viral replication is occurring, albeit at low levels, in each patient evaluated. Viral RNA levels were lower in most patients' genital fluids compared with blood plasma and in <em>1</em>2 patients were undetectable.

CONCLUSIONS

These data suggest that low-level replication of HIV-<em>1</em> in patients taking suppressive HAART may be demonstrated not only in peripheral blood mononuclear cells but also in peripheral plasma as cell-free virion RNA. Complete ablation of viral replication may require intensification of antiretroviral therapies beyond standard suppressive HAART.

BACKGROUND

Long-term effects of abacavir (ABC)-lamivudine (3TC), compared with tenofovir (TDF)-emtricitabine (FTC) with efavirenz (EFV) or atazanavir plus ritonavir (ATV/r), on bone mineral density (BMD) have not been analyzed.

METHODS

A5224s was a substudy of A5202, in which HIV-infected treatment-naive participants were randomized and blinded to receive ABC-3TC or TDF-FTC with open-label EFV or ATV/r. Primary bone end points included Dual-emission X-ray absorbtiometry (DXA)-measured percent changes in spine and hip BMD at week 96. Primary analyses were intent-to-treat. Statistical tests used the factorial design and included linear regression, 2-sample t, log-rank, and Fisher's exact tests.

RESULTS

Two hundred sixty-nine persons randomized to 4 arms of ABC-3TC or TDF-FTC with EFV or ATV/r. At baseline, 85% were male, and 47% were white non-Hispanic; the median HIV-<em>1</em> RNA load was 4.6 log(<em>1</em>0) copies/<em>mL</em>, the median age was 38 years, the median weight was 76 kg, and the median CD4 cell count was 233 cells/<em>μL</em>. At week 96, the mean percentage changes from baseline in spine and hip BMD for ABC-3TC versus TDF-FTC were -<em>1</em>.3% and -3.3% (P = .004) and -2.6% and -4.0% (P = .024), respectively; and for EFV versus ATV/r were -<em>1</em>.7% and -3.<em>1</em>% (P = .035) and -3.<em>1</em>% and -3.4% (P = .6<em>1</em>), respectively. Bone fracture was observed in 5.6% of participants. The probability of bone fractures and time to first fracture were not different across components.

CONCLUSIONS

Compared with ABC-3TC, TDF-FTC-treated participants had significantly greater decreases in spine and hip BMD, whereas ATV/r led to more significant losses in spine, but not hip, BMD than EFV. Clinical Trials Registration. NCT00<em>1</em><em>1</em>8898.

OBJECTIVE

Kupffer's cells participate in alcohol-induced liver injury, and endotoxemia is observed in human alcoholics and in a rat model. This study evaluated the effect of reducing bacterial endotoxin production by intestinal sterilization on alcohol-induced liver injury.

METHODS

Male Wistar rats were exposed to ethanol continuously for up to 3 weeks via intragastric feeding. The gut was sterilized with polymyxin B and neomycin.

RESULTS

Fecal culture of stool samples from ethanol-fed rats treated with antibiotics showed virtually no growth of gram-negative bacteria. Endotoxin levels of 80-90 pg/<em>mL</em> in plasma of ethanol-fed rats were reduced to < 25 pg/<em>mL</em> by antibiotics. Antibiotic treatment also completely prevented elevated aspartate aminotransferase levels and significantly reduced the average hepatic pathological score in rats exposed to ethanol. Oxygen tension on the surface of the liver measured in vivo was decreased significantly from control values of 48 +/- <em>1</em> to 39 +/- <em>1</em> mumol/L in ethanol-treated rats. This hypoxia was prevented by treatment with antibiotics. Moreover, the increase in rates of ethanol elimination due to long-term ethanol treatment was prevented by antibiotic treatment.

CONCLUSIONS

Intestinal sterilization prevented alcohol-induced liver injury in the rat, supporting the idea that hypermetabolism and consequent hypoxia caused by activation of Kupffer's cells by endotoxin is involved in the mechanism.

BACKGROUND

Comorbidities contribute to disease severity and mortality in patients with chronic obstructive pulmonary disease (COPD). Comorbidities have been studied individually and were mostly based on self-reports. The coexistence of objectively identified comorbidities and the role of low-grade systemic inflammation in the pathophysiology of COPD remain to be elucidated.

OBJECTIVE

To cluster <em>1</em>3 clinically important objectively identified comorbidities, and to characterize the comorbidity clusters in terms of clinical outcomes and systemic inflammation.

METHODS

A total of 2<em>1</em>3 patients with COPD (FEV<em>1</em>, 5<em>1</em> ± <em>1</em>7% predicted; men, 59%; age, 64 ± 7 yr) were included prospectively. Comorbidities were based on well-known cut-offs identified in the peer-reviewed English literature. Systemic inflammatory biomarkers were determined in all patients. Self-organizing maps were used to generate comorbidity clusters.

RESULTS

A total of 97.7% of all patients had one or more comorbidities and 53.5% had four or more comorbidities. Five comorbidity clusters were identified: (<em>1</em>) less comorbidity, (2) cardiovascular, (3) cachectic, (4) metabolic, and (5) psychological. Comorbidity clusters differed in health status but were comparable with respect to disease severity. An increased inflammatory state was observed only for tumor necrosis factor (TNF) receptors in the metabolic cluster (geometric mean [lower and upper limit]; TNF-R<em>1</em>, 2,377 [<em>1</em>,850, 3,055] pg/<em>ml</em>, confidence, 98.5%; TNF-R2, 4,080 [3,<em>1</em><em>1</em>5, 5,344] pg/<em>ml</em>, confidence, 98.8%) and only for IL-6 in the cardiovascular cluster (IL-6, 3.4 [<em>1</em>.8, 6.6] pg/<em>ml</em>; confidence, 99.8%).

CONCLUSIONS

Multimorbidity is common in patients with COPD, and different comorbidity clusters can be identified. Low-grade systemic inflammation is mostly comparable among comorbidity clusters. Increasing knowledge on the interactions between comorbidities increases the understanding of their development and contributes to strategies for prevention or improved treatment.

OBJECTIVE

To evaluate CSF levels of beta-amyloid(<em>1</em>-42) (Abeta42) alone and in combination with CSF tau for distinguishing AD from other conditions.

METHODS

At <em>1</em>0 centers in Europe and the United States, <em>1</em>50 CSF samples from AD patients were analyzed and compared with <em>1</em>00 CSF samples from healthy volunteers or patients with disorders not associated with pathologic conditions of the brain (CON), 84 patients with other neurologic disorders (ND), and 79 patients with non-Alzheimer types of dementia (NAD). Sandwich ELISA techniques were used on site for measuring Abeta42 and tau.

RESULTS

Median levels of Abeta42 in CSF were significantly lower in AD (487 pg/mL) than in CON (849 pg/mL; p = 0.00<em>1</em>), ND (643 pg/mL; p = 0.00<em>1</em>), and NAD (603 pg/mL; p = 0.00<em>1</em>). Discrimination of AD from CON and ND was significantly improved by the combined assessment of Abeta42 and tau. At 85% sensitivity, specificity of the combined test was 86% (95% CI: 8<em>1</em>% to 9<em>1</em>%) compared with 55% (95% CI: 47% to 62%) for Abeta42 alone and 65% (95% CI: 58% to 72%) for tau. The combined test at 85% sensitivity was 58% (95% CI: 47% to 69%) specific for NAD. The APOE e4 gene load was negatively correlated with Abeta42 levels not only in AD but also in NAD.

CONCLUSIONS

The combined measure of CSF Abeta42 and tau meets the requirements for clinical use in discriminating AD from normal aging and specific neurologic disorders.

OBJECTIVE

We examined whether endothelial dysfunction occurs when acute hyperglycemia is induced by oral glucose loading.

BACKGROUND

Endothelial dysfunction has been shown to occur in patients with diabetes mellitus (DM), and chronic hyperglycemia is implicated as a cause of endothelial dysfunction. However, in many patients with Type 2 DM and in those with impaired glucose tolerance (IGT), fasting blood glucose may be within normal limits, and hyperglycemia occurred only post-prandially.

METHODS

With ultrasound technique, we measured flow-mediated endothelium-dependent vasodilation during oral glucose tolerance test in 58 subjects: (<em>1</em>7 patients with normal glucose tolerance [NGT], 24 with IGT, and <em>1</em>7 with type 2 DM). In addition, we measured the levels of thiobarbituric acid reactive substances (TBARS) and nitrite/nitrate.

RESULTS

Flow-mediated vasodilation decreased after glucose loading (NGT: 7.53+/-0.40, 4.24+/-0.28 and 6.35+/-0.40, in fasting, at <em>1</em>- and 2-h, respectively, IGT: 6.50+/-0.48, <em>1</em>.40+/-0.4<em>1</em>** and 4.00+/-0.47*, respectively; DM: 4.77+/-0.37, <em>1</em>.35+/-0.38** and <em>1</em>.29+/-0.29%**, respectively; *p < 0.0<em>1</em> vs. fasting, **p < 0.005 vs. fasting). The TBARS concentration increased in parallel with plasma glucose level in each group (NGT: <em>1</em>.43+/-0.07, 2.03+/-0.<em>1</em>2 and <em>1</em>.80+/-0.<em>1</em>2, respectively; IGT: <em>1</em>.65+/-0.<em>1</em><em>1</em>, 2.46+/-0.<em>1</em>2** and <em>1</em>.94+/-0.08*, respectively; DM: <em>1</em>.73+/-0.07, 2.34+/-0.08** and 2.47+/-0.09** nmol/<em>ml</em>, respectively; *p < 0.05 vs. fasting, **p < 0.0<em>1</em> vs. fasting). Glucose loading did not change nitrite/nitrate concentration in any of the groups.

CONCLUSIONS

Hyperglycemia in response to oral glucose loading rapidly suppresses endothelium-dependent vasodilation, probably through increased production of oxygen-derived free radicals. These findings strongly suggest that prolonged and repeated post-prandial hyperglycemia may play an important role in the development and progression of atherosclerosis.

Insulin resistance plays an important role in the pathogenesis of type 2 diabetes; however, the multiple mechanisms causing insulin resistance are not yet fully understood. The aim of this study was to explore the possible contribution of intramyocellular lipid content in the pathogenesis of skeletal muscle insulin resistance. We compared insulin-resistant and insulin-sensitive subjects. To meet stringent matching criteria for other known confounders of insulin resistance, these individuals were selected from an extensively metabolically characterized group of 280 first-degree relatives of type 2 diabetic subjects. Some <em>1</em>3 lean insulin-resistant and <em>1</em>3 lean insulin-sensitive subjects were matched for sex, age, BMI, percent body fat, physical fitness, and waist-to-hip ratio. Insulin sensitivity was determined by the hyperinsulinemic-euglycemic clamp method (for insulin-resistant subjects, glucose metabolic clearance rate [MCR] was 5.77+/-0.28 <em>ml</em> x kg(-<em>1</em>) x min(-<em>1</em>) [mean +/- SE]; for insulin-sensitive subjects, MCR was <em>1</em>0.<em>1</em>5+/-0.7 <em>ml</em> x kg(-<em>1</em>) x min(-<em>1</em>); P<0.002). Proton magnetic resonance spectroscopy (MRS) was used to measure intramyocellular lipid content (IMCL) in both groups. MRS studies demonstrated that in soleus muscle, IMCL was increased by 84% (<em>1</em><em>1</em>.8+/-<em>1</em>.6 vs. 6.4+/-0.59 arbitrary units; P = 0.008 ), and in tibialis anterior muscle, IMCL was increased by 57% (3.26+/-0.36 vs. 2.08+/-0.3 arbitrary units; P = 0.0<em>1</em>7) in the insulin-resistant offspring, whereas the extramyocellular lipid content and total muscle lipid content were not statistically different between the two groups. These data demonstrate that in these well-matched groups of lean subjects, IMCL is increased in insulin-resistant offspring of type 2 diabetic subjects when compared with an insulin-sensitive group matched for age, BMI, body fat distribution, percent body fat, and degree of physical fitness. These results indicate that increased IMCL represents an early abnormality in the pathogenesis of insulin resistance and suggest that increased IMCL may contribute to the defective glucose uptake in skeletal muscle in insulin-resistant subjects.

OBJECTIVE

To study the efficacy and safety of dutasteride, a dual inhibitor of the 5-alpha-reductase isoenzymes types I and II.

METHODS

A total of 4325 men (295<em>1</em> completed) with clinical benign prostatic hyperplasia, moderate to severe symptoms (American Urological Association-Symptom Index score of <em>1</em>2 points or greater), a peak flow rate of <em>1</em>5 <em>mL</em>/s or less, a prostate volume of 30 cm3 or greater (as measured by transrectal ultrasonography), and a serum prostate-specific antigen level of <em>1</em>.5 to <em>1</em>0.0 ng/<em>mL</em> (inclusive) were enrolled into three identical clinical trials and randomized to 0.5 mg dutasteride daily or placebo. After a <em>1</em>-month, single-blind, placebo lead-in, patients were followed up for 24 months in a double-blind trial with multiple interval assessments.

RESULTS

At 24 months, serum dihydrotestosterone was reduced from baseline by a mean of 90.2% (median -93.7%; P <0.00<em>1</em>), and the total prostate and transition zone volumes were reduced by a mean of 25.7% and 20.4%, respectively (P <0.00<em>1</em>). The symptom score was improved by as early as 3 months, with pooled significance from 6 months onward (P <0.00<em>1</em>) and a reduction of 4.5 points (2<em>1</em>.4%) at 24 months (P <0.00<em>1</em>). The maximal flow rate improved significantly from <em>1</em> month (P <0.0<em>1</em>), with an increase of 2.2 <em>mL</em>/s reported at 24 months (P <0.00<em>1</em>). Hence, the risk reduction of acute urinary retention was 57% and the risk reduction of benign prostatic hyperplasia-related surgical intervention was 48% compared with placebo. The drug was well tolerated.

CONCLUSIONS

Dutasteride is a potent inhibitor of dihydrotestosterone production that is safe and effective in terms of the reduction of prostate volume and symptoms, flow rate improvement, and the reduction of the risk of acute urinary retention and surgery during a 24-month study period.

BACKGROUND

Many secondary abnormalities in chronic heart failure (CHF) may reflect physical deconditioning. There has been no prospective, controlled study of the effects of physical training on hemodynamics and autonomic function in CHF.

RESULTS

In a controlled crossover trial of 8 weeks of exercise training, <em>1</em>7 men with stable moderate to severe CHF (age, 6<em>1</em>.8 +/- <em>1</em>.5 years; left ventricular ejection fraction, <em>1</em>9.6 +/- 2.3%), increased exercise tolerance (<em>1</em>3.9 +/- <em>1</em>.0 to <em>1</em>6.5 +/- <em>1</em>.0 minutes, p less than 0.00<em>1</em>), and peak oxygen uptake (<em>1</em>3.2 +/- 0.9 to <em>1</em>5.6 +/- <em>1</em>.0 <em>ml</em>/kg/min, p less than 0.0<em>1</em>) significantly compared with controls. Training increased cardiac output at submaximal (5.9-6.7 l/min, p less than 0.05) and peak exercise (6.3-7.<em>1</em> l/min, p less than 0.05), with a significant reduction in systemic vascular resistance. Training reduced minute ventilation and the slope relating minute ventilation to carbon dioxide production (-<em>1</em>0.5%, p less than 0.05). Sympathovagal balance was altered by physical training when assessed by three methods: <em>1</em>) RR variability (+<em>1</em>9.2%, p less than 0.05); 2) autoregressive power spectral analysis of the resting ECG divided into low-frequency (-2<em>1</em>.2%, p less than 0.0<em>1</em>) and high-frequency (+5<em>1</em>.3%, p less than 0.05) components; and 3) whole-body radiolabeled norepinephrine spillover (-<em>1</em>6%, p less than 0.05). These measurements all showed a significant shift away from sympathetic toward enhanced vagal activity after training.

CONCLUSIONS

Carefully selected patients with moderate to severe CHF can achieve significant, worthwhile improvements with exercise training. Physical deconditioning may be partly responsible for some of the associated abnormalities and exercise limitation of CHF, including abnormalities in autonomic balance.

Alterations in renal function and structure are found even at the onset of diabetes mellitus. Studies performed over the last decade now allow definition of a series of stages in the development of renal changes in diabetes. Such a classification may be useful both in clinical work and in research activities. Stage <em>1</em> is characterized by early hyperfunction and hypertrophy. These changes are found at diagnosis, before insulin treatment. Increased urinary albumin excretion, aggravated during physical exercise, is also a characteristic finding. Changes are at least partly reversible by insulin treatment. Stage 2 develops silently over many years and is characterized by morphologic lesions without signs of clinical disease. However, kidney function tests and morphometry on biopsy specimens reveal changes. The function is characterized by increased GFR. During good diabetes control, albumin excretion is normal; however, physical exercise unmasks changes in albuminuria not demonstrable in the resting situation. During poor diabetes control albumin excretion goes up both at rest and during exercise. A number of patients continue in stage 2 throughout their lives. Stage 3, incipient diabetic nephropathy, is the forerunner of overt diabetic nephropathy. Its main manifestation is abnormally elevated urinary albumin excretion, as measured by radioimmunoassay. A level higher than the values found in normal subjects but lower than in clinical disease is the main characteristic of this stage, which appeared to be between <em>1</em>5 and 300 micrograms/min in the baseline situation. A slow, gradual increase over the years is a prominent feature in this very decisive phase of renal disease in diabetes when blood pressure is rising. The increased rate in albumin excretion is higher in patients with increased blood pressure. GFR is still supranormal and antihypertensive treatment in this phase is under investigation, using the physical exercise test. Stage 4 is overt diabetic nephropathy, the classic entity characterized by persistent proteinuria (greater than 0.5 g/24 h). When the associated high blood pressure is left untreated, renal function (GFR) declines, the mean fall rate being around <em>1</em> <em>ml</em>/min/mo. Long-term antihypertensive treatment reduces the fall rate by about 60% and thus postpones uremia considerably. Stage 5 is end-stage renal failure with uremia due to diabetic nephropathy. As many as 25% of the population presently entering the end-stage renal failure programs in the United States are diabetic. Diabetic nephropathy and diabetic vasculopathy constitute a major medical problem in society today.

Macrophages are induced by LPS to release a number of products that determine the host response during gram negative sepsis. To examine the role of one such substance, tumor necrosis factor (TNF), in mediating LPS-induced injury, we employed a rabbit model of endotoxic shock to (a) determine the kinetics and extent of release of TNF into plasma after injection of LPS, and (b) to evaluate the protective effect of in vivo neutralization of LPS-induced TNF by prior infusion of anti-TNF antibody. TNF was maximally induced 45-<em>1</em>00 min after injection of <em>1</em>0 micrograms i.v. parent Salmonella minnesota Re595 LPS or 250 micrograms Re595 LPS-HDL complexes. Maximal induction of TNF by LPS was associated with development of hypotension, focal hepatic necrosis, intravascular fibrin deposition and lethality. Based on (a) the peak levels of TNF observed in serum, 2.5 X <em>1</em>0(3) U/<em>ml</em>, (b) the specific activity of purified rabbit macrophage-derived TNF, <em>1</em> X <em>1</em>0(8) U/mg, and (c) the biphasic disappearance of intravenously injected purified TNF (t<em>1</em>/2 = 0.5 min, <em>1</em><em>1</em> min) we constructed a kinetic model showing that at least <em>1</em>30 micrograms of TNF (<em>1</em>.3 X <em>1</em>0(7) U) was released into plasma 30-200 min postinjection of LPS. Prior infusion of anti-TNF antibody (30-45 min before LPS injection) resulted in neutralization of the LPS-induced serum TNF activity and provided significant protection from the development of hypotension, fibrin deposition, and lethality. Thus, these results provide further evidence that TNF plays a central role mediating the pathophysiologic changes that occur during gram negative endotoxic shock.

BACKGROUND

Due to excellent efficacy for weight loss in the short-term follow-up, sleeve gastrectomy (SG) has gained enormous popularity as bariatric procedure, not only as first step in high-risk or super-obese patients but mainly as a sole and definitive operation in morbidly obese. In contrast to a large number of short and intermediate-term results, no series of SG with a follow-up of 5 years or more has been published so far.

METHODS

We report on the weight loss results of our first consecutive 26 patients with a complete follow-up of 5 years. Furthermore in a subgroup of <em>1</em>2 patients, plasma ghrelin levels were measured preoperatively, and up to 5 years following SG.

RESULTS

Weight loss defined as mean percent excess weight loss (%EWL) was found as 57.5 +/- 4.5, 60.3 +/- 5.0, 60.0 +/- 5.7, 58.4 +/- 5.4, and 55.0 +/- 6.8 (not converted, n = 2<em>1</em>) for the first 5 years. Weight regain of more than <em>1</em>0 kg from nadir was observed in five (<em>1</em>9.2%) of the 26 patients. Four of the patients (<em>1</em>5.4%) were converted to gastric bypass due to severe reflux (n = <em>1</em>, 3.8%) and weight loss failure (n = 3, <em>1</em><em>1</em>.5%). A total of eight patients (30.8%) were at chronic need for proton pump inhibitor medication due to severe reflux. Plasma ghrelin levels were reduced from 593 +/- 52 to 2<em>1</em>9 +/- 23 pg/<em>ml</em> <em>1</em>2 months postoperatively, with a slightly, non-significant increase toward the 5-years values of mean 257 +/- 23 pg/<em>ml</em>.

CONCLUSIONS

At 5-year follow-up, a mean EWL of 55.0 +/- 6.8% was achieved, indicating that SG leads to stable weight loss. Beside significant weight regain, severe reflux might necessitate conversion to gastric bypass or duodenal switch. After an immediate reduction postoperatively, plasma ghrelin levels remained low for the first 5 years postoperatively.

OBJECTIVE

The objective of this study was to systematically characterize the incidence and determinants of antiretroviral resistance in the HOMER (Highly Active Antiretroviral Therapy [HAART] Observational Medical Evaluation and Research) cohort of 1191 human immunodeficiency virus-infected, antiretroviral-naive adults initiating HAART in British Columbia, Canada.

METHODS

All plasma samples with plasma virus loads (pVLs) >1000 copies/mL collected during the first 30 months of follow-up were genotyped for drug resistance. The primary outcome measure was time to the first detection of major drug-resistance mutation(s). Cox proportional hazard regression was used to identify factors significantly associated with the detection of drug-resistance mutations.

RESULTS

Drug-resistance mutations were detected in 298 subjects (25%). Factors significantly associated with detection of drug-resistance mutations included high baseline pVL (multivariate hazard ratio [HR], 1.59; P<.001) and adherence (estimated using prescription-refill data and/or untimed plasma drug-concentration measurements). When compared with subjects with low (0%-<20%) prescription-refill percentages, subjects at an elevated risk of harboring drug-resistance mutations were those with relatively high but imperfect prescription-refill percentages (80%-<90%; multivariate HR, 4.15; P<.001) and those with essentially perfect >>/=95%) refill percentages but with 2 plasma drug concentrations below the steady-state trough concentration minus 1 standard deviation (multivariate HR, 4.57; P<.001). Initial use of nonnucleoside reverse-transcriptase inhibitor-based HAART was significantly associated with multiclass drug resistance (multivariate HR, 1.84; P=.001).

CONCLUSIONS

High baseline pVLs and substantial but imperfect levels of adherence were major predictors of antiretroviral resistance.

Most drugs of abuse increase dopamine (DA) in the nucleus accumbens (NAc), and do so every time as a pharmacological response. Palatable food also releases accumbens-shell DA, but in naïve rats the effect can wane during a long meal and disappears with repetition. Under select dietary circumstances, sugar can have effects similar to a drug of abuse. Rats show signs of DA sensitization and opioid dependence when given intermittent access to sucrose, such as alterations in DA and mu-opioid receptors, cross-sensitization with amphetamine and alcohol, and behavioral and neurochemical signs of naloxone-precipitated withdrawal. The present experiment asks whether sucrose-dependent rats release DA each time they binge. We also predict that acetylcholine (ACh), which rises as the end of a meal, will be delayed in rats with intermittent access to sucrose. To create dependency, the experimental group (Daily Intermittent Sucrose) was maintained on a diet of <em>1</em>2-h food deprivation that extended 4 h into the dark, followed by <em>1</em>2-h access to a <em>1</em>0% sucrose solution and chow, daily, for 2<em>1</em> days. As the main result, these rats gradually increased their sucrose intake from 37 to <em>1</em><em>1</em>2 <em>ml</em> per day (from <em>1</em>3 to 20 <em>ml</em> in the first hour of access), and repeatedly increased extracellular DA to <em>1</em>30% of baseline as measured in the NAc shell by microdialysis during the first hour of sucrose access on day <em>1</em>, day 2 and day 2<em>1</em>. Three control groups failed to show a significant increase in extracellular DA on day 2<em>1</em>: Sucrose only for <em>1</em> h on days <em>1</em> and 2<em>1</em> (Sucrose Twice), ad libitum access to sucrose and chow (Daily Ad libitum Sucrose), and intermittent chow instead of sucrose (Daily Intermittent Chow). Acetylcholine measured at the same time as DA, increased significantly toward the end and after each test meal in all groups. In the Daily Intermittent Sucrose group, the highest ACh levels (<em>1</em>33%) occurred during the first sample after the sucrose meal ended. In summary, sucrose-dependent animals have a delayed ACh satiation response, drink more sucrose, and release more DA than sucrose- or binge-experienced, but non-dependent animals. These results suggest another neurochemical similarity between intermittent bingeing on sucrose and drugs of abuse: both can repeatedly increase extracellular DA in the NAc shell.

BACKGROUND

Men with benign prostatic hyperplasia can be treated with alpha <em>1</em>-adrenergic-antagonist drugs that relax prostatic smooth muscle or with drugs that inhibit 5 alpha-reductase and therefore reduce tissue androgen concentrations. However, the effects of the two types of drugs have not been compared.

METHODS

We compared the safety and efficacy of placebo, terazosin (<em>1</em>0 mg daily), finasteride (5 mg daily), and the combination of both drugs in <em>1</em>229 men with benign prostatic hyperplasia. American Urological Association symptom scores and peak urinary-flow rates were determined at base line and periodically for one year.

RESULTS

The mean changes from base line in the symptom scores in the placebo, finasteride, terazosin, and combination-therapy groups at one year were decreases of 2.6, 3.2, 6.<em>1</em>, and 6.2 points, respectively (P<0.00<em>1</em> for the comparisons of both terazosin and combination therapy with finasteride and with placebo). The mean changes at one year in the peak urinary-flow rates were increases of <em>1</em>.4, <em>1</em>.6, 2.7, and 3.2 ml per second, respectively (P<0.00<em>1</em> for the comparisons of both terazosin and combination therapy with finasteride and with placebo). Finasteride had no more effect on either measure than placebo. In the placebo group, <em>1</em>.6 percent of the men discontinued the study because of adverse effects, as did 4.8 to 7.8 percent of the men in the other three groups.

CONCLUSIONS

In men with benign prostatic hyperplasia, terazosin was effective therapy, whereas finasteride was not, and the combination of terazosin and finasteride was no more effective than terazosin alone.

OBJECTIVE

To study the diagnostic potential of the 42 amino acid form of beta-amyloid (beta-amyloid(<em>1</em>-42)) in cerebrospinal fluid (CSF) as a biochemical marker for Alzheimer disease (AD), the intra-individual biological variation of CSF-beta-amyloid(<em>1</em>-42) level in patients with AD, and the possible effects of differential binding between beta-amyloid and apolipoprotein E isoforms on CSF-beta-amyloid(<em>1</em>-42) levels.

METHODS

A 20-month prospective follow-up study.

METHODS

Community population-based sample of consecutive patients with AD referred to the Piteå River Valley Hospital, Piteå, Sweden.

METHODS

Fifty-three patients with AD (mean +/- SD age, 7<em>1</em>.4 +/- 7.4 years) diagnosed according to the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association criteria and 2<em>1</em> healthy, age-matched (mean +/- SD age, 68.8 +/- 8.0 years) control subjects.

METHODS

Cerebrospinal fluid beta-amyloid(<em>1</em>-42) level--analyzed using enzyme-linked immunosorbent assay--and severity of dementia--analyzed using the Mini-Mental State Examination.

RESULTS

Mean +/- SD levels of CSF-beta-amyloid(<em>1</em>-42) were decreased (P<.00<em>1</em>) in patients with AD (709 +/- 304 pg/mL) compared with controls (<em>1</em>678 +/- 436 pg/mL). Most patients with AD (49 [92%] of 53 patients) had reduced levels ((<em>1</em><em>1</em>30 pg/mL). A highly significant correlation (r = 0.90; P<.00<em>1</em>) between baseline and <em>1</em>-year follow-up CSF-beta-amyloid(<em>1</em>-42) levels was found. There were no significant correlations between CSF-beta-amyloid(<em>1</em>-42) level and duration (r = -0.<em>1</em>6) or severity (r = -0.02) of dementia. Low levels were also found in patients with mild dementia (Mini-Mental State Examination score, >25).

CONCLUSIONS

The sensitivity of CSF-beta-amyloid(<em>1</em>-42) level as a diagnostic marker for AD is high. The intra-individual biological variation in CSF-beta-amyloid(<em>1</em>-42) level is low. Low CSF-beta-amyloid(<em>1</em>-42) levels are also found in the earlier stages of dementia in patients with AD. These findings suggest that CSF-beta-amyloid(<em>1</em>-42) analyses may be of value in the clinical diagnosis of AD, especially in the early course of the disease, when drug therapy may have the greatest potential of being effective but clinical diagnosis is particularly difficult.