Neuronal vacuole formation in the rat posterior cingulate/retrosplenial cortex after treatment with the N-methyl-d-aspartate (NMDA) antagonist MK-801 (dizocilpine maleate)

Cytoplasmic vacuoles appear in neurons of the posterior cingulate/retrosplenial cortex (PC/RS) of rats after treatment with N-methyl-d-aspartate (NMDA) receptor antagonists. Prominent dilatation of mitochondria and endoplasmic reticulum has been described within 2 h; however, the ultrastructural features of vacuole formation are unknown. To investigate this, the present study examined the PC/RS cortex of male rats (age 60–70 days) at 15, 30, 45, 60, 90, and 120 min after subcutaneous treatment with 1 mg/kg of the noncompetitive NMDA antagonist MK-801 (dizocilpine maleate, 5-methyl-10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine). Subtle mitochondrial dilatation was identified in a few neurons as early as 15 min postdose (MPD). By 30 MPD, dilatation was more pronounced in mitochondria and also involved the endoplasmic reticulum and perinuclear space. Ribosomal disaggregation and degranulation were also evident by 30 MPD. At all subsequent time points, dilatation of mitochondria and endoplasmic reticulum progressed in severity. Although the relative involvement of mitochondria and endoplasmic reticulum varied, glia were not involved. These ultrastructural data suggest that after treatment with MK-801, mitochondrial dilatation precedes involvement of endoplasmic reticulum in vacuolization of susceptible PC/RS cortical neurons. The early mitochondrial effects identified in this study suggest an initial metabolic insult that rapidly progresses to affect endoplasmic reticulum and ribosomes. This strengthens the relationship between the ability of certain NMDA antagonists to induce energy perturbations and neuronal vacuoles in the same region of the rat cerebral cortex.     

The adverse impact of cytomegalovirus infection on clinical outcome in cyclosporine-prednisone treated renal allograft recipients

Cytomegalovirus (CMV) infection was diagnosed in 28% (n = 144) of 516 renal allograft recipients treated with cyclosporine-prednisone (CsA-Pred) immunosuppressive therapy. The majority of infections produced either asymptomatic (n = 37) or mild-to-moderate (n = 75) clinical disease, while 10% were lethal (n = 14). Transplantation from a seropositive donor to a seronegative recipient was associated with an increased incidence of (CMV) infection but did not predispose to more severe clinical disease. Similarly, donor source (cadaver [CAD] vs. living-related donor [LRD]), age greater than or equal to 45 years, and antecedent pulse steroid therapy for the treatment of acute rejection were not correlated with clinically more severe disease. An increase in serum creatinine to greater than or equal to 25% of preinfection nadir values occurred in association with CMV infection in 106 patients, returning to nadir values or below in 74.5% of these individuals. CMV infection did not impact on actual patient survival among recipients of LRD or CAD allografts or on actual 1-year HLA-haploidentical or HLA-identical LRD graft survival. In contrast, actual 1-year cadaveric graft survival was significantly lower among CMV-infected (n = 95) vs. uninfected (n = 198) patients (75.8% vs. 87.8%, P = .01). In association with the finding of reduced actual 1-year CAD graft survival, CMV-infected patients were found to be more predisposed to develop acute rejection episodes. Of the CMV-infected CAD graft recipients, 48.4% developed greater than or equal to 1 acute rejection episode during the first year following transplantation vs. 25.3% of their uninfected counterparts (P less than .001). The impact of CMV infection in CsA-Pred treated renal transplant recipients does not differ substantially from that reported historically in association with prednisone-azathioprine immunosuppressive therapy.     

LONG-TERM OUABAIN ADMINISTRATION DOES NOT ALTER BLOOD PRESSURE IN CONSCIOUS SPRAGUE-DAWLEY RATS

1. We tested the ability of ouabain to cause chronic hyper tension by continuously infusing ouabain for 28 days (mini-osmotic pump implantation; i.p.). The blood pressure and metabolic effects of sham (150 mmol/L NaCI; n= 12) or ouabain infusion (10 μg/kg per day; n= 14; 100 μg/kg per day; n = 14) were examined in conscious Sprague-Dawley rats. 2. Plasma ouabain concentrations measured after 28 days of ouabain infusion were as follows: sham, not detectable (n= 11); ouabain 10 μg/kg per day, 0.60 ± 0.07 nmol/L (n= 14); and ouabain 100 μg/kg per day, 7.17 ± 0.57 nmol/L (n= 14; P < 0.001). 3. Sham or ouabain infusion did not alter food intake, bodyweight, water intake or urine output in conscious rats. 4. Blood pressure was not altered by sham treatment. Ouabain at 10 μg/kg per day or 100 μg/kg per day did not produce consistent rises in blood pressure. Ouabain at 10 μg/kg per day increased blood pressure on treatment day 12 only (+ 6mmHg; P < 0.05), while at 100μg/kg per day blood pres sure increased on treatment days 16 (+ 9 mmHg; P < 0.05) and day 18 (+ 8mmHg; P < 0.05) only. There was no significant difference in blood pressure between sham and ouabain groups. 5. Renal blood flow was decreased in rats infused with ouabain at 10 μg/kg per day (2.0 ± 0.3 mL/min per 100 g body-weight; n= 5; P < 0.01) and 100 μg/kg per day (2.2 ± 0.4 mL/ min per 100 g bodyweight; n= 7; P < 0.05) compared with sham treatment (3.5 ± 0.2 mL/min per 100 g bodyweight; n= 6). Renal vascular resistance was increased in rats treated with ouabain at 10 μg/kg per day (65.5 ± 12.6 mmHg/mL per min per 100 g bodyweight; n= 5; P < 0.01) and 100 μg/kg per day (66.0 ± 15.6 mmHg/mL per min per 100 g bodyweight; n= 7; P < 0.05) compared with sham treatment (32.6 ± 2.5 mmHg/mL per min per 100 g bodyweight; n= 6). 6. High plasma concentrations of ouabain do not cause consistent increases in blood pressure in conscious Sprague-Dawley rats.     

Treatment of an infected silicone right atrial catheter with combined fibrinolytic and antibiotic therapy: case report and review of the literature

Tunnelled silicone rubber right atrial catheters are commonly used to administer long-term total parenteral nutrition (TPN), cancer chemotherapeutic agents, and antimicrobial agents. The indwelling devices potentiate platelet-fibrin thrombi formation, providing a nidus for infection. Although many episodes of sepsis associated with thrombotic tunnelled catheters respond to antimicrobial therapy alone, a significant number require catheter removal. Evidence from case studies and small clinical trials suggests that fibrinolytic agents may increase the response rate and prevent removal of the device when combined with antimicrobial therapy. We present the first case reported of bacterial sepsis secondary to a thrombotic indwelling Hickman catheter for long-term TPN successfully treated with a combination of streptokinase and antibiotic therapies.     

Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment

The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumor progression and metastasis. Of particular interest in this setting is interleukin-1 (IL-1), a pleiotropic cytokine with numerous roles in both physiological and pathological states. It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors. A number of studies have reported that high IL-1 concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype. Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas, and patients with IL-1 producing tumors have generally bad prognoses. The exact mechanisms by which IL-1 promotes tumor growth remain unclear, though the protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNFα, and TGFβ. The IL-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor to IL-1 and acts by binding to the IL-1 receptor without activating it. The protein has been shown to decrease tumor growth, angiogenesis, and metastases in murine xenograft models. Our focus in this review is to summarize the known data on the role of IL-1 in tumor progression and metastasis and the use of IL-1 inhibition as a novel therapeutic approach in the treatment of solid organ malignancies.     

An analysis of panel data. The impact of a psychiatric consultation letter on the expenditures and outcomes of care for patients with somatization disorder.

In this study, the cost and health outcomes of a psychiatric consultation letter to primary care physicians caring for a sample of patients diagnosed with somatization disorder, a psychiatric condition associated with multiple, unexplained medical complaints, was assessed. To accommodate the small sample size of 73 patients, outcome effects were calculated using panel analysis. Study patients were randomized to a consultation or noconsultation group, and were repeatedly assessed at equal time intervals. Data were analyzed using parsimonious regression models derived from economic theory. During the 1-year follow-up period, a psychiatric consultation letter was associated with a 12% reduction in health care costs ($455 per patient within first year), with no evidence of deterioration in physical, mental, or general health. Less powerful t-test comparisons between treated and control groups lead to different conclusions. Reasons for these differences are discussed.     

Prospective evaluation of complications in an endoscopy unit: use of the A/S/G/E quality care guidelines.

In 1989, the American Society for Gastrointestinal Endoscopy released a quality assurance monograph in which a procedure review process was outlined. The major elements of the program for quality assurance in gastrointestinal endoscopy included: (1) procedure reports, (2) an endoscopic unit record, and (3) a procedure review. This study was designed to use the procedure review process to determine the incidence of complications, to identify quality assurance issues, and to determine whether audits and/or studies would result from this process. To make a meaningful interpretation as to what constitutes an important complication, a classification to define potential problems was established. Using this classification, a complication was identified in 64 of 3287 procedures (1.9%). These complications were discussed in a monthly morbidity and mortality conference. Additionally, 21 quality assurance issues were identified that led to four studies addressing these quality assurance issues.