Polyomavirus simian virus 40 infection associated with nephropathy in a lung-transplant recipient

BACKGROUND: Between 1955 and 1963, millions of individuals worldwide received vaccines contaminated with polyomavirus simian virus (SV)40. Recent data suggest that some individuals may develop renal dysfunction related to SV40 infection, including individuals too young to have received contaminated vaccines. CASE REPORT AND RESULTS: Three years after bilateral lung transplantation, a 32-year-old man with cystic fibrosis developed nephrotic syndrome and progressed to end-stage renal failure over 1.5 years. He was shown to have nephropathy caused by SV40. The diagnosis was documented by detecting and confirming sequences of SV40 (but not BK or JC virus) in his kidney biopsy and urine by polymerase chain reaction, Southern blot, and DNA sequencing. Positive immunohistochemistry for SV40 was found in his kidney, and neutralizing antibodies for SV40 were detected in his serum, before and after the onset of renal dysfunction. A source for the virus was not determined. His household contacts did not have serologic or molecular evidence of SV40 infection. No serum or tissue samples were available from his 27-year-old donor. DISCUSSION: This report shows that SV40 is circulating in the community and can cause nephropathy in transplant patients.     

Centrally administered oxytocin elicits exaggerated grooming in oxytocin null mice

Experiments were conducted to determine if the chronic absence of the neurotransmitter oxytocin (OT) in null mice resulted in alterations in the responsiveness and abundance of central OT receptors. Self-grooming elicited by intracerebroventricularly administered OT was studied as an indicator of the activation of central OT receptors and autoradiography was used to map the distribution and density of OT receptors in OT null and wild type mice. The intracerebroventricular administration of OT, but not vehicle, artificial cerebrospinal fluid (aCSF), produced a robust increase in grooming behavior in both OT null and wild type animals, P<.001. However, OT-induced grooming was significantly greater in OT null than wild type mice, P<.005. The enhanced grooming was selective to OT as indicated by the finding that grooming to intracerebroventricular arginine vasopressin (AVP) was of the same magnitude in both OT null and wild type mice. OT-induced grooming appears to be mediated through the activation of OT receptors because pretreatment of animals with an OT antagonist, Atosiban, abolished OT-induced grooming, but not AVP-induced grooming. OT receptor distribution and binding in brains of OT null and wild type mice were examined by autoradiography and were not significantly different. The results indicate that the chronic absence of OT in null mice leads to an increase in OT receptor responsiveness that contributes to the augmented grooming activity elicited by centrally administered OT.     

Fenfluramine-induced hypothermia is associated with cutaneous dilation in conscious rats

The antiobesity agent, fenfluramine, produces hypothermia in rodents by an, as yet, uncharacterized mechanism. The present study was conducted in conscious rats to determine if fenfluramine-induced hypothermia was associated with cutaneous dilation. In animals maintained at 16 degrees C, core body temperature (T(CORE)) was measured telemetrically, and tail surface temperature was monitored with thermocouples fixed to the tail (T(TAIL)). D-Fenfluramine (10 mg/kg ip) produced a rapid increase in T(TAIL) of 7.7+/-0.4 degrees C (P<.001) and a decline in T(CORE) of 4+/-0.3 degrees C (P<.001). Two findings indicate that the increase in T(TAIL) was due to the withdrawal of a sympathetic vasoconstrictor tone. First, pretreatment with the ganglionic blocker, pentolinium, prevented fenfluramine-induced changes in T(TAIL). Second, when sympathetic tone to the tail was physiologically withdrawn by increasing the environmental temperature to 28 degrees C, fenfluramine treatment produced no increase in T(TAIL). Moreover, the effects of fenfluramine on T(TAIL) and T(CORE) depended on the uptake of fenfluramine into serotonergic neurons because these effects were markedly attenuated by pretreatment with the selective serotonin re-uptake inhibitor, fluoxetine. The hypothermic effect of fenfluramine occurred despite the fact that total body oxygen consumption increased by 20%. The results suggest that heat loss due to the dilation of the cutaneous circulation contributes to fenfluramine-induced hypothermia.     

Regulation of cytokine production in carcinoembryonic antigen stimulated Kupffer cells by beta-2 adrenergic receptors: implications for hepatic metastasis

Elevated Carcinoembryonic antigen (CEA) levels in the serum indicate a poor prognosis for colorectal cancer patients. Induction of proinflammatory cytokines by CEA interaction with Kupffer cells has been proposed as a mechanism for hepatic metastasis formation. Studies show that the cytokine response in circulating and peritoneal macrophages is regulated by beta-adrenergic receptor signals, though little information is available regarding Kupffer cells. We investigated the relationship between beta-adrenergic receptor stimulation and the response of Kupffer cells to CEA. Comparisons between unstimulated and CEA stimulated rat Kupffer cells, using cDNA arrays, showed up-regulation (>4 fold) of the beta2-adrenergic receptor mRNA. Peak up-regulation occurred after 30 min with a decline at 1 h. We examined the effects of the specific beta2-adrenergic receptor agonist terbutaline on cytokine production by CEA stimulated rat Kupffer cells. Pre-treatment of Kupffer cells with terbutaline followed by CEA caused a significant increase in IL-6 and IL-10 production, but a significant reduction in TNF-alpha production (>3 fold). mRNA levels reflected those of the ELISA assays for IL-6 and IL-10 but not for TNF-alpha. For IL-6 and TNF-alpha, these changes were serum independent, while IL-10 was serum dependent. This response is different from LPS treated Kupffer cells where all three cytokines showed serum dependency. Overall, these data suggest that Kupffer cell stimulation by CEA is under beta-adrenergic receptor control and induction of the beta-receptor is an early event following CEA binding to its receptor. Control of TNF-alpha production is negatively affected by terbutaline, while that of IL-6 and IL-10 is positively controlled suggesting that very different beta-adrenergic receptor signaling pathways are involved.     

Early prophylactic inhaled beclomethasone in infants less than 1250 g for the prevention of chronic lung disease

OBJECTIVE:

Inflammation plays an important role in the development of chronic lung disease (CLD), which has become a major cause of morbidity in surviving infants less than 1250 g at birth. The authors hypothesized that the progression of this inflammation and, therefore, the establishment of CLD would be decreased with the use of early prophylactic inhaled corticosteroids. Short, and long term respiratory and neurodevelopmental outcomes were also examined.

DESIGN:

A double-blind, randomized placebo controlled trial.

SETTING:

Level-III neonatal intensive care unit.

POPULATION STUDIED:

Sixty infants less than 1250 g at birth, diagnosed with respiratory distress syndrome and requiring ventilatory support at 72 h of age were enrolled in the study.

INTERVENTION:

Infants enrolled received either placebo or beclomethasone diproprionate by a metered dose inhaler, which was used in-line with the ventilator circuit while the infant was ventilated and then via a spacer until 28 days of age.

RESULTS:

Thirty infants were given beclomethasone and 30 were given placebo. There were two deaths in each group. Among the surviving infants, the frequency of moderate-to-severe CLD was 17% in each study group. Mean time to extubation was not different for beclomethasone compared with placebo at 16.4 and 12.5 days (P=0.12), respectively. The requirement for intravenous corticosteroids was lower in the beclomethasone-treated group (RR 0.67, 95% CI 0.43 to 1.04), although this difference was not statistically significant. The incidence of growth failure, infection and intraventricular hemmorhage did not differ between the two groups. Long term outcomes were not different with respect to the incidence of respiratory re-admissions, cerebral palsy, developmental delay, blindness or deafness.

CONCLUSIONS:

Early treatment with inhaled beclomethasone diproprionate did not reduce the incidence of CLD or decrease the duration of mechanical ventilation. The decrease in intravenous corticosteroid use was not statistically significant. Long term outcome was not affected.     

Expression profiling and interferon-beta regulation of liver metastases in colorectal cancer cells

Liver metastasis is the major cause of death among colorectal cancer patients. Many gene products have been associated with the colon cancer cells' ability to metastasize to the liver, including carcinoembryonic antigen (CEA) and mucins. In this study we examined changes in expression of 384 genes in a model of human colorectal cancer metastasis in nude mice. Using DNA microarrays, we compared expression between MIP-101 cells, a poorly metastatic human colon cancer cell line, with an interferon-beta (IFN-β) resistant subline of MIP-101 (β-MIP) that is metastatic to the liver. Treatment of β-MIP cells with increasing concentrations of IFN-β caused a reversion to the non-metastatic phenotype. The array data showed down-regulation of genes involved in apoptosis in β-MIP cells and their return to the MIP-101 pattern upon IFN-β treatment. Cluster analysis also showed involvement of genes belonging to cell cycle, angiogenesis and invasion pathways. Selected genes were chosen to validate the microarray data by semi-quantitative RT-PCR. Association between gene expression pattern and metastatic phenotype was verified by intra-splenic injection in nude mice. The number of genes examined in this study was small, but carefully selected. Significant changes associated with cell growth and survival were observed, which gave the metastatic cells an advantage to grow in the liver. This information may help identifying new markers for colorectal cancer prognosis as well as aid the development of new therapeutic approaches. This revised version was published online in July 2006 with corrections to the Cover Date.     

Longitudinal study of cryptococcosis in adult solid-organ transplant recipients

While studies in kidney recipients have found meningitis to be the most common clinical manifestation of cryptococcosis (Cry), it is unclear if the clinical presentation of Cry differs among various solid-organ transplant (SOT) recipients and whether the serum cryptococcal antigen (SCA) might predict the site of infection. We report the clinical manifestations and the correlation with a positive SCA among 55 consecutive SOT recipients diagnosed with Cry at the University of Pittsburgh Medical Center. These included: heart (n=13), lung (n=4), liver (n=28), kidney (n=9) and small bowel (n=1) recipients. While there were no significant differences in the manifestations of Cry in heart and lung recipients, kidney recipients had disseminated disease as the most common presentation (P=0.02). In contrast, pneumonia (P=0.003) and meningitis (P=0.02) were more frequent than disseminated disease in liver recipients. Positive SCA was higher in patients with disseminated disease and meningitis than in patients with isolated pneumonia (P=0.0001). Significant differences in the manifestations of Cry were observed among types of SOT populations. A positive SCA may be predictive of dissemination and meningitis, but it may not be sensitive for pulmonary disease.     

Infectious disease: changing antibiotic susceptibility

The field of ophthalmology is fortunate to have an array of antibiotics to treat bacterial infections. Because many of the older antibiotics are no longer useful for treating systemic infections, their use and associated acquired resistance have been reduced. These antibiotics, therefore, likely will continue to be effective for treating ophthalmic infections. The bacteria that cause recurrent infections (e.g., blepharitis) may acquire antibiotic resistance because of the repeated use of one particular agent for therapy (e.g., erythromycin). Recurrent pathologies and those that are treated with antibiotics that have varied broadspectrum activities should be cultured routinely to confirm infection and to institute appropriate therapy. Resistant trends of Staphylococcus aureus to the second-generation fluoroquinolones have been confirmed, and new trends of resistance for Pseudomonas aeruginosa have emerged. These antibiotics are effective but should be used judiciously to avoid bacterial resistance to them and to ensure their future potency.     

Association between SV40 and non-Hodgkin's lymphoma

Millions of people worldwide were inadvertently exposed to live simian virus 40 (SV40) between 1955 and 1963 through immunization with SV40-contaminated polio vaccines. Although the prevalence of SV40 infections in humans is not known, numerous studies suggest that SV40 is a pathogen resident in the human population today. SV40 is a potent DNA tumor virus that is known to induce primary brain cancers, bone cancers, mesotheliomas, and lymphomas in laboratory animals. SV40 oncogenesis is mediated by the viral large tumor antigen (T-ag), which inactivates the tumor suppressor proteins p53 and pRb. During the last decade, independent studies using different molecular biology techniques have shown the presence of SV40 DNA, T-ag, or other viral markers in primary human brain and bone cancers and malignant mesotheliomas. Evidence suggests that there may be geographic differences in the frequency of these virus-positive tumors. Recent large independent controlled studies have shown that SV40 T-ag DNA is significantly associated with human non-Hodgkin's lymphoma (NHL). In our study, we analyzed systemic NHL from 76 HIV-1-positive and 78 HIV-1-negative patients, and nonmalignant lymphoid samples from 79 HIV-1-positive and 107 HIV-1-negative patients without tumors; 54 colon and breast carcinoma samples served as cancer controls. We used polymerase chain reaction (PCR) followed by Southern blot hybridization and DNA sequence analysis to detect DNAs of polyomaviruses and herpesviruses. SV40-specific DNA sequences were detected in 64 (42%) of 154 NHL, none of 186 nonmalignant lymphoid samples, and none of 54 control cancers. For NHL from HIV-1-positive patients, 33% contained SV40 DNA and 39% Epstein Barr virus (EBV) DNA, whereas NHLs from HIV-1-negative patients were 50% positive for SV40 and 15% positive for EBV. Few tumors were positive for both SV40 and EBV. Human herpesvirus type 8 was not detected. SV40 sequences were found most frequently in diffuse large B cell and follicular-type lymphomas. We conclude that SV40 is significantly associated with some types of NHL and that lymphomas should be added to the types of human cancers associated with SV40.     

Ventral hernia repair: a study of current practice

Ventral wall hernias are common; despite this, there are no guidelines on the best surgical management. The aim of this study was to examine the types of repair in use for abdominal wall hernias in the West of Scotland over a 3-month period. Data were gathered on 120 patients. There were 60 incisional, 32 umbilical, and 28 epigastric hernias. The main indication for repair was pain (78%), while 12 patients (10%), presented acutely with incarceration or strangulation. The most common method of repair was sutured (55%), followed by mesh (29%) and Mayo repair (16%). There was no correlation between use of mesh and hernia size or whether repair was for a recurrent hernia. Surgical practice varies widely in the repair of ventral wall hernias. Clinical trials are required to establish the best method of repair for this common condition. Electronic Publication