Predicting population responses to environmental change from individual-level mechanisms: towards a standardized mechanistic approach.

Animal populations will mediate the response of global biodiversity to environmental changes. Population models are thus important tools for both understanding and predicting animal responses to uncertain future conditions. Most approaches, however, are correlative and ignore the individual-level mechanisms that give rise to population dynamics. Here, we assess several existing population modelling approaches and find limitations to both 'correlative' and 'mechanistic' models. We advocate the need for a standardized mechanistic approach for linking individual mechanisms (physiology, behaviour, and evolution) to population dynamics in spatially explicit landscapes. Such an approach is potentially more flexible and informative than current population models. Key to realizing this goal, however, is overcoming current data limitations, the development and testing of eco-evolutionary theory to represent interactions between individual mechanisms, and standardized multi-dimensional environmental change scenarios which incorporate multiple stressors. Such progress is essential in supporting environmental decisions in uncertain future conditions.

Quantitative telomerase expression in glioblastomas shows regional variation and down-regulation with therapy but no correlation with patient outcome.

Despite the nearly ubiquitous expression of telomerase in almost all types of malignant human tumors, studies have shown widely varying positivity in the highest-grade glioma, the glioblastomas (GBMs), ranging from 26% to 100% of tumors analyzed. We have previously shown significant variability in positive versus negative telomerase expression from region to region within the same GBM. In this study, we hypothesized that application of new quantitative methodology would extend our previous observations and identify whether there is heterogeneity in levels of protein expression even within areas positive for telomerase in high-grade gliomas. Finally, we sought to correlate quantitative telomerase expression with patient outcome and therapeutic response. Quantitative analysis was achieved by polymerase chain-based TRAP assay with phosphorimager analysis and compared with clinical information obtained from 19 patients, most with primary, untreated GBMs. Results showed up to 3-fold variability in telomerase levels across multiple regional samples from the same patient, as well as between patients. In 5 of 6 patients with recurrent tumors who had received intervening radiation therapy or chemotherapy, telomerase was downregulated in the second, post-therapy sample. These data provide in vivo corroboration of recent in vitro experiments showing telomerase downregulation after radiation therapy or chemotherapy treatment of cell lines. Our finding of variability in levels of telomerase expression in GBMs parallels the known heterogeneity of these tumors for histologic features and cell growth-related factors. Statistical analysis showed no relationship between TRAP score and either time to clinical progression or time to death.

Cerebral granular cell astrocytomas: a Mib-1, bcl-2, and telomerase study.

Granular cell (GC) astrocytoma is an uncommon variant of glioma that shares the cytologic features and high cytoplasmic lysosomal content with granular cell tumors elsewhere in the body. While the histogenesis and behavior of these neoplasms was originally in dispute because most were reported as single cases, the accumulated literature on approximately three dozen such lesions has now verified their usual astrocytic lineage and poor prognosis. Although the GC cell is thought to represent a degenerative process, little is known in these tumors about cell cycle regulation, as measured by Mib-1 and bcl-2 immunolabeling, or expression of other biomarkers of malignancy, such as telomerase. In our study, GC astrocytomas were similar to gemistocytic astrocytomas in their bland histology, often prominent perivascular lymphocytic cuffing and low Mib-1 labeling indices. Like gemistocytes, GCs appear to represent senescent, non-cycling cells. Absence of significant bcl-2 immunolabeling in our three cases, however, suggests that unlike gemistocytes, GC astrocytes develop senescence by mechanisms other than bcl-2 mediated apoptosis suppression. In one case in which frozen tissue was available for assay, we noted relatively high quantitative telomerase expression. The level paralleled that seen in other glioblastomas. Demise for our three patients occurred 3-25 months post-biopsy. Like gemistocytes, the presence of non-proliferative GCs signifies severe abnormalities in cell cycle regulation and maybe hallmarks of tumors with poor prognosis.

Coronary artery bypass with "snake" grafts: fifteen-year follow-up.

BACKGROUND: Since 1970 we have used the "snake" graft in more than 8000 cases of coronary artery bypass grafting (CABG). We followed, for over 15 years, 214 patients who underwent CABG in 1981 with only a "snake" graft by one surgeon (William H. Sewell, M.D.). METHODS: Eighty-four percent (180/214) were male and 16% (34/214) were female with an average age of 58 and 66 years, respectively. The average left ventricular ejection fraction (LVEF) was > 55% in 63% (135/214) of the patients and < 55% in 37% (79/214); 15% (33/214) had diabetes and 77% (164/214) were smokers. The mean preoperative New York Heart Association (NYHA) functional class was 3.1+/-0.6 (range I-IV). Diagnostic arteriography demonstrated two vessel disease in 5% (9/214), three vessel disease in 89% (191/214), and left main disease in 6% (14/214). The average number of distal grafts per patient was 3.4. Coronary arteriography was performed 8-weeks postoperatively. Annual follow-up with a questionnaire determined incidence of redo procedures and survival. RESULTS: The perioperative 30-day mortality was 1% (2/214). At 8 weeks there was a graft patency rate end-to-side of 85%, side-to-side 97%, and the proximal segment of 95%. Four percent (9/214) had redo surgery while 6% (13/214) underwent angioplasty during the 15 years. Sixty-seven percent (144/214) were alive at 15 years with a significantly improved mean NYHA functional class of 1.2+/-0.9 (p < 0.001). Twenty-four percent of those 166 live patients (35/144) had an average LVEF of 50% by echocardiography. There were 34 (16%) noncardiac deaths, 32 (15%) cardiac deaths, and 2 (1%) unknown causes. CONCLUSIONS: The results of this study suggest that survival using the "snake" graft conduit is competitive with that observed using the internal mammary artery.

Part I. Telomerase levels in human metastatic brain tumors show four-fold logarithmic variability but no correlation with tumor type or interval to patient demise.

Telomerase expression has been found in the majority of human neoplasms at their primary sites and, in some tumor types, has been correlated with patient prognosis. In part one of this two-part study, we investigated whether telomerase was expressed ubiquitously in metastases to the brain and whether varying levels of expression existed or correlated with patient prognosis. A second aim of this study was to acquire data on brain metastases preliminary to the investigation of whether the telomerase assay could be used for the detection of tumor cells in cerebrospinal fluid (CSF). We investigated 35 brain metastases utilizing the sensitive telomeric repeat amplification protocol (TRAP) assay coupled with densitometric quantitation of telomerase levels on frozen, banked tissue specimens. Specimens metastatic to the brain analyzed in this study included melanoma, adenocarcinoma, hepatocellular carcinoma, germ cell neoplasm, squamous cell carcinoma, osteogenic sarcoma, and secondary lymphoma. Telomerase was found in 32 of 35 metastases. Quantitation of the telomerase products showed a fourfold logarithmic variation, following standardization of protein concentrations. Levels of telomerase expression showed no statistical correlation with either tumor subtype or interval from date of procedure to patient demise. Interestingly, in two patients with two metastatic samples each taken at discordant times, the telomerase levels were higher in the metastasis specimen taken closer to the time of demise. This suggests a possible increase in telomerase level within a given patient's neoplasm as the disease became more advanced, although too few cases were available to reach a firm conclusion in this regard. We conclude that most brain metastases express telomerase, albeit at widely varying levels, which are not clearly correlated with patient survival. These results influence the potential utility of telomerase analysis for the detection of small numbers of metastatic tumor cells in CSF, as addressed in the companion manuscript.

Part II. Telomerase expression in cerebrospinal fluid specimens as an adjunct to cytologic diagnosis.

The diagnosis of meningeal carcinomatosis hinges on the cytologic examination of cerebrospinal fluid (CSF), which has a known low sensitivity for the identification of malignant cells. Often only 'suspicious' or 'atypical' diagnoses can be rendered, and specimens are commonly unsatisfactory for evaluation due to poor morphologic preservation. Telomerase is widely expressed in most brain metastases, medulloblastomas, lymphomas, oligodendrogliomas, and is expressed focally in glioblastomas. Little is known about the level of telomerase expression in these tumors, except for brain metastases, where a four-fold variation in telomerase levels exists. In our laboratory, as few as ten carcinoma cells can be detected by a sensitive polymerase chain reaction-based assay, the telomeric repeat amplification protocol (TRAP), for telomerase, but it was unclear whether varying levels of telomerase expressed by different types of metastases would influence detection. Using the TRAP protocol, we studied 281 CSF samples from a wide variety of patients with neurologic and non-neurologic conditions for telomerase expression. An adjusted specificity of 90% and a sensitivity of 64% were achieved for detection of malignant cells in CSF by telomerase expression. The TRAP assay for telomerase detection may serve as an adjunct to the traditional examination of CSF. Neither previously documented four-fold variation in the levels of telomerase expression in brain metastases, high CSF protein levels nor high white blood cell counts precluded detection of malignant cells in CSF.

Increased maternal morbidity after cesarean delivery before 28 weeks of gestation.

To test the hypothesis that there is increased maternal morbidity associated with cesarean section at very early gestational ages compared to cesarean section at term, a case-control study was performed. Eighty consecutive cases of cesarean section before 28 weeks of gestation were chronologically matched to 80 controls with cesareans at term. Compared to term controls, preterm cases were more frequently complicated by postpartum endomyometritis (32% vs. 9%, P < 0.001) and blood transfusion (14% vs. 1%, P < 0.01), resulting in a significantly longer postpartum stay and longer duration of antibiotic use. One or more major complications occurred in 45% of preterm cases versus 14% of controls (P < 0.001); two major complications occurred in 11% of cases versus 1% of controls (P < 0.05). Some, but not all, of the higher risk for postpartum complications was attributable to pre-existing differences in risk factors for infection and hemorrhage between the two groups. We conclude that cesarean section before 28 weeks of gestation is associated with a high risk of postoperative complications and that patients should be counseled accordingly.