Stage progression and neurological symptoms in Trypanosoma brucei rhodesiense sleeping sickness: role of the CNS inflammatory response

Background: Human African trypanosomiasis progresses from an early (hemolymphatic) stage, through CNS invasion to the late (meningoencephalitic) stage. In experimental infections disease progression is associated with neuroinflammatory responses and neurological symptoms, but this concept requires evaluation in African trypanosomiasis patients, where correct diagnosis of the disease stage is of critical therapeutic importance. Methodology/Principal Findings: This was a retrospective study on a cohort of 115 T.b.rhodesiense HAT patients recruited in Eastern Uganda. Paired plasma and CSF samples allowed the measurement of peripheral and CNS immunoglobulin and of CSF cytokine synthesis. Cytokine and immunoglobulin expression were evaluated in relation to disease duration, stage progression and neurological symptoms. Neurological symptoms were not related to stage progression (with the exception of moderate coma). Increases in CNS immunoglobulin, IL-10 and TNF-α synthesis were associated with stage progression and were mirrored by a reduction in TGF-β levels in the CSF. There were no significant associations between CNS immunoglobulin and cytokine production and neurological signs of disease with the exception of moderate coma cases. Within the study group we identified diagnostically early stage cases with no CSF pleocytosis but intrathecal immunoglobulin synthesis and diagnostically late stage cases with marginal CSF pleocytosis and no detectable trypanosomes in the CSF. Conclusions: Our results demonstrate that there is not a direct linkage between stage progression, neurological signs of infection and neuroinflammatory responses in rhodesiense HAT. Neurological signs are observed in both early and late stages, and while intrathecal immunoglobulin synthesis is associated with neurological signs, these are also observed in cases lacking a CNS inflammatory response. While there is an increase in inflammatory cytokine production with stage progression, this is paralleled by increases in CSF IL-10. As stage diagnostics, the CSF immunoglobulins and cytokines studied do not have sufficient sensitivity to be of clinical value

Central Nervous System Parasitosis and Neuroinflammation Ameliorated by Systemic IL-10 Administration in Trypanosoma brucei-Infected Mice

Peer reviewedPublisher PD

Spatially and genetically distinct African trypanosome virulence variants defined by host interferon-g response

We describe 2 spatially distinct foci of human African trypansomiasis in eastern Uganda. The Tororo and Soroti foci of <i>Trypanosoma brucei rhodesiense</i> infection were genetically distinct as characterized by 6 microsatellite and 1 minisatellite polymorphic markers and were characterized by differences in disease progression and host-immune response. In particular, infections with the Tororo genotype exhibited an increased frequency of progression to and severity of the meningoencephalitic stage and higher plasma interferon (IFN)–γ concentration, compared with those with the Soroti genotype. We propose that the magnitude of the systemic IFN-γ response determines the time at which infected individuals develop central nervous system infection and that this is consistent with the recently described role of IFN-γ in facilitating blood-brain barrier transmigration of trypanosomes in an experimental model of infection. The identification of trypanosome isolates with differing disease progression phenotypes provides the first field-based genetic evidence for virulence variants in T. <i>brucei rhodesiense</i>

The use of adherence aids by adults with diabetes: A cross-sectional survey

BACKGROUND: Adherence with medication taking is a major barrier to physiologic control in diabetes and many strategies for improving adherence are in use. We sought to describe the use of mnemonic devices and other adherence aids by adults with diabetes and to investigate their association with control of hyperglycemia, hyperlipidemia and hypertension. METHODS: Cross sectional survey of diabetic adults randomly selected from Primary Care practices in the Vermont Diabetes Information System. We used linear regression to examine the associations between the use of various aids and physiologic control among subjects who used oral agents for hyperglycemia, hypercholesterolemia, and hypertension. RESULTS: 289 subjects (mean age 65.4 years; 51% female) used medications for all three conditions. Adherence aids were reported by 80%. The most popular were day-of-the-week pill boxes (50%), putting the pills in a special place (41%), and associating pill taking with a daily event such as a meal, TV show, or bedtime (11%). After adjusting for age, sex, marital status, income, and education, those who used a special place had better glycemic control (A1C -0.36%; P = .04) and systolic blood pressure (-5.9 mm Hg; P = .05) than those who used no aids. Those who used a daily event had better A1C (-0.56%; P = .01) than patients who used no aids. CONCLUSION: Although adherence aids are in common use among adults with diabetes, there is little evidence that they are efficacious. In this study, we found a few statistically significant associations with adherence aids and better diabetes control. However, these findings could be attributed to multiple comparisons or unmeasured confounders. Until more rigorous evaluations are available, it seems reasonable to recommend keeping medicines in a special place for diabetic adults prescribed multiple medications

<i>Trypanosoma brucei rhodesiense</i> transmitted by a single tsetse fly bite in vervet monkeys as a model of human African trypanosomiasis

Sleeping sickness is caused by a species of trypanosome blood parasite that is transmitted by tsetse flies. To understand better how infection with this parasite leads to disease, we provide here the most detailed description yet of the course of infection and disease onset in vervet monkeys. One infected tsetse fly was allowed to feed on each host individual, and in all cases infections were successful. The characteristics of infection and disease were similar in all hosts, but the rate of progression varied considerably. Parasites were first detected in the blood 4-10 days after infection, showing that migration of parasites from the site of fly bite was very rapid. Anaemia was a key feature of disease, with a reduction in the numbers and average size of red blood cells and associated decline in numbers of platelets and white blood cells. One to six weeks after infection, parasites were observed in the cerebrospinal fluid (CSF), indicating that they had moved from the blood into the brain; this was associated with a white cell infiltration. This study shows that fly-transmitted infection in vervets accurately mimics human disease and provides a robust model to understand better how sleeping sickness develops

Change escalation processes and complex adaptive systems: from incremental reconfigurations to discontinuous restructuring

This study examines when “incremental” change is likely to trigger “discontinuous” change, using the lens of complex adaptive systems theory. Going beyond the simulations and case studies through which complex adaptive systems have been approached so far, we study the relationship between incremental organizational reconfigurations and discontinuous organizational restructurings using a large-scale database of U.S. Fortune 50 industrial corporations. We develop two types of escalation process in organizations: accumulation and perturbation. Under ordinary conditions, it is perturbation rather than the accumulation that is more likely to trigger subsequent discontinuous change. Consistent with complex adaptive systems theory, organizations are more sensitive to both accumulation and perturbation in conditions of heightened disequilibrium. Contrary to expectations, highly interconnected organizations are not more liable to discontinuous change. We conclude with implications for further research, especially the need to attend to the potential role of managerial design and coping when transferring complex adaptive systems theory from natural systems to organizational systems

A preliminary report of an educational intervention in practice management

BACKGROUND: Practice management education continues to evolve, and little information exists regarding its curriculum design and effectiveness for resident education. We report the results of an exploratory study of a practice management curriculum for primary care residents. METHODS: After performing a needs assessment with a group of primary care residents at Wright State University, we designed a monthly seminar series covering twelve practice management topics. The curriculum consisted of interactive lectures and practice-based application, whenever possible. We descriptively evaluated two cognitive components (practice management knowledge and skills) and the residents' evaluation of the curriculum. RESULTS: The mean correct on the knowledge test for this group of residents was 74% (n = 12) and 91% (n = 12) before and after the curriculum, respectively. The mean scores for the practice management skill assessments were 2.62 before (n = 12), and 3.65 after (n = 12) the curriculum (modified Likert, 1 = strongly disagree, 5 = strongly agree). The residents rated the curriculum consistently high. CONCLUSIONS: This exploratory study suggests that this curriculum may be useful in developing knowledge and skills in practice management for primary care residents. This study suggests further research into evaluation of this curriculum may be informative for practice-based education

Association between cancer prevalence and use of thiazolidinediones: results from the Vermont Diabetes Information System

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferator-activated receptors (PPARs) have emerged as important drug targets for diabetes. Drugs that activate PPARγ, such as the thiazolidinediones (TZDs), are widely used for treatment of Type 2 diabetes mellitus. PPARγ signaling could also play an anti-neoplastic role in several <it>in vitro </it>models, although conflicting results are reported from <it>in vivo </it>models. The effects of TZDs on cancer risk in humans needs to be resolved as these drugs are prescribed for long periods of time in patients with diabetes.</p> <p>Methods</p> <p>A total of 1003 subjects in community practice settings were interviewed at home at the time of enrolment into the Vermont Diabetes Information System, a clinical decision support program. Patients self-reported their personal and clinical characteristics, including any history of malignancy. Laboratory data were obtained directly from the clinical laboratory and current medications were obtained by direct observation of medication containers. We performed a cross-sectional analysis of the interviewed subjects to assess a possible association between cancer diagnosis and the use of TZDs.</p> <p>Results</p> <p>In a multivariate logistic regression model, a diagnosis of cancer was significantly associated with TZD use, even after correcting for potential confounders including other oral anti-diabetic agents (sulfonylureas and biguanides), age, glycosylated hemoglobin A1C, body mass index, cigarette smoking, high comorbidity, and number of prescription medications (odds ratio = 1.59, <it>P </it>= 0.04). This association was particularly strong among patients using rosiglitazone (OR = 1.89, <it>P </it>= 0.02), and among women (OR = 2.07, <it>P </it>= 0.01).</p> <p>Conclusion</p> <p>These data suggest an association between TZD use and cancer in patients with diabetes. Further studies are required to determine if this association is causal.</p

Resection of the liver for colorectal carcinoma metastases - A multi-institutional study of long-term survivors

In this review of a collected series of patients undergoing hepatic resection for colorectal metastases, 100 patients were found to have survived greater than five years from the time of resection. Of these 100 long-term survivors, 71 remain disease-free through the last follow-up, 19 recurred prior to five years, and ten recurred after five years. Patient characteristics that may have contributed to survival were examined. Procedures performed included five trisegmentectomies, 32 lobectomies, 16 left lateral segmentectomies, and 45 wedge resections. The margin of resection was recorded in 27 patients, one of whom had a positive margin, nine of whom had a less than or equal to 1-cm margin, and 17 of whom had a greater than 1-cm margin. Eighty-one patients had a solitary metastasis to the liver, 11 patients had two metastases, one patient had three metastases, and four patients had four metastases. Thirty patients had Stage C primary carcinoma, 40 had Stage B primary carcinoma, and one had Stage A primarycarcinoma. The disease-free interval from the time of colon resection to the time of liver resection was less than one year in 65 patients, and greater than one year in 34 patients. Three patients had bilobar metastases. Four of the patients had extrahepatic disease resected simultaneously with the liver resection. Though several contraindications to hepatic resection have been proposed in the past, five-year survival has been found in patients with extrahepatic disease resected simultaneously, patients with bilobar metastases, patients with multiple metastases, and patients with positive margins. Five-year disease-free survivors are also present in each of these subsets. It is concluded that five-year survival is possible in the presence of reported contraindications to resection, and therefore that the decision to resect the liver must be individualized. © 1988 American Society of Colon and Rectal Surgeons