Long-term outcome of acute encephalitis of unknown aetiology in adults

Encephalitis is caused by a variety of conditions, including infections of the brain by a wide range of pathogens. A substantial number of cases of encephalitis defy all attempts at identifying a specific cause. Little is known about the long-term prognosis in patients with encephalitis of unknown aetiology, which complicates their management during the acute illness. To learn more about the prognosis of patients with encephalitis of unknown aetiology, patients in whom no aetiology could be identified were examined in a large, single-centre encephalitis cohort. In addition to analysing the clinical data of the acute illness, surviving patients were assessed by telephone interview a minimum of 2 years after the acute illness by applying a standardized test battery. Of the patients with encephalitis who qualified for inclusion (n = 203), 39 patients (19.2%) had encephalitis of unknown aetiology. The case fatality in these patients was 12.8%. Among the survivors, 53% suffered from various neurological sequelae, most often attention and sensory deficits. Among the features at presentation that were associated with adverse outcome were older age, increased C-reactive protein, coma and a high percentage of polymorphonuclear cells in the cerebrospinal fluid. In conclusion, the outcome in an unselected cohort of patients with encephalitis of unknown aetiology was marked by substantial case fatality and by long-term neurological deficits in approximately one-half of the surviving patients. Certain features on admission predicted an unfavourable outcome.

Inhibition of the kynurenine-NAD+ pathway leads to energy failure and exacerbates apoptosis in pneumococcal meningitis

Pneumococcal meningitis causes neurological sequelae, including learning and memory deficits in up to half of the survivors. In both humans and in animal models of the disease, there is apoptotic cell death in the hippocampus, a brain region involved in learning and memory function. We previously demonstrated that in an infant rat model of pneumococcal meningitis, there is activation of the kynurenine (KYN) pathway in the hippocampus, and that there was a positive correlation between the concentration of 3-hydroxykynurenine and the extent of hippocampal apoptosis. To clarify the role of the KYN pathway in the pathogenesis of hippocampal apoptosis in pneumococcal meningitis, we specifically inhibited 2 key enzymes of the KYN pathway and assessed hippocampal apoptosis, KYN pathway metabolites, and nicotinamide adenine dinucleotide (NAD) concentrations by high-performance liquid chromatography. Pharmacological inhibition of kynurenine 3-hydroxylase and kynureninase led to decreased cellular NAD levels and increased apoptosis in the hippocampus. The cerebrospinal fluid levels of tumor necrosis factor and interleukin-1? and -? were not affected. Our data suggest that activation of the KYN pathway in pneumococcal meningitis is neuroprotective by compensating for an increased NAD demand caused by infection and inflammation;this mechanism may prevent energy failure and apoptosis in the hippocampus.

Restoration of Akt activity by the bisperoxovanadium compound bpV(pic) attenuates hippocampal apoptosis in experimental neonatal pneumococcal meningitis

Pneumococcal meningitis causes apoptosis of developing neurons in the dentate gyrus of the hippocampus. The death of these cells is accompanied with long-term learning and memory deficits in meningitis survivors. Here, we studied the role of the PI3K/Akt (protein kinase B) survival pathway in hippocampal apoptosis in a well-characterized infant rat model of pneumococcal meningitis. Meningitis was accompanied by a significant decrease of the PI3K product phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and of phosphorylated (i.e., activated) Akt in the hippocampus. At the cellular level, phosphorylated Akt was decreased in both the granular layer and the subgranular zone of the dentate gyrus, the region where the developing neurons undergo apoptosis. Protein levels and activity of PTEN, the major antagonist of PI3K, were unaltered by infection, suggesting that the observed decrease in PIP(3) and Akt phosphorylation is a result of decreased PI3K signaling. Treatment with the PTEN inhibitor bpV(pic) restored Akt activity and significantly attenuated hippocampal apoptosis. Co-treatment with the specific PI3K inhibitor LY294002 reversed the restoration of Akt activity and attenuation of hippocampal apoptosis, while it had no significant effect on these parameters on its own. These results indicate that the inhibitory effect of bpV(pic) on apoptosis was mediated by PI3K-dependent activation of Akt, strongly suggesting that bpV(pic) acted on PTEN. Treatment with bpV(pic) also partially inhibited the concentration of bacteria and cytokines in the CSF, but this effect was not reversed by LY294002, indicating that the effect of bpV(pic) on apoptosis was independent of its effect on CSF bacterial burden and cytokine levels. These results indicate that the PI3K/Akt pathway plays an important role in the death and survival of developing hippocampal neurons during the acute phase of pneumococcal meningitis.

Survival and relapse in patients with thrombotic thrombocytopenic purpura

Survival of patients with thrombotic thrombocytopenic purpura (TTP) improved dramatically with plasma exchange treatment, revealing risk for relapse. The Oklahoma TTP Registry is a population-based inception cohort of all 376 consecutive patients with an initial episode of clinically diagnosed TTP (defined as microangiopathic hemolytic anemia and thrombocytopenia with or without signs and symptoms of ischemic organ dysfunctions) for whom plasma exchange was requested, 1989 to 2008. Survival was not different between the first and second 10-year periods for all patients (68% and 69%, P = .83) and for patients with idiopathic TTP (83% and 77%, P = .33). ADAMTS13 activity was measured in 261 (93%) of 282 patients since 1995. Survival was not different between patients with ADAMTS13 activity < 10% (47 of 60, 78%) and patients with 10% or more (136 of 201, 68%, P = .11). Among patients with ADAMTS13 activity < 10%, an inhibitor titer of 2 or more Bethesda units/mL was associated with lower survival (P = .05). Relapse rate was greater among survivors with ADAMTS13 activity < 10% (16 of 47, 34%; estimated risk for relapse at 7.5 years, 41%) than among survivors with ADAMTS13 activity of 10% or more (5 of 136, 4%; P < .001). In 41 (93%) of 44 survivors, ADAMTS13 deficiency during remission was not clearly related to subsequent relapse.

Longitudinal patterns in survival, comorbidity, healthcare utilization and quality of care among older women following breast cancer diagnosis

OBJECTIVES To compare longitudinal patterns of health care utilization and quality of care for other health conditions between breast cancer-surviving older women and a matched cohort without breast cancer. DESIGN Prospective five-year longitudinal comparison of cases and matched controls. SUBJECTS Newly identified breast cancer patients recruited during 1997–1999 from four geographic regions (Los Angeles, CA; Minnesota; North Carolina; and Rhode Island; N = 422) were matched by age, race, baseline comorbidity and zip code location with up to four non-breast-cancer controls (N = 1,656). OUTCOMES Survival; numbers of hospitalized days and physician visits; total inpatient and outpatient Medicare payments; guideline monitoring for patients with cardiovascular disease and diabetes, and bone density testing and colorectal cancer screening. RESULTS Five-year survival was similar for cases and controls (80% and 82%, respectively; p = 0.18). In the first follow-up year, comorbidity burden and health care utilization were higher for cases (p < 0.01), with most differences diminishing over time. However, the number of physician visits was higher for cases (p < 0.01) in every year, driven partly by more cancer and surgical specialist visits. Cases and controls adhered similarly to recommended bone density testing, and monitoring of cardiovascular disease and diabetes; adherence to recommended colorectal cancer screening was better among cases. CONCLUSION Breast cancer survivors’ health care utilization and disease burden return to pre-diagnosis levels after one year, yet their greater use of outpatient care persists at least five years. Quality of care for other chronic health problems is similar for cases and controls.

Sperm analysis of patients after successful treatment of childhood acute lymphoblastic leukemia with chemotherapy

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with radiotherapy are at risk for impaired fertility. Whether chemotherapy alone is also long-term gonadotoxic is unclear. We assessed gonadal function in 11 male ALL-survivors treated with the same chemotherapy regimen and compared sperm analysis to healthy men. While sex hormone levels were normal in all subjects, 5/11 survivors showed pathological sperm concentration and 4/11 a decreased total sperm count compared to WHO criteria. Compared to healthy controls, all quantitative parameters in semen analysis of survivors were decreased. This suggests that treatment with chemotherapeutic agents alone, even in moderate doses, might have a gonadotoxic effect.

Can health beliefs help in explaining attendance to follow-up care? The Swiss Childhood Cancer Survivor Study

Objective: Improved treatment has increased the survival of childhood cancer patients in recent decades, but follow-up care is recommended to detect and treat late effects. We investigated relationships between health beliefs and follow-up attendance in adult childhood cancer survivors. Methods: Childhood cancer survivors aged younger than 16 years when diagnosed between 1976 and 2003, who had survived for more than 5 years and were currently aged 201 years, received a postal questionnaire. We asked survivors whether they attended follow-up in the past year. Concepts from the Health Belief Model (perceived susceptibility and severity of future late effects, potential benefits and barriers to follow-up, general health value and cues to action) were assessed. Medical information was extracted from the Swiss Childhood Cancer Registry. Results: Of 1075 survivors (response rate 72.3%), 250 (23.3%) still attended regular followup care. In unadjusted analyses, all health belief concepts were significantly associated with follow-up (po0.05). Adjusting for other health beliefs, demographic, and medical variables, only barriers (OR50.59; 95%CI: 0.43–0.82) remained significant. Younger survivors, those with lower educational background, diagnosed at an older age, treated with chemotherapy, radiotherapy, or bone marrow transplantation and with a relapse were more likely to attend follow-up care. Conclusions: Our study showed that more survivors at high risk of cancer- and treatmentrelated late effects attend follow-up care in Switzerland. Patient-perceived barriers hinder attendance even after accounting for medical variables. Information about the potential effectiveness and value of follow-up needs to be available to increase the attendance among childhood cancer survivors.

Meningitis in neonates: bench to bedside

The clinical outcome of central nervous system infection is determined by the characteristics of the pathogen and the brain's response to the invading bacteria. How infection leads to brain injury remains unresolved. An impediment to progress is the complexity of pathophysiologic processes. Some of the mechanisms involved have been identified in experimental models, providing insights into the molecular basis of brain injury and regeneration, and hinting at targets for therapy. Adjuvant therapies have been proposed. Interventions that protect the brain are evaluated for their potential to preserve neuro-integrative functions in long-term survivors of bacterial meningitis. This article summarizes current studies evaluating pharmacologic interventions in experimental models of bacterial meningitis and discusses how the knowledge gathered could translate into more effective therapies.

Recruitment dynamics of the grove-dominant tree Microberlinia bisulcata in African rain forest: extending the light response versus adult longevity trade-off concept

In groves of ectomycorrhizal caesalpiniaceous species in the Atlantic coastal forest of Central Africa the dominant tree Microberlinia bisulcata, which is shade-intolerant as a seedling but highly light-responding as a sapling, shows very limited regeneration. M. bisulcata saplings were mapped in an 82.5-ha plot at Korup and found to be located significantly far (>40 m) away from adults, a result confirmed by direct testing in a second 56-ha plot. Sapling growth over 6 years, the distribution of newly emerging seedlings around adults, recruitment of saplings in a large opening and the outward extent of seedlings at the grove edge were also investigated. Two processes appear to have been operating: (1) a very strong and consistent restriction of the very numerous seedlings establishing after masting close to adults, and (2) a strong but highly spatially variable promotion of distant survivors by increased light from the deaths of large trees of species other than M. bisulcata (which itself has very low mortality rate). This leads to an apparent escape-from-adults effect. To maintain saplings in the shade between multiple short periods of release ectomycorrhizal connections to other co-occurring caesalp species may enable a rachet-type mechanism. The recorded sapling dynamics currently contribute an essential part of the long-term cycling of the groves. M. bisulcata is an interesting example of an important group of tropical trees, particularly in Africa, which are both highly light-demanding when young yet capable also of forming very large forest emergents. To more comprehensively explain tropical tree responses, the case is made for adding a new dimension to the trade-off concept of early tree light-response versus adult longevity.

Satisfaction with follow-up consultations among younger adults treated for cancer: the role of quality of life and psychological variables

Given increased survival rates and treatment-related late effects, follow-up for cancer survivors is increasingly recommended. However, information about adverse events (e.g. possibility of late effects) may be distressing for the cancer survivor and lead to poor clinic attendance. Survivor satisfaction with appointments and the information provided are important. The Monitoring Process Model provides a theoretical framework to understand how survivors cope with threatening information, and consequences for follow-up care. Our aims were to describe satisfaction with routine follow-up and association between monitoring/blunting and satisfaction with care.

RecNcMIC3-1-R is a microneme- and rhoptry-based chimeric antigen that protects against acute neosporosis and limits cerebral parasite load in the mouse model for Neospora caninum infection

In order to achieve host cell entry, the apicomplexan parasite Neospora caninum relies on the contents of distinct organelles, named micronemes, rhoptries and dense granules, which are secreted at defined timepoints during and after host cell entry. It was shown previously that a vaccine composed of a mixture of three recombinant antigens, corresponding to the two microneme antigens NcMIC1 and NcMIC3 and the rhoptry protein NcROP2, prevented disease and limited cerebral infection and transplacental transmission in mice. In this study, we selected predicted immunogenic domains of each of these proteins and created four different chimeric antigens, with the respective domains incorporated into these chimers in different orders. Following vaccination, mice were challenged intraperitoneally with 2 × 10(6)N. caninum tachzyoites and were then carefully monitored for clinical symptoms during 4 weeks post-infection. Of the four chimeric antigens, only recNcMIC3-1-R provided complete protection against disease with 100% survivors, compared to 40-80% of survivors in the other groups. Serology did not show any clear differences in total IgG, IgG1 and IgG2a levels between the different treatment groups. Vaccination with all four chimeric variants generated an IL-4 biased cytokine expression, which then shifted to an IFN-γ-dominated response following experimental infection. Sera of recNcMIC3-1-R vaccinated mice reacted with each individual recombinant antigen, as well as with three distinct bands in Neospora extracts with similar Mr as NcMIC1, NcMIC3 and NcROP2, and exhibited distinct apical labeling in tachyzoites. These results suggest that recNcMIC3-1-R is an interesting chimeric vaccine candidate and should be followed up in subsequent studies in a fetal infection model.

Clinical assessment of deficits after SAH: hasty neurosurgeons and accurate neurologists

For survivors of aneurysmal subarachnoid hemorrhage (SAH), somatic and cognitive deficits can affect long-term outcomes. We were interested in comparing the deficits identified in SAH patients, including cognitive deficits, at discharge by neurosurgeons and deficits identified by neurologists upon admission to the rehabilitation unit on the same day. The assessment of deficits might have an impact on referring patients to rehabilitation. This retrospective study included 494 SAH patients treated between 2005 and 2010. Of these, 50 patients were discharged to an affiliated rehabilitation unit. Deficits were grouped into 18 categories and summarized into three groups: major somatic, minor somatic, and cognitive deficits. Major somatic deficits were identified in 16 and 20 patients (p = 0.53), minor somatic deficits in 16 and 44 (p < 0.0001) patients, and cognitive deficits in 36 and 45 (p < 0.04) patients by neurosurgeons and neurologists, respectively. The absolute number of deficits in daily activities identified by the neurosurgeon and neurologist were 21 and 31 major somatic deficits (p = 0.2), 18 and 97 minor somatic deficits (p < 0.0001), and 61 and 147 cognitive deficits (p < 0.0001), respectively. Significant differences in assessment of cognitive and minor somatic deficits between neurosurgeons and neurologists exist. Based on these findings, it is evident that for the neurosurgeon, there needs to be an increased awareness of the assessment of cognitive deficits and a more routine interdisciplinary approach, including the use of neuropsychological evaluations, to ensure a better triage of patients to rehabilitation or for discharge home.

Occurrence of systemic hypertension in dogs with acute kidney injury and treatment with amlodipine besylate

OBJECTIVES: To describe the occurrence of systemic hypertension in dogs with acute kidney injury and the efficacy of amlodipine besylate for its treatment. METHODS: This retrospective study included 52 dogs with acute kidney injury (2007 to 2008) grouped based on the use of amlodipine in their treatment. Systemic blood pressure was measured with an oscillometric device at admission, before, during, and after amlodipine therapy. RESULTS: Occurrence of systolic systemic hypertension (>/=160 mmHg) and severe systolic systemic hypertension (>/=180 mmHg) was 37% and 15% at admission and increased with hospitalisation to 81% and 62%, respectively. Twenty-two dogs were treated with amlodipine, at a median daily dosage of 0.38 mg/kg (interquartile range 0.28 to 0.49) divided in one to two applications per day. Amlodipine therapy was associated with a decrease in systolic systemic blood pressure of 24 mmHg (12 to 34) and a correction of severe systemic hypertension in 10 of 11 dogs within 24 hours. Overall, 73% of the dogs survived with a significantly lower proportion of survivors in treated compared to non-treated dogs (59% versus 83%, respectively, P=0.05). CLINICAL SIGNIFICANCE: Results of this study reveal that systemic hypertension is common in canine acute kidney injury and that treatment with amlodipine is beneficial in reducing systemic hypertension. The potential effect of amlodipine on global outcome requires prospective assessment.

European outbreak of atypical myopathy in the autumn 2009

BACKGROUND: Atypical myopathy is an acute, severe rhabdomyolysis occurring in grazing horses. In the beginning of October 2009, a new outbreak occurred in several European countries. Geographic, demographic and clinical data of the reported cases in the month October 2009 are described. KEY FINDINGS: The survival rate in this outbreak was 25%. The most frequently observed clinical signs were congested mucous membranes, dyspnea, tachycardia, depression, weakness, stiffness, recumbency, trembling, sweating, and myoglobinuria. Nonsurvivors were significantly more likely to be recumbent than survivors. Prognostic factors, symptomatic treatment, and preventive measures are discussed. SIGNIFICANCE: Differences were encountered during the described outbreak of atypical myopathy in October 2009 compared with previous outbreaks reported. Equine practitioners should be aware that previous epidemiological studies have shown that after a high prevalence in the autumn, new cases are likely to occur in the following spring.