Potential of chemo-immunotherapy and radioimmunotherapy in relapsed primary central nervous system (CNS) lymphoma

Five patients with relapsed PCNSL were given chemo-immunotherapy (rituximab followed by carboplatin and methotrexate) with osmotic blood-brain barrier (BBB) opening. Four patients achieved CR and one patient had stable disease. Two patients (2/5) had durable responses (survival: 230+, 122+, 82, 42, 38 weeks). One patient later received Indium-111-ibritumomab tiuxetan and Yttrium-90-ibritumomab tiuxetan intravenous, without BBB opening. There was good uptake of Indium-111 ibritumomab tiuxetan in tumor on SPECT scan after 48 h. Estimated radiation doses to brain around and distant from tumor were within safe limits. After Ytrium-90 ibritumomab tiuxetan there was CR in enhancing tumor where the BBB was leaky, but lesions occurred in other brain regions, where the BBB was intact during Yttrium-90 ibritumomab tiuxetan infusion. Imaging and dosimetry with Indium-111 ibritumomab tiuxetan and efficacy with Yttrium-90 ibritumomab tiuxetan suggest the need for future enhanced CNS delivery when using monoclonal or radiolabeled antibodies, as intravenous delivery alone may provide modest clinical benefit due to limited BBB permeability.     

Spatial deficits in a mouse model of Parkinson disease

Rationale Accumulating evidence in humans demonstrated that visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson disease (PD). These deficits have been generally attributed to cortical dopamine degeneration. However, more recent evidence suggests that dopamine loss in the striatum is responsible for the visuo-spatial abnormalities in PD. Studies based on animal models of PD did not specifically address this question. Objectives Thus, the first goal of this study was to analyze the role of dopamine within the dorsal striatum in spatial memory. We tested bilateral 6-OHDA striatal lesioned CD1 mice in an object–place association spatial task. Furthermore, to see whether the effects were selective for spatial information, we measured how the 6-OHDA-lesioned animals responded to a non-spatial change and learned in the one-trial inhibitory avoidance task. Results The results demonstrated that bilateral (approximately 75%) dopamine depletion of the striatum impaired spatial change discrimination. On the contrary, no effect of the lesion was observed on non-spatial novelty detection or on passive avoidance learning. Conclusions These results confirm that dopamine depletion is accompanied by cognitive deficits and demonstrate that striatal dopamine dysfunction is sufficient to induce spatial information processing deficits.     

Isolation of lymph shows dysregulation of STAT3 and CREB pathways in the spleen and liver during leukemia development in a rat model

Background and aims

Acute myeloid leukemia (AML) is a heterogeneous malignant condition characterized by massive infiltration of poorly differentiated white blood cells in the blood stream, bone marrow, and extramedullary sites. During leukemic development, hepatosplenomegaly is expected to occur because large blood volumes are continuously filtered through these organs. We asked whether infiltration of leukemic blasts initiated a response that could be detected in the interstitial fluid phase of the spleen and liver.

Material and Methods

We used a rat model known to mimic human AML in growth characteristics and behavior. By cannulating efferent lymphatic vessels from the spleen and liver, we were able to monitor the response of the microenvironment during AML development.

Results and Discussion

Flow cytometric analysis of lymphocytes showed increased STAT3 and CREB signaling in spleen and depressed signaling in liver, and proteins related to these pathways were identified with a different profile in lymph and plasma in AML compared with control. Additionally, several proteins were differently regulated in the microenvironment of spleen and liver in AML when compared with control.

Conclusion

Interstitial fluid, and its surrogate efferent lymph, can be used to provide unique information about responses in AML-infiltered organs and substances released to the general circulation during leukemia development.     

Correction to: Risk factors for readmission among patients receiving outpatient parenteral antimicrobial therapy: a retrospective cohort study

International Journal of Clinical Pharmacy - An amendment to this paper has been published and can be accessed via a link at the top of the paper.     

Which seizure-precipitating factors do patients with epilepsy most frequently report?

When treating patients with epilepsy, dealing with seizure-precipitating factors is a partly neglected and underestimated supplement to more traditional therapies. The aim of this study was to investigate the incidence of seizure precipitants in a large epilepsy population and to determine which precipitants patients most often reported. Study participants included twins and their family members ascertained from the Norwegian Twin Panel (NTP), the Danish Twin Registry (DTR), and the Mid-Atlantic Twin Registry (MATR). One thousand six hundred seventy-seven patients with epilepsy were identified and were asked about seizure precipitants using a closed-ended questionnaire. Fifty-three percent reported at least one seizure-precipitating factor, while 30% claimed to have experienced two or more such factors. Emotional stress, sleep deprivation, and tiredness were the three most frequently reported precipitants. Patients with generalized seizures seemed to be more sensitive to sleep deprivation and flickering light than those with partial seizures, while women with partial seizures appeared to be more prone to seizures during menstruation than women with generalized seizures. Knowledge of seizure precipitants has practical implications, not only in patient treatment and counseling, but also for diagnosis, in that it may be helpful in facilitating the appearance of interictal epileptiform discharges in EEG and ictal EEG recordings.     

Perceptions of the family,personality characteristics,and adolescent internalizing symptoms

OBJECTIVE: To explore the influences of adolescent self-reported and interviewer-rated perceptions of family functioning, parent perceptions of the family, and adolescent personality on internalizing symptoms. METHOD: Two hundred one adolescent twins (mean age = 16.2 +/- 2.0 years; 90% white) completed the Family Assessment Device (FAD), Eysenck Personality Inventory, Children's Depression Inventory, and Multidimensional Anxiety Scale for Children and participated in an interview about their relationships with parents. Parents completed the FAD. Twins were divided into two samples for analysis. RESULTS: Multiple regression analyses in sample A showed that adolescent perceptions of family function accounted for 35% of the variance in depressive symptoms, but did not significantly predict anxiety. Self-reported perceptions were more strongly associated with symptoms than were interviewer-rated perceptions. Parent FAD and adolescent neuroticism accounted for 24% of the variance in adolescent self-reported perceptions. Results were similar in sample B. CONCLUSIONS: Adolescent perceptions of the family are linked to their depressive symptoms and associated with neuroticism. Adolescents who are high in neuroticism may perceive their families more negatively. Clinicians need to carefully discern components of family function that lead to teen depression versus biased cognitions that lead teenagers to perceive family relationships as negative.     

Functional consequences of a neutral pH in neonatal rat stratum corneum

At birth, neonatal stratum corneum (SC) pH is close to neutral but acidifies with maturation, which can be ascribed, in part, to secretory phospholipase A(2) and sodium/hydrogen antiporter 1 (NHE1) activities. Here we assessed the functional consequences of a neutral SC pH in a newborn rat model. While basal transepidermal water loss rates are near normal, barrier recovery (BR) rates after acute barrier disruption were delayed in newborn animals. The abnormality in barrier homeostasis could be improved by topical applications of an acidic buffer, indicating that barrier abnormality is primarily due to high SC pH. The delay in BR correlated with incompletely processed lamellar membranes and decreased activity of beta-glucocerebrosidase. Inhibition of NHE1 delayed BR after acute barrier perturbation. SC integrity was abnormal in newborn animals. Electron microscopy demonstrated decreased corneodesmosomes (CD) in newborn animals with decreased expression of desmoglein 1 and corneodesmosin. Serine protease activation appears to be responsible for CD degradation in newborn animals, because serine protease activity is increased in the SC and it can be reduced by acidification of the SC. The delay in acidification of neonatal SC results in abnormalities in permeability barrier homeostasis and SC integrity and are likely due to pH-induced modulations in enzyme activity.