Positive argument for debate in J Neural Transmission: Alzheimer's disease: are we intervening too late? Yes, by years if not decades.

The ongoing debate as to whether we are or are not early enough in treatment for Alzheimer's disease presents distinct vantage points. Points expressed range from stressing the need for early preventive measures to highlighting the failure of "alternative" therapies, and concluding that we are unfortunately doing all that we can at present. Herein, we stress the worth of nutritional intervention, and review why such studies are often inherently compromised. We conclude that considerable education is needed to advance lifestyle modifications early enough to obtain their optimal effect, and instead of positioning "classical" interventions against "alternative" interventions, the combinations of both may impart maximal benefit. The introduction of novel detection methods at the earliest indications of cognitive impairment may provide a window of opportunity for initiation of preventative approaches.

Evaluating the role of prophylaxis in the management of invasive fungal infections in patients with hematologic malignancy.

Invasive fungal infection (IFI) is a persistent problem among critically ill and immunocompromised patients, especially hematopoietic stem cell transplant or solid organ transplant recipients, or patients on intensive chemotherapy for acute leukemia. Although numerous antifungal agents are available, IFI remains a serious problem because of obstacles to timely diagnosis and high morbidity and mortality rates associated with such infection. Improvements in treatment of underlying diseases have rapidly expanded the patient populations at risk for IFI with increased use of immunosuppressants, aggressive chemotherapy, broad-spectrum antibiotics, and narrow-spectrum antifungal prophylaxis. There are various treatment strategies that can be used to manage IFI: prophylaxis, empiric, preemptive, and directed. As the infection progresses, the prospect of successfully treating an infection diminishes; conversely, the earlier the intervention, the greater the possibility of unnecessary treatment. This article discusses the epidemiology of the most important fungal pathogens, identifies high-risk patient groups and risk factors associated with IFI, and critically evaluates the advantages and disadvantages of available diagnostic tests and treatment strategies and the rationale for antifungal prophylaxis. For patients at high risk for IFI, antifungal prophylaxis is an attractive strategy, and numerous randomized, controlled clinical studies have documented the benefit of such prophylaxis as well as the most efficacious of currently available agents.

The effects of an exercise program in leukemia patients.

PURPOSE: To examine the feasibility of administering an in-hospital exercise program to acute leukemia patients undergoing chemotherapy. A secondary purpose explored the impact of exercise on selected physiological, psychological, and inflammatory markers. METHODS: Ten patients, aged 18 to 50 years, diagnosed with acute leukemia or newly relapsed were assessed for body weight, height, body composition (skinfolds), cardiorespiratory endurance (total minutes on bicycle ergometer at 60% heart rate reserve), dynamic muscular endurance (Rocky Mountain Cancer Rehabilitation Institute protocol), fatigue (Revised Piper Fatigue Scale), depression (Center for Epidemiologic Studies Depression scale, National Institute of Mental Health questionnaire), and quality of life (Functional Assessment of Cancer Therapy-General) at baseline (within 3 days of diagnosis) and at the end of induction phase of treatment. Blood draws were taken at baseline, midpoint, and at the end of induction for analyses of inflammatory markers (Linco Luminex assay). Combined aerobic and strength training exercises were administered 3 times per week, twice daily, for 30 minutes. Paired-samples t-tests were used for the analyses of physiological and psychological parameters. One-way repeated measures analysis of variance was used for the analyses of inflammatory markers. RESULTS: Significant improvements in cardiorespiratory endurance (P = .009, baseline 8.9 +/- 8.8 minutes, postexercise intervention 17 +/- 14.3 minutes) with significant reductions in total fatigue scores (P = .009, baseline 4.6 +/- 1.7, postexercise intervention 1.8 +/- 1.6) and depression scores (P = .023, baseline 19 +/- 11.5, postexercise intervention 12 +/- 8.2) were observed. Marginally significant decrease in interleukin-6 (IL-6; P = .059) with no significant changes in IL-10 (P = .223) or interferon-gamma (P = .882) were observed. CONCLUSION: Administration of exercise to acute leukemia patients undergoing treatment is feasible. The exercise protocol used increased cardiovascular endurance, reduced fatigue and depression scores, and maintained quality of life. Although no significant change in inflammation was observed, a trend demonstrating a reduction in IL-6 and an increase in IL-10 warrants further investigation.

Diagnosis, treatment, and prevention of cerebral palsy.

Cerebral palsy is the most prevalent cause of persisting motor function impairment with a frequency of about 1/500 births. In developed countries, the prevalence rose after introduction of neonatal intensive care, but in the past decade, this trend has reversed. A recent international workshop defined cerebral palsy as "a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain." In a majority of cases, the predominant motor abnormality is spasticity; other forms of cerebral palsy include dyskinetic (dystonia or choreo-athetosis) and ataxic cerebral palsy. In preterm infants, about one-half of the cases have neuroimaging abnormalities, such as echolucency in the periventricular white matter or ventricular enlargement on cranial ultrasound. Among children born at or near term, about two-thirds have neuroimaging abnormalities, including focal infarction, brain malformations, and periventricular leukomalacia. In addition to the motor impairment, individuals with cerebral palsy may have sensory impairments, cognitive impairment, and epilepsy. Ambulation status, intelligence quotient, quality of speech, and hand function together are predictive of employment status. Mortality risk increases incrementally with increasing number of impairments, including intellectual, limb function, hearing, and vision. The care of individuals with cerebral palsy should include the provision of a primary care medical home for care coordination and support; diagnostic evaluations to identify brain abnormalities, severity of neurologic and functional abnormalities, and associated impairments; management of spasticity; and care for associated problems such as nutritional deficiencies, pain, dental care, bowel and bladder continence, and orthopedic complications. Current strategies to decrease the risk of cerebral palsy include interventions to prolong pregnancy (eg, 17alpha-progesterone), limiting the number of multiple gestations related to assisted reproductive technology, antenatal steroids for mothers expected to deliver prematurely, caffeine for extremely low birth weight neonates, and induced hypothermia for a subgroup of neonates diagnosed with hypoxic-ischemic encephalopathy.

Neurocognitive Correlates of Attention-Deficit Hyperactivity Disorder Symptoms in Children Born at Extremely Low Gestational Age.

OBJECTIVE: Compared with children born near term, those born extremely preterm (EP) are at much higher risk for attention-deficit hyperactivity disorder (ADHD). Little information is available about differences in neuropsychological outcomes among EP children with and without ADHD. Our analyses aimed to evaluate the neuropsychological correlates of ADHD symptoms in extremely low gestational age newborns (ELGANs). METHODS: We obtained Child Symptom Inventory-4 reports from parents (n = 871) and teachers (n = 634) of 10-year-old children born before the 28th week of gestation. Participants completed standardized assessments of neurocognitive and academic functioning. RESULTS: In the total sample, children who screened positive for ADHD symptoms were at increased risk for neurocognitive limitations. These associations were weaker when the sample was limited to those with intelligence quotient (IQ) ≥70 or ≥85. Even those with IQ ≥85 who screened positive for ADHD symptoms were more likely than their peers to have deficits on the DAS-II Working Memory Cluster and the NEPSY-II Auditory Response subtest. The risks for impaired academic performance (Z ≤ -1) on components of the WIAT-III were 2-to-3 times higher in this group than among ELGANs not classified as having ADHD symptoms. CONCLUSION: Among children born EP, those with ADHD symptoms are more likely to have global neurocognitive impairment. When IQ is within normal limits, ADHD symptoms are associated with deficits in executive functioning skills. These findings highlight a group at risk for executive functioning deficits and related academic difficulties, even in the absence of intellectual disability.

Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.

PURPOSE: To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies. PATIENTS AND METHODS: Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m(2), followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity. RESULTS: Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m(2) MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease. CONCLUSION: PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations.

Lifetime requirement of the methionine cycle for neuronal development and maintenance.

PURPOSE OF REVIEW: Nutrition exerts a pervasive impact on normal and pathological conditions of the nervous system. One critical pathway is the methionine cycle, in which folate and B12 convert homocysteine to methionine, which is in turn converted to S-adenosyl methionine (SAM; the major methyl donor). As a consequence of methylation, however, SAM is converted to the neurotoxin homocysteine and must be excreted or drawn back into the methionine cycle, which requires additional folate and B12. Dietary or genetic folate deficiency impairs this cycle, leading to developmental disorders, including those of the nervous system. RECENT FINDINGS: Folate and SAM exert profound epigenetic effects via DNA and histone methylation. Maternal supplementation during pregnancy has fostered an increase in individuals harboring genetic polymorphisms that compromise folate usage. Such individuals harbor a lifetime requirement for additional dietary folate, often not met beyond peri/postnatal periods. Herein, we consider the potential link of failure to meet this additional requirement to early and age-related cognitive compromise. SUMMARY: Compromises in the methionine cycle can manifest as a spectrum of disorders throughout life. These considerations underscore how prenatal nutritional supplementation can alleviate developmental disorders by inadvertently establishing latent conditions that, in the absence of continued supplementation, may lead to age-related cognitive decline.

Has prenatal folate supplementation established an at-risk population for age-related cognitive decline?

Nutrition exerts a pervasive impact on normal and pathological conditions of the nervous system throughout life. Maternal folate supplementation during pregnancy has reduced developmental disorders of the nervous system, but may have also fostered an increase in individuals harboring genetic polymorphisms that compromise folate usage. Such individuals may harbor a lifetime requirement for additional dietary folate, often not met beyond peri/postnatal periods. An increased association of such polymorphisms has been detected in individuals with autism. Prenatal nutritional supplementation may have inadvertently established latent conditions that, in the absence of continued supplementation, may lead to age-related cognitive decline.

Phase 1 trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients with advanced hematologic malignancies.

Proteasome inhibitors, a novel class of chemotherapeutic agents, enhance the antitumor efficacy of anthracyclines in vitro and in vivo. We therefore sought to determine the maximum tolerated dose (MTD) and dose-limiting toxicities of bortezomib and pegylated liposomal doxorubicin (PegLD). Bortezomib was given on days 1, 4, 8, and 11 from 0.90 to 1.50 mg/m2 and PegLD on day 4 at 30 mg/m2 to 42 patients with advanced hematologic malignancies. Grade 3 or 4 toxicities in at least 10% of patients included thrombocytopenia, lymphopenia, neutropenia, fatigue, pneumonia, peripheral neuropathy, febrile neutropenia, and diarrhea. The MTD based on cycle 1 was 1.50 and 30 mg/m2 of bortezomib and PegLD, respectively. However, due to frequent dose reductions and delays at this level, 1.30 and 30 mg/m2 are recommended for further study. Pharmacokinetic and pharmacodynamic studies did not find significant drug interactions between these agents. Antitumor activity was seen against multiple myeloma, with 8 of 22 evaluable patients having a complete response (CR) or near-CR, including several with anthracycline-refractory disease, and another 8 having partial responses (PRs). One patient with relapsed/refractory T-cell non-Hodgkin lymphoma (NHL) achieved a CR, whereas 2 patients each with acute myeloid leukemia and B-cell NHL had PRs. Bortezomib/PegLD was safely administered in this study with promising antitumor activity, supporting further testing of this regimen.