Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma.

This trial tested a dendritic cell (DC) therapeutic cancer vaccine in which antigen is loaded using a novel non-viral transfection method enabling the uptake of plasmid DNA condensed with a cationic peptide. Proof of principle required the demonstration of diverse T lymphocyte responses following vaccination, including multiple reactivities restricted through both major histocompatibility complex (MHC) class I and II. Patients with advanced melanoma were offered four cycles of vaccination with autologous DC expressing melan A and gp100. Disease response was measured using Response Evaluation Criteria in Solid Tumours. Circulating MHC class I- and II-restricted responses were measured against peptide and whole antigen targets using interferon-γ ELIspot and enzyme-linked immunosorbent assay assays, respectively. Responses were analyzed across the trial population and presented descriptively for some individuals. Twenty-five patients received at least one cycle. Vaccination was well tolerated. Three patients had reduction in disease volume. Across the trial population, vaccination resulted in an expansion of effector responses to both antigens, to the human leukocyte antigen A2-restricted modified epitope, melan A ELAGIGILTV, and to a panel of MHC class I- and II-restricted epitopes. Vaccination with mature DC non-virally transfected with DNA encoding antigen had biological effect causing tumour regression and inducing diverse T lymphocyte responses.

Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options.

Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson-dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.

Assessing antibiotic therapy for Acinetobacter baumannii infections in an academic medical center.

In 2006, our clinical microbiology laboratory suspected that our institution was experiencing an increase in Acinetobacter baumannii infections and was concerned about resistance. A cross-sectional study was conducted to determine the A. baumannii antibiogram for 2006 and assess the appropriateness of antibiotics therapy. The study included all adult inpatients with a positive culture for A. baumannii between January 1 2006 and December 31 2006. A total of 129 isolates were identified. A. baumannii was highly susceptible to imipenem (97.7%) and meropenem (95.3%). Among the aminoglycosides, A. baumannii had reduced susceptibility to gentamicin (40.5%). Based on their susceptibility patterns, only 76 (58.9%) antibiotics regimens were susceptible against the isolates. At our institution, A. baumannii remains highly susceptible to the carbapenems and aminoglycosides. We encourage our practitioners to analyze the susceptibility pattern of each isolate when ordering antibiotics, which will help increase our rate of appropriate antibiotic selection.

Alpha-lipoic acid treatment of 31 patients with sore, burning mouth.

OBJECTIVE: To review a series of patients with sore, burning mouth treated with alpha-lipoic acid between 2000 and May 2006 and subjectively evaluate improvement in symptoms. DESIGN: Retrospective review of medical records of 195 consecutive patients who sought treatment for sore, burning mouth. Treatment of 47 patients was a prescription/recommendation for alpha-lipoic acid. Of these patients, 35 were available for follow-up. SETTING: Tertiary care academic medical center. SUBJECTS: Ambulatory patients given prescription /recommendation for alpha-lipoic acid 600 mg per day, in divided doses. MAIN OUTCOME MEASURE: Reported improvement in symptoms documented in medical records and at follow-up (visits or telephone interviews). RESULTS: Thirty-one of the 35 patients (66% of all 47) actually took alpha-lipoic acid as recommended. No patient reported a complete alleviation of symptoms. Six (19%) of these 31 patients felt mostly better, five (16%) felt somewhat better, and 14 (45%) reported no difference. Two patients (7%) reported a worsening of symptoms and four (13%) did not know whether there had been improvement. CONCLUSION: Eleven of 31 patients (35%) reported benefit from taking alpha-lipoic acid. Because we examined only a small number of patients and relied on a subjective outcome assessment, further larger studies using a prospective, randomized, controlled, and double-blind structure are warranted.

Sensitivity to ionising radiation of transformed human cells containing mutant ras genes.

Measurement of colony forming ability following exposure to gamma-rays has been performed on human retinoblasts transformed with either adenovirus 5 or 12 early region 1 DNA, adenovirus early region 1A plus activated N- or H-ras DNA or SV40 DNA. In contrast to recently reported results (M.D. Sklar, 1988, Science, 239, 645-647), we found no general correlation between transformation with activated ras and increased radiation resistance. Similarly, there was no correlation between D0 values and the level of expression of ras p21 in transformed human retinoblasts as determined by liquid competition assay. Indeed, cell lines with very similar D0 values had ras contents varying by up to one hundred fold. Cell lines transformed with SV40 DNA were generally less sensitive to ionising radiation than adenovirus and/or ras transformants, but even so the variation in sensitivity within these encompassed the whole spectrum of values obtained for the ras transformants. It may be interesting to note, however, that two out of the three ras transformants which were least sensitive to gamma-rays were cell lines expressing the highest levels of p21.

On the survival time of a tangled neuron in the hippocampal CA4 region in parkinsonism dementia complex of Guam.

In diseases such as the Parkinson dementia complex of Guam (PDC) or Alzheimer's disease, susceptible neurons develop intracellular tangles (iNFTs) and then die, leaving behind extracellular tangles (eNFTs). We performed counts of healthy neurons, iNFTs, and eNFTs in the hippocampus of Guamanian Chamorros who were neurologically normal or who suffered from PDC. The total of surviving and dead neurons in the CA4 region was remarkably constant from case to case, indicating that eNFTs are not phagocytosed. Since cases of recent PDC showed only marginal tangle formation in CA4, we concluded that tangle development in CA4 commenced close to the onset of the disease. Based on this assumption, as well as the further assumption that the average rate of tangle development and the average lifetime of a tangled neuron do not alter as the disease progresses, we derived equations to determine the average lifetime of tangled neurons. The results varied from 0.13 years for the most rapidly progressing case to 7.98 years for the most slowly developing case. The average for 8 cases was 2.51 years.

2-Amino-3-(methylamino)-propanoic acid (BMAA) in cycad flour: an unlikely cause of amyotrophic lateral sclerosis and parkinsonism-dementia of Guam.

We conducted an investigation of the levels of the neurotoxin 2-amino-3-(methylamino)-propanoic acid (BMAA) in cycad flour. Analysis of 30 flour samples processed from the endosperm of Cycas circinalis seeds collected on Guam indicated that more than 87% of the total BMAA content was removed during processing. Furthermore, in 1/2 the samples almost all (greater than 99%) of the total BMAA was removed. We found no significant regional differences in the BMAA content of flour prepared from cycad seeds collected from several villages on Guam. Testing of different samples prepared by the same Chamorro woman over 2 years suggests that the washing procedure probably varies in thoroughness from preparation to preparation but is routinely efficient in removing at least 85% of the total BMAA from all batches. Analysis of a flour sample that had undergone only 24 hours of soaking indicated that this single wash removed 90% of the total BMAA. We conclude that processed cycad flour as prepared by the Chamorros of Guam and Rota contains extremely low levels of BMAA, which are in the order of only 0.005% by weight (mean values for all samples). Thus, even when cycad flour is a dietary staple and eaten regularly, it seems unlikely that these low levels could cause the delayed and widespread neurofibrillary degeneration of nerve cells observed in amyotrophic lateral sclerosis and the parkinsonism-dementia complex of Guam (ALS-PD).

Familial nature and continuing morbidity of the amyotrophic lateral sclerosis-parkinsonism dementia complex of Guam.

Chamorros suffer from two neurologic syndromes known as ALS and the parkinsonism-dementia complex (PDC) of Guam. We report mortality figures for these syndromes during 1991 to 1995 and compare them with those at 5-year intervals dating back to 1951. In contrast to predictions of disease disappearance, both syndromes remain prevalent. However, age of onset and age at death have increased for both syndromes, suggesting that shifting environmental factors are causing disease postponement. We also report the clinical, familial, neuropathologic, and immunohistochemical findings on a consecutive autopsy series of Guamanian Chamorro cases. Twelve cases were diagnosed as PDC, known locally as "bodig," and three as ALS, known locally as "lytico." All but three of these fifteen patients had a pronounced family history of similar illness. Eight of twelve boding patients had siblings who were also affected with bodig; two of three lytico cases had siblings afflicted with lytico. The family histories are compatible with genetic transmission of each syndrome. The neuropathology of bodig is characterized by severe and widespread neurofibrillary tangle (NFT) development. NFTs are surrounded by reactive microglia and reactive astrocytes, and complement proteins and other molecules connected with inflammation are associated with them. Similar inflammatory responses also occur in Alzheimer's disease (AD) but have been largely attributed to the presence of senile plaques. These data indicate that tangles, as well as plaques, generate inflammatory reactions that such reactions may exacerbate the fundamental pathology in bodig as well as in AD.

Odor identification deficit of the parkinsonism-dementia complex of Guam: equivalence to that of Alzheimer's and idiopathic Parkinson's disease.

Olfactory dysfunction is among the first signs of Alzheimer's disease (AD), idiopathic Parkinson's disease (PD), and the parkinsonism-dementia complex (PDC) of Guam. We have recently demonstrated that the odor identification and detection deficits of patients with PD are equivalent to those of patients with mild AD when subtle differences in cognitive function are statistically controlled for by analysis of covariance. In contrast, patients with progressive supranuclear palsy (PSP) and patients with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism evidence olfactory function much more similar to that of normal controls. In the present study, we administered the University of Pennsylvania Smell Identification Test and the Picture Identification Test to 24 patients with early signs of the PDC of Guam and statistically compared their test scores to those of 24 early-stage AD and 24 early-stage PD patients of similar age and gender from the United States mainland. Although the PDC group evidenced slightly more difficulty in identifying pictures than did the other 2 groups, the odor identification deficit associated with this disorder was of the same magnitude as that observed in AD and PD, suggesting that olfactory testing cannot be used to distinguish among these 3 diseases and that the olfactory dysfunction of these disorders may reflect a common neurologic substrate.

Supranuclear disturbances of ocular motility in Lytico-Bodig.

We found abnormal supranuclear ocular or lid motility in all of 37 patients with Lytico-Bodig (amyotrophic lateral sclerosis/parkinsonism-dementia complex). Twenty-one patients had pursuit paresis, 18 abnormal vestibulo-ocular reflex (VOR) cancellation, 15 abnormal convergence, 13 abnormal optokinetic nystagmus (OKN), 12 conjugate gaze limitation, nine nystagmus, nine saccadic paresis, and six abnormal fixation. Lid abnormalities included glabellar hyperreflexia in 21, involuntary levator inhibition in three, and blepharospasm in two. Earlier reports have indicated infrequent ocular disturbances in Lytico-Bodig, but we now find supranuclear eye and lid deficits are universal and sometimes very prominent.

Neurodegenerative diseases of Guam: analysis of TAU.

Mutations in the tau gene have been described in families affected by frontotemporal dementia with parkinsonism linked to chromosome 17. The authors performed a genetic and biochemical analysis of this gene and its product in the parkinsonism dementia complex of Guam, a disorder characterized by the extensive formation of neurofibrillary tangles. The tau gene is not a primary cause of the parkinsonism dementia complex of Guam.

Cross-cultural cognitive examination: validation of a dementia screening instrument for neuroepidemiological research.

OBJECTIVE: Validation of a new instrument for screening dementia, the Cross Cultural Cognitive Examination (CCCE), is described. DESIGN: Criterion and concurrent validation and cross-cultural comparison of a new instrument. PARTICIPANTS: All individuals over the age of 40 in a village in southern Guam participated in a door-to-door survey. Alzheimer's and Parkinson's Disease patients and healthy controls aged 40-90 participated in the US mainland study. MEASUREMENTS: The CCCE was administered to all subjects. Effects of age, language, education, and gender on test performances and social-cultural differences were assessed. Concurrent validation of the test with respect to other well accepted screening instruments was determined. RESULTS: High specificity (> 94%) and sensitivity (> 99%) for detecting dementia were found in Guam and US mainland samples, and these were not biased by differences in gender, linguistic preference, education, or cultural background. Sensitivity and specificity of the CCCE matched or exceeded that of already accepted dementia screening instruments. CONCLUSIONS: These validation studies support the usefulness of the CCCE for identifying patients with generalized dementia, rather than focal types of cognitive impairment, quickly and reliably in cross-cultural neuroepidemiological research.

Neurofibrillary tangles of Guam parkinson-dementia are associated with reactive microglia and complement proteins.

Guamanian parkinsonism-dementia, locally described as bodig, is characterized by the widespread appearance of neurofibrillary tangles in cortical and subcortical areas. These tangles have similar regional distribution and immunohistochemical profile to those found in Alzheimer disease (AD). We studied the immunohistochemical staining of these tangles, as well as those of AD, using antibodies to complement proteins and related molecules. In bodig, as in AD, extracellular tangles were intensely decorated with antibodies to C1q, C4d and C3d, but not fraction Bb of factor B, properidin or immunoglobulins. This is evidence that the classical, but not the alternative complement pathway is activated on extracellular tangles and that the activation is independent of antibodies. Immunohistochemical staining for amyloid P, an in vitro activator of complement, was remarkably similar to that for the C1q, C4d and C3d in both bodig and AD. This was not the case for beta-amyloid protein (BAP), another in vitro complement activator. Positive staining was observed in only a minority of extracellular tangles in bodig and was only rarely observed in those of AD. BAP would therefore not appear to be a candidate for activating complement on extracellular neurofibrillary tangles. Reactive microglia and reactive astrocytes were closely associated with complement positive extracellular neurofibrillary tangles, indicating an inflammatory response similar to that seen in AD.

Amyotrophic lateral sclerosis and parkinsonism-dementia from Guam: differences in neurofibrillary tangle distribution and density in the hippocampal formation and neocortex.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex is a highly prevalent neurodegenerative disorder among the native Chamorro population of Guam, and is characterized by widespread formation of neurofibrillary tangles. In the present study, the distribution of neurofibrillary tangles was quantitatively assessed in the cerebral cortex of cases presenting with either predominant amyotrophic lateral sclerosis or parkinsonism-dementia symptomatology. Results show that although the regional and laminar lesion distribution is qualitatively similar in both groups, cases with predominant parkinsonism-dementia generally have higher lesion densities than cases with amyotrophic lateral sclerosis. Interestingly, layer II of the entorhinal cortex was affected to the same degree in both conditions. In both groups, the CA1 field of the hippocampus, subiculum, and entorhinal cortex were the most affected areas. In the neocortex, the perirhinal and inferior temporal cortex consistently had higher lesion densities than the frontal, parietal, and cingulate cortex, whereas the visual cortex was practically devoid of lesions. Also, most of the neurofibrillary tangles were located in the supragranular layers of the neocortex, with relatively low densities in the infragranular layers, in both brain groups. Interestingly, the primary motor cortex contained more neurofibrillary tangles in parkinsonism-dementia than in amyotrophic lateral sclerosis cases. It is possible that the differences in regional neurofibrillary tangle densities reflect the variable severity of the dementing process observed between the two groups of patients. Several studies on Alzheimer's disease and related disorders indicate that the regional and laminar cortical localization of neurofibrillary tangles may parallel the degeneration of specific corticocortical projections. The present data suggest that the population of corticocortical projections involved in Guamanian cases differs substantially from that affected in Alzheimer's disease. The differential distribution and densities of the lesions may contribute to the differences in symptomatology and severity of dementia among Alzheimer's disease and Guamanian cases, although these neurodegenerative disorders as well as related illnesses may share certain etiopathogenetic mechanisms.

Midkine-like immunoreactivity in extracellular neurofibrillary tangles in brains of patients with parkinsonism-dementia complex of Guam.

Midkine (MK) has been shown to be present in amyloid deposits in Alzheimer's disease (AD). In the present study, expression of midkine was examined immunohistochemically in brains of patients with the parkinsonism-dementia complex of Guam, lytico bodig disease (LB), using an affinity purified antibody to midkine. Positive staining was identified on some extracellular neurofibrillary tangles. The relative prevalence was somewhat less than for beta-amyloid protein (Abeta)-positive extracellular tangles. The results demonstrate that expression of MK and Abeta is not an exclusive feature of amyloid deposits in Alzheimer brain, but is also found in LB brain.

The effect of hyperlipoproteinemia on thrombolysis: in vitro studies using purified lipoproteins from normolipemic donors.

To determine whether or not lipoproteins affect thrombolysis in vitro using Chandler's loop method, VLDL, LDL, and HDL fractions from healthy male donors were obtained by ultracentrifugation. The lipoproteins were used to enrich whole blood or fibrin thrombi radiolabeled with 125-I-fibrinogen. Lipoprotein-enriched or unenriched thrombi were perfused in rotating Chandler loops with lipoprotein-enriched or unenriched plasma, respectively. Lysis was initiated by adding high molecular weight urokinase or single chain pro-urokinase to the perfusion medium. In some experiments, plasminogen was also added. Variation in the amounts of these activators and plasminogen permitted study of the effect of lipoproteins over a range of thrombolysis. No consistent statistically significant difference in the degree or time course of lysis of lipoprotein-enriched vs. unenriched thrombi or perfusion media was found. These studies, using normal lipoproteins, do not preclude the possibility that lipoproteins from patients with type IIa, IIb, or IV hyperlipoproteinemia may be genetically abnormal or may function pathologically, resulting in an effect on thrombolysis.

Brain amino acid contents are dissimilar in sporadic and Guamanian amyotrophic lateral sclerosis.

Amino acid contents were measured in autopsied brains of five Guamanian patients with amyotrophic lateral sclerosis (ALS) or parkinsonism-dementia. Absence of the glutamate deficiency and taurine excess characteristic of sporadic ALS suggest that, despite clinical similarities, Guamanian ALS is a different disorder from sporadic ALS.

Progressive supranuclear palsy. Historical notes.

Progressive supranuclear palsy (PSP) is the name Dr. J. Clifford Richardson chose to designate an unusual clinical syndrome he first identified in the 1950s. Neurofibrillary degeneration is the hallmark of this fatal brain disease, and during our study of Richardson's patients, Professor Jerzy Olszewski and I also observed granulovacuolar degeneration, and widespread nerve cell loss and gliosis in subcortical and brain stem nuclei. The histopathological features bear a striking resemblance to those seen in postencephalitic parkinsonism after von Economo's epidemic encephalitis, and in the parkinsonism-dementia complex of Guam (PDC). During the past 30 years, neurologists confirm that progressive supranuclear palsy is a universal, sporadic and not uncommon neurodegeneration of middle and late life. Many fine studies, as reported here, have advanced our understanding of PSP but its cause, and thereby its cure, is still to be revealed. These historical notes tell of our observations from 1955 to 1975. We are pleased that colleagues remember these early descriptions and honor us by calling this disease, the Steele-Richardson-Olszewski (SRO) syndrome.

Rotavirus.

Rotavirus is the leading cause of nonbacterial gastroenteritis in young children and may infect neonates, older children, and adults as well. A large number of serogroups and types complicates the study, epidemiology, diagnosis, and prevention of rotaviral illness. Currently, routine diagnostic methods are satisfactory only for group A rotaviruses, and most commercially available kits in widespread use detect only this serogroup. Rehydration therapy and electrolyte management remain the primary treatment modalities. Recent vaccine developments offer the promise of a reduced burden of the viral pathogen worldwide.