Relationship between clinical and radiological diagnostic criteria for Alzheimer's disease and the extent of neuropathology as reflected by 'stages': a prospective study

The distribution of pathology related to Alzheimer's disease (AD) is not uniform throughout the brain. Sites which have a predilection for the development of Alzheimer-type pathology are the limbic regions and neocortical association areas. The changes in these areas of the brain develop gradually, following a well-determined sequence that allows a pathological staging of the disease process. According to the staging hypothesis, the first pathological alterations develop in the transentorhinal and entorhinal regions. The neurofibrillary pathology then spreads into the hippocampus, but not until the final stages does it affect the neocortex. In this study we analyse the relationship between the pathological stages of AD, according ot the staging hypothesis, and the clinical diagnosis in a prospectively assessed patient group. Prediction of any given pathological stage from the clinical diagnosis was found to be poor. This may be partly due to the fact that additional pathologies can alter the clinical picture and severity of dementia in patients who are only in the initial stages of AD. Nevertheless, the NINCDS-ADRDA clinical criteria had a high sensitivity for detection of AD-related pathology: the 'probable AD' category included 22/38 (57.9%) of those in the late isocortical stage, while the 'possible AD' category included 19/23 (82.6%) of those in the limbic stage. Using proposed neuro-imaging protocols for improved identification of patients with AD-related pathology, we largely identified subjects in whom the extent of pathology had spread to the neocortex.     

The effect of the nitric oxide donor glyceryl trinitrate on global and regional cerebral blood flow in man

Despite their potential use as cerebral vasodilatory agents there are few studies of the effect of nitric oxide (NO) donors on the cerebral circulation in non-anaesthetised man. We determined the effect of the NO donor glyceryl trinitrate (GTN) at clinically relevant doses on global and regional cerebral blood flow (CBF) in healthy non-anaesthetised volunteers, using H(2)(15)O PET, ultrasonic colour velocity flow imaging of carotid artery flow, and transcranial Doppler (TCD) of middle cerebral artery velocities (MCAv). Three rates of GTN infusion (0.1, 0.4, 1.0 microg/kg/min) were used. There was no significant change in common or internal carotid artery flow following GTN administration although a dose dependent fall in MCAv post GTN was observed. There was no significant change in either global or regional CBF following GTN. Thus intravenous GTN at therapeutic doses in awake humans does not alter global or regional CBF. However it does produce basal cerebral artery vasodilatation as evidenced by a fall in MCAv in the absence of a change in internal carotid artery flow.     

Survival and developmental disability in infants with birth weights of 501 to 800 grams, born between 1979 and 1994

OBJECTIVE: Because the survival rate has increased for extremely low birth weight neonates, many have raised the concern that the rate of developmental disability among survivors will also increase. To address this concern, we analyzed changes over time in survival and major neurosensory impairment in a sample of extremely low birth weight infants born between July 1, 1979, and June 30, 1994. METHODS: The study sample included 513 infants with birth weights of 501 to 800 g who were cared for in either of the two neonatal intensive care units that serve a 17-county region in northwest North Carolina and who were born to mothers residing in that region. At 1 year of age (corrected for gestation), survivors were examined by a pediatrician and were tested using the Bayley Scales of Infant Development. Major neurosensory impairment was defined as cerebral palsy, a Bayley Mental Developmental Index <68, or blindness. A total of 209/216 (97%) of survivors were examined at 1 year of age. Epoch of birth was defined as follows: epoch 1, July 1, 1979 to June 30, 1984; epoch 2, July 1, 1984 to June 30, 1989; and epoch 3, July 1, 1989 to June 30, 1994. RESULTS: Survival rates for epochs 1, 2, and 3 were, respectively, 24/120 (20%), 63/175 (36%), and 129/218 (59%). In contrast, the proportions with a major neurosensory impairment did not increase over time; rates for successive epochs were 6/24 (25%), 17/61 (28%), and 26/124 (21%). Rates of cerebral palsy were 3/24 (13%), 12/61 (20%), and 9/124 (7%); rates of delayed mental development were 4/24 (17%), 12/61 (20%), and 17/124 (14%); and rates of blindness were 2/24 (8%), 0/62, and 5/124 (4%), respectively. CONCLUSIONS: This analysis suggests that the increasing survival of extremely low birth weight neonates since the late 1970s has not resulted in an increased rate of major developmental problems identifiable at 1 year of age.     

MUSHROOM BODY INFLUENCE ON LOCOMOTOR ACTIVITY AND CIRCADIAN RHYTHMS IN DROSOPHILA MELANOGASTER

Whether or not mechanisms underlying circadian locomotor rhythms and learning are related anatomically through the mushroom bodies (MBs) was investigated by monitoring behavioral rhythmicity in flies with MB lesions induced by chemical ablation and by mutations in five different genes. All flies tested were later examined histologically to assess (1) MB neuroanatomy, and (2) the condition of the putative pacemaker cells -- the ventral Lateral Neurons (LN v s) and their terminals that project to the vicinity of the MB calyces. All groups of flies had normal rhythms except for mushroom body miniature ( mbm ; only in a wild-type Berlin genetic background) and mushroom body defect ( mud ). MB ablation had no effect on the gender-specific differences in the rhythmic activity profile that are typical of wild-type flies. However, ablated males had a slightly longer period than untreated males and were more active under constant dark conditions. LN v s and their arborization patterns appeared normal in MB-ablated and in most mutant flies. Activity defects of mbm flies were attributed to genetic background rather than to the mutation alone. Misrouted LN v projections and ～14% arrhythmia of mud flies were uncorrelated and attributed to pleiotropy rather than to specific effects of MB lesions. Our results imply that MBs are not involved in circadian activity rhythms but that they do have an inhibitory effect on activity levels of male flies.     

Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.     

A double mobility acetabular implant for primary hip arthroplasty in patients at high risk of dislocation

IntroductionDislocation following total hip replacement continues to be a problem for which no completely satisfactory solution has been found. Several methods have been proposed to reduce the incidence of hip dislocations with varying degrees of success, including elevated rim liners, constrained liners and large diameter bearings. We present our experience with the double mobility acetabular component in patients at high risk of instability.MethodsThis was a retrospective review of 65 primary total hip arthroplasties in 55 patients (15 men, 40 women), performed between October 2005 and November 2009. The majority (80%) of patients had at least two and 26% had at least three risk factors for instability. The mean age was 76 years (range: 44–92 years). The patients were followed up for a mean duration of 60 months (range: 36–85 months).ResultsFourteen patients died and one was lost to follow-up, leaving fifty hips for final assessment. Until the final follow-up appointment, no patients had dislocation and none required revision surgery. The mean Oxford hip score improved from 45.0 to 26.5 (p<0.0001). The mean Merle d’Aubigné pain score improved from 1.4 to 4.9 (p<0.0001), the walking score from 2.3 to 3.1 (p<0.07) and the absolute hip function score from 5.4 to 10.8 (p<0.0001). There were no clinical or radiographic signs of loosening.ConclusionsThe double mobility acetabular component was successful at preventing dislocation during early to medium-term follow-up. However, as data are still lacking with regard to polyethylene wear rates at the additional bearing surface, it would be prudent to restrict the use of this implant to selected patients at high risk of instability.     

Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.