A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease,seizures and cotton wool plaques,but not spastic paraparesis

Over 100 mutations in the presenilin‐1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. Aβ was identified in leptomeningeal vessels and in cerebral plaques. A single point mutation, p.L420R (g.1508T > G) that gives rise to a missense mutation in the eighth transmembrane (TM8) domain of PS1 was identified in two affected members of the family. p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family.     

Acetabular blood flow during Bernese periacetabular osteotomy: an intraoperative study using laser Doppler flowmetry.

BACKGROUND: The blood flow to the acetabular fragment is of some concern in juxtaarticular pelvic osteotomies used for the treatment of hip dysplasia. No direct measurements have determined the effect of the Bernese periacetabular osteotomy (PAO) on acetabular perfusion. METHODS: Acetabular perfusion was measured by means of laser Doppler flowmetry in 10 patients undergoing a PAO for symptomatic acetabular dysplasia. During the surgical procedure, the intraosseous high energy laser Doppler reliably depicts dynamic changes of small vessel blood flow. Measurements were performed after defined surgical steps to obtain sequential information on the blood perfusion of the acetabular fragment. RESULTS: After complete separation of the acetabular fragment, nine out of 10 patients had pulsatile signals, but the blood flow (BF) significantly decreased by 77%. Corrective positioning of the fragment induced no further drop of the BF signal but a loss of pulsatility in six patients. After a recovery period of about 30 min following preliminary fixation of the fragment, reestablishment of the pulsatile signal and an increase of the BF signal was seen. At termination of the surgical procedure, five out of eight patients, who could be followed throughout the whole procedure, showed a clear pulsatile signal in the supraacetabular area. Bleeding of the supraacetabular cancellous surface could be observed in all acetabula. CONCLUSION: Despite careful preservation of soft tissues during the surgical procedure, a significant reduction of the blood flow in the supraacetabular region has been observed. Nevertheless, a pulsatile signal in more than 60% of the fragments after fragment correction and an increasing signal during the recovery period showed ongoing blood perfusion indicating reversible changes in the measured supraacetabular area. All osteotomies healed within eight weeks without showing signs of necrosis during a minimum follow up of 1 year.     

Multimodality evoked potentials and early prognosis in comatose patients

In 112 comatose patients somatosensory, visual and auditory evoked potentials were registered within 36 hours after the onset of coma or admission. Main causes of coma were head injury, and intracerebral and subarachnoid haemorrhage. The initial bilateral loss of any evoked potential was associated with a mortality of 98%. Normal somatosensory evoked potentials were associated with a survival rate of 74%, while normal visual and normal auditory evoked potentials had a survival rate of 60% and 66%, respectively. It is concluded that SEPs can be valuable for the prognosis of coma after primary brain lesions.     

Modeling spheroid growth, PET tracer uptake, and treatment effects of the Hsp90 inhibitor NVP-AUY922.

For a PET agent to be successful as a biomarker in early clinical trials of new anticancer agents, some conditions need to be fulfilled: the selected tracer should show a response that is related to the antitumoral effects, the quantitative value of this response should be interpretable to the antitumoral action, and the timing of the PET scan should be optimized to action of the drug. These conditions are not necessarily known at the start of a drug-development program and need to be explored. We proposed a translational imaging activity in which experiments in spheroids and later in xenografts are coupled to modeling of growth inhibition and to the related changes in the kinetics of PET tracers and other biomarkers. In addition, we demonstrated how this information can be used for planning clinical trials. METHODS: The first part of this concept is illustrated in a spheroid model with BT474 breast cancer cells treated with the heat shock protein 90 (Hsp90) inhibitor NVP-AUY922. The growth-inhibitory effect after a pulse treatment with the drug was measured with digital image analysis to determine effects on volume with high accuracy. The growth-inhibitory effect was described mathematically by a combined E(max) and time course model fitted to the data. The model was then used to simulate a once-per-week treatment; in these experiments the uptake of the PET tracers (18)F-FDG and 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) was determined at different doses and different time points. RESULTS: A drug exposure of 2 h followed by washout of the drug from the culture medium generated growth inhibition that was maximal at the earliest time point of 1 d and decreased exponentially with time during 10-12 d. The uptake of (18)F-FDG per viable tumor volume was minimally affected by the treatment, whereas the (18)F-FLT uptake decreased in correlation with the growth inhibition. CONCLUSION: The study suggests a prolonged action of the Hsp90 inhibitor that supports a once-per-week schedule. (18)F-FLT is a suitable tracer for the monitoring of effect, and the (18)F-FLT PET study might be performed within 3 d after dosing.     

Improved anchorage in osteoporotic vertebrae with new implant designs.

The goal of our study was to evaluate two newly developed implant designs and their behavior in terms of subsidence in lumbar vertebral bodies under cyclic loading. The new implants were evaluated in two different configurations (two small prototypes vs. one large prototype with similar load-bearing area) in comparison to a conventional screw-based implant (MACS TL). A pool of 13 spines with a total of 65 vertebrae was used to establish five testing groups of similar bone mineral density (BMD) distribution with eight lumbar vertebrae each. In additional to BMD assessment via dual-energy X-ray absorptiometry, cancellous BMD and structural parameters were determined using a new generation in vivo 3D-pQCT. The specimens were loaded sinusoidally in force control at 1 Hz for 1000 cycles at three load levels (100, 200, and 400 N). A survival analysis using the number of cycles until failure (Cox regression with covariates) was applied to reveal differences between implant groups. All new prototype configurations except the large cylinder survived significantly longer than the control group. The number of cycles until failure was significantly correlated with the structural parameter Tb.Sp. and similarly with the cancellous BMD for three of five implants. In both large prototypes the cycle number until failure significantly correlated with the preoperative distance to the upper endplates. Although the direct relationship between bone structure or density and mechanical breakage behavior cannot be conclusively proven, all the prototypes adapted for poor bone structure performed better than the comparable conventional implant.     

Efficacy of prophylactic antibiotics in vascular surgery: an arterial wall microbiologic and pharmacokinetic perspective

This prospective study examined microbiologic features of arterial tissue and pharmacokinetics and bioactivity of cefamandole and cefazolin in patients undergoing elective primary prosthetic aortoiliofemoral/infrainguinal reconstruction. Double-blind, randomized, perioperative prophylaxis (1 gm intravenously every 6 hours for nine doses) with cefamandole or cefazolin was administered to 47 patients. Specimens of blood serum, subcutaneous fat, thrombus, atheroma, and arterial wall were obtained for culture and minimal inhibitory concentration and drug level analysis by high-pressure liquid chromatography. The serum half-life (hr +/- SEM) was 1.43 +/- 0.36 for cefamandole and 2.22 +/- 0.40 for cefazolin. Over the first 2 hours of surgery and for all time intervals combined, the serum concentration of cefazolin was significantly higher (p less than 0.025) than cefamandole. Irrespective of sampling time, the tissue concentration of cefazolin was significantly greater (p less than 0.005) than cefamandole. Positive arterial tissue cultures were obtained in 12 of 29 patients (41.4%) from 23 of 116 (19.8%) arterial tissue specimens. Coagulase-negative Staphylococcus was the predominant isolate, 64 of 93 (68.8%). Twenty-five of the 51 coagulase-negative staphylocci tested (49%) were slime-producers. During surgery, the arterial tissue concentration of cefamandole fell below the geometric mean minimal inhibitory concentration against all organisms combined, and against S. aureus (with the highest minimal inhibitory concentration of the prevalent isolates), significantly more often than the concentration of cefazolin. The data show that a significant number of primary elective aortoiliofemoral/infrainguinal reconstructions are associated with positive arterial tissue cultures, which represent a potential source of graft infection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Radiofrequency capacitive heating of deep-seated tumours using pre-cooling of the subcutaneous tissues: results on thermometry in Dutch patients.

The capacity of a radiofrequency, 13.56 MHz, capacitive hyperthermia system using extensive pre-cooling of the subcutaneous tissue to induce locoregional deep heating has been investigated in 11 patients. Tumour location was presacral in nine--and eccentric towards the lateral side of the pelvis in two patients. For thermometry multiple catheters (mean 2.7) were inserted into the treatment volume. The mean numbers of temperature measuring points per treatment were 9.4 in tumour, 5.5 in muscle and 7.2 in subcutaneous fat. RF energy was applied after 30 min of cooling through two flexible boli perfused with saline water at 5-10 degrees C. Patient tolerance to pre-cooling was very good and after some initial discomfort the patient became rapidly accustomed to the cold water boli. For some patients better temperatures were achieved when the conventional anterior-posterior applicator set-up was replaced by a set-up with an applicator on each lateral side of the patient. As patients can tolerate temperatures within the fat tissue as high as 45.5 degrees C without complaining it appears important to monitor the temperature at the transition of fat to muscle tissue to prevent subcutaneous burns. The study shows that pre-cooling cannot avoid preferential heating at the interface from fat to muscle tissue. In this patient group the quality of the hyperthermia treatment appeared to be rather poor: 60% of the measured tumour temperatures were below 40 degrees D.     

No regression of renal AL amyloid in monoclonal gammopathy after successful autologous blood stem cell transplantation and significant clinical improvement.

BACKGROUND: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown. METHODS: In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow. RESULTS: In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy. CONCLUSION: Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress.