Carbon-11 labelled tyrosine to study tumor metabolism by positron emission tomography (PET)

To measure the rate of protein synthesis in human neoplasms by positron emission tomography, we prepared no carrier added DL-(1-¹¹C)-tyrosine by ¹¹C-carboxylation of the appropriate -lithioisocyanide followed by hydrolysis of the isocyanide function and removal of the protecting methoxy group. The purification, resolution and solvent switch to saline was performed by high performance liquid chromatography (HPLC). DL-(1-¹¹C)-Tyrosine in 0.1 N NaH₂PO₄ buffer was prepared with a radiochemical yield of 8%–16% (EOS, 35 min). The enantiomeric separation and solvent switch to saline were achieved in 5 min and 10 min respectively. Consequently L-(1-¹¹C)-tyrosine in physiological saline was obtained in 2%–4% radiochemical yield. Tumor accumulation in rats with the experimental WALKER 256 carcinosarcoma was observed for both the L- and D-isomer. Using positron emission tomography a tumor/muscle ratio of two was observed for the L-isomer 15 min after injection. The corresponding figure for the D-isomer was 2.5. The first clinical results with DL-(1-¹¹C)-tyrosine show accumulation of radioactivity in meningioma, a primary breast carcinoma and in liver metastases of a colonic carcinoma.     

Pharmacokinetics of the antitumor antibiotic n-pentyl-sparsomycin in beagle dogs

Summary N-pentyl-sparsomycin (PSm) is a lipophilic analogue of sparsomycin (Sm), which is a well known inhibitor of protein synthesis. This compound was selected for preclinical pharmacokinetic studies because of its high in vitro and in vivo antitumor activity. In this study in which the drug was evaluated in beagle dogs under anaesthesia, the drug concentrations in plasma, urine and bile samples were determined using high performance liquid chromatography (HPLC). Plasma protein binding was approximately 54%. The mean t1/2 was 0.2 hours (12 minutes) and t1/2 was 0.75 ± 0.1 hours (45 ± 6 minutes). During continuous infusions up to 5.25 hours, the steady state was reached in 3 out of 6 experiments, suggesting that in some cases the real t1/2 was longer than measured. PSm was actively reabsorbed from the renal tubuli. This process was saturable at the higher doses. Tubular reabsorption played only a minor role in pharmacokinetics as most of the drug (67%) was eliminated by the non-renal clearance. The non-renal clearance was saturable at higher doses of PSm and was the reason for non-linearity of pharmacokinetics.     

Photorefractive keratectomy with the erbium: YAG laser

BACKGROUND: Ablation experiments and preclinical studies have shown increased thermal damage and surface roughness after photorefractive keratectomy (PRK) with the erbium: YAG laser. MATERIALS AND METHODS: In this study, the thermal damage was investigated on enucleated pig corneas for various laser pulse durations (80 ns to 1 ms) and radiant exposures (0.2-5 J/cm2). The "scanning-spot" method and the fundamental mode photo-ablation were used for spherical corrections. SEM pictures and surface roughness measurements enabled comparison with the morphology after ArF-excimer laser treatment. The surface roughness is one order of magnitude higher compared to the ArF-excimer laser ablation. The surface of the tissue after ablation looks melted. RESULTS: The thermal damage reduces with increased intensity, and at high intensities the thermal damage results in a constant thickness of > 5 microns. CONCLUSIONS: Laser-induced melting processes might be the main reason for the high thermal damage and the increased surface roughness after erbium: YAG laser treatment. This leads to the conclusion that the erbium: YAG laser is not a real alternative to the ArF-excimer laser in PRK.     

BDNF Is Needed for Postnatal Maturation of Basal Forebrain and Neostriatum Cholinergic Neurons In Vivo

Neurotrophins regulate survival, neurite outgrowth, and phenotypic maturation of developing neurons. Brain-derived neurotrophic factor (BDNF) can promote the survival of developing cholinergic forebrain neurons in vitro and reduce their degeneration following injury in adult rats. We investigated the role of endogenous BDNF during postnatal development of these cholinergic neurons by analyzing homozygous BDNF-deficient (−/−) mice and their littermates (+/+, +/−). At P6, the number of choline acetyltransferase- (ChAT) positive neurons in the medial septum was 23% lower in BDNF−/− mice, although their brain and body weight was normal. At P15, control (+/+) littermates had 45% more and 45% larger ChAT-positive neurons and a much denser cholinergic hippocampal innervation than at P6, indicative of maturation of the septohippocampal system. In BDNF−/− mice, the number, size, and ChAT-immunostaining intensity of the cholinergic neurons remained the same between P6 and P15 (few mice survive longer). BDNF−/− mice had about three times more TUNEL-labeled (a marker of apoptosis) cells in the medial septum at P6, consistent with (but not proof of) the possibility that the cholinergic neurons were dying. The cholinergic hippocampal innervation in BDNF−/− mice expanded to a lesser extent than in controls and had reduced levels of acetylcholinesterase staining at P15. The developmental deficits were largely similar in the neostriatum of BDNF−/− mice. These findings suggest that BDNF is critical for postnatal development and maturation of cholinergic forebrain neurons.     

Risk Factors for Non-Sentinel Lymph Node Metastases in Patients with Breast Cancer. The Outcome of a Multi-institutional Study

Background In this multi-institutional prospective study, we evaluated whether we could identify risk factors predictive for non-sentinel lymph node (non-SN) metastases in breast cancer patients with a positive sentinel lymph node (SN). Methods In this multi-institutional study, 541 eligible breast cancer patients were included prospectively. Results The occurrence of non-SN metastases was related to the size of the SN metastasis (P = .02), primary tumor size (P = .001), and lymphovascular invasion (P = .07). The adjusted odds ratio was 3.1 for SN micro-metastasis compared with SN isolated tumor cells, 4.0 for SN macro-metastasis versus SN isolated tumor cells, 3.1 for tumor size (>3.0 cm compared with ≤3.0 cm), and 2.0 for lymphovascular invasion (yes versus no). There were no positive non-SNs when the primary tumor size was ≤1.0 cm (n = 24) [95% confidence interval (95% CI) 0%–14.0%]. The proportion of positive non-SNs ranged in a prognostic logistic regression model from 9.7% (95% CI 4.0%–23.0%) for patients with SN isolated tumor cells, tumor size of 1.1–3.0 cm, and without vessel invasion, to 72.6% (95% CI 47.0%–89.0%) for patients with SN macro-metastasis, tumor size >3.0 cm, and with vessel invasion. Conclusion We identified three predictive factors for non-SN metastases in breast cancer patients with a positive SN: size of the SN metastasis; primary tumor size; and vessel invasion. We were not able to identify a specific group of patients with a positive SN in whom the risk for non-SN metastases was less than 5%.     

Static cold storage preservation of ischemically damaged kidneys. a comparison between IGL-1 and UW solution.

Especially in damaged organs, adequate organ preservation is critically important to maintain viability. Institut Georges Lopez-1 (IGL-1) is a new preservation solution, with an extracellular sodium/potassium ratio and polyethylene glycol as a colloid. The influence of warm and cold ischemia was evaluated in a rat Lewis-Lewis transplant model with a follow up of 14 days. Eight groups of donation after cardiac death donor kidneys were studied with warm ischemia of 0 and 15 min followed by 0- or 24-h cold storage (CS) preservation in IGL-1 or UW-CSS. Blood was collected daily during the first week and at day 14. Recipients were placed in metabolic cages at day 4 and 14 after transplantation allowing urine collection and adequate measurement of glomerular filtration rate. Focussing on inflammation, reactive oxygen species production, proximal tubule damage, proteinuria, histology, and renal function after transplantation we could not show any relevant difference between IGL-1 and UW-CSS. Furthermore, the combination of 15-min warm ischemia and by 24-h cold ischemia did not result in life sustaining kidney function after transplantation, irrespective of the used solution. In the present experiment, static CS preservation of ischemically damaged rat kidneys in either IGL-1 or UW-CSS rendered equal results after transplantation.     

Replacement of the aortic root for acute prosthetic valve endocarditis: prosthetic composite versus aortic allograft root replacement

OBJECTIVE: Aortic root replacement for prosthetic aortic valve endocarditis with accompanying destruction of the aortic root is a well-established surgical intervention. However, there is still no consensus whether prosthetic material or allogeneic material should be used. Here we report on our experience with prosthetic composite and aortic allograft root replacement in such patients during a 10-year interval. METHODS: From 1991 through 2001, 29 patients with prosthetic aortic valve endocarditis combined with aortic root destruction underwent reoperation at our institution. Sixteen patients received aortic root replacement with a cryopreserved aortic root allograft (group A) and 13 with a prosthetic composite graft (group B). The interval between the initial operation and reoperation was 29 months (range, 5-168 months) in group A and 55 months (range, 7-248 months) in group B. RESULTS: Hospital mortality was 18.5% (n = 5 patients, 3 in group A and 2 in group B). Median follow-up was 21 months (range, 1-48 months) for group A and 34 months (range, 1-152 months) for group B (P >.2). Survival at 1 and 5 years was 81% +/- 10% and 81% +/- 10% in group A and 85% +/- 10% and 85% +/- 10% in group B, respectively. No patient underwent reoperation for recurrent prosthetic aortic valve endocarditis. CONCLUSIONS: Our results indicate that excellent long-term results can be achieved regardless of the material used for aortic root replacement in patients with prosthetic aortic valve endocarditis.     

Causes of frequency and nocturia after renal transplantation

OBJECTIVE

To explore the role of bladder capacity, bladder pain, dysfunctional voiding, urgency, urinary tract infections (UTIs), and urinary output as potential causes of frequency and nocturia after renal transplantation.

PATIENTS AND METHODS

Data were gathered from 52 adult renal transplant patients (35 men and 17 women, mean age 49 years), using a written questionnaire, medical records, frequency/volume charts, and urinary cultures. The mean time between transplantation and data collection was 5 months. Structural equation modelling (SEM) was used for the simultaneous assessment of direct and indirect relationships between explanatory variables and voiding frequency.

RESULTS

Frequency and nocturia were found in 54% and 60% of the study population, respectively. Frequency was directly associated with a small bladder capacity, bladder pain, urgency, and a high daytime urine volume, and indirectly by UTIs (via urgency and bladder pain). Nocturia was associated with high nocturnal urine volume, small bladder capacity and dysfunctional voiding. A quarter of the patients had small bladders and another quarter had large bladders, the latter being associated with nocturnal polyuria.

CONCLUSIONS

The presence of frequency, especially when accompanied by bladder pain, might aid the physician to identify patients with small bladders. The presence of nocturia can be the result of a high nocturnal urine volume, which increases the risk of bladder enlargement. Because both abnormal bladder conditions can contribute to graft dysfunction, we recommend a urological follow‐up after renal transplantation, using frequency/volume charts.     

Alterations in midline cortical thickness and gyrification patterns mapped in children with 22q11.2 deletions

The 22q11.2 deletion syndrome (velocardiofacial/DiGeorge syndrome)is a neurogenetic condition associated with visuospatial deficits,as well as elevated rates of attentional disturbance, mood disorder,and psychosis. Previously, we detected pronounced cortical thinningin superior parietal and right parieto-occipital cortices inpatients with this syndrome, regions critical for visuospatialprocessing. Here we applied cortical pattern-matching algorithmsto structural magnetic resonance images obtained from 21 childrenwith confirmed 22q11.2 deletions (ages 8–17) and 13 demographicallymatched comparison subjects, in order to map cortical thicknessacross the medial hemispheric surfaces. In addition, corticalmodels were remeshed in frequency space to compute their surfacecomplexity. Cortical maps revealed a pattern of localized thinningin the ventromedial occipital–temporal cortex, criticalfor visuospatial representation, and the anterior cingulate,a key area for attentional control. However, children with 22q11.2DSshowed significantly increased gyral complexity bilaterallyin occipital cortex. Regional gray matter volumes, particularlyin medial frontal cortex, were strongly correlated with bothverbal and nonverbal cognitive functions. These findings suggestthat aberrant parieto-occipital brain development, as evidencedby both increased complexity and cortical thinning in theseregions, may be a neural substrate for the deficits in visuospatialand numerical understanding characteristic of this syndrome.