Reference and target region modeling of [11C]-(R)-PK11195 brain studies.

PET with [(11)C]-(R)-PK11195 is currently the modality of choice for the in vivo imaging of microglial activation in the human brain. In this work we devised a supervised clustering procedure and a new quantification methodology capable of producing binding potential (BP) estimates quantitatively comparable with those derived from plasma input with robust quantitative implementation at the pixel level. METHODS: The new methodology uses predefined kinetic classes to extract a gray matter reference tissue without specific tracer binding and devoid of spurious signals (in particular, blood pool and muscle). Kinetic classes were derived from an historical database of 12 healthy control subjects and from 3 patients with Huntington's disease. BP estimates were obtained using rank-shaping exponential spectral analysis (RS-ESA) (both plasma and reference input) and the simplified reference tissue model (SRTM). Comparison between plasma- derived BPs and those produced with the new reference methodology was performed using 6 additional healthy control subjects. Reliability of the new methodology was performed on 4 test-retest studies of patients with Alzheimer's disease. RESULTS: The new algorithm selected reference voxels in gray matter tissue avoiding regions with specific binding located, in particular, in the venous and arterial circulation. Using the new reference, BP values obtained using a plasma input and a reference input were in excellent agreement and highly correlated (r = 0.811, P < 10(-5)) when calculated with RS-ESA and less so (r = 0.507, P < 0.005) when SRTM was used. In the production of parametric maps, SRTM was used with the new reference extraction, resulting in test-retest variability (10.6%; mean ICC = 0.878) that was superior to that obtained using the previous unsupervised clustering approach (mean ICC = 0.596). CONCLUSION: Reference region modeling combined with supervised reference tissue extraction produces a robust and reproducible quantitative assessment of [(11)C]-(R)-PK11195 studies in the human brain.     

Utilization of preoperative cerebrospinal fluid drain in skull base surgery.

OBJECTIVE: Retrospectively assess the efficacy of lumbar cerebrospinal fluid (CSF) drainage placed preoperatively in skull base operations in decreasing the incidence of postoperative CSF fistula. METHODS: A retrospective review of 150 patients undergoing a posterior fossa craniotomy from 1989 to 2000 was conducted. Patients were divided into those receiving preoperative lumbar drains and those that did not. The rates of postoperative CSF leakage were compared between the two groups. Patient data were analyzed to determine if there were other comorbidities affecting the postoperative incidence of CSF leakage such as smoking, diabetes, or hypertension. RESULTS: Between 1989 and 1994, 25/72 (35%) patients with no preoperative lumbar drain had a postoperative CSF leak. From 1995 to 2000, 9/78 (12%) patients with a preoperative lumbar drain had a CSF leak. This was a 23% decreased incidence of postoperative CSF leakage and a significant decrease in the probability (p < 0.001) of CSF leakage in patients treated with a preoperative lumbar drain. The comorbidities of diabetes, smoking, or hypertension did not increase the probability of a CSF leak (p = 0.43). CONCLUSIONS: A preoperatively placed lumbar drain can significantly lower the rate of postoperative CSF leakage after skull base surgery. The drain is a well-tolerated adjunct to dural closure and helps increase surgical exposure of the posterior fossa. The comorbidities of diabetes, smoking, or hypertension do not contribute to an increased rate of CSF leakage.dagger Lyal Leibrock M.D., F.A.C.S. is Deceased.     

The impact of serum sodium concentration on mortality after liver transplantation: a cohort multicenter study.

Modification of the current allocation system for donor livers in the United States to incorporate recipient serum sodium concentration ([Na]) has recently been proposed. However, the impact of this parameter on posttransplantation mortality has not been previously examined in a large risk-adjusted analysis. We assessed the effect of recipient [Na] on the survival of all adults with chronic liver disease who received a first single organ liver transplant in the UK and Ireland during the period March 1, 1994 to March 31, 2005 (n=5,152) at 3 years, during the first 90 days, and beyond the first 90 days, adjusting for a wide range of recipient, donor, and graft characteristics. Compared to those with normal [Na] (135-145 meq/L; n=3,066), severely hyponatremic recipients ([Na]<130 meq/L, n=541), had a higher risk-adjusted mortality at 3 years (hazard ratio [HR] 1.28; 95% confidence interval [CI], 1.04-1.59; P<0.02). The excess mortality was, however, confined to the first 90 days (HR 1.55; 95% CI, 1.18-2.04; P<0.002) with no significant difference thereafter. This was also true for hypernatremic recipients ([Na]>45 meq/L, n=81), who had an even greater risk-adjusted mortality compared to normonatremic recipients (overall: HR 1.85; 95% CI, 1.25-2.73; P<0.002; 90 days: HR 1.12; 95% CI, 0.55-2.29; P=0.8), whereas mildly hyponatremic recipients ([Na] 130-134 meq/L, n=1,127) had similar risk-adjusted mortality to those with normal [Na] at the same time points. In conclusion, recipient [Na] is an independent predictor of death following liver transplantation. Attempts to correct the [Na] toward the normal reference range are an important aspect of pretransplantation management.     

Cerebral Cortical Aquaporin-4 Expression in Brain Edema following Cardiac Arrest in Rats

OBJECTIVES: Brain edema occurs following clinical as well as experimental cardiac arrest (CA) and predicts a poor neurologic outcome. The objective of this study was to determine the expression of cerebral cortex aquaporin (AQP)-4, a member of a family of membrane water-channel proteins, in brain edema formation following normothermic or hypothermic CA. METHODS: Twenty-four rats were subjected to time-matched normothermic (N-Sham, 37.5 degrees C +/- 0.5 degrees C, n = 6) or hypothermic (H-Sham, 34 degrees C +/- 0.5 degrees C, n = 6) sham experiments and normothermic (N-CA, n = 6) or hypothermic (H-CA, n = 6) CA induced by asphyxiation for 8 minutes. Hypothermia was induced before CA. The animals were resuscitated with cardiopulmonary resuscitation, ventilation, and epinephrine administration. Brain edema was determined by brain wet-to-dry weight ratio at one hour of resuscitation. AQP4 immunoactivity in the cerebral cortex was determined using immunohistochemical staining and was semiquantified as an intensity of staining with an automated cell imaging system. RESULTS: Mild hypothermia in the sham experiments did not alter cerebral cortex AQP4 immunoactivity (mean +/- SD) (55.0 +/- 3.7 in H-Sham vs. 53.3 +/- 1.7 in N-Sham, p > 0.05). N-CA resulted in a significant increase in AQP4 immunoactivity (61.8 +/- 4.5) compared with N-Sham (p = 0.01) and H-Sham (p = 0.03). H-CA attenuated AQP4 compared with N-CA (53.4 +/- 1.3, p = 0.01). Brain wet-to-dry weight ratios were 4.41 +/- 0.07 in N-Sham, 4.40 +/- 0.08 in H-Sham (p > 0.05 vs. N-Sham), 4.55 +/- 0.04 in N-CA (p = 0.004 vs. N-Sham; p = 0.005 vs. H-Sham), and 4.43 +/- 0.09 in H-CA (p = 0.02 vs. N-CA; p > 0.05 vs. N-Sham and H-Sham). CONCLUSIONS: Cerebral cortical AQP4 expression is up-regulated after normothermic CA, which is attenuated by hypothermia induced before CA.     

Minimal Acute Rejection after Lung Transplantation: A Risk for Bronchiolitis Obliterans Syndrome

Bronchiolitis obliterans syndrome (BOS) is a major cause of lung allograft dysfunction. Although previous studies have identified mild to severe rejection (grade>or=A2) as a risk factor for BOS, the role of minimal rejection (grade A1) remains unclear. To determine if A1 rejection by itself is a risk factor for BOS, we performed a retrospective cohort study on 228 adult lung transplant recipients over a 7-year period. Cohorts were defined by their most severe rejection episode (none, A1 only, and >or=A2) and analyzed for the subsequent development and progression of BOS using univariate and multivariate time-dependent Cox regression analysis. In the univariate model, the occurrence of isolated minimal rejection was a risk factor for all stages of BOS. Similarly, multivariate models that included HLA mismatch, cytomegalovirus pneumonitis, community acquired viral infection, underlying disease and type of transplant demonstrated that A1 rejection was a distinct risk factor for BOS. Furthermore, the associated risk with A1 rejection was slightly greater than the risk from >or=A2 and treatment of A1 rejection decreased the risk for subsequent BOS stage 1. We conclude that minimal rejection is associated with an increased risk for BOS development and progression that is comparable to A2 rejection.     

Risk factors for wheezing in Ukrainian children: Ukraine European Longitudinal Study of Pregnancy and Childhood Group

The prevalence of wheezing in children varies widely around the world. The reasons for this geographic variability remain unclear but may be related in part to exposures in the home environment during pregnancy and early childhood. We investigated the prenatal and early childhood risk factors for wheezing symptoms among 2127 children aged 6–8 years who were participants in the Ukrainian component of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC). Cases included the 169 children whose parents answered yes to the International Study of Asthma and Allergy in Children (ISAAC) question: 'Has your child had wheezing or whistling in the chest in the past 12 months' during the ELSPAC assessment of the children at age 7. These were compared with the 1861 children in the cohort whose parents answered 'no' to this question.
Factors significantly associated with increased risk of wheezing illness at age 7 in adjusted analyses included mother's asthma [adjusted odds ratio (OR) 3.46, 95% confidence interval (CI) 1.22, 9.85]; mother's allergy problems (OR 1.43, [1.00, 2.05]); rarely playing with other children at age 3 (OR 1.84, [1.09, 3.11]); water intrusion (OR 1.62, [1.09, 2.39]) and inadequate heating of the home (OR 1.52, [1.06, 2.16]) during pregnancy. Factors protective of wheezing at age 7 included being first-born (adjusted OR 0.70, 95% CI 0.50, 0.98); living in the city of Dniprodzerzynsk as compared with Kyiv (OR 0.36, [0.24, 0.54]) and weekly contact with furry animals (OR 0.44, [0.20, 0.97]) before age 3. The constellation of risk factors for wheezing in Ukrainian children is similar to that of children in other parts of the world. Known risk factors do not account for the significant between-city variability of wheezing in Ukrainian children.     

Differential Cellular Gene Expression in Ganglioglioma

Summary:  Purpose:  Gangliogliomas (GGs) are neuronal-glial tumors highly associated with epilepsy. We hypothesized that the expression of select gene families including neurotransmitter receptor subunits and growth factors would be distinct in neurons and astrocytes within GG compared with adjacent cortex and that these changes would yield insights into seizure onset and lesion formation.
Methods:  Candidate gene expression was defined in single immunohistochemically labeled neurons and astrocytes microdissected from GG specimens compared with neurons and astrocytes microdissected from morphologically intact cortex adjacent to the GG or normal control cortex.
Results:  Differential expression of 16 genes including glutamate transporter (EAAC1) and receptor (NMDA2C, mGluR5), growth factor (hepatocyte growth factor), and receptor (platelet derived growth factor receptor β, fibroblast growth factor receptor 3) mRNAs was detected in GG neurons compared with control neurons. In astrocytes, altered expression of p75NGF, mGluR3, TGFβ3 and Glt-1 mRNAs was detected. Nestin mRNA, a gene that exhibits enhanced expression in balloon cell cortical dysplasia, was increased in GG neurons. Because of the morphological similarities between GG and cortical dysplasia, we show that there is activation of the mTOR cascade in GG as evidenced by enhanced expression of phospho-p70S6kinase and phosphoribosomal S6 proteins.
Conclusion:  We find differential candidate gene expression in neurons and astrocytes in GG compared with adjacent cortex and show that there is activation of the mTOR pathway. These changes highlight pathways that may be pivotal for epileptogenesis and lesion growth.     

Mammalian nuclear transfer.

During development, the genetic content of each cell remains, with a few exceptions, identical to that of the zygote. Differentiated cells, therefore, retain all the genetic information necessary to generate an entire organism (nuclear totipotency). Nuclear transfer (NT) was initially developed to test experimentally this concept by cloning animals from differentiated cells. It has, since then, been used to study the role of genetic and epigenetic alterations during development and disease. In this review, we highlight some of the milestones in mammalian NT reached in the 50 years after the first nuclear transplantations in frogs. We also address problems associated with mammalian nuclear transfer and provide a survey on current NT and stem cell technology. In the long term, nuclear transfer or alternative strategies aim to generate customized pluripotent cells, which would be invaluable to medical research and therapy.     

The outcome of nonoperatively treated complete tears of the anterior cruciate ligament in active young adults

The results of nonoperative treatment of 72 patients with complete anterior cruciate ligament (ACL) tears, documented by examination under anesthesia and arthroscopy, were evaluated. All patients had an acute injury with hemarthrosis in a previously normal knee. Patients having meniscal repair were excluded as were those with collateral or posterior cruciate ligament tears or associated fractures. Treatment in all cases consisted of a standard protocol of early rehabilitation and bracing. A detailed rating of symptoms and function was performed at an average of 38 months postinjury (range, eight to 84 months). Overall results were 11% excellent, 20% good, 15% fair, and 54% poor. Thirty-five percent had ACL reconstruction during the follow-up period. Results indicate that young adults who return to a vocation requiring strenuous physical activity frequently can expect unsatisfactory results after nonoperative treatment of an acute complete tear of the ACL.