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Supplementary Fig. S1 from Cytotoxicity of the matrix metalloproteinase–activated anthrax lethal toxin is dependent on gelatinase expression and B-RAF status in human melanoma cells

Anthrax lethal toxin (LeTx) shows potent mitogen-activated protein kinase pathway inhibition and apoptosis in melanoma cells that harbor the activating V600E B-RAF mutation. LeTx is composed of two proteins, protective antigen and lethal factor. Uptake of the toxin into cells is dependent on proteolytic activation of protective antigen by the ubiquitously expressed furin or furin-like proteases. To circumvent nonspecific LeTx activation, a substrate preferably cleaved by gelatinases was substituted for the furin LeTx activation site. Here, we have shown that the toxicity of this matrix metalloproteinase (MMP)–activated LeTx is dependent on host cell surface MMP-2 and MMP-9 activity as well as the presence of the activating V600E B-RAF mutation, making this toxin dual specific. This additional layer of tumor cell specificity would potentially decrease systemic toxicity from the reduction of nonspecific toxin activation while retaining antitumor efficacy in patients with V600E B-RAF melanomas. Moreover, our results indicate that cell surface-associated gelatinase expression can be used to predict sensitivity among V600E B-RAF melanomas. This finding will aid in the better selection of patients that will potentially respond to MMP-activated LeTx therapy. [Mol Cancer Ther 2008;7(5):1218–26]

Background: breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. Patients and methods: we included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (Results: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10 −5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10 −4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. Conclusions: this is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Purpose: Uveal (ocular) melanoma (UM) is a highly aggressive and frequently fatal cancer of the eye. While only 2-4% of patients have metastases at diagnosis, up to 50% of develop metastatic disease, overwhelmingly to the liver. Almost all UM harbor an initiating mutation in the Gαq signaling pathway, most commonly in GNAQ. Most UM also contain secondary mutations that drive tumor progression, the most common being BAP1 loss. Targeted therapies such as MEK inhibitors have been utilized in UM, but tumors rapidly become refractory. The aims of this study were to identify novel mechanisms specifically activated in UM cells that drive proliferation and escape from MEK inhibitor therapy. Procedures: We performed CRISPR-Cas9 mediated gene disruption screening of UM cell lines 92.1, Mel202 and Mel270 using the Brunello sgRNA library targeting the whole genome. Cells were transduced at 0.3 MOI and 500X coverage then split into two groups to compare treatment with the MEK inhibitor (MEKi) trametinib (6nM) vs. untreated control cells. Cell pellets were collected at day 2 (baseline) and after every 3 cell divisions for 21 cell divisions (treated and control). In addition, we generated 92.1 and Mel270 cell lines stably expressing Cas9 and transduced cells at 1000x coverage with a sgRNA library targeting either 192 epigenetic regulators or 482 kinases. At least two replicates for each screen were performed. sgRNA representation between samples was compared using MAGeCK. Genes specifically essential in UM cell lines were distinguished from commonly essential genes using the Broad institute dependency map (DepMap). These hits were validated by individual sgRNAs and pharmacological inhibition. Results: Whole genome screens revealed a set of 84 genetic dependencies unique for UM cells that were required for proliferation. Among these genes were those required for the lipoic acid biosynthesis pathway: MCAT, MECR, LIPT2, LIAS as well as genes encoding the MITF-SOX10-TFAP2 transcription factors, the H3K9 methyltransferase SETDB1, and members of the MLL3/4 complex. Screening of UM cell lines with a focused guide RNA library targeting epigenetic regulators revealed that BRD2, TRIM28, KMT2D, SETD1B and HDAC1 were specifically required for UM survival. Screens with a sgRNA library targeting the kinome revealed CDK2, CDK4 and TRRAP were required for UM survival. After 1 week of treatment with MEKi trametinib, we identified 112 genes whose disruption increased the anti-proliferative effects of trametinib in Mel202 and Mel270 cells and 10 of these genes were essential only in UM. These genes included metabolic enzymes critical for fatty and lipoic acid synthesis such as MECR, MCAT and TAZ. By contrast disruption of TP53, NF1, or PTEN led to MEKi resistance. Conclusions: These results identify novel mechanisms of proliferation and therapy resistance specifically required in GNAQ mutant UM cells that may represent new therapeutic targets. Citation Format: Richard L. Bennett, Darby Monagle, Katelyn R. Raburn Smith, Amin Sobh, Keiran S. Smalley, J William Harbour, Jonathan D. Licht. CRISPR/Cas9 screens to identify proliferation and resistance mechanisms in uveal melanoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3935.

Introduction The majority of publications regarding breast cancer GEPTs rarely supply detailed breast tumor histopathology in their outcome studies. As a result, the cost effective role of clinical risk assessment with histopathology of breast carcinomas tends to be minimized. The aims of this study are to characterize the details of breast tumor histopathology of patients with Oncotype Dx Recurrence Scores (RS) of 10 or less, and determine if Oncotype Dx offers value and clinical utility for patients with these low grade tumors Methods A total of 459 patients (18%) with Oncotype Dx RS of 10 or less were retrieved from a registry of 2558 patients with Oncotype Dx results. Patients had five years of follow-up with tumor registry and were treated with endocrine therapy alone. Tissue slides were available to review on 441/459 patients. Recorded details included (1) histopathologic type of carcinoma (2) mitotic score (MS), tubule formation, nuclear pleomorphism and Notttingham histologc (NG) grade. (3) Estrogen (ER) and progesterone (PgR) semiquantitated by Allred Score and Histologic Score (H Score: strong 200-300, moderate 100-199, weak Results Patient ages were 33-92, with mean/median age of 60, and all had endocrine therapy alone. 148 of 441(34%) patients had carcinomas of “special types”, notable for low grade/good prognosis including tubular 22(15%), cribriform 15 (10.1%), papillary 17 (11.5%), and mucinous 28 (21%), along with 63 (42.5%) low grade classic lobular carcinomas and 3 (2%) low grade mixed ductal and lobular carcinomas. All 148 tumors had a MS of 1, were NG1 and had high ER HScores (280 median/263 mean) (Allred Scores 7-8) and high PR HScores (210 median/201 mean) (Allred Scores 6-8). The remaining 293 tumors were ductal carcinomas of no special type (NST), and 261/293 (89%) of these had a MS of 1/NG2. Of the remaining cases, 10 (3%) had a MS of 2/NG2, 18 (6%) had MS of 2/NG3 and four (1%) were MS3/NG3. Estrogen receptor H Score/Allred Score was strong (Allred Score 7-8) in 395/441 (89.6%), moderate in 45 (10.2%) and weak in 1 patient (0.2%). Progesterone HScores were strong in (Allred Score 6-8) 269/441 (76%) and moderate in the remainder. Strong and moderate ER comprised 99.8% of tumors. Thus, tumors with MS1, and NG1, all with ER HScore >200 (Allred Score of 7-8) were enriched in the RS At 5 years, 433 patients (98%) were alive, 8 were dead, 1 from breast cancer due to distant recurrence. The 5-year breast cancer specific survival for this group was 99.7%. [95%CI 98.5-99.9.] 87 cases were accrued in the ongoing prospective study to date. There were 15/87 (17%) cases, 95% of which were correctly identified by pathologists as having an RS 22. Conclusions Pathologists can identify these low risk tumors with high accuracy. Oncotype Dx lacks clinical value and utility in this setting. Citation Format: Dabbs DJ, Serdy K, Onisko A, Clark BZ, Bhargava R, Smalley S, Perkins S, Brufsky AM. The clinical utility of oncotype Dx for patients with recurrence scores of 10 or less: A value based pathology study of tumor histopathology and outcomes analysis in an integrated delivery and finance health system [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-08-04.

We report investigations on gold single crystals carried out with the help of an original experimental set-up, combining a scanning tunneling microscope and a compression device under ultra high vacuum, that allows for in situ observations of stressed surfaces at the atomic scale. It is observed that a macroscopic compression strain may induce a reorganization of the Au(111) surface reconstruction, known as the chevron-like pattern. Molecular dynamics simulations using a modified embedded atom method potential have been carried out to highlight the elementary dislocation mechanisms at the origin of such an evolution.

Cell therapy with autologous or allogeneic keratinocytes applied as a single-cell suspension is well established in clinical practice in the treatment of severe burn injuries to augment epithelial barrier restoration. Yet, the application of cell sprays can lead to significant cell loss owing to lack of adhesion of cell suspension to the wound bed. The development of a robust and controllable method of transplanting cells onto the wound bed is yet to be established. The ability to control adhesion and distribution of cells by using a cell carrier embedded in a biodegradable scaffold could significantly improve the treatment of cutaneous wounds with keratinocyte cell therapy. Several microcarrier-based systems for expanding keratinocytes already exist. A new method for expansion of human keratinocytes in a feeder-free, defined medium system on microcarriers has been developed. The cells retained their basal, proliferative phenotype after rapid expansion in a clinically relevant time-frame. The cell-laden microcarriers were further incorporated into collagen scaffolds fabricated by plastic compression. When cultured in vitro, cells continued to proliferate and migrate along the surface of the collagen scaffold. Using an in vitro wound bed model, cells were observed to form mostly single cell layers and in some areas multiple cell layers within 8 days, while retaining their basal, proliferative phenotype, indicating the suitability of this cell transplantation method to improve epithelial barrier restoration. This advanced cell expansion and delivery method for cutaneous cell therapy provides a flexible tool for use in clinical application. Copyright © 2017 John Wiley & Sons, Ltd.

OBJECTIVE Paraplegia and paraparesis following aortic aneurysm repair occur at a substantially high rate and are often catastrophic to patients, their families, and the overall health care system. Spinal cord injury (SCI) following open thoracoabdominal aortic aneurysm (TAAA) repair is reported to be as high as 20% in historical controls. The goal of this study was to determine the impact of CSF drainage (CSFD) on SCI following TAAA repair. METHODS In August 2015 a systematic literature search was performed using clinicaltrials.gov, the Cochrane Library, PubMed/MEDLINE, and Scopus that identified 3478 articles. Of these articles, 10 met inclusion criteria. Random and fixed-effect meta-analyses were performed using both pooled and subset analyses based on study type. RESULTS The meta-analysis demonstrated that CSFD decreased SCI by nearly half (relative risk 0.42, 95% confidence interval 0.25–0.70; p = 0.0009) in the pooled analysis. This effect remained in the subgroup analysis of early SCI but did not remain significant in late SCI. CONCLUSIONS This meta-analysis showed that CSFD could be an effective strategy in preventing SCI following aortic aneurysm repair. Care should be taken to prevent complications related to overdrainage. No firm conclusions can be drawn about the newer endovascular procedures at the current time.

OBJECT Surgery for CSF diversion is the most common procedure performed by pediatric neurosurgeons. The failure rates for shunts remain frustratingly high, resulting in a burden to patients, families, providers, and healthcare systems. The goal of this study was to quantify the risk of a shunt malfunction in patients with an existing shunt who undergo an elective intradural operation. METHODS All elective intradural surgeries (cranial and spinal) at Le Bonheur Children’s Hospital from January 2010 through June 2014 were reviewed to identify those patients who had a functional ventricular shunt at the time of surgery. Patient records were reviewed to collect demographic, surgical, clinical, radiological, and pathologic data, including all details related to any subsequent shunt revision surgery. The primary outcome was all-cause shunt revision (i.e., malfunction or infection) within 90 days of elective intradural surgery. RESULTS One hundred and fifty elective intradural surgeries were identified in 109 patients during the study period. There were 14 patients (12.8%, 13 male) who experienced 16 shunt malfunctions (10.7%) within 90 days of elective intradural surgery. These 14 patients underwent 13 craniotomies, 2 endoscopic fenestrations for loculated hydrocephalus, and 1 laminectomy for dorsal rhizotomy. Median time to failure was 9 days, with the shunts in half of our patients failing within 5 postoperative days. Those patients with failed shunts were younger (median 4.2 years [range 0.33–26 years] vs median 10 years [range 0.58–34 years]), had a shorter time interval from their previous shunt surgery (median 11 months [range 0–81 months] vs median 20 months [range 0–238 months]), and were more likely to have had intraventricular surgery (80.0% vs 60.3%). CONCLUSIONS This is the first study to quantify the risk of a shunt malfunction after elective intradural surgery. The 90-day all-cause shunt failure rate (per procedure) was 10.7%, with half of the failures occurring within the first 5 postoperative days. Possible risk factors for shunt malfunction after elective intradural surgeries are intraventricular surgical approach, shorter time since last shunt-related surgery, and young age.

OBJECTIVE Shunt surgery consumes a large amount of pediatric neurosurgical health care resources. Although many studies have sought to identify risk factors for shunt failure, there is no consensus within the literature on variables that are predictive or protective. In this era of “quality outcome measures,” some authors have proposed various metrics to assess quality outcomes for shunt surgery. In this paper, the Preventable Shunt Revision Rate (PSRR) is proposed as a novel quality metric. METHODS An institutional shunt database was queried to identify all shunt surgeries performed from January 1, 2010, to December 31, 2014, at Le Bonheur Children's Hospital. Patients' records were reviewed for 90 days following each “index” shunt surgery to identify those patients who required a return to the operating room. Clinical, demographic, and radiological factors were reviewed for each index operation, and each failure was analyzed for potentially preventable causes. RESULTS During the study period, there were 927 de novo or revision shunt operations in 525 patients. A return to the operating room occurred 202 times within 90 days of shunt surgery in 927 index surgeries (21.8%). In 67 cases (33% of failures), the revision surgery was due to potentially preventable causes, defined as inaccurate proximal or distal catheter placement, infection, or inadequately secured or assembled shunt apparatus. Comparing cases in which failure was due to preventable causes and those in which it was due to nonpreventable causes showed that in cases in which failure was due to preventable causes, the patients were significantly younger (median 3.1 vs 6.7 years, p = 0.01) and the failure was more likely to occur within 30 days of the index surgery (80.6% vs 64.4% of cases, p = 0.02). The most common causes of preventable shunt failure were inaccurate proximal catheter placement (33 [49.3%] of 67 cases) and infection (28 [41.8%] of 67 cases). No variables were found to be predictive of preventable shunt failure with multivariate logistic regression. CONCLUSIONS With economic and governmental pressures to identify and implement “quality measures” for shunt surgery, pediatric neurosurgeons and hospital administrators must be careful to avoid linking all shunt revisions with “poor” or less-than-optimal quality care. To date, many of the purported risk factors for shunt failure and causes of shunt revision surgery are beyond the influence and control of the surgeon. We propose the PSRR as a specific, meaningful, measurable, and—hopefully—modifiable quality metric for shunt surgery in children.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition with a birth incidence of 1/3,500. Around 50% of cases are due to new mutations. The NF1 gene maps to 17q11.2 and encodes neurofibromin. NF1 is a "classical" tumor suppressor gene. Congenital disseminated NF1 is rare with just two cases previously reported. We present a deceased baby with congenital disseminated NF1 in whom we performed molecular studies. A germline mutation (R461X) in exon 10a of the NF1 gene was found. A 2 bp deletion (3508delCA) in codon 1170 of exon 21 was identified in DNA derived from some tumor tissue. Loss of heterozygosity in NF1 and TP53 was observed in other tumor samples. No microsatellite instability was observed in the tumor samples. This is the first report of molecular analysis of the NF1 locus in a patient with disseminated congenital neurofibromatosis. This case had a de novo germline mutation in NF1 and three documented somatic mutations in the NF1 and TP53 genes in tumor specimens.

Cell therapy with autologous or allogeneic keratinocytes applied as a single-cell suspension is well established in clinical practice in the treatment of severe burn injuries to augment epithelial barrier restoration. Yet, the application of cell sprays can lead to significant cell loss owing to lack of adhesion of cell suspension to the wound bed. The development of a robust and controllable method of transplanting cells onto the wound bed is yet to be established. The ability to control adhesion and distribution of cells by using a cell carrier embedded in a biodegradable scaffold could significantly improve the treatment of cutaneous wounds with keratinocyte cell therapy. Several microcarrier-based systems for expanding keratinocytes already exist. A new method for expansion of human keratinocytes in a feeder-free, defined medium system on microcarriers has been developed. The cells retained their basal, proliferative phenotype after rapid expansion in a clinically relevant time-frame. The cell-laden microcarriers were further incorporated into collagen scaffolds fabricated by plastic compression. When cultured in vitro, cells continued to proliferate and migrate along the surface of the collagen scaffold. Using an in vitro wound bed model, cells were observed to form mostly single cell layers and in some areas multiple cell layers within 8 days, while retaining their basal, proliferative phenotype, indicating the suitability of this cell transplantation method to improve epithelial barrier restoration. This advanced cell expansion and delivery method for cutaneous cell therapy provides a flexible tool for use in clinical application. Copyright © 2017 John WileySons, Ltd.

Tanks 241-AN-102 and 241-AN-107 supernatants contain soluble Sr-90 and transuranic elements that require removal prior to vitrification to comply with the Waste Treatment and Immobilization Plant immobilized low-activity waste specification (WTP Contract, DE-AC27-01RV 14136, Specification 2.2.2.8, "Radionuclide Concentration Limitations") and the U.S. Nuclear Regulatory Commission provisional agreement on waste incidental to reprocessing (letter, Paperiello, C. J., "Classification of Hanford Low-Activity Tank Waste Fraction"). These two tanks have high concentrations of organics and organic complexants and are referred to as complexant concentrate tanks. A precipitation process using sodium permanganate (NaMnO{sub 4}) and strontium nitrate (Sr(NO{sub 3}){sub 2}) was developed and tested with tank waste samples to precipitate Sr-90 and transuranic elements from the supernate (PNWD-3141, Optimization of Sr/TRU Removal Conditions with Samples of AN-102 Tank Waste). Testing documented in this report was conducted to further evaluate the use of the strontium nitrate/sodium permanganate process in tank farms with a retention time of up to 12 months. Previous testing was focused on developing a process for deployment in the ultrafiltration vessels in the Waste Treatment and Immobilization Plant. This environment is different from tank farms in two important ways: the waste is diluted in the Waste Treatment and Immobilization Plant to ~5.5 M sodium, whereas the supernate in the tank farms is ~9 M Na. Secondly, while the Waste Treatment and Immobilization Plant allows for a maximum treatment time of hours to days, the in-tank farms treatment of tanks 241-AN102 and 241-AN-107 will result in a retention time of months (perhaps up to12 months) before processing. A comparative compilation of separation processes for Sr/transuranics has been published as RPP-RPT-48340, Evaluation of Alternative Strontium and Transuranic Separation Processes. This report also listed the testing needs for the permanganate precipitation process to be field-deployable. A more comprehensive listing of future testing needs to allow the process to be field deployable are contained in RPP-PLAN-51288, Development Test Plan for Sr/TRU Precipitation Process.

Radiographic inspection of thinwall stainless steel piping welds can present difficulties and anomalies with regard to the achievement of radiographic sensitivity 1 . This paper describes a series of practical investigations which looked at the attained values of radiographic sensitivity when radiation type, film type and IQIs are varied on pipe butt welds ≤14 in O x ≤9.5 mm-thick. Results from the investigations show that improved radiographic sensitivity can be achieved when the radiation, film and IQI type are manipulated (in several combinations). Whilst it is recognised that a series of specific investigations such as these cannot be construed to be definitive, they serve as a reminder that the achievement of code-compliant radiographic sensitivity does not always guarantee the detection of important planar flaws.

Tuberous sclerosis (TSC) is a dominantly inherited disorder characterized by hamartomas and hamartias in one or more organs, most often in skin, brain, and kidneys. Analysis of the basic genetic defect in tuberous sclerosis would be greatly expedited by definitive determination of the chromosomal location of the TSC gene or genes. We have carried out genetic linkage studies in 15 TSC families, using 34 polymorphic markers including protein markers and DNA markers. Pairwise lod scores were calculated using LIPED, and multipoint analyses were carried out using MENDEL. In the pairwise linkage analysis, using a penetrance value of 90%, a significant positive lod score was obtained with MCT128.1 (D11S144), 11q22-11q23, Zmax 3.26 at theta = 0.08. The tyrosinase probe TYR (11q14-11q22) gave a maximum lod score of 2.88 at theta = 0. In the multipoint analyses the most likely order is (TYR,TSC)-MCT128.1-HHH172. Homogeneity analysis was carried out using the USERM9 subprogram of MENDEL, which conducts the admixture test of C. Smith (1963, Ann. Hum. Genet. 27: 175-182). This test provided no evidence for genetic heterogeneity (that is, non-11-linked families) in this data set.

A survey of district general hospitals in North West region shows a considerable reduction in paediatric activity over the past seven years. This raises training and staffing issues as doctors in DGHs will not be exposed to a variety of childhood conditions. At the same time, referrals to specialist centres have increased. The public should be involved in discussions about the best place to treat children.

Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.

Local cerebral glucose utilization was assessed during whisker stimulation by 2-deoxyglucose autoradiography. Whisker stimulation increased local cerebral glucose utilization in brainstem, thalamus and whisker sensory cortex in normal rats. Whereas whisker stimulation increased glucose metabolism in brainstem, whisker stimulation failed to increase glucose metabolism in thalamus of rats that had whisker sensory cortex ablated 5 h to five weeks previously. The failure of whisker stimulation to activate thalamus after cortical ablations was probably not due to decreased cortical input to thalamus because whisker stimulation activated thalamus after large cortical tetrodotoxin injections. Failure of whisker stimulation to activate thalamus at early times (5 h and one day) after cortical ablations was not due to thalamic neuronal death, since it takes days to weeks for axotomized thalamic neurons to die. The failure of whisker stimulation to activate thalamus at early times after cortical ablations was likely due to the failure of trigeminal brainstem neurons that project to thalamus to activate axotomized thalamic neurons. This might occur because of synaptic retraction, glial stripping or inhibition of trigeminal brainstem synapses onto thalamic neurons. The thalamic neuronal death that occurs over the days and weeks following cortical ablations was associated with thalamic hypometabolism. This is consistent with the idea that the thalamic neurons die because of the absence of a cortically derived trophic factor, since the excitotoxic thalamic cell death that occurs following cortical kainate injections is associated with thalamic hypermetabolism. The glucose metabolism of parts of the host thalamus was higher and the glucose metabolism in surrounding nuclei lower than the normal side of thalamus in rats that sat quietly and had fetal cortex transplants placed into cavities in whisker sensory cortex five to 16 weeks previously. Whisker stimulation in these subjects activated the contralateral host thalamus and fetal cortical transplants. This was accomplished using a double-label 2-deoxyglucose method to assess brain glucose metabolism in the same rat while it was resting and during whisker stimulation. The high glucose metabolism of parts of host thalamus ipsilateral to the fetal cortical transplants is consistent with prolonged survival of some axotomized thalamic neurons. The finding that whisker stimulation activates portions of host thalamus further suggests that the cortical transplants maintained survival of the host thalamic neurons and that synaptic connections between whisker brainstem and thalamic neurons were functional.

PATIENTS Case 1 Ten days prior to being seen a 65-year-old man suffered a Wallenberg stroke involving the lateral medulla. This left him with difficulty swallowing. Since that time he had been treated with intravenous fluids, and attempts at eating led to mild aspiration with pneumonia. In that period he lost 6% of his usual body weight and was continuing to lose weight. He felt weak and was able to ambulate only with difficulty, both because of his stroke-related ataxia and generalized weakness. On physical examination there was an obvious squared-off appearance to his shoulders from subcutaneous tissue and muscle wasting. There was no edema. Case 2 A 63-year-old man was admitted to the hospital for gastric resection of an obstructing gastric carcinoma. He was well until 6 weeks prior to admission when he began to notice the rapid onset of early satiety. This progressed to the point where he