Maternal obesity heritably perturbs offspring metabolism for three generations without serial programming.

Maternal obesity can program offspring metabolism across multiple generations. It is not known whether multigenerational effects reflect true inheritance of the induced phenotype, or are due to serial propagation of the phenotype through repeated exposure to a compromised gestational milieu. Here we sought to distinguish these possibilities, using the Avy mouse model of maternal obesity. In this model, F1 sons of obese dams display a predisposition to hepatic insulin resistance, which remains latent unless the offspring are challenged with a Western diet. We find that F2 grandsons and F3 great grandsons of obese dams also carry the latent predisposition to metabolic dysfunction, but remain metabolically normal on a healthy diet. Given that the breeding animals giving rise to F2 and F3 were maintained on a healthy diet, the latency of the phenotype permits exclusion of serial programming; we also confirmed that F1 females remained metabolically healthy during pregnancy. Molecular analyses of male descendants identified upregulation of hepatic Apoa4 as a consistent signature of the latent phenotype across all generations. Our results exclude serial programming as a factor in transmission of the metabolic phenotype induced by ancestral maternal obesity, and indicate inheritance through the germline, probably via some form of epigenetic inheritance.

Loss of Rearranged L-Myc Fusion (RLF) results in defects in heart development in the mouse.

Recently we reported that Rearranged L-Myc Fusion, RLF, acts as an epigenetic modifier maintaining low levels of DNA methylation at CpG island shores and enhancers across the genome. Here we focus on the phenotype of Rlf null mutant mice generated via an ENU mutagenesis screen, to identify genes required for epigenetic regulation. RLF is expressed in a range of fetal mouse tissues, including the fetal heart. Comprehensive timed-mating studies are consistent with our previously reported findings that Rlf homozygous mutant mice rarely survive to adulthood, with the majority dying shortly after birth. Histological analysis of two independent Rlf ENU mutant lines at E11.5-E14.5 showed heart defects resembling those present in humans with Left Ventricular Non-Compaction (LVNC). In situ hybridisation analysis localized expression of Rlf to the endocardium and epicardium of embryonic and postnatal hearts, and transiently to cardiomyocytes during heart looping and early chamber formation stages. RNA-seq analysis of Rlf mutant hearts highlighted defective NOTCH pathway signalling, recently describe as one cause of LVNC. This study provides the first evidence that RLF is required for normal heart development in the mouse. The heart morphological defects present at high penetrance in Rlf mutants are consistent with features of LVNC in humans, and molecular analysis identified attenuated JAGGED 1 expression and NOTCH signalling as likely contributors to these defects. Our study highlights the importance of RLF-dependent epigenetic modifications to DNA for maintaining correct gene regulatory network and intercellular signalling interactions during heart chamber and septal development. Further investigations are needed to define the biochemical role of RLF in the developing heart, and whether RLF mutations are a cause of heart defects in humans.

Modeling and analysis of repeat RNA toxicity in Drosophila.

Expansion of repeat sequences beyond a pathogenic threshold is the cause of a series of dominantly inherited neurodegenerative diseases that includes Huntington's disease, several spinocerebellar ataxias, and myotonic dystrophy types 1 and 2. Expansion of repeat sequences occurring in coding regions of various genes frequently produces an expanded polyglutamine tract that is thought to result in a toxic protein. However, in a number of diseases that present with similar clinical symptoms, the expansions occur in untranslated regions of the gene that cannot encode toxic peptide products. As expanded repeat-containing RNA is common to both translated and untranslated repeat expansion diseases, this repeat RNA is hypothesized as a potential common toxic agent.We have established Drosophila models for expanded repeat diseases in order to investigate the role of multiple candidate toxic agents and the potential molecular pathways that lead to pathogenesis. In this chapter we describe methods to identify candidate pathogenic pathways and their constituent steps. This includes establishing novel phenotypes using Drosophila and developing methods for using this system to screen for possible modifiers of pathology. Additionally, we describe a method for quantifying progressive neurodegeneration using a motor functional assay as well as small RNA profiling techniques, which are useful in identifying RNA intermediates of pathogenesis that can then be used to validate potential pathogenic pathways in humans.

Maternal undernutrition during the first week after conception results in decreased expression of glucocorticoid receptor mRNA in the absence of GR exon 17 hypermethylation in the fetal pituitary in late gestation.

Exposure to maternal undernutrition during the periconceptional period results in an earlier prepartum activation of the fetal hypothalamo-pituitary-adrenal (HPA) axis and altered stress responsiveness in the offspring. It is not known whether such changes are a consequence of exposure of the oocyte and/or the early embryo to maternal undernutrition in the periconceptional period. We have compared the effects of 'periconceptional' undernutrition (PCUN: maternal undernutrition imposed from at least 45 days before until 6 days after conception), and 'early preimplantation' undernutrition (PIUN: maternal undernutrition imposed for only 6 days after conception) on the expression of genes in the fetal anterior pituitary that regulate adrenal growth and steroidogenesis, proopiomelanorcortin (POMC), prohormone convertase 1 (PC1), 11ß-hydroxysteroid dehydrogenase type 1 and 2 (11ßHSD1 and 2) and the glucocorticoid receptor (GR) in fetal sheep at 136-138 days of gestation. Pituitary GR mRNA expression was significantly lower in the PCUN and PIUN groups in both singletons and twins compared with controls, although this suppression of GR expression was not associated with hypermethylation of the exon 17 region of the GR gene. In twin fetuses, the pituitary 11ßHSD1 mRNA expression was significantly higher in the PIUN group compared with the PCUN but not the control group. Thus, exposure of the single or twin embryo to maternal undernutrition for only 1 week after conception is sufficient to cause a suppression of the pituitary GR expression in late gestation. These changes may contribute to the increased stress responsiveness of the HPA axis in the offspring after exposure to poor nutrition during the periconceptional period.

Periconceptional nutrition and the early programming of a life of obesity or adversity.

Women entering pregnancy with a high body weight and fat mass have babies at increased risk of becoming overweight or obese in childhood and later life. It is not known, whether exposure to a high level of maternal nutrition before pregnancy and exposure to a high transplacental nutrient supply in later pregnancy act through similar mechanisms to program later obesity. Using the pregnant sheep we have shown that maternal overnutrition in late pregnancy results in an upregulation of PPARγ activated genes in fetal visceral fat and a subsequent increase in the mass of subcutaneous fat in the postnatal lamb. Exposure to maternal overnutrition during the periconceptional period alone, however, results in an increase in total body fat mass in female lambs only with a dominant effect on visceral fat depots. Thus the early programming of later obesity may result from 'two hits', the first occurring as a result of maternal overnutrition during the periconceptional period and the second occurring as a result of increased fetal nutrition in late pregnancy. Whilst a short period of dietary restriction during the periconceptional period reverses the impact of periconceptional overnutrition on the programming of obesity, it also results in an increased lamb adrenal weight and cortisol stress response, together with changes in the epigenetic state of the insulin like growth factor 2 (IGF2) gene in the adrenal. Thus, not all of the effects of dietary restriction in overweight or obese mother in the periconceptional period may be beneficial in the longer term.

CpG island methylation is a common finding in colorectal cancer cell lines.

Tumour cell lines are commonly used in colorectal cancer (CRC) research, including studies designed to assess methylation defects. Although many of the known genetic aberrations in CRC cell lines have been comprehensively described, no studies have been performed on their methylation status. In this study, 30 commonly used CRC cell lines as well as seven primary tumours from individuals with hereditary nonpolyposis colorectal cancer (HNPCC) were assessed for methylation at six CpG islands known to be hypermethylated in colorectal cancer: hMLH1, p16, methylated in tumour (MINT-)-1, -2, -12 and -31. The cell lines were also assessed for microsatellite instability (MSI), ploidy status, hMLH1 expression, and mutations in APC and Ki-ras. Methylation was frequently observed at all examined loci in most cell lines, and no differences were observed between germline-derived and sporadic cell lines. Methylation was found at MINT 1 in 63%, MINT 2 in 57%, MINT 12 in 71%, MINT 31 in 53%, p16 in 71%, and hMLH1 in 30% of cell lines. Overall only one cell line, SW1417, did not show methylation at any locus. Methylation was found with equal frequency in MSI and chromosomally unstable lines. MSI was over-represented in the cell lines relative to sporadic CRC, being detected in 47% of cell lines. The rate of codon 13 Ki-ras mutations was also over three times that expected from in vivo studies. We conclude that CpG island hypermethylation, whether acquired in vivo or in culture, is a ubiquitous phenomenon in CRC cell lines. We suggest that CRC cell lines may be only representative of a small subset of real tumours, and this should be taken into account in the use of CRC cell lines for epigenetic studies.

Identification and characterisation of a platelet GPIb/V/IX-like complex on human breast cancers: implications for the metastatic process.

The glycoprotein (GP) Ib /V/IX receptor complex is an important adhesion molecule, originally thought to be unique to the megakaryocytic lineage. Recent evidence now indicates that GPIb /V/IX may be more widely expressed. In this study we report the presence of all subunits of the complex on four breast cancer cell lines, and 51 / 80 primary breast tumours. The surface expression of GPIb /V/IX was confirmed by flow cytometry, and by immunoprecipitation of biotin surface-labelled tumour cells. Western blotting of cell lysates under reducing conditions revealed that tumour cell-GPIb alpha had a relative molecular weight of 95 kDa as compared to 135 kDa on platelets. Despite the discrepant protein size, molecular analyses on the tumour cell-GPIb alpha subunit using RT-PCR and DNA sequencing revealed 100% sequence homology to platelet GPIb alpha. Tumour cell-GPIb /V/IX was capable of binding human von Willebrand factor (vWf), and this binding caused aggregation of tumour cells in suspension. Tumour cells bound to immobilised vWf in the presence of EDTA and demonstrated prominent filapodial extensions indicative of cytoskeletal reorganisation. Furthermore, in a modified Boyden chamber assay, prior exposure to vWf or a GPIb alpha monoclonal antibody, AK2, enhanced cell migration. The presence of a functional GPIb /V/IX-like complex in tumour cells suggests that this complex may participate in the process of haematogenous breast cancer metastasis.

Superior sulcus (Pancoast) tumor: experience with 105 patients.

BACKGROUND: The evolution of therapy in 105 patients with superior sulcus (Pancoast) tumor over the past 42 years was reviewed. METHODS: There were 82 men and 23 women aged 30 to 75 years. Tumor cell types were: squamous, 41 (39%); adenocarcinoma, 23 (21.9%); anaplastic, 14 (13.3%); undetermined, 12 (11.4%); mixed, 9 (8.7%); and large cell 6 (5.7%). Therapy was based on extent of disease and lymph node involvement. There were 5 treatment groups: I, preoperative radiation and operation (n = 28); II, operation and postoperative radiation (n = 16); III, radiation (n = 37); IV, preoperative chemotherapy, radiation, and operation (n = 11); and V, operation (n = 12). RESULTS: The median survival for group I was 21.6 months; group II, 6.9 months; group III, 6 months; and group V, 36.7 months. Median survival for group IV has not yet been reached (estimated at 72% at 5 years). On univariate analysis, mediastinal lymph node involvement, Horner syndrome, TNM classification, and method of therapy affected survival. On multivariate regression analysis, only N2 and N3 disease and method of therapy were significant (p < 0.05). CONCLUSIONS: The optimal treatment for superior sulcus tumor was preoperative radiation and operation. However, triple modality therapy, although promising, requires longer follow-up.

Adjuvant immunotherapy in melanoma with irradiated autologous tumor cells and low dose cyclophosphamide.

BACKGROUND: Patients with metastatic melanoma to their regional lymph nodes have a poor prognosis despite lymphadenectomy. In an attempt to improve their survival, this feasibility study was undertaken. METHODS: Twenty-two melanoma patients, who presented with enlarged regional lymph nodes, underwent therapeutic lymphadenectomy. They were found to have N2 nodal disease, with no evidence of distant metastases, i.e., advanced Stage III disease. One month after the lymphadenectomy, each patient received five autologous tumor vaccines. Each vaccine consisted of 20 x 10(6) irradiated autologous tumor cells (20,000 cGy) injected intradermally. The first two vaccines contained BCG and were given 1 week apart. The other three vaccines consisted of irradiated tumor cells only without BCG, administered over 2-, 4-, and 8- week intervals, respectively. Cyclophosphamide was administered intravenously as 300 mgm/m2 3 days prior to vaccines 1, 4, and 5 to reduce the population of T-suppressor cells. The patients were observed with no additional therapy. Three patients developed recurrences and these site were resected, and the patients were revaccinated in the same fashion utilizing the new tumor cells. RESULTS: After a follow-up of 4-6 years, 15 patients (including 3 who were revaccinated) of the initial 22 patients (68.2%) are alive free of disease. CONCLUSIONS: Adjuvant immunotherapy with irradiated autologous melanoma cells and low dose cyclophosphamide seemed to yield better relapse-free survival than the historically reported 10-25%.

The behaviour of healthy awake cats following intravenous and intramuscular administration of midazolam.

The onset of action and behavioural effects following intravenous (i.v.) and intramuscular (i.m.) administration of 0.05, 0.5, 1.0, 2.0 and 5.0 mg/kg of midazolam were studied for 2 h in 20 awake, healthy cats. All cats, except one that received 0.05 mg/kg i.m., showed effects of the drug, whereas no effects were observed in cats administered only the vehicle in which midazolam was dissolved. The onset of action was rapid following both i.v. and i.m. administration, some cats became ataxic, while others assumed positions of sternal or lateral recumbency. Even after administration of the highest dose (5.0 mg/kg), anaesthesia was not induced, with swallowing reflexes and conscious perception of a clamp placed on the tail still present in all cats. An abnormal arousal state was observed in many cats after administration of midazolam. During the first hour, restlessness was more commonly observed, while from 1 to 2 h, sedation was more prominent in cats that received the highest dose. Ataxia occurred in all but one cat, was short-lived in cats that received the lower doses, but still present at 2 h in all cats that received 2.0 and 5.0 mg/kg. Midazolam caused some of the cats to behave differently when approached and restrained compared with behavioural patterns identified prior to administration of the drug. The cats were more likely to behave abnormally following i.v. administration rather than i.m. administration and, for the most part, abnormal behaviour was equally distributed between the two extremes; cats being easier to approach and restrain and cats being more difficult to approach and restrain. Food consumption increased significantly, during the 2 h period, following all i.m. doses and all but the highest (5.0 mg/kg) i.v. dose, with most of the food being consumed in the first hour after administration.

The effect of intravenous administration of variable-dose midazolam after fixed-dose ketamine in healthy awake cats.

The effects of intravenous administration of variable-dose midazolam and ketamine (3 mg/kg) were studied in twelve healthy unmedicated cats from time of administration until full recovery. A range of midazolam doses (0.0, 0.05, 0.5, 1.0, 2.0 and 5.0 mg/kg) was chosen, so that beneficial and/or detrimental effects could be documented and the therapeutic window for further study determined. One minute after administration of ketamine, all cats had assumed a lateral position, mostly with head up. Muscle tone was increased (100%), apneustic breathing pattern evident in 92% of cats, chewing without stimulation of the oropharyngeal area was observed in most cats (97%), but most cats did not salivate (87%). At 2.5 min after completion of ketamine injection and 1 min after administration of saline, a similar picture was observed, except that salivation was evident. All cats chewed or swallowed in response to a finger or laryngoscope placed in the oropharyngeal area and, while most cats were not aware of a noxious stimulus to the tail, some cats were aware of a noxious stimulus to the paw. Recovery from ketamine alone was rapid and smooth with cats rolling into sternal recumbency and then cautiously walking with ataxia. Recovery to walking without incoordination was also rapid (< 2 h) and no abnormal behavioural patterns were observed during recovery. Administration of midazolam after ketamine, had beneficial effects and the therapeutic window for midazolam was found to lie between 0.05 mg/kg and 0.5 mg/kg. Administration of any dose of midazolam after ketamine caused a greater proportion of cats to assume a laterally recumbent position with head down compared with ketamine alone, however, the time period of recumbency was only significantly longer with a midazolam dose of 2.0 mg/kg or above. Doses of midazolam of 0.5 mg/kg or above decreased muscle rigidity but did not affect salivation or respiratory pattern observed in cats which received ketamine alone. A significantly greater proportion of cats which received ketamine and midazolam 0.5 mg/kg or above did not swallow in response to a finger or a laryngoscope placed in the mouth compared with that which received ketamine alone. The length of time in which cats did not swallow was only significantly longer at midazolam doses of 1.0 mg/kg and above. At midazolam doses of 0.5 mg/kg or above, the proportion of cats without a nociceptive response to a tail or paw clamp was significantly greater than cats which received ketamine alone. The time period without nociceptive response, however, was not influenced by midazolam administration. The time taken for cats which received ketamine and midazolam 0.05 mg/kg or 0.5 mg/kg to assume sternal position, walk with ataxia, walk without ataxia, behave normally when approached or restrained and recover normal arousal state was not significantly different from cats which received ketamine alone. Ketamine and midazolam 5.0 mg/kg significantly prolonged all recovery times compared with ketamine alone. Unfortunately, a greater proportion of cats which received ketamine and midazolam 0.5 or 5.0 mg/kg exhibited detrimental behavioural effects. These were more likely to be adverse and included restlessness, vocalization and difficulty approaching and restraining cats. In this study, an effect of sex of the cats was found, with male cats taking a significantly longer to recover to sternal recumbency and walk with ataxia, while female cats took longer to recover to a normal arousal state.

Survival differences between black and white women with breast cancer.

Several reports have indicated that black women with breast cancer have a poorer prognosis than white women. To investigate this phenomenon and to identify some of the underlying reasons, 172 patients with infiltrating ductal carcinoma of the breast, who were managed similarly, were studied. Survival analysis comparing the two populations with breast cancer revealed that white women had significantly longer overall survival (OS), P = 0.015 by Wilcoxon and 0.019 by log-rank, and borderline significantly longer disease-free survival (DFS), P = 0.04 by Wilcoxon and 0.07 by log-rank. While there was no significant difference in OS and DFS between the two groups with negative nodes, significantly poorer DFS and OS was noted in black patients with one to three positive lymph nodes compared to white patients, P = 0.008. The white patients had a higher incidence of hormone receptor-positive tumors, especially progesterone receptor (P = 0.0016). However, survival analysis failed to show any difference between the black and the white populations based on hormonal receptors. Such findings suggested that further investigation of other factor(s) is warranted.

Paravertebral thoracolumbar anaesthesia in 10 horses.

The caudal border of the last rib was used as a reliable point of orientation while performing paravertebral thoracolumbar anaesthesia (PTLA) on 10 horses undergoing standing flank laparotomy. The local anaesthetic in all horses was 2% lidocaine. The PTLA procedure was completed in 9.8 +/- 1.8 mins (mean +/- sd). Sedation was provided by a combination of intravenous morphine with xylazine or detomidine. Overall analgesia, provided by the combination of PTLA and sedation, was rated as excellent in 2 horses and good in 6 horses. In the remaining 2 horses, overall analgesia was rated as fair because of incomplete analgesia at the ventral portion of the incision. Total time, from start of PTLA to end of surgery was 143.5 +/- 24.2 mins. Five horses responded mildly to suturing of the ventral portion of the incision. Apart from 1 horse which developed transient, unilateral hindlimb weakness intraoperatively, no other complications were noticed. We conclude that PTLA can easily be performed in the horse and, combined with systemic sedation, is an effective and safe method of providing analgesia for standing flank laparotomy.

Penetrating cardiac injuries.

One hundred nine penetrating cardiac injuries were reviewed: 49 gunshot wounds and 60 stab wounds. They were classified into four groups: group 1 (lifeless), 38; group 2 (agonal), 16; group 3 (shock), 33; and group 4 (stable), 22. Thirty-six patients in group 1 (94%) and 8 of 16 patients in group 2 (50%) underwent emergency room thoracotomy; 24 of 33 in group 3 (73%) and 20 of 22 (90%) underwent thoracotomy in the operating room. Twenty-one (38%) of 55 patients undergoing emergency room thoracotomy survived, whereas 47 (87%) of 54 patients undergoing operating room thoracotomy survived. Survival was 12 of 38 (31%) in group 1, 11 of 16 (69%) in group 2, 26 of 33 (79%) in group 3, and 18 of 22 (82%) in group 4 with an overall survival of 67 of 109 (61%). Gunshot wounds of the heart portend a worse prognosis than stab wounds. Survival of gunshot wounds was 20 of 49 (40%) compared with 47 survivors of 60 stab wounds (78%). Aggressive treatment, including emergency room thoracotomy, is justified for lifeless and deteriorating cardiac injury victims.

Esophageal perforation: a therapeutic challenge.

The records of 64 patients with esophageal perforation treated since 1958 were reviewed. There were 19 cervical perforations, 44 thoracic perforations, and one abdominal perforation. Thirty-one perforations (48%) were due to injury from intraluminal causes. Twenty (31%) resulted from extraluminal causes: penetrating wounds, 11; blunt trauma, 3; and paraesophageal operations, 6. Eleven (17%) were spontaneous perforations, and two (3%) were caused by perforation of an esophageal malignancy. Ten (91%) of 11 patients with cervical perforations treated less than 24 hours after injury survived compared with 6 (75%) of 8 patients treated more than 24 hours after injury; hence 16 (84%) of the 19 patients in the cervical group survived. In the thoracic group, 19 patients were treated within 24 hours with 16 survivors (84%) compared with 25 patients treated beyond 24 hours with 12 survivors (48%); hence 28 (64%) of the 44 patients in the thoracic group survived. The patient with an abdominal perforation survived. Thirty patients underwent primary suture closure of the perforation, and 25 (83%) lived. Seventeen patients had drainage, and 10 (59%) lived. Total esophagectomy was performed in 9 patients, 7 (78%) of whom survived. Exclusion-diversion procedures were performed in 5 patients, and 1 (20%) survived.

Flow cytometric DNA analysis of primary and concurrent metastatic squamous cell carcinoma of the head and neck.

Adequate flow cytometric DNA analysis comparing primary and concurrent metastatic squamous cell carcinoma of the head and neck has not been done in the past. The purpose of this study was to define any differences between the primary and concurrent metastasis of each patient with respect to flow cytometric parameters and histologic grade. Paraffin-embedded archival specimens from 28 patients with primary and metastatic tumors were prepared into nuclei and analyzed by flow cytometry using human lymphocyte standards. The mean DNA index was 0.82 for primary tumors and 0.83 for the metastases. Aneuploidy was found in 68 percent of primary tumors and in 82 percent of metastases. The percentage of cells in the proliferative fraction was 40.4 in the primary tumors and 24.5 in the metastases. A direct correlation was found between the differentiation of the primary and metastatic tumors. No survival difference was discovered among the flow cytometric parameters and histologic grade. We conclude that there is no difference between the primary and concurrent metastasis in squamous cell carcinoma of the head and neck with regard to DNA index, aneuploidy, or histologic grade.

Prognostic factors in squamous cell carcinoma of the larynx.

One hundred fifty-two patients with squamous cell carcinoma of the larynx were studied. The disease-free survival and overall survival rates were correlated to 12 variables. Seven of them seemed to affect survival. Poor prognosis was related to (1) advanced stage of disease at diagnosis, (2) cord fixation and massive local invasion, (3) ulceration of the primary tumor, (4) lymph node metastases at diagnosis, (5) glottic lesions had a poorer prognosis than supraglottic ones, (6) locoregional recurrences, and (7) male gender. However, most of these significant differences were in disease-free survival, and only primary tumor staging; lymph node status; and locoregional recurrences affected overall survival. On the other hand, the other five variables showed no effect on either disease-free or overall survival rates. These included age, race, cell differentiation, type of recurrence, and the initial definitive therapeutic modality.

Risk factors before hepatectomy, hepatic function after hepatectomy and computed tomographic changes as indicators of mortality from hepatic failure.

The mortality rate from hepatic failure after extensive resection should be negligible in the presence of normal results from preoperative liver function tests in patients without pre-existing hepatitis and cirrhosis. Despite conventionally acceptable results from preoperative hepatic function tests in 56 patients undergoing extensive hepatic resection for tumours (47 metastatic, six hepatomas and three adenomas), however, five patients died of hepatic failure. Among the many preoperative and intraoperative risk factors studied, the important factors in the group with hepatic failure were very high levels of serum alkaline phosphatase (p less than 0.05) in the presence of normal levels of bilirubin and large tumor, preoperative administration of chemotherapy, the presence of hepatomas rather than metastatic carcinoma (p = 0.083) and intraoperative blood loss of greater than 5,000 milliliters (p = 0.03). The patients receiving preoperative chemotherapy or those with hepatoma showed a minimal rise of alkaline phosphatase (p less than 0.03) and a minimal regeneration of liver on computed tomographic (CT) scan after hepatic resection. In the group with hepatic failure, a consistent postoperative pattern of increasing bilirubin with normal or subnormal alkaline phosphatase levels corresponded with lack of regeneration of liver on repeated CT scans. Conversely, the pattern of decreasing bilirubin with reciprocal increase in alkaline phosphatase corresponded with hepatic regeneration on CT scan in the group of survivors. Thus, we observe that alkaline phosphatase is a good indicator of hepatic regeneration in the absence of jaundice in patients after hepatectomy. To avoid postoperative hepatic failure, we recommend more discriminant tests than conventional hepatic function tests in patients with large tumors associated with high alkaline phosphatase levels, preoperative chemotherapy and hepatoma even without pre-existing cirrhosis or hepatitis.

Carcinoma of the esophagus: a comparison of the results of transhiatal versus transthoracic resection.

The cases of 78 patients with primary esophageal carcinoma treated from 1977 to mid-1987 were retrospectively analyzed. Fifty-two of the patients underwent transthoracic esophagogastrectomy (TTE) and 26, transhiatal esophagectomy (THE). The two groups were statistically similar in preoperative characteristics except that more of the THE group had received chemotherapy; this group had relatively more tumors of the upper esophagus; and 20 (77%) of the THE group, compared with 50 (96%) of the TTE group, had tumors in stages III and IV. The incidence of major postoperative complications did not differ significantly between the two groups. There were five (19%) anastomotic leaks in the THE group, but only one led to a prolongation of hospital stay by more than 14 days, whereas all three (6%) of the leaks in the TTE group caused hospital stay to be prolonged several weeks. Overall morbidity was high: 75% (39/52) for the TTE patients and 85% (22/26) for the THE patients (p greater than 0.10). Hospital mortality was 6% (3/52) in the TTE group and 8% (2/26) in the THE patients (p greater than 0.10). There was no significant difference in actuarial survival either between the two groups as a whole or between those patients in each group who had stage III or IV tumors. We conclude that THE, among the types of patients for whom we used the procedure, provides long-term survival comparable with that provided by TTE without causing a significant increase in hospital mortality or morbidity.(ABSTRACT TRUNCATED AT 250 WORDS)

Neonatal deafening alters nonpyramidal dendrite orientation in auditory cortex: a computer microscope study in the rabbit.

In order to examine the influence of afferent input on nonpyramidal dendrite development in the auditory cortex, unilateral deafening was carried out in neonatal rabbits at birth, approximately 6 days prior to the onset of hearing. Deafening was produced by surgical removal of the incus and stapes ossicles, aspiration of the cochlear perilymph, and kanamycin injection into the oval window. At 60 days of age, acoustic stimulation of the deafened ear was unable to evoke auditory brainstem responses. The brains of experimental and littermate control rabbits were processed according to the Golgi-Cox Nissl method. The dendritic systems of lamina III/IV spine-free nonpyramidal cells in the auditory cortex contralateral to the deafened ear were digitized from 340-micron-thick coronal sections with the aid of a computer microscope. Three-dimensional spatial and statistical analyses revealed that nonpyramidal dendrite length in neonatally deafened rabbits increased 27% relative to littermate controls. A fan-in projection analysis revealed that the increased dendrite length in the deafened animals was maximum in the tangential direction and toward the white matter. Computer rotation of digitized neurons from neonatally deafened rabbits also revealed evidence of abnormal dendritic growth in the form of recurved dendrites. We interpret our results to indicate that unilateral cochlear destruction early in development causes a reorganization of the ascending auditory pathway which extends to the contralateral cerebral cortex. Because the auditory cortex contralateral to the deafened ear still receives acoustic input from the undamaged ipsilateral ear, normal nonpyramidal dendritic growth in the auditory cortex is, in part, dependent upon afferent activity arising from both ears.