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.

Acute respiratory distress syndrome secondary to antisynthetase syndrome is reversible with tacrolimus.

Polymyositis and interstitial lung diseases, predominantly nonspecific interstitial pneumonia (NSIP), are known to be frequent in antisynthetase syndrome, where anti-aminoacyl-tRNA synthetase antibodies are often identified. An unusual case of acute respiratory distress syndrome, secondary to such proven NSIP of cellular type with predominant CD8 lymphocytes, is described herein. The patient described in the present case study initially had a poor recovery with high dose of steroids, but this was followed by a good improvement after the prescription of tacrolimus and a low dose of prednisone. A precise diagnosis in similar circumstances may be life-saving, allowing the successful application of new immunosuppressants.

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.

Thymic factor-induced reduction of pulmonary metastases in mice with FSA-1 fibrosarcoma.

The biological activities of two thymic factors, serum thymic factor thymulin normally present in serum and thymosin alpha-1 (Ta-1) extracted from the thymus gland, have been studied. The effects of the factors on the growth of pulmonary metastases and survival of mice were evaluated in pathogen-free C3H/fSed males. Mice were injected i.v. with the single cell suspension of the syngeneic methylcholanthrene-induced fibrosarcoma. The treatment with thymulin and Ta-1 started two days after injection of 5 x 10(4) to 2 x 10(5) tumor cells per mouse. Different doses of the thymic factors were administered S.C. in sets of 5 daily injections through a period of 2 or 3 weeks. Numbers of tumor colonies in the lung were determined two weeks after the cell injection. Treatment with 0.1 micrograms Ta-1 per injection through the period of two or three weeks, prolonged the survival of tumor-injected mice. Similar effects were observed in mice treated with 0.01 microgram thymulin per injection. Numbers of tumor colonies in lungs of these mice two weeks after the cell injection were also reduced in comparison with saline-treated controls. These findings correlated with prolonged survival time of identically treated mice. The effectiveness of thymic factors in reducing tumor growth was dependent on the tumour load. In addition, the effects induced by Ta-1 persisted longer than observed in thymulin-treated mice. Mice challenged 150 days after the primary tumor cell injection and treatment with Ta-1 demonstrated increased resistance to tumor, while mice treated with other factors behaved as saline-treated controls. The results indicate that both factors exert beneficial effects against tumor growth, although mode of action for each factor may be different.

CD103+ intraepithelial lymphocytes--a unique population in microsatellite unstable sporadic colorectal cancer.

Colorectal cancers with microsatellite instability (MSI) typically show increased numbers of intraepithelial lymphocytes (IEL) in comparison to microsatellite stable (MSS) cancers. The aim of this study was to determine the phenotype of this unique lymphocyte population in MSI and MSS colorectal cancers. Twenty-four individuals with sporadic colorectal cancer (17 MSI, 7 MSS) were included in this study. Intraepithelial and stromal lymphocytes were detected using immunohistochemistry with anti-CD8 and anti-CD103 antibodies, and two observers independently quantified the numbers of lymphocytes. CD103+ (alpha E beta 7+) IELs detected within tumour tissue co-expressed CD8+ while the stromal lymphocytes were phenotypically heterogeneous, with respect to CD8+ and CD103+ expression. MSI colorectal cancers harboured increased numbers of CD8+ CD103+ IELs, as well as CD8+ CD103- and CD8+ CD103+ stromal lymphocytes, when compared with MSS colorectal cancers. CD103+ IELs were found at 27-fold greater numbers in the tumour epithelium than in normal epithelium from the same patient (P = 0.001, Wilcoxon matched pairs test). From our findings, we have proposed a mechanism for the homing of these alpha E beta 7+ lymphocytes to tumour tissue in MSI and MSS colorectal cancers.

Electroencephalographic abnormalities in interferon encephalopathy: a preliminary report.

Although several studies have shown that interferon does not readily cross the blood-brain barrier, recent reports have described central nervous system effects in patients receiving interferon. At our institution, we encountered three patients who had symptoms of toxicity of the central nervous system (somnolence, confusion, and gait difficulties) in association with electroencephalographic abnormalities while receiving alpha 2-interferon therapy for multiple myeloma. The electroencephalogram showed diffuse slow-wave abnormalities in two of the patients and generalized sharp-wave discharges in the third patient. Because the use of interferon is increasing, physicians should be aware of the central nervous system complications and the electroencephalographic changes that can be associated with such therapy.

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.

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.

Bronchial adenoma: a review of 51 patients.

The cases of 51 patients with bronchial adenomas were reviewed. There were 43 bronchial carcinoids, 5 adenoid cystic carcinomas, 2 mixed tumors, and 1 mucoepidermoid carcinoma. The carcinoid group was divided into typical (31, 72%) and atypical (12, 28%) subgroups. Nine carcinoids (20%) were categorized as metastasizing adenomas; in this group, 7 lesions were atypical and 2 were typical. Thirty-two lobectomies, 7 bilobectomies, 8 pneumonectomies, 2 sleeve resections, and 2 tracheal resections were performed. Ten-year survival was 88% for patients with typical carcinoids and 59% for those with atypical carcinoids. In the group with adenoid cystic carcinoma, 1 patient died postoperatively, 1 had recurrence of the tumor, 2 were alive and free from disease 16 and 23 years later, and 1 died of heart disease at 11 years. The patient with mucoepidermoid carcinoma was alive without recurrence 15 years after operation. In conclusion, bronchial adenomas of the carcinoid type are potentially malignant. Their prognosis depends on the histology of the tumor, and on the presence of metastasis to the regional lymph nodes and distant organs.

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)

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.

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.

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.

Maternal and infant nutrition recommendations: a review.

New knowledge of maternal and infant nutrition has resulted in several changes within the past decade. Major changes in recommendations for maternal and infant nutrition have been highlighted. These recommendations are important to update dietitians, extension nutritionists, home economists, nurses, and other health professionals and paraprofessionals on the current maternal and infant nutrition recommendations.

Tympanometry in the evaluation of vascular lesions of the middle ear and tinnitus of vascular origin.

The occurrence of vascular perturbations in the tympanogram in association with glomus tumors has previously been noted in the literature. We have broadened the scope of this method of diagnosis in the study of 3 glomus tympanicum and 3 glomus jugulare tumors, 1 dehiscent high jugular bulb, 1 aberrant carotid artery in the middle ear and 2 cases of pulsatile tinnitus of vascular origin. Analysis of illustrative tympanograms at standard and at increased sensitivity (x 20) obtained in these cases are presented. The following factors as they relate to the mechanism of recording the vascular perturbations are presented: air pressure and/or presence of fluid in the middle ear; compliance of the tympanic membrane and ossicular chain as affected by the mass, size and degree of vascularity of the mass and presence of extraneous sounds. A new method of recording the vascular perturbations utilizing a time-base generator affixed to an X-Y plotter is described. It is the purpose of this study to demonstrate the utility of obtaining tympanograms at standard and at increased sensitivity in the evaluation of vascular middle ear lesions and tinnitus of vascular origin.

Nystagmus responses to water and air caloric stimulation in clinical populations.

The nystagmus responses of two groups of patients referred for electronystagraphy were compared to test for differences between air and water caloric stimulation. Responses from patients with spontaneous or positional nystagmus or who showed greater than 30% directional preponderance or excitability of labyrinth were removed from the data. The 30 degree C and 44 degree C water and the 24 degree C air produced equivalent responses. The 50 degree C air produced responses with slow component velocities greater than expected; however, the distributions of computed directional preponderance and excitability of labyrinth showed no differences between the air and water caloric stimulation.

The effects of carbocisplatin and radiation on skin flap survival.

Carbocisplatin is used as an inductive chemotherapeutic agent prior to irradiation in the treatment of head and neck cancers. Controversy exists whether carbocisplatin sensitizes normal epithelial tissues, including skin, to radiation. The combined effect of radiation and carbocisplatin on the survival of skin flaps was studied in an experimental model using dorsal flaps in Sprague-Dawley rats. Skin flaps were created 6 weeks after exposure to irradiation and carbocisplatin. Flap survival was assessed 7, 14, and 21 days after the flaps were initially created. Exposure of the flaps to irradiation alone, carbocisplatin alone, combined irradiation and carbocisplatin, or combined irradiation and fractionated carbocisplatin did not result in any significant decrease in flap survival when compared with untreated animals.

Suppression of cellular immunity by head and neck irradiation. Precipitating factors and reparative mechanisms in an experimental model.

A model was developed in C3H mice to investigate the immunosuppressive effects of head and neck irradiation and to explore mechanisms for repair of the defects. Mice receiving 1200 rad (12 Gy) of head and neck irradiation showed significant depression of delayed-type hypersensitivity, peripheral blood lymphocyte counts, spleen cell counts, and spleen cell production of interleukin-2. Treatment with optimal dosages of thymosin alpha 1 (T alpha-1) produced significant increases in all of these values, in some instances to levels higher than in the nonirradiated controls. In identical experiments with mice irradiated to a portal limited to the pelvic region, T alpha-1 induced only partial remission of the abnormalities. The dose response of T alpha-1 with head and neck irradiation showed a relatively limited dose range for immune restoration, a finding that warrants similar determinations in clinical trials with immunomodulating agents. The results suggest a potential clinical usefulness of T alpha-1 and also interleukin-2 in restoring cellular immunity after irradiation for head and neck cancers. The model appears to be useful for investigating immunomodulating agents before they are clinically evaluated as adjuvants with head and neck irradiation regimens.

Effects of radiation therapy on T-lymphocyte subpopulations in patients with head and neck cancer.

Cellular immunity was assessed in 85 patients with head and neck cancer with monoclonal antibodies to lymphocyte surface antigens that identify total T cells, helper cells, and suppressor cells. The control group consisted of 22 healthy volunteers. Nine patients who had surgical procedures for benign diseases were also studied. Compared with the controls, the patients with cancer who received radiation therapy had a significant decrease in total lymphocytes, T cells, helper cells, suppressor cells, and decreased helper/suppressor cell ratio. Significant decreases in lymphocyte subpopulations were not detected in patients tested before treatment or in patients treated with surgery alone. The immune deficits observed were prolonged in duration, with some present in the patients studied up to 11 years after radiation therapy. This long-lasting immune depression may have relevance to tumor recurrences and second primaries in patients with head and neck cancer treated by radiation therapy and to attempts at increasing cure rates with adjuvant agents that improve immune reactivity.