Cyr61 protects against hyperoxia-induced cell death via Akt pathway in pulmonary epithelial cells

We have used gene expression profiling approaches to identify new molecular targets in various models of lung injury and human lung diseases. Among the many genes that are significantly induced in these studies, cysteine-rich61 (Cyr61) consistently ranks as one of the most significant genes. Here, we use the well-established model of hyperoxia to better understand the function of Cyr61 in acute lung injury. Cyr61, a stress-related immediate-early response gene, has known diverse functions involving angiogenesis, tumorigenesis, and wound repair. It belongs to the newly discovered "CCN" family containing six growth and regulatory factors. We showed that hyperoxia induces Cyr61 expression in a variety of pulmonary cells and in lung tissue in vivo. Loss of function studies, by suppressing Cyr61 expression by siRNA, accelerated lung epithelial cell death after hyperoxia. Gain of function studies, by overexpressing Cyr61, significantly conferred increased resistance to hyperoxia-induced cell death. Moreover, cells overexpressing Cyr61 induce Akt activation. Inhibition of Akt by siRNA abrogated the protective effects of Cyr61-overexpressing cells in response to hyperoxia. Taken together, our data demonstrate that Cyr61 expression provides cytoprotection in hyperoxia-induced pulmonary epithelial cell death and that this effect was in part mediated via the Akt signaling pathway.     

Laboratory compliance with federal government and professional society recommendations

Quality assurance issues have assumed growing importance in the cytology laboratory. The 1988 Clinical Laboratories Improvement Amendment (CLIA '88) (United States Department of Health and Human Services, Federal Register: U.S. Government Printing Office 1990;55:9495) regulates the patient identifiers and clinical data on the requisition form but does not mandate physician compliance to provide the information. We investigated the use of patient identifiers and clinical data by laboratories as specimen acceptance/rejection criteria. We surveyed 81 board certified cytopathologists and 235 randomly selected cytology laboratories for acceptance criteria of cytology specimens and received responses from 104. Approximately two thirds of all responding laboratories had specific criteria for rejecting specimens on the basis of inadequate identification or clinical data. While the vast majority required the specimens to be identified with patient name, collection date, and specimen source, a minority of laboratories required clinical information such as LMP, prior atypical cytologic/histologic specimens, and history of previous therapy. Little correlation was found between practice setting and the use of rejection criteria. Diagn Cytopathol 1994; 11:85–92. © 1994 Wiley-Liss, Inc.     

Ullrich-Turner syndrome with a small ring X chromosome and presence of mental retardation

Since some patients with Ullrich-Turner syndrome (UTS) have mental retardation, we reviewed our experience to look for a high-risk subgroup. Among 190 UTS and gonadal dysgenesis patients with X chromosome abnormalities, 12 had mental retardation. All of the six (100%) with a small ring X were educable (EMI) or trainable mentally impaired (TMI) with more severe delay than expected in UTS. Among the 184 with other X abnormalities, only 6 had similar delays (2 from postnatal catastrophes), for a frequency of 3.3% mental retardation among those without a small ring X; only 2.2% of these had unexplained mental retardation. Polymerase chain reaction studies showed no Y-derived material in the 2 patients who were evaluated, and in situ hybridization confirmed X origin of the ring in the 6 subjects who were evaluated. We describe the phenotype of the 6 individuals with a small ring X, and an additional 2 patients with a small ring X who were identified outside the survey. The subjects with a small ring X comprised a clinically distinct subgroup which had EMI/TMI and shorter stature than expected in UTS. Seizures and a head circumference <10th centile were observed in half of the patients with a small ring X, and strabismus, epicanthus, and single palmar creases were present in more than half. A “triangular” face in childhood, pigmentary dysplasia, sacral dimple, and heart defects were also common. Neck webbing appeared to be less frequent than in 45, X. We hypothesize that the high risk of mental retardation in this form of the UTS results from lack of lyonization of the ring X due to loss of the X inactivation center. Excluding those with a small ring X, mental retardation is not significantly increased in patients with UTS. © 1992 Wiley-Liss, Inc.     

Diffuse sclerosing variant of papillary thyroid carcinoma: A clinicopathologic and immunophenotypic analysis of 22 cases

Background: The diffuse sclerosing variant of papillary thyroid carcinoma (DSV-PTC) is an uncommon tumor making up about 2% of all papillary thyroid carcinomas. Previous studies have not comprehensively evaluated these tumors in a large series of patients. Design: Twenty-two cases of DSV-PTC diagnosed between 1970 and 2000 were identified in the files of the AFIP. Histologic and immunohistochemical features were evaluated and patient follow-up was obtained. Results: The tumors affected 14 females and 8 males, aged 6 to 49 yr (mean, 18 yr), with males presenting at a mean older age than females (24 vs 14 yr). Symptoms included an enlarging mass in the thyroid, present for a mean of 9.5 mo. While a dominant tumor was identified in a single lobe, bilateral disease was common (n=16). The dominant mass ranged in size from 1.7 to 5.8 cm in diameter (mean, 3.8 cm). Histologically, all cases demonstrated a papillary carcinoma (conventional, solid, or follicular pattern) diffusely involving the gland. Extrathyroidal extension, lymphocytic thyroiditis, squamous metaplasia, increased fibrosis/sclerosis, and psammoma bodies were present to a variable degree. Both the papillary carcinoma and squamous metaplasia cells were strongly immunoreactive with CK19, thyroglobulin, and TTF-1. An increased number of S-100 protein immunoreactive dendritic cells were recognized. p53 was increased (>15%) in the tumor cells in 12 patients, while Ki-67 was increased in the tumor cells in two patients. Perithyroidal and cervical lymph node metastasis occurred in 18 (82%) patients. All metastases demonstrated histologic features similar to the primary. Complete resection (thyroidectomy in 18 patients) with lymph node dissection, yielded a 95% 5-yr survival without evidence of disease. One patient died of disease after a malignant transformation of the squamous metaplasia into squamous cell carcinoma. Conclusions: The recognition of DSV-PTC can be made with the following features: classic to solid foci of PTC, lymphocytic thyroiditis, squamous metaplasia, increased fibrosis, and innumerable psammoma bodies. DSV-PTC is more biologically aggressive than conventional PTC, but the patients’ survival is not significantly different. This diagnosis should lead the clinician to aggressively manage these patients (thyroidectomy and lymph node dissection) in an effort to achieve an excellent long-term clinical outcome.     

The anticonvulsant and proconvulsant effects of alpha2-adrenoreceptor agonists are mediated by distinct populations of alpha2A-adrenoreceptors

The alpha2-adrenoreceptor (AR) is the most investigated noradrenergic receptor with regard to modulation of seizure activity. However, because of the complexity of multiple alpha2-AR subtypes and their distribution, the exact role of this receptor in modulating seizure activity is not clear. alpha2A- and alpha2C-ARs function as both autoreceptors (presynaptic) on noradrenergic neurons, where they regulate norepinephrine (NE) release, and as postsynaptic receptors on neurons that receive noradrenergic innervation, where they regulate the release of other neurotransmitters (heteroreceptor). The nonselective alpha2-AR agonist clonidine produced a proconvulsant effect on seizure susceptibility, while the selective alpha2A-AR agonist guanfacine was anticonvulsant. The effects of both alpha2-AR agonists were absent in alpha2a knockout mice, suggesting that the alpha2A-AR mediates the proconvulsant and anticonvulsant effect of alpha2-AR agonists on seizure susceptibility. To determine whether the alpha2-AR agonists were acting on inhibitory presynaptic autoreceptors to decrease NE release or on postsynaptic receptors on NE target neurons, the effects of clonidine and guanfacine were determined in dopamine beta-hydroxylase knockout (Dbh -/-) mice that lack NE. The anticonvulsant effect of guanfacine persisted in Dbh -/- mice, suggesting that guanfacine may act preferentially on alpha2A-postsynaptic receptors that regulate the action of NE on target neurons. In contrast, the proconvulsant effect of clonidine was lost in Dbh -/- mice, suggesting that clonidine may act on presynaptic autoreceptors to decrease NE release. We hypothesize that the alpha2A-presynaptic autoreceptor is responsible for the proconvulsant effect of alpha2-AR agonists, while the alpha2A-postsynaptic receptor is responsible for the anticonvulsant effect of alpha2-AR agonists. These data help to clarify the inconsistent effects of alpha2-AR agonists on seizure activity.     

Increase in radiosensitivity of lung micrometastases by hyperbaric oxygen

Four-day-old artificial pulmonary micrometastases of two murine fibrosarcomas, designated FSA and NFSA, showed increased sensitivity to ionizing radiation by a factor of 1·13 when animals were exposed to hyperbaric oxygen breathing before and during irradiation, implying the presence of hypoxia in the micrometastases. At the time of irradiation the diameter of FSA and NFSA metastases was smaller than 200 and 100m, respectively, which, on the basis of oxygen diffusion, could not be responsible for hypoxia. It is assumed that hypoxia of micrometastases is passive, reflecting the radiobiological hypoxia of lung tissue that could exist under normal breathing conditions.     

Antifluoridationists Persist: the Constitutional Basis for Fluoridation

The controversy surrounding fluoridation persists. In recent years opponents of fluoridation have resorted to the courts with increasing frequency and have achieved a few victories in the trial courts. To date, however, no appellate court has ruled against fluoridation. This article discusses the constitutional basis for the court decisions upholding fluoridation and the main arguments put forth by the antifluoridationists. Five of the more recent cases are summarized, as is the first fluoridation case to be appealed to the US Supreme Court. The article concludes that the legal validity of fluoridation in the United States has been thoroughly tested in the courts and confirmed. It appears that the antifluoridationists will concentrate their future legal attacks on the "harmful effects" of fluoridation on health and the environment. If they can convince the courts that even a few people were truly harmed, the delicate balance between the rights of the state to fluoridate in order to protect the public's health and the rights of the individual not to be harmed could well shift. In closing, the question is raised whether the US Congress has the power to pass legislation either to mandate or forbid fluoridation.     

Surgical management of a pulsatile chest wall mass secondary to an ascending aortic aneurysm in a patient with bovine arch

Ascending aortic pseudoaneurysms are rare, but life‐threatening conditions, that often require intervention. While endovascular techniques have advanced significantly, the majority of these clinical scenarios preclude endovascular options and the primary treatment modality remains open surgical repair. Repair of an aortic pseudoaneurysm eroding through the sternum resulting in a pulsatile chest wall mass is technically challenging. We report the successful repair of a large ascending aortic pseudoaneurysm in a 62‐year‐old male with bovine arch anatomy and prior Type A dissection repair, presenting with contained rupture and a pulsatile chest wall mass.     

Transoral laser resection of hypopharyngeal liposarcoma

Liposarcomas are rare malignant tumours of the connective tissue. Microscopically they resemble lipomas. They are usually found on the limbs or trunk. Fewer than 40 cases of hypopharyngeal liposarcoma have been reported in the literature. Surgical excision with a cervical or endoscopic approach has been the first-line treatment for these cases. We present a patient with the first documented primary excision via carbon dioxide laser using an entirely transoral approach. This case suggests a new standard of management but also highlights the difficulties with investigation and diagnosis in a rare presentation.