Dyke Award. The search for human telencephalic ventriculofugal arteries

Our study traced the vascular development of the fetal telencephalon in the last two trimesters of gestation and the first 15 years of life in 60 fetal and childhood brains. We filled the macro- and microvascular beds with Microfil and made stereoscopic observations of cleared 0.5- to 1.0-cm-thick sections. Separately, we identified developing vascular structures histologically. In our youngest specimen (16-weeks gestation), transcerebral channels with walls consisting of a single layer of endothelium and varying in diameter from 10 to 50 microns originated from leptomeningeal arteries and veins at right angles to the surface and passed through the cortical plate (future cortex). They branched at varying depths within the mantle and germinal matrix surrounding the lateral ventricles. At deeper levels the channels freely anastomosed with each other. A cortical microvascular network did not appear until 22 to 24 weeks. The new endothelial channels were derived from leptomeningeal vessels and from larger transcerebral channels. Most regions of isocortex developed a microvascular plexus simultaneously, regardless of degree of maturation. Striatal channels matured earlier than extrastriatal channels, having developed a muscularis to within 100 microns of the ganglionic eminence by 22- to 24-weeks gestation. Maturation of the vascular walls of extrastriatal channels into proper arteries and veins occurred during the first postnatal year. Anastomotic channels were present throughout the leptomeningeal, striatal, and extrastriatal regions in all of our specimens from 16 weeks gestation to 15 years old. Our study does not support the existence of ventriculofugal arteries and deep white matter arterial border zones in the human fetus and neonate, which have been postulated to be the basis of "periventricular" leukomalacia.     

Primary cutaneous mucoepidermoid carcinoma: report of a case

Primary mucoepidermoid carcinomas of the skin are extremely rare tumors. We describe a primary cutaneous mucoepidermoid carcinoma arising in the right ear (posterior mid helix) of a 66-year-old white man. The tumor was 0.6 cm in diameter, ulcerated and nonencapsulated. No other tumors were found in the patient. Histologically the tumor showed the characteristics of a "low grade" mucoepidermoid carcinoma, consisting of lobules of polygonal cells with vesicular nuclei. In the center of the lobules were large vacuolated cells (goblet cells). Transitions between the two cell populations were present throughout the tumor. An epidermal attachment of the tumor, as well as epidermal dysplasia, predominantly at the acrosyringium was present, consistent with the theory of sweat duct histogenesis of these tumors. Immunoperoxidase staining showed positivity for epithelial membrane antigen, keratin and carcinoembryonic antigen. The latter was predominantly positive in the goblet cells. Cutaneous metastasis of mucoepidermoid carcinomas with epidermal attachment has been reported. Our case showed only ear involvement and follow-up at 8 months has revealed no evidence of recurrence. These findings are consistent with the diagnosis of primary cutaneous mucoepidermoid carcinoma.     

Scorpion alpha and alpha-like toxins differentially interact with sodium channels in mammalian CNS and periphery

Scorpion alpha-toxins from Leiurus quinquestriatus hebraeus, LqhII and LqhIII, are similarly toxic to mice when administered by a subcutaneous route, but in mouse brain LqhII is 25-fold more toxic. Examination of the two toxins effects in central nervous system (CNS), peripheral preparations and expressed sodium channels revealed the basis for their differential toxicity. In rat brain synaptosomes, LqhII binds with high affinity, whereas LqhIII competes only at high concentration for LqhII-binding sites in a voltage-dependent manner. LqhII strongly inhibits sodium current inactivation of brain rBII subtype expressed in HEK293 cells, whereas LqhIII is weakly active at 2 microM, suggesting that LqhIII affects sodium channel subtypes other than rBII in the brain. In the periphery, both toxins inhibit tetrodotoxin-sensitive sodium current inactivation in dorsal root ganglion neurons, and are strongly active directly on the muscle and on expressed muI channels. Only LqhII, however, induced repetitive end-plate potentials in mouse phrenic nerve-hemidiaphragm muscle preparation by direct effect on the motor nerve. Thus, rBII and sodium channel subtypes expressed in peripheral nervous system (PNS) serve as the main targets for LqhII but are mostly not sensitive to LqhIII. Toxicity of both toxins in periphery may be attributed to the direct effect on muscle. Our data elucidate, for the first time, how different toxins affect mammalian central and peripheral excitable cells, and reveal unexpected subtype specificity of toxins that interact with receptor site 3.     

Spray-dried redispersible oil-in-water emulsion to improve oral bioavailability of poorly soluble drugs.

A physically stabilized dry emulsion dosage form reforming the original emulsion after rehydration was developed by spray-drying a liquid oil-in-water emulsion containing maltodextrin as carrier and sodium caseinate as emulsifying agent. Several oil:water as well as maltodextrin:water ratios were tested, the homogenization and spray-drying processes and the reconstitution properties were investigated and an optimum formulation was selected for poorly soluble drug incorporation, having an identical oil:water and carrier:water ratio of 10% (w/w) and a load of solid material of 20% (w/w). Lipophilic 5-phenyl-1,2-dithiole-3-thione (5-PDTT) was selected as a model drug. 5-PDTT release from the solid state emulsion was studied using an in vitro two-phase stirred model and the relative bioavailability of 5-PDTT in the dry emulsion was obtained in the rabbit after oral administration of the reconstituted emulsion, compared to a 5-PDTT-sulfobutyl ether 7 beta-cyclodextrin complex in solution. Incorporation of 5-PDTT in the oil phase neither affects the surface morphology of the powder nor the reconstitution, the droplet size or the drug releasing properties and, furthermore, allows a 3-fold improvement of 5-PDTT relative bioavailability in rabbit after oral administration. These results indicate that dry emulsions may be considered as relevant dosage forms to improve bioavailability of poorly absorbable lipophilic drugs.     

Loss of RhoB expression in human lung cancer progression.

PURPOSE: RhoB is a low molecular weight GTPase belonging to the Ras protein superfamily. Whereas most Rho proteins have been shown to have a positive role in proliferation and malignant transformation, the specific role of RhoB appears more divergent. We reported previously that RhoB inhibits cell proliferation in various human cancer cells. Here, we studied the specific role played by RhoB in human lung cancer. EXPERIMENTAL DESIGN: We analyzed the expression of RhoB protein by immunostaining in human lung tissues ranging from normal to invasive carcinoma from different histological types in two large independent studies of, respectively, 94 and 45 samples. We then studied the cellular effect of RhoB overexpression in a model of lung cancer (A549, adenocarcinoma) and tumorigenicity in nude mice. RESULTS: We showed in both studies that RhoB protein was expressed in normal lung and decreased dramatically through lung cancer progression (P < 0.01). Interestingly, RhoB expression was lost in 96% of invasive tumors and reduced by 86% in poorly differentiated tumors compared with the nonneoplastic epithelium. Moreover, the loss of expression of RhoB correlated significantly with tumor stage and proliferative index, whereas no correlation was found between RhoB and p53 or Bcl-2 expression. We then showed that ectopic expression of RhoB in lung cancer cell line A549 suppressed cell proliferation, anchorage-independent growth, and xenograft tumor growth in nude mice. CONCLUSIONS: RhoB loss of expression occurs very frequently in lung carcinogenesis, reinforcing its putative tumor suppressive activity, and raising the value of its potential use in cancer therapy.     

Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer.

PURPOSE: This randomized, noncomparative, parallel-group study was designed to evaluate the pathologic complete response (pCR) rate of combined doxorubicin plus paclitaxel (AP) and doxorubicin plus cyclophosphamide (AC) as neoadjuvant chemotherapy in patients with previously untreated breast cancer who were unsuitable for conservative surgery. PATIENTS AND METHODS: A total of 200 patients with T2-3, N0-1, M0 disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either doxorubicin 60 mg/m(2) plus paclitaxel 200 mg/m(2) as a 3-hour infusion (AP) or doxorubicin 60 mg/m(2) plus cyclophosphamide 600 mg/m(2) (AC) every 3 weeks for 4 courses followed by surgery. RESULTS: A pCR (eradication of invasive carcinoma in tumor and in axillary lymph nodes) was found in 16% and 10% of patients in the AP and AC arms, respectively, by study center pathologists, and in 8% and 6% of patients, respectively, by independent pathologists. Patients with pCRs tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (Scarff, Bloom, and Richardson scale grade 3). Breast-conserving surgery was performed in 58% and 45% of patients in the AP and AC arms, respectively. An objective clinical response was achieved in 89% of patients in the AP arm and 70% in the AC arm. At a median follow-up of 31 months, disease-free survival (DFS) was higher in patients who reached pCR versus those without pCR (91% v 70%). CONCLUSION: The encouraging pathologic and clinical responses of patients with breast cancer after neoadjuvant chemotherapy with doxorubicin plus paclitaxel warrant additional investigation of paclitaxel in the neoadjuvant setting of breast cancer management.     

Domestic violence in Australia: definition, prevalence and nature of presentation in clinical practice

Domestic violence is a complex pattern of behaviours that may include, in addition to physical acts of violence, sexual abuse and emotional abuse. Women experience domestic violence at far greater rates than men do, and women and children often live in fear as a result of the abuse that is used by men to maintain control over their partners. Domestic violence is a major public health problem and is very common in women attending clinical practice. Women present most commonly with a range of chronic symptoms to unsuspecting general practitioners, emergency department doctors or medical specialists. Women who have experienced partner abuse want to be asked about it and are more likely to disclose if asked in an empathic, non-judgemental way. Doctors can make a difference.     

Posterior Laryngeal Clefts: Preliminary Report of a New Surgical Procedure Using Tibial Periosteum As an Interposition Graft

Objective: To present the preliminary results of a new surgical procedure for posterior laryngeal cleft repair. Design: Retrospective study in an academic tertiary care center. Method: The study included three male patients (age at surgery, 2, 13, and 14 mo). One presented with severe aspiration and cyanotic attacks, the two others with aspiration and recurrent chest infections. The types of laryngeal clefts included complete cleft of the cricoid with varying degrees of tracheal involvement but not further than the first six tracheal rings. Associated malformations included one VATER syndrome, one esophageal atresia, and one tracheoesophageal fistula. Surgery was performed under general anesthesia with nasotracheaI intubation. A vertical anterior laryngofissure was performed. The mucosal margins of the clefts were incised and then repaired in two layers with polyglactin sutures. The original feature of this procedure was the interposition of a small piece of tibial periosteum between the two layers. This fascia graft is known to be strong and resistant in cleft palate surgery. Main Outcome Measure: Clinical and endoscopic follow-up was used for evaluation of results. Results: The three patients had successful laryngeal repair at a mean follow-up of 6 months (range, 4-14 mo). Conclusion: The anterior laryngofissure provides a good surgical access to the cleft. The interposition of tibial periosteum allows durability of the cleft repair. A longer follow-up is needed to confirm these preliminary results. A computed tomography scan study and a study on the rabbit are planned in order to evaluate the outcome of these periosteal grafts.     

Analysis of the p21 gene in gliomas

The p21 gene encodes a cyclin dependent kinase inhibitor protein (p21) which has a tumor suppressive activity in a variety of tumor cell lines. Since, the p21 gene is up-regulated by the p53 tumor suppressor gene, which is frequently mutated in gliomas, acting therefore in the same control pathway, it constitutes a good candidate gene to be also inactivated in these tumors. To test this hypothesis, DNAs from 81 gliomas (48 glioblastomas, 11 anaplastic astrocytomas, 10 low-grade astrocytomas, 12 oligodendrogliomas and mixed gliomas), were investigated for mutations in the p21 coding sequence by denaturant gradient gel electrophoresis followed by sequencing. All these tumors have been previously screened for p53 mutations. Three different DNA variants were identified on codon 31 (17 cases), 27 (1 case) and 117 (1 case) and shown to be also present in matching constitutional DNA, suggesting they were polymorphisms. None of the tumors demonstrated a somatic mutation. No significant correlation between the presence of a p21 variant and the p53 mutation tumor status was observed. In conclusion, mutation in the p21 gene unlikely contributes to the development of gliomas.