Ultrastructural, physiological, and molecular defects in the inner ear of a gene-knockout mouse model for autosomal Alport syndrome

It is well documented that damage to the chick cochlea caused by acoustic overstimulation or ototoxic drugs is reversible. Second-order auditory neurons in nucleus magnocellularis (NM) are sensitive to changes in input from the cochlea. However, few experiments studying changes in NM during cochlear hair cell loss and regeneration have been reported. Chicks were given a single systemic dose of gentamicin, which results in maximal hair cell loss in the base of the cochlea after 5 days. Many new hair cells are present by 9 days. These new hair cells are mature but not completely recovered in organization by 70 days. We counted neurons in Nissl-stained sections of the brainstem within specific tonotopic regions of NM, comparing absolute cell number between gentamicin- and saline-treated animals at both short and long survival times. Our data suggest that neuronal number in rostral NM parallels hair cell number in the base of the cochlea. That is, after a single dose of gentamicin, we see a loss of both cochlear hair cells and NM neurons early, followed by a recovery of both cochlear hair cells and NM neurons later. These results suggest that neurons, like cochlear hair cells, can recover following gentamicin-induced damage.     

Synthesis and antilipidemic properties of cis-7-chloro-3a, 8b-dihydro-3a-methylfuro[3,4-b]benzofuran-3(1H)-one, a tricyclic clofibrate related lactone having a structural resemblance to mevalonolactone

The synthesis for the title lactone 2, designed to be an antagonist of the enzyme HMG-CoA reductase (E.C.1.1.1.34), is described. Lactone 2, its synthetic tricyclic hemiacetal precursor 4, and clofibrate were investigated for their antilipidemic activity in 7-day treated normal and in Triton WR-1339 induced hyperlipidemic male Sprague-Dawley rats. After 7-day drug administration to normal rats, lactone 2 was less effective than clofibrate in lowering HMG-CoA reductase activity and serum cholesterol; however, unlike clofibrate, lactone 2 did not increase liver weight or liver-body weight ratio or lower serum triglycerides. Since hemiacetal 4 selectively influenced triglycerides in normal animals, lactone 2 and hemiacetal 4 appear to have differential hypolipidemic effects. In the Triton hyperlipidemic model 2 and 4 lowered elevated triglycerides; only 4 significantly reduced elevated cholesterol levels; but neither 2 nor 4 was as effective as clofibrate. Differences in the observed antilipidemic properties for clofibrate, 2, and 4 in the two animal models are discussed. On the basis of preliminary biological data described in this article it is concluded that tricyclic analogues 2 and 4 represent reasonable leads for the development of new antilipidemic agents.     

4'-Epi-doxorubicin and hyperthermia in a murine mammary carcinoma: influence of the dose and fractionation

Our aim was to analyse the dose-response rate of 4'-epi-doxorubicin (EP) alone and of EP combined with hyperthermia (HT) treatments in tumor-bearing mice. A spontaneous mammary carcinoma, transplanted into the right foot of female hybrid (C3H/RIxDBA/2J) mice, was used. EP (from 5 to 30 mg/kg) was administered i.p. and local HT (45-60 minutes at 42 or 43 degrees C) was carried out. Mice were treated with EP and/or HT in 1, 2 or 3 doses at 8 day intervals; in the case of 3 HT treatments EP was administered before the first or before each HT session (same EP total dose). When EP was given alone, in 1 or 2 fractions, results showed a clear dose-response relationship: tumor growth delay depended on the total dose only. Combining different EP single doses and 1 HT treatment (43 degrees C), an additive effect and perhaps a synergistic effect at the highest doses was observed. Among all tested combinations, the best results were observed combining 3 HT with only 1 EP treatment.     

Neurovascular morbidity from the lithotomy position

The lithotomy position is used in pediatric surgery when it is necessary to have simultaneous access to the abdomen and perineum. At the authors' institution, after a prolonged period in the lithotomy position, significant lower limb complications developed in four patients. Two patients with Hirschsprung's disease underwent a redo Duhamel procedure, one had an anorectal leiomyoma excised, and one had an ileoanal anastomosis for ulcerative colitis. Sciatic nerve injury developed in two patients and deep venous thrombosis and bilateral compartment syndrome resulting in myonecrosis developed in one each. There is an association between operations that require prolonged lithotomy position and the development of postoperative neurovascular complications. By placing the child in the lithotomy position only when access to the perineum is required, these significant injuries may be avoided.     

The genetic selection aspects of the "Holsteinization" of dairy cattle breeding in Ukraine

Results of the use of Holstein-Friesian bulls in milk-production cattle breeding in Ukraine have been stated. Genetic consequences of crossbreeding have been noted. An analysis of pedigrees of Holstein bull has shown the availability of predecessors carriers of genes BLAD, mule-foot, dumps with frequency of their recessive forms 34, 19.3, 3.2%, respectively.     

Intracellular expression of a single-chain antibody directed against human papillomavirus type 16 E7 oncoprotein achieves targeted antineoplastic effects

Human papillomavirus type 16 (HPV16) E7 is a viral oncoprotein that is believed to play a major role in cervical neoplasia. Anti-HPV16 E7 intracellular single-chain antibodies (scFvs) were constructed to down-regulate HPV16 E7 oncoprotein in HPV DNA-containing cell lines. In these studies, we transfected anti-E7 scFvs into the HPV16-positive human cervical carcinoma cell lines CaSki and SiHa and tested them for their ability to inhibit cell proliferation and alter the level of HPV16 E7 oncoprotein. Our results showed that anti-HPV16 E7 scFvs inhibited cell proliferation by >85% in CaSki cells and by 95% in SiHa cells. E7 oncoprotein was down-regulated by anti-HPV16 E7 scFv, and its expression was inversely related to the amount of scFv transfected. However, there were no effects of transfecting scFvs alone in HPV-negative cell lines. These results imply that anti-HPV16 E7 scFvs only have specific anti-HPV16 E7 effects on cell proliferation and on the synthesis of virally encoded proteins in HPV-positive cell lines. Thus, transfection of HPV16 E7-positive tumors with antigen-specific scFvs may be a viable strategy for cervical cancer gene therapy.     

Temporal lobe pathology in amyotrophic lateral sclerosis. Do amyotrophic lateral sclerosis and Alzheimer's disease share a common etiological factor?

An autopsy study was performed on temporal lobe samples from 20 non-demented patients with amyotrophic lateral sclerosis (ALS), 17 age-matched non-demented controls and 4 Alzheimer's disease (AD) patients. Formalin fixed, paraffin embedded sections from the hippocampus with adjacent parahippocampal gyrus and from the superior temporal gyrus were stained with conventional and immunohistochemical stains. Immunohistochemical staining for the A4 protein was enhanced by pretreatment with 0.25% pepsin before 100% formic acid. The incidence and severity of AD-like pathological changes were similar in ALS patients and non-demented controls. In both groups, pathological changes increased with age. This study does not support the hypothesis that ALS and AD share an etiopathogenetic background.     

Type I A-kinase is activated by platelet-derived growth factor in mesangial cells

In the glomerular mesangial cell, platelet-derived growth factor (PDGF) activates several signal transduction pathways. We examined the effect of PDGF on cAMP production and on cAMP-dependent protein kinase (A-kinase) activation. In mesangial cells, PDGF stimulated cAMP production in a dose- and time-dependent manner. This effect of PDGF was not prevented by pre-incubation with 50 microM indomethicin. PDGF also activated type I A-kinase, the predominate A-kinase isoform in mesangial cells, measured either by a decrease in A-kinase photoaffinity labeling with 8-azido-[32P]-cAMP, or by an increase in A-kinase substrate phosphorylation. The activation of A-kinase by PDGF is not dependent on the intermediate production of prostaglandins or cGMP. These data suggest that A-kinase participates in PDGF-induced signaling events in mesangial cells.