Distribution of protein kinase Mzeta and the complete protein kinase C isoform family in rat brain

Protein kinase C (PKC) is a multigene family of at least ten isoforms, nine of which are expressed in brain (alpha, betaI, betaII, gamma, delta, straightepsilon, eta, zeta, iota/lambda). Our previous studies have shown that many of these PKCs participate in synaptic plasticity in the CA1 region of the hippocampus. Multiple isoforms are transiently activated in the induction phase of long-term potentiation (LTP). In contrast, a single species, zeta, is persistently activated during the maintenance phase of LTP through the formation of an independent, constitutively active catalytic domain, protein kinase Mzeta (PKMzeta). In this study, we used immunoblot and immunocytochemical techniques with isoform-specific antisera to examine the distribution of the complete family of PKC isozymes and PKMzeta in rat brain. Each form of PKC showed a widespread distribution in the brain with a distinct regional pattern of high and low levels of expression. PKMzeta, the predominant form of PKM in brain, had high levels in hippocampus, frontal and occipital cortex, striatum, and hypothalamus. In the hippocampus, each isoform was expressed in a characteristic pattern, with zeta prominent in the CA1 stratum radiatum. These results suggest that the compartmentalization of PKC isoforms in neurons may contribute to their function, with the location of PKMzeta prominent in areas notable for long-term synaptic plasticity.     

Placental site trophoblastic tumor in a patient with brain and lung metastases

Placental site trophoblastic tumor is a rare neoplasm that arises from intermediate trophoblasts and shows diversity of biological behaviors, resulting in the absence of consistency in treatment modalities. A case of placental site trophoblastic tumor that extended to the cervix, with primary manifestation of amenorrhea and yellow foul-smelling vaginal discharge, is presented. Total abdominal hysterectomy was performed initially, and serial measurements of human chorionic gonadotropin levels were obtained. She was admitted with metastases to brain and lung 1.5 years after surgery. Combination chemotherapy (etoposide-methotrexate-dactinomycin/cyclophosphamide-vincristine) and radiotherapy were administered. There was no significant response to chemoradiotherapy. Despite changing chemotherapy regimen, she is still alive with progressive disease.     

Tympanometric changes in an experimental myringosclerosis model after myringotomy.

HYPOTHESIS: The goal of this experimental study was to investigate the specific effect of myringosclerosis on tympanograms in the tympanic membranes of myringotomized rats by using otomicroscopy, tympanometry, and histopathology. BACKGROUND: Myringosclerosis is a common sequela of ventilation tube treatment of otitis media with effusion. The condition involves the hyalinization and calcification of the collagen layer in certain areas of the tympanic membrane. Previous animal experiments suggest an intimate relationship between the formation of myringosclerosis and an increased oxygen concentration in the environment of the wound after myringotomy. The result of a myringotomy therefore is an increased production of free oxygen radicals, initiating irreversible tissue damage involving fibrosis, hyalin degeneration, and finally apoptosis as observed in myringosclerosis. We propose an experimental model specific for creating sclerotic plaques solely on the tympanic membrane and for performing tympanometric measurements on this pure myringosclerosis model without creating any abnormality in the middle ear to test in what proportion myringosclerosis contributes to decrease of amplitude in tympanograms. METHODS: To assess the normal tympanometric values of Wistar albino rats, the pressure and peak admittance of the left middle ears were measured using a semiquantitative computerized clinical admittance meter using a sound frequency of 226 Hz. Twelve animals were randomly selected for the myringotomy group and perforations in the left ears were created. All tympanic membrane perforations in this group had healed and closed prior to the otomicroscopic examination and no pathologic reaction was observed in the external ear canals of rats. Otomicroscopic and tympanometric measurements were carried out on Day 15 and the degree of myringosclerosis was noted before the animals were killed. Twelve specimens in the myringotomy group were histopathologically examined for the presence of myringosclerotic plaques. RESULTS: Under light microscopy, extensive sclerotic lesions were found in the tympanic membranes of the myringotomy group, and these sclerotic deposits were located in the lamina propria. The myringosclerosis occurred predominantly adjacent to the handle of the malleus, but also near the annular region. In all ears with myringosclerosis, the magnitude of the maximum admittance reduced to approximately 50% of the Day-0 values, and this reduction was statistically significant (Z=-3.061, p=0.002). CONCLUSION: The present findings in this study are consistent with the fact that the movement of the tympanic membrane is hampered by lesions of sclerotic material, resulting in a decrease of amplitude in tympanograms (such as Type As) without any effusion or inflammation in the middle ear.     

The Manchester operation for uterine prolapse.

OBJECTIVE: To evaluate the clinical characteristics, complications, and satisfaction scores of patients who underwent the Manchester operation. METHODS: This retrospective observational study evaluated data from 204 women who underwent the Manchester operation at the Department of Obstetrics and Gynecology of Hacettepe University School of Medicine, Ankara, Turkey, from January 1985 to April 2004. RESULTS: Mean age was 34.68+/-4.24 years and parity 2.47+/-0.96; 85.8% of the patients were premenopausal; 176 patients (86.28%) had grade 3 and 28 (13.72%) had grade 2 uterine prolapse; 95.1% of the patients had associated cystoceles and 51.3% had associated rectoceles; and 81.4% had urinary incontinence. Regarding early postoperative complications, 27 patients (13.23%) had febrile morbidity; retroperitoneal hematoma occurred in 1 patient (0.49%); urinary retention occurred in 45 patients (22.05%), and cervical stenosis occurred in 23 patients (11.27%). At 1 year, 1 patient had undergone abdominal hysterectomy because of unsuccessful cervical dilatation; and a mean of 3.6 years following the operation, 8 patients (3.9%) had undergone the tension-free vaginal tape procedure plus a vaginal hysterectomy for recurrent stress urinary incontinence and uterine prolapse. The mean satisfaction/acceptance score for the operation was 8.52+/-2.13 (range, 2-10). CONCLUSION: A high degree of acceptance/satisfaction and a low morbidity rate show the Manchester operation to be a good option for the treatment of uterine prolapse in women who wish to keep their uterus.     

Medical treatment of vulvar squamous cell hyperplasia.

OBJECTIVE: To evaluate symptomatic response and recurrence rates of graduated topical fluorinated corticosteroid in patients with vulvar squamous cell hyperplasia. METHODS: Nine hundred seventy-six patients with biopsy-proven vulvar squamous cell hyperplasia from 1990 to 2003 were reviewed in this retrospective study. All patients were treated with graduated topical fluorinated corticosteroid. Data were obtained from hospital records. Symptomatic remission and recurrence rates were noted following six months local therapy. RESULTS: The mean age was 42.55+/-10.93 (15-85). The remission rate was 93.8% in six months. The remission rate was non-significantly higher in postmenopausal patients than that in their premenopausal counterpart (94.9% vs 93.0%, p=0.15). The disease recurred in 6.9% of patients. Of the patients that suffered recurrence 47.5% had persistent disease initially. The patients with following factors older ages (>40 years), postmenopausal period had significantly higher recurrence rates. Four patients with recurrent disease and six patients with persistent disease in the form of vulvar intraepithelial neoplasia I-II or atypical squamous hyperplasia, were treated with skinning vulvectomy. CONCLUSION: Corticosteroid in the treatment of vulvar squamous cell hyperplasia yielded excellent response rates. In the evaluation of patients without symptomatic relief, the first step should be a vulvar biopsy to exclude the presence of atypical components.     

The interaction of the diltiazem with oral and intravenous cyclosporine in rats.

This study investigated the effect of diltiazem on the bioavailability of oral and intravenous cyclosporine (CsA) in rats. While control rats received normal saline, experimental groups received 60 or 90 mg/kg diltiazem orally for 3 days. Each group divided into 2 equal groups that received a single oral dose or i.v. injection of CsA. Pharmacokinetic parameters were analyzed by nonparametric analysis of variance. Pretreatment with 60 or 90 mg/kg diltiazem decreased the area under the blood CsA concentration-time curve (AUC) of oral CsA compared to control group (54.5% and 65.5% for AUC(0-24), 57.6% and 62.2% for AUC(0-infinity), respectively, p<0.05). Mean CsA maximum concentration (Cmax) decreased from 0.4 +/- 0.1 microg/ml to 0.1 +/- 0.0 microg/mL in rats pretreated with 90 mg/kg diltiazem (p<0.05). The absolute bioavailability after oral administration (F(p.o.)) in the 60 or 90 mg/kg diltiazem groups were lower than the control group (9.6% and 8.5% versus 22.6%). Pretreatment with 90 mg/kg but not 60 mg/kg of diltiazem increased the AUC(0-infinity), elimination half-life (t1/2) of intravenous CsA (116.0%, 219.2%, respectively, p<0.05) and decreased the intravenous CsA clearence (CL(i.v.)) (62.9%, p<0.05). Diltiazem decreased the bioavailability of oral CsA, while it increased the bioavailability of intravenous CsA. One must consider this interaction when administering oral or intravenous CsA concomitantly with diltiazem.     

Dextromethorphan Abuse in Texas, 2000–2009

ABSTRACT

This article aims at identifying a threshold number of drinks per day beyond which there is a high risk of developing alcoholic behavior that would enable physicians to more confidently support the use of alcohol for cardiovascular risk prevention. In a randomly selected, population-based sample of 2,042 adults 45 years or older, we graded alcohol drinking behavior using the Self-Administered Alcoholism Screening Test, quantified alcohol amount by questionnaire, and assessed the prevalence of cardiovascular disease (coronary, peripheral, or cerebrovascular disease) by medical record review. Although optimal alcohol use (≤2 drinks/day) was associated with reduced odds of cardiovascular disease, 43% of alcoholics and 82% of problem drinkers reported alcohol use in the optimal range as well. The association of alcohol use in the optimal range with alcohol-related behavioral problems supports the reluctance in physicians from recommending alcohol use for cardiovascular benefit, not withstanding the underreporting of alcohol use by alcoholics.     

Lack of BCL-2 confers interferon-alpha sensitivity to B-cell lymphomas

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with pathological manifestations usually including splenomegaly and panctopenia. Interferons (IFNs), specifically of the α subtypes have shown a significant anti-tumor effect in HCL patients, with improvement of hematological parameters within the first few months of treatment. However, the therapeutic effect of IFN-α is still rather limited. The mechanisms responsible for the beneficial action of IFN-α in HCL patients are unclear. A continuous line of cells (Eskol) from a patient diagnosed with HCL was established and shown to have several properties of HCL. Even though, Eskol cells are very resistant to anti-proliferative activity of IFN-α, Daudi cells, another human B-cell-derived cell line, are very sensitive to anti-proliferative activity of IFN-α and are commonly used as a model cell to test anti-proliferative effect of IFN-α. To understand the molecular reason(s) behind the observed obvious differences to IFN sensitivity of above cells, we have analyzed the expression levels of BCL2, caspase-1, Laminin and PARP in these cells. We found that Daudi cells do not express BCL2 at all, and probably because of that, these cells have constantly cleaved, and probably activated form of caspase-1. However, when we overexpresed BCL2 in these cells, they lost processed form of caspase-1 and became resistant to anti-proliferative activity of IFN-α. These results let us to suggest that IFN-α sensitivity of B-cell lymphomas, once again, depends on the presence or absence of BCL2.