Alcohol-exacerbates post-traumatic stress psychiatric behavior and its neuropathological sequalae in experimental mice: preventive effects of morin.

Posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) are very prevalent and co-occurring. It is unclear how alcohol exacerbates PTSD predicaments owing to less characterized pathophysiological mechanisms. Also, studies on pharmacological agents that can effectively reverse PTSD-AUD comorbidity have, to date, been scarce. Hence, we designed a methodological approach to investigate the pathophysiological mechanisms and pharmacological outcomes of morin, a neuroprotective flavonoid in mice. After 7 days of PTSD following single-prolonged stress (SPS) induction in mice, the PTSD mice were exposed to intermittent binge ethanol administration using ethanol (2g/kg, oral gavage) every other day, alongside daily morin (50 and 100mg/kg) or fluoxetine (10mg/kg) from days 8-21. The consequences of PTSD-AUD behavior, hypothalamic-pituitary-adrenal-axis (HPA-axis) dysfunction, neurochemistry, oxidative/nitrergic stress, and inflammation were evaluated in the prefrontal-cortex (PFC), striatum, and hippocampus of mice. The exacerbated anxiety-like behavior, and spatial/non-spatial memory deficits, with general depressive phenotypes and social stress susceptibility by SPS-ethanol interaction, were alleviated by morin and fluoxetine, evidenced by reduced corticosterone release and adrenal hypertrophy. SPS-ethanol exacerbates dopamine, serotonin, and glutamic acid decarboxylase alterations, and monoamine oxidase-B and acetylcholinesterase hyperactivities in the striatum, PFC, and hippocampus, respectively, which were prevented by morin. Compared to SPS-ethanol aggravation, morin prevented TNF-α, and IL-6 release, malondialdehyde and nitrite levels, with improved antioxidant (glutathione, superoxide-dismutase, catalase) levels in the hippocampus, PFC, and striatum. Overall, these findings suggest that AUD exacerbated PTSD might be primarily connected, among other mechanisms, with aggravated HPA-axis dysfunction, upregulated neurochemical degradative enzymes, enhancement of oxidative/nitrergic stress and neuroinflammation, stereo-selectively in the mice brains, which morin abated via the preventive mechanisms.

The effect of leukocyte interleukin injection (Multikine) treatment on the peritumoral and intratumoral subpopulation of mononuclear cells and on tumor epithelia: a possible new approach to augmenting sensitivity to radiation therapy and chemotherapy in oral cancer--a multicenter phase I/II clinical Trial.

OBJECTIVES/HYPOTHESIS: The main objective of this study was to investigate the effect of the administration of a novel immunoadjuvant, leukocyte interleukin injection, as part of an immuno-augmenting treatment regimen on the peritumoral and intratumoral subpopulations of the tumor infiltrating mononuclear cells and on the epithelial and stromal components, when administered to patients with advanced primary oral squamous cell carcinoma classified as T2-3N0-2M0, as compared with disease-matched control patients (not treated with leukocyte interleukin injection). STUDY DESIGN: Multicenter Phase I/II clinical trial. Fifty-four patients from four clinical centers were included in the dose-escalating study (27 in each group [leukocyte interleukin injection-treated and control groups]). Cumulative leukocyte inter-leukin injection doses were 2400, 4800, and 8000 IU (as interleukin-2 equivalent). METHODS: Paraffin-embedded tumor samples obtained at surgical resection of the residual tumor (between days 21 and 28 after treatment initiation) were used. Histological analysis, necrosis evaluation, and American Joint Committee on Cancer grading were performed from H&E-stained sections. Immunohistochemical analysis was performed on three different tumor regions (surface, zone 1; center, zone 2; and tumor-stroma interface, zone 3). Trichrome staining was used to evaluate connective tissue, and morphometric measurements were made using ImagePro analysis software. Cell cycling was determined by the use of Ki-67 marker. RESULTS: Leukocyte interleukin injection treatment induced a shift from stromal infiltrating T cells toward intraepithelial T cells and posted a significant (P <.05) increase in intraepithelial CD3-positive T cells independent of the leukocyte interleukin injection dose, whereas the increase in CD25 (interleukin-2 receptor alpha [IL-2Ralpha])-positive lymphoid cells was significant only at the lowest leukocyte interleukin injection dose (P <.05). Furthermore, both low- and medium-dose leukocyte interleukin injection treatment induced a significant (P <.05) increase in the number of cycling tumor cells, as compared with control values. CONCLUSION: The results could be highly beneficial for patients with oral squamous cell carcinoma. First, leukocyte interleukin injection treatment induces T-cell migration into cancer nests and, second, noncycling cancer cells may enter cell cycling on administration of leukocyte interleukin injection. This latter effect may modulate the susceptibility of cancer cells to radiation therapy and chemotherapy. The findings may indicate a need to re-evaluate the way in which follow-up treatment (with radiation therapy and chemotherapy) of patients with head and neck cancer is currently approached.

Technical modifications for improving the success rate of PEG tube placement in patients with head and neck cancer.

BACKGROUND: Patients with head and neck cancer (HNC) benefit from nutritional support by means of PEG tubes, but endoscopy may be impossible when there is partial or complete trismus and/or stenosis or occlusion of the upper aerodigestive tract. METHODS: PEG tubes were placed in 277 patients with HNC. Oral insertion of an endoscope into the esophagus was impossible in 27 patients. Transnasal endoscopy was performed (n = 4). In the cases of high-grade tumor obstruction, the endoscope was introduced into the esophagus through a straight laryngoscope (n = 9). When upper aerodigestive tract occlusion was present, endoscopy with PEG placement was successfully performed during surgery by means of the opened pharynx after tumor resection (n = 12). RESULTS: In 25 of the 27 cases PEG tubes could be placed by using the above alternative techniques. There were no immediate complications, and no complications occurred within 30 days of PEG placement. CONCLUSIONS: Transnasal, straight laryngoscopic, or intraoperative open endoscopy can improve the success rate for PEG tube placement in patients with HNC.

Molecular genetics of prostate cancer.

The molecular mechanisms underlying the development and progression of prostate cancer are poorly understood. Epidemiological studies have suggested that 5-10% of all prostate cancers are familial, and numerous chromosomal loci have been associated with prostate cancer in multicentre linkage studies. However, no putative susceptibility genes harboured in these chromosomal regions have thus far been identified. Several recurrent chromosomal alterations in prostate cancer have been detected in comparative genomic hybridization (CGH) and loss of heterozygosity (LOH) analysis. The target genes for many of these aberrations are still not known. It seems that the androgen receptor (AR) signalling pathway plays a crucial role in both early development as well as in late progression of the disease. Both germ-line and somatic genetic alterations in the AR gene have been demonstrated in prostate cancer patients. The intention of this review is to summarize the current knowledge of molecular mechanisms in the development of prostate cancer.

[Otorhinolaryngeal and phonation aspects of gastroesophageal reflux disease]. / A gastrooesophagealis refluxbetegség fül-orr-gégészeti, foniátriai vonatkozásai.

Experts dealing with patients of chronic upper and lower airway disorders have drawn a lot of interest in the last decades to gastrooesophageal reflux disease (GORD). Nowadays it is obvious that 'occult GORD' may be an aetiological factor in this group of patients. GORD may has a role in lot of organic laryngeal diseases and functional voice disorders. Symptoms are triggered by gastric content refluxed into the oesophagus, which cause irritation and inflammation. At laryngeal and phoniatric examinations gastrointestinal signs might remain hidden behind chronic cough, hoarseness and globus sensation. Authors summarise the diagnostic and therapeutic possibilities of GORD and its typical laryngeal and phoniatric manifestations. Although the first step is medication of GORD, it might come to surgical intervention of the laryngeal alterations, sometimes followed by voice therapy as well. Authors draw attention to patients after laryngectomy, whose voice rehabilitation therapy is extremely hindered by medical therapy resistant GORD. These patients may benefit of anti-reflux surgery.

A new method for reconstruction of the larynx after vertical partial resections.

The indications and problems of organ-preserving vertical partial laryngectomy (VPL) in cases of T1b glottic or T2 glottic and subglottic cancers are well known. The first and imperative requirement for the surgeon is adequate resection of tumor while the second prerequisite is the safe and successful correction of the excised portion of the anterolateral wall of the larynx. Since reconstruction of the defect can cause significant challenges for surgeons, the main requirements are an adequate lumen for breathing, a smooth surface for epithelialization, voice restoration and good deglution. Krajina's method for reconstruction of the larynx utilizes pedicled sternohyoid fascia, which is thin, elastic, well adaptable to defects, and resistent to infection or saliva. By providing a large surface for covering defects, granulations and synechiae can be prevented. We now use the superficial fascia colli as a new method for reconstruction of laryngeal defects after frontolateral partial resections. The technique was first refined experimentally in dogs. A Leroux-Robert partial laryngectomy was carried aut on five animals and laterally pedicled fascia was sutured to the edge of the defect created. At 2-week intervals through 8 weeks after the operation fixation, vascularization and epithelialization were examined histologically. To date, clinical reconstruction with the fascial flap has been used in 29 cases. Because the flap has a very low metabolism, no necrosis was seen. Functional results of respiration, phonation and swallowing have been good. These findings show that laterally pedicled fascia with the bipedicled sternohyoid muscles can play an important role in laryngeal reconstruction.

Indication and surgical technique for extended hemilaryngectomy.

Previous experience has shown that conservation of the healthy hemilarynx is possible for the treatment of extended lateralized laryngeal and hypopharyngeal cancers. One major indication for supracricoid hemilaryngectomy is glottic cancer involving either the arytenoid or Morgagni's ventricle. Hemilaryngopharyngectomy is also indicated when tumor of the pyriform sinus involves its anterior part, lateral wall, medial wall and ary- and pharyngoepiglottic folds. Supracricoid hemilaryngopharyngectomy was performed in seven cases. The resection consisted of removal of the surpacricoid hemilarynx and ipsilateral pyriform sinus. The reconstruction was performed by elevating the posterior pharyngeal wall and suturing the mucosa to the midline. This surgical technique provided good functional results. Patients had no airway impairments, but the recovery of satisfactory deglutition may require 14-32 days. Phonatory rehabilitation was successful, and each patient had a satisfactory vocal quality. Postoperative irradiation did not affect the functional results.

Three independently deleted regions at chromosome arm 16q in human prostate cancer: allelic loss at 16q24.1-q24.2 is associated with aggressive behaviour of the disease, recurrent growth, poor differentiation of the tumour and poor prognosis for the patient.

Loss of heterozygosity at chromosome arm 16q is a frequent event in human prostate cancer. In this study, loss of heterozygosity at 16q was studied in 44 prostate cancer patients exhibiting various clinical features. Fifteen polymorphic polymerase chain reaction (PCR) markers were used to identify the separately deleted areas and the findings were compared with clinicopathological variables and 5-year survival of the patients. The results indicated that there are at least three independently deleted regions at 16q. Allelic losses at the central and distal areas were associated significantly with aggressive behaviour of the disease (16q24.1-q24.2, P < 0.01, and 16q24.3-qter, P < 0.05), and the central area of deletion was further significantly associated with poorly differentiated tumour cells (P < 0.05) and with recurrent (P < 0.01) growth of the tumour. During the follow-up period, 28% of the patients initially with M0 disease developed distant metastases. Of the patients showing allelic loss at 16q24.1-q24.2, distant metastasis were found in 45% during the 5-year follow-up period, and 31% of the patients showing loss at 16q21.1 also developed distant metastases. After the 5-year follow-up period, 14 (32%) of the patients remained alive, whereas 19 (43%) had died because of their prostate cancer. The overall survival rate of the patients showing allelic loss at 16q21.1 or 16q24.1-q24.2 was significantly lower than that of the patients with retained heterozygosity.

Comparison of the bronchodilating efficacies of a novel salbutamol metered dose powder inhaler and a pressurised metered dose aerosol with a spacer.

In a two-day, randomised, double-blind, double-dummy, cross-over multicenter study, the bronchodilating effect of 100 micrograms of salbutamol (CAS 18559-94-9) inhaled from a new metered dose powder inhaler (MDPI; Taifun) was compared with that of an identical dose of salbutamol inhaled from a conventional pressurised metered dose inhaler connected to a spacer (pMDI + S). Thirty-six non-smoking, adult asthmatic outpatients with a baseline forced expiratory volume in 1 s (FEV1) between 35 and 70% of the predicted value participated in the study. After inhalation of the study medication pulmonary function, FEV1 and airway resistance (R(aw)), blood pressure (BP), and heart rate (HR) were measured up to 6 h. Area under the FEV1 vs. time curve (AUCFEV1) was used as the primary efficacy parameter, and the 90% confidence intervals (CI) were used to judge clinical equivalence. Other efficacy parameters were used in supportive analyses as secondary parameters. Both treatments produced a clear improvement in pulmonary function. The mean +/- SD AUCFEV1 were 893 +/- 281 and 889 +/- 2761.min after MDPI and pMDI + S, respectively. The 90% CI for the relative efficacy of the MDPI is from 98 to 103% of that of the pMDI + S. Also the other efficacy parameters gave similar results without significant differences: the mean +/- SD values of percent increase in FEV1 were 47.2 +/- 19.3 and 44.7 +/- 20.8, the maximum absolute value of FEV1 were 2.87 +/- 0.77 and 2.86 +/- 0.77, the maximum percent decrease in R(aw) 53.2 +/- 20.5 and 55.0 +/- 19.1, and the minimum absolute value of R(aw) 0.27 +/- 0.11 and 0.30 +/- 0.12 kPa.s.l-1 for the MDPI and pMDI + S, respectively. The salbutamol doses had no significant effect on BP or HR, and were equally well tolerated. Furthermore, 57.5% of the patients preferred the MDPI, 35% the pMDI + S, and 7.5% considered that there was no difference between the devices. In conclusion, this study demonstrates that the new MDPI is as effective and safe a device as a conventional pMDI connected to a spacer in administering inhaled salbutamol for asthmatic patients. Further, most patients considered the MDPI easier to handle, and preferred it over the pMDI + S.

Loss of heterozygosity at 16q24.1-q24.2 is significantly associated with metastatic and aggressive behavior of prostate cancer.

Several studies have indicated that in prostate cancer, frequent aberrations take place in several genomic regions. In the present study, we have analyzed allelic losses in chromosome 16 region q in 50 prostate cancer specimens of various histological grades. The most frequently deleted region was located at 16q23-16q24.2 between loci D16S504 and D16S422. The highest percentage of loss of heterozygosity (LOH) at 16q was also found within this area at loci HSD17B2 and D16S422 located at 16q24.1-q24.2. The LOH at 16q24.1-q24.2 was significantly associated with clinically aggressive behavior of the disease, metastatic disease, and higher tumor grade. Of the metastatic diseases, 83% showed LOH, whereas only 40% of the nonmetastatic diseases were found to show it. Similarly, LOH was found in 76% of the clinically aggressive diseases and in 33% of the nonaggressive diseases. The data suggest that a potentially important gene associated with prostate cancer progression is located close to 16q24.1-q24.2.

Characterization of 17beta-hydroxysteroid dehydrogenase isoenzyme expression in benign and malignant human prostate.

In the present study, expressions of 17beta-hydroxysteroid dehydrogenase (17HSD) types 1, 2, and 3, 5alpha-reductase type 2 and human androgen receptor mRNAs were determined in 12 benign prostatic hyperplasia and 17 prostatic carcinoma specimens. 17HSD type 2 was found to be the principle isoenzyme expressed in the prostate. Significantly higher expressions of 17HSD type 2 and 5alpha-reductase type 2 were detected in benign prostatic hyperplasia compared with the carcinoma specimens. Expression of the androgen receptor in the 2 groups was not significantly different. 17HSD type 3 mRNA was not detected in any of the specimens investigated. Only low constructive expression of the 2.3 kb mRNA of 17HSD type 1 was seen. Immunohistochemical analysis indicated that this did not lead to significant enzyme expression, only faint staining for the enzyme protein being detected, mainly in uroepithelial cells. No significant correlation was found between any of the mRNAs analysed, but the data on 5alpha-reductase type 2 mRNA support the presence of an increased proportion of 5alpha-dihydrotesterone in the hyperplastic prostate. In cultured PC-3 prostatic cancer cells and in the transiently transfected human embryonic kidney 293 cells, 17HSD type 2 was found exclusively to convert 5alpha-dihydrotestosterone and testosterone into the less potent 17-keto compounds 5alpha-androstanedione and 4-androstenedione, respectively. We suggest that the 17HSD type 2 isoenzyme plays a part in the metabolic pathway, resulting in the inactivation of testosterone and 5alpha-dihydrotestosterone locally in the prostate. The enzyme expressed in the prostate could, therefore, protect cells from excessive androgen action.

Mutated human androgen receptor gene detected in a prostatic cancer patient is also activated by estradiol.

Androgens are necessary for the development of prostatic cancer. The mechanisms by which the originally androgen-dependent prostatic cancer cells are relieved of the requirement to use androgen for their growth are largely unknown. The human prostatic cancer cell line LNCaP has been shown to contain a point mutation in the human androgen receptor gene (hAR), suggesting that changes in the hAR may contribute to the abnormal hormone response of prostatic cells. To search for point mutations in the hAR, we used single strand conformation polymorphism analysis and a polymerase chain reaction direct sequencing method to screen 23 prostatic cancer specimens from untreated patients, 6 prostatic cancer specimens from treated patients, and 11 benign prostatic hyperplasia specimens. One mutation was identified in DNA isolated from prostatic cancer tissue, and the mutation was also detected in the leukocyte DNA of the patient and his offspring. The mutation changed codon 726 in exon E from arginine to leucine and was a germ line mutation. The mutation we found in exon E of the hAR gene does not alter the ligand binding specificity of the AR, but the mutated receptor was activated by estradiol to a significantly greater extent than the wild-type receptor. The AR gene mutation described in this study might be one explanation for the altered biological activity of prostatic cancer.

Papova viruses and recurrent laryngeal papillomatosis.

The pathogenesis of larynx papillomas has been a challenge of medical science for a long time. Both clinical observations and electronmicroscopical examinations have made it possible to establish the viral origin. Final evidence, however, has been achieved only by complicated immunohistochemical investigations. The Papova viruses--types 6 and/or 11--can be detected with in situ hybridization polymerase chain reaction amplification. HPV can be positivity demonstrated not only from visible papillomas but--in significant percentage--in neighboring healthy-looking mucous membranes. It may reveal the inadequacies of removal of lesions and the need for adjuvant therapy. To make treatment more effective we have developed a therapeutic regimen that combines CO2 laser microsurgery with immunostimulants.

[Granular cell (Abrikosov) tumors treated with CO2 laser]. / Szemcsés sejtes daganatok (Abrikoszov) CO2 laser kezelése.

In five cases Abrikosoff-tumors were recognized and examined by electron microscope and immunohistochemical methods. The site of origin was at three patients the larynx and at 2 patients the tongue. The authors are dealing with the CO2-laser as a new treatment possibility of granular cell tumors. Since years they have not seen recurrences. Because of the painless postoperative period, the quick recovery and good functional results CO2-laser surgery seems to be the treatment of choice in these cases.

Investigation of premalignant lesions of larynx epithelium with histoautoradiography and HPV-assay.

The histological evaluation of precancerous alterations of larynx epithelium is, in transitional cases, very difficult. The differentiation of harmless metaplasia, hyperplasia and keratosis from abnormal proliferation depends on the pathologist's training and experience. Fine diagnostic lines separate the different grades of dysplastic epithelial alterations. The tritiated thymidine, 3H-TdR, labelling and histoautoradiographic procedure of biopsy specimens taken from the larynx provide the possibility to recognise the DNA synthetiser cells. The number, location and distribution of 3H-TdR labelled cells in the epithelial layers help us to distinguish with clarity the growth activity, the degree of dysplasia. After 3 weeks' exposition time of sections prepared by photoemulsion and stained with haematoxilin-eosin, the result can be assessed. In addition to histoautoradiography HPV-assay was applied, as HPV may play a role in the pathogenesis of laryngeal preneoplastic alterations.

Terbutaline controlled-release tablets and ipratropium aerosol in nocturnal asthma.

The effect of oral terbutaline (controlled-release [CR] tablets) was compared with that of inhaled ipratropium bromide (aerosol) in 21 patients with nocturnal asthma. In a randomized, double-blind, crossover study, the patients were treated with terbutaline CR 10 mg twice daily, ipratropium 40 micrograms four times daily, and the two drugs in combination. Each treatment was given for 3 weeks. Before the start of the study, the patients participated in a 1-week run-in period. The mean nocturnal decline in peak expiratory flow rate (PEFR) was 29% in the run-in period and was reduced to 22% in the terbutaline CR period, 27% in the ipratropium period, and 23% in the period with the combination of the two drugs. The mean night PEFR was significantly (P < 0.05) higher in the period with terbutaline CR, as compared with the period with ipratropium. The mean morning PEFR was also highest in the terbutaline CR period. The mean evening PEFR was significantly (P < 0.05) higher during treatment with terbutaline CR alone and with the combination, as compared with treatment with ipratropium alone. Treatment with terbutaline CR alone or the combination was preferred by as many patients as was treatment with ipratropium alone. When present, adverse reactions were judged to be mild or moderate. Treatment with terbutaline CR alone and the combination significantly improved the evening and night PEFR, as compared with treatment with ipratropium alone.

Synovial sarcoma of the hypopharynx in an 11-year-old boy: treatment by partial supraglottic laryngopharyngectomy.

Synovial sarcoma in an extra-articular location is a very rare tumor, particularly in relation to childhood tumors. We report our experiences with an 11-year-old boy who suffered from swallowing difficulties caused by a polypoid tumor of the hypopharynx. Biopsy demonstrated a fusocellular carcinoma, while the epithelial components showed cytokeratin and neuron-specific enolase positivity. A correct final diagnosis could only be established by the histology of the surgical preparation following partial laryngopharyngectomy. The presence of spindle cells associated with glandular-like ones proved the synovial character of the tumor. The spindle cells were negative for epithelial marker but were positive for vimentin. S-100 protein positivity could only be demonstrated in the nerve elements encapsulated in the tumor. Ultrastructural examinations confirmed the presence of the different cell types. The spindle cells were rich in intermediate fibers, as demonstrated by electron microscopy.