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.

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.

North Karelia (Finland) hypertension detection project. Five-year follow-up of hypertensive cohort.

A 5-year follow-up study of a random sample of middle-aged hypertensives indicated that the North Karelia (Finland) Hypertension Detection Project was effective in reducing blood pressure levels. This analysis indicated that the intensification of drug treatment caused marked blood pressure reduction in the community, especially among individuals with previously undetected cases of hypertension. Reduction of blood pressure levels among nontreated persons was observed in this study and may reflect in part the importance of both active case finding and follow-up including health education and preventive services. The community approach used in this study reached and brought under control most of those people who were undetected at the beginning of the study and most of the hypertensives. On the basis of the results, it is concluded that a well-organized hypertension control program can meet the challenge of hypertension care and benefit millions of people throughout the world.

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.

Experience with labetalol in essential hypertension.

A study was carried out in 73 patients with mild or moderate hypertension to assess the effectiveness of treatment with labetalol. After a 2 to 4-week period on placebo, patients received 200 mg labetalol daily for 4 weeks, after which time dosage was doubled if the blood pressure was not satisfactorily controlled. Treatment was continued for a further 4 weeks and was followed by another period on placebo. Pre-treatment levels of 157/99 mmHg were significantly reduced after 2 weeks, and after 4 weeks the mean reduction was 14/8 mmHg. Half the patients had their dosage increased to 400 mg daily. At the end of the 8-week active treatment period, 80% were adequately controlled, the mean reduction in blood pressure being 22/12 mmHg compared with placebo values. Heart rate was significantly reduced from 78 to 69 beats per min during labetalol therapy. The reduction in blood pressure was similar whether or not patients had been previously treated or untreated, but heart rate was reduced more in the previously treated group. Four weeks after the end of labetalol therapy blood pressure and heart rate had increased but were less than during the initial placebo period and did not give rise to any severe problems.

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.

Implementation of a hypertension control program in the county of North Karelia, Finland.

A hypertension control program was established as part of the more comprehensive North Karelia Project. This project was started in 1972 in response to a petition from the population of North Karelia, a county in Finland, asking for national assistance to reduce the exceptionally high cardiovascular disease mortality and morbidity in the area. The North Karelia Project was carried out from 1972 to 1977.The hypertension control program was implemented mainly in local health centers by physicians and public health nurses, who followed guidelines issued by the project staff and worked under its supervision.Although the target population for the North Karelia Project was the entire population of North Karelia, the project focused on middle-aged men. The hypertension subprogram was introduced in steps. Its objectives included the training of health personnel, establishment of an information system in the county to educate people about hypertension, and organization of the detection, treatment, and followup of hypertensives. A hypertension dispensary was established in each of the 12 health centers in the county. Continuous training of the local public health nurses and physicians faciliated integration of the hypertension program into the operations of the health centers.A central hypertension register and the hypertension control clinics at the health centers were the essential tools in the systematic followup of hypertensives. Some 17,000 hypertensives were on the register by the end of the 5-year project.The main aim in providing health education about hypertension, as well as in treating hypertension itself, was to prevent severe cardiovascular diseases as a whole. Therefore the hypertension control program was integrated into the comprehensive cardiovascular disease control program, and hypertensives received advice concerning smoking and dietary changes as well as about high blood pressure.A survey of health care personnel in North Karelia and in a reference area showed that the care of hypertensives was more systematic in North Karelia and that its health care personnel were more satisfied with the cardiovascular disease care that was provided.

Relationship between "dynamic histology" and metastases of laryngeal tumors.

The clinical characteristics of laryngeal cancer, its site and extent, determine the incidence of regional metastases. However, data have also shown that lymph node involvement is influenced by the degree of malignancy of the tumor. In the course of histoautoradiographic processing of 79 laryngeal tumors and a 5-8-year follow-up study of the patients, a correlation between proliferative activity and incidence of metastasis was found. Well differentiated tumors with low proliferative activity rarely metastasized whereas in cases of slightly differentiated tumors of strong proliferative activity the occurrence of manifested or occult metastases should always be taken into consideration. The state of the lymph node determines decisively the prognosis and treatment of laryngeal cancer. In some cases, preventive interventions may improve the therapeutical results in seriously endangered patients.

[The value of cell proliferation and histomorphology in the planned treatment of laryngeal neoplasms]. / Die Bedeutung der Zellproliferation und Histomorphologie bei der Geplanten Behandlung der Kehlkopfkarzinome.

The separation of phases in cell division and the recognition gained in tissue population kinetics have contributed to enhance our knowledge of the biological behaviour of the tumours. Besides the determination of clinical characteristics (localization, TNM state) and the onchotype of a given tumour, findings obtained by cell-kinetic parameters seem to be of great importance. Relations between the degree of malignity and the data obtained by autoradiography were studied in patients suffering from laryngeal cancer. On the basis of the simple clinical determination of L.I. and Ts, estimation of further cell-kinetic parameters in a given tumour has become possible and the number of cells in the same cycle, the growth faction, and the potential doubling-time can be deduced. After the radiographic investigation of 78 cases of laryngeal tumour a relation was found between the extent of the labelling index and the biological behaviour of the tumour.

The morphological basis for development of Reinke's oedema.

Normal human vocal cords and surgically removed Reinke's oedema were studied by light and electron microscopy. The Reinke's space between the lamina propria and vocal ligament was filled with loose connective tissue sheets, which seemed to be an organic part of the vocal ligament. The structure suggested the possibility of the lamellae moving on each other. This could be important for the vibratory function of vocal cords. Inside the lamellae, masses of inmature young elastic fibres were found. Reinke's oedema develops in the superficial elastic sheets. Therefore in the case of surgical intervention the specially structured rubbery elastic vocal cord mucosa must be removed, which is essential to perfect vibratory function.

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.

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.

[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.

[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.