Epidemiology and molecular diversity of rabies viruses in Bulgaria.

A health emergency situation occurred in Bulgaria in 2007 when positive rabies cases were notified in Sofia district in the central-western part of the country, suggesting a southward spread of the disease for the first time in the last 10 years. Phylogenetic analysis on 49 isolates sampled between 2009 and 2011 showed, for the first time, evidence of the existence of NEE and D clustered lineages in Bulgaria. Their geographical distribution clearly reveals the permeability of natural barriers, as already suggested by the disease spread that occurred across the Balkan mountain range in 2007. The monitoring and passive surveillance programmes conducted since the first 2009 oral vaccination campaign, the spatio-temporal evolution of the disease in the country since 2007, and the need for further investigation of the role of jackals in virus dispersion are discussed.

Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer.

Human breast tumors comprise a minor sub-population of tumor-initiating cells (TICs), commonly termed cancer stem cells. TICs are thought to sustain tumor growth and to confer resistance to current anticancer therapies. Hence, targeting TIC may be essential to achieving durable cancer cures. To identify molecular targets in breast TIC, we employed a transgenic mouse model of ERBB2 breast cancer; tumors arising in this model comprise a very high frequency of TIC, which is maintained in tumor cell populations propagated in vitro as non-adherent tumorspheres. The Notch pathway is dysregulated in human breast tumors and overexpression of constitutively active Notch proteins induces mammary tumors in mice. The Notch pathway has also been implicated in stem cell processes including those of mammary epithelial stem cells. Hence, we investigated the potential that the Notch pathway is required for TIC activity. We found that an antagonist of Notch signaling, a gamma (γ)-secretase inhibitor termed MRK-003, inhibited the survival of tumorsphere-derived cells in vitro and eliminated TIC as assessed by cell transplantation into syngeneic mice. Whereas MRK-003 also inhibited the self-renewal and/or proliferation of mammosphere-resident cells, this effect of the inhibitor was reversible thus suggesting that it did not compromise the survival of these cells. MRK-003 administration to tumor-bearing mice eliminated tumor-resident TIC and resulted in rapid and durable tumor regression. MRK-003 inhibited the proliferation of tumor cells, and induced their apoptosis and differentiation. These findings suggest that MRK-003 targets breast TIC and illustrate that eradicating these cells in breast tumors ensures long-term, recurrence-free survival.

Systematic strength training as a model of therapeutic intervention. A controlled trial in postmenopausal women with osteopenia.

Physical exercise is often recommended as a therapeutic tool to combat pre- and postmenopausal loss of bone density. However, the relationship between training dosage (intensity, duration, frequency) and the effect on bone density still is undergoing discussion. Furthermore, the exercise quantification programs are often described so inadequately that they are neither quantitatively nor qualitatively reproducible. The aim of this investigation was to determine whether a clearly defined training of muscle strength, under defined safety aspects, performed only twice weekly, can counteract bone density loss in women with postmenopausal osteopenia. Data from 16 women in the training group (age, 63.6 +/- 6.2 yr) and 15 women in the control group (age, 67.4 +/-9.7 yr), of comparable height and weight, were evaluated. Strength training was performed for 6 mo as continually adapted strength training, providing an intensity of about 70% of each test person's one repetition maximum. Bone mineral density of lumbar vertebrae 2 to 4 and the femoral neck was measured by dual-energy x-ray absorptiometry. Maximum performance in watts and parameters of hemodynamics were controlled with a bicycle ergometer test to maximal effort. In addition, metabolic data were assessed. In the lumbar spine and femoral neck, the training group showed no significant changes, whereas the control group demonstrated a significant loss of bone mineral density, especially in the femoral neck (P<0.05). The strength increase was highly significant in all exercised muscle groups, rising to about 70% above the pretraining status (P<0.001). Heart rate and blood pressure data indicated a slight economization, metabolism was not significantly influenced. Based on these findings, we conclude that continually adapted strength training is an effective, safe, reproducible, and adaptable method of therapeutic strength training, following only two exercise sessions per week.

D2 receptor blockade by flunarizine and cinnarizine explains extrapyramidal side effects. A SPECT study.

Twenty-six patients under treatment with the calcium channel blockers flunarizine (Fz) or cinnarizine (Cz) were examined-with single-photon emission computed tomography using [123I]iodobenzamide as a ligand. The striatal dopamine D2 receptor-binding potential was determined and found to be reduced by 14 to 63% (39.5 +/- 15.0%; p < 0.0001) in patients compared with age-matched control values. This reduction was larger in 12 patients with extrapyramidal symptoms and was only slowly reversible after discontinuation of treatment. Patients treated for > 6 months had significantly larger reductions than patients treated for a shorter period. Parkinsonian symptoms were only seen in patients older than 50 years. Our findings prove a neuroleptic-like action of Fz and Cz, which seems to be the major reason for their extrapyramidal side effects. Older age and long-term treatment are predisposing factors for these effects.

[Tension headache--new evaluation of symptomatology based on International Headache Society diagnostic criteria]. / Spannungskopfschmerz--Neubewertung der Symptomatologie anhand der IHS-Diagnosekriterien.

This study presents the history and clinical findings in 80 patients suffering from tension-type headache diagnosed according to the criteria (group 2) proposed in 1988 by the Headache Classification Committee of the International Headache Society (IHS). The aim of this investigation was to evaluate the extent to which the symptomatology in our cases still corresponds with the clinical picture of tension headache described in the older literature. A positive family history of headache was obtained in 59% of the patients; mothers of headache patients were affected five times more often than fathers; a history of migraine was reported as frequently as tension-type headache in the families of the investigated patients. The first manifestation of headaches arose almost exclusively in the first four decades of life, whereby two peaks (15-20 and 35-40 years) were observed in patients with the episodic form. Headache in younger patients showed no distinct diurnal pattern; headache in older patients, however, predominantly occurred immediately after awakening from sleep or in the morning. Changes of weather and psychosocial stress were the most frequent precipitating factors; additionally, the premenstrual period, occupational stress, and sleep deprivation were precipitating factors in female patients. Bilateral pain was most often located in the occipital/nuchal, in the frontal, and the periorbital regions. Headache was usually described as pressing/tightening in quality. Difficulties in concentration and the need of rest were the most important associated symptoms. Photophobia, phonophobia and autonomic symptoms were less frequent and are probably partially drug-related and may also be due to the fact that the selected group of patients suffered from severe forms of headache. 33 of our 80 patients belonged to the subgroup "with disorders of pericranial muscles" (IHS criteria: groups 2.1.1., 2.2.1). A remarkable low percentage of patients, especially of the male sufferers, reported regular smoking and/or drinking habits. Oral contraceptives influenced neither frequency nor intensity of headache attacks. Signs of depressive disorders were present in 28% of the female patients. The differences in symptomatology of tension-type headache between patients with episodic and chronic forms, between female and male patients, and also between younger and elderly patients are documented and have to be taken into account in the diagnostik evaluation of this condition.

Effect of combined acyclovir and ribavirin on experimental herpes simplex virus type 1 keratoconjunctivitis in rabbits.

The combination of acyclovir and ribavirin has been established to be more effective on experimental herpes simplex keratoconjunctivitis in rabbits than the treatment with individual drugs. The better therapeutic effect of the combination is proved by the decreased severity of the ocular infection and the reduction of the virus shedding in tear film, as well as by the diminished duration of the infection.

Antiherpes effect of Melissa officinalis L. extracts.

Studies were carried out on the virucidal and antiviral effects of Melissa officinalis L. extracts (M1, M3, M3 and M4) with respect to Herpes simplex virus type 1 (HSV-1). Virucidal effect was registered within 3 and 6 hours of treatment using M4 administered in MTC. The remaining extracts inactivate the virus at the 12th and 24th hour. No significant values of inhibiting activity of M1, M2, and M3 on the same virus in vitro or in vivo were demonstrated. The presence of caffeic, rosmarinic and ferulic acids was demonstrated by thin-layer chromatography. Their role in the antiviral activity of M. officinalis L. is discussed.