Tavipec in acute rhinosinusitis: a multi-centre, doubleblind, randomized, placebo-controlled, clinical trial.

BACKGROUND: This randomized clinical trial was designed to evaluate the efficacy and safety of Tavipec® (Spicae aetheroleum), a phytomedicine obtained by steam distillation of the flowering tops of Lavandula latifolia, as compared to placebo in adult patients suffering from acute viral rhinosinusitis. METHODOLOGY: Patients with acute viral rhinosinusitis were randomly assigned to treatment with 2 capsules Tavipec® 150 mg or placebo thrice daily over a period of 7 days in a double-blind, parallel-group design. No additional treatment was admitted. The efficacy endpoints comprised the improvement of the main rhinosinusitis symptoms as per Major Symptom Score (MSS) and Sino-Nasal Outcome Test (SNOT-22) as well as of quality of life (QoL) by global assessment scale, evaluated at baseline, day 5 and day 8, respectively. RESULTS: 288 patients were enrolled and randomized to treatment. At day 8 the patients in the Tavipec® group had a significantly lower MSS compared to placebo and the impact of rhinosinusitis symptoms on QoL was significantly reduced. A significantly higher proportion of Tavipec® treated patients experienced a change in SNOT-22 score greater than or equal to 10 points at day 5 or day 8. No new safety signals were identified. CONCLUSIONS: The treatment with Tavipec® effectively reduced the symptoms of acute rhinosinusitis in adult patients.

Morphometric study of the human suprarenal gland in the first postnatal year.

The aim of present, study was to describe adrenal volume, volumes of adrenocortical zones, and stroma volume in 40 adrenals obtained from children between 1st and 370th day during autopsy. The postnatal decrease in adrenal volume was caused mainly by rapid fall of fetal zone (FZ) volume (from 70 to 3% of total adrenal volume), that can be divided into two phases: rapid phase (from birth to the end of the second week) and a slow phase from the 3rd week on. Involution was accompanied by increase of zona glomerulosa (ZG) (from 10 to 25% of total adrenal volume), zona fasciculata ZF (from 10 to 38%) and zona reticularis (ZR), volume (from 1 to 23%). During the whole investigated period the volume of medulla remained constant. The volume fraction of stroma (connective tissue and blood vessels) was highest at the beginning of the first postnatal week and then decreased rapidly at the end of the 2nd week, with the most pronounced changes in the fetal zone and medulla. Performed present stereological study confirms opinion that hemorrhagic mechanisms are involved in the involution process of the human fetal zone.

Polyhormonal aspect of the endocrine cells of the human fetal pancreas.

Histological studies were performed on 30 pancreases obtained from normal human fetuses aged between the 9th and 38th week. For immunocytochemistry, the avidin-biotin-peroxidase method was used to identify and colocalise insulin, glucagon, somatostatin, pancreatic polypeptide and proliferating cell nuclear antigen. In the 9th week, cells containing all investigated peptides were present. During the fetal period, two populations of endocrine cells have been distinguished, Langerhans islets and freely dispersed cells. The free cells were polyhormonal, containing insulin, glucagon, somatostatin and pancreatic polypeptide, and were localised in the walls of pancreatic ducts throughout the whole gland. During the development of the islets we have observed four stages: (1) the scattered polyhormonal cell stage (9th-10th week), (2) the immature polyhormonal islet stage (11th-15th week), (3) the insulin monohormonal core islet stage (16th-29th week), in which zonular and mantle islets are observed, and (4) the polymorphic islet stage (from the 30th week onwards), which is characterised by the presence of monohormonal cells expressing glucagon or somatostatin. Bigeminal and polar islets also appeared during this last stage. The islets consisted of an insulin core surrounded by a thick (in the part developing from the dorsal primordium) or thin rim (part of the pancreas concerned with the ventral primordium) of intermingled mono- or dihormonal glucagon-positive or somatostatin-positive cells. The most externally located polyhormonal cells exhibited a reaction for glucagon, somatostatin and pancreatic polypeptide. Apart from the above-mentioned types of islets, all arrangements observed in earlier stages were present. Proliferating cell nuclear antigen-positive cells (single in the large islets and more numerous in the smaller ones) were predominantly observed in the outermost layer. Taken together our data indicate that, during the human prenatal development of the islet, endocrine cells are able to synthesise several different hormones. Maturation of these cells involved or depended on a change from a polyhormonal to a monohormonal state and is concerned with decreasing proliferative capacity. This supports the concept of a common precursor stem cell for the hormone-producing cells of the fetal human pancreas.

Proliferating-cell nuclear antigen (PCNA) in the human adrenal glands at the end of the embryonic period.

Studies were performed on adrenal glands of 7 human embryos between 6 and 8 weeks of intra-uterine life using clone PC-10 mouse serum (Dako, No. M879). During the 6th week, immunoreactivity for the proliferating-cell nuclear antigen (PCNA) was observed only in the central and medial parts of the developing fetal zone of the adrenal gland (75.2 +/- 3.1% of adrenocortical cells showed nuclei stained with anti-PCNA), while the peripheral part was immunonegative. One week later the second outer layer, i.e. the permanent cortex appeared. During the 8th week, the cortex formed two distinct zones: a relatively large and centrally located fetal zone and a thin rim of definitive (permanent) cortex, the later adult adrenal cortex. PCNA-positive cells were present throughout the surface of the gland being most numerous in the center (76.4 +/- 1.4%) and less numerous in the peripheral part (16.6 +/- 2.6%). A very thin layer of permanent cortex surrounding the fetal zone showed less numerous cells stained for PCNA (36.4 +/- 3.4%) as compared with the inner fetal zone. During the 8th week the proliferative cells activity was similar in both zones. The middle proliferative center of the fetal zone disappeared, and all cells of this zone had similar PCNA reactivity.

Postnatal involution of the human adrenal fetal zone: stereologic description and apoptosis.

During the first weeks of postnatal development the fetal zone (FZ) of the human adrenal cortex rapidly disappears. Present studies aimed to describe cellular aspects of this involution and to correlate them with apoptosis. Adrenals of 38 newborns and infants (aged 1-240 days) were obtained from autopsies due to accidental death. Postnatal decrease in the adrenal gland weight may be divided into 2 distinct phases: rapid one lasting from the birth till the end of the second week of life, and followed by a slower one. This decrease is highly correlated with the decrease of both: the volume of FZ and quantity of its cells. During the whole investigated period, volume of the FZ decreases from 8,017 to 248 mm3 (from 70 to 3% of total adrenal volume) and the quantity of its parenchymal cells from 3 x 10(9) to 0.15 x 10(9) (from 40 to 5% of all parenchymal cells). The average volume of the FZ cell decreases from 2,200 to 1,400 microm3. The volume of FZ stroma (connective tissue and blood vessels) expands notably during the first day and decreases from day 5th of life. The apoptotic index of the FZ parenchymal cells is the highest during the second week of life (ca 30%), and subsequently declines (ca 20%). Thus, the rapid involution of the FZ is connected with marked hemorrhagic changes and increased apoptotic index of parenchymal cells, while during the slow phase (after 2nd week on) apoptotic index is lower and rather constant.

Comparative stereological study on zonation and cellular composition of adrenal glands of normal and anencephalic human fetuses. I. Zonation of the gland.

Comparative stereological studies were performed on zonation of adrenal glands in 10 anencephalic and 11 normal fetuses, aged between 24 and 39 postovulatory weeks. The development of adrenal fetal zone (FZ) is the main factor responsible for normal adrenal gland growth during the intra-uterine life. At the end of fetal period volume of this zone attains over 8200 mm3 and constitutes 69-70% of the total gland volume, while respective values for zona glomerulosa (ZG), zona fasciculata (ZF) and medulla (M) are 1665 mm3 (14%), 833 mm3 (7%) and 1071 mm3 (9%). These data were in striking contrast with those found in adrenals of anencephalic fetuses, in which volume of the gland attained only ca 35% of that in normal fetuses. In the oldest anencephalic fetus studied (39 weeks) the volume of the fetal zone was 962 mm3 (ca 8-folds lower than in normal fetus) comprising only 25% of the total gland volume. For the remaining zones the values were: ZG-1501 mm3 (ca 90% of the normal value and 39% of the total gland volume); ZF-770 mm3 (ca 92% and 20% respectively), and M-539 mm3 (ca 50% and 14%, respectively). This stereological study provides the first systemic description of the development of adrenal gland of anencephalic fetuses in comparison with the normally developing gland. Moreover, evidence is given that the growth of adrenal medulla is also retarded in anencephaly while the growth of the zona glomerulosa remains rather unaffected.

Comparative stereological studies on zonation and cellular composition of adrenal glands of normal and anencephalic human fetuses. II. Cellular composition of the gland.

In our previous paper (Bocian-Sobkowska et al., 1997) we demonstrated a striking difference in development of zonation in adrenals of normal and anencephalic human fetuses. The purpose of the present study was to characterize, by means of stereology, the cellular composition of developing adrenals in the same case. Studies were performed on 11 pairs of adrenal glands from normal fetuses and 10 from anencephalic fetuses. In the studied period of development (24 to 39 weeks of intra-uterine life) the average volume of cells in normal glands increased as follows: zona glomerulosa (ZG) from 355 to 870 microns3; zona fasciculata (ZF) from 779 to 1200 microns3; fetal zone (FZ) from 2004 to 2380 microns3: and medulla (M) from 600 to 970 microns3. In anencephalic fetuses, the appropriate values were: ZG-380-680 microns3; ZF-460-680 microns3; FZ-1820-1680 microns3; and M-870-1400 microns3. At the end of the studied period the number of ZG cells in normal fetuses was two fold higher than in anencephalics, ZF cells-6-fold and in FZ-5-fold higher, while in the M the number of cells was nearly equal in both groups. During the whole investigated period of intra-uterine development the total number of adrenocortical cells in normal glands increased ca 2.5-fold, while in anencephalic glands only ca 0.5-fold, reaching at the end ca 40% of normal value. In both normal and anencephalic adrenals the number of ZG and M cells was highly correlated with ZG/M cell ratio, being slightly higher in normal glands. No such relation was demonstrated for cells of the remaining adrenocortical zones.

17 alpha-Hydroxylase and chromogranin A in 6th week human fetal adrenals.

The development of the human fetal adrenals starts in the 6th week gestational age and adrenal C19 steroid production becomes of major importance for the maintenance of the pregnancy. Therefore, in the present study, human fetal adrenals at 6 weeks of gestational age were immunostained for 17 alpha-hydroxylase, the key enzyme for the production of C19-steroids. In parallel, chromaffin cells were characterized by immunohistochemical staining for chromogranin A, the major soluble protein in adrenal chromaffin granules. Large 17 alpha-hydroxylase-immunoreactive cells were found in the center of the adrenal anlagen during the 6th week of gestation. At the same developmental stage, chromaffin cells with a neuronal-like appearance occurred in the paraortic area and started to invade the adrenal primordium. Our results show that, even at week 6 gestational age, when chromaffin cells start to enter the adrenal anlagen, human adrenals already contain differentiated, 17 alpha-hydroxylase immunoreactive cortical cells which were located to the center of the primordium.

Morphometric studies on the development of the human thyroid gland. II. The late fetal life.

Histological and morphometric studies were performed on 27 thyroid glands obtained from normal fetuses ranging between 23 to 40 weeks of intra-uterine life. In the thyroids the volume of gland, colloid, and stroma were calculated by means of differential pointcounting method and the height of the thyroid follicular cells was measured. Moreover, the epithelium/colloid ratio in the thyroid gland, a very sensitive parameter of stimulation of the glands by TSH, was calculated. Regarding the values of this ratio in human fetal thyroid gland, the intra-uterine development of the gland may be divided into three distinct stages. The first one, between weeks 10-18 is characterized by massive folliculogenesis and gradual accumulation of the colloid. The second stage, between weeks 19-29 of fetal life is characterized by rather unchanged values of epithelium/colloid ratio and the size of follicles. The third stage, after the 29th week of development is characterized by a gradual increase in the epithelium/colloid ratio and a decrease in the size of follicles.

Prenatal development of the human pancreatic islets. Immunocytochemical identification of insulin-, glucagon-, somatostatin- and pancreatic polypeptide-containing cells.

Histological studies were performed on 24 pancreases of normal human embryos and fetuses aged 7 to 38 weeks. For immunocytochemistry, the avidin-biotin-peroxidase method was used to identify and localize insulin, glucagon, somatostatin, and pancreatic polypeptide (PP) cells. In 7 wk old embryos, cells containing somatostatin and PP are observed. One week later appear single glucagon-positive cells. In the 9th wk, insulin producing cells are visible. During the fetal period two populations of the investigated cells are found: Langerhans islets and dispersed cells. The latter cells containing insulin, glucagon or somatostatin are localized in the walls of pancreatic ducts throughout the whole gland, while PP-positive cells are seen mainly in the part of the pancreas, which develops from the ventral anlage (anteroinferior part of the head and adjacent part of the main pancreatic duct). During the development of islets we have observed four stages: (1) scattered cells (7 to 10 weeks); (2) grouping cells (11 to 15 weeks); (3) mantle and zonular islets (10 to 29 weeks), in which B cells located inside are surrounded by a thick zone of A, PP and somatostatin-producing cells; (4) mixed islets (from 30 weeks on) - all cells are scattered over the whole transverse section of the islet. In the developing pancreas, the glucagon- and somatostatin-containing cells are the most numerous, while the insulin and PP-containing cells occur in lesser quantities.

Stereology of human fetal adrenal medulla.

Stereological studies were performed on 27 pairs of adrenal glands of human fetuses (9-38 weeks of intra-uterine development). Medullary chromaffin cells were identified by immunostaining for chromogranin-A. The volume of adrenal medulla, average cell volume, and the number of chromaffin cells were calculated. The volume of adrenal medulla increased slowly up to the 20th week and afterwards it enlarged rapidly to the 31 st week of the fetal period. A gradual, linear increase in the number of chromaffin cells of developing adrenal medulla was observed during the studied period. On the contrary, the average volume of the adrenal medullary cells remained quite constant until the 17th week of the development. Afterwards, a gradual, linear increase in the cell volume was observed until the 31 st week, reaching a plateau by the end of intra-uterine development.

PAS positive substance in the human embryonic thyroid gland at stage 23.

Human thyroid gland was investigated in 6 embryos at stage 23. In 4 embryos, in the peripheral part of the thyroid gland, distinct follicles were observed. Some of them were filled with PAS positive substance.

Cytological aspects of the human adrenal cortex development in the course of intra-uterine life.

Stereological studies were performed on 20 pairs of adrenal glands of human foetuses. The volume of particular adrenocortical zones, average cell volume and number of parenchymal cells were calculated. In 50 to 320 mm crown-rump length (C.-R.L.) foetuses (9-38 weeks of the intra-uterine life) an exponential increase in adrenal gland weight was found. If compared with the earlier period, the rate of increase was evidently higher beginning from the 20th week and depended mainly upon enlargement of the foetal zone, with less marked changes in the glomerulosa-fasciculata zone. The zona glomerulosa (ZG) and the outer zona fasciculata (ZF) began to delineate by the 20th week of gestation. Zona reticularis was not observed in our material. From the beginning of development, fasciculata cell volume was markedly higher than that of ZG cells and lower than foetal zona (ZX) cells. Until the 20th week of intra-uterine life the volume of glomerulosa-fasciculata zone (G-FZ) increased at a slow rate, while the rate of increase in volume of ZX was higher. After 20 weeks the rate of increase in volume of all adrenocortical zones was markedly higher (the same as that of the stroma). The volume of stroma in ZX markedly exceeded that in the remaining parts of the cortex. The average cell volume of ZG and ZF remained constant during the foetal period, while the average cell volume of ZX cells increased gradually from the 9th to the 20th foetal week and afterwards remained unchanged. (ABSTRACT TRUNCATED AT 250 WORDS)

Morphometric studies on the development of human thyroid gland in early fetal life.

Histological and morphometric studies were performed on 30 thyroid glands obtained from normal human fetuses. Their crown-rump length (CRL) ranged from 57 to 190 mm, corresponding to the gestational age of 10-20 weeks. The weight of the thyroid gland increased proportionally in relation to CRL, foot length and fetus weight. The first follicles containing PAS-positive colloid were observed in the peripheral part of the thyroid gland of 57 mm CRL fetus. The number of follicles per 1 mm2 of thyroid surface section increased up to 85 mm CRL and thereafter gradually declined for the end of studied period of fetal life. The volumes (in mm3) of thyroid epithelium, colloid and stroma, beginning from 85 mm increased proportionally to the CRL while the height of epithelial cells did not change. The epithelium/colloid ratio decreased notably to 165 mm CRL and thereafter remained constant. Results of the present study suggest that the thyroid gland of human fetus approaches structural maturity in 17.5 week of gestation.