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The aetiology of dystonia disorders is complex, and next-generation sequencing has become a useful tool in elucidating the variable genetic background of these diseases. Here we report a deleterious heterozygous truncating variant in the inosine monophosphate dehydrogenase gene (IMPDH2) by whole-exome sequencing, co-segregating with a dominantly inherited dystonia-tremor disease in a large Finnish family. We show that the defect results in degradation of the gene product, causing IMPDH2 deficiency in patient cells. IMPDH2 is the first and rate-limiting enzyme in the de novo biosynthesis of guanine nucleotides, a dopamine synthetic pathway previously linked to childhood or adolescence-onset dystonia disorders. We report IMPDH2 as a new gene to the dystonia disease entity. The evidence underlines the important link between guanine metabolism, dopamine biosynthesis and dystonia., (© 2021. The Author(s).)

Background, Material and Methods: All cases of acute dental, oral and pharyngeal infections that were referred to Mikkeli Central Hospital during a 25-month period were retrospectively analyzed., Results: Thirty-nine percent of the total of 394 cases needed intravenous antibiotics. Tonsillar infections were most prevalent (27%), followed by peritonsillar abscesses (25%) and dental infections (20%). Twenty patients (5%) had cervical or submandibular cellulitis or abscess requiring immediate surgery and an average 8.5 days of in-patient treatment. The most prevalent (45%) bacteriological result was miscellaneous "normal flora"., Conclusions: Imminent oropharyngeal infection may require immediate surgery and intravenous antibiotics.

Background. Endoscopic sinus surgery (ESS) is considered for chronic rhinosinusitis (CRS) after failure of conservative therapy. Objective. The aim of this study was to evaluate endoscopically ostium patency and mucosal recovery after ESS, with either maxillary sinus ostium-preserving or -enlarging techniques. Materials and Methods. Thirty patients with non-polypous CRS were enrolled. Uncinectomy-only and additional middle meatal antrostomy were randomly and single-blindly performed for each side. Pre- and postoperative endoscopic scores were semi-quantitatively determined according to findings in the ostiomeatal complex area. Adhesions, maxillary sinus mucosal swelling, secretions, and ostium obstruction were also endoscopically evaluated. In addition, symptoms were asked and computed tomography scans were taken preoperatively and 9 months postoperatively. Results. At 16 days postoperatively, a better endoscopic score and a less obstructed ostium were found with antrosomy. At 9 months postoperatively the endoscopic score improved significantly and identically with both procedures, however, obstructed ostia and sinus mucosal swelling/secretions were insignificantly more frequently found on the uncinectomy-only side. Endoscopic and radiologic findings of the maxillary sinus mucosa and ostium correlated significantly 9 months postoperatively. Conclusion. There was a good long-term mucosal recovery with both surgical procedures. In terms of early mucosal recovery and ostium patency, antrostomy might be slighly superior.

Endoscopic sinus surgery (ESS) is the most used surgical approach in the treatment of chronic and recurrent maxillary rhinosinusitis. However, it still remains unclear how well surgery restores the mucociliary function in damaged maxillary sinus mucosa. There is also controversy whether to enlargen the natural ostium or not. We examined the mucociliary clearance (MCC) of maxillary sinuses in 27 patients with chronic and recurrent rhinosinusitis. On one side only an uncinectomy was done, on the contralateral side a middle meatal antrostomy was additionally performed. The mucociliary clearance (MCC) was measured in both sides preoperatively and 9 months after the operation. Measurements of the mucociliary clearance in maxillary sinuses were done using an isotope method. Preoperative mean residual activity on the uncinectomy side was 87.2 % and postoperative mean residual activity 94.1 %. On the middle meatal antrostomy side mean preoperative residual activity was 92.3 % and postoperative mean residual activity 88.4 %. Residual activity was considered as good (< or = 50 %) on the uncinectomy side in 2 sinuses (7.4 %) preoperatively and in 1 sinus (3.7 %) postoperatively. On the middle meatal antrostomy side residual activity was considered good in 1 sinus (3.7 %) preoperatively and in 4 sinuses (14.8 %) postoperatively. Mucociliary function remained poor even 9 months postoperatively. Surgery did not significantly improve the mucociliary function of maxillary sinus mucosa in chronic or recurrent rhinosinusitis. There was no statistical difference between operative techniques. In this study it seemed however, that uncinectomy combined with the enlargening of the natural ostium may restore maxillary sinus mucociliary clearance (MCC) better than uncinectomy alone.

Mesothelioma represents an aggressive tumor type with high resistance to all treatment modalities. Its pathogenesis is strongly associated with exposure to asbestos fibers and probably with free radicals. One of the most important free radical scavenging enzymes, mitochondrial manganese superoxide dismutase (MnSOD), has been shown to be elevated in mesothelioma (K. Kahlos et al., 1998, Am. J. Respir. Cell Mol. Biol. 18:570-580). In the present study, we could detect intense ultrastructural accumulation of MnSOD in the mitochondrial compartment of malignant mesothelioma cells. There was no association between the immunohistochemical reactivity and the most common and functional polymorphic variant of MnSOD, the Ala to Val amino acid change at 9 position (16th amino acid from the beginning of the signal sequence), in the 31 mesothelioma cases investigated. Comparative genomic hybridization and fluorescence in situ hybridization did not reveal any changes in chromosome 6, where the MnSOD gene is located. Sequencing of the MnSOD promoter region in four mesothelioma cell lines showed similar nucleotide variables in the malignant and nonmalignant cells. Therefore, the intense expression of MnSOD in the mitochondria of mesothelioma cells does not appear be associated with any major chromosomal alterations or the polymorphism of MnSOD gene. Association with oxidative/nitrosative stress in mesothelioma using nitrotyrosine immunostaining pointed to a tendency for more intense reactivity in those mesotheliomas with higher MnSOD expression (P = 0.069).

The ciliary ultrastructure studied by scanning electron microscopy (SEM), nasal mucociliary transport rate (MTR) measured by a radioisotopic method and their correlation with each other were studied in 56 patients with recurrent or chronic respiratory infections. Patients were divided into three groups according to MTR. The number of pathological SEM findings increased remarkably in groups with moderate or poor MTR. Loss of ciliated cells and microvilli were seen in 86% of specimens with poor MTR, in 71% with moderate MTR, and in 50% with good MTR. There was ciliary disorientation in 45% of cases with poor MTR compared with 25% in cases with good MTR. Epithelial metaplasia and the number of short cilia increased in groups with poor or moderate MTR.

Secretion of the Hormoconis resinae glucoamylase P (GAMP) enzyme from Trichoderma reesei using either the natural N-terminal extension of the premature glucoamylase P or the cellobiohydrolase I (CBHI) signal peptide was examined. The expression conditions for the heterologous glucoamylase P (gamP) gene in T. reesei were standardized by targeting one copy of a plasmid fragment, containing the gamP gene, to the cbh1 locus of the host. The results showed that the transient N-terminal extension of the premature GAMP acts as an efficient secretion signal in T. reesei and leads to a higher yield of extracellular glucoamylase activity than does the signal peptide of CBHI.

A cDNA encoding for the glucoamylase P enzyme (GAMP) of the fungus Hormoconis resinae was introduced into the cellulolytic filamentous fungus Trichoderma reesei under the control of the promoter of the major cellulase gene (cbh1) of Trichoderma. The transforming vector plasmid used was found to be integrated into the genome of T. reesei at various locations and in multiple copies. The size of the GAMP secreted by Trichoderma varied because of different glycosylation patterns. The best transformant strains secreted about 700 mg/l of active GAMP, which is 20-fold more than obtained with H. resinae.

Impaired mucociliary function is a common finding in patients with recurrent respiratory infections, sinusitis and otitis media. One main component of mucociliary transport, ciliary beating activity, is sensitive to environmental hydrogen ion concentration (pH). The pH of secretion in 103 specimens from acute or chronic sinusitis and in 98 specimens from acute or secretory otitis media were measured. There were no differences between acute and chronic sinusitis (mean of pH 7.5 +/- 0.5 and 7.4 +/- 0.6) or between mucous and purulent secretions. In acute otitis media, secretion was significantly more acidic than in secretory otitis media (mean of pH 7.7 +/- 0.5 versus 8.2 +/- 0.4). The pH was less than 7.0 in 16 (15.5%) patients with chronic sinusitis and in two (8%) patients with acute otitis. The study shows that pH of sinusal or tympanal secretion is, in the majority of patients, within limits that do not cause ciliostasis.

The glucoamylase P gene of the fungus Hormoconis resinae has been cloned and sequenced from a genomic library. The gene consists of a 2153-bp protein coding region including three introns. The usual number of introns in cloned fungal glucoamylase genes has been four and in some cases five. Two of the glucoamylase P gene introns contain a sequence resembling the consensus sequence found near the 3' splice site in the introns of the fungus Trichoderma reesei cellobiohydrolase 1 (cbh1) gene. The H. resinae glucoamylase P gene, under its own promoter, was introduced into T. reesei, but no expression could be detected.

The variation sources relevant to a diagnostic morphometric study were analysed. The influence of each source was estimated in two experiments, performed in systems applying computer assisted interactive morphometry. In the first experiment one observer measured the areas of a large number of nuclei in a section from a grade II transitional cell carcinoma of the bladder. In the second experiment two groups of researchers, from Ancona and Kuopio, measured one field from five different samples of transitional cell tumours (including the case of grade II carcinoma). It turned out that pure interobserver variation was responsible for about a half of the total variation present in the diagnostic system. When the variation characteristics of the diagnostic system had been determined, the number of nuclei that had to be measured to reach a defined level of accuracy could be estimated. Such an estimate was also dependent on the predefined expectancy probability of reaching a correct estimate. The study showed that group morphometry (statistical, investigative morphometry) and diagnostic morphometry must be understood as two different approaches in histopathology. By applying group morphometry, good research results can be gathered with cruder measurements than in diagnostic morphometry. Because investigations in group morphometry are more standardized than in diagnostic morphometry, a larger number of structures has to be measured in diagnostic histopathology for the same level of accuracy.

Investigations were conducted to quantify activity of uteroglobin mRNA and secretion of uteroglobin in rabbit uterus after administration of progesterone and 5alpha-dihydrotestosterone, either alone or concomitantly with oestradiol-17beta and tamoxifen, a non-steroidal anti-oestrogen. Poly(A)-containing mRNA was isolated from the uterine tissue by extraction with phenol/chloroform, precipitation with ethanol and chromatography on oligo(dT)-cellulose. Cell-free translation in vitro of the poly(A)-containing mRNA was carried out in a wheat-germ lysate, and the product isolated by specific immuno-precipitation with anti-uteroglobin antiserum purified by affinity chromatography. Radioimmunoassay was utilized to determine uteroglobin content in the uterine flushings and tissue preparations. When given for 5 days, both progesterone (1mg/kg per day) and 5alpha-dihydrotestosterone (25mg/kg per day) elicited a marked induction of uteroglobin secretion, which was accompanied with accumulation of uteroglobin mRNA in the tissue. Concomitant administration of oestradiol-17beta (50mug/kg per day) or tamoxifen (12.5mg/kg per day) significantly decreased both progesterone- and 5alpha-dihydrotestosterone-induced uteroglobin secretion, with a parallel decrease in the uteroglobin-mRNA activity. The decline in the uteroglobin content of the uterine flushes brought about by oestradiol-17beta or tamoxifen administration was not due to inhibition of secretion of this protein by the endometrial cells, since a simultaneous decrease occurred in the tissue uteroglobin content. After a 5-day pretreatment with progesterone (1mg/kg per day), administration of oestradiol-17beta (50mug/kg per day) during the ensuing 4 days greatly accelerated the decay of the uteroglobin content in the uterine fluid.

The influence of magnification on light microscopic morphometry was studied. Morphometry was performed on 34 hepatocytes by using a digitizer plate with micrographs of the nuclei, and with digitized image of the nuclei on a separate monitor. Intraobserver variation was smallest at objective magnifications of 40 and 100 X (CV of form factor, maximum diameter and nuclear perimeter under 1%, of nuclear area under 2%, when measured from the monitor). The results show that more reproducible measurements are possible with higher magnifications. The authors recommend objective magnifications of 40 and 100 X for morphometric measurements on nuclei. The results also suggest that morphometric grading should apply an intermediate third grade in dichotomous grading scales.

The validity of a test system in morphometric histopathology depends on the variation sources involved. Biological variation is one of the variation sources, but is also the object to be studied with morphometry. We studied the variation sources in interactive computerized morphometry in two test systems involving two different commercially available image analyzers. The measurements were made on nuclei in a microscopic field of 5 transitional cell tumors (papilloma and WHO grade I-III carcinomas) of the urinary bladder. It turned out that different observers selected a variable number of nuclei for measurements, the coefficient of variation (CV) in the number of nuclei being 11-11.5%. Mean CV in nuclear perimeter measurements was 4.4-4.8%, and in nuclear area measurements 8.2-8.6%. The variation in measurements by 1 observer was smaller, the CV values being 2.8% for the number of nuclei, 1.2% for nuclear perimeter, and 2.4% for nuclear area. The results showed that interobserver variation can be considerable in these systems. It is suggested that special sampling rules should be tested with the idea of finding the relevant approach with the smallest interobserver variation.

Previous studies have shown that several rabbit tissues contain proteins which cross-react in the radioimmunoassay for uteroglobin, a progestin-regulated protein in rabbit uterus (Torkkeli et al. (1977) Mol. Cell. Endocrinol. 9, 101-118). In the present study, a uteroglobin-like protein was purified to an apparent homogeneity from an extra-uterine tissue, rabbit lung, by successive chromatographies on hydroxyapatite, Sephadex G-75, SP-Sephadex, DEAE-cellulose and CM-cellulose. The final preparation behaved homogeneously in various polyacrylamide gel electrophoretic systems and in isoelectric focusing. The uteroglobin-like protein isolated from the lung had very similar physicochemical and immunological properties to those of uteroglobin present in the rabbit uterine fluid. The two proteins had: (i) the same molecular weight, of approx. 13 000, with a two subunit structure (each approx. Mr 7000); (ii) identical behavior in polyacrylamide gel electrophoresis under non-denaturing and denaturing conditions; (iii) the same isoelectric point at pH 5.4; (iv) absence of carbohydrate in the molecule; (v) very similar amino acid compositions; (vi) lack of tryptophan among the amino acids; (vii) the same N-terminal amino acid (glycine), and (viii) indistinguishable immunological characteristics. Collectively, these data strongly suggest that uterine and lung uteroglobins are identical proteins. In contrast to the induction of the uterine uteroglobin by steroids with progestational activity, the synthesis of extra-uterine uteroglobins was no affected by these steroid hormones to any major extent. In keeping with the concept that lung is a target tissue for glucocorticoid action, cortisol and dexamethasone were capable of increasing the concentration of lung uteroglobin 3-fold (from 3 to 9 microgram/mg soluble protein). These compounds did not, however, alter the secretion of the uterine protein. Administration of high doses of testosterone and 5alpha-dihydrotestosterone elevated significantly the content of both uterine and lung uteroglobin. Only approx. one-fifth of the adult pulmonary uteroglobin levels were present in lungs of newborn rabbits indicating that developmental changes occur in the lung uteroglobin content.

The application of morphometry in tumor pathology is discussed, e.g., its use in studying the biology of tumors, in creating tumor classification(s), in creating methods for the identification of a tumor in the diagnostic context, and in characterizing diagnostic histopathology in absolute terms. In traditional subjective diagnostic histopathology, reproducibility can be defined satisfactorily, but the definition of accuracy is ambiguous; in morphometric histopathology, a satisfactory definition is found for both concepts but it may be difficult to separate them in practice. Morphometric histopathology can study parameters measured from sections or parameters derived from the primary measurements through calculations. In the histopathology of tumors, the following parameters have turned out to be specially valuable: densitometric measurements of nuclei, nuclear area, perimeter and form factors, nucleolar parameters, the number of mitotic cells per area, the cellularity, the volume fraction of the epithelium, and parameters associated with the fraction of tumor tissue in the sample. The standard deviation or other moments of the distribution of these measurements can be more relevant than the mean values of the results. This indicates that more attention should be given to sampling rules, which are important in defining the efficiency of the methods. For rational application of morphometric methods, it is very important to make a distinction between group morphometry and diagnostic morphometry. The latter engenders numerous sources of variation (variation in section thickness, variation in tissue processing, variation in the techniques of measurement, interobserver variation, interlaboratory variation, variation due to subjective interpretation, etc.), which are usually better controlled in group morphometry. The influence on morphometric parameters of variation in section thickness and tissue shrinkage during processing are discussed.