Invasive pneumococcal diseases in adults admitted to the Na Bulovce Hospital: Serotype replacement after the implementation of general childhood pneumococcal vaccination.

OBJECTIVE: The aim of this study was to analyse epidemiological and clinical characteristics of invasive pneumococcal disease (IPD) in adults before and after the introduction of the general childhood conjugate pneumococcal vaccination programme in the Czech Republic. MATERIAL AND METHODS: The retrospective observational sentinel study included adults with IPD admitted to the Na Bulovce Hospital in Prague from 1/2000 through 12/2019. A case of IPD was defined as isolation of Streptococcus pneumoniae from a primarily sterile site. RESULTS: A total of 304 IPD cases were diagnosed during the study period, with a male to female ratio of 1.49:1 and age median of 58 years (IQR 43-73). The most prevalent clinical forms were bacteraemic pneumonia (185 cases; 60.9%) and purulent meningitis (90; 29.6%). A total of 157/293 patients (53.6%) required intensive care, and the case fatality rate was 25.3% (n = 77). The serotype was determined in 292 (96.0%) isolates, the most prevalent being serotypes 3 (38; 12.5%), 4 (28; 9.2%), 7F (24; 7.9%), 8 (21; 6.9%), and 1 (18; 5.9%). Both clinical and epidemiological characteristics of IPD caused by the most prevalent serotypes differed considerably. Patients diagnosed with serotype 3 were older, more frequently required intensive care, and showed higher mortality. The proportion of IPD caused by non-PCV13 serotypes increased from 28.8% (19/66) in 2000-2005 to 54.8% (40/70) in 2015-2019 (p = 0.001). CONCLUSION: The study demonstrated that invasive diseases caused by the most prevalent pneumococcal serotypes differ in their epidemiological and clinical characteristics and case fatality rate. During the study period, there was a significant increase in IPD caused by non-PCV 13 serotypes, limiting the effect of vaccination in adults.

Gangrenous herpes zoster with multidermatomal involvement in a patient after kidney transplantation.

We present the case of a 66-year-old female after renal transplant with severe course of herpes zoster (HZ). Although HZ represents a common infectious complication of transplant patients, its variable manifestation and ability to disseminate warrants serious consideration. Prompt diagnosis and treatment are essential in preventing further spread and disastrous complications.

Cardiac hormones eliminate some human squamous lung carcinomas in athymic mice.

BACKGROUND: Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, have anticancer effects in vitro. MATERIALS AND METHODS: These cardiac hormones were infused subcutaneously for 28 days with weekly fresh hormones at 0.3 nM kg(-1) body weight in athymic mice bearing human squamous cell carcinomas. RESULTS: Vessel dilator, atrial natriuretic peptide and kaliuretic peptide each eliminated one in six (17%) of the human squamous cell lung carcinomas. Long-acting natriuretic peptide, although it did not eliminate any of the human squamous cell lung carcinomas did decrease the volume of one carcinoma to only 2% (P < 0.0001) of the untreated carcinomas. The squamous cell lung carcinomas that were not eliminated, with the exception of the one LANP-treated tumour that decreased to only 2% of the volume of the untreated cancers, grew rapidly but their growth velocity compared to controls decreased by 76%, 40%, 38% and 25% in the vessel dilator, atrial natriuretic peptide, kaliuretic peptide and long-acting natriuretic peptide groups respectively (P < 0.05). CONCLUSIONS: Three of four cardiac hormones synthesized by the atrial natriuretic peptide gene can eliminate human squamous cell lung carcinomas in athymic mice when treated subcutaneously for 4 weeks. The 4th cardiac hormone, i.e. long-acting natriuretic peptide, decreased the volume of one squamous cell lung carcinoma to 2% of that of untreated animals, suggesting that it, too, has beneficial effects on squamous cell lung cancers.

BRAFV600E mutation in the pathogenesis of a large series of papillary thyroid carcinoma in Czech Republic.

BACKGROUND: Activating point mutation of the BRAF gene, the most common genetic alteration reported in papillary thyroid carcinomas (PTC), has been associated with poor prognostic characteristics. AIM: Our objective was to determine the frequency of BRAFV600E mutation in PTC tumor tissues from the period 1960-2007 and to correlate it with clinicopathological parameters. SUBJECTS AND METHODS: DNAs were extracted from 242 PTCs, 23 sporadic medullary carcinomas, one anaplastic carcinoma and 6 poorly differentiated carcinomas. The presence of BRAFV600E mutation was determined using single strand conformation polymorphism method and verified by direct sequencing. RESULTS: BRAFV600E mutation was detected in 81 of 242 PTCs (33.5%), in one of 6 poorly differentiated carcinomas (16.7%) and in anaplastic carcinoma. BRAFV600E mutation was much less frequent in the follicular variant compared to classical variant and mixed follicular- classical variant of PTCs (p=0.001). BRAFV600E mutation was significantly associated with presence of nodal metastasis (p=0.029), more advanced TNM stage (p=0.014) and recurrence of disease (p=0.008). The mutation correlated with a higher age at diagnosis (p=0.049) and with a greater tumor size (p=0.041). Multivariate analysis confirmed these findings. The prevalence of BRAFV600E mutation before 1986 was significantly lower than after it (p=0.008). CONCLUSIONS: Our data suggest that BRAFV600E mutation is associated with high-risk clinicopathological characteristics of PTC and worse prognosis of patients. The frequency of the mutation significantly varied during the observed period but rather because of the different age distribution of patients in particular periods than as a consequence of Chernobyl accident.

Biotin enhances guanylate cyclase activity.

Biotin and its analog, (+)-biotin-p-nitrophenyl ester enhanced guanylate cyclase activity two- to threefold in rat liver, kidney, colon, cerebellum, and heart. Dose-response relationships revealed that at concentrations as low as 1 micromolar, both biotin and its analog caused maximal augmentation of guanylate cyclase activity. These data suggest a role for the activation of guanylate cyclase in the mechanism of action of this vitamin.

Bee venom enhances guanylate cyclase activity.

Bee venom and phospholipase A2 extracted from bee venom enhanced guanylate cyclase (E.C. 4.6.1.2) activity two- to threefold in rat liver, lung, heart, kidney, ileum, and cerebellum. Dose-response relationships revealed that bee venom at concentrations as low as 1 microgram per milliliter and phospholipase A2 at 1 microunit per milliliter caused a maximal enhancement of guanylate cyclase.

Calcium requirement for melanophore-stimulating hormone action on melanophores.

The calcium ion is specifically required for the action of melanophorestimulating hormone on melanosome dispersion within lizard (Anolis carolinensis) melanophores in vitro. The response to this hormone is directly related to the concentration of the Ca(2+) ion. Lithium, choline, rubidium, and cesium will replace the sodium and potassium of Ringer solution if Ca(2+) is present. Calcium ions are not required for melanosome dispersion itself, since theophylline or dibutyryl cyclic adenosine monophosphate reversibly darkens lizard skins in the absence of calcium.

Cardiac hormones activate ERK 1/2 kinases in human fibroblasts.

Two cardiac hormones, vessel dilator and kaliuretic peptide, localize to fibroblasts with immunohistochemistry. Vessel dilator and kaliuretic peptide were investigated in dose-response and time-sequenced experiments for their cell signaling of extracellular signal-regulated kinases 1/2 in human fibroblasts to test the hypothesis that these two cardiovascular hormones contribute to fibroblast proliferation by activating extracellular signal-regulated kinases 1/2. Vessel dilator at 10 pM (physiological range) enhanced the phosphorylation of extracellular signal-regulated kinases 1/2 by 188+/-9% (p<0.001) in 10 min and, maximally, by 200+/-10% in 15 min (p<0.001). Vessel dilator at 10 nM enhanced the phosphorylation of extracellular signal-regulated kinases 1/2 by 107+/-5% (p<0.01) in 10 min. Kaliuretic peptide at 10 pM enhanced the activation of extracellular signal-regulated kinases 1/2 by 389+/-19% in 10 min (p<0.001). Kaliuretic peptide at 10 nM enhanced the phosphorylation of extracellular signal-regulated kinases 1/2 by 82+/-4% (p<0.01). Our results show that both cardiac hormones activate extracellular signal-regulated kinases 1/2 in human fibroblasts, suggesting that they may have a role in enhancing fibroblast proliferation.

Phosphatidylinositol 3-kinase/Akt signaling mediates interleukin-6 protection against p53-induced apoptosis in M1 myeloid leukemic cells.

M1 myeloid leukemic cells were used to dissect the molecular mechanisms of myeloid cell survival and apoptosis. A salient feature of M1 cells is that they respond to the physiological survival factor interleukin-6 (IL-6), yet lack the tumor suppressor gene p53. Functional wild-type activation of temperature-sensitive p53 protein (p53 val) at permissive temperature in M1-t-p53 cells results in rapid apoptosis, which is blocked by IL-6. How p53 induces M1 apoptosis and how IL-6 protects against p53-induced apoptosis are not fully understood. Here it is shown that p53-mediated apoptosis of M1 cells involves rapid activation of the proapoptotic Fas/CD95 death pathway, which activates caspases 8 and 10. Functional p53 also targets the mitochondria, causing upregulation of proapoptotic Bax, downregulation of prosurvival Bcl-2 and activation of caspase 9. IL-6 was found to protect against p53-induced apoptosis via activation of the PI3K/Akt survival pathway, which in turn counters both the Fas/CD95 and mitochondrial apoptotic pathways and activates the prosurvival transcription factor nuclear factor-kappaB (NF-kappaB). Taken together, this work supports a novel model for leukemic progression where cells that acquire the ability to produce an autocrine survival factor, such as IL-6, can bypass normal p53 surveillance function by targeting Akt, which in turn can exert effects on the regulators of apoptosis, such as the Fas/CD95 pathway, the mitochondria and NF-kappaB.

Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinomas.

The frequency and prognostic relevance of RET proto-oncogene somatic mutations in sporadic medullary thyroid carcinoma (MTC) remain controversial. In order to study somatic mutations in the RET proto-oncogene in sporadic MTCs found in the Czech population and to correlate these mutations with clinical and pathological characteristics, we investigated 48 truly sporadic MTCs by sequencing classical risk exons 10, 11, 13, 14, 15 and 16. From the 48 tumors studied, 23 (48%) had somatic mutation in the RET proto-oncogene in exons 10, 11, 15 or 16. The classical somatic mutation Met918Thr in exon 16 was only found in 13 tumors (27%). In five cases, multiple somatic mutations and deletions were detected. A statistically significant correlation between the presence of somatic mutation with more advanced pathological TNM stages was observed. Other clinical and pathological characteristics did not show any statistical significant association with the presence or absence of somatic mutation.

Cardiac and kidney hormones cure up to 86% of human small-cell lung cancers in mice.

BACKGROUND: Four cardiac hormones synthesized by the same gene, i.e. atrial natriuretic peptide, vessel dilator, long acting natriuretic peptide and kaliuretic peptide, and the kidney hormone urodilatin have anticancer effects in vitro. MATERIALS AND METHODS: These cardiac hormones and urodilatin were infused subcutaneously for 28 days with weekly fresh hormones since they lose biological effects at body temperature for more than a week at 0.3 nm kg(-1) body weight in athymic mice bearing human small-cell lung carcinomas. RESULTS: Long acting natriuretic peptide, vessel dilator, kaliuretic peptide, atrial natriuretic peptide and urodilatin eliminated 86%, 71%, 57%, 43% (P < 0.001 for the cardiac hormones) and 25% (P < 0.05; urodilatin) of the human small-cell lung carcinomas. The treated small-cell lung carcinomas that were not cured grew rapidly, similar to the untreated controls, whose volume was 7 fold larger in 1 week, 18-fold increased in 2 weeks, 39-fold increased in 3 weeks, 63-fold increased in 1 month and 97-fold increased in volume in 6 weeks. One vessel dilator treated small-cell lung carcinoma animal developed a large tumour (8428 mm3 volume) on treatment and this tumour was eliminated with utilizing atrial natriuretic peptide and then long acting natriuretic peptide sequentially. CONCLUSIONS: Four cardiac hormones eliminate up to 86% of human small-cell lung carcinomas in athymic mice. Urodilatin can also eliminate small-cell lung carcinomas but at a lower cure rate of 25%. Unresponsive lesions can be eliminated by utilizing different hormones synthesized by the atrial natriuretic peptide gene in a sequential manner.

Expression of endothelial and inducible nitric oxide synthase and caspase-3 in tonsillar cancer, chronic tonsillitis and healthy tonsils.

Neoangiogenesis and inhibition of apoptosis are two factors considered as major leading causes of tumorigenesis. NO, synthesized by NOS, plays an important role in tumour growth, dissemination and vascularization. Caspase-3 is an executive enzyme of apoptosis. The presented research work has been focused on the comparative evaluation of localization of the angiogenic and proapoptotic cytokines expressed in tonsillar diseases. The immunohistochemical reaction of eNOS, iNOS and caspase-3 in tonsillar cancer (N = 17), chronic tonsillitis (N = 11) and clinically healthy tonsils (N = 8) was detected. High eNOS occurrence in endothelial cells of highly vascularized regions in tonsillar cancer, variable eNOS expression in the vessels of lamina propria in chronic tonsillitis and high expression in the cytoplasm of endothelial cells of small veins in healthy tonsillar tissue was ascertained. Increased iNOS expression was found in cancer tissue in comparison with the healthy tonsils. Nevertheless, the highest expression of iNOS was found in chronic tonsillitis. Higher expression of caspase-3 was discovered in germinal centres of lymphoid follicles of the chronic tonsillitis tissue. However, the positivity in the interfollicular zone and surface squamous epithelium was weak only. Merely isolated caspase-3-positive cells were found in tonsillar cancer. Very low expression of caspase-3 was detected in the lymphatic follicles of the healthy tonsils. Research results showed high expression of eNOS in the carcinomatous tissue. The eNOS expression in chronic tonsillitis confirms its role in regulating the lymphocyte circulation. Low expression of caspase-3 in malignant epithelial cells of tonsillar cancer shows decreased capability of apoptosis compared to chronic tonsillitis tissue, where apoptosis seems to be rather frequent and concentrated in the germinal centres of lymphatic follicles. The differences in localization of eNOS and caspase-3 expression between benign and malignant processes may be a promising tool for precise morphological distinction of chronic inflammation and tumours.

Circadian distribution of hematology variables in subjects with multiple sclerosis.

Hematology variables were measured in blood samples obtained every 3h (8/24h) from 10 multiple sclerosis (MS) patients and 34 healthy subjects and analyzed for circadian characteristics using the population multiple-components method. Red blood cell (RBC) and hemoglobin levels as well as hematocrits exhibited circadian rhythms with minimal amplitudes in healthy individuals and insignificant variability in the smaller group of MS patients. In contrast the total white blood cell (WBC) and platelet counts for MS patients and healthy individuals both showed significant circadian characteristics while the mean 24h WBC and platelet levels did not significantly differ between the two groups. When the different WBC subsets were examined independently, statistically significant circadian rhythms were seen for lymphocytes and eosinophils for both MS patients and healthy individuals and for neutrophils only in the latter. Moreover, the 24h mean levels of lymphocytes, basophils, and eosinophils were significantly higher for the healthy controls while those of monocytes were higher for the MS patients. However, of all the variables tested with significant circadian rhythms in both groups of individuals, only those of lymphocyte numbers exhibited different patterns with somewhat higher amplitude in healthy individuals and a peak level occurring over an hour after that of MS patients. These changes may be the reflection of a disturbance in the regulation of patterns of lymphocyte activity and migration in MS patients. In addition, the elevation in circulating monocytes in MS patients is consistent with the inflammatory nature of the disease.

Activation of guanylate cyclase by streptozotocin and 1-methyl-1-nitrosourea.

Streptozotocin has been shown to induce the production of a variety of tumors in rats. The present report demonstrates that streptozotocin and 1-methyl-1-nitrosourea, a component of the streptozotocin molecule and a known carcinogen, stimulate the enzyme guanylate cyclase which catalyzes the production of guanosine 3',5'-monophosphate. At a maximal concentration of 3 mg/ml, these agents activated guanylate cyclase approximately 30-fold in liver, 20-fold in kidney, 15-fold in cerebellum. 15- to 30-fold in cerebrum, 4- to 20-fold inheart, 12-fold in brain stem, 10-fold in lung, and 2-fold in pancreas. Since recent evidence suggests a role for guanosine 3',5'-monophosphate in malignant transformation, the data may help explain the tumor-inducing capacity of these agents.

Decreased rat hepatic guanylate cyclase activity in streptozotocin-induced diabetes mellitus.

Guanylate cyclase is found in virtually all cells, but its physiologic role and the effect of hormones on its activity have not been clarified. Hepatic soluble guanylate cyclase activity (37,000 g supernatant) in rats with diabetes-mellitus-like syndrome induced by streptozotocin, 65 mg./kg. i.v., was 140 +/- 8 pmoles accumulated/mg. protein/10 min. (n = 13 rats) as against 279 +/- 16 pmoles accumulated/mg. protein/10 min. (n = 12 rats) in normal rats. The average blood sugar for the 12 normal rats was 100 +/- 4 mg./100 ml. and 546 +/- 32 mg./100 ml. for 13 diabetic rats. The decreased soluble hepatic guanylate cyclase activity in diabetic rats was completely restored to normal with 10 U. regular insulin, i.p. The maximum increase in guanylate cyclase activity was observed as early as five minutes and as late as two hours after insulin administration. Insulin restoration of guanylate cyclase was dose-related over a range of 1 U. to 10 U., i.p. Hepatic cyclic GMP levels in vivo paralleled in-vitro guanylate cyclase activity, being 29 +/- 0.4 pmoles/gm. wet weight in normals, 17 +/- 0.4 pmoles/gm. wet weight in streptozotocin-diabetic rats, and 38 +/- 0.4 pmoles/gm. wet weight two hours after the injection of 10 U. regular insulin. We conclude that rat hepatic guanylate cyclase is decreased in streptozotocin-induced diabetes and that insulin modulates this enzyme. The administration of exogenous insulin in normal animals did not further augment hepatic guanylate cyclase activity.

Acute renal failure in insulin-dependent diabetics: episodes secondary to intravenous pyelography.

Diabetic patients with chronic renal failure are known to be at risk for exacerbation of renal failure if they undergo intravenous pyelography (IVP). The present report demonstrates that diabetic patients with normal serum creatinine levels can sustain irreversible renal failure following an IVP. The experiences with this case suggest that, if the creatinine clearance is decreased in an insulin-dependent patient irrespective of the serum creatinine value, one must be aware of the possible hazard of acute renal failure and irreversible renal damage following the IVP. This would appear to be especially true if the diabetic patient has proteinuria in combination with the decreased creatinine clearance.

Somogyi effect in patient with hypopituitarism.

A patient with diabetes mellitus and hypopituitarism developed the Somogyi effect that was characterized by insulin-induced hypoglycemia and rebound insulin-resistant hypoglycemia. This compensatory insulin-resistant hyperglycemia has generally been ascribed to the release of anterior hypophyseal hormones; however, our findings suggest that factors other than anterior hypophyseal hormones are involved.

Bilateral deep brachial vein thrombophlebitis due to vibrio fetus.

A patient had bilateral deep brachial vein thrombophlebitis in which Vibrio fetus was recovered from six blood cultures of the six drawn. Fever and phlebitis continued with treatment with intravenous doses of heparin and oxacillin but rapidly improved with treatment change of oxacillin to clindamycin. In vitro antibiotic disk susceptibility testing confirmed resistance to oxacillin and susceptibility to clindamycin. Vibrio fetus infection is associated with the vascular endothelium in this and previously reported cases

Congestive heart failure: increased cardiac and extracardiac atrial natriuretic peptide gene expression.

OBJECTIVES: The present investigation was designed to determine if atrial natriuretic peptide (ANP) gene expression increases in extracardiac as well as within the heart in congestive heart failure. METHODS: Congestive heart failure (CHF) was induced by producing cardiac hypertrophy secondary to an aortocaval fistula in Sprague-Dawley rats. To characterize this model, control and CHF rats had cardiac catheterizations and transthoracic echocardiography. ANP messenger RNA was measured by RNAase protection analysis in atria, ventricles, liver, colon, and stomach of CHF and sham rats and quantitated by 2-D scanning. The product of ANP gene expression was determined in each of these tissues with high performance-gel permeation chromatography. To help determine if increased degradation of atrial natriuretic peptides occur in congestive heart failure, the circulating concentrations and the excretion of the atrial natriuretic peptides into urine were measured by specific radioimmunoassays. RESULTS: ANP steady-state mRNA increased 4.2 +/- 0.05 and 4.3 +/- 0.06-fold, respectively, in the antrum of the stomach and within the heart ventricle of CHF rats compared with age-matched sham rats. ANP gene expression was present but not increased in atria, liver, and gastrointestinal tract of the CHF rats. High-performance gel permeation chromatography revealed that the product of this ANP gene expression within the stomach and heart ventricle in CHF animals was the ANP prohormone. There was not any decrease in the metabolism of these peptides by the kidney in CHF. CONCLUSIONS: ANP steady-state mRNA increases in extracardiac (i.e., stomach antrum) tissue as well as in the ventricle of the heart in CHF. The product of the ANP gene expression, i.e., the ANP prohormone is the same in the extracardiac tissues as within the heart. Whether the increased extracardiac ANP steady-state mRNA and its resultant increased atrial natriuretic peptides helps prevent bowel wall edema in CHF needs to be elucidated.