The usage of procalcitonin in Finland.

BACKGROUND: We have surveyed the use of procalcitonin (PCT) in Finland with a specific emphasis on intensive care unit (ICU) patients. METHODS: The PCT use was surveyed from all 11 laboratories providing services for all 15 secondary and all five tertiary care hospitals in Finland. The laboratories reported the PCT use of each hospital in 2014 and 2015. Four hospitals were analysed for the first 100 adult ICU patients with PCT measurements in 2015. The indication for PCT measurement and whether PCT values affected antibiotic treatment were collected from patient records. RESULTS: The overall national PCT use was similar between 2014 and 2015 with around 15 000 measurements annually. The PCT use varied greatly between hospitals and specialities; one tertiary care hospital used 5600 measurements annually, while another tertiary care hospital did not use PCT at all. Over half of the requests for PCT were in the ICU. There were significant differences in PCT use for ICU patients: in the most frequent user, PCT was mainly used for follow-up of antibiotic treatment, whereas in the other three hospitals, PCT was mainly used for differential diagnosis. The most frequent user also had the highest per patient rate of PCT measurements, with a mean of six PCT tests/patient compared to two PCT tests/patient in the three other hospitals. PCT had an effect on antibiotic treatment in every 5th case. CONCLUSION: The use of PCT in Finland varies significantly between hospitals, even though the national guideline proposes its use for septic patients.

Metacaspases versus caspases in development and cell fate regulation.

Initially found to be critically involved in inflammation and apoptosis, caspases have since then been implicated in the regulation of various signaling pathways in animals. How caspases and caspase-mediated processes evolved is a topic of great interest and hot debate. In fact, caspases are just the tip of the iceberg, representing a relatively small group of mostly animal-specific enzymes within a broad family of structurally related cysteine proteases (family C14 of CD clan) found in all kingdoms of life. Apart from caspases, this family encompasses para- and metacaspases, and all three groups of proteases exhibit significant variation in biochemistry and function in vivo. Notably, metacaspases are present in all eukaryotic lineages with a remarkable absence in animals. Thus, metacaspases and caspases must have adapted to operate under distinct cellular and physiological settings. Here we discuss biochemical properties and biological functions of metacaspases in comparison to caspases, with a major focus on the regulation of developmental aspects in plants versus animals.

Guillain-Barré syndrome and ulceroglandular tularemia.

Francisella tularensis is a small Gram-negative aerobic intracellular bacterium that should be considered as a possible pathogen in patients with fever, pharyngitis, and lymphadenopathia. Central nervous system manifestations have been rarely reported. We describe a patient who developed serious Guillain-Barré polyneuropathy as a rare complication of ulceroglandular tularemia.

Crystal structures of the CBS and DRTGG domains of the regulatory region of Clostridiumperfringens pyrophosphatase complexed with the inhibitor, AMP, and activator, diadenosine tetraphosphate.

Nucleotide-binding cystathionine beta-synthase (CBS) domains serve as regulatory units in numerous proteins distributed in all kingdoms of life. However, the underlying regulatory mechanisms remain to be established. Recently, we described a subfamily of CBS domain-containing pyrophosphatases (PPases) within family II PPases. Here, we express a novel CBS-PPase from Clostridium perfringens (CPE2055) and show that the enzyme is inhibited by AMP and activated by a novel effector, diadenosine 5',5-P1,P4-tetraphosphate (AP(4)A). The structures of the AMP and AP(4)A complexes of the regulatory region of C. perfringens PPase (cpCBS), comprising a pair of CBS domains interlinked by a DRTGG domain, were determined at 2.3 A resolution using X-ray crystallography. The structures obtained are the first structures of a DRTGG domain as part of a larger protein structure. The AMP complex contains two AMP molecules per cpCBS dimer, each bound to a single monomer, whereas in the activator-bound complex, one AP(4)A molecule bridges two monomers. In the nucleotide-bound structures, activator binding induces significant opening of the CBS domain interface, compared with the inhibitor complex. These results provide structural insight into the mechanism of CBS-PPase regulation by nucleotides.

Episodic muscle pain, stiffness, and weakness associated with tubular aggregates and myoedema.

We report a 28-year-old man who suffered from episodic muscle pain, stiffness and weakness. His serum creatine kinase (CK) levels were found to be elevated. He presented with slight proximal muscle weakness and calf hypertrophy. Muscle biopsy revealed fiber size variation and tubular aggregates (TA). Muscle magnetic resonance imaging showed areas of edema. Other muscle pathologies known to be associated with TAs or myoedema were ruled out.

Low-field MR imaging of meningiomas including dynamic contrast enhancement study: evaluation of surgical and histopathologic characteristics.

BACKGROUND AND PURPOSE: Risks associated with surgery of meningiomas, especially those located in the skull base, are influenced by tumor consistency and vascularity. The purpose of this study was to find out if vascularity, consistency, and histologic characteristics of meningioma can be predicted preoperatively by using low-field MR imaging, including dynamic imaging of contrast enhancement. MATERIALS AND METHODS: Twenty-one patients (mean age, 56; range, 34-73 years; 16 women, 5 men) with meningioma requiring first surgery were imaged by a 0.23T scanner. Time to maximum enhancement, maximum enhancement, and maximum intensity increase were noted from the enhancement curve of dynamic imaging. Relative intensity of tumor in fluid-attenuated inversion recovery (FLAIR) and T2-weighted images was calculated. The neurosurgeon evaluated surgical bleeding and hardness of tumor on a visual analog scale. Histopathologic analysis included subtype, World Health Organization grade, mitotic activity, grades of progesterone receptor expression and collagen content, proliferation activity by Ki-67 (MIB-1), and microvessel density by CD34. Correlations were studied with Kendall tau statistics. RESULTS: The most powerful association was found between time to maximum enhancement and microvessel density (tau = -0.60, P < .001). Surgical bleeding (tau = 0.49, P = .002), blood loss during surgery (tau = 0.49, P = .002), progesterone receptor expression (tau = 0.59, P < .001), and collagen content (tau = -0.54, P < .001) were statistically best correlated with the relative intensity of meningioma on FLAIR images. Tissue hardness correlated best with relative intensity on T2-weighted images (tau = 0.40, P = .012). CONCLUSION: Assessment of microvessel density, collagen content, and progesterone receptor expression of meningioma may be clinically feasible by using low-field MR imaging.

Glutamatergic drugs for schizophrenia.

BACKGROUND: It has been shown that central nervous system dopamine can play a major role in the pathophysiology of schizophrenia. Brain glutamate is thought to mediate symptoms in schizophrenia due to the influence of glutamate neurons on the dopaminergic transmission in the brain. It might be possible to decrease negative symptoms and the cognitive impairment of people with schizophrenia by treatment with glutamatergic drugs. OBJECTIVES: To determine the efficacy of glutamatergic drugs in the treatment of schizophrenia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Trials Register (May 2002 and October 2003), inspected references of all identified studies and contacted relevant authors. SELECTION CRITERIA: We included all randomised controlled trials in which glutamatergic medication was administered to people with schizophrenia. DATA COLLECTION AND ANALYSIS: We reliably selected studies, quality rated them and extracted data. For dichotomous data, we estimated relative risks (RR), with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat/harm statistic (NNT/H) and used intention-to-treat analysis. MAIN RESULTS: We included eighteen short-term trials with 358 randomised participants. The single studies were small with numbers of participants ranging between six and 51. All trials were short-term trials with a maximum duration of 12 weeks. In all of these trials, glycine, D-serine, D-cycloserine, or ampakine CX516 was used to augment the effect of antipsychotic drugs. D-cycloserine, a partial agonist of NMDA receptors' glycine site, seemed ineffective towards the symptoms of schizophrenia. NMDA receptor co-agonists glycine and D-serine showed some effects in reducing the negative symptoms of schizophrenia (n=132, SMD -0.66, CI -1.0 to -0.3, p=0.0004), but the magnitude of the effect was moderate. Furthermore, when responder rates rather than mean scores of negative symptoms were analysed the data were inconsistent: There was no difference in responder rates between glycine and the control in terms of more than 20% improvement of negative symptoms (n=62, RR 0.70, CI 0.3 to 1.71) and only a borderline significant superiority in terms of more than 50% improvement (n=62, RR 0.87, CI 0.8 to 1.00). There were also some effects in favour of glycine and/or D-serine in terms of overall and general symptoms, but the results were again inconsistent and depended on the response definition applied. Available rating scale data on positive symptoms and cognitive functioning did not indicate a statistically significant effect of glycine or D-serine. AUTHORS' CONCLUSIONS: In general, all glutamatergic drugs appeared to be ineffective in further reducing positive symptoms of the disease when added to the existing antipsychotic treatment. Glycine and D-serine may somewhat improve negative symptoms when added to regular antipsychotic medication, but the results were not fully consistent and data are too few to allow any firm conclusions. Many participants in the included trials were treatment-resistant which may have reduced treatment response. Additional research on glutamatergic mechanisms of schizophrenia is needed.

Hereditary dementia with intracerebral hemorrhages and cerebral amyloid angiopathy.

BACKGROUND: Deposition of the beta-amyloid peptide (Abeta) in neuritic plaques is a hallmark of Alzheimer disease (AD). Mutations in genes encoding amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1, PSEN2) are associated with increased accumulation of Abeta in neuritic plaques or in the walls of cerebral vessels. Intracerebral hemorrhage occasionally affects patients with AD. METHODS: A Finnish family with dementia in four generations and with frequent co-occurrence of dementia and intracerebral hemorrhage was identified. Clinical features of 14 family members with a cognitive decline were evaluated. All exons in genes encoding APP, PSEN1, PSEN2, cystatin C, transthyretin, gelsolin, and ITM2B were sequenced, and an association study of APP was conducted by identification of single-nucleotide polymorphisms. RESULTS: Neuropathologic examination revealed Alzheimer-type changes with Abeta in neuritic plaques and vessel walls, but the cognitive profile of the patients differed from that in AD, as the visuoconstructive functions and verbal fluency were well preserved even in the moderate stage of the disease. In addition to cognitive decline, five patients had had lobar intracerebral hemorrhages and one was diagnosed with hemosiderin deposits in MRI, suggesting previous cerebral microbleeds. No causative mutations were identified in candidate genes associated with amyloid diseases, but linkage to APP region could not be entirely excluded. CONCLUSIONS: The family presents an autosomal dominant form of beta-amyloidogenic disease that resembles the Italian, Flemish, and Iowa types of AD. No amyloidogenic mutations were identified, but the role of the APP region could not be entirely excluded.

Lymphoma of the cervix. Imaging and transcatheter arterial embolization.

A case of uterine cervix lymphoma with selective embolization after angiography is described. Chemotherapy and radiotherapy were carried out and surgery was avoided.

Isolated neurosarcoidosis - MR findings and pathologic correlation.

Neurosarcoidosis is a diagnostic challenge, especially if systemic symptoms are absent. We present a 49-year-old woman with isolated neurosarcoidosis. The main symptom was loss of vision in the left eye. Brain MR imaging showed 6 high-signal white matter lesions frontotemporally on proton density and T2-weighted turbo spin-echo images. Coronal fat-saturated turbo FLAIR images of the orbits showed a swollen left optic nerve with increased signal intensity, which finding has not been previously published in sarcoid optic neuropathy. A control MR examination showed meningeal enhancement of the left optic nerve and leptomeningeal enhancing lesions around the brain stem. Spinal MR revealed leptomeningeal enhancement throughout the spinal cord and asymptomatic enhancing cauda equina lesions, mimicking subarachnoid tumour seeding, and an enhancing nerve root mass at Th12/L1. Biopsy of the latter lesion revealed non-caseating granulomas consistent with sarcoidosis.

Expression and glycosylation studies of human FGF receptor 4.

Fibroblast growth factor receptor subtype 4 (FGFR4) has been shown to have special activation properties and just one splicing form, unlike the other FGFRs. FGFR4 overexpression is correlated with breast cancer and therefore FGFR4 is a target for drug design. Our aim is to overexpress high amounts of homogeneous FGFR4 extracellular domain (FGFR4(ed)) for structural studies. We show that baculovirus-insect cell-expressed FGFR4(ed) is glycosylated on three (N88, N234, and N266) of the six possible N-glycosylation sites but is not O-glycosylated. The deglycosylated triple mutant was expressed and had binding properties similar to those of glycosylated FGFR4(ed), but was still heterogeneous. Large amounts of FGFR4(ed) have been produced into inclusion bodies in Escherichia coli and refolded at least partly correctly but the refolded E. coli-produced FGFR4(ed) still aggregates.

Ozone-sensitive arabidopsis rcd1 mutant reveals opposite roles for ethylene and jasmonate signaling pathways in regulating superoxide-dependent cell death.

We have isolated a codominant Arabidopsis mutant, radical-induced cell death1 (rcd1), in which ozone (O(3)) and extracellular superoxide (O(2)(*)-), but not hydrogen peroxide, induce cellular O(2)(*)- accumulation and transient spreading lesions. The cellular O(2)(*)- accumulation is ethylene dependent, occurs ahead of the expanding lesions before visible symptoms appear, and is required for lesion propagation. Exogenous ethylene increased O(2)(*)--dependent cell death, whereas impairment of ethylene perception by norbornadiene in rcd1 or ethylene insensitivity in the ethylene-insensitive mutant ein2 and in the rcd1 ein2 double mutant blocked O(2)(*)- accumulation and lesion propagation. Exogenous methyl jasmonate inhibited propagation of cell death in rcd1. Accordingly, the O(3)-exposed jasmonate-insensitive mutant jar1 displayed spreading cell death and a prolonged O(2)(*)- accumulation pattern. These results suggest that ethylene acts as a promoting factor during the propagation phase of developing oxyradical-dependent lesions, whereas jasmonates have a role in lesion containment. Interaction and balance between these pathways may serve to fine-tune propagation and containment processes, resulting in alternate lesion size and formation kinetics.

Cambial-region-specific expression of the Agrobacterium iaa genes in transgenic aspen visualized by a linked uidA reporter gene.

The level of indole-3-acetic acid (IAA) was locally modified in cambial tissues of transgenic aspen (Populus tremula L. x Populus tremuloides Michx.). We also demonstrate the use of a linked reporter gene to visualize the expression of the iaa genes. The rate-limiting bacterial IAA-biosynthetic gene iaaM and the reporter gene for beta-glucuronidase (GUS), uidA, were each fused to the cambial-region-specific Agrobacterium rhizogenes rolC promoter and linked on the same T-DNA. In situ hybridization of the iaaM gene confirmed that histochemical analysis of GUS activity could be used to predict iaaM gene expression. Moreover, quantitative fluorometric analysis of GUS activity allowed estimation of the level of de novo production of IAA in transgenic lines carrying a single-copy insert of the iaaM, uidA T-DNA. Microscale analysis of the IAA concentration across the cambial region tissues showed an increase in IAA concentration of about 35% to 40% in the two transgenic lines, but no changes in the radial distribution pattern of IAA compared with wild-type plants. This increase did not result in any changes in the developmental pattern of cambial derivatives or the cambial growth rate, which emphasizes the importance of the radial distribution pattern of IAA in controlling the development of secondary xylem, and suggests that a moderate increase in IAA concentration does not necessarily stimulate growth.

Accurate and high resolution in situ hybridization analysis of gene expression in secondary stem tissues.

Accurate in situ hybridization analysis in secondary stem tissues of plants has been hindered by specific characteristics of these tissues. First, secondary cell walls non-specifically bind probes used for in situ hybridization thus preventing gene expression analysis in the lignified regions of the stem, such as the xylem. Second, the mRNA in the cambial meristem and its recent derivatives are prone to inadequate fixation when conventional techniques are used. Here we describe an in situ hybridization technique which uses fast freezing and freeze substitution to cryoimmobilize the mRNA followed by embedding in a methacrylate resin for high-resolution analysis of gene expression. By using a transgenic poplar line harbouring rolC:uidA, rolC:iaaM, the gene expression pattern could be compared with histochemical GUS staining. This in situ hybridization technique results in superior preservation of cellular contents, retention of mRNA in all cell types in the poplar stem, a significant reduction of non-specific binding to secondary cell walls and a resolution not previously possible in secondary tissues. This technique will be particularly valuable for the expression analysis of genes involved in xylogenesis and wood formation.

The effect of felodipine on endothelin-1 levels, peripheral vasoconstriction and flap survival during microvascular breast reconstruction.

Endothelin-1 (ET-1) may contribute to vasoconstriction and flap blood flow during microvascular surgery. Calcium antagonists have suppressed ET-1 release in some studies. The effect of 5 mg of felodipine, a vasodilating calcium antagonist, administered the evening and morning before a microvascular TRAM (transverse rectus abdominis musculocutaneous) flap breast reconstruction, on perioperative plasma ET-1 concentrations, peripheral temperature gradient (Tgrad), rectal temperature (Trect), flap skin blood flow with transcutaneous oxygen tension (ptcO2), heart rate (HR) and mean arterial pressure (MAP) was evaluated in this clinical, randomised, double blind, prospective study. Felodipine did not cause any statistically significant changes in ET-1 levels, Tgrad, Trect, Ptc O2, flap survival or pre- or intraoperative MAP. HR was significantly higher in the felodipine group before induction and at 10 min postoperatively. We conclude that in patients undergoing a microvascular TRAM flap breast reconstruction, preoperatively administered felodipine has no effect on perioperative ET-1 levels, temperature changes, or flap skin blood flow.

A Radial Concentration Gradient of Indole-3-Acetic Acid Is Related to Secondary Xylem Development in Hybrid Aspen.

The radial distribution pattern of indole-3-acetic acid (IAA) was determined across the developing tissues of the cambial region in the stem of hybrid aspen (Populus tremula L. x Populus tremuloides Michx). IAA content was measured in consecutive tangential cryo-sections using a microscale mass spectrometry technique. Analysis was performed with wild-type and transgenic trees with an ectopic expression of Agrobacterium tumefaciens IAA-biosynthetic genes. In all tested trees IAA was distributed as a steep concentration gradient across the developing tissues of the cambial region. The peak level of IAA was within the cambial zone, where cell division takes place. Low levels were reached in the region where secondary wall formation was initiated. The transgenic trees displayed a lower peak level and a wider radial gradient of IAA compared with the wild type. This alteration was related to a lower rate of cambial cell division and a longer duration of xylem cell expansion in the transgenic trees, resulting in a decreased xylem production and a larger fiber lumen area. The results indicate that IAA has a role in regulating not only the rate of physiological processes such as cell division, but also the duration of developmental processes such as xylem fiber expansion, suggesting that IAA functions as a morphogen, conveying positional information during xylem development.

Indices of obesity and behaviour of the pedicled tram flap in breast reconstruction.

The association between obesity and the outcome of pedicled transverse rectus abdominis musculocutaneous (TRAM) flaps was studied in 12 patients. Obesity was assessed preoperatively by body mass index (BMI) and waist:hip circumference ratio (WHCR). The thickness of the abdominal fat and muscles was measured preoperatively with ultrasonography on the abdomen and during the nine postoperative months on the flap. Marginal or fat necrosis was more common among patients with lower body type fat distribution (WHCR less than 0.80) than in patients with medium or upper body type fat distribution. BMI and abdominal muscle and fat thicknesses were not associated with marginal or fat necrosis of the flaps. We conclude that lower body (female type) fat distribution may be associated with marginal cutaneous or fat necrosis in pedicled TRAM flaps.

Multicellular origin of tenascin in skin tumors--an in situ hybridization study.

Tenascin mRNA expression was studied by an in situ hybridization method in 27 skin tumors. Tenascin synthesis was increased in all skin tumors when compared to uninvolved skin but there was variation in the site of cellular synthesis between different types of tumors. In melanocytic nevi and precancerous keratinocyte lesions, tenascin seemed to be of epidermal or stromal origin. In basal cell carcinoma, squamous cell carcinoma and malignant melanoma, there was tenascin synthesis also in tumor cells. These findings are in concordance with earlier studies which suggest a role of tenascin as an anti-adhesive and motility-promoting factor in malignant skin tumors.