Intensive Care Unit Analgosedation After Cardiac Surgery in Children with Williams Syndrome : a Matched Case-Control Study.

OBJECTIVE: Cardiovascular abnormalities are common in patients with Williams syndrome and frequently require surgical intervention necessitating analgesia and sedation in a population with a unique neuropsychiatric profile, potentially increasing the risk of adverse cardiac events during the perioperative period. Despite this risk, the overall postoperative analgosedative requirements in patients with WS in the cardiac intensive care unit have not yet been investigated. Our primary aim was to examine the analgosedative requirement in patients with WS after cardiac surgery compared to a control group. Our secondary aim was to compare the frequency of major ACE and mortality between the two groups. DESIGN: Matched case-control study. SETTING: Pediatric CICU at a Tertiary Children's Hospital. PATIENTS: Patients with WS and age-matched controls who underwent cardiac surgery and were admitted to the CICU after cardiac surgery between July 2014 and January 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Postoperative outcomes and total doses of analgosedative medications were collected in the first six days after surgery for the study groups. Median age was 29.8 (12.4-70.8) months for WS and 23.5 (11.2-42.3) months for controls. Across all study intervals (48 h and first 6 postoperative days), there were no differences between groups in total doses of morphine equivalents (5.0 mg/kg vs 5.6 mg/kg, p = 0.7 and 8.2 mg/kg vs 10.0 mg/kg, p = 0.7), midazolam equivalents (1.8 mg/kg vs 1.5 mg/kg, p = 0.4 and 3.4 mg/kg vs 3.8 mg/kg, p = 0.4), or dexmedetomidine (20.5 mcg/kg vs 24.4 mcg/kg, p = 0.5 and 42.3 mcg/kg vs 39.1 mcg/kg, p = 0.3). There was no difference in frequency of major ACE or mortality. CONCLUSIONS: Patients with WS received similar analgosedative medication doses compared with controls. There was no significant difference in the frequency of major ACE (including cardiac arrest, extracorporeal membrane oxygenation, and surgical re-intervention) or mortality between the two groups, though these findings must be interpreted with caution. Further investigation is necessary to elucidate the adequacy of pain/sedation control, factors that might affect analgosedative needs in this unique population, and the impact on clinical outcomes.

Padlock probes reveal single-nucleotide differences, parent of origin and in situ distribution of centromeric sequences in human chromosomes 13 and 21.

Chromosome centromeres, composed of repeated DNA sequences, orchestrate the correct segregation of chromatids in cell division. We have examined the centromeres of human chromosomes 13 and 21 by studying the distribution, in situ, of two alpha satellite sequences that differ in a single nucleotide position. This was possible using padlock probes, oligo-nucleotides that can be ligated into circles upon target recognition. The segregation of individual 13 and 21 homologues in a family was followed by monitoring of the signals from two differentially labelled probes, specific for either sequence variant. A characteristic arrangement of the repeat motifs in three separate spots, oriented transverse to the length axis of the metaphase chromosomes and bilaterally symmetric, indicates that only parts of the detected regions are involved in the centromeric region, joining the sister chromatids before anaphase.

Processes occurring in the NaCMC/glauconite suspension under the cold plasma treatment. Influence of plasma on adsorptive and stabilizing properties of the system.

The paper presents the studies on the processes at the interface of the colloidal suspensions composed of clay mineral - glauconite (GT) and polysaccharide - sodium carboxymethyl cellulose (NaCMC) with the cold plasma treatment (CPT). The surface composition and chemical binding in NaCMC and GT changes are determined by means of FTIR and XPS (both methods detected the incorporation of oxygen-related functional groups). Moreover, the additional information about both the textural properties and morphological changes on the surfaces before and after CPT are studied using the BET, CHN, SEM HRTEM and STEM-EDS methods. The elemental mapping and scanning electron microscope imaging confirmed the NaCMC adsorption on GT (carbon mapping) and proved the GT surface lost its "house of card structure" after the CPT. As follows the CPT causes the protonation of NaCMC and the polymer cross-linking whereas the GT sample is more oxidized. Moreover, it was found that a significant improvement in the GT/NaCMC system stability and the NaCMC adsorption on the GT surface were a result of the CPT. The obtained data could be used for the colloidal stability of polymer/solid suspensions, thus providing new opportunities for the chemical industry; particularly for preparation of new functionalized materials.

Identification of a calcitonin-like diuretic hormone that functions as an intrinsic modulator of the American lobster, Homarus americanus, cardiac neuromuscular system.

In insects, a family of peptides with sequence homology to the vertebrate calcitonins has been implicated in the control of diuresis, a process that includes mixing of the hemolymph. Here, we show that a member of the insect calcitonin-like diuretic hormone (CLDH) family is present in the American lobster, Homarus americanus, serving, at least in part, as a powerful modulator of cardiac output. Specifically, during an ongoing EST project, a transcript encoding a putative H. americanus CLDH precursor was identified; a full-length cDNA was subsequently cloned. In silico analyses of the deduced prepro-hormone predicted the mature structure of the encoded CLDH to be GLDLGLGRGFSGSQAAKHLMGLAAANFAGGPamide (Homam-CLDH), which is identical to a known Tribolium castaneum peptide. RT-PCR tissue profiling suggests that Homam-CLDH is broadly distributed within the lobster nervous system, including the cardiac ganglion (CG), which controls the movement of the neurogenic heart. RT-PCR analysis conducted on pacemaker neuron- and motor neuron-specific cDNAs suggests that the motor neurons are the source of the CLDH message in the CG. Perfusion of Homam-CLDH through the isolated lobster heart produced dose-dependent increases in both contraction frequency and amplitude and a dose-dependent decrease in contraction duration, with threshold concentrations for all parameters in the range 10(-11) to 10(-10) mol l(-1) or less, among the lowest for any peptide on this system. This report is the first documentation of a decapod CLDH, the first demonstration of CLDH bioactivity outside the Insecta, and the first detection of an intrinsic neuropeptide transcript in the crustacean CG.

Padlock probes: circularizing oligonucleotides for localized DNA detection.

Nucleotide sequence information derived from DNA segments of the human and other genomes is accumulating rapidly. However, it frequently proves difficult to use such short DNA segments to identify clones in genomic libraries or fragments in blots of the whole genome or for in situ analysis of chromosomes. Oligonucleotide probes, consisting of two target-complementary segments, connected by a linker sequence, were designed. Upon recognition of the specific nucleic acid molecule the ends of the probes were joined through the action of a ligase, creating circular DNA molecules catenated to the target sequence. These probes thus provide highly specific detection with minimal background.

[Status of care for prostate cancer in 2008]. / Stand der Prostatakarzinomvorsorge im Jahr 2008.

Prostate cancer as the second most frequent cause of death due to malignancy in men increasingly represents a problem for health care policy that is further intensified by demographic developments."Not every prostate carcinoma identified early must be treated, but those that require therapy must be detected early!" is the current key message in individual screening programs. This means that the measures undertaken for early detection have to be discussed with the patients to inform them about their disease risk, the need for timely initiation of curative treatment, and on possible side effects. On the other hand,"overtreatment" should be avoided. Study results on the general screening benefit with level A evidence are first expected around 2010. Interim analyses with metastasis rate as the endpoint show a benefit of screening in comparison to the control group. Results of trials with level B evidence support the benefit of individual screening. The"overdiagnosis" of latent carcinomas (2-20%) as a consequence of prostate cancer screening should be dealt with by increasing the use of more precise models for active surveillance. Studies that militate against screening should be considered inadequate upon closer scrutiny since they were conducted in a patient cohort that was too old, the follow-up period was too short, and inappropriate endpoints were set.

Ureteral Rupture Caused by Accidental Intubation of the Ureter with a Foley-Catheter during Ureterorenoscopy.

We would like to present the case of a 64-year-old woman who underwent ureterorenoscopy and suffered an iatrogenic ureteral lesion due to an accidental intubation of the left ureter with a Foley-Catheter during the procedure. A Double-J-Stent was implanted into the damaged ureter, and 6 weeks later it fully recovered. To our knowledge there are few similar cases described in the literature with none of those having happened during ureterorenoscopy so far.

The fluoride cleavable 2-(cyanoethoxy)methyl (CEM) group as reversible 3'-O-terminator for DNA sequencing-by-synthesis - synthesis, incorporation, and cleavage.

A new and promising sequencing technology called sequencing-by-synthesis (SBS) enables fast determination of DNA sequences. 2'-Deoxynucleotides containing the (2-cyanoethoxy)methyl (CEM) group at the 3'-O-position are potential reversible terminators for the SBS technology. Herein we describe the synthesis, the incorporation by several polymerases, and the cleavage of this 3'-O-blocking group using 3'-O-CEM-thymidinyl-5'-O-triphosphate 7 as an example.

Inversion of in situ synthesized oligonucleotides: improved reagents for hybridization and primer extension in DNA microarrays.

Oligonucleotides synthesized in array format suffer from contamination by truncated species. We have developed a method to invert DNA molecules in situ after completed synthesis. Reactive functions at the 5'-ends of the oligonucleotides are permitted to react with functions on the support before the 3'-ends are released, in effect reversing the orientation of full-length oligonucleotides, while any 5'-truncated molecules are lost. This strategy serves both to purify in situ synthesized reagents and to reorient the oligonucleotides, causing them to expose free 3'-hydroxyls. In situ inverted oligonucleotides can be used in assays based on DNA polymerase-assisted extension of immobilized primers, and we demonstrate their utility in minisequencing and in pyrosequencing.

Homogenization of tissues via picosecond-infrared laser (PIRL) ablation: Giving a closer view on the in-vivo composition of protein species as compared to mechanical homogenization.

Posttranslational modifications and proteolytic processing regulate almost all physiological processes. Dysregulation can potentially result in pathologic protein species causing diseases. Thus, tissue species proteomes of diseased individuals provide diagnostic information. Since the composition of tissue proteomes can rapidly change during tissue homogenization by the action of enzymes released from their compartments, disease specific protein species patterns can vanish. Recently, we described a novel, ultrafast and soft method for cold vaporization of tissue via desorption by impulsive vibrational excitation (DIVE) using a picosecond-infrared-laser (PIRL). Given that DIVE extraction may provide improved access to the original composition of protein species in tissues, we compared the proteome composition of tissue protein homogenates after DIVE homogenization with conventional homogenizations. A higher number of intact protein species was observed in DIVE homogenates. Due to the ultrafast transfer of proteins from tissues via gas phase into frozen condensates of the aerosols, intact protein species were exposed to a lesser extent to enzymatic degradation reactions compared with conventional protein extraction. In addition, total yield of the number of proteins is higher in DIVE homogenates, because they are very homogenous and contain almost no insoluble particles, allowing direct analysis with subsequent analytical methods without the necessity of centrifugation. BIOLOGICAL SIGNIFICANCE: Enzymatic protein modifications during tissue homogenization are responsible for changes of the in-vivo protein species composition. Cold vaporization of tissues by PIRL-DIVE is comparable with taking a snapshot at the time of the laser irradiation of the dynamic changes that occur continuously under in-vivo conditions. At that time point all biomolecules are transferred into an aerosol, which is immediately frozen.

Detecting Genes with Ligases

The combination of synthetic oligonucleotide probes and DNA ligases is central to several recently developed genetic assays. Among the advantages of ligase-mediated gene detection is that ligation of probe pairs provides highly specific detection of unique DNA sequences in genomic samples. The technique also allows for convenient distinction between sequence variants, since mismatched bases at the junction of the probe pair prevent ligation. Moreover, the circumstance that two probes are joined into one molecule can be exploited for detection in several ways, for instance by observing the change in probe size upon ligation. Alternatively, a detectable function on one probe can be demonstrated to become linked to a retrievable function on another one through ligation. Ligation products can also be recruited as templates for subsequent ligation reactions in powerful amplification schemes. So-called padlock probes lock to their targets by encircling them, remaining in place even after denaturing washes. Here, we will describe two ligase-mediated assays: one that serves to monitor the presence of common sequence variants in amplified samples of genomic DNA and another that is suitable to detect localized gene sequences.

Cost-effectiveness of prostate cancer screening: a simulation study based on ERSPC data.

BACKGROUND: The results of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial showed a statistically significant 29% prostate cancer mortality reduction for the men screened in the intervention arm and a 23% negative impact on the life-years gained because of quality of life. However, alternative prostate-specific antigen (PSA) screening strategies for the population may exist, optimizing the effects on mortality reduction, quality of life, overdiagnosis, and costs. METHODS: Based on data of the ERSPC trial, we predicted the numbers of prostate cancers diagnosed, prostate cancer deaths averted, life-years and quality-adjusted life-years (QALY) gained, and cost-effectiveness of 68 screening strategies starting at age 55 years, with a PSA threshold of 3, using microsimulation modeling. The screening strategies varied by age to stop screening and screening interval (one to 14 years or once in a lifetime screens), and therefore number of tests. RESULTS: Screening at short intervals of three years or less was more cost-effective than using longer intervals. Screening at ages 55 to 59 years with two-year intervals had an incremental cost-effectiveness ratio of $73000 per QALY gained and was considered optimal. With this strategy, lifetime prostate cancer mortality reduction was predicted as 13%, and 33% of the screen-detected cancers were overdiagnosed. When better quality of life for the post-treatment period could be achieved, an older age of 65 to 72 years for ending screening was obtained. CONCLUSION: Prostate cancer screening can be cost-effective when it is limited to two or three screens between ages 55 to 59 years. Screening above age 63 years is less cost-effective because of loss of QALYs because of overdiagnosis.

A high-capacity manifold support for the detection of specific IgE antibodies in allergic individuals.

A high-capacity manifold support with immobilized antigen was developed for the analysis of IgE-mediated immune reactivity in allergic subjects. Using this 96-pronged support, specific antibodies were trapped and detected from large sets of serum samples. We describe the binding of large amounts of antigen onto the expanded surface of the manifold support, permitting efficient identification of allergic individuals.

Human biodistribution, dosimetry and clinical use of technetium(III)-99m-Q12.

UNLABELLED: Technetium(III)-99m-Q12, trans-(1,2-bis(dihydro-2,2,5,5-tetramethyl- 3(2H)furanone-4-methyleneimino)ethane)bis(tris(3-methoxy-1-propyl) - phosphine)technetium(III)-99m, is a nonreducible complex of Tc(III) which is herein evaluated as a myocardial perfusion imaging agent. METHODS: The biodistribution and dosimetry of 99mTc-Q12 were assessed in 10 normal volunteers, while its potential clinical use was evaluated in 70 patients. RESULTS: Safety parameters measured up to 24 hr postinjection demonstrate no clinically significant drug-related adverse reactions. Technetium(III)-99m-Q12 exhibits good heart uptake (2.2% injected dose at 1 hr postinjection under resting conditions) and no detectable myocardial washout or redistribution up to 5 hr postinjection. The biodistribution is characterized by very rapid hepatobiliary clearance which allows effective myocardial imaging at times as short as 15 min postinjection. Blood and plasma clearances and myocardial uptake are rapid, while lung uptake is minimal. The heart-to-lung and heart-to-liver ratios are higher at stress than at rest, independent of the time elapsed between injection and image acquisition, and independent of whether the patient is fasted or fed after tracer administration. A preliminary correlation shows that 46/47 patients with angiographically demonstrated CAD also have perfusion defects demonstrated by 99mTc-Q12. CONCLUSIONS: On the basis of the studies reported herein, 99mTc-Q12 appears to be a promising myocardial perfusion imaging agent.

In prostatism patients the ratio of human glandular kallikrein to free PSA improves the discrimination between prostate cancer and benign hyperplasia within the diagnostic "gray zone" of total PSA 4 to 10 ng/mL.

OBJECTIVES: Human glandular kallikrein (hK2) possesses approximately 80% structure identity with prostate-specific antigen (PSA). Moreover, messenger ribonucleic acid for hK2 and for PSA is expressed in both benign and malignant prostatic tissue. We investigated whether the hK2 serum measurement may improve the detection of prostate cancer (PCa) in patients with total PSA of 4 to 10 ng/mL (diagnostic "gray zone"). METHODS: Blood samples were obtained from 90 consecutive male patients with lower urinary tract symptoms and total PSA values of 4 to 10 ng/mL. Eighty-one patients underwent transurethral resection of the prostate and 6 radical prostatectomy. The patients were divided into two groups: I, patients with PCa (n = 20) and II, patients with benign prostatic hyperplasia (BPH) (n = 70). An "in-house" immunofluorometric assay with analytical sensitivity of 0.01 ng/mL and the functional sensitivity of 0.05 ng/mL (at this level the mean coefficient of variation, calculated from the precision profile based on the assays of serum samples, was less than 20%) was used to determine serum hK2 concentrations. Total PSA, free PSA (ProStatus), and PSA complexed to alpha1-antichymotrypsin (PSA-ACT) were also measured. Free/total PSA, hK2/total PSA, and hK2/free PSA ratios were calculated. RESULTS: The serum hK2 could be detected in all samples and in 76 (84.4%) of 90 samples (PCa, n = 18; BPH, n = 58) at given functional sensitivity level. For these cases the median concentration of hK2 was 0.135 ng/mL in PCa and 0.09 ng/mL in BPH (P < 0.1). The median hK2/total PSA ratio was 2% for PCa and 1.6% for BPH (P < 0.2). The median free/total PSA ratio was 0.122 for PCa and 0.215 for BPH (P < 0.0008) and the hK2/free PSA ratio was 0.139 for PCa and 0.075 for BPH (P < 0.000003). At a 7.2% cutoff, the specificity of hK2/free PSA ratio was 48.2% at 100% sensitivity and increased to 60.3% at 94.4% sensitivity level (the area under the receiver operating characteristic curve was 0.86). In comparison, the free/total PSA ratio at a 25.2% cutoff had a sensitivity of 94.4% and a specificity of 27.6% (area under the curve = 0.76). CONCLUSIONS: hK2 was detected in all sera with total PSA values of 4 to 10 ng/mL. Of particular clinical interest is the finding that the hK2/free PSA ratio had a better specificity without loss of sensitivity for PCa than total PSA or the PSA free/total ratio within the range of 4 to 10 ng/mL total PSA. hK2 in combination with free PSA may offer a new diagnostic means for PCa detection.

Failure to detect radioimmunoassayable arginine vasotocin in mammalian pineals.

The presence of arginine vasopressin (AVP) and arginine vasotocin (AVT) in pineal and neural lobes of a variety of species was evaluated by radioimmunoassay using two antisera. One antiserum recognizes only AVP, while the other cross-reacts 100% with both AVP and AVT. Only traces of AVP were detected in toad and chicken pituitaries and chicken pineals, tissues found to contain abundant AVT. On the other hand, pineals from rats and rabbits, while containing measurable quantities of AVP, did not contain detectable levels (less than 6 pg) of AVT. These results fail to demonstrate the presence of AVT in rat and rabbit pineals and strongly question the role of AVT as a physiological pineal hormone in mammals.

Prostate cancer screening: results of a prospective trial in Canton Aargau, Switzerland.

INTRODUCTION: Prostate cancer is the most commonly diagnosed cancer in Swiss men and the second leading cause of cancer related death among them (e.g. CH: 1,267 in year 1998). With the population at risk constantly growing these absolute numbers are expected to further increase. While there is no question that aggressive treatment of localised tumour is required for definitive cure of prostate cancer, the application of screening for early stage disease remains controversial. Since 1998 the Clinic of Urology in Kantonsspital Aarau has participated in the ERSPC (European Randomised Study of Screening for Prostate Cancer) study, which is designed to provide data on prostate cancer screening within a prospective randomised controlled setting. METHODS: Men aged between 55 and 70 years were enrolled in the study. From n = 18,361 men invited by a letter to participate, 7,124 (38.8%) agreed and gave their informed consent to be randomised in either a PSA measurement (n = 3,562, group 1) or a control group (n = 3,562, group 2). Men in group 1 with a PSA level ?3.0 ng/ml, n = 372 (10.5%) then underwent ultrasound guided transrectal sextant biopsy of the prostate. RESULTS: Prostate cancer was detected at presentation in every fourth man biopsied (n = 89). Neither the free-to-total PSA ratio nor the PSA density could significantly spare biopsies while sustaining a high sensitivity level. The overall cancer detection rate amounted to 2.5% in PSA tested men. In 7% (n = 5) distant disease was already present. 93% of men with clinically organ confined disease underwent prostatectomy (n = 59) or radiotherapy (n = 22), whilst only (n = 3) chose to follow a policy of watchful waiting. In 92% the histology of the prostatectomy specimens revealed aggressive cancer characteristics according to the criteria of Epstein et al. CONCLUSIONS: Although the clinically relevant tumour characteristics and the relatively low cancer detection rate of 2.5% (less than the lifetime mortality risk of 3% and the morbidity risk of 8%) seem to justify screening in terms of adequate diagnosis and treatment, follow-up until 2008 is needed to prove the benefit in mortality for the prostate cancer screening group over the control group. Furthermore, information from the ongoing ERSPC study is needed in order to assess uncertainties i.e. the degree of overdiagnosis caused by repeated screening and the quality of life adjusted gain in life years. For daily practice a "PSA grey zone" of 4-10 ng/ml can no longer be postulated as only 70% of men in this range presented with organ confined disease. Once the PSA level exceeds 4.0 ng/ml. prostate biopsy should be performed immediately.

A case of the subacute brainstem encephalitis.

A case of brainstem encephalitis of undetermined etiology is reported in 66-year-old woman who had a sudden onset of illness with left abducens palsy, nystagmus and ataxia. The symptoms progressed to complete paralysis of eye movements, dysphagia and left hemiparesis with generalized hyperreflexia. Examination of CSF, CT scan and MRI of the brain were normal. The patient died 4 months after onset of disease. Neuropathologic study disclosed in the brainstem numerous perivascular and nodular inflammatory cell infiltrations composed predominantly of lymphocytes T and B. Most intensive inflammation concerned midbrain and pontine tegmentum and to a lesser degree medulla oblongata, pontine nuclei and cerebellar nuclei. Basal ganglia, cerebral and cerebellar cortex were unaffected. Neuropathological finding was reminiscent of brainstem encephalitides related to viral infection or to paraneoplastic syndrome. However, HSV-1, EBV, and CMV antigens were not detected by immunohistochemistry, as well as evidences of malignancy were not present in this case.

[PSA-screening for prostate cancer--yes or no?]. / PSA-screening für das Prostata-Karzinom-- ja oder nein?

Prostate cancer is a mayor health care problem, especially in the industrialised countries of the Western world. At this time it is the second most common cancer reason for death (CH: 1500 men/year) which will even get more importance in the future by demographic developments. While there is no doubt that in individuals early detection of organ confined disease with localised treatment the prostate cancer can be eradicated and individual men be cured there are uncertainties whether mass screening a population will contribute to reducing prostate cancer related mortality. Its value has not been proved definitively by prospective randomised controlled studies. Most of Medical Societies recommend a "well informed" decision by family physicians, where the men between 50-70 years know about the benefits and harms including: risk of cancer, diagnostic procedures, therapeutic consequences and possible side effects. After agreement of early detection a biopsy has to be done directly above a PSA level of 4.0 ng/ml or a suspicious digital rectal examination. A PSA "grey zone" 4-10 ng/ml can not further be postulated. The ratio of free/total PSA gives no support to prolong biopsy in this moment, because an elevated benign prostate with a higher production of free PSA can mask the tumor in the peripheral zone. Results of the ERSPC and the PLCO trials are expected to give information about the benefits and harms of mass screening in 2006/8.