Vaccination rates in cochlear implant patients: a review of paediatric recipients.

OBJECTIVE: This study aimed to investigate whether children with cochlear implants received the recommended vaccinations according to New Zealand national immunisation guidelines and to report the incidence of meningitis in this population after intervention. METHOD: A retrospective review of the vaccination coverage of paediatric patients receiving cochlear implants between 2005 and 2019 was performed. RESULTS: Data were collected on 203 children. Evidence of immunisation against Haemophilus influenza B was documented in 94.1 per cent of this cohort and 21.2 per cent received the seasonal influenza vaccine. The pneumococcal conjugate vaccine was fully administered in 81.8 per cent of children; however, only 16.9 per cent of eligible children had received the pneumococcal polysaccharide vaccine. There was marked improvement in compliance to the pneumococcal conjugate vaccine once it became fully funded for cochlear implant patients. CONCLUSION: Despite established guidelines, the paediatric vaccination rates were less than expected. Work is in progress to address this.

Five decades of northern land carbon uptake revealed by the interhemispheric CO2 gradient.

The global land and ocean carbon sinks have increased proportionally with increasing carbon dioxide emissions during the past decades1. It is thought that Northern Hemisphere lands make a dominant contribution to the global land carbon sink2-7; however, the long-term trend of the northern land sink remains uncertain. Here, using measurements of the interhemispheric gradient of atmospheric carbon dioxide from 1958 to 2016, we show that the northern land sink remained stable between the 1960s and the late 1980s, then increased by 0.5 ± 0.4 petagrams of carbon per year during the 1990s and by 0.6 ± 0.5 petagrams of carbon per year during the 2000s. The increase of the northern land sink in the 1990s accounts for 65% of the increase in the global land carbon flux during that period. The subsequent increase in the 2000s is larger than the increase in the global land carbon flux, suggesting a coincident decrease of carbon uptake in the Southern Hemisphere. Comparison of our findings with the simulations of an ensemble of terrestrial carbon models5,8 over the same period suggests that the decadal change in the northern land sink between the 1960s and the 1990s can be explained by a combination of increasing concentrations of atmospheric carbon dioxide, climate variability and changes in land cover. However, the increase during the 2000s is underestimated by all models, which suggests the need for improved consideration of changes in drivers such as nitrogen deposition, diffuse light and land-use change. Overall, our findings underscore the importance of Northern Hemispheric land as a carbon sink.

Dexmedetomidine, high-flow nasal oxygen and sugammadex-reversal of rocuronium: overcoming anaesthetic challenges in a parturient with congenital muscular dystrophy presenting for caesarean section.

Congenital muscular dystrophies are characterised by progressive skeletal muscle weakness from birth or early infancy. Maternal respiratory compromise, joint contractures and presence of spinal instrumentation or fusion are some of the anaesthetic challenges that may be encountered in the obstetric setting. The choice of anaesthetic technique for surgical delivery needs to be considered on an individual basis. Multidisciplinary involvement is paramount to optimise peripartum care and outcomes. In this case report, we present the use of dexmedetomidine, humidified high-flow nasal oxygen, rocuronium and sugammadex in the anaesthetic management of a wheelchair-bound, non-invasive bilevel positive airway pressure ventilation-dependent parturient with congenital muscular dystrophy, who was presenting for caesarean section.

Escherichia coli induces platelet aggregation in an FcγRIIa-dependent manner.

BACKGROUND: The discovery of pathogen-recognition receptors such as Toll-like receptors on platelets has led to the emergence of the concept of platelets as important components of the host response to infection. Escherichia coli (E. coli)-mediated sepsis is a serious illness characterized by the occurrence of thrombocytopenia. Whereas there has been a wealth of research on platelet activation by Gram-positive bacteria, little is known about the mechanisms associated with Gram-negative bacteria-induced platelet activation with Gram-negative bacteria. OBJECTIVES: To determine the mechanisms by which Gram-negative E. coli induces platelet aggregation. METHODS: Induction of platelet aggregation with E. coli strain O157:H7 was tested in platelet-rich plasma (PRP), washed platelets, and serum depleted of complement factors. Platelet inhibitors (against αII b ß3 , glycoprotein Ibα and FcγRIIa) were used. Platelet thromboxane synthesis was analyzed after E. coli stimulation. Cell binding assays were used to assess the ability of E. coli to support platelet adhesion. Trypsinization was used to determine the role of E. coli surface proteins. RESULTS AND CONCLUSION: E. coli-induced aggregation in PRP was donor-dependent. E. coli O157:H7 induced aggregation with a lag time of 6.9 ± 1.3 min in an αII b ß3 -dependent and FcγRIIa-dependent manner. Furthermore, this interaction was enhanced by the presence of complement, and was dependent on thromboxane synthesis. These results show E. coli to be a potent inducer of platelet aggregation.

The application of water soluble, mega-Stokes-shifted BODIPY fluorophores to cell and tissue imaging.

BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) fluorophores are widely used in bioimaging to label proteins, lipids and nucleotides, but in spite of their attractive optical properties they tend to be prone to self-quenching because of their notably small Stokes shift. Herein, we compare two BODIPY compounds from a recently developed family of naphthyridine substituted BODIPY derivatives, one a visible emitting derivative (BODIPY-VIS) and one a near-infrared emitting fluorophore with a Stokes shift of approximately 165 nm as contrast reagents for live mammalian cells and murine brain tissue. The compounds were rendered water soluble by their conjugation to polyethylene glycol (PEG). Both PEGylated compounds exhibited good cell uptake compared with their parent compounds and confocal fluorescence microscopy revealed all dyes explored to be nuclear excluding, localizing predominantly within the lipophilic organelles; the endoplasmic reticulum and mitochondria. Cytotoxicity studies revealed that these BODIPY derivatives are modestly cytotoxic at concentrations exceeding 10 µM where they induce apoptosis and necrosis. Although the quantum yield of emission of the visible emitting fluorophore was over an order of magnitude greater than the Mega-Stokes shifted probe, the latter showed considerably reduced tendency to self quench and less interference from autofluorescence. The near-infrared probe also showed good penetrability and staining in live tissue samples. In the latter case similar tendency to exclude the nucleus and to localize in the mitochondria and endoplasmic reticulum was observed as in live cells. This to our knowledge is the first demonstration of such a Mega-Stokes BODIPY probe applied to cell and tissue imaging.

In vitro assessment of intestinal permeability and hepatic metabolism of 4'-bromoflavone, a promising cancer chemopreventive agent.

1. The intestinal permeability and hepatic metabolism of the investigational cancer chemoprevention agent 4'-bromoflavone were investigated in vitro using human intestinal Caco-2 cell monolayers, human liver microsomes and human hepatocytes. Liquid chromatography-mass spectrometry and tandem mass spectrometry were used for quantitative analysis in support of the Caco-2 cell studies and for the characterization of metabolites of 4'-bromoflavone. 2. The Caco-2 cell model indicated that 4'-bromoflavone would be absorbed by the intestine at a moderate rate by means of direction-independent, passive diffusion. There was no indication of active transport or efflux. 3. Three monohydroxylated metabolites and one monohydroxylated, hydrated metabolite of 4'-bromoflavone were detected at relatively low levels in the human liver microsomal and hepatocyte incubations. The structures of these metabolites were confirmed by comparison with synthetic standards. Hydroxylation occurred on the A-ring of 4'-bromoflavone but not on the B-ring, probably due to deactivation of the B-ring by bromine. No phase II metabolites were detected following incubation of 4'-bromoflavone in these in vitro systems. 4. In conclusion, these studies predict that 4'-bromoflavone should show moderate oral bioavailability, and that it would probably be excreted as unchanged compound and monohydroxylated metabolites. The results might be helpful in the design of clinical trials and in the interpretation of pharmacokinetic studies of 4'-bromoflavone.

alpha-thiocyanation of carbonyl and beta-dicarbonyl compounds using (dichloroiodo)benzene-lead(II) thiocyanate.

The combination reagent (dichloroiodo)benzene and lead(II) thiocyanate in dichloromethane effects oxidation of various enol silyl ethers, ketene silyl acetals, and beta-dicarbonyl compounds, thereby providing an efficient and convenient method for alpha-thiocyanation of carbonyl and beta-dicarbonyl compounds.

Pharmacokinetics of deguelin, a cancer chemopreventive agent in rats.

PURPOSE: To study the pharmacokinetics of deguelin, a naturally occurring potential cancer chemopreventive agent, in rats. METHODS: [3H]Deguelin was administered intravenously (i.v.) under anesthesia, and blood samples were collected over 24 h. [3H]Deguelin and metabolites were extracted from plasma with ethyl acetate, and quantified by HPLC. Data were analyzed with the WinNolin pharmacokinetic software package to determine pharmacokinetic parameters. A three-compartment first-order elimination model was used to fit the plasma concentration-time curve. In addition, deguelin concentrations in tissues after i.v. and intragastric (i.g.) administration were determined by HPLC, and excretion (feces and urine) was evaluated over a 5-day period after i.g. administration. RESULTS: Deguelin exhibited a mean residence time (MRT) of 6.98 h and terminal half-life (t1/2(gamma)) of 9.26 h. The area under the curve (AUC) and total clearance (Cl) were 57.3 ng.h/ml and 4.37 l/h per kg, respectively, with an apparent volume of distribution (V) and volume of distribution at steady-state (Vss) of 3.421 l/kg and 30.46 l/kg, respectively. Following i.v. administration, the relative levels of tissue distribution were as follows: heart > fat > mammary gland > colon > liver > kidney > brain > lung. Following i.g. administration, the relative levels of tissue distribution were as follows: perirenal fat > heart > mammary gland > colon > kidney > liver > lung > brain > skin. Within 5 days of i.g. administration, about 58.1% of the [3H]deguelin was eliminated via the feces and 14.4% via the urine. Approximately 1.7% of unchanged deguelin was found in the feces, and 0.4% in the urine. CONCLUSIONS: An initial pharmacokinetic investigation of deguelin showed that this rotenoid has a relatively long MRT and half-life in plasma in the rat. The compound distributed in the tissues and excreted as metabolites, mainly via the feces.

Bilateral testicular lymphoma treated with chemotherapy and radiation without orchiectomy: complete response relapsed at 52 months in the vitreous humor.

We report the first detailed case of testicular lymphoma managed with chemotherapy and radiation without orchiectomy. A 60-year-old man with Stage II extralymphatic bilateral testicular lymphoma refused orchiectomy, but underwent cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy and radiation. He remained disease free for 52 months, when a solitary central nervous system relapse to the vitreous humor was diagnosed. The optimal therapy for testicular lymphoma is unclear but often includes orchiectomy with adjuvant chemotherapy and radiation. Stage I testicular lymphoma can be cured by surgery alone; however, the relapse rates for all stages of testicular lymphoma are high despite systemic therapy. For Stage II disease and higher, chemotherapy/radiation is recommended; orchiectomy may not be mandatory.

Prevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in rats by 1alpha-hydroxyvitamin D(5).

BACKGROUND: Although the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D(3), is a potent cell-differentiating agent, its use in cancer prevention or therapy is precluded because it induces excessive blood calcium levels (hypercalcemia). However, less calcemic or noncalcemic synthetic analogues of vitamin D(3) are poorly effective against mammary carcinogenesis. We synthesized an analogue of vitamin D(5), 1alpha-hydroxy-24-ethylcholecalciferol (1alpha-hydroxyvitamin D(5)), which was less calcemic than 1,25-dihydroxyvitamin D(3) and prevented the development of precancerous lesions in mammary glands. Here, we evaluate its efficacy in an experimental rat mammary carcinogenesis model. METHODS: Sprague-Dawley rats were treated with 1alpha-hydroxyvitamin D(5) beginning 2 weeks before carcinogen treatment. Animals received an intravenous injection of N-methyl-N-nitrosourea at 80 days of age and continued to receive dietary 1alpha-hydroxyvitamin D(5) for an additional 105 days. Tumor incidence and multiplicity were determined, and plasma concentrations of calcium and phosphorus were measured. The efficacy of 1alpha-hydroxyvitamin D(5) at different stages of carcinogenesis was determined in mouse mammary gland organ culture. All statistical tests were two-sided. RESULTS: The tumor incidence was reduced from 80% (95% confidence interval [CI] = 51.9%-95.7%) in control rats to 53.3% (95% CI = 26.6%-78.8%) and 46.6% (95% CI = 21.3%-73.4%) in rats treated with 1alpha-hydroxyvitamin D(5) at 25 microg/kg diet and 50 microg/kg diet, respectively. The tumor multiplicity was reduced from 1.6 tumors per rat to 1.2 (95% CI for the difference = -0.45 to 1.25; P=.34) and 0.8 (95% CI for the difference = 0.14-1.46; P =.02), respectively. There was no statistically significant increase in the plasma calcium or phosphorus concentration at either dose level. The vitamin D(5) analogue was effective during both the initiation and the promotion stages of mammary lesion formation in organ culture. CONCLUSION: Our findings indicate that 1alpha-hydroxyvitamin D(5) reduces the incidence of mammary carcinogenesis in vivo. This analogue appears to be a good candidate for further development as a chemopreventive agent.

Implicit and explicit memory in pregnant women: an analysis of data-driven and conceptually driven processes.

A study by Brindle, Brown, Brown, Griffith, and Turner (1991), reported that pregnant women showed impaired implicit memory (as measured by a stem completion task) in the presence of intact explicit memory. The present study was an attempt to replicate and extend this finding by employing a read/generate encoding manipulation across data-driven (word fragment completion and graphemic cued recall) and conceptually driven (semantic cued recall and category generation) tests. A total of 64 women (32 pregnant) were tested on both data-driven and conceptually driven tasks either directly or indirectly. No differences emerged between pregnant subjects and non-pregnant controls across tasks. Subjects experiencing their first pregnancy did report their memory in the previous 2 weeks as being considerably worse than normal.

Overexpression of p53 in prostate carcinoma is associated with improved overall survival but not predictive of response to radiotherapy.

p53 gene mutations are among the most common specific genetic alterations in human cancer. Inactivation of p53 and subsequent protein accumulation has been implicated in a variety of human malignancies and associated with prostate cancer progression. In this study, we assessed p53 protein overexpression and gene mutations in prostate carcinoma and investigated associations between p53 alterations and clinicopathological parameters, survival, and response to radiotherapy. We evaluated 58 archival formalin-fixed, paraffin-embedded prostate carcinomas to detect abnormal p53 nuclear protein accumulation using immunohistochemistry. p53 mutational status of tumor DNA was evaluated using polymerase chain reaction-single-strand conformation polymorphism analysis of exons 5-9 and confirmed by direct DNA sequencing. Univariate and multivariate statistical analysis was used to determine the association of p53 status with clinical characteristics and response to radiotherapy. Overexpression of p53 was detected in 42 (72%) of 58 primary prostate carcinomas, but was undetectable in 7 samples of benign prostatic hyperplasias or 5 samples of normal prostate tissue. p53 exon 5-9 mutations were detected in 8 (14%) of 58 patient specimens. p53 mutational status, but not overexpression, was associated with higher Gleason scores (p=0.0145). Neither p53 overexpression nor mutation was associated with clinical stage, biochemical disease-free probability, or predictive of response to radiotherapy. p53 protein accumulation was inversely associated with improved overall survival (p=0.0108). Our studies demonstrate that p53 protein accumulation is a frequent alteration in prostate cancer. The disparity between p53 protein overexpression and p53 exon 5-9 mutations suggests the possibility of mutations outside this region or stabilization of wild-type p53 by alternative mechanisms. In our patient population, p53 protein overexpression or mutational status was not predictive of outcome in patients treated with radiation therapy. Additional studies are needed to further evaluate the association between p53 protein overexpression and improved overall survival.

Fifteen-year minimum follow-up of a prostate brachytherapy series: comparing the past with the present.

OBJECTIVES: To report the overall survival for 126 patients more than 15 years after iodine-125 interstitial therapy; to report the biochemical progression status for those alive and clinically without evidence of disease for longer than 15 years; to document the upward migration of grade by date of grade assignment; to compare the tumor stage and grade profile of this mature series with our current experience; and to clarify the prostate-specific antigen (PSA) data when this series is used as a historical comparison. METHODS: The records of 126 patients who underwent interstitial therapy more than 15 years previously were reviewed for assessment of the current TNM stage and Gleason grade and the current PSA level for patients clinically free of disease. The tumor grade and stage of these patients were compared with those of the first 126 patients treated by transrectal ultrasound-guided brachymonotherapy at our center between January 1995 and January 1999. The methodology of our 1993 publication was also reviewed. RESULTS: Of the 16 patients clinically free of disease (13 still alive and 3 dead of other causes more than 15 years after therapy), a review of the initial diagnostic needle biopsy was unable to confirm the presence of tumor in 3 patients. Of the remaining 13, 4 had a PSA level of 0.2 ng/mL or less, 4 a PSA level between 0.21 and 0.9 ng/mL, and 5 a PSA level between 1 and 2.5 ng/mL. Re-evaluation of the histopathologic findings using current criteria increased the Gleason score and World Health Organization grade. Patients currently selected for brachytherapy have a lower Gleason grade and TNM stage than recorded for patients treated in the past. The actuarial progression probability curves using the 0.5 or less cutpoint published in 1993 represented the best possible outcome and cannot serve as a historical control for current series comparisons. CONCLUSIONS: For patients who were alive and clinically free of disease longer than 15 years after therapy, the biochemical PSA levels were low. This may be attributed to the therapeutic radiation effect. Whether the improved technology of current transrectal ultrasound-guided implants can extend these favorable results from a small minority to a significant majority and whether it can approach the therapeutic results of radical prostatectomy may be partially answered with a longer follow-up of the current series. The histopathologic criteria have been refined, and upgrading from the initially assigned grade is common. In some cases, a prostate cancer diagnosis could not be confirmed. These findings limit the ability to match patients across time and institution. The results of our 1993 report of biochemical chemical progression-free probability 10 years after iodine-125 implantation cannot be used as a comparator for current studies. Ultimately, a valid comparison between treatment options will only be achieved through a randomized controlled trial.

Induction of differentiation by 1alpha-hydroxyvitamin D(5) in T47D human breast cancer cells and its interaction with vitamin D receptors.

The role of the active metabolite of vitamin D, 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), in cell differentiation is well established. However, its use as a differentiating agent in a clinical setting is precluded due to its hypercalcaemic activity. Recently, we synthesised a relatively non-calcaemic analogue of vitamin D(5), 1alpha-hydroxyvitamin D(5) (1alpha(OH)D(5)), which inhibited the development of carcinogen-induced mammary lesions in culture and suppressed the incidence of chemically induced mammary carcinogmas in rats. In the present study, we determined the differentiating effects of 1alpha-(OH)D(5) in T47D human breast cancer cells and compared its effects with 1,25(OH)(2)D(3). Cells incubated with either 10 or 100 nM of the analogues inhibited cell proliferation in a dose-dependent manner, as measured by the dimethylthiazolyl-2,5-diphenyltetrazolium bromide (MTT) assay. Similar growth-inhibitory effects were also observed for MCF10(neo) cells. Both vitamin D analogues induced cell differentiation, as determined by induction of casein expression and lipid production. However, MCF10(neo) cells failed to respond to either vitamin D analogue and did not undergo cell differentiation. Since the cell differentiating effect of vitamin D is considered to be mediated via the vitamin D receptor (VDR), we examined the induction of VDR using reverse transcriptase-polymerase chain reaction (RT-PCR) in both cells. The results showed that, in T47D cells, both 1,25(OH)(2)D(3) and 1alpha(OH)D(5) induced VDR in a dose-dependent manner. Moreover, both analogues of vitamin D upregulated the expression of vitamin D response element-chloramphenicol acetyl transferase (VDRE-CAT). These results collectively indicate that 1alpha-(OH)D(5) may mediate its cell-differentiating action via VDR in a manner similar to that of 1,25(OH)(2)D(3).

Cancer chemopreventive activity mediated by 4'-bromoflavone, a potent inducer of phase II detoxification enzymes.

Induction of phase II enzymes is an important mechanism of chemoprevention. In our search for novel cancer chemopreventive agents, 4'-bromoflavone (4'BF) was found to significantly induce quinone reductase (QR) activity in cultured murine hepatoma 1c1c7 cells (concentration to double activity: 10 nM) and effectively induce the alpha- and mu-isoforms of glutathione S-transferase in cultured H4IIE rat hepatoma cells with no observed toxicity. In short-term dietary studies, 4'BF was also shown to increase QR activity and glutathione levels in rat liver, mammary gland, colon, stomach, and lung in a dose-dependent manner. Induction mediated by 4'BF was bifunctional (induction of both phase I and phase II enzymes) and regulated at the transcriptional level, as revealed by transient transfection studies with plasmid constructs (pDTD-1097CAT, XRE-CAT, and ARE-CAT) and reverse transcription-PCR-based analysis of QR mRNA. In studies conducted with female Sprague Dawley rats, the effects of 4'BF on the relative induction levels of phase I and phase II enzyme activities were investigated in liver and mammary gland. Treatment with 4'BF and 7,12-dimethylbenz[a]anthracene (DMBA) or 4'BF alone did not significantly alter DMBA-induced cytochrome P4501A1 activity (phase I enzyme), but it significantly increased QR activity (phase II enzyme), compared with the DMBA treatment group. In addition, 4'BF was found to be a potent inhibitor of cytochrome P4501A1-mediated ethoxyresorufin-O-deethylase activity, with an IC50 of 0.86 microM. Furthermore, in studies conducted with cultured HepG2 or MCF-7 cells, 4'BF significantly reduced the covalent binding of metabolically activated benzo[a]pyrene to cellular DNA. On the basis of these results, a full-term cancer chemoprevention study was conducted with DMBA-treated female Sprague Dawley rats. Dietary administration of 4'BF (2000 and 4000 mg per kg of diet, from 1 week before to 1 week after DMBA) significantly inhibited the incidence and multiplicity of mammary tumors and greatly increased tumor latency. In summary, 4'BF can be viewed as a relatively simple, readily available, inexpensive compound that is a highly effective cancer chemopreventive agent. The full mechanism of action remains to be defined, but enhancement of detoxification pathways appears to be important.

Intravesical dimethyl sulfoxide for primary amyloidosis of the bladder.

Primary bladder amyloidosis is a rare disease. Treatment recommendations are necessarily anecdotal. We report a case of a 52-year-old woman treated successfully with intravesical dimethyl sulfoxide instillation.

Rigid phencyclidine analogues. Binding to the phencyclidine and sigma 1 receptors.

Three phencyclidine (PCP) analogues possessing a highly rigid carbocyclic structure and an attached piperidine ring which is free to rotate were synthesized. Each analogue has a specific fixed orientation of the ammonium center of the piperidinium ring to the centrum of the phenyl ring. The binding affinities of the rigid analogues 1-piperidino-7,8-benzobicyclo[4.2.0]octene (14), 1-piperidinobenzobicyclo[2.2.1]heptene (16), and 1-piperidinobenzobicyclo[2.2.2]octene (13) for the PCP receptor ([3H]TCP) and th-receptor (NANM) were determined. The three analogues show low to no affinity for the PCP receptor but good affinity for the th-receptor and can be considered th-receptor selective ligands with PCP/th ratios of 13, 293, and 368, respectively. The binding affinities for the th-receptor are rationalized in terms of a model for the th-pharmacophore.