Decreased phenylalanine uptake and turnover in patients with vitiligo

The human epidermis has the full machinery for autocrine L-phenylalanine turnover to L-tyrosine in keratinocytes and melanocytes. Phenylalanine hydroxylase (PAH) activities increase linearly with inherited skin colour (skin phototype I-VI, Fitzpatrick classification) yielding eightfold more activities in black skin compared to white skin. Moreover, UVB irradiation (1 MED) significantly increases epidermal PAH activities 24 h after exposure. Importantly, L-phenylalanine uptake and turnover in the pigment forming melanocytes is vital for initiation of melanogenesis. In this context it was shown that the uptake of this amino acid is regulated by calcium. The depigmentation disorder vitiligo provides a unique model to follow impaired L-phenylalanine turnover in the skin as well as in serum because affected individuals hold an impaired epidermal 6BH4 de novo synthesis/recycling and regulation including low epidermal PAH activities. After overnight fasting and oral loading with L-phenylalanine (100 mg/kg body weight), 29.6% of 970 patients tested (n=287/970) yielded serum phenylalanine/tyrosine ratios >or=4 and 35.3% (n=342/970) had mild to moderate hyperphenylalaninaemia (HPA), while 9.3% (n=90/970) had both serum L-phenylalanine levels >or=2.0 mg/dl and phe/tyr ratios >or=4.0. Isolated HPA was found in 26% (n=252/970), whereas 20.3% had only increased ratios (n=197/970). None of the patients had phenylketonuria and the family history for this metabolic disease was negative. The IQ followed normal Gaussian distribution. In vitro L-phenylalanine uptake/turnover studies on primary epidermal melanocytes originating from these patients demonstrated a significantly decreased calcium dependent L-phenylalanine uptake and turnover compared to healthy control cells. Based on our observation, we would like to propose that phenylalanine uptake/turnover is under tight control by calcium which in turn could offer an additional novel mechanism in the aetiology of HPA.     

Ultrasensitive and bifunctional ZnO nanoplates for an oxidative electrochemical and chemical sensor of NO2: implications towards environmental monitoring of the nitrite reaction

Herein, we focused on the one pot synthesis of ZnO nanoplates (NP edge thickness of ∼100 nm) using a chemical emulsion approach for chemical (direct) and electrochemical (indirect) determination of NO₂. The structural and morphological elucidation of the as-synthesized ZnO NPs was carried out by X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive analysis of X-ray (EDAX), thermogravimetric analysis (TGA) and BET-surface area measurements. The XRD studies of the as-synthesised NPs reveal that ZnO NPs have a Wurtzite type crystal structure with a crystallite size of ∼100 nm. Such ZnO NPs were found to be highly sensitive to NO₂ gas at an operating temperature of 200 °C. Electrocatalytic abilities of these ZnO NPs towards NO₂/NO₂⁻ were verified through cyclic voltammetry (CV) and linear sweep voltammetry (LSV) using aqueous 1 mM NO₂⁻ (nitrite) in phosphate buffer (pH 7) solution. The results revealed enhanced activity at an onset potential of 0.60 V vs. RCE, achieved at a current density of 0.14 mA cm⁻². These ZnO NPs show selective NO₂ detection in the presence of other reactive species including CO, SO₂, CH₃OH and Cl₂. These obtained results show that this chemical route is a low cost and promising method for ZnO NPs synthesis and recommend further exploration into its applicability towards tunable electrochemical as well as solid state gas sensing of other toxic gases.

Herein, we focused on the one pot synthesis of ZnO nanoplates (NP edge thickness of ∼100 nm) using a chemical emulsion approach for chemical (direct) and electrochemical (indirect) determination of NO₂.      

Impact of dosing regimen of custirsen,an antisense oligonucleotide,on safety,tolerability and cardiac repolarization in healthy subjects

Aims

Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide (ASO) that reduces clusterin production, is under investigation with chemotherapy in patients with solid tumours. Custirsen is associated with constitutional symptoms (CS) that may interfere with clinical pharmacology investigations, such as QT interval studies. Experience with other ASOs suggests NSAID premedication may ameliorate CS, but we observed suboptimal outcomes in healthy subjects given custirsen and NSAIDs. We sought to establish a custirsen regimen for future clinical pharmacology studies in healthy subjects.

Methods

Subjects received custirsen (640 mg intravenously over 120 min) with dexamethasone premedication or increasing doses (320, 480, 640 mg over 6 days) of custirsen with dexamethasone premedication, then one full custirsen dose without premedication on day 8. Incidence/severity of adverse events (AEs) and extensive electrocardiogram readings were evaluated. Pharmacokinetic parameters were estimated.

Results

AEs included CS, elevated transaminases and prolonged activated partial thromboplastin time (aPTT) that were predominantly grade 1/2. Administration of increasing custirsen doses and dexamethasone premedication reduced the incidence of CS associated with full dose custirsen. Transaminase elevation showed a dose-dependent effect (0% at days 2, 4, 27% at day 6) with the highest custirsen doses. Increasing doses of custirsen may have mitigated the severity but not incidence of aPTT prolongation. Neither regimen was associated with cardiac repolarization changes in QT values or concentration–effect analyses. The custirsen pharmacokinetic profile was consistent with previous experience.

Conclusion

Escalation of custirsen dose combined with dexamethasone premedication reduced CS associated with full dose custirsen and should be considered in future clinical pharmacology studies of custirsen.     

A prolonged observational study of tracheal tube displacements: Benchmarking an incidence <0.5-1% in a medical-surgical adult intensive care unit

Background and Aims:

Tracheal tubes are commonly used in intensive care unit (ICU) and lead to complications like displacements. The primary aim of the study was to evaluate if the rate of tracheal tube displacement benchmarked at <1% per patient and <0.5% per tracheal tube day, could be sustained over a prolonged period. The secondary aim was to document the patterns of all forms airway accident and to evaluate their consequences.

Subjects and Methods:

This was a prospective observational study of Intubated and ventilated patients in a General Medical-Surgical Adult ICU. The incidence of accidental extubation, self extubation, partial displacement and blockages of tracheal tubes were recorded.

Results:

The overall tracheal tube displacement rate was 61/10,112 (0.6%) per patient and 61/28,464 (0.22%) per tracheal tube day. There were 30 additional incidents of blockage, kinking or biting of the tracheal tube. Physiological consequences-69 were mild, 10 moderate, 12 major and one death. Of the 91 accidents, 30 were partly and 30 were completely preventable. 76 incidents involved an endotracheal tube (54 displaced, 12 blocked and 10 bitten-kinked) and 15 a tracheostomy tube (seven displaced and eight blocked). Accidents were more common in medical than surgical patients (medical = 48, cardiac surgical = 17 and other surgical/trauma = 26).

Conclusion:

Tracheal tube displacement rate in a mixed medical-surgical adult ICU was maintained below the pre-set benchmark of <1% per patient and <0.5% per intubated day over nearly a decade.     

From the Cover: JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation

Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation induces HMGB1 translocation from nucleus to cytoplasm. Mass spectrometric analysis unequivocally revealed that pharmacological inhibition of the JAK/STAT1 pathway or genetic deletion of STAT1 abrogated LPS- or type 1 IFN-induced HMGB1 acetylation within the NLS sites. Together, these results identify a critical role of the JAK/STAT1 pathway in mediating HMGB1 cytoplasmic accumulation for subsequent release, suggesting that the JAK/STAT1 pathway is a potential drug target for inhibiting HMGB1 release.High-mobility group box 1 (HMGB1), a ubiquitous DNA-binding protein, is a promiscuous sensor driving nucleic acid-mediated immune responses and a pathogenic inflammatory mediator in sepsis, arthritis, colitis, and other disease syndromes (1–5). Immune cells actively release HMGB1 after activation by exposure to pathogen-associated molecular patterns or damage-associated molecular patterns, including lipopolysaccharide (LPS) and inflammasome agonists (1, 6, 7). High levels of extracellular HMGB1 accumulate in patients with infectious and sterile inflammatory diseases. Extracellular disulfide HMGB1 stimulates macrophages to release TNF and other inflammatory mediators by binding and signaling through Toll-like receptor (TLR)4. Reduced HMGB1 facilitates immune cell migration by interacting with the receptor for advanced glycation end products (RAGE) and CXCL12 (8–12), a process regulated by posttranslational redox-dependent mechanisms. Administration of neutralizing anti-HMGB1 mAbs or other HMGB1 antagonists significantly reduces the severity of inflammatory disease, promotes bacterial clearance during Pseudomonas aeruginosa or Salmonella typhimurium infection and attenuates memory impairment in sepsis survivors (1, 13–15). Together, these and other findings indicate the importance of a mechanistic understanding of HMGB1 release from activated immune cells and the regulatory signaling pathways controlling these processes.Most cytokines harbor a leader peptide that facilitates secretion through the endoplasmic reticulum–Golgi exocytotic route. HMGB1, which lacks a leader peptide, is released via unconventional protein secretion pathways (1, 6, 7). In quiescent cells, most HMGB1 is localized in the nucleus. Upon activation of immune cells, efficient HMGB1 release requires acetylation of HMGB1 within the two nuclear localization sequence (NLS) sites and subsequent HMGB1 accumulation in the cytoplasm (1, 6, 16–20). HMGB1 release is mediated by inflammasome activation during pyroptosis, a form of proinflammatory programmed cell death (6, 7, 22–24). Protein kinase (PK)R is a critical regulator of inflammasome-dependent HMGB1 release (6, 25). Pharmacological inhibition of PKR abrogates LPS-induced HMGB1 release by macrophages but does not prevent nuclear translocation of HMGB1 to cytoplasm. This suggests that some other, as yet unknown, inflammasome-independent pathway regulates HMGB1 translocation from nucleus to cytoplasm.We and others have previously established an important role of type 1 and type 2 interferons (IFNs) and downstream JAK/STAT1 signaling activation in mediating HMGB1 release (26–28). Pharmacological inhibition of JAK/STAT, genetic deletion of STAT1, or inhibition of extracellular IFN-β with neutralizing antibodies significantly abrogates LPS-induced HMGB1 release from macrophages (26–28). Importantly, pharmacological inhibition of the JAK/STAT1 pathway, genetic deletion of STAT1, or inhibition of IFN-β expression by genetic deletion of IRF3 significantly promotes survival in both lethal endotoxemia and experimental sepsis (28–30). Accordingly, we reasoned here that JAK/STAT1 may represent a critical signaling mechanism controlling HMGB1 translocation from nucleus to cytoplasm.     

Multidisciplinary treatment approach with one piece implants for congenitally missing maxillary lateral incisors: a case report

Congenitally missing lateral incisors are a common clinical occurrence. Dental Implants have become a primary treatment option for replacement of these teeth. Many times in prosthodontic treatment planning a multidisciplinary approach is needed for a comprehensive out come. Prosthodontic treatment planning is needed prior to the patient's consultation and following treatment acceptance; the prosthodontist may need to coordinate treatment needs with other specialists, including an orthodontist and an implant surgeon. This article describes multidisciplinary management of a case presenting with spaced maxillary anteriors due to the congenitally missing lateral incisors. Treatment consisted of initial orthodontic space management to obtain adequate space for missing lateral incisors. Single piece, narrow diameter implants were placed in edentulous spaces on both sides. Aesthetic crown lengthening procedure was performed with all anterior teeth along with tissues surrounding the implants. Metal-ceramic crowns were given as definitive restorations, resulting into an acceptable aesthetic outcome.     

International Variations in Bladder Cancer Incidence and Mortality

Context

Previous studies have reported substantial worldwide regional variations in bladder cancer (BCa) incidence and mortality.

Objective

To describe contemporary international variations in BCa incidence and mortality rates and trends using the most recent data from the International Agency for Research on Cancer (IARC).

Evidence acquisition

Estimated 2008 BCa incidence and mortality rates for each country by sex were obtained from GLOBOCAN. Recent trends in incidence for 43 countries and in mortality for 64 countries were assessed by join-point model using data from the IARC's Cancer Incidence in Five Continents and from the World Health Organisation's mortality database, respectively.

Evidence synthesis

The highest incidence rates for both men and women are found in Europe, the United States, and Egypt, and the lowest rates are found in sub-Saharan Africa, Asia, and South America. Mortality rates are highest in parts of Europe and northern Africa and lowest in Asia, Central America, and middle Africa. Incidence rates among men decreased in 11 of 43 countries (46 registries) (North America, western and northern Europe), remained stable in 20, and increased in 12 countries (southern, central, and eastern Europe). Among women, incidence rates decreased in 10 countries, stabilised in 22 countries, and increased in 12 countries. Mortality rates among men decreased in 32 of 65 countries (throughout all world regions except Central and South America), stabilised in 30 countries, and increased in 3 (Romania, Slovenia, and Cuba). Among women, mortality rates decreased in 24 countries, remained stable in 36 countries, and increased in 5 countries (central and eastern Europe).

Conclusions

Incidence and mortality rates in general decreased in most Western countries but increased in some eastern European and developing countries. These patterns in part may reflect differences in the stage and extent of the tobacco epidemic, changes in coding practices, prevalence of schistosomiasis (Africa), and occupational exposure.     

Effects of Stocking Density on Growth Performance,Survival and Production of Catla catla and Labeo rohita During Nursery Rearing in Cages

Proceedings of the National Academy of Sciences, India Section B: Biological Sciences - A nursery rearing experiment of fry to fingerling was conducted in cages in Dimbhe reservoir of Pune District...     

High sensitive C-reactive protein-Effective tool in determining postoperative recovery in lumbar disc disease

Background:

It is common in medical practice to see patients having persistent pain and radiculopathy even after undergoing discectomy surgery. Inflammatory cytokines, such as interleukins are produced at the site of disc herniation and are now considered responsible for the pain perceived by the patient. This study has used high sensitive C-reactive protein (HSCRP) assay for predicting inflammation around the nerve roots on very same principle, which has used HSCRP for predicting coronary artery diseases in current clinical practice. Thus, purpose of this study is to test whether HSCRP can stand as an objective tool to predict postoperative recovery in patients undergoing lumbar discectomy. That is, to study association between preoperative HSCRP blood level and postoperative recovery with the help of modified Oswestry Back Disability Score.

Materials and Methods:

A study group consisting of 50 cases of established lumbar disc disease and control group of 50 normal subjects, matched with the study group. Both the study and control groups were subjected to detailed evaluation with the help of modified Oswestry Low Back Pain Scale both pre and postoperatively at 3 months, 6 months and 1-year. The preoperative blood samples were analyzed to assess the HSCRP concentration. All the cases underwent surgery over a period of 1-year by the same surgeon.

Results:

The level of HSCRP in the study group was between 0.050– and 0.710 mg/dL and in the control group, 0.005-0.020 mg/dL. There was highly significant positive correlation between preoperative HSCRP level and postoperative score at P < 0.005. Cases with HSCRP level in the range of 0.1820 ± 0.079 mg/dL, showed better recovery (score improved > 10 points), while those with HSCRP level in the range of 0.470 ± 0.163 mg/dL, showed poor recovery (score improved < 10 points).

Conclusion:

HSCRP will serve as a good supplementary prognostic marker for operative decision making in borderline and troublesome cases of lumbar disc disease.