Sacubitril/Valsartan: The Newest Addition to the Toolbox for Guideline-Directed Medical Therapy of Heart Failure.
Sacubitril/valsartan combines a neprilysin inhibitor with an angiotensin receptor blocker. As an inhibitor of neprilysin, an enzyme that degrades biologically active natriuretic peptides, this first-in-class therapy increases levels of circulating natriuretic peptides, resulting in natriuretic, diuretic, and vasodilatory effects. In patients with chronic New York Heart Association class II-IV heart failure with reduced ejection fraction, the PARADIGM-HF trial demonstrated that sacubitril/valsartan significantly reduced the primary endpoint of cardiovascular mortality and heart failure hospitalization, compared with enalapril. The rate of all-cause mortality was also significantly reduced. Subsequently, the American College of Cardiology/American Heart Association/Heart Failure Society of America recently updated guideline recommendations for Stage C patients with heart failure with reduced ejection fraction to recommend angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril/valsartan in conjunction with other evidence-based therapies to reduce morbidity and mortality. Several analyses have suggested the cost-effectiveness of this new therapy. To ensure tolerability, initiating the lower dosage form of sacubitril/valsartan is warranted in patients with severe renal impairment, moderate hepatic impairment, and low blood pressure, and close monitoring is warranted in such patients. A 36-hour washout period is recommended when switching patients from an angiotensin-converting enzyme inhibitor to sacubitril/valsartan. Similarly, sacubitril/valsartan is contraindicated in patients receiving concomitant angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and those with a history of angioedema.


Protein stains for proteomic applications: which, when, why?
This review recollects literature data on sensitivity and dynamic range for the most commonly used colorimetric and fluorescent dyes for general protein staining, and summarizes procedures for the most common PTM-specific detection methods. It also compiles some important points to be considered in imaging and evaluation. In addition to theoretical considerations, examples are provided to illustrate differential staining of specific proteins with different detection methods. This includes a large body of original data on the comparative evaluation of several pre- and post-electrophoresis stains used in parallel on a single specimen, horse serum run in 2-DE (IPG-DALT). A number of proteins/protein spots are found to be over- or under-revealed with some of the staining procedures.


A prevalence study of errors in opioid prescribing in a large teaching hospital.
In 2007, the National Patient Safety Agency performed a study demonstrating that errors in prescribing led to nearly 12,000 adverse clinical incidents a year. The following year, they issued a rapid response report entitled 'Reducing Dosing Errors with Opioid Medicines' designed to be implemented by all NHS trusts. We performed a prevalence study to assess opioid prescribing errors in our large multi-speciality teaching hospital prior to implementation of these recommendations. We conducted a 1 day snapshot of opioid prescriptions on inpatient drug charts. For every chart, all opioid information was entered into the study proforma. All data were reviewed by consensus group and errors categorised by quality and whether they were potentially lethal, serious, significant or minor. A total of 330/722 (46%) charts were found to have opioid prescriptions. On the study day, there were 74 charts with errors and on expert review another 16 erroneous charts were found giving a total of 90/330 (27.2%). The largest quality statement error group was 'unclear prescription, missing information'. There were 4 potentially lethal, 26 serious, 38 significant and 22 minor errors. Previous studies have reported opioid prescription error rates of 51.2-70%. Compared with the opioid literature, our trust fares well with an error rate of 27%- four of these errors being potentially lethal. This study has identified where there are weaknesses in our hospital opioid prescribing practice and has aided us in rewriting our acute and chronic pain guidelines with the explicit inclusion of the National Patient Safety Agency recommendations. We have also disseminated the study results at the Trust academic meeting and developed an opioid e-learning package which will be mandatory for all new staff.


INCIDENCE OF ENDOPHTHALMITIS AFTER VITRECTOMY: A Systematic Review and Meta-analysis.
The purpose of this study was to review the literature reporting rates of postoperative endophthalmitis after pars plana vitrectomy and investigate whether modern microincision vitrectomy surgery (MIVS) increases the postoperative endophthalmitis rate, compared with traditional 20-gauge (20 G) vitrectomy. A comprehensive literature search was performed to identify studies describing the incidence of post-pars plana vitrectomy endophthalmitis. A meta-analysis of comparative studies reporting the endophthalmitis rates after MIVS versus 20 G vitrectomy was also conducted. A total of 31 studies reported 199 endophthalmitis cases in 363,544 participants (0.05%). The incidence of endophthalmitis after 20 G vitrectomy was 0.04% (88/229,435), compared with 0.03% (8/27,326) after 23 G and 0.11% (33/29,676) after 25 G. The meta-analysis demonstrated that the incidence of endophthalmitis was higher after MIVS (23 G/25 G) compared with 20 G vitrectomy (odds ratio = 3.39, 95% confidence interval, 1.39-8.23). In a subgroup analysis, we also found an increased risk of endophthalmitis after 25 G compared with 20 G vitrectomy (odds ratio = 4.09, 95% confidence interval, 2.33-7.18), but not for 23 G versus 20 G (odds ratio = 1.14, 95% confidence interval, 0.47-2.78). The incidence of post-pars plana vitrectomy endophthalmitis was low, with no significant differences between 23 G MIVS and 20 G vitrectomy, but 25 G MIVS may result in a higher postoperative endophthalmitis rate.


Opioid addiction and misuse in adult and adolescent patients with cancer.
In the context of a therapeutic opioid epidemic, particularly in the USA, where increasingly stringent screening for 'at risk' individuals and close monitoring of opioid prescription and use is strongly recommended, the issue of misuse within the cancer population must be addressed. Most patients with advanced cancer will have pain requiring opioid therapy at some stage during their disease course. In the majority, this will provide good pain relief with no short- or longer-term adverse sequelae. A subset will present with substance misuse issues that will influence management and prescribing practice. The potential ethical issues of limiting effective analgesia on the basis of addiction risk or history must be acknowledged. Both a judgemental or 'relaxed' approach to such patients is problematic. Ignoring the situation will not be in the patient's best interest, but an undue focus on this aspect may damage therapeutic relationships with clinicians and adversely affect a holistic approach to care. Clinical practitioners must be aware of the risk factors for opioid misuse and in patients who are not under palliative care consider screening prior to commencing opioids. Clinicians must be able to manage and monitor those identified as having an opioid misuse problem.


Partial mediation role of self-efficacy between positive social interaction and mental health in family caregivers for dementia patients in Shanghai.
We explored the mediation effect of caregiver self-efficacy on the influences of behavioral and psychological symptoms (BPSD) of dementia care recipients (CRs) or family caregivers' (CGs) social supports (informational, tangible and affectionate support and positive social interaction) on CGs' mental health. We interviewed 196 CGs, using a battery of measures including demographic data of the dyads, CRs' dementia-related impairments, and CGs' social support, self-efficacy and the Medical Outcome Study (MOS) Short-Form (SF-36) Health Survey. Multiple regression analyses showed that gathering information on self-efficacy and managing CG distress self-efficacy were the partial mediators of the relationship between positive social interaction and CG mental health. Managing caregiving distress self-efficacy also partial mediated the impact of BPSD on CG mental health. We discuss implications of the results for improving mental health of the target population in mainland China.


Revealing the dynamics of the 20 S proteasome phosphoproteome: a combined CID and electron transfer dissociation approach.
The 20 S proteasomes play a critical role in intracellular homeostasis and stress response. Their function is tuned by covalent modifications, such as phosphorylation. In this study, we performed a comprehensive characterization of the phosphoproteome for the 20 S proteasome complexes in both the murine heart and liver. A platform combining parallel approaches in differential sample fractionation (SDS-PAGE, IEF, and two-dimensional electrophoresis), enzymatic digestion (trypsin and chymotrypsin), phosphopeptide enrichment (TiO(2)), and peptide fragmentation (CID and electron transfer dissociation (ETD)) has proven to be essential for identifying low abundance phosphopeptides. As a result, a total of 52 phosphorylation identifications were made in mammalian tissues; 44 of them were novel. These identifications include single (serine, threonine, and tyrosine) and dual phosphorylation peptides. 34 phosphopeptides were identified by CID; 10 phosphopeptides, including a key modification on the catalytically essential beta5 subunit, were identified only by ETD; eight phosphopeptides were shared identifications by both CID and ETD. Besides the commonly shared phosphorylation sites, unique sites were detected in the murine heart and liver, documenting variances in phosphorylation between tissues within the proteasome populations. Furthermore the biological significance of these 20 S phosphoproteomes was evaluated. The role of cAMP-dependent protein kinase A (PKA) to modulate these phosphoproteomes was examined. Using a proteomics approach, many of the cardiac and hepatic 20 S subunits were found to be substrate targets of PKA. Incubation of the intact 20 S proteasome complexes with active PKA enhanced phosphorylation in both existing PKA phosphorylation sites as well as novel sites in these 20 S subunits. Furthermore treatment with active PKA significantly elevated all three peptidase activities (beta1 caspase-like, beta2 trypsin-like, and beta5 chymotrypsin-like), demonstrating a functional role of PKA in governing these 20 S phosphoproteomes.


Viruses selectively upregulate Toll-like receptors in the central nervous system.
The resting CNS is an immunospecialized environment, devoid of most immune processes, although substantial inflammatory responses can be initiated. The innate immune mechanisms mediating recognition of CNS infections are unknown. This study provides a comprehensive analysis of Toll-like receptor (TLR) gene expression in the resting and virus-infected murine CNS. TLR transcripts were expressed in the resting CNS with strikingly high expression of TLR 3. Extraneural infection with neuroinvasive Semliki Forest virus resulted in CNS infection followed by rapid selective upregulation of TLR gene expression. Upregulation was independent of T-cell responses. Upregulation of TLR gene expression was also observed following rabies virus infection. TLR upregulation was appropriate to the pathogen and proportional to the virus load. Upregulation of TLR 3 and 9 was dependent upon the type-I interferon response and may act to increase the threshold of sensitivity to detect virus infection in cells surrounding virally infected cells.


Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer.
Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.


Intake of Sugar Substitute Gummy Candies Benefits the Glycemic Response in Healthy Adults: A Prospective Crossover Clinical Trial.
Sugar reduction in food has attracted great health concerns worldwide. Gummies have been one of the most popular and highly favored candies due to their chewable properties, simplicity to swallow, and delicious taste. The general perception is that gummies raise blood sugar levels, but the truth is that gummies with the right formula can control glycemic response. The purpose of this study is to investigate the effects of the gummy dosage form and sugar types on the glycemic response control. Maltitol and erythritol as sweetener alternatives were applied in gummy candies (total and partial sugar substitutes gummy, T-SG and P-SG), with sucrose-based gummies used as comparisons (CG). A prospective crossover study was then conducted on 17 healthy adults. The effects of different types of gummies on glycemic response in healthy adults were evaluated on the basis of the participants' glycemic index (GI) and glycemic load (GL) values. Every three-day interval, participants took CG, P-SG, T-SG, and glucose solution, respectively, and the theoretical glucose conversion content was kept the same in all groups for each trial. Each participant performed four tests with each sample and recorded the changes in blood glucose after food consumption. It was found that all three types of gummies slowed down subjects' glycemic response when not taken in excess, and the improvement effect was in the trend of T-SG > P-SG > CG. Both P-SG and T-SG were low-GI candies (54.1 and 49.9). CG that was not consumed in excess of 17.2 g had a high GI (81.9) but a low GL (<10). Texture analysis and in vitro digestion were used to explore the effect of gummy matrix on glucose release. T-SG and P-SG retained a higher hardness and were less hydrolyzed to release glucose during digestion compared with CG. Additionally, experiments have revealed that gummies can reverse the poor glucose tolerance in women. In conclusion, gummies are a good carrier for dietary supplements due to their sustained-release characteristic of available carbohydrates and provide healthier options for people in control of glucose homeostasis.


Percutaneous interventions below the knee in patients with critical limb ischemia using drug eluting stents.
Midterm technical and clinical evaluation of stent angioplasty with drug-eluting stents in infrapopliteal lesions in patients with critical limb ischemia (CLI). Percutaneous stent angioplasty was performed in 128 limbs in 114 patients presenting with 320 vascular lesions. Lesions with up to 6 cm in length and at least one patent vessel below the obstruction were treated; 341 drug-eluting Cypher(R) stents (diameter of 2.5-3.5 mm; length of 18-33 mm) were implanted. Follow-up examinations were performed up to 18 months postinterventionally using clinical examination, ankle-brachial index (ABI) calculation, and color coded Duplex sonography. Patency rates were calculated on the basis of the Kaplan-Meier life-table analysis. Technical success was achieved in 99.06%. Minor complications (hematoma, distal emboli, and vessel dissection) were documented in 8.77% of the patients. The 6, 12, and 18 months primary patency rate as controlled by Duplex sonography was 89.8, 84.2 and 83.3%, respectively; 77.6% of the lesions healed postinterventionally. The cumulative limb salvage rate was 95.6%. Drug-eluting stent (DES) angioplasty in infrapopliteal arteries is a safe and effective technique for the treatment of patients with CLI. The use of a DES results in favorable technical and clinical outcome in the midterm follow-up.


[Effect of monoamine neurotransmitters, enkephalin and morphine on substance P contents of several brain regions and pain threshold in rats].
The present work was carried out to observe the effect of intra-cerebroventricular (icv) injection of monoamine neurotransmitters, enkephalin and morphine on immunoreactive substance P(Ir-SP) contents in hypothalamus, striatum, hippocampus and pain threshold. The results were as follows: (1) After icv or intra-DR (dorsal raphe nucleus) injection of 5-HTP, the content of Ir-SP in hypothalamus significantly decreased and pain threshold markedly increased; After depletion of the 5-HT content in brain by pCPA or destruction of DR, the contents of Ir-SP were remarkably elevated in three brain regions by the former and in hypothalamus, striatum by the later. (2) The Ir-SP levels in the three brain regions and the pain threshold were not affected by the icv injection of NE, however, icv injection of DA caused a increase of Ir-SP concentration in striatum which was reversed by the DA receptor antagonist haloperidol, but without any change of the pain threshold. 7th day after icv injection of 6-OHDA, the content of Ir-SP in striatum significantly reduced. (3) Icv injection of met-enkephalin (MEK) or morphine could increase the Ir-SP levels in hypothalamus, striatum and the pain threshold, and above-mentioned effect of morphine could be prevented by the opioid receptor antagonist naloxone. Icv injection of leu-enkephalin (LEK) had no effects both on Ir-SP contents in three brain regions and the pain threshold.


Nitrosative stress and pathogenesis of insulin resistance.
Insulin resistance is a major causative factor for type 2 diabetes and is associated with increased risk of cardiovascular disease. Despite intense investigation for a number of years, molecular mechanisms underlying insulin resistance remain to be determined. Recently, chronic inflammation has been highlighted as a culprit for obesity-induced insulin resistance. Nonetheless, upstream regulators and downstream effectors of chronic inflammation in insulin resistance remain unclarified. Inducible nitric oxide synthase (iNOS), a mediator of inflammation, has emerged as an important player in insulin resistance. Obesity is associated with increased iNOS expression in insulin-sensitive tissues in rodents and humans. Inhibition of iNOS ameliorates obesity-induced insulin resistance. However, molecular mechanisms by which iNOS mediates insulin resistance remain largely unknown. Protein S-nitrosylation, a covalent attachment of NO moiety to thiol sulfhydryls, has emerged as a major mediator of a broad array of NO actions. S-nitrosylation is elevated in patients with type 2 diabetes, and increased S-nitrosylation of insulin signaling molecules, including insulin receptor, insulin receptor substrate-1, and Akt/PKB, has been shown in skeletal muscle of obese, diabetic mice. Akt/PKB is reversibly inactivated by S-nitrosylation. Based on these findings, S-nitrosylation has recently been proposed to play an important role in the pathogenesis of insulin resistance.


Clinical analysis of the etiology of optic neuritis in patients at different ages in china.
To determine the etiology of optic neuritis in patients of different ages in China. Records of optic neuritis patients who were hospitalized in the Department of Neuro-ophthalmology, General PLA Hospital, Beijing, between January 1, 2011 and December 31, 2011 were retrospectively reviewed. A total of 132 patients were divided into three groups by age. The percentage of patients aged ≤ 16 years, 16-45 years and >45 years were 17.4% (23/132), 54.6% (72/132), and 28.0% (37/132) respectively. The distribution of etiologies differed significantly among the three groups (X2=23.2, P=0.026). The percentage of idiopathic demyelinating optic neuritis was the highest in the 16-45 group (44.4%), and the proportion of neuromyelitis optical was the highest in the ≤ 16 years group. Infectious optic neuritis was more frequently seen in patients aged ≤ 16 years and >45 years. The source of infection was viral (n=2), nasosinusitis (n=1) and bacterial (n=1) in the ≤ 16 years group and neurosyphilis (n=3) and nasosinusitis (n=1) in the >45 years group. The percentage of paraneoplastic syndrome in the >45 years group was 8.11% (3/37). The etiology of optic neuritis in patients at various ages differed significantly.


Diffuse well-differentiated lymphocytic lymphoma: chemotherapy with BCNU, cyclophosphamide, vincristine, melphalan and prednisone.
Twenty patients with stage III and IV diffuse well-differentiated lymphocytic lymphoma were treated with combination chemotherapy consisting of BCNU, cyclophosphamide, vincristine, melphalan and prednisone (M-2). Treatment was given every 5 weeks for 11 cycles in responding patients. The median age of the patients was 62 years (range 45-76). There were 12 complete remissions and 6 partial remissions for an overall response rate of 90%. The median duration of remission was 24 months (range 12-79 months) and was identical for complete responders and partial responders. All but 2 responding patients have been subsequently retreated for relapse. The median survival was 84 months (range 1-108 months). Myelosuppression was mild. Nausea/vomiting, neuropathy, alopecia and gastrointestinal symptoms from prednisone were seen in the minority of patients. One patient expired from sepsis/neutropenia during the first cycle of therapy. The M-2 protocol produces effective remissions in diffuse well-differentiated lymphocytic lymphoma. The relapse and survival pattern are similar to the results achieved with other chemotherapy regimens in low-grade lymphoma.


Catalyst-dependent selectivity in sulfonium ylide cycloisomerization reactions.
Divergent catalysis is an emerging field whereby access to structurally diverse compounds from a common precursor is achieved through controlled reaction pathways. Herein we present an unusual example of π-acid catalyst dependent selectivity in the cycloisomerization of alkene-tethered sulfonium ylides. Computational mechanistic studies revealed how the ability of palladium to cycle through oxidation states largely controls the selectivity.


Surgery of carcinoma of the pancreas.
The surgical treatment of pancreatic cancer depends upon the site and extent of the tumour and in particular the experience of the surgeon, as pancreatic resection performed outside specialized centres carries a high risk. Within the specialized unit the Whipple operation is the treatment of choice for periampullary carcinomas, but the results of resection for more extensive tumours of the pancreatic head are disappointing even with adjuvant chemotherapy and radiotherapy. Resection, however, provides the only prospect of cure and may be the best palliative procedure. The place of total and "regional" pancreatectomy is undecided. The choice of palliative operations to relieve malignant biliary, duodenal and pancreatic duct obstruction should be carefully considered to avoid early recurrence of symptoms. The prognosis for patients with cancer of the body of the pancreas remains poor.


Mycological and cytological examination of oral candidal carriage in diabetic patients and non-diabetic control subjects: thorough analysis of local aetiologic and systemic factors.
In this study, 55 diabetic patients and 45 non-diabetic control subjects were examined to determine oral candidal carriage state. The influence of some local aetiologic and systemic factors such as: salivary flow rate and pH, heredity, alcohol drinking, smoking habits, antimicrobial therapy, wearing of denture, burning sensation, dry mouth, taste alteration and tooth brushing habit on candidal carriage rate were investigated. Imprint culture, cytological smears and biochemical tests were used. Oral carrier rate and density of Candida species were non-significantly higher in the diabetic patients than in the non-diabetic control subjects. This increase was confirmed cytologically too. In both groups, Candida albicans was found to be a predominant species on tongue dorsum. Cigarette and alcohol habits of men were higher while tooth brushing habit was less than in women in diabetic and control groups. Salivary flow rate and pH values of diabetic patients were significantly lower while serum glucose values were significantly higher than of non-diabetic controls. The rate of diabetic patients suffering from dry mouth and having diabetic heredity in the family were significantly higher than control subjects. The candidal colonization was higher and keratinization was lower while diabetic treatment tended from diet and oral antidiabetic towards insulin. The decrease in salivary pH, the increase in serum glucose and wearing denture were correlated with the increased rate and density of C. albicans in both groups. Keratinization was also accompanied with the increase in leucocytes. In diabetic group, positive correlations were found between antimicrobial therapy and C. glabrata carriage; the increase in leucocytes and C. albicans carriage; the increase in keratinization and alcohol habit; serum glucose and smoking habit; dry mouth complaint and antimicrobial therapy. There was a negative correlation between salivary flow rate and C. albicans carriage. In control group a positive correlation was found between antimicrobial therapy and keratinization.


Olanzapine in Huntington's disease.
To study the effect of olanzapine (OL) in Huntington's disease (HD) patients. Eleven HD patients (five men), aged 47.6 +/- 11.4 years and with disease duration of 11.2 +/- 3.3 years received OL. Assessment was carried out using the Clinical Global Impression of Change Scale (CGIC) and the Unified Huntington's Disease Rating Scale behavioral (UHDRS - b) and motor (UHDRS - m) at 6 month intervals. Nine patients were treated for 9.8 +/- 5.9 months. The mean OL dose/patient was 11.4 +/- 8.5 mg/day (median 10 mg/day). Mean CGIC was 2.1 +/- 0.8. UHDRS - b improved significantly (P < 0.0001) and UHDRS - m did not change. Chorea improved in five patients and two dropped out because of drug eruption and lack of efficacy. OL is a good alternative treatment in HD, mainly for the psychiatric symptoms and moderately effective for the motor symptoms, possibly because of its effect on chorea. We suggest OL should be used in HD patients with the adult onset form, severe chorea and/or severe psychiatric disturbances.


Expression of Foxi3 is regulated by ectodysplasin in skin appendage placodes.
Foxi3 is a member of the large forkhead box family of transcriptional regulators, which have a wide range of biological activities including manifold developmental processes. Heterozygous mutation in Foxi3 was identified in several hairless dog breeds characterized by sparse fur coat and missing teeth. A related phenotype called hypohidrotic ectodermal dysplasia (HED) is caused by mutations in the ectodysplasin (Eda) pathway genes. Expression of Foxi3 was strictly confined to the epithelium in developing ectodermal appendages in mouse embryos, but no expression was detected in the epidermis. Foxi3 was expressed in teeth and hair follicles throughout embryogenesis, but in mammary glands only during the earliest stages of development. Foxi3 expression was decreased and increased in Eda loss- and gain-of-function embryos, respectively, and was highly induced by Eda protein in embryonic skin explants. Also activin A treatment up-regulated Foxi3 mRNA levels in vitro. Eda and activin A were identified as upstream regulators of Foxi3. Foxi3 is a likely transcriptional target of Eda in ectodermal appendage placodes suggesting that HED phenotype may in part be produced by compromised Foxi3 activity. In addition to hair and teeth, Foxi3 may have a role in nail, eye, and mammary, sweat, and salivary gland development.


Health seeking behavior of the mothers for the special care new-born unit discharged children: a comparative study.
Establishment of special care new-born units (SCNU) in hospitals not only serves to provide the intensive care to sick neonates, but presents with opportunities to enhance knowledge and modify attitude and practices of their parents through behavior change communication (BCC). A cross-sectional study was conducted in Dibrugarh District, Assam from January to June, 2011 to assess differences in health-care seeking behavior of these mothers from mothers of newborns who were born at home and mothers who had normal uneventful institutional deliveries. Mothers of 29 SCNU discharged, 34 institutions delivered and 26 home delivered children were interviewed using a semi-structured interview schedule and a knowledge, attitude and practice (KAP) survey tool. Mothers of children admitted to SCNU scored better in questions related to vaccination, contraception, protection of child from infections and cold and perceptions about traditional healers, but overall KAP scores in the three groups were not found significantly different.


Microtiter assay for colorimetric detection of in vitro amplified Chlamydia trachomatis sequences.
An integrated diagnostic method for colorimetric detection of polymerase chain reaction (PCR) products in a microtitre format is described. The amplified material is labelled by using modified PCR primers introducing a biotin molecule and a lac operator handle. Positive samples are identified, after immobilization onto streptavidin-coated microtitre wells, using a reporter fusion protein consisting of the Escherichia coli lac repressor and beta-galactosidase. The analysis of the PCR products is thus, from a practical point of view, identical with the enzyme-linked immunosorbent assay (ELISA) using the enzymatic activity of beta-galactosidase. Here, we show that the assay can be used for rapid and simple detection of Chlamydia trachomatis in an automated format. The reported analysis of 90 urethral patient samples, using this microtitre assay, indicates that this technique is more sensitive and more specific than culture technique.


Supplementation with Silk Amino Acids improves physiological parameters defining stamina in elite fin-swimmers.
Previous animal study has shown that supplementation with silk amino acid hydrolysate (SAA) increases stamina in mice. The presented study was the first formal evaluation of the influence of SAA supplementation on parameters defining physiological fitness level in humans. It was a randomized controlled trial with a parallel-group design on elite male fin-swimmers. The experimental group was supplemented with 500 mg of SAA per kg of body mass, dissolved in 250 ml of a Carborade Drink®; the control group with Carborade Drink® alone; 3 times a day, 30 minutes prior to the training session. Changes discerned in the experimental group were more pronounced than those observed in the control group. For example, the change in the serum lactic acid concentration observed in the experimental group was sevenfold less than in the control group [21.8 vs. -3.7 L% for the control and experimental groups, respectively]. An analysis of a lactate profile as a function of a maximal swimming velocity exposed a statistically significant positive shift in the swimming velocity of 0.05 m/s, at the lactate concentration of 4 mmol/L in the experimental group. There was also a positive, although statistically insignificant, increase of 2.6 L% in serum testosterone levels in the experimental group. This study showed that a 12-day SAA supplementation combined with an extensive and rigorous training schedule was sufficient to increase an aerobic stamina. However, this phenomenon was associated with an augmented level of muscular damage (an increased level of creatine phosphokinase in the experimental group).


The effect of intravaginal electrical stimulation on the feline urethra and urinary bladder. Electrical parameters.
Intravaginal electrical stimulation (IVS) in cats caused urethral closure and bladder inhibition. The aim was to ascertain the electrical parameters most appropriate for these effects. Minimum voltage was used as main criterion to select an effective, non-destructive stimulation when the shape, frequency and duration of the pulses were systematically varied. Urethral closure was achieved at minimum voltage (3 V) with alternating pulses at a frequency of 50 Hz and a pulse duration of 1.5 ms. Corresponding optimal parameters for bladder inhibition were: alternating pulses, 10 Hz and 1.5 ms. Minimum voltage was 1 V. Moreover, the positions of the electrodes were of significance for the responses. The clinical implications of these findings are that: 1)more differentiated treatment of incontinence could be achieved by adapting the stimulation parameters to the cause of incontinence, and 2) specific electrode positions would probably give optimal responses.


Sympathetic influence on the pupillary light response in three red-eared slider turtles (Trachemys scripta elegans).
We investigated the effects of phenylephrine and its combination with vecuronium bromide on the iris of turtles to determine if the pupillary light response is affected by sympathetic innervation. Three red-eared slider turtles, Trachemys scripta elegans. Diameters of light-adapted pupils were tracked before and after topical application of drugs to eyes. Phenylephrine was applied independently; in a second group of trials, vecuronium bromide was applied with phenylephrine. Rates of pupil dilation in response to drugs were quantified by fitting data with time constant (tau) equations. Phenylephrine dilated the pupil 24%, tau = 29 min. Combination of phenylephrine with vecuronium bromide increased the pupil size 35%, and dilation was more rapid, tau = 14 min. We also were able to predict these time constants by performing different mathematical operations with an equation developed from a prior study using only vecuronium bromide. When this equation was subtracted from the equation for eyes treated with both vecuronium bromide and phenylephrine, the difference gave the observed tau for phenylephrine; when added to phenylephrine, the sum closely matched the tau for eyes treated with vecuronium bromide and phenylephrine. Further, the tau for vecuronium bromide treated eyes was predicted by subtracting the equation for phenylephrine from that of eyes treated with both vecuronium bromide and phenylephrine. Our results suggest that sympathetic innervation interacts with the parasympathetic pathway to control the pupillary light response in turtles.


Cranio-orbital reconstruction: safety and image quality of metallic implants on CT and MRI scanning.
A study was undertaken to evaluate the safety of magnetic resonance imaging (MRI) of metallic implants used in cranio-orbital reconstruction (stainless steel wire and titanium and Vitallium plates) and also to compare the degree of artifact created on computed tomographic (CT) scanning and MRI by each material. Samples of each material were tested for deflection (movement) in a 1.5-T MRI field and for temperature change under conditions simulating a clinical MRI scan. None of the materials exhibited any deflection, and none exhibited any significant temperature change compared with water. Standardized bars of each material and commonly used, commercially available titanium and Vitallium implants (plates, mesh) were evaluated for artifact. On blinded evaluation by three radiologists and on quantitative computer analysis of the CT images, the stainless steel produced the most artifact on both CT scan and MRI, followed by the Vitallium, with the least artifact caused by titanium. All the titanium images were felt to be acceptable to detect orbital pathology, while only the images with the thinnest Vitallium (micromesh) implant were acceptable.


Salzmann's nodular degeneration of the cornea: a review and case series.
Salzmann's nodular degeneration is a rare, noninflammatory, slowly progressive, degenerative condition. Bluish-white nodules raised above the surface of the cornea characterize it. It has usually developed in corneas with a history of phlyctenulosis, trachoma, vernal keratoconjunctivitis, measles, scarlet fever, and various other viral diseases. However, today the majority of cases have been seen without recognized previous keratitis. It is composed of dense irregularly arranged collagen tissue with hyalinization between epithelium and Bowman's layer or beyond. Manual removal, phototherapeutic keratectomy (PTK) with or without the use of topical mitomycin-C, lamellar or penetrating keratoplasty have been used in the treatment of this disease. Salzmann's nodular degeneration does not seem to consist of one clinical entity. In some cases, elevated and pannus-like tissue can be separated easily from the corneal surface leaving Bowman's layer almost untouched. In these eyes, subsequent PTK may be necessary to smooth the surface. Recurrences are rare in these eyes. In contrast, some eyes (often with major peripheral vascularization) are left with deep defects in Bowman's layer and superficial stroma after difficult mechanical removal of nodules. In these eyes, multiple masking/laser ablation procedures are mandatory to acquire a homogenous surface. In our experience, the required laser ablation depth is significantly greater and the best-corrected visual acuity to be expected is reduced in contrast to the eyes with easy removal of the nodules. In these eyes recurrences seem to occur more frequently after treatment. Of 35 eyes documented to have Salzmann's nodular degeneration during the last 15 years in our department, 22 needed PTK treatment. Visual acuity increased from 0.4 to 0.7 on average. As a routine, laser ablation should be combined with previous conventional removal of nodules and excessive pannus tissue. By doing so, lamellar and penetrating keratoplasty techniques are hardly ever required in those eyes.


A single center case series of immune checkpoint inhibitor-induced type 1 diabetes mellitus, patterns of disease onset and long-term clinical outcome.
Type 1 diabetes mellitus (T1DM) is a rare, but serious immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). Our goal was to characterize treatment outcomes associated with ICI-induced T1DM through analysis of clinical, immunological and proteomic data. This was a single-center case series of patients with solid tumors who received ICIs and subsequently had a new diagnosis of T1DM. ICD codes and C-peptide levels were used to identify patients for chart review to confirm ICI-induced T1DM. Baseline blood specimens were studied for proteomic and immunophenotypic changes. Between 2011 and 2023, 18 of 3744 patients treated at Huntsman Cancer Institute with ICIs were confirmed to have ICI-induced T1DM (0.48%). Eleven of the 18 patients received anti-PD1 monotherapy, 4 received anti-PD1 plus chemotherapy or targeted therapy, and 3 received ipilimumab plus nivolumab. The mean time to onset was 218 days (range 22-418 days). Patients had sudden elevated serum glucose within 2-3 weeks prior to diagnosis. Sixteen (89%) presented with diabetic ketoacidosis. Three of 12 patients had positive T1DM-associated autoantibodies. All patients with T1DM became insulin-dependent through follow-up. At median follow-up of 21.9 months (range 8.4-82.4), no patients in the melanoma group had progressed or died from disease. In the melanoma group, best responses were 2 complete response and 2 partial response while on active treatment; none in the adjuvant group had disease recurrence. Proteomic analysis of baseline blood suggested low inflammatory (IL-6, OSMR) markers and high metabolic (GLO1, DXCR) markers in ICI-induced T1DM cohort. Our case series demonstrates rapid onset and irreversibility of ICI-induced T1DM. Melanoma patients with ICI-induced T1DM display excellent clinical response and survival. Limited proteomic data also suggested a unique proteomic profile. Our study helps clinicians to understand the unique clinical presentation and long-term outcomes of this rare irAE for best clinical management.


Absorption and transport of fat in mammals with emphasis on n-3 polyunsaturated fatty acids.
The current state of knowledge concerning the absorption and transport of dietary fat with emphasis on long-chain polyunsaturated n-3 fatty acids in mammals is reviewed. It is apparent that long-chain polyunsaturated n-3 fatty acids, either as free acids or as part of triglycerides, are readily absorbed in the gut and transported by the circulatory system. Indeed, it would appear that long-chain polyunsaturated n-3 fatty acids are digested, absorbed and transported similarly to other long-chain fatty acids with only minor variations, although there is much that is still not understood about these processes. The main unresolved issues in the area of the absorption and transport of long-chain polyunsaturated n-3 fatty acids appear to be: 1) If they, when located in the 2-position of triglycerides, have unique metabolic pathways; and 2) whether the unnatural forms, i.e., methyl or ethyl ester derivatives, are suitable vehicles for administration as dietary supplements. The effect in man of dietary, long-chain polyunsaturated n-3 fatty acids on blood serum lipid and lipoprotein levels, particularly the low density lipoproteins, remains controversial, except for the well-documented reduction in serum triglyceride levels. Also, there is uncertainty regarding their distribution and metabolism in tissues. Finally, if the consumption of long-chain polyunsaturated n-3 fatty acids has beneficial health consequences, what is the appropriate therapeutic dose? In view of these important, unresolved issues and uncertainties, it would seem prudent to direct additional research toward a better understanding of the overall process by which fat is digested, absorbed and transported.


[Comment on the publication "Sonographic follow-up of hip dysplasia with expanding trouser therapy"].
It should be pointed out that hipsonography by application of a flexible control procedure is not only suitable for introduction of therapy for CHD at an early stage, but also for avoiding superfluous treatment. Secondly, the authors are of the opinion that universal screening for CHD by means of hipsonography is for financial considerations not justifiable.


Endotoxin-mediated S-nitrosylation of p50 alters NF-kappa B-dependent gene transcription in ANA-1 murine macrophages.
Nitric oxide (NO) regulates cellular function, in part, by S-nitrosylating active site thiol groups of proteins. Ex vivo S-nitrosylation of NF-kappa B p50 significantly decreases its capacity for DNA binding. To determine the cellular relevance of this observation, we utilized the ANA-l murine macrophage model of endotoxin (LPS)-mediated NO synthesis. In selected instances, the NO synthase inhibitor, L-arginine methyl ester (L-NAME; 100 microM), or the NO donor, S-nitroso-N-acetylcysteine (SNAC; 100 microM), was added. In contrast to that of LPS cells, nuclear extracts from LPS + L-NAME cells demonstrated increased NF-kappa B DNA binding on gel shift analysis. Addition of SNAC to LPS + L-NAME cells restored binding to a level equivalent to that of LPS cells. Spectrophotometric analysis of NF-kappa B p50 immunoprecipitates demonstrated S-NO bonds exclusively in LPS cells; these p50 protein isolates retained the same DNA binding characteristics as that of the nuclear extracts. Transfection assays utilizing NF-kappa B-dependent promoter-reporter constructs demonstrated increased activity in LPS + L-NAME cells compared with LPS cells; nuclear run-on assays confirmed increased transcription of the corresponding genes. These results suggest that LPS-mediated NO synthesis is associated with S-nitrosylation of NF-kappa B p50 and inhibition of NF-kappa B-dependent DNA binding, promoter activity, and gene transcription. We conclude that NO can regulate gene transcription by S-nitrosylation of NF-kappa B.


Apoptosis in procyclic Trypanosoma brucei rhodesiense in vitro.
Apoptosis is a phenomenon previously associated exclusively with metazoan organisms. We show here that procyclic insect form Trypanosoma brucei rhodesiense, a protozoan parasite, when treated in vitro with concanavalin A displayed several features normally associated with apoptosis in metazoan cells. Lectin treatment induced cleavage of nuclear DNA into oligonucleosomal fragments, suggesting activation of an endogenous nuclease in the parasite. Treated trypanosomes, although agglutinated and non-motile, exhibited fluorescence after treatment with the vital stain fluorescein diacetate and retained (3)H-uridine indicating that their cell membranes remained intact during the period of DNA fragmentation. Electron micrographs showed characteristic morphology of cells undergoing apoptosis, including surface membrane vesiculation and migration of chromatin to the periphery of the nuclear membrane while mitochondria remained intact. These results suggest that treatment with concanavalin A triggers a cell death mechanism in T. b. rhodesiense similar to the process of apoptosis described in metazoa.


The linguistic roots of natural pedagogy.
Natural pedagogy is a human-specific capacity that allows us to acquire cultural information from communication even before the emergence of the first words, encompassing three core elements: (i) a sensitivity to ostensive signals like eye contact that indicate to infants that they are being addressed through communication, (ii) a subsequent referential expectation (satisfied by the use of declarative gestures) and (iii) a biased interpretation of ostensive-referential communication as conveying relevant information about the referent's kind (Csibra and Gergely, 2006, 2009, 2011). Remarkably, the link between natural pedagogy and another human-specific capacity, namely language, has rarely been investigated in detail. We here argue that children's production and comprehension of declarative gestures around 10 months of age are in fact expressions of an evolving faculty of language. Through both declarative gestures and ostensive signals, infants can assign the roles of third, second, and first person, building the 'deictic space' that grounds both natural pedagogy and language use. Secondly, we argue that the emergence of two kinds of linguistic structures (i.e., proto-determiner phrases and proto-sentences) in the one-word period sheds light on the different kinds of information that children can acquire or convey at different stages of development (namely, generic knowledge about kinds and knowledge about particular events/actions/state of affairs, respectively). Furthermore, the development of nominal and temporal reference in speech allows children to cognize information in terms of spatial and temporal relations. In this way, natural pedagogy transpires as an inherent aspect of our faculty of language, rather than as an independent adaptation that pre-dates language in evolution or development (Csibra and Gergely, 2006). This hypothesis is further testable through predictions it makes on the different linguistic profiles of toddlers with developmental disorders.


Sono-assisted preparation of bio-nanocomposite for removal of Pb2+ ions: Study of morphology, thermal and wettability properties.
Multi-walled carbon nanotubes (MWCNT) loaded poly(ethylene terephthalate) (PET) composites, with different CNT contents, were fabricated through an ultrasound assisted method as a fast and green way. Then, the obtained composites were fully characterized via FT-IR, UV-Vis, XRD, TGA, FE-SEM and TEM, etc. For this purpose, PET bottle was recycled and applied as matrix of nanocomposites (NC)s. Then, we dispersed the covalent functionalization of MWCNTs with a protein dispersant and obtained a powder of protein-functionalized CNTs. Bio-functionalized MWCNTs showed higher Pb2+ removal efficiency compared to MWCNT-COOH as ascertained via batch equilibrium adsorption experiments. Also, the results indicated the novel NCs presents a high affinity for Pb2+ heavy metal owing to the presence of several good sites. The contact angle results indicated that the addition of MWCNT-BSA increased significantly the contact angle compared to the pure PET. It was concluded that inflame retarding feature of NC was higher than pure polymer.


Increased Carotid Intima-Media Thickness in Children with a History of Dengue Hemorrhagic Fever.
We assessed carotid intima-media thickness (cIMT) and arterial stiffness in 28 children and adolescents with previous dengue hemorrhagic fever (DHF) (mean interval between DHF and cardiovascular assessment, 8.4 years), and 34 controls in a low-resource setting. Participants with previous DHF had an adjusted increased cIMT of 42.6 µm (95% confidence interval [CI]: 10.0-75.3, P = 0.01), and 61.7 µm (95% CI: 21.5-102.0, P < 0.01) in a subgroup analysis on dengue shock syndrome. There were no differences in arterial stiffness. In this first exploratory study, children and adolescents with a history of DHF had an increased cIMT, which may be modulated by dengue severity.


Genome survey for susceptibility loci for recurrent, early-onset major depression: results at 10cM resolution.
Recurrent (two or more episodes), early-onset (first episode at < or = 25 years) major depressive disorder (RE-MDD) is a strongly familial condition (lambda(first-degree relatives) = 8) whose malignant effects have a significant negative impact on the health and longevity of patients and their family members. The goal of this study was to identify candidate susceptibility loci that influence the development of RE-MDD. We completed a systematic survey of the human genome, conducted at an average resolution of 10 cM, for the identification of simple sequence tandem repeat polymorphisms (SSTRPs) that target susceptibility genes for RE-MDD by virtue of linkage disequilibrium. The efficiency of our association study was enhanced by genotyping pools of DNA from 100 adults with RE-MDD and 100 adult controls who had no personal or family history of mental disorders. Both groups included equal numbers of Caucasian men and women and were matched as closely as possible for age and ethnicity. Allelic associations with RE-MDD were observed for 19 of the 387 SSTRPs in the CHLC Human Screening Set/Weber Version 9. Sixteen of the 19 candidate susceptibility loci revealed significant allelic associations with RE-MDD in men (n = 7) or women (n = 9), but not in both sexes. Evidence for both risk and protective alleles was detected. Two of the candidate susceptibility loci reside within several Mb of loci previously reported-megabases to be linked to "comorbid alcoholism and depression" in families of individuals with alcoholism and to a broadly defined affected phenotype that included recurrent major depression in the families of patients with bipolar disorder. Although it has been suggested that the genes that influence risk for MDD in the two sexes may not be entirely the same, the results of our study suggest that sex specificity of susceptibility loci for RE-MDD may be the rule rather than the exception. The observed preponderance of sex-specific susceptibility loci for RE-MDD suggests that there may be important differences in the molecular pathophysiology of RE-MDD in men and women. Alternatively, our findings may reflect the existence of sex-specific differences in the molecular mechanisms that determine resilience to endogenous or environmental depressogenic stimuli.


Use of MALDI-MS Combined with Differential Hydrogen-Deuterium Exchange for Semiautomated Protein Global Conformational Screening.
Matrix-assisted laser desorption/ionization (MALDI) coupled with a time-of-flight (TOF) mass-spectrometry (MS) detector is acknowledged to be very useful for analysis of biological molecules. At the same time, hydrogen-deuterium exchange (HDX) is a well-known technique for studying protein higher-order structure. However, coupling MALDI with HDX has been challenging because of undesired back-exchange reactions during analysis. In this report, we survey an approach that utilizes MALDI coupled with an automated sample preparation to compare global conformational changes of proteins under different solution conditions using differential HDX. A nonaqueous matrix was proposed for MALDI sample preparation to minimize undesirable back-exchange. An automated experimental setup based on the use of a liquid-handling robot and automated data acquisition allowed for tracking protein conformational changes as a difference in the number of protons exchanged to deuterons at specified solution conditions. Experimental time points to study the deuteration-labeling kinetics were obtained in a fully automated manner. The use of a nonaqueous matrix solution allowed experimental error to be minimized to within 1% RSD. We applied this newly developed MALDI-HDX workflow to study the effect of several common excipients on insulin folding stability. The observed results were corroborated by literature data and were obtained in a high-throughput and automated manner. The proposed MALDI-HDX approach can also be applied in a high-throughput manner for batch-to-batch higher-order structure comparison, as well as for the optimization of protein chemical modification reactions.


Human lung tumours: does intermediate filament co-expression correlate with other morphological or immunocytochemical features?
Co-expression of intermediate filaments is being increasingly reported for many human tumours including carcinoma of the lung. However, it is unclear whether such findings are unusual or restricted to a group of highly atypical tumours. In the present study the pattern of co-expression of intermediate filaments in 94 human lung tumours has been correlated with light and electron microscopical features which are thought to be atypical for particular tumour types. These same aberrant patterns of intermediate filament co-expression have also been compared with the proliferative rate of these tumours as determined by labelling with the monoclonal antibody Ki67. The results of this study have shown that the aberrant expression of intermediate filaments is not a feature unique to a group of highly unusual tumours but is found throughout the spectrum of lung cancer. The implications of these findings for the use of anti-intermediate filament antibodies in pulmonary pathology are discussed with suggestions for future directions which might be taken in this field.


Current Experience of Ultrasound Training in Otolaryngology Residency Programs.
The applications of using ultrasound for the evaluation and management of otolaryngologic diagnoses are expanding. The purpose of this study was to evaluate the current experience of ultrasound training in otolaryngology residency programs. All allopathic and osteopathic otolaryngology residency programs in the United States were surveyed online via an e-mailed survey link to the resident representatives of the Section for Residents and Fellows in Training of the American Academy of Otolaryngology-Head and Neck Surgery. We present a descriptive analysis of the survey results. A total of 110 responses were obtained from resident representatives at MD and DO otolaryngology residency programs, representing a response rate of 94.8%. Forty-four percent of residents reported that they would not feel comfortable with performing ultrasound-guided procedures after residency; 43% reported that they do not perform ultrasound procedures as a part of their residency training; and 60% of those trainees performing ultrasound procedures do not log the procedures. Twenty-three percent of residents did not have access to an ultrasound machine. Most respondents (71%) desired more exposure to diagnostic and/or interventional ultrasound training during residency. Although current experience is variable, there is a strong interest in increasing resident skill acquisition in ultrasound training among otolaryngology residents. Some barriers to these goals may be a lack of trained faculty members using ultrasound and insufficient recording mechanisms for residents performing ultrasound procedures.


Systematic review of NSAID-induced adverse reactions in patients with rheumatoid arthritis in Japan.
Abstract A systematic review of randomized controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients was conducted to evaluate the risk of NSAID-induced adverse reactions. Double-blind, randomized, controlled trials with 6-week treatments for RA patients were included in the study. The endpoints for the analysis included any adverse reactions, digestive adverse reactions, and upper gastrointestinal (GI) adverse reactions. A fixed-effect model was used for estimation of the risk. Time-to-event analysis of the incidence of adverse reactions was also conducted. A total of 28 trials was included for the analysis, and a total of 30 NSAIDs were used in the trials. The proportion of patients who experienced any adverse reaction was as follows: piroxicam 18.9% (3 trials), diclofenac 18.8% (4 trials), indomethacin 22.1% (14 trials), and aspirin 25.0% (4 trials). The proportion of patients who experienced digestive adverse reactions was as follows: piroxicam 10.2%, diclofenac 10.6%, indomethacin 13.1%, and aspirin 14.1%. Most withdrawals due to adverse reaction occurred during the first 3 weeks after administration of the NSAID. Although the risk of NSAID-induced adverse reaction was different from drug to drug, the risk of adverse reaction was clinically significant.


Dopamine D2-receptor affinity of antipsychotics in relation to subjective well-being in patients with a psychotic disorder.
Dopamine D2-receptor blockade by antipsychotic medication reduces psychotic symptoms, but may reduce subjective well-being. The current study aims to further explore the relation between dopamine D2-receptor affinity and subjective well-being within a large sample of patients with psychotic disorders. Patients participated in a longitudinal naturalistic cohort study: the Genetic Risk and Outcome of Psychosis (GROUP) study. Three groups of antipsychotic medication were created on the basis of their affinity for the D2-receptor: (i) loose or partial agonistic binding, (ii) moderate binding, and (iii) tight binding. Subjective well-being was assessed using the Subjective Well-being under Neuroleptics scale (SWN) at baseline and the 3-year follow-up. In addition, we compared changes in SWN scores when switching to a more 'loose or partial agonistic' binding agent or to a 'tighter' binding agent between baseline and the 3-year follow-up. The final group included 388 patients at baseline and 290 at the 3-year follow-up. No significant differences in the SWN scores were found between the three affinity groups at baseline and the 3-year follow-up. In addition, analyses yielded no significant changes in SWN scores after switching to a more 'loose or partial agonistic' or more 'tight' binding antipsychotic agent. We did not find further support for the hypothesis that subjective well-being is associated with antipsychotics affinity for dopamine D2-receptors. This might imply that the effect of antipsychotic D2-receptors binding on subjective well-being is not large enough to be detected in this cross-sectional study. Other factors besides dopamine antagonism are probably more relevant for subjective well-being.


Regioisomeric and enantiomeric analysis of primary triglycerides in human milk by silver ion and chiral HPLC atmospheric pressure chemical ionization-MS.
Triglycerides (TG) not only provide energy for infants but have important physiological functions. Understanding the composition and structure of TG in human milk is conducive to the development of infant formulas. In this study, TG species in human milk from 3 provincial capitals (Zhengzhou, Wuhan, and Harbin) in different regions of China were determined through C18 HPLC electrospray ionization tandem mass spectrometry (MS). The results showed that in human milk from these 3 regions, oleoyl-palmitoyl-linoleoylglycerol (OPL; 16.55, 19.20, and 18.67%, respectively) was more abundant than oleoyl-palmitoyl-oleoylglycerol (OPO; 10.08, 10.22, and 12.03%, respectively). Subsequently, regioisomeric and enantiomeric analysis of main TG in the human milk were performed on silver ion and chiral HPLC atmospheric pressure chemical ionization mass spectrometry (APCI)-MS, respectively. The results showed that rac-OPL (above 85%), rac-OPO (above 85%), rac-palmitoyl-oleoyl-oleoylglycerol (PPO; above 90%), and rac-OLaO (above 70%) were the main regioisomers of OPL, OPO, PPO, and lauroyl-oleoyl-oleoylglycerol (LaOO), respectively. The relative ratios of enantiomer pairs of rac-OPL (rac-OPL1 and rac-OPL2) were about 37 and 63%, respectively.


Profiling of root canal bacterial communities associated with chronic apical periodontitis from Brazilian and Norwegian subjects.
The aim of this study was to compare the bacterial community profiles of the root canal microbiota associated with chronic apical periodontitis from Brazilian and Norwegian patients using the denaturing gradient gel electrophoresis (DGGE) and the ribosomal intergenic spacer analysis (RISA) approaches. DNA extracted from root canal samples was subjected to polymerase chain reaction using primers appropriate for further DGGE or RISA analysis. The resulting banding patterns representative of the bacterial community structures in samples from the two locations were compared. DGGE and RISA fingerprints showed a great interindividual variability in the bacterial community profiles, irrespective of the geographic location of the patient. However, similarities among the bacterial community DGGE profiles revealed the existence of a geography-related pattern.


The DevBCA exporter is essential for envelope formation in heterocysts of the cyanobacterium Anabaena sp. strain PCC 7120.
The gene devA of the filamentous heterocyst-form-ing cyanobacterium Anabaena sp. strain PCC 7120 encodes a protein with high similarity to ATP-binding cassettes of ABC transporters. Mutant M7 defective in the devA gene is arrested in the development of heterocysts at an early stage and is not able to fix N2 under aerobic conditions. The devA gene is differentially expressed in heterocysts. To gain a better understanding of the structural components of this putative ABC transporter, we determined the complete nucleotide sequence of the entire gene cluster. The two additional genes, named devB and devC, encode proteins with similarities to membrane fusion proteins (DevB) of several ABC exporters and to membrane-spanning proteins (DevC) of ABC transporters in general. Site-directed mutations in each of the three genes resulted in identical phenotypes. Heterocyst-specific glycolipids forming the laminated layer of the envelope were identified in lipid extracts of M7 and in the site-directed mutants. However, transmission electron microscopy revealed unequivocally that the glycolipid layer is missing in mutant M7. Ultrastructural analysis also confirmed a developmental block at an early stage of differentiation. The results of this study suggest that the devBCA operon encodes an exporter of glycolipids or of an enzyme that is necessary for the formation of the laminated layer. The hypothesis is proposed that an intact envelope could be required for further heterocyst differentiation.


Special consideration regarding the assessment and management of patients being treated with mandibular advancement oral appliance therapy for snoring and obstructive sleep apnea.
This position paper, as developed by a Task Force of the American Academy of Craniofacial Pain on Mandibular Advancement Oral Appliance Therapy for Snoring and Obstructive Sleep Apnea, contains recommendations for dentists engaged in the management of patients with snoring and obstructive sleep apnea utilizing mandibular advancement oral appliances. The recommendations are supported by current scientific evidence, published standards and guidelines, and expert panel consensus. Snoring and obstructive sleep apnea (OSA) affects millions of people. Oral appliance therapy (OAT) is recognized as an effective therapy for many with primary snoring and mild to moderate OSA, as well as those with more severe OSA who cannot tolerate positive airway pressure (PAP) therapies. Dentists are playing a much larger role in the screening and management of patients with snoring and OSA as part of a multi-disciplinary team. It is also recognized that OAT has the potential to cause untoward side effects, including temporomandibular joint (TMJ) pain and dysfunction. The present paper highlights the need for dentists who manage patients using mandibular advancement OAT to be competent in the assessment, diagnosis and management of temporomandibular disorders (TMDs) and craniofacial pain disorders. The authors of this article are all clinically engaged in the management of patients with snoring and OSA, and reached consensus based on their review of the current evidence, published guidelines and clinical experience. It is the opinion of the authors that dentists experienced and knowledgeable in the assessment, diagnosis and management of TMD and craniofacial pain applying this knowledge to the management of patients with snoring and OSA using OAT will provide their patients with the best prognosis and most successful treatment outcomes.


Regulation of proliferation of bone marrow-derived macrophages.
The rate of mobilisation of macrophages from marrow is an important determinant of the outcome of many pathological lesions. Studies of BMDM have provided insight into the complex feedback regulation that may control macrophage production. In addition BMDM possess several properties in common with transformed cells of other tissue origins and an understanding of their growth regulation may provide an insight into the mechanism of malignant transformation.


Growth and tissue accretion rates of swine expressing an insulin-like growth factor I transgene.
The goal of this research was to determine whether directing expression of an insulin-like growth factor I (IGF-I) transgene specifically to striated muscle would alter the growth characteristics in swine. Transgenic pigs were produced with a fusion gene composed of avian skeletal alpha-actin regulatory sequences and a cDNA encoding human IGF-I. Six founder transgenic pigs were mated to nontransgenic pigs to produce 11 litters of G1 transgenic and sibling control progeny. Birth weight, weaning weight, and proportion of pig survival did not differ between transgenic and control pigs. The ADG of pigs as they grew incrementally from 20 to 60 kg, 60 to 90 kg, and 90 to 120 kg, respectively, did not significantly differ between transgenic and control pigs. Efficiency of feed utilization (gain:feed) was also similar for transgenic and control pigs. Plasma IGF-I and porcine growth hormone (pGH) concentrations were determined at 60, 90, and 120 kg body weight. Plasma IGF-I concentrations were 19% higher in transgenic gilts than control gilts and 11.1% higher in transgenic boars than control boars (P=0.0005). Plasma IGF-I concentrations for boars were also higher than for gilts (P=0.0001). At 60, 90, and 120 kg body weight each pig was scanned by dual energy X-ray absorptiometry (DXA) to derive comparative estimates of carcass fat, lean, bone content of the live animal. Control pigs had more fat and less lean tissue than transgenic pigs at each of the scanning periods and the difference became more pronounced as the pigs grew heavier (P<0.005 at each weight). Transgenic pigs also had a slightly lower percentage of bone than control pigs (P<0.05 at each weight). While daily rates of lean tissue accretion did not differ for transgenic and control pigs, daily rates of fat accretion were lower in transgenic pigs than in control pigs (P<0.05). Based on these results we conclude that expression of IGF-I in the skeletal muscles gradually altered body composition as pigs became older but did not have a major affect on growth performance.


Two years of newborn screening for Duchenne muscular dystrophy as a part of the statewide Early Check research program in North Carolina.
Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States. We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS. We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns. Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.


Circulatory events following spontaneous muscle exercise in normotensive and hypertensive rats.
In previous studies we have shown that spontaneously hypertensive rats (SHR) develop a running behaviour and, secondary to the running behaviour, develop an endorphin-mediated analgesic effect. In the present study the role of the central endorphin system in the cardiovascular responses to spontaneous exercise in normotensive Wistar Kyoto rats (WKY) and SHR was investigated. The experimental design allowed us to record mean arterial pressure (MAP) and heart rate (HR) continuously for more than 1 week without interfering with the daily activities of the animals. They were active in running wheels during the dark period (19.00-07.00 h) and the activity was accompanied by a marked rise in HR. In SHR, a clear depression of blood pressure lasting for about for about 50 min was noted following each running period. The MAP during the post-running depression was 131.4 +/- 1.6 mmHg which was significantly lower than the pre-running control value (145.2 +/- 2.3 mmHg, P less than 0.01). In contrast, MAP in the post-running period in WKY was not significantly different from the pre-running values. In addition, the depression period of SHR had a mean post-running length of 49.7 +/- 3.4 min, which is significantly longer than in the WKYs (37.8 +/- 3.5 min, P less than 0.05). In control rats, naloxone infusion had no effect on blood pressure but a marked bradycardia was observed. In nine running SHR receiving a naloxone infusion, their MAP during the depression period was not different from the control pressure. Our study indicates that endorphin systems are involved in the regulating of blood pressure and HR during muscle exercise in SHR. These systems trigger the transient depression of blood pressure observed immediately after a running period in the SHR.


Identification of two proteins encoded by the Saccharomyces cerevisiae GAL4 gene.
We placed the Saccharomyces cerevisiae GAL4 gene under control of the galactose regulatory system by fusing it to the S. cerevisiae GAL1 promoter. After induction with galactose, GAL4 is now transcribed at about 1,000-fold higher levels than in wild-type S. cerevisiae. This regulated high-level expression has enabled us to tentatively identify two GAL4-encoded proteins.


[Influence of food intake on the bioavailability of ponsinomycin administered in a syrup form].
Ponsinomycin is a new macrolide. Following oral administration, ponsinomycin is totally metabolized, even before reaching blood circulation. Metabolite Mb12 is the first compound on the main metabolic route, which can be assayed. The influence of food on ponsinomycin bioavailability has therefore been estimated from measurements of Mb12 plasma levels. Twelve young healthy volunteers received 800 mg of ponsinomycin as a syrup on two separate occasions, 2 hours before and during a standard meal. The Mb12 metabolite was assayed in plasma by High Pressure Liquid Chromatography (HPLC). Plasma peak concentrations and areas under curves were not significantly different but time to peak was significantly shorter when ponsinomycin was administered during meal. The results suggest that ponsinomycin absorption is faster when administered with food but quantitatively unchanged.


Selective 3-phosphoinositide-dependent kinase 1 (PDK1) inhibitors: dissecting the function and pharmacology of PDK1.
3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a protein target that has generated considerable interest in both academia and the pharmaceutical industry. PDK1 is responsible for regulating the activity of related kinases in the AGC kinase family, including AKT, by phosphorylating a specific threonine or serine residue within the activation loop which is critical for kinase activation. Many of the kinases activated by PDK1 regulate cellular process such as cell survival, differentiation, growth, and protein expression. Although significant work has been done to understand the role of PDK1 function in cells, recently discovered potent and selective small molecule PDK1 inhibitors are providing a unique opportunity to further dissect PDK1 function and predict the pharmacological consequences of PDK1 inhibition. This Miniperspective reviews the discovery of these selective PDK1 inhibitors and highlights their value in cellular studies, the understanding of PDK1 biology, and the impact on the therapeutic potential of PDK1 inhibition in cancer.


A Feasibility Study on a Telemedicine Hybrid Protocol for Preoperative Anesthetic Assessment.
Background Over the past decade, telemedicine has experienced significant growth due to technological advancement, and the coronavirus disease 2019 (COVID-19) pandemic further accelerated its adoption. However, the field of anesthesiology has been slow in integrating and embracing telemedicine compared to other medical specialties. Methods We conducted an observational pilot feasibility study at a tertiary hospital in Singapore to assess the viability of a telemedicine hybrid protocol for preoperative anesthetic assessment. The study included patients aged 21 to 65 years, classified as American Society of Anesthesiology (ASA) physical status class 1 or 2, with a body mass index (BMI) below 35 kg/m2, who were capable of managing video conferencing. The patients selected were scheduled for low-risk surgeries. The primary objective was to evaluate the medical and technical feasibility of our telemedicine hybrid protocol, while the secondary objectives included assessing patient satisfaction and obtaining feedback from relevant stakeholders. Results From November 2021 to April 2022, a total of 116 patients were recruited, with 96 patients completing the study. No technical difficulties, surgical case cancellations, or incidents of unanticipated difficult airways were reported. The majority of survey respondents (88%) expressed satisfaction with the video consultation and indicated a preference for it over physical consultations for future preoperative anesthesia evaluations. Conclusion Based on our findings, a telemedicine hybrid protocol for preoperative anesthetic assessment demonstrated both technical and medical feasibility while yielding high patient satisfaction. Future research could focus on expanding the protocol to encompass more complex surgeries and include patients with higher ASA status.


Methylammonium Tetrel Halide Perovskite Ion Pairs and Their Dimers: The Interplay between the Hydrogen-, Pnictogen- and Tetrel-Bonding Interactions.
The structural stability of the extensively studied organic-inorganic hybrid methylammonium tetrel halide perovskite semiconductors, MATtX3 (MA = CH3NH3+; Tt = Ge, Sn, Pb; X = Cl, Br, I), arises as a result of non-covalent interactions between an organic cation (CH3NH3+) and an inorganic anion (TtX3-). However, the basic understanding of the underlying chemical bonding interactions in these systems that link the ionic moieties together in complex configurations is still limited. In this study, ion pair models constituting the organic and inorganic ions were regarded as the repeating units of periodic crystal systems and density functional theory simulations were performed to elucidate the nature of the non-covalent interactions between them. It is demonstrated that not only the charge-assisted N-H···X and C-H···X hydrogen bonds but also the C-N···X pnictogen bonds interact to stabilize the ion pairs and to define their geometries in the gas phase. Similar interactions are also responsible for the formation of crystalline MATtX3 in the low-temperature phase, some of which have been delineated in previous studies. In contrast, the Tt···X tetrel bonding interactions, which are hidden as coordinate bonds in the crystals, play a vital role in holding the inorganic anionic moieties (TtX3-) together. We have demonstrated that each Tt in each [CH3NH3+•TtX3-] ion pair has the capacity to donate three tetrel (σ-hole) bonds to the halides of three nearest neighbor TtX3- units, thus causing the emergence of an infinite array of 3D TtX64- octahedra in the crystalline phase. The TtX44- octahedra are corner-shared to form cage-like inorganic frameworks that host the organic cation, leading to the formation of functional tetrel halide perovskite materials that have outstanding optoelectronic properties in the solid state. We harnessed the results using the quantum theory of atoms in molecules, natural bond orbital, molecular electrostatic surface potential and independent gradient models to validate these conclusions.


[Prognosis of acute myocardial infarction in the elderly. SPRINT Study Group].
In countries with aging populations acute myocardial infarction (MI) in the elderly is increasing rapidly and hospital and long-term mortality remain high. During 1981-83, 5839 consecutive patients with acute MI were hospitalized in 13 coronary care units in Israel. Of these, 653 (11%) were older than 75 years, 41% were women, and 70% had a first MI. The hospital mortality in these very elderly patients was 35%. The mortality rates 1 and 5 years postdischarge were 24% and 55%, respectively. In view of this high risk and the promising results obtained elsewhere with thrombolysis, particularly in the elderly, this treatment should be routinely considered in elderly patients with acute MI when there are no specific contraindications.


Participation of cathepsin L in modori phenomenon in carp (Cyprinus carpio) surimi gel.
Cathepsin L (Cat L) in carp (Cyprinus carpio) dorsal muscles was purified and its molecular weight determined by SDS polyacrylamide gel electrophoresis (SDS-PAGE) was 36 kDa. Its optimal temperature and pH were 50 °C and 5.5, respectively. The results of the effects of specific substrates, activators and inhibitors on the enzymatic activity showed that Cat L belongs to the family of cysteine proteinases containing thiol. Compared to the control, the gel strength of surimi with the addition of purified Cat L decreased significantly by 24.33% while that of surimi with both purified Cat L and inhibitors increased by 13.7% and 21.6%, respectively, suggesting the participation of Cat L in the modori phenomenon occurring in carp surimi. Both the SDS-PAGE electrophoretic pattern and microstructure figure revealed that Cat L could hydrolyse the main protein in carp surimi and was one of the enzymes involved in the modori phenomenon.


Brentuximab vedotin in CD30+ cutaneous lymphoma: How do we treat, how shall we treat? A review of the literature.
Brentuximab vedotin is an antibody-drug conjugate that brings the antimicrotubule agent monomethyl auristatin E into CD30-expressing cells. Some prior studies demonstrated good efficacy in cutaneous lymphomas. The standard therapeutic scheme is 1·8 mg kg-1 every 3 weeks. The background of this work is the fact that cutaneous lymphoma has a different pathophysiology and a dynamic other than systemic lymphomas. The objectives of this review were to get an overview of the currently used therapeutic regimen, and to check whether dose reduction or modified time intervals could be of benefit in a similar way with less toxicity. Therefore, we conducted a systematic review of the literature indexed in PubMed and the Cochrane Central Register of Controlled Trials up to April 2016. The procedure was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The review showed that the currently used therapeutic regimen is 1·8 mg kg-1 every 3 weeks. No publications of dose-finding studies in CD30+ cutaneous T-cell lymphoma (CTCL) were found. Two cases of patients, treated with a dose < 1·8 mg kg-1 , have been published. Brentuximab vedotin seems to be a powerful treatment option in refractory CD30+ CTCL, and there is a trend that dose reductions, as well as prolonged treatment intervals, work without any loss of response and with fewer side-effects.


'And not a drop to drink'--why water is harmful for newborns.
Breastmilk is a species-specific food, that is, milk made by human mothers for human infants, and thus is the only natural fluid appropriate for the newborn human. There is a plethora of information available discussing the dangers of water supplementation to babies. This article aims to collate the more recent research papers. Fully breastfed babies do not require water, even in the hottest weather. The dangers of newborn water intoxication, risk of reduction in breastmilk supply and early weaning as well as not following the Ten Steps to Successful Breastfeeding's step six, are discussed. The impact of the attitude of and information from influential persons in the mother's life is also noted.


NO2 interfacial transfer is reduced by phospholipid monolayers.
Nitrogen dioxide (NO2) is a ubiquitous, pollutant gas that produces a broad range of pathological and physiological effects on the lung. Absorption of inhaled NO2 is coupled to near-interfacial reactions between the solute gas and constituents of the airway and alveolar epithelial lining fluid. Although alveolar surfactant imparts limited resistance to respiratory gas exchange compared with that contributed by either the pulmonary membrane or uptake in red blood cells, resistance to NO2 flux could have a significant effect on NO2 absorption kinetics. To investigate the effect of interfacial surfactant on NO2 absorption, we designed an apparatus permitting exposure of variably compressed monolayers. Our results suggest that compressed monolayers enriched in 1,2-dipalmitoyl-sn-3-glycero-phosphocholine present significant resistance to NO2 absorption even at surface tensions greater than those achieved in vivo. However, monolayers composed of pure unsaturated phospholipids failed to alter NO2 absorption significantly when compressed, in spite of similar reductions in surface tension. The results demonstrate that phospholipid monolayers appreciably limit NO2 absorption and further that monolayer-induced resistance to NO2 flux is related to physicochemical properties of the film itself rather than alterations within the aqueous and gas phases. On the basis of these findings, we propose that pulmonary surfactant may influence the intrapulmonary gas phase distribution of inhaled NO2.


Wnt/β-catenin, an oncogenic pathway targeted by H. pylori in gastric carcinogenesis.
A section of gastric cancers presents nuclear β-catenin accumulation correlated with H. pylori infection. H. pylori stimulate Wnt/β-catenin pathway by activating oncogenic c-Met and epidermal growth factor receptor (EGFR), or by inhibiting tumor suppressor Runx3 and Trefoil factor 1 (TFF1). H. pylori also trigger Wnt/β-catenin pathway by recruiting macrophages. Moreover, Wnt/β-catenin pathway is found involved in H. pylori-induced gastric cancer stem cell generation. Recently, by using gastroids, researchers have further revealed that H. pylori induce gastric epithelial cell proliferation through β-catenin. These findings indicate that Wnt/β-catenin is an oncogenic pathway activated by H. pylori. Therefore, this pathway is a potential therapy target for H. pylori-related gastric cancer.


Primary extra-cranial meningioma of head and neck: clinical, histopathological and immunohistochemical study of three cases.
Extracranial meningiomas of the head and neck region are rare neoplasms, the majority being a secondary location of a primary intracranial tumour. We herewith report three rare cases of extracranial meningiomas, located in the temporal muscle, parotid gland and nasal cavity, together with complete pathological, immunohistochemical and ultrastructural studies. Prognosis of this tumour is generally excellent. Surgical excision is the treatment of choice, with no need for further treatment; nevertheless, differential diagnosis must consider other more common tumours of the head and neck and be based on histopathologic examination and relative techniques, including examination of frozen sections. This procedure is particularly useful assessing surgical treatment and should be performed whenever possible to exclude the malignant nature of the lesion and avoid over-treatment. All three patients underwent surgery and are alive and disease-free.


The combined use of non-radioactive in situ hybridization and real-time RT-PCR to assess gene expression in cryosections.
Gene expression changes in pathophysiological states can be spatiotemporally monitored by in situ hybridization and reliably quantified by real-time RT-PCR. Here we developed a new method whereby adjacent slides of frozen sections can be used for gene expression analysis by in situ hybridization and real-time RT-PCR. We applied this method to assess the mRNA expression of connexin 43 (Cx43), the major astrocytic connexin, after kainate-induced seizures in rat hippocampus. Gap junction-building connexins play a role in the pathogenesis of several diseases of the brain, including epilepsy. The number of Cx43 mRNA-positive cells in the hippocampus of kainate-treated and control rats was automatically quantified by computerized image analysis of brain sections hybridized with DIG-labeled RNA probes. In parallel, real-time RT-PCR was used to examine the relative Cx43 mRNA levels in hippocampal tissue from adjacent brain sections. Applying these two very sensitive methods we showed that kainate induced seizures do not affect hippocampal connexin 43 mRNA expression.


Novel systemic drugs in treatment of atopic dermatitis: results from phase II and phase III studies published in 2017/2018.
The present review will give an update of recently published clinical studies on novel systemic treatment approaches in atopic dermatitis. Until 2017 immunosuppressive drugs such as cyclosporine had to be used in atopic dermatitis when the disease could not sufficiently be treated with topical drugs. Several new substances specifically targeting inflammation in atopic dermatitis are currently studied. In 2017, dupilumab was approved in the United States and in Europe for first-line biologic treatment of moderate to severe atopic dermatitis in adults. The antibody blocks a subunit of the interleukin (IL)-4 and IL-13 receptor, thus inhibiting effects of two key cytokines in type 2 polarized inflammation. In addition to the studies on dupilumab recent clinical investigations on the effects on anti-IL-13 (lebrikizumab, tralokinumab), anti-IL-31 receptor (nemolizumab), anti-IL-22 (fezakinumab), and on small molecules targeting the histamine-4-receptor (ZPL389) and the Janus kinase inhibitor baricitinib have been published as full papers in the last 2 years. A couple of promising novel therapeutical targets have recently been investigated and published in clinical trials on atopic dermatitis.


Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients.
Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors- group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children.


C-deletion mutation of the p53 gene at exon 4 of codon 63 in the saliva of oral squamous cell carcinoma in central India: a preliminary study.
The purpose of this study was to detect the C-deletion mutation of the p53 gene at exon 4 of codon 63 in the saliva of oral squamous cell carcinoma in central India. The study was carried out in 30 oral squamous cell carcinoma cases and five healthy controls with no habit of betel nut and tobacco chewing. The C-deletion mutation of the p53 gene at exon 4 of codon 63 was detected in the saliva samples by using polymerase chain reaction. In this study, C-deletion at exon 4 of codon 63 was detected in 28 of 30 oral squamous cell carcinoma cases (93.33%), but was negative in all five healthy controls and two oral squamous cell carcinoma cases. The results indicated that C-deletion mutation at exon 4 of codon 63 of the p53 gene in the saliva might be a plausible molecular marker for oral squamous cell carcinoma patients with a habit of betel nut and tobacco lime quid chewing. The results further emphasize the presence of p53 gene mutation in patients with oral squamous cell carcinoma, which can be detected in the saliva through polymerase chain reaction.


PCI-24781 down-regulates EZH2 expression and then promotes glioma apoptosis by suppressing the PIK3K/Akt/mTOR pathway.
PCI-24781 is a novel histone deacetylase inhibitor that inhibits tumor proliferation and promotes cell apoptosis. However, it is unclear whether PCI-24781 inhibits Enhancer of Zeste 2 (EZH2) expression in malignant gliomas. In this work, three glioma cell lines were incubated with various concentrations of PCI-24781 (0, 0.25, 0.5, 1, 2.5 and 5 μM) and analyzed for cell proliferation by the MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay and colony formation, and cell cycle and apoptosis were assessed by flow cytometry. The expression of EZH2 and apoptosis-related proteins was assessed by western blotting. Malignant glioma cells were also transfected with EZH2 siRNA to examine how PCI-24781 suppresses tumor cells. EZH2 was highly expressed in the three glioma cell lines. Incubation with PCI-24781 reduced cell proliferation and increased cell apoptosis by down-regulating EZH2 in a concentration-dependent manner. These effects were simulated by EZH2 siRNA. In addition, PCI-24781 or EZH2 siRNA accelerated cell apoptosis by down-regulating the expression of AKT, mTOR, p70 ribosomal protein S6 kinase (p70s6k), glycogen synthase kinase 3A and B (GSK3a/b) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1). These data suggest that PCI-24781 may be a promising therapeutic agent for treating gliomas by down-regulating EZH2 which promotes cell apoptosis by suppressing the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of the rapamycin (mTOR) pathway.


Hyperlipidemia in kidney disease: causes and consequences.
Dyslipidemias are common in patients with chronic kidney disease. The causes vary with the stage of kidney disease, the degree of proteinuria, and the modality of end-stage renal disease treatment. Dyslipidemias have been associated with kidney disease progression, and a number of small, randomized, controlled trials of lipid-lowering agents have been conducted. Unfortunately, the results of these trials, although encouraging, have been inconclusive because of the small numbers of patients enrolled. Dyslipidemias may also contribute to the high incidence of cardiovascular disease in patients with chronic kidney disease. This is most likely for patients with chronic renal insufficiency and for kidney transplant recipients. Less certain is the role of dyslipidemias in the pathogenesis of cardiovascular disease among dialysis patients.


[Endovascular therapy of abdominal aortic aneurysm: results of a mid-term follow-up].
Prospective study to evaluate clinical results and complications of endovascular abdominal aortic aneurysm treatment in a mid-term follow-up. A total of 122 patients (9 females, 113 males, average age 70.9 +/- 7.9 years) with abdominal aortic aneurysms were treated with stent grafts (53 Vanguard or Stentor endografts, 69 Talent endografts). Group I consisted of 40 patients who had all aortic tributaries of the aneurysm sac occluded prior to endovascular grafting, either spontaneously by parietal thrombosis or by selective coil embolization of the respective ostia preserving collateral circulation distal to the vessel occlusion. Group II consisted of 82 patients and included all cases without or with incomplete coil embolization with at least one patent vessel. Stent grafting was performed in general anesthesia in the first 21 patients, followed by peridural anesthesia in 15 cases, and local anesthesia with conscious sedation in 86 cases. The results were evaluated with Spiral-CT, MRI and radiographs of the endovascular graft, with follow-up examinations obtained at 3, 6, 12 months, and every year. Implantation was successfully completed in all cases without primary conversion surgery, laparotomy, or any significant complication. Mean follow-up was 29 +/- 21 months (maximum 84 months). The 30-day mortality was 0.8 % due to a myocardial infarction 3 days after discharge from the hospital. A total of 47 re-interventions were performed in 29 patients (23.8 %), with 35 re-interventions in 18 cases with Vanguard or Stentor endografts and 12 re-interventions in 11 patients with Talent endografts. 23 percutaneous re-interventions included distal graft extension (n = 11), Wallstents for kinking and limb stenosis (n = 3), and secondary coil embolization of collateral vessels (n = 9). 24 surgical re-interventions included proximal graft extension (n = 6), new endovascular grafts (n = 3), surgical clipping of lumbar and mesenteric artery branches for type-II endoleaks following ineffective secondary coil embolization (n = 1), and femorofemoral crossover bypasses (n = 4). A total of 10 secondary conversion operations were performed because of damage to the membrane (n = 4; 3 Vanguard endografts, 1 Talent endograft), significant caudal migrations (n = 5; 4 Vanguard endografts, 1 Talent endograft) associated with type-I endoleaks (n = 2), limb occlusion (n = 1), disconnection of graft components (n = 1), and significant endoluminal thrombus deposits (n = 1). One patient, who was followed for 82 months, suffered from a significant endoleak for 10 months with increasing aneurysm diameter but he refused surgery. He was admitted with aneurysm perforation and was successfully operated with aortic graft replacement. Compared to group II, the incidence and size of endoleaks was reduced in group I (incidence 19.2 % versus 29.9 %, p < 0.05). Group I demonstrated significantly better aneurysm shrinkage at 36 months follow-up (Delta sagittal diameter - 11.1 +/- 8.4 mm versus - 4.9 +/- 6.2 mm, p < 0.05). In selected patients, endovascular aneurysm treatment is an effective alternative to open surgery. It is safely performed in local anesthesia with low mortality rate and a low number of acute complications. Intermediate follow-up revealed re-interventions in around one quarer of all patients, especially when Vanguard or Stentor endografts were implanted. Primary coil embolization of all aortic branches prior to endovascular grafting improves clinical outcome. Insufficient proximal fixation and its consecutive complications remains a major problem of this method.


[Hepatic trauma--a 10-year Swedish study. Conservative treatment generally the best option when the circulation is stable].
We studied retrospectively 60 patients with hepatic injuries, 30 of which were referrals. Blunt trauma dominated (90%). Twelve unstable patients had immediate surgery and 41 an initial CT-scan. The injury was graded according to the Liver Injury Scale (AAST). Moderate injuries (grade I-II) were seen in 40 patients, of which 29 had successful conservative treatment. Fifteen of the severe injuries required surgery. Minimally invasive techniques facilitated management of postoperative complications. In all, 16 died, 4 due to the hepatic injury. The material presented is small and heterogeneous, but our results are similar to those reported internationally. A multidisciplinary approach facilitates management.