Enhanced inhibition of Pseudomonas aeruginosa virulence factor production and biofilm development by sublethal concentrations of eugenol and phenyllactic acid.

Biofilm development in Pseudomonas aeruginosa is regulated by its quorum sensing (QS) systems. It has three major QS systems: LasI/R, RhlI/R and PQS/MvfR. Previous studies showed that phenyllactic acid (PLA) binds to RhlR and PqsR and inhibits the Rhl and PQS QS; and eugenol at sublethal concentration inhibits Las and PQS QS systems. Here, we have demonstrated that a combination of sublethal doses of eugenol and PLA enhanced the inhibition of the QS mediated production of the virulence factors and biofilm development of this pathogen. A combination of 50 µmol l-1 eugenol and 0·3 mmol l-1 PLA significantly inhibited the pyocyanin production, protease activity, swarming motility and cytotoxic activities of P. aeruginosa strain PAO1, whereas eugenol and PLA when added individually to PAO1 cultures were less effective in inhibiting its virulence factor expression. Biofilm formation of PAO1 was reduced by 32, 19 and 87% on glass surfaces; and 54, 49 and 93% on catheter surfaces when treated using 50 µmol l-1 eugenol or 0·3 mmol l-1 PLA and their combinations, respectively. The in vitro finding in the reduction of biofilm development was further validated in vivo using a catheter associated medaka fish biofilm model. Our results indicate that a combination of QS inhibitors targeting different QS pathways should be selected while designing therapeutic molecules to achieve maximum QS mediated biofilm inhibition and clinical outcome against P. aeruginosa.

Direct health care costs of managing perianal Crohn's Disease in a population based cohort.

BACKGROUND: Crohn's disease is a chronic condition that places a high health care cost burden. Perianal Crohn's disease (pCD) is a difficult phenotype to treat due to poorer response to medical and surgical therapies. No study has assessed if this translates to higher healthcare costs. The aim is to assess the cost of treating pCD and compare to the cost of non-perianal Crohn's disease (CD). METHODS: This is a retrospective case-control cohort study in a population-based setting. The direct healthcare costs for patients with pCD were calculated over 12 months. Data was compared to the control group of non-perianal CD patients on biologic treatment, with the use of the Mann-Whitney rank test to assess significance. RESULTS: 187 Crohn's patients were included (39 pCD, 148 CD). Per patient, annual cost was €17,779.19 and €17,576.86 respectively (p = .9391). Medications were responsible for the majority of cost at 78% and 92% of total cost in pCD and CD, respectively (€13,886.04 in pCD, and €16,007.10 in CD), of which biologics were the main driver. Surgical costs were higher in the pCD group due to a higher cost of luminal surgery (€2633.88 in pCD vs €209.79 in CD, p = .0270). CONCLUSION: This is the first study to assess the cost of treating perianal Crohn's disease in a real-world population. Although the costs were similar overall to non-perianal Crohn's patients, the perianal cohort had higher surgical costs from luminal surgery. This demonstrates the potential to apply early intensive treatment to reduce future surgical cost.

Crohn's disease is a lifelong disease where high-cost drugs are required to achieve optimal outcomes. There is minimal data regarding the cost of managing perianal fistulising Crohn's disease and whether the clinical complexity of these patients translates to higher healthcare costs. Costs were similar between luminal Crohn's disease patients treated with a biologic and those with perianal disease, though the distribution of costs varied. Knowing this distribution will allow for more effective allocation of resources.

The Fetus with Ganglionic Eminence Abnormality: Head Size and Extracranial Sonographic Findings Predict Genetic Diagnoses and Postnatal Outcomes.

BACKGROUND AND PURPOSE: Ganglionic eminence abnormalities on fetal MR imaging are associated with cerebral malformations. Their presumed genetic basis and associated postnatal outcomes remain largely unknown. We aimed to elucidate these through a multicenter study. MATERIALS AND METHODS: Between January 2010 and June 2020, seven hospitals in 2 countries performing fetal MR imaging examinations identified fetal MR imaging studies demonstrating ganglionic eminence enlargement, cavitation, or both. Cases with no genetic diagnosis, no whole exome sequencing, or no outcome of a liveborn child were excluded. Head size was classified as large (fronto-occipital diameter > 95th centile), small (fronto-occipital diameter <5th centile), or normal. RESULTS: Twenty-two fetuses with ganglionic eminence abnormalities were identified. Of 8 with large heads, 2 were diagnosed with MTOR mutations; 1 with PIK3CA mutation-producing megalencephaly, polymicrogyria, polydactyly, hydrocephalus (MPPH) syndrome; 3 with TSC mutations; 1 with megalencephaly capillary malformation syndrome; and 1 with hemimegalencephaly. Cardiac rhabdomyoma was present prenatally in all cases of TSC; mutation postaxial polydactyly accompanied megalencephaly capillary malformation and MPPH. Of 12 fetuses with small heads, 7 had TUBA1A mutations, 1 had a TUBB3 mutation, 2 had cobblestone lissencephaly postnatally with no genetic diagnosis, 1 had a PDHA1 mutation, and 1 had a fetal akinesia dyskinesia sequence with no pathogenic mutation on trio whole exome sequencing. One of the fetuses with a normal head size had an OPHN1 mutation with postnatal febrile seizures, and the other had peri-Sylvian polymicrogyria, seizures, and severe developmental delay but no explanatory mutation on whole exome sequencing. CONCLUSIONS: Fetal head size and extracranial prenatal sonographic findings can refine the phenotype and facilitate genetic diagnosis when ganglionic eminence abnormality is diagnosed with MR imaging.

Rhodococcus equi: Another great masquerader.

Rhodococcosis is a serious infection specially affecting immunocompromised populations. We report a case of disseminated infection by Rhodococcus equi in a renal transplant patient, that was initially diagnosed as histoplasmosis, highlighting the potential for confusion between rhodococcosis and other infections. Clinicians and pathologists should correlate histopathology findings with the clinical and microbiological data.

Burning Feet, Dilated Heart and Failed Kidneys.

Fabry's disease, X-linked lysosomal storage disease, results from deficient activity of alpha galactosidaseA (α-GalA). Renal manifestation usually begins at third decade of life. We report a 16 year male with initial presentation with end stage renal disease (ESRD) and the diagnosis confirmed by presence of myeloid bodies on electron microscopy of kidney biopsy and low serum α-GalA level.

Tetracyclines for Treatment of Tularemia: A Case Series.

Tetracyclines for tularemia have been associated with higher failure rates. There were 48 cases of tularemia at the University of Missouri between 1988 and 2015. We retrospectively analyzed 17 patients with tularemia who were successfully treated with tetracyclines, and 9 of these patients also underwent aspiration or incision and drainage.

Enabling Chemistry Technologies and Parallel Synthesis-Accelerators of Drug Discovery Programmes.

There is a pressing need to improve overall productivity in the pharmaceutical industry. Judicious investments in chemistry technologies can have a significant impact on cycle times, cost of goods and probability of technical success. This perspective describes some of these technologies developed and implemented at AbbVie, and their applications to the synthesis of novel scaffolds and to parallel synthesis.

Use of erythrocyte sedimentation rate and C-reactive protein to predict osteomyelitis recurrence.

PURPOSE: To determine the association between both erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) and osteomyelitis recurrence. METHODS: Records of 81 males and 27 females aged 10 to 87 (median, 54) years who underwent antibiotic/ surgical treatment for primary (n=68) or recurrent (n=40) osteomyelitis that was related (n=26) or unrelated (n=82) to a prosthesis were reviewed. Of the 40 cases of osteomyelitis recurrence followed up for a median of 23.4 (range, 0.6-74.0) months, 7 and 33 were related and unrelated to a prosthesis, respectively. The cutoff points of lowest ESR and CRP for osteomyelitis recurrence were calculated. Risk factors for osteomyelitis recurrence were determined. RESULTS: Osteomyelitis recurrence was associated with diabetes mellitus, ischaemic heart disease, non-healing wound, infection in the lower limb, and infection with methicillin-resistant Staphylococcus aureus. The cutoff points of CRP ≥5 mg/l and ESR ≥20 mm/h were used for osteomyelitis recurrence. Risk factors for osteomyelitis recurrence were ESR ≥20 mm/h, infection with methicillin-resistant S aureus, and infection in the lower limb. CONCLUSION: ESR was more sensitive, specific, and independently associated with osteomyelitis recurrence and should be used to guide the duration of antibiotic treatment.

What accounts for ethnic differences in newborn skinfold thickness comparing South Asians and White Caucasians? Findings from the START and FAMILY Birth Cohorts.

OBJECTIVE: South Asians are a high-risk group for type 2 diabetes and coronary heart disease. We sought to determine ethnic differences in newborn adiposity comparing South Asians (SA) to White Caucasians (Whites). METHODS: Seven hundred ninety pregnant women (401 SA, 389 Whites) and their full-term offspring from two birth cohorts in Canada were analyzed. Pregnant women completed a health assessment including a 75-g oral glucose tolerance test to assess for dysglycemia. Birthweight, length, waist and hip circumference, and triceps and subscapular skinfold thickness (a surrogate measure of body adiposity) were measured in all newborns. Multivariate regression was used to identify maternal factors associated with newborn skinfold measurements. RESULTS: South Asian women were younger (30.1 vs 31.8 years, P<0.001), their prepregnancy body mass index was lower (23.7 vs 26.2, P<0.0001) and gestational diabetes was substantially higher (21% vs 13%, P=0.005) compared with Whites. Among full-term newborns, South Asians had lower birthweight (3283 vs 3517 g, P=0.0001), had greater skinfold thickness (11.7 vs 10.6 mm; P=0.0001) and higher waist circumference (31.1 vs 29.9 cm, P=0.0001) compared with Whites. Risk factors for newborn skinfold thickness included South Asian ethnicity (standardized estimate (s.e.): 0.24; P<0.0001), maternal glucose (s.e.: 0.079; P=0.04) and maternal body fat (s.e.: 0.14; P=0.0002). CONCLUSIONS: South Asian newborns are lower birthweight and have greater skinfold thickness, compared with White newborns, and this is influenced by maternal body fat and glucose. Interventions aimed at reducing body fat prior to pregnancy and gestational diabetes during pregnancy in South Asians may favorably alter newborn body composition and require evaluation.

Effect of postural changes on inferior vena cava dimensions and its influence on haemodynamics during caesarean section under spinal anaesthesia.

The effect of postural changes on inferior vena cava (IVC) dimensions and its influence on intra-operative haemodynamics in term parturients can be studied using abdominal ultrasound by a subcostal approach. Thirty-two term parturients scheduled to undergo elective caesarean section under spinal anaesthesia were recruited in this observational study. End expiratory diameter and collapsibility index of IVC was measured preoperatively in 3 different positions - supine, recumbent with wedge and left lateral positions. End expiratory diameter was significantly high in recumbent (10.79) and left lateral (12.27) compared with supine (9.96) position (P < 0.0001). A greater fall in systolic blood pressure (>20%) was noted in patients with collapsibility index of more than 11.5 in recumbent with wedge position with a positive predictive value of 86%. IVC dimensions change significantly with change in position and collapsibility index in recumbent position can be a useful parameter for predicting hypotension during caesarean section under spinal anaesthesia.

Prevention versus treatment of intrathecal morphine-induced pruritus with ondansetron.

BACKGROUND: Intrathecal morphine is used for post-cesarean analgesia, but pruritus is a common side effect. Ondansetron would be an attractive treatment because it prevents nausea, is non-sedative or has no anti-analgesic effect. We undertook a study to assess the efficacy of ondansetron for treatment or prophylaxis of intrathecal morphine-induced pruritus. METHODS: Healthy paturients undergoing cesarean delivery with intrathecal morphine 250µg and fentanyl 25µg were randomized to receive: prophylaxis (ondansetron 8mg at cord clamping, normal saline 4mL for treatment of pruritus in the post-anaesthesia care unit); treatment (normal saline 4mL at cord clamping, ondansetron 8mg as required in the post-anesthesia care unit) or control (normal saline 4mL in both). Visual analogue scale scores for pruritus, nausea and pain were recorded preoperatively, on arrival to, at 30, 60, and 120min and on discharge from the post-anesthesia care unit. The primary outcome was the peak pruritus score. ANOVA with Bonferroni correction or Fisher's exact test were used to analyze data; P<0.05 was considered significant. RESULTS: The study was terminated early when interim analysis indicated no effect. Eighty-two of the intended 180 paturients completed the protocol (26 in control group, 32 in treatment group and 24 in prophylaxis). There were no differences in the rate or severity of pruritus at any assessment point, or the request for treatment. Pruritus was reduced after administration of treatment syringe. CONCLUSION: Prophylactic ondansetron did not reduce pruritus when compared with placebo. The use of ondansetron as a treatment did not decrease the severity of pruritus when compared with placebo.

Ocular complications in children with nephrotic syndrome on long term oral steroids.

OBJECTIVES: To estimate the burden of ocular complications like posterior subcapsular cataract (PSCC) and raised intra ocular pressure (IOP) in children with nephrotic syndrome on long term steroid therapy and to assess the correlation of cumulative dosage and duration of consumption of steroids with these ocular complications. METHODS: Children between 4-18 y with nephrotic syndrome, who received steroids for at least six months, were included in this cross sectional study. Demographic, clinical and treatment details were obtained from case records. Detailed ocular evaluation was performed to detect PSCC and to measure IOP. RESULTS: One hundred and eighteen children were screened and 82 with a median (IQR=Interquartile range) follow up of 4.2 y (2.4, 6.3 y) were included in the final analysis. The median (IQR) age of children was 9.3 y (6, 12.5 y) at recruitment. The proportion of children with PSCC and raised IOP were 22/82 (26.8 %) and 9/82 (10.97 %) respectively. PSCC was associated with older age (p = 0.009). The median cumulative dose of steroids in those with and without cataract was 338.4 mg/kg and 343.2 mg/kg respectively (p = 0.58). The median duration of steroid theraphy was 58 wk and 59 wk in the two groups respectively (p = 0.73). Of children with PSCC, 9 (42.8 %) had mild diminution of vision. CONCLUSIONS: One in 4 and 1 in 9 children with nephrotic syndrome in the present study had PSCC and raised IOP respectively. Cumulative dose and duration of steroid therapy were not significantly associated with PSCC or raised IOP. The present study emphasizes the need for regular ocular evaluation and also to explore additional factors in causation of steroid induced ocular complications.

Building pharmacogenetics into a pharmacovigilance program in Singapore: using serious skin rash as a pilot study.

To study the possible genetic associations with adverse drug reactions (ADR), the Singapore Health Sciences Authority (HSA) has piloted a program to collect DNA and phenotype data of ADR cases as part of its pharmacovigilance program. Between 2009 and 2012, HSA screened 158 cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). To assess the association between HLA-B*1502 and carbamazepine (CBZ)-induced SJS/TEN, 13 cases and 26 drug-tolerant controls were analyzed. All 13 CBZ-SJS/TEN cases and 3/26 controls were HLA-B*1502 positive (odds ratio 181, 95% confidence interval: 8.7-3785, P=6.9 × 10(-8)). Discussions of the finding with the Ministry of Health and an expert panel led to the decision to make HLA-B*1502 testing the standard of care prior to first use of CBZ in Asians and to subsidize the genotyping test at public hospitals. This program illustrates the role of a regulatory authority in advancing the use of pharmacogenetics for drug safety.

Biochemical basis and clinical consequences of glucolipotoxicity: a primer.

Both glucose and fatty acids may have good/adaptive or toxic/maladaptive actions on the pancreatic beta cell, depending on their concentrations. Hyperglycemia, via metabolic intermediates, may result in multiple cellular effects that are toxic to the pancreatic beta cell and indeed other tissues. While free fatty acids may affect cellular processes beyond lipid metabolism by interacting with transcription factors, triglyceride rich lipoproteins are endothelial cell-toxic and facilitate atherogenesis. The paradigm of "glucolipotoxicity" espouses that increased glucose and fatty acid levels act synergistically in causing toxicity to pancreatic islets and other organs, a process that eventually leads to the multiple defects seen in the metabolic syndrome and diabetes mellitus.

Insulin resistance and atherosclerosis.

Insulin resistance is a complex metabolic defect that has several causes dependent on an individual's genetic substrate and the underlying pathophysiologic state. Atherogenic dyslipidemia, hyperinsulinemia, dysglycemia, inflammation associated with obesity, and ectopic steatosis in liver and skeletal muscle all collude to facilitate endothelial dysfunction and predispose to the initiation and propagation of atherosclerosis. As aggressive management of the various risk factors does not seem to abrogate the so-called residual risk, more research is needed to define ways by which intervention can fundamentally alter the metabolic and vascular milieu and slow the pace of atherosclerosis, thus favorably affecting outcomes.

Modality of choice for renal replacement therapy for children with acute kidney injury: Results of a survey.

Information on current practices in India for management of renal replacement therapy (RRT) in acute kidney injury (AKI) is lacking. We mailed a questionnaire to 26 pediatric nephrology centers across India to obtain information on the current choice of dialysis modality for management of AKI in children. Acute intermittent peritoneal dialysis was available at all centers surveyed, whereas intermittent hemodialysis and continuous RRT were available in 86% and 17% centers, respectively. Peritoneal dialysis was the predominant modality (accounting for more than 80% of all dialysis) in 14 of the 22 centers, while 4 centers used hemodialysis more commonly. The most important factors influencing the modality choice were patient size, hemodynamic stability, and duration of AKI. These results provide insight into the choice of modality and factors influencing their selection in the management of pediatric AKI in our country.

Objective measures of physical functional capacity warrant exploration to complement or replace the subjective physician estimated performance status.

Performance status, a measure of physical functioning, can be influenced by several undefined physician and patient-related factors, and is inherently subjective. Although disappointing results in phase 3 trials may reflect a lack of improved outcomes due to biological mechanisms, a confounding effect of imbalances of physical functioning cannot be excluded in the context of modest increments in antitumor activity. Therefore, performance status estimation may complicate drug development, and an objective measure of physical reserve is desirable and may complement or outperform performance status. We explore and discuss attractive candidates for objective measures of physical functioning.

Urinary indices during relapse of childhood nephrotic syndrome.

Sodium retention is the hallmark of idiopathic nephrotic syndrome (INS). Sodium retention could be secondary to activation of renin-angiotensin-aldosterone axis or due to an intrinsic activation of Na(+)K(+) ATPase in the cortical collecting duct. Urine potassium/urine potassium + urine sodium (UK(+)/UK(+) + UNa(+)) is a surrogate marker for aldosterone activity and can be useful in differentiating primary sodium retention from secondary sodium retention in children with INS. This was a cross-sectional study of children with INS, presenting to our center from June 2007 to June 2008. Children were categorized into those with steroid responsive and steroid nonresponsive nephrotic syndrome. One hundred and thirty-four children with nephrotic syndrome were analyzed. The FeNa(+) was significantly lower during relapse than in remission but no such difference was observed with UK(+)/UK(+) + UNa(+). The values of FeNa(+) and UK(+)/UK(+) + UNa(+) across various categories of nephrotic syndrome were similar. Correlating FeNa(+) and UK(+)/UK(+) + UNa(+) with cut-off of 0.5 and 60%, respectively, we found 50% of steroid responsive children and 36% of steroid nonresponders having a corresponding UK(+)/UK(+) + UNa(+) of <60% along with low FeNa(+) of <0.5%, favoring primary sodium retention. Urinary indices did not vary with the type of steroid response. In early relapse, the urinary indices revealed an overlap of both primary and secondary sodium retention in most stable edematous children with nephrotic syndrome.

Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus.

OBJECTIVE: Neuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events. METHODS: Patients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-ß(2) glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression. RESULTS: Disease duration at enrolment was 5.4 ± 4.2 months, follow-up was 3.6 ± 2.6 years. Patients were 89.1% female with mean (±SD) age 35.2 ± 13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-ß(2) glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events. CONCLUSION: In a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.