Rare Hybrid Perineurioma and Granular Cell Tumor: A Pediatric Case.

We present a case of a 13-year-old patient with a distinct tumor with both granular cell and perineurial elements, located on the lower lip. The patient presented with a long-standing lip mass that was clinically felt to most likely represent a mucocele. Following surgical excision, histopathological examination revealed a well-circumscribed tumor composed of granular cells with positive S100 protein staining and spindled cells positive for EMA and GLUT-1, confirming mixed neuroectodermal and perineurial origin. This is the first case documenting a perineurial-granular cell hybrid tumor in a patient under 18 years old, and the first to be reported in the head and neck. This case expands our understanding of hybrid PNSTs, emphasizing the importance of considering diverse clinical presentations, especially in the context of rare pediatric occurrences in atypical locations.

Peripartum management of a parturient with Klippel-Trénaunay syndrome.

Klippel-Trénaunay syndrome is a rare congenital disorder affecting the vascular and lymphatic systems. The clinical presentation can vary widely, but the syndrome is broadly characterised by capillary, venous and lymphatic malformations as well as limb hypertrophy. We present the case of a 35-year-old parturient who underwent an emergency caesarean section for suspected fetal distress, and describe the anaesthetic management during the peripartum period. Only a small number of similar cases have been described, and the multisystem nature of the condition presents several challenges to both the obstetric and anaesthetic management. The major points of concern to the anaesthetist are haematological, with a tendency to both abnormal bleeding and clotting disorders, compounded by vascular malformations which may present anywhere in the body including the epidural space and airway. Other considerations relate to limb hypertrophy and spinal abnormalities, as well as pulmonary and ocular sequelae and chronic pain. Strategies for safe patient management include early multidisciplinary involvement, and assessment of the presence and extent of any vascular anomalies with advanced imaging techniques. The risk of significant blood loss can be mitigated with antifibrinolytic and uterotonic medication as well as cell salvage, with treatment carefully balanced against the concurrent risk of thrombosis.

Amyloid Deposition of the Bilateral Ureters in a Patient With Chronic Systemic AL Amyloidosis.

Amyloid of the ureter is a rare disease with less than 25 cases reported in the literature. Despite being rare, it remains an important entity as it is typically confused with a primary neoplastic process of the urinary system. We report a case of a 68-year-old male with a history of cutaneous amyloid with late presentation of bilateral ureteral involvement.

The long-term protective effects of neonatal administration of curcumin against nonalcoholic steatohepatitis in high-fructose-fed adolescent rats.

There is an increased prevalence of nonalcoholic steatohepatitis (NASH) in adolescents. The suckling period is developmentally plastic, affecting later health outcomes. We investigated whether neonatal administration of curcumin would provide protection against the development of NASH later in adolescence in rats fed a high-fructose diet. From postnatal day (PN) 6 to PN 21, the pups (N = 128) were allocated to four groups and orally gavaged daily with either 0.5% dimethyl sulfoxide solution (vehicle control), curcumin (500 mg·kg-1 ), fructose (20%, w/v) or curcumin and fructose combined. All the pups were weaned and half the rats in each group had tap water, whereas the other received fructose (20%) as their drinking fluid ad libitum for 6 weeks. The rats' liver NASH scores, lipid content, and RNA gene expression ratios of AMPKα and TNFα were determined. Hepatic lipid content was similar across the treatment groups in the males (P > 0.05, ANOVA). In the females, the hepatic lipid content in the treatment groups ranged from 2.7 to 4.3%. The livers of male and female rats that had fructose either as neonates and/or postweaning had significantly marked inflammation (P = 0.0112, Kruskal-Wallis) and fibrosis (P < 0.0001, ANOVA) which were attenuated by curcumin. The hepatic gene expression ratios for AMPKα in both sexes were significantly downregulated (P < 0.0001, ANOVA), whereas the expression ratios of TNFα were significantly upregulated (P < 0.0001) in rats fed a high-fructose diet pre and/or postweaning compared to the other groups. Neonatal curcumin administration is a potential natural pharmacological candidate for the prevention of NASH.

Insulinotropic Effect of S-Allyl Cysteine in Rat Pups.

S-Allyl cysteine (SAC) is found in garlic and has been reported to exert antidiabetic and antiobesity properties in drug-induced adult experimental models of metabolic dysfunction, but its potential beneficial effects in high-fructose diet neonatal rat models have not been determined. This study investigated the potential prophylactic effects of SAC in high-fructose diet fed suckling rat pups modelling human neonates fed a high-fructose diet. Four-day-old male (n=32) and female (n=32) Wistar rat pups, were randomly assigned to and administered the following treatment regimens daily for 15 days: group I, distilled water; group II, 20% fructose solution (FS); group III, SAC; group IV, SAC+FS. The pups' blood glucose, triglyceride, cholesterol, plasma leptin and insulin concentration, liver lipid content, and liver histology were determined at termination. In female rat pups, orally administered SAC prevented FS-induced hypoinsulinemia but significantly increased (P≤0.05) liver lipid content. Oral administration of SAC significantly increased (P≤0.05) plasma insulin concentration and homeostasis model assessment for insulin resistance in the male pups. The potential sexually dimorphic effects of SAC (insulinotropic effects in male pups and protection of female pups against fructose-induced hypoinsulinemia) suggest that SAC could be potentially exploited as an antidiabetic and insulinotropic agent. Caution should, however, be exercised in the use of SAC during suckling as it could result in excessive liver lipid accumulation and insulin resistance.

Growth and hormone profiling in children with congenital melanocytic naevi.

BACKGROUND: Multiple congenital melanocytic naevi (CMN) is a rare mosaic RASopathy, caused by postzygotic activating mutations in NRAS. Growth and hormonal disturbances are described in germline RASopathies, but growth and hormone status have not previously been investigated in individuals with CMN. OBJECTIVES: To explore premature thelarche, undescended testes, and a clinically abnormal fat distribution with CMN through prospective endocrinological assessment of a cohort of subjects with CMN, and a retrospective review of longitudinal growth of a larger group of patients with CMN from outpatient clinics (which included all subjects in the endocrinological assessment group). PATIENTS AND METHODS: Longitudinal growth in a cohort of 202 patients with single or multiple CMN was compared with the U.K. National Child Measurement Programme 2010. Forty-seven children had hormonal profiling including measurement of circulating luteinizing hormone, follicle-stimulating hormone, thyroid stimulating hormone, adrenocorticotrophic hormone, growth hormone, prolactin, pro-opiomelanocortin, estradiol, testosterone, cortisol, thyroxine, insulin-like growth factor-1 and leptin; 10 had oral glucose tolerance testing 25 had dual-energy X-ray absorptiometry scans for body composition. RESULTS: Body mass index increased markedly with age (coefficient 0·119, SE 0·016 standard deviation scores per year), at twice the rate of the U.K. population, due to increased adiposity. Three per cent of girls had premature thelarche variant and 6% of boys had persistent undescended testes. Both fat and muscle mass were reduced in areas underlying large naevi, resulting in limb asymmetry and abnormal truncal fat distribution. Anterior pituitary hormone profiling revealed subtle and variable abnormalities. Oral glucose tolerance tests revealed moderate-severe insulin insensitivity in five of 10, and impaired glucose tolerance in one. CONCLUSIONS: Interpersonal variation may reflect the mosaic nature of this disease and patients should be considered individually. Postnatal weight gain is potentially related to the underlying genetic defect; however, environmental reasons cannot be excluded. Naevus-related reduction of fat and muscle mass suggests local hormonal or metabolic effects on development or growth of adjacent tissues, or mosaic involvement of these tissues at the genetic level. Premature thelarche and undescended testes should be looked for, and investigated, as for any child.

Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia.

Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165a and VEGF-A165b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165a is upregulated and predominates over the VEGF-A165b isoform. We show here that in rats and mice VEGF-A165a and VEGF-A165b have opposing effects on pain, and that blocking the proximal splicing event - leading to the preferential expression of VEGF-A165b over VEGF165a - prevents pain in vivo. VEGF-A165a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165b blocks the effect of VEGF-A165a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxxa compared to VEGF-Axxxb, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxxa expression and reversed associated neuropathic pain. Exogenous VEGF-A165b also ameliorated neuropathic pain. We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxxa/VEGF-Axxxb balance by targeting alternative RNA splicing may be a new analgesic strategy.

Long-term (37 years) clinical outcome of older women with early operable primary breast cancer managed in a dedicated clinic.

BACKGROUND: A dedicated clinic for older women with early primary breast cancer, established in 1973, has recently evolved into a combined surgical/oncology facility. This study aimed to compare the clinical outcome across these periods. METHODS: From 1973 to 2010, 1758 women were managed. Analysis was carried out based on retrospective review and continued update of patient records. RESULTS: In the recent decade, 56.3% had surgery, followed by primary endocrine therapy (PET; 41.1%) and primary radiotherapy (1.5%). Before 1999, 42.8%, 55.6% and 1% of patients had surgery, PET and primary radiotherapy, respectively. The use of adjuvant endocrine therapy and radiotherapy has increased from 33.6% to 54.9% and 5.8% to 34.6%, respectively. A significant improvement was seen in the annual rates of local (2.2% versus 0.5%, P < 0.001), regional (1.8% versus 0.4%, P < 0.001) and distant (2.9% versus 1.9%, P = 0.002) recurrences. Similarly, the 5-year breast cancer-specific and overall survival rates showed improvement [81% versus 91% (P < 0.001) and 56% versus 71% (P < 0.001), respectively]. CONCLUSIONS: In the recent decade, while surgery became the predominant treatment, a significant proportion of patients had non-operative therapies, selection of which was based on multidisciplinary assessment in the clinic. This management approach appears to produce excellent clinical outcome, which is significantly better than that in earlier period.

Aspirin in the aetiology of Crohn's disease and ulcerative colitis: a European prospective cohort study.

BACKGROUND: Aspirin has detrimental effects on the gastrointestinal tract mucosa and may play a role in the aetiology of inflammatory bowel disease. AIM: To investigate if the regular use of aspirin is associated with the development of Crohn's disease (CD) and ulcerative colitis (UC) using, for the first time, a prospective cohort study design. METHODS: A total of 135,780 men and women in Europe, aged 30-74years, were recruited into the European Prospective Investigation into Cancer and Nutrition study. Participants completed questionnaires at baseline detailing their regular aspirin use and were then followed up to identify those who developed either incident CD or UC. Each case was matched with four controls and odds ratios (OR) were calculated, adjusting for cigarette smoking. Potential interactions between aspirin and smoking were assessed. RESULTS: A total of 35 participants developed CD and a further 84 were diagnosed with UC. Regular aspirin intake was positively associated with the risk of developing CD (OR=6.14, 95% CI=1.76-21.35). In those who took aspirin and smoked there was no detectable increased risk of CD (OR=0.30, 95% CI=0.03-3.08). No association was found between regular aspirin use and UC (OR=1.29, 95% CI=0.67-2.46). CONCLUSIONS: A strong positive association between regular aspirin use and CD, but not UC, was observed. The data suggest that regular aspirin use should be measured in epidemiological work on CD. If such findings are consistent in other work then aspirin may affect the development of CD in a middle-aged to elderly population.

Long-term clinical outcome of oestrogen receptor-positive operable primary breast cancer in older women: a large series from a single centre.

INTRODUCTION: A Cochrane review of seven randomised trials (N=1571) comparing surgery and primary endocrine therapy (PET) (oestrogen receptor (ER) unselected) shows no difference in overall survival (OS). We report outcome of a large series with ER-positive (ER+) early invasive primary breast cancer. METHODS: Between 1973 and 2009, 1065 older (≥ 70 years) women (median age 78 years (70-99)) had either surgery (N=449) or PET (N=616) as initial treatment. RESULTS: At 49-month median follow-up (longest 230 months), the 5-year breast cancer-specific survival (BCSS) and OS were 90 and 62%, respectively. Majority (74.2%) died from causes other than breast cancer. The rates (per annum) of local/regional recurrence (<1%) (following surgery), contralateral tumour (<1%) and metastases (<3%) were low. For patients on PET, 97.9% achieved clinical benefit (CB) at 6 months, with median time to progression of 49 months (longest 132 months) and significantly longer BCSS when compared with those who progressed (P<0.001). All patients with strongly ER+ (H-score >250) tumours achieved CB and had better BCSS (P<0.01). Patients with tumours having an H-score >250 were found to have equivalent BCSS regardless of treatment (surgery or PET; P=0.175), whereas for those with H-score ≤ 250, surgery produced better outcome (P<0.001). CONCLUSION: Older women with ER+ breast cancer appear to have excellent long-term outcome regardless of initial treatment. Majority also die from non-breast cancer causes. Although surgery remains the treatment of choice, patients with ER-rich (H-score >250) tumours tend to do equally well when treated by PET. This should be taken into account when therapies are considered.

Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study.

OBJECTIVE: Dietary linoleic acid, an n-6 polyunsaturated fatty acid, is metabolised to arachidonic acid, a component of colonocyte membranes. Metabolites of arachidonic acid have pro-inflammatory properties and are increased in the mucosa of patients with ulcerative colitis. The aim of this investigation was to conduct the first prospective cohort study investigating if a high dietary intake of linoleic acid increases the risk of developing incident ulcerative colitis. DESIGN AND SETTING: Dietary data from food frequency questionnaires were available for 203 193 men and women aged 30-74 years, resident in the UK, Sweden, Denmark, Germany or Italy and participating in a prospective cohort study, the European Prospective Investigation into Cancer and Nutrition (EPIC). These participants were followed up for the diagnosis of ulcerative colitis. Each case was matched with four controls and the risk of disease calculated by quartile of intake of linoleic acid adjusted for gender, age, smoking, total energy intake and centre. RESULTS: A total of 126 participants developed ulcerative colitis (47% women) after a median follow-up of 4.0 years (range, 1.7-11.3 years). The highest quartile of intake of linoleic acid was associated with an increased risk of ulcerative colitis (odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.23 to 5.07, p = 0.01) with a significant trend across quartiles (OR = 1.32 per quartile increase, 95% CI = 1.04 to 1.66, p = 0.02 for trend). CONCLUSIONS: The data support a role for dietary linoleic acid in the aetiology of ulcerative colitis. An estimated 30% of cases could be attributed to having dietary intakes higher than the lowest quartile of linoleic acid intake.

A pilot study showing pulsed-dye laser treatment improves localized areas of chronic atopic dermatitis.

BACKGROUND: Eczematous skin changes overlying port-wine stains have been reported to improve with pulsed-dye laser (PDL) treatment. However, PDL has not as yet been evaluated for the treatment of atopic dermatitis (AD; eczema). AIM: To evaluate in a controlled trial the effects and safety of PDL treatment in children with AD who had chronic localized lesions. METHODS: Twelve children with localized, chronic eczema were treated with PDL (595 nm), with untreated areas used as an intrapatient control. Treatment was given at baseline and patients were followed up at 2 and 6 weeks. Clinical outcome measures were localized Eczema Severity Score (ESS), a visual analogue scale (VAS) indicating eczema severity assessed by photographs, and adverse events. RESULTS: After 2 and 6 weeks, a significant decrease in ESS was seen for the PDL-treated areas compared with the control areas (mean +/- SEM reduction in ESS 7.0 +/- 1.0 vs. 3.3 +/- 0.8 at 2 weeks, P = 0.003, and 7.8 +/- 1.4 vs. 4.9 +/- 1.3 at 6 weeks, P = 0.002). A significant difference in eczema severity assessed by VAS at 6 weeks was seen in favour of PDL (mean +/- SEM improvement 78% +/- 20% vs. 52% +/- 10%, P = 0.003). Treatment was well-tolerated. CONCLUSIONS: In this pilot study, PDL treatment was effective in treating small areas of chronic localized eczema. This may suggest that in AD dermal vasculature plays an important role or that PDL may have an effect on cutaneous immunological activation.

Fluconazole and itraconazole susceptibilities of Candida spp. isolated from oropharyngeal specimens and blood cultures of paediatric haematology/oncology patients.

This study examined the in vitro susceptibilities to fluconazole and itraconazole of isolates of Candida spp. from surveillance oropharyngeal specimens and blood cultures from paediatric patients with malignancy. The species distribution of 100 isolates from oropharyngeal specimens was C. albicans 86%, C. glabrata 7%, C. lusitaniae 4%, C. parapsilosis 2% and C. tropicalis 1%. From a total of nine isolates from blood cultures the species distribution was C. albicans 33.3%, C. parapsilosis 33.3 % and C. guilliermondii 33.3%. Only three of the oropharyngeal isolates were resistant to fluconazole (MIC > or = 64 mg l(-1)) and only two were resistant to itraconazole (MIC > or = 1 mg l(-1)). None of the blood culture isolates was resistant to either agent. At this centre, C. albicans is the predominant species from oropharyngeal specimens, but non-albicans Candida species predominate in blood cultures. Although resistance to fluconazole and itraconazole is rare at present, continued surveillance is warranted to monitor trends in species distribution and antifungal susceptibility.

Do calcium channel blockers and antimuscarinics protect against perforated colonic diverticular disease? A case control study.

BACKGROUND: The aetiology of perforated colonic diverticular disease (PCDD) remains largely unknown. Perforation may result from a combination of high intracolonic pressures, secondary to excessive colonic segmentation, and impairment of the mucosal barrier. Calcium channel blockers and antimuscarinic drugs, which reduce colonic contractility and tone, could potentially protect against perforation. The aim of this study was to test this hypothesis using a case control design. METHODS: All cases of acute PCDD were identified over a five year period in two hospitals in Norfolk, UK. Each case was matched for age, sex, and date of admission to two controls groups: (1) patients undergoing cataract surgery and (2) patients with basal cell carcinoma. Data on drug use prior to hospital admission were obtained from medical and nursing records and compared between cases and controls. RESULTS: A total of 120 cases of PCDD were identified and matched to 240 controls in each group. A statistically significant protective association was seen between calcium channel blocker use and PCDD using both control groups. The odds ratios were 0.41 (95% confidence interval (CI) 0.18-0.93) using the ophthalmology control group and 0.36 (95% CI 0.16-0.82) using the dermatology control group. CONCLUSIONS: This study has shown for the first time that a protective association exists between calcium channel blockers and PCDD. The validity of this association is supported by the consistent finding in both control groups and the plausible biological mechanisms. Further studies are required to confirm this association but calcium channel blockers may represent a potential preventive therapy in PCDD.

Anti-inflammatory drugs, analgesics and the risk of perforated colonic diverticular disease.

BACKGROUND: Acute perforated colonic diverticular disease has a mortality rate of up to 30 per cent, but little is known about its aetiology. The aim of this study was to test the hypothesis that three classes of drugs, namely non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics and corticosteroids, are risk factors for perforated diverticular disease. METHODS: All patients with confirmed perforated colonic diverticular disease were identified over a 5-year period in two hospitals in Norfolk, UK. Two control groups were selected and matched for age, sex and hospital of admission. Data on medication use were obtained from hospital records. Odds ratios for each drug were calculated using conditional logistic regression. RESULTS: Opioid analgesics, NSAIDs and corticosteroids were all positively associated with perforated colonic diverticular disease. The odds ratio for opioid analgesics was 1.8 (95 per cent confidence interval (c.i.) 1.1 to 3.0) in the analysis with ophthalmology controls and 3.1 (95 per cent c.i. 1.8 to 5.5) in that with dermatology controls. Respective odds ratios for NSAIDs were 4.0 (95 per cent c.i. 2.1 to 7.6) and 3.7 (95 per cent c.i. 2.0 to 6.8), and those for corticosteroids were 5.7 (95 per cent c.i. 2.2 to 14.4) and 7.8 (95 per cent c.i. 2.6 to 23.3). CONCLUSION: Opioid analgesics, NSAIDs and corticosteroids are all positively associated with perforated colonic diverticular disease. The consistency of these associations, together with plausible biological mechanisms, suggests that these drugs may have a causative role in this condition.

Gingivitis and toothbrushes: potential roles in viridans streptococcal bacteraemia.

We report a case of Streptococcus oralis bacteraemia in a paediatric neutropenic patient with acute myeloid leukaemia whose predominant form of oral compromise was severe gingivitis, rather than mucositis. By phenotypic and genotypic analyses, the strain of S. oralis from blood culture was indistinguishable from an isolate from his mouth, suggesting that gingivitis may have provided a portal of entry for viridans streptococci into the bloodstream. To improve the patient's oral and dental hygiene and reduce gingivitis, conventional disposable foam toothettes were substituted with a new soft toothbrush for use as part of the oral care protocol. As there are no guidelines regarding the frequency of replacement of toothbrushes used by immunocompromised patients, the brush was swabbed regularly and culture performed to detect microbial colonization. Viridans streptococci were cultured from the toothbrush after 2 weeks of use. Phenotypic, followed by genotypic analyses, demonstrated that a strain of S. oralis from the toothbrush was indistinguishable from the strain previously isolated from blood culture and mouth. Soft toothbrushes may be useful tools for maintaining oral hygiene in immunocompromised individuals. However the results of this study indicate that regular replacement is warranted, as the toothbrush itself may become colonized with the organisms responsible for bacteraemia.

Epidemiology of perforated colonic diverticular disease.

Perforated colonic diverticular disease results in considerable mortality and morbidity. This review appraises existing evidence on the epidemiology and mechanisms of perforation, highlights areas of further study, and suggests an epidemiological approach towards preventing the condition. Computerised searches were used to identify published articles relating to the epidemiology, pathophysiology, and clinical features of perforated colonic diverticular disease. Several drug and dietary exposures have potential biological mechanisms for causing perforation. Of these only non-steroidal anti-inflammatory drugs have been consistently identified as risk factors in aetiological studies. The causes of perforated colonic diverticular disease remain largely unknown. Further aetiological studies, looking specifically at perforation, are required to investigate whether cause-effect relationships exist for both drug and dietary exposures. The identification of risk factors for perforation would allow primary public health prevention, secondary risk factor modification, and early prophylactic surgery to be aimed at people at high risk.

FM1-43 dye behaves as a permeant blocker of the hair-cell mechanotransducer channel.

Hair cells in mouse cochlear cultures are selectively labeled by brief exposure to FM1-43, a styryl dye used to study endocytosis and exocytosis. Real-time confocal microscopy indicates that dye entry is rapid and via the apical surface. Cooling to 4 degrees C and high extracellular calcium both reduce dye loading. Pretreatment with EGTA, a condition that breaks tip links and prevents mechanotransducer channel gating, abolishes subsequent dye loading in the presence of calcium. Dye loading recovers after calcium chelation with a time course similar to that described for tip-link regeneration. Myo7a mutant hair cells, which can transduce but have all mechanotransducer channels normally closed at rest, do not label with FM1-43 unless the bundles are stimulated by large excitatory stimuli. Extracellular perfusion of FM1-43 reversibly blocks mechanotransduction with half-blocking concentrations in the low micromolar range. The block is reduced by high extracellular calcium and is voltage dependent, decreasing at extreme positive and negative potentials, indicating that FM1-43 behaves as a permeant blocker of the mechanotransducer channel. The time course for the relief of block after voltage steps to extreme potentials further suggests that FM1-43 competes with other cations for binding sites within the pore of the channel. FM1-43 does not block the transducer channel from the intracellular side at concentrations that would cause complete block when applied extracellularly. Calcium chelation and FM1-43 both reduce the ototoxic effects of the aminoglycoside antibiotic neomycin sulfate, suggesting that FM1-43 and aminoglycosides enter hair cells via the same pathway.