Structural and functional differences in skin of colour.

The term 'skin of colour' (SOC), refers to individuals of African, Latinx, Asian, Native Hawaiian, Pacific Islander and Indigenous descent. These individuals typically have darker skin tones compared with white individuals and they often present with unique disorders of the skin or with common disorders that have a unique appearance. Certain skin conditions commonly associated with SOC patients, in contrast to individuals with lighter skin tones, are explained by structural and functional differences between this population and the white population. Variations in functional differences between these two groups are dependent on structural differences in melanosomes, stratum corneum, epidermis and dermis. Understanding the structural distinctions between white populations and SOC populations will provide insight into common disorders in SOC patients, including hyperpigmentation, hypopigmentation, dry skin, scaliness, xerosis, sensitive skin and keloids. Furthermore, understanding structural and functional skin difference will encourage more research regarding aetiology of disease and therapeutic interventions.

Test-retest reliability of the two-point discrimination test on the sole of the foot in people with multiple sclerosis.

BACKGROUND: Two-point discrimination (TPD) is an assessment of tactile acuity. People with multiple sclerosis (MS) can have reduced foot sole tactile acuity, which has been linked to impaired balance. OBJECTIVE: To quantify the test-retest reliability of TPD on the sole of the foot in people with MS. APPROACH: 41 participants (32 females), with mean (SD) age of 60 (9) years, and Expanded Disability Status Scale of <7.5, had their TPD measured at the head of the first metatarsal and the heel on two occasions, 2-14 d apart. Mean systematic change, within-subjects SD, limits of agreement (LOA), coefficient of variation and the intraclass correlation coefficient (ICC) were quantified as point estimates (95% CI). MAIN RESULTS: Systematic learning effects were evident. The within-subjects SD at the metatarsal and the heel was 6.7 mm (5.5-8.6) and 8.3 mm (6.7-10.8), and the LOAs were 18.6 mm (15.2-24.) and 23.7 mm (18.7-30.1), respectively. ICCs for metatarsal and heel was 0.87 (0.76-0.93) and 0.90 (0.80-0.95), respectively, but these were likely inflated by sample heterogeneity. SIGNIFICANCE: In people with MS, TPD on the sole of the foot has an adequate test-retest reliability for research purposes, but there is substantial measurement variability for individual patients.

Survival outcome and cost-effectiveness with docetaxel and paclitaxel in patients with metastatic breast cancer: a population-based evaluation.

BACKGROUND: A randomized controlled trial showed longer overall survival (OS) with docetaxel compared with paclitaxel in metastatic breast cancer patients with prior exposure to anthracycline. We report a similar comparison using population-based data. METHODS: Data on patients treated with single-agent paclitaxel or docetaxel were retrospectively reviewed. OS was compared using a two-tailed log-rank test and expressed as Kaplan-Meier plots. A cost-effectiveness analysis was carried out using cost/patient and OS. RESULTS: Four hundred and thirty-five patients met eligibility criteria. Prognostic factors were balanced between docetaxel and paclitaxel groups. Median OS was significantly longer for docetaxel versus paclitaxel [10.9 versus 8.3 months; hazard ratio 0.76; 95% confidence interval (CI), 0.62-0.92; P = 0.006]. The median number of cycles administered were four (docetaxel) and three (paclitaxel). The incremental cost-effectiveness ratio was $2434/per month of median survival gained. In the sensitivity analysis, the results were robust except that paclitaxel dominated when the low end of the 95% CI of survival for docetaxel was compared with the high end for paclitaxel. CONCLUSION: This population-based study corroborated the randomized trial's conclusion that for patients with metastatic breast cancer, docetaxel provided superior survival compared with paclitaxel. Each additional month of survival had an incremental cost of $2434.

Serotypes and analysis of distribution of Shiga toxin producing Escherichia coli from cattle and sheep in the lower North Island, New Zealand.

AIMS: To serotype a subset of Shiga toxin-producing Escherichia coli (STEC) isolates from cattle and sheep to determine whether any corresponding serotypes have been implicated in human diarrhoeal disease, both in New Zealand and worldwide, and to examine the distribution of STEC and enteropathogenic Escherichia coli (EPEC) amongst cattle (calves, heifers and dairy) and sheep (lambs, rams and ewes), to assess whether carriage of identified bacterial genotypes may be associated with a particular age of animal. METHODS: Recto-anal mucosal swabs (RAMS) were taken from 91 calves, 24 heifers and 72 dairy cattle, and 46 lambs, 50 ewes and 36 rams, from four sites in the Manawatu and Rangitikei regions of New Zealand. Strains of E. coli selected from primary isolation plates were subjected to a multiplex polymerase chain reaction (PCR), to determine the presence of Shiga toxin genes (stx1 and stx2) and the E. coli attaching and effacing gene (eae). RESULTS: Overall, 186/319 (58.3%) animals sampled were positive for stx1, stx2, or eae isolates. More sheep (43.9%) were stx1-positive than cattle (2.7%; p = 0.036), and amongst sheep more lambs and ewes were stx1-positive than rams (p = 0.036). Amongst cattle, more calves and heifers were eae-positive than dairy cows (p = 0.030). Two or more different STEC were isolated from at least 28 (9%) animals (three cattle and 25 sheep), based on their stx/eae genotype. Enterohaemolysin genes were found in 39/51 (76%) isolates serotyped. Twenty-one different serotypes were detected, including O5:H-, O9:H51, O26:H11, O84:H-/H2 and O149:H8 from cattle, and O26:H11, O65:H-, O75:H8, O84:H-, O91:H-, O128:H2 and O174:H8 from sheep; O84:H-, O26:H11, O5:H-, O91:H- and O128:H2 serotypes have been associated with human disease. CONCLUSIONS: If nationally representative, this study confirms that cattle and sheep in New Zealand may be a major reservoir of STEC serotypes that have been recognised as causative agents of diarrhoeal disease in humans. Distribution of STEC and EPEC in cattle and sheep indicates that direct contact with, in particular, calves or their faeces, or exposure to environments cross contaminated with ruminant faeces, may represent an increased risk factor for human disease in New Zealand.

The prevalence of Shiga toxin-producing Escherichia coli in cattle and sheep in the lower North Island, New Zealand.

AIM: To genotype Escherichia coli cultured from the faeces of healthy cattle and sheep in the lower North Island, in order to investigate the possible role of ruminants as a reservoir for Shiga toxin-producing E. coli (STEC) in New Zealand. METHODS: A total of 952 strains of E. coli were isolated on selective media, from faecal swabs from 319 animals (187 cattle and 132 sheep) from four sites in the Manawatu and Rangitikei regions of New Zealand. A multiplex polymerase chain reaction (PCR) was used to genotype the E. coli isolates, using amplification of Shiga toxin genes (stx1 and stx2) and the E. coli attaching and effacing gene (eae). RESULTS: Isolates of E. coli were cultured from swabs from 178/187 (95.2%) cattle and all 132 (100%) sheep. Ninety-nine (10.4%) of the isolates were stx1 only, 83 (8.7%) stx2 only, 33 (3.5%) stx1 and stx2, 23 (2.4%) stx1 and eae, one (0.1%) stx2 and eae, and 115 (12.1%) were eae only. Overall, 51 (27.3%) cattle and 87 (65.9%) sheep were stx-positive, whereas 69 (36.9%) cattle and 36 (27.3%) sheep were eae-positive. CONCLUSIONS: Both healthy cattle and sheep are asymptomatic reservoirs of STEC in New Zealand. Direct contact with cattle and sheep or consumption of water or foodstuffs contaminated with cattle of sheep faeces may represent a significant source of infection for humans.

Preparing for the MFAEM examination.

The MFAEM may take over as the primary membership examination for progression to higher professional training in Emergency Medicine. As a relatively young examination it still suffers from a lack of associated study material and a formal syllabus. The emergence of a specific membership examination such as MFAEM represents the growth in stature of A&E as a speciality in its own right. As the examination becomes more popular and growing numbers of doctors apply there will be a similar expansion of study material and available resources. MRCSEd(A&E) remains a solid alternative and eligibility for this examination is similar to MFAEM part B. However, success at a relevant part one is required before sitting this. The MFAEM part A is more balanced and relevant primary examination for A&E trainees but if one is interested in dual accreditation or has a specific interest in another speciality then sitting the MRCP, MRCS or FRCA may be more appropriate before approaching the MFAEM part B or MRCSEd(A&E).

Infection with an avirulent phoP mutant of Neisseria meningitidis confers broad cross-reactive immunity.

Successful vaccines against serogroup A and C meningococcal strains have been developed, but current serogroup B vaccines provide protection against only a limited range of strains. The ideal meningococcal vaccine would provide cross-reactive immunity against the variety of strains that may be encountered in any community, but it is unclear whether the meningococcus possesses immune targets that have the necessary level of cross-reactivity. We have generated a phoP mutant of the meningococcus by allele exchange. PhoP is a component of a two-component regulatory system which in other bacteria is an important regulator of virulence gene expression. Inactivation of the PhoP-PhoQ system in Salmonella leads to avirulence, and phoP mutants have been shown to confer protection against virulent challenge. These mutants have been examined as potential live attenuated vaccines. We here show that a phoP mutant of the meningococcus is avirulent in a mouse model of infection. Moreover, infection of mice with the phoP mutant stimulated a bactericidal immune response that not only killed the infecting strain but also showed cross-reactive bactericidal activity against a range of strains with different serogroup, serotype, and serosubtyping antigens. Sera from the mutant-infected mice contained immunoglobulin G that bound to the surface of a range of meningococcal strains and mediated opsonophagocytosis of meningococci by human phagocytic cells. The meningococcal phoP mutant is thus a candidate live, attenuated vaccine strain and may also be used to identify cross-reactive protective antigens in the meningococcus.

Hypoparathyroidism and 22q11 deletion syndrome.

AIMS: To investigate a population of individuals with 22q11 deletion syndrome for hypocalcaemia. METHODS: A detailed clinical history enquiring into symptoms of hypocalcaemia and blood sampling to assess for hypocalcaemia and hypoparathyroidism, of patients outside the neonatal period known to have the 22q11 microdeletion from fluorescent in situ hybridisation studies was taken. RESULTS: Sixty one individuals were identified, of whom 23 were untraceable and one was unable to give informed consent. Biochemical investigations were performed on 27 subjects. Ten subjects had review of notes only. Four subjects had previously identified hypoparathyroidism. A new case of hypoparathyroidism was identified. Three subjects had borderline hypocalcaemia. DISCUSSION: In this population of patients with 22q11 deletion syndrome, 13% of the total or 30% of those biochemically assessed had evidence of reduced serum calcium concentrations. It is likely that 13-30% of patients with 22q11 deletion syndrome have possible hypoparathyroidism outside the neonatal period. Reported symptoms of hypocalcaemia did not correlate with biochemical evidence of persisting hypocalcaemia. We have shown that previously undiagnosed asymptomatic hypoparathyroidism occurs in patients with 22q11 deletion syndrome and conclude that screening of this population should be considered.

Prion protein fragment 106-126 potentiates catecholamine secretion from PC-12 cells.

The toxic actions of scrapie prion protein (PrP(sc)) are poorly understood. We investigated the ability of the toxic PrP(sc) fragment 106-126 to interfere with evoked catecholamine secretion from PC-12 cells. Prion protein fragment 106-126 (PrP106-126) caused a time- and concentration-dependent augmentation of exocytosis due to the emergence of a Ca(2+) influx pathway resistant to Cd(2+) but sensitive to other inorganic cations. In control cells, secretion was dependent on Ca(2+) influx through L- and N-type Ca(2+) channels, but after exposure to PrP106-126, secretion was unaffected by N-type channel blockade. Instead, selective L-type channel blockade was as effective as Cd(2+) in suppressing secretion. Patch-clamp recordings revealed no change in total Ca(2+) current density in PrP106-126-treated cells or in the contribution to total current of L-type channels, but a small Cd(2+)-resistant current was found only in PrP106-126-treated cells. Thus PrP106-126 augments secretion by inducing a Cd(2+)-resistant Ca(2+) influx pathway and alters coupling of native Ca(2+) channels to exocytosis. These effects are likely contributory factors in the toxic cellular actions of PrP(sc).

Malignant melanoma in African Americans.

Although rare, malignant melanoma (MM) is a real and serious risk for African Americans. African Americans have a proportionately higher incidence of acral melanoma, both the acral lentiginous melanoma (ALM) histologic subtype and subungual melanoma (SM). MM is more likely to be diagnosed at a later stage in African Americans and carries a worse prognosis. Given these facts, the relatively simple and inexpensive primary and secondary preventions for MM should be standard, particularly in the African American patient.

Differential coupling of voltage-gated Ca(2+) channels to catecholamine secretion from separate PC12 cell batches.

Amperometric recordings were employed to investigate the coupling of Ca(2+) channels to catecholamine secretion in two batches of pheochromocytoma (PC12) cells. In 'new' (freshly obtained) cells (PC12n cells), secretion was dependent on Ca(2+) influx through L-type and N-type Ca(2+) channels. By contrast, in 'aged' cells (maintained in liquid nitrogen for 6-8 years; PC12a cells), secretion was mostly dependent on Ca(2+) influx through N-type channels. Patch clamp recordings revealed that L-type channels accounted for only ca. 26% of total whole-cell current in PC12a cells (determined by blockade caused by 2 microM nifedipine). In contrast, nifedipine suppressed currents by ca. 59% in PC12n cells. Thus important differences in fundamental physiological properties can be observed in PC12 cell batches even when obtained from the same source and maintained under identical conditions.

Three distinct Ca(2+) influx pathways couple acetylcholine receptor activation to catecholamine secretion from PC12 cells.

Amperometry and microfluorimetry were employed to investigate the Ca(2+)-dependence of catecholamine release induced from PC12 cells by cholinergic agonists. Nicotine-evoked exocytosis was entirely dependent on extracellular Ca(2+) but was only partly blocked by Cd(2+), a nonselective blocker of voltage-gated Ca(2+) channels. Secretion and rises of [Ca(2+)](i) observed in response to nicotine could be almost completely blocked by methyllycaconitine and alpha-bungarotoxin, indicating that such release was mediated by receptors composed of alpha7 nicotinic acetylcholine receptor subunits. Secretion and [Ca(2+)](i) rises could also be fully blocked by co-application of Cd(2+) and Zn(2+). Release evoked by muscarine was also fully dependent on extracellular Ca(2+). Muscarinic receptor activation stimulated release of Ca(2+) from a caffeine-sensitive intracellular store, and release from this store induced capacitative Ca(2+) entry that could be blocked by La(3+) and Zn(2+). This Ca(2+) entry pathway mediated all secretion evoked by muscarine. Thus, activation of acetylcholine receptors stimulated rises of [Ca(2+)](i) and exocytosis via Ca(2+) influx through voltage-gated Ca(2+) channels, alpha7 subunit-containing nicotinic acetylcholine receptors, and channels underlying capacitative Ca(2+) entry.

Mitochondrial inhibitors evoke catecholamine release from pheochromocytoma cells.

Quantal catecholamine secretion evoked from individual pheochromocytoma (PC12) cells by exposure to mitochondrial inhibitors and uncouplers was monitored in real time using amperometry. Cyanide (0.05-5 mM) caused a concentration-dependent increase in the frequency of amperometric events. This secretory response was abolished by removal of extracellular Ca(2+) and by the application of Cd(2+) (200 microM), a nonselective blocker of voltage-gated Ca(2+) channels. Secretion was also inhibited by ca. 75% following pretreatment of cells with omega-conotoxin GVIA to inhibit N-type Ca(2+) channels selectively. Secretion was also detected when cells were exposed to rotenone (10 microM), dinitrophenol (250 microM) and p-trifluoromethoxyphenyl hydrazone (1 microM) and, as for cyanide, these secretory responses were abolished by removal of extracellular Ca(2+) or application of 200 microM Cd(2+). These results indicate that, like hypoxia, mitochondrial inhibitors and uncouplers evoke catecholamine secretion from PC12 cells which is wholly dependent on Ca(2+) influx through voltage-gated Ca(2+) channels.

Protein kinase C evokes quantal catecholamine release from PC12 cells via activation of L-type Ca2+ channels.

Application of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) to PC12 cells under resting conditions evoked quantal catecholamine secretion, as detected amperometrically. This effect was not mimicked by 4alpha-phorbol-12,13-didecanoate, another phorbol ester, which is inactive with respect to protein kinase C activation, and was prevented by the protein kinase C inhibitor bisindolylmaleimide. TPA also caused a rise of [Ca(2+)](i) in Fura-2-loaded PC12 cells, and again this was not mimicked by 4alpha-phorbol-12,13-didecanoate and could be blocked by bisindolylmaleimide. TPA-evoked secretion was entirely dependent on extracellular Ca(2+) and was fully abolished by nifedipine, as were TPA-induced rises of [Ca(2+)](i). Resting membrane potential, monitored using perforated patch recordings, was unaffected by TPA. However, a small (6-8 mV) hyperpolarizing shift in the voltage dependence of Ca(2+) channel currents (determined using whole-cell patch clamp recordings) was induced by TPA, and this could be fully prevented by nifedipine. In contrast to results with depolarizing stimuli, which evoke exocytosis because of Ca(2+) influx through N-type channels in these cells, the present results indicate that protein kinase C activation leads directly to quantal catecholamine secretion in the absence of depolarizing stimuli via a selective shift in the activation of L-type Ca(2+) channels.

Hypoxic enhancement of quantal catecholamine secretion. Evidence for the involvement of amyloid beta-peptides.

Prolonged exposure to hypoxia (10% O(2)) enhanced quantal catecholamine release evoked from O(2)-sensing pheochromocytoma (PC12) cells, as monitored using single-cell amperometric recordings. The enhancement of exocytosis was apparent after 12 h of hypoxia and was maximal at 24 h. Elevated levels of secretion were due to the emergence of a Ca(2+) influx pathway that persisted during complete blockade of known voltage-gated Ca(2+) channels. Secretion triggered by this Ca(2+) influx was severely reduced by known inhibitors of Alzheimer's amyloid beta-peptides (AbetaPs), including an N terminus-directed monoclonal antibody. The enhancing effect on secretion of chronic hypoxia was mimicked closely by direct application of AbetaP to cells under normoxic conditions, although the effects of AbetaP were more rapid at onset, being maximal after only 6 h. The present results suggest that prolonged hypoxia can induce formation of Ca(2+)-permeable AbetaP channels and that such induction can lead directly to excessive neurosecretion. This is a potential contributory factor to AbetaP pathophysiology following cerebral ischemia.