Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD.

Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4-/-) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease.

Outcomes of adolescents with acute lymphoblastic leukaemia.

INTRODUCTION: Compared with young children who have acute lymphoblastic leukaemia (ALL), adolescents with ALL have unfavourable disease profiles and worse survival. However, limited data are available regarding the characteristics and outcomes of adolescents with ALL who underwent treatment in clinical trials. The aim of this study was to investigate the causes of treatment failure in adolescents with ALL. METHODS: We retrospectively analysed the outcomes of 711 children with ALL, aged 1-18 years, who were enrolled in five clinical trials of paediatric ALL treatment between 1993 and 2015. RESULTS: Among the 711 children with ALL, 530 were young children (1-9 years at diagnosis) and 181 were adolescents (including 136 younger adolescents [10-14 years] and 45 older adolescents [15-18 years]). Compared with young children who had ALL, adolescents with ALL were less likely to have favourable genetic features and more likely to demonstrate poor early response to treatment. The 10-year overall survival and event-free survival rates were significantly lower among adolescents than among young children (77.9% vs 87.6%, P=0.0003; 69.7% vs 76.5%, P=0.0117). There were no significant differences in the 10-year cumulative incidence of relapse, but the 10-year cumulative incidence of treatment-related death (TRD) was significantly greater among adolescents (7.2%) than among young children (2.3%; P=0.002). Multivariable analysis showed that both younger and older adolescents (vs young children) had worse survival and greater incidence of TRD. CONCLUSION: Adolescents with ALL had worse survival because they experienced a greater incidence of TRD. There is a need to investigate optimal treatment adjustments and novel targeted agents to achieve better survival rates (without excessive toxicity) among adolescents with ALL.

Self-reported waist circumference: a screening tool for classifying children with overweight/obesity and cardiometabolic risk factor clustering.

OBJECTIVES: The objectives of this study were twofold - (i) to assess the agreement between self-reported waist circumference (SRWC) and assessor measured waist circumference (MWC) and (ii) to evaluate the diagnostic ability of SRWC for classifying (i) a clustering of cardiometabolic risk factors (CMRFs) and (ii) overweight/obese status in Hong Kong Chinese children aged 6-18 years. METHODS: A cross-sectional study with cluster random sampling was conducted. A self-administrated questionnaire, which included demographic data, body weight, body height and waist circumference, was given to children to bring home for completion. Children were asked to return the questionnaire and fast themselves for at least 8 h on the day of the survey. Anthropometric measurements and blood pressure were taken by trained research staff and fasting blood samples were collected for measurements of fasting plasma glucose, total cholesterol, triglyceride, high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. RESULTS: A total of 515 boys and 711 girls were included in the data analysis. Agreement between SRWC and MWC was assessed by intra-class correlation coefficient and it ranged from 0.77 to 0.87. The ability of sex-specific SRWC values to classify children with a clustering of CMRFs and overweight/obesity exhibited moderately high to high sensitivity and specificity, and the area under the receiver operating characteristics ranged from acceptable to excellent (from 0.76 to 0.84). CONCLUSIONS: SRWC has good agreement with MWC and could be used as a screening tool to classify children with a clustering of CMRFs and overweight/obesity status in Hong Kong Chinese children.

A retrospective analysis of the management of freckles and lentigines using four different pigment lasers on Asian skin.

BACKGROUND: The risk of post-inflammatory hyperpigmentation (PIH) is increased during freckles and lentigines treatment in Asians. OBJECTIVE: To determine the effectiveness and safety of using 595-nm long pulsed dye laser (LPDL), 755-nm LP Alexandrite laser, 532-nm QS Nd:YAG laser and 532-nm LP potassium-titanyl-phosphate (KTP) laser for the treatment of freckles or lentigines in Asian patients. METHODS: This is a retrospective study of 40 Chinese patients, who were divided into four groups based on treatment modality using four different pigment lasers. Each patient attended between 1 and 4 treatments (mean of 1.8), at 4-6 weeks intervals, depending on clinical response. Lesional clearance and PIH were assessed by two independent clinicians. RESULTS: Statistically significant improvement of global and focal facial pigmentation was found after treatment with LPDL, QS Nd:YAG and LP KTP lasers. No significant improvement was found after LP Alexandrite laser. PIH risk was 20% after LP Alexandrite treatment, 10% with QS Nd:YAG, and absent after LPDL and LP KTP treatment. CONCLUSION: A long pulse laser and small spot size appear to reduce the risks of lentigines treatment in darker skin types.

A comparison of Q-switched and long-pulsed alexandrite laser for the treatment of freckles and lentigines in oriental patients.

BACKGROUND: Q-switched (QS) lasers are effective in the treatment of freckles and lentigines in Type I and II skin, with minimal adverse effects. Long pulsed (LP) lasers have been proposed to be more suitable for treatment of darker skin types. OBJECTIVES: To investigate the efficacy and adverse effects of using QS or LP Alexandrite laser for the treatment of freckles and lentigines in Oriental patients. METHODS: A prospective split-face study of 20 Chinese patients who were randomly assigned to undergo a single QS (50 nanosecond) or LP (100 microseconds) laser treatment to either side of their face was carried out. Two blinded physicians assessed clinical efficacy using visual analogue scales of pre- and post-treatment photographs. Subjective assessment was evaluated using questionnaires which detailed the degree of pain, erythema and edema sustained during treatment, and improvement and satisfaction levels at 4, 8, and 12 weeks. RESULTS: There was statistically significant improvement in pigmentation (P < 0.05) in both groups throughout the study, with no statistical difference found between the groups. Postinflammatory hyperpigmentation was more frequently found after QS treatment (22%), compared to LP treatment (6%). Majority of patients reported moderate to marked improvement in pigmentation throughout the study with both pulse widths, and correspondingly high levels of satisfaction rates. More severe pain, erythema and edema were experienced during QS Alexandrite treatment. CONCLUSION: LP Alexandrite is quick and effective, and carries a lower risk of adverse effects than QS Alexandrite, for the removal of freckles and lentigines in darker skin types.

A retrospective analysis of the management of acne post-inflammatory hyperpigmentation using topical treatment, laser treatment, or combination topical and laser treatments in oriental patients.

BACKGROUND: Post-inflammatory hyperpigmentation (PIH) is characterized by an acquired increase in pigmentation secondary to an inflammatory process, and is a commonly observed response to cutaneous injury in Fitzpatrick types III-VI patients. OBJECTIVES: To determine the effectiveness and safety of using topical treatment, laser treatment, or combination topical and laser treatments to treat acne PIH in Oriental patients. METHODS: This is a retrospective study of 34 randomly selected Chinese patients with acne PIH. They were divided into three groups, and treated with topical agents, 595 nm long pulsed dye laser and/or 1064 nm Q-switched Nd:YAG, or combination topical and laser treatments. An independent clinician assessed pre- and post-treatment photographs to determine efficacy and timing to visible and optimum improvement. RESULTS: There was significant global and focal improvement of acne PIH in patients in all three groups. However, no significant difference was found between the groups. An investigator global assessment showed improvement with all treatment modalities, with 70.6% moderate to marked improvement seen in the combination treatment group, compared to 55.6% in the laser only group, and 50% in the topical treatment only group. Visible and optimum improvement was seen by 3 months in majority of patients treated. One patient developed PIH as a result of laser treatment. CONCLUSION: Topical treatment, laser therapy, and combination topical and laser treatments all appear to be effective management strategies for acne PIH in Fitzpatrick types III and IV skin with little complications. Topical agents may be considered as first-line therapy for acne PIH, taking into consideration its effectiveness, ease of use and cost. Combined topical and laser therapy is also effective, and may be considered as second-line treatment.

Genetic predisposition of white matter infarction with protein S deficiency and R355C mutation.

BACKGROUND: The association between protein S deficiency (PSD) and ischemic stroke is controversial and warrants further investigation. METHODS: We conducted a genotype and MRI correlation study in a Chinese family in which hereditary PSD cosegregated with premature ischemic strokes. Six out of 11 family members inherited PSD type III in an autosomal dominant manner. RESULTS: Among all PSD members, a novel missense mutation 1063C→T in exon 10 of protein S alpha (PROS1) was identified, which encoded a substitution of arginine to cysteine at position 355 (R355C) in the first globular domain of laminin A of protein S. Wild-type PROS1 sequences were retained in non-PSD members. MRI detected deep white matter infarctions predominantly distributed in the borderzone regions. The infarct topography was homogeneous in all adult mutant carriers. By contrast, cerebral infarction was absent in nonmutant carriers. Extensive investigation in the family did not reveal any confounding stroke risk. Haplotype analysis with high-density single nucleotide polymorphism markers revealed a 6.1-Mb minimally rearranged region (rs12494685 to rs1598240) in 3q11.2, lod = 3.0. Among the 7 annotated genes in this region, PROS1 is known to be associated with thrombotic disorders. MRI screening in an additional 10 PSD families without R355C showed no cerebral infarction. CONCLUSIONS: PROS1 R355C mutation cosegregated with PSD type III and premature white matter infarctions in the index family. The findings substantiate an association between PSD and stroke. Study of the mechanism underlying this association may improve our understanding of premature cryptogenic white matter infarction.

JAK2 V617F mutation is associated with 5q- syndrome in Chinese.

JAK2 V617F mutation is mostly seen in BCR-ABLI negative myeloproliferative neoplasms. Among other myeloid neoplasms, it occurs with remarkably high frequency in refractory anemia with ring sideroblasts associated with marked thrombocytosis, a group of myeloid neoplasms with both dysplastic and proliferative features. It has also been reported in occasional cases of myelodysplastic syndrome with isolated del(5q), often with a diagnosis of refractory cytopenia with multilineage dysplasia. We performed a retrospective analysis of JAK2 V617F mutation in Chinese patients with myeloid neoplasms and isolated del(5q), and were able to demonstrate the frequent occurrence of JAK2 V617F mutation in 5q- syndrome.

Provision of phenotype-matched blood units: no need for pre-transfusion antibody screening.

BACKGROUND AND OBJECTIVES: The Hong Kong government is planning to introduce an electronic smart identity card for all seven million citizens in 2003. If the smart card contains the full red cell phenotype/genotype of the individual, it may be possible to transfuse phenotype-matched blood units without pre-transfusion antibody screening. We conducted a feasibility study. DESIGN AND METHODS: Red cell phenotype was determined for 407 donor blood units and 493 patients for whom an antibody screen had been ordered. The computer program selected phenotype-matched blood from the donor stock for the patients according to actual transfusion request. For patients with a positive antibody screen, full crossmatching was carried out with the computer-selected phenotype units. The frequencies of the various red cell phenotypes in the population were calculated from Red Cross data of antigen frequencies. The probabilities of finding at least one unit of phenotype-matched blood from a 300-unit hospital stock and a 4,000-unit Red Cross stock were determined for each phenotype. Cost analysis was performed. RESULTS: Ninety-two out of 493 patients received a total of 395 blood units. The required number of phenotype-matched blood units could be found for 92 patients using a 300-unit pool and for all patients using a 4,000-unit pool. We calculated that phenotype-matched blood could be provided for more than 98% of patients without antibody screening. The total cost of the project is US$ 98 million with potential savings of US$ 14 million per year. INTERPRETATION AND CONCLUSIONS: It is feasible and cost-effective to transfuse patients with phenotype-matched blood without antibody screening using a smart card system.