Immune response in melanoma: an in-depth analysis of the primary tumor and corresponding sentinel lymph node

The sentinel lymph node is the initial site of metastasis. Downregulation of antitumor immunity has a role in nodal progression. Our objective was to investigate the relationship between immune modulation and sentinel lymph node positivity, correlating it with outcome in melanoma patients. Lymph node/primary tissues from melanoma patients prospectively accrued and followed at New York University Medical Center were evaluated for the presence of regulatory T cells (Foxp3(+)) and dendritic cells (conventional: CD11c(+), mature: CD86(+)) using immunohistochemistry. Primary melanoma immune cell profiles from sentinel lymph node-positive/-negative patients were compared. Logistic regression models inclusive of standard-of-care/immunological primary tumor characteristics were constructed to predict the risk of sentinel lymph node positivity. Immunological responses in the positive sentinel lymph node were also compared with those in the negative non-sentinel node from the same nodal basin and matched negative sentinel lymph node. Decreased immune response was defined as increased regulatory T cells or decreased dendritic cells. Associations between the expression of these immune modulators, clinicopathological variables, and clinical outcome were evaluated using univariate/multivariate analyses. Primary tumor conventional dendritic cells and regression were protective against sentinel lymph node metastasis (odds ratio=0.714, 0.067; P=0.0099, 0.0816, respectively). Antitumor immunity was downregulated in the positive sentinel lymph node with an increase in regulatory T cells compared with the negative non-sentinel node from the same nodal basin (P=0.0005) and matched negative sentinel lymph node (P=0.0002). The positive sentinel lymph node also had decreased numbers of conventional dendritic cells compared with the negative sentinel lymph node (P<0.0001). Adding sentinel lymph node regulatory T cell expression improved the discriminative power of a recurrence risk assessment model using clinical stage. Primary tumor regression was associated with prolonged disease-free (P=0.025) and melanoma-specific (P=0.014) survival. Our results support an assessment of local immune profiles in both the primary tumor and sentinel lymph node to help guide therapeutic decisions.     

Biallelic Pathogenic GFRA1 Variants Cause Autosomal Recessive Bilateral Renal Agenesis

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Zinc absorption and kinetics during pregnancy and lactation in Brazilian women

BACKGROUND: Adjustments in zinc absorption and endogenous excretion maintain zinc homeostasis in nonpregnant adults fed low-zinc diets. The effects on zinc homeostasis of a low zinc intake during pregnancy and lactation have not been described in a longitudinal study. OBJECTIVE: We examined longitudinal changes in fractional zinc absorption (FZA) and zinc kinetics in 10 healthy Brazilian women who habitually consumed a marginal zinc diet ( approximately 9 mg Zn/d). DESIGN: Zinc status was measured at 10-12 (early pregnancy; EP) and 34-36 (late pregnancy; LP) wk of pregnancy and at 7-8 wk after delivery (early lactation; EL). Zinc kinetics and FZA were studied by using stable isotopic tracers. RESULTS: Zinc intake averaged 9 +/- 3 mg/d throughout the study. FZA increased from 29 +/- 6% at EP to 43 +/- 10% at LP and to 39 +/- 13% at EL (P < 0.05). FZA was inversely related to plasma zinc at EL (r = -0.73, P = 0.02) and LP (r = -0.72, P = 0.07). Plasma zinc mass was 23% greater at LP than at EP or EL (P < 0.05). The amount of zinc (mg/d) that fluxed between plasma and the most-rapidly-turning-over extravascular pool was 53% greater at LP than at EP or EL (P < 0.05). The zinc flux between plasma and the less-rapidly-turning-over zinc pool at EL was 27% greater than that at EP or LP, but this difference was not significant. CONCLUSIONS: FZA increased significantly in women with marginal zinc intakes during pregnancy and lactation; the increase was higher in women with low plasma zinc. Plasma zinc was distributed into a different exchangeable pool at LP than at EL.     

Dysmorphology diagnosis

A patient with multiple malformations poses a diagnostic dilemma to the pediatrician. There are thousands of malformation syndromes described and diagnosis of a syndrome appears a daunting task. An approach to diagnosis of a malformation syndrome is presented. Relevant details in the history and examination, important investigations, the process of differential diagnosis, and search engines used to aid in diagnosis of a malformation syndrome are described     

Enhancing knowledge and awareness of dengue during a prospective study of dengue fever

In 1992, the Indonesian CDC implemented strategies to control and prevent dengue fever (DF) by including community involvement to reduce larva breeding sites and a mass health education program. To contribute to this effort, we incorporated an educational component into a prospective study of DF conducted at two textile factories in Bandung. This education provided: a lecture on the signs and symptoms of dengue and ways to prevent the disease, posters in the health clinic at each factory and handouts given to each volunteer with an explanation of symptoms. Upon enrollment, each participant completed a questionnaire to gather demographic information. Additionally they were given a brief (non-standardized) test (PRE-test) of their dengue knowledge, which was verbally administered by the study physicians. Five questions (15 point system) were designed to assess the participant's ability to recognize and describe aspects of dengue in lay terms. The subject material included: the symptoms of acute DF, transmission of dengue virus, and basic steps for disease prevention. The same questionnaire was re-administered 18 months later (POST-test), and the results were compared. A total of 2,340 participants completed both the PRE- and POST-tests; there were 1,373 males and 967 females, median age 36 years (range 18-59). Only 0.3% of participants scored EXCELLENT (15-14 points) on the PRE-test whereas 8.4% scored EXCELLENT on the POST-test. Fewer participants scored VERY BAD (2-0 points) on the POST-test compared to the PRE-test (1.4% vs 4.0%). The average raw scores for the PRE- and POST-tests were 7.8 and 10.1, respectively. Improvement of individual scores correlated highly with educational level. No significant correlation was identified for gender, age, factory location or a diagnosis of dengue during the study. These findings demonstrate that our prospective study enhanced knowledge and awareness of dengue in the volunteers.     

Intrathecal therapy with trastuzumab may be beneficial in cases of refractory schizophrenia

Refractory schizophrenia has limited therapeutic options. Schizophrenia can be considered to be a disease of abnormal synaptic plasticity. Neuregulin is a member of the epithelial growth factor family, which induces growth and differentiation of epithelial, glial and muscle cells in culture. Neuregulin has been documented to be important in synaptic plasticity. The important role of neuregulin in synaptic plasticity as well as its developmental role have increasingly been documented recently. The actions of neuregulin are mediated through ERB receptors. Neuregulin can bind directly to erbB3 and erbB4 receptors and receptor heterodimerization allows neuregulin dependent activation of erbB2. The role of Erb 2 could make it possible to use the monoclonal antibody against it for improving the synaptic plasticity through the action on neuregulin. The use of trastuzumab (Her2 antibody) as targeted therapy is well documented in metastatic carcinoma of breast. Also intra-thecal administration of trastuzumab has been reported to be safe in carcinomatous meningitis. Here it is being hypothesized that intra-thecal administration of trastuzumab would improve synaptic plasticity there by making refractory schizophrenia amenable to treatment.     

A systematic review of the effectiveness of ofloxaxin otic solution for the treatment of suppurative otitis media

The objectives of the study were to determine the effectiveness and incidence of adverse events of ofloxacin otic solution for suppurative otitis media compared with other treatments. All randomized controlled trials and nonrandomized comparative clinical trials published from 1966 to 2000 using ofloxacin otic solution as one of the interventions were reviewed and data were extracted and analyzed. Eleven clinical trials (9 randomized and 2 nonrandomized) enrolling 1,484 adults and children were finally included in the analysis. Five studies employed clear concealment procedure in the allocation of treatment whereas evaluation of outcome was at least single-blinded in 6 trials. The probability of overall cure rate was higher with 0.3% ofloxacin otic solution than with other topical or systemic antibiotics in 9 of the studies analyzed (OR = 2.67; 95% CI = 2.04, 3.50). Resolution of secondary outcome parameters evaluated at least 1 week after treatment was higher with 0.3% ofloxacin otic solution: resolution of otalgia (4 trials; OR = 2.41; 95% CI = 1.2, 4.82); resolution of otorrhea (11 trials; OR = 2.78; 95% CI = 2.12, 3.65), and bacterial eradication rate (6 trials; OR = 3.86; 95% CI = 2.54, 5.87). A subgroup analysis of 4 studies comparing ofloxacin otic solution with antibiotic- and steroid-containing otic solution showed a higher cure rate for ofloxacin otic solution (OR = 2.73; 95% CI = 1.52, 4.90). Another subgroup analysis on 3 studies comparing ofloxacin otic solution with oral systemic antibiotics showed higher resolution of otorrhea with ofloxacin otic solution (OR = 2.78; 95% CI = 2.12, 3.65). Of 4 studies with data on adverse events, the probability of adverse events was lower with ofloxacin otic solution than with other topical antibiotics (OR = 0.28; 95% CI = 0.19, 0.42). Subgroup analysis showed that 0.3% ofloxacin otic solution showed better results in terms of overall cure rate, resolution of otorrhea, otalgia, bacterial eradication rate and incidence of adverse events. Whether due to chronic suppurative otitis media (CSOM) or draining tympanostomy tube, the overall cure rate (CSOM OR = 4.86; with tympanostomy tube OR = 2.13) and resolution of otorrhea (CSOM OR = 4.42; with tympanostomy tube OR = 1.66) were likewise in favor of 0.3% ofloxacin otic solution. The studies included in this meta-analysis showed generally homogenous results in all clinical and laboratory outcomes analyzed, except for the evaluation of adverse events. The authors conclude that 0.3% ofloxacin otic solution is better than other otic antibiotic drops and other oral antibiotics in terms of overall cure rate and resolution of secondary outcome parameters. Estimates on the beneficial effects of ofloxacin otic solution are limited to the period of study included in this review.     

Synergistic effect of modified pore and heterojunction of MOF-derived α-Fe2O3/ZnO for superior photocatalytic degradation of methylene blue

Mesoporous heterojunction MOF-derived α-Fe₂O₃/ZnO composites were prepared by a simple calcination of α-Fe₂O₃/ZIF-8 as a sacrificial template. The optical properties confirm that coupling of both the modified pore and the n–n heterojunction effectively reduces the possibility of photoinduced charge carrier recombination under irradiation. The mesoporous Fe(25)ZnO with 25% loading of α-Fe₂O₃ exhibited the best performance in MB degradation, up to ∼100% after 150 minutes irradiation, higher than that of pristine ZnO and α-Fe₂O₃. Furthermore, after three cycles reusability, mesoporous Fe(25)ZnO still showed an excellent stability performance of up to 95.42% for degradation of MB. The proposed photocatalytic mechanism of mesoporous Fe(25)ZnO for the degradation of MB corresponds to the n–n heterojunction system. This study provides a valuable reference for preparing mesoporous MOF-derived metal oxides with an n–n heterojunction system to enhance MB photodegradation.

Mesoporous heterojunction MOF-derived α-Fe₂O₃/ZnO composites were prepared by a simple calcination of α-Fe₂O₃/ZIF-8 as a sacrificial template.