Ethnic variation in the HER-2 codon 655 genetic polymorphism previously associated with breast cancer

HER-2, a protooncogene located on chromosome 17q21, encodes a transmembrane glycoprotein (p185) with tyrosine kinase activity. Alterations of the HER-2 gene have been implicated in the carcinogenesis and prognosis of breast cancer and other solid tumors. It is also a cancer-therapeutic target for antibody-based therapy against the HER-2 protein. A single-nucleotide polymorphism (SNP) at codon 655, resulting in a G-to-A transition (Ile655Val) in the transmembrane domain-coding region of this gene has been associated with an increased risk of breast cancer, particularly among younger women. To understand the importance of this finding throughout the world, we evaluated this polymorphism in Ghanaian, Kenyan, Sudanese, Caucasian, African–American, Saudi, and Filipino subjects using a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of the Val allele, which is associated with increased breast cancer risk, was highly variable between populations (0%–24%). Continental African populations had a lower frequency of the Val allele than did Saudi, Chinese, Filipino, Caucasian, and African–American subjects. The data suggest that this SNP has variable frequency in different ethnic groups. The findings in this study correspond with the lower incidence and lower risk of breast cancer in African women compared with Caucasian and African–American women. Received: December 13, 2001 / Accepted: January 16, 2002     

Effects of an ethanol extract and the diterpene,xylopic acid,of Xylopia aethiopica fruits in murine models of musculoskeletal pain

Context: Fruits of Xylopia aethiopica (Dunal) A. Rich. (Annonaceae) are used traditionally to manage arthritis, headache and other pain disorders.

Objective: The analgesic properties of the X. aethiopica ethanol fruit extract (XAE) and xylopic acid (XA) were evaluated in musculoskeletal pain models.

Materials and methods: Acute muscle pain was induced in gastrocnemius muscle of Sprague–Dawley rats with 3% carrageenan (i.m.). Rats received XAE (30–300?mg/kg), XA (10–100?mg/kg) or morphine (1–10?mg/kg) after 12?h. Effects of XAE and XA on muscle pain were assessed by measuring post-treatment grip strength of the rats. Chronic muscle pain was similarly induced, but drug treatment was on the eighth day and effects of XAE and XA assessed with Randall–Selitto test for hyperlagesia. Acute-skeletal pain was induced in knee joints of rats with 3% carrageenan-kaolin mixture and effects determined 12-h later. Similar induction protocol was used for chronic knee pain with treatment and measurement as done for chronic muscle pain.

Results: XAE and XA significantly and dose-dependently ameliorated both acute muscle (ED₅₀ mg/kg: XAE?=?22.9; XA?=?6.2) and skeletal hyperalgesia (XAE?=?39.9; XA?=?17.7) induced by 3% carrageenan. Similarly, chronic skeletal hyperalgesia was reduced by XAE and XA treatment similar to morphine (ED₅₀: XAE?=?13.0; XA?=?4.6). This reduction was also seen in chronic muscle hyperalgesia (ED₅₀: XAE?=?79.1; XA?=?42.7). XAE and XA significantly reduced the spread of hyperalgesia to contralateral limbs in both models of chronic hyperalgesia.

Conclusion: These findings establish analgesic properties of the ethanol fruit extract of X. aethiopica and xylopic acid in musculoskeletal pain.     

Analysis of risk and protective factors for psychosocial distress among in-school adolescents in Tanzania

Introduction

Psychosocial distress has emerged as one of the world’s major public health problems, especially among adolescents in both low- and middle-income countries. This study used data from the 2015 version of the Global School-Based Health Survey to determine the risk and protective factors for psychosocial distress among in-school adolescents in Tanzania.

Materials and methods

Chi-square and logistic regression analyses were used to estimate the magnitude of associations. A total of 2936 students participated in the study, of which 52.3% were female.

Results

Psychosocial distress was found in 16.9% of the students at similar rates for both males and females. The risk factors associated with psychosocial distress were hunger (OR?=?1.57, p?<?0.001), being bullied (OR?=?1.92, p?<?0.001), being attacked (OR?=?1.31, p?<?0.05), engaging in physical activity (OR?=?1.33, p?<?0.05), truancy (OR?=?1.28, p?<?0.05) and tobacco use (OR?=?2.40, p?<?0.01). However, the protective factors were grade (OR?=?0.55, p?<?0.01) and having one or two (OR?=?0.56, p?<?0.01) and three or more close friends (OR?=?0.57, p?<?0.01).

Conclusions

The prevalence of psychosocial distress among adolescents in Tanzania is relatively high and appears to be common among both sexes. To reduce psychosocial distress among in-school adolescents, more attention needs to be paid to the risk factors whiles encouraging healthy relationships among adolescents and their close friends.

     

Evaluation of dihydropyrimidine dehydrogenase activity in South-west Asian, Kenyan and Ghanaian populations

AIMS: Dihydropyrimidine dehydrogenase (DPD) reduces endogenous pyrimidines and therapeutic analogues such as the anticancer agent 5-fluorouracil (5FU). Among Caucasian populations DPD activity is highly variable and subject to polymorphic regulation. To evaluate interethnic influence, DPD activity was assessed in South-west Asian, Kenyan and Ghanaian populations. METHODS: DPD activity was determined in peripheral mononuclear cells using[14C]-5-fluorouracil and h.p.l.c. analysis. RESULTS: A high degree of variation in DPD activity was observed within each population (range CV = 34-48%). Median DPD activity also varied between these populations. South-west Asian and Kenyan subjects exhibited almost identical median values (192 and 193.5 pmol min(-1) mg(-1), respectively), which were similar to Caucasians (median 215 pmol min(-1) mg(-1). A significantly lower median DPD activity (119 pmol min(-1) mg(-1)) was observed in the Ghanaian population. CONCLUSIONS: The similarity in DPD activity between Caucasian, Kenyan and South-west Asian populations suggests that the incidence of 5FU-related toxicity may be comparable in these groups. The pharmacokinetic implications of lower activity amongst Ghanaians needs to be evaluated.     

MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity

P-glycoprotein (PGP), the product of the multidrug resistance gene (MDR1), acts as an energy-dependent efflux pump that exports its substrates out of the cell. PGP expression is an important factor regulating absorption of a wide variety of medications. It has also been associated with intrinsic and acquired cross resistance to a number of structurally unrelated anticancer drugs. A single nucleotide polymorphism (SNP) in exon 26 of the MDR1 gene, C3435T, was recently correlated with PGP protein levels and substrate uptake. Individuals homozygous for the T allele have more than four-fold lower PGP expression compared with CC individuals. As overexpression of PGP has been associated with altered drug absorption, therapy-resistant malignancies, and lower concentrations of HIV-1 protease inhibitors, this SNP may provide a useful approach to individualize therapy. To facilitate clinical application throughout the world, 1280 subjects from 10 different ethnic groups were evaluated for this SNP using the polymerase chain reaction-restriction fragment length polymorphism assay and the genotype and allele frequency for each group were ascertained. Marked differences in genotype and allele frequency were apparent between the African populations and the Caucasian/Asian populations (P < 0.0001). The Ghanaian, Kenyan, African American and Sudanese populations studied had frequencies of 83%, 83%, 84% and 73%, respectively, for the C allele. The British Caucasian, Portuguese, South-west Asian, Chinese, Filipino and Saudi populations had lower frequencies of the C allele compared to the African group (48%, 43%, 34%, 53%, 59%, and 55%, respectively). The high frequency of the C allele in the African group implies overexpression of PGP and may have important therapeutic and prognostic implications for use of PGP dependent drugs in individuals of African origin.     

Persistence of onchocerciasis and associated dermatologic and ophthalmic pathologies after 27 years of ivermectin mass drug administration in the middle belt of Ghana

Objectives

There is a pressing need to regularly evaluate the progress of onchocerciasis elimination programmes to timely identify and mitigate potential risks hindering the reaching of the 2030 targets proposed by the World Health Organization (WHO) in its roadmap on neglected tropical diseases (NTDs). We determined the prevalence of onchocerciasis and associated dermatological and ophthalmological manifestations in six endemic communities in the Bono Region of Ghana after 27 years of ivermectin mass treatment.

Methods

In a cross-sectional study, 564 participants aged ≥5 years were enrolled (49.1% females), with a median age of 26 (range: 5–89) years. In 54% and 47%, skin-snip microscopy and Ov16 rapid diagnostic tests were performed, respectively. Skin disease was determined using the WHO Skin NTD App. Visual function assessments included tests of visual acuity.

Results

The overall microfilarial prevalence was 12.5% (38/305) and Ov16 seroprevalence was 24.2% (64/265). Severe itching was recorded in 24.3%, acute papular onchodermatitis in 52.8%, chronic papular onchodermatitis in 12.5%, lichenified onchodermatitis in 0.7%, skin atrophy in 11.3%, depigmentation in 1.7% and palpable nodules in 5.3%. Of the 301 persons in which visual acuity was examined, 17% were visually impaired and 5.3% were blind and 47.3% presented with cataract. Chronic papular onchodermatitis, lichenified onchodermatitis, depigmentation and visual impairment were significantly associated with the presence of skin microfilariae and Ov16 seropositivity.

Conclusions

The persistence of Onchocerca volvulus infection and onchocerciasis-associated dermatological and ophthalmological pathologies after prolonged treatment is of concern. There is a need to include morbidity management in onchocerciasis elimination programmes and understand better patterns of treatment coverage, adherence and actual intake of ivermectin.     

Possible mechanisms involved in the anti-nociceptive effects of hydro-ethanolic leaf extract of Ziziphus abyssinica

Context: Various parts of Ziziphus abyssinica Hochst ex. A. Rich (Rhamnaceae) have been used in Ghanaian and African traditional medicine as an analgesic. However, there are little scientific data to support the anti-nociceptive effects of the hydro-ethanolic leaf extract of Ziziphus abyssinica (EthE) as well as the possible mechanisms involved in its anti-nociceptive effects.

Purpose: To predict possible nociceptive pathways involved in the anti-nociceptive effects of EthE.

Materials and methods: The effect of EthE (30, 100 and 300?mg/kg) on intraplantar injection of pain mediators such as interleukin-1β, tumour necrosis factor-α, prostaglandin E₂ and bradykinin was evaluated in male Sprague Dawley rats using Randall–Selitto test for 5?h. The effect of specific antagonists to the opioidergic, adenosinergic, ATP-sensitive K⁺ channels, nitric oxide, serotonergic, muscarinic, adrenergic and voltage-gated calcium channel on the anti-nociceptive effect of EthE (100?mg/kg) was evaluated using the formalin test in male imprinting control region (ICR) mice for 1?h.

Results: Pretreatment of the rats with EthE significantly reversed the hypernociception induced by intraplantar injection of TNF-α (F_4,120?=?10.86, p?F_4,120?=?14.71, p?0.0001), bradykinin (F_4,80?=?12.52, p?0.0001) and prostaglandin E₂ (F_5,144?=?6.165, p?=?0.0001). The anti-nociceptive effect exhibited by EthE in the formalin test was reversed by systemic administration of N^G-l-nitro-arginine methyl ester, naloxone, theophylline and glibenclamide.

Conclusions: EthE inhibits hypernociception induced by TNF-α, IL-1β, bradykinin and prostaglandin E₂. EthE exhibited anti-nociceptive effects possibly mediated through opioidergic, adenosinergic, ATP-sensitive potassium channels and nitric oxide cyclic GMP pathways.