Severe beta(0) thalassemia/hemoglobin E disease caused by de novo 22-base pair duplication in the paternal allele of beta globin gene

beta Thalassemia is a major public health concern in Southeast Asia. A prevention program has been implemented in Thailand comprising mass carrier screening and genetic testing. In this study, a Thai girl with severe beta thalassemia/hemoglobin (Hb) E disease was born from the mother with Hb E trait and the genotypically normal father. DNA sequencing revealed novel 22-bp tandem duplication in the paternal allele of beta globin gene, producing a severely truncated product. A short recurring nucleotide at the insertion site suggested a predisposition to this mutation. Therefore, spontaneous beta globin mutations occasionally occur in normal population. Its clinical significance is noteworthy in countries with high prevalence of beta thalassemia.     

Use of a rhesus Plasmodium cynomolgi model to screen for anti-hypnozoite activity of pharmaceutical substances

There remains a need for new drugs to prevent relapse of Plasmodium vivax or P. ovale infection. The relapsing primate malaria P. cynomolgi has been used for decades to assess drugs for anti-hypnozoite activity. After sporozoite inoculation and blood-stage cure of initial parasitemia with chloroquine, rhesus macaques were treated on subsequent relapses with chloroquine in conjunction with test regimens of approved drugs. Tested drugs were selected for known liver or blood-stage activity and were tested alone or in conjunction with low-dose primaquine. Tinidazole and pyrazinamide prevented relapse when used in conjunction with chloroquine and low-dose primaquine. Triamterene and tinidazole administered without primaquine achieved radical cure in some animals. All other tested drugs or combinations failed to prevent relapse. The rhesus macaque-P. cynomolgi model remains a useful tool for screening drugs with anti-hypnozoite activity. Tinidazole and pyrazinamide require further investigation as agents to enable dose reduction of primaquine.     

Simple method for screening of α-thalassaemia 1 carriers

α-Thalassaemia 1 genetic disorder occurs when there is a deletion of two linked α-globin genes. The interaction between these abnormal genes leads to the most severe type of thalassaemia disease, haemoglobin (Hb) Bart’s hydrops fetalis. The identification of α-thalassaemia 1 carriers and genetic counselling are essential for the prevention and control of severe thalassaemia diseases. In this study, we have developed a rapid screening method for identifying α-thalassaemia 1. A sandwich-type immunochromatographic (IC) strip test was developed, using the generated monoclonal anti-Hb Bart’s antibody, to trace the Hb Bart’s in haemolysates. When assayed by our IC strip test, all α-thalassaemia 1, HbH disease, HbH-Constant Spring (H-CS) disease, HbH-CS and heterozygous HbE (CSEA) Bart’s disease, and homozygous α-thalassaemia 2 showed positive results. No false negative results were observed in these blood samples. In α-thalassaemia 2 heterozygotes, 83% of them showed positive reactivity. Among HbE (both homozygotes and heterozygotes), β-thalassaemia (heterozygotes, homozygotes and β-thalassaemia/HbE) and normal subjects, the IC strip test revealed negative reactivity of 100, 85 and 97%, respectively. These results indicate that this novel immunodiagnostic kit, in combination with red blood cell indices, is suitable for screening and ruling out mass populations for the presence of α-thalassaemia 1.     

Multicenter Study of the Molecular Basis of Thalassemia Intermedia in Different Ethnic Populations

We studied 325 thalassemia intermedia patients from Iran, India, Pakistan, Thailand, Mauritius and Cyprus to examine factors which influence the phenotype. The β-thalassemia (thal) mutations were determined for 219 β-thal/β-thal and 106 β-thal/Hb E [β26(B8)Glu→Lys, GAG→AAG] thalassemia intermedia patients. Thirty-one different mutations were identified, and their combination gave rise to more than 44 different genotypes, of which 14 (31.8%) had the β⁰/β⁰, 21 (47.7%) the β⁰/β⁺ and nine (20.5%) the β⁺/β⁺ types. Thus, the β⁺-thal mutations were present in 68.2% of patients.

α-Thalassemia mutations were present in frequencies higher than in the general population of all ethnic groups studied, as 45% of the patients carried α-thal mutations. Correlation of α-thal mutations with β-globin mutations showed that the α-thal mutations were mainly co-inherited with the β⁺-thal mutations.

The XmnI ^Gγ polymorphic site at ?158 (C→T) was positive (T) in nine (8.8%) of 102 patients of the β⁺/β⁺ genotype, and the percentage of both XmnI ^Gγ polymorphism [+/?] (T/C) and [+/+] (T/T) genotypes increased to 42.9 and 87.3, respectively, in the β⁰/β⁺ and β⁰/β⁰ patients. This polymorphism was found in the majority of β⁺-thal/Hb E compound heterozygote patients (88.6%), and β⁰-thal/Hb E patients (84.8%), suggesting that it could be linked to the Hb E chromosome. Therefore, the XmnI ^Gγ polymorphism at ?158 (C→T) was associated with β⁰-thal mutations as well as the Hb E chromosome.

The present study demonstrates that in cases of thalassemia intermedia with β⁺ mutations, the common ameliorating factor is the presence of α-thal mutations, while in cases with β⁰ mutations, the common ameliorating factor is the presence of the XmnI ^Gγ polymorphism at ?158 (C→T).     

Nondeletional type of hereditary persistence of fetal haemoglobin: molecular characterization of three unrelated Thai HPFH

The β-globin gene clusters of three unrelated Thai families with a nondeletional type of hereditary persistence of fetal haemoglobin (HPFH) were studied using polymerase chain reaction-related techniques. All appeared to have normal nucleotide sequences from the Cap site to position -400 of both the ^Gγ- and ^Aγ-globin genes. Two individuals suspected of having a β-thalassaemia gene linked to the high HbF condition also had a normal β-globin gene sequence, spanning from position -108 from the Cap site to the polyadenylation site. Deletion of four nucleotides, AGCA, at positions -225 to -222 of one ^Aγ-globin allele was detected in one subject and was confirmed by dot-blot hybridization. Restriction fragment length polymorphisms in the β-globin gene cluster showed that the 5' haplotype (- + - ++) and the presence (+) of an Xmn 1 polymorphic site at -158 of the ^Gγ-globin gene are associated with the high F phenotype in these families. Direct sequencing of the 5' hypersensitive-2 (5' HS-2) site of the locus control region (LCR) showed that this Xmn , 1 (+) site is also linked to a specific rearrangement of TA repeats (TA)₉CACATATACG(TA)₁₀, in HS-2 segment.     

Reproductive Health Care Experiences of People with Physical Disabilities in Vietnam

This qualitative research explored the reproductive health care experiences of people with physical disabilities in Vietnam. Data from 20 participants (10 males and 10 females) was collected from in-depth interviews with the use of drawing and photo elicitation methods. The findings revealed that people with physical disabilities in Vietnam experienced difficulties with their reproductive health care that included: physically inaccessible hospitals; negative attitudes from health care providers; discouraging experiences with reproductive healthcare including assistance with fertility control; and limitations with public health insurance. Almost all the participants only saw a doctor if they became ill, but often bought over-the-counter medication from pharmacies. Some participants chose private rather than public hospitals where environments were inaccessibility, and health care providers were perceived as insensitive. In terms of contraception, study participants mostly used condoms, although some did not use any contraceptive methods resulting in unplanned pregnancies or abortion. People with disabilities in Vietnam have access to public health insurance but its limitations can affect the experiences of people with physical disabilities attempting to access reproductive health care. In Vietnam, people with physical disabilities work hard to overcome discrimination to achieve full and satisfying lives.

     

‘I need help’: Reasons new and re‐engaging callers contact the PANDA—Perinatal Anxiety and Depression Australia National Helpline

In Australia, the PANDA—Perinatal Anxiety & Depression Australia National Helpline (the Helpline) offers support to callers impacted by emotional health challenges in the perinatal period. Callers receive counselling from professional staff and peer support from volunteers. An understanding of factors that contribute to callers’ experiences of emotional distress, as well as potential barriers and facilitators to help‐seeking, can be used to inform future service design and delivery. A caller intake form is completed by Helpline staff when an individual contacts the service for the first time, or re‐engages after a period of non‐contact. We analysed all intake forms of individuals calling about their own emotional wellbeing from the middle month of each season in 2014: January, April, July, and October. Content analysis was undertaken, focusing on caller profile, patterns of help‐seeking, and reasons for caller engagement. Of the 365 calls, the majority were from women (n = 358, 98%) who were pregnant (n = 59, 16%) or had a child ≤12 months of age (n = 241, 75%). Many were seeking support regarding depression (n = 186, 51%) or anxiety (n = 162, 44%), with a number seeking help for both (n = 71, 20%). Almost a third were identified as being ‘at risk’, including a number who were experiencing thoughts of suicide or self‐harm. Complex interrelating factors contributed to callers’ emotional distress, including: stressful life events; pregnancy, birthing and parenting experiences; social isolation; and histories of mental health difficulties. Significant numbers of parents experience emotional health challenges in the perinatal period, but many do not receive adequate treatment. Complex factors contribute to callers’ distress, highlighting the need for health professionals to undertake thorough psychosocial assessments during the perinatal period so those that need additional support are identified, and appropriate care provided. Telephone Helplines like PANDAs assist overcoming barriers to care and provide specialised perinatal mental health support to families.     

A holistic programme for mothers with postnatal depression: pilot study

Title.  A holistic programme for mothers with postnatal depression: pilot study.
Aim. This paper is a report of a pilot study to identify women's perceptions of participation in a holistic intervention for postnatal depression.
Background. Approximately 10–15% of women suffer from postnatal depression following childbirth. Most programmes for women with postnatal depression include pharmaceutical interventions; however, evaluation of women's perceptions of participation in holistic programmes for those suffering from postnatal depression show that non-pharmaceutical programmes can also be effective.
Method. In-depth interviews were conducted in 2004 with a self-selected sample of 10 women prior to and after an intervention to treat postnatal depression.
Findings. The intervention seemed capable of encouraging and facilitating a positive mother–infant relationship while also effectively reducing the mother's anxiety levels. Participants commented on the supportive environment of other mothers and said that they found playing with their babies difficult and needed guidance and facilitation to do this.
Conclusion. The pilot programme was well accepted and could easily be used by midwives, maternal and child health nurses and other appropriately trained allied health professionals.     

Effects of combined UDP-glucuronosyltransferase (UGT) 1A1*28 and 1A6*2 on paracetamol pharmacokinetics in beta-thalassemia/HbE

In addition to pathophysiological changes, genetic variations can alter drug pharmacokinetics in patients with thalassemia. Numerous drugs are metabolized by UDP-glucuronosyltransferases (UGT) including paracetamol (PCM), a widely used analgesic. Co-occurrence of the UGT1A1 polymorphism (UGT1A1*28) and the UGT1A6 polymorphism (UGT1A6*2) may affect PCM glucuronidation. To elucidate the effect of these combined polymorphisms on the PCM metabolism in thalassemic patients, 15 beta-thalassemia/hemoglobin E subjects with three different UGT1A genotypes received a single oral dose of 1,000 mg PCM. Drug disposition was determined by HPLC. Patients who have UGT1A6*2 without UGT1A1*28 showed a significant, lower area under concentration-time curve (AUC(0)-->infinity) of PCM, PCM-glucuronide and PCM-sulfate than those of the patients with wild-type UGT1A1 and UGT1A6 (p < 0.05). In addition, a high elimination rate constant and clearance of PCM and its metabolites were also found in these patients (p < 0.05). Ourstudy suggests that a subtherapeutic level of PCM may occur in patients who have UGT1A6*2 without UGT1A1*28.