Wrist Deformity in Children and Adolescents with b-thalassemia on Oral Iron Chelation Therapy

Objective: To describe a novel wrist deformity in β-thalassemia major patients, and theirradiographic and magnetic resonance imaging findings. Methods: 30 patients withβ-thalassemia major who were noticed to have ulnar deviation at wrist joint were evaluated forprevious history of medications, serum ferritin levels, presence of pain and swelling at thewrist joint, and the duration of iron chelation therapy. Radiographs of wrist and limitedmagnetic resonance imaging (MRI) sequences were obtained in 30 and 15 patients,respectively. Results: Radiographs revealed varying severity of distal ulnar shortening, distalradial slanting and presence of soft tissue distal to the ulna. MRI showed similar deformitiesalong with abnormal marrow signal at distal ulnar ends; in 8 patients, a soft tissue distal to thedistal end of ulna was noted.Conclusion: Varying severity of radiological abnormalities,predominantly affecting the distal ulna, are present in children and adolescents with β-thalassemia receiving oral chelation therapy

Evaluation of carotid artery dynamics & correlation with cardiac & hepatic iron in β-thalassaemia patients.

Background & objectives: Early atherosclerosis and vascular complication have been described in thalassaemia patients. There is lack of data or guidelines regarding monitoring of vascular health in thalassaemia. This study was conducted to compare carotid artery structural and functional indices such as carotid artery intima-media thickness (CIMT), stiffness index (SI) and Young’s elastic modulus (YEM) in β-thalassemia patients with age and sex matched controls, and to correlate these parameters with serum ferritin, cardiac iron, and hepatic iron. Methods: This cross-sectional study included 53 β-thalassaemia patients receiving regular blood transfusions. Carotid artery indices such as CIMT, SI, and YEM were calculated by duplex ultrasound and colour Doppler. Serum ferritin levels were measured by chemiluminescence. Cardiac and hepatic iron estimation were done using MRI T2* sequences analyzed by a special thalassaemia software. Results: Mean CIMT of cases and controls were 0.48 ± 0.04 and 0.44±0.02 mm, respectively and these were significantly different (P<0.001). Similarly significant differences were noted in SI and YEM of cases (2.45±0.79 and 96.12±34.85, respectively) as compared to controls (1.98±0.54 and 68.60±24.29, respectively) (P<0.001). There was significant inverse correlation between stiffness index and cardiac iron overload assessed by MRI cardiac T2* (P=0.03). Mean SI and YEM of cases were (2.1736 ± 0.2986 and 107.3± 41.6, respectively) significantly higher among non-splenectomized patients compared to splenectomized patients (2.0136 ± 0.263 and 86.9 ± 25.2, respectively) (P<0.05). Interpretation & conclusions: CIMT and arterial stiffness indices were significantly increased in β-thalassaemia patients compared to controls which was indicative of early atherogenic changes. This study supports the hypothesis that iron overload is a risk factor for early atherosclerosis and cardiovascular disease.

Comparison of in-vitro and in-vivo response to fetal hemoglobin production and γ-mRNA expression by hydroxyurea in Hemoglobinopathies.

BACKGROUND: Hydroxyurea, which induces Fetal hemoglobin (HbF) synthesis, is the only drug widely used in different hemoglobinopathies; however, the response is very variable. We compared the efficacy of hydroxyurea in-vitro in erythroid cultures and in-vivo in the same patients with different hemoglobinopathies to induce HbF production and enhance γ-messenger RNA expression. MATERIALS AND METHODS: A total of 24-patients with different Hemoglobinopathies were given hydroxyurea and their response was studied in-vivo and in-vitro on mononuclear cells collected from them simultaneously. RESULTS: A total of 57.7% of patients (responders) showed no further crisis or transfusion requirements after hydroxyurea therapy with a mean increase in fetal cells (F-cells) of 63.8 ± 59.1% and γ-mRNA expression of 205.5 ± 120.8%. In-vitro results also showed a mean increase in F-cells of 27.2 ± 24.7% and γ-mRNA expression of 119.6% ± 65.4% among the treated cells. Nearly 19.0% of the partial-responders reduced their transfusion requirements by 50% with a mean increase in F-cells of 61.2 ± 25.0% and 28.4 ± 25.3% and γ-mRNA-expression of 21.0% ± 1.4% and 80.0% ± 14.1% in-vivo and in-vitro respectively. The non-responders (15.3%) showed no change in their clinical status and there was no significant increase in F-cells levels and γ-mRNA expression in-vivo or in-vitro. CONCLUSION: Thus, this method may help to predict the in-vivo response to hydroxyurea therapy; however, a much larger study is required.

Efficacy and Safety of Deferasirox for Reducing Total Body and Cardiac Iron in Thalassemia.

Objective: To assess the efficacy of deferasirox as an iron chelator, with specific reference to reducing cardiac iron overload. Design: Prospective, open label, single arm study between 2008- 2010. Setup: Thalassemia center at a teaching hospital. Participants: 30 multitransfused Thalassemia Major (TM) patients receiving deferasirox (DFX) therapy. Methods: All patients had MRI T2*evaluation for cardiac iron load before starting DFX therapy. MRI T2* was performed on a 1.5 tesla Siemens sonata machine using thalassemia tools software and the ejection fraction measured using standard cardiac magnetic resonance sequence. Quantification of cardiac iron deposit was categorized into T2* <10 ms as high cardiac risk, 10- 20 ms as intermediate risk, and >20 ms as low risk. We also estimated left ventricular ejection fraction (LVEF), end systolic volume (ESV) and end diastolic volume (EDV) using standard sequence. EF <56 % was considered to be significant cardiac dysfunction. DFX was administered in an initial dose of 20mg/kg/ day and increased to a maximum of 35mg/kg/day. Serum ferritin level was estimated in pretransfusion samples at 1-3 monthly intervals. The primary end point of the study was change in serum ferritin level and cardiac MRI T2* value after 12-18 months therapy. Results: Of the 30 patients, cardiac iron value of >20 ms was seen in 15 (50%), whereas 9 (30% ) had 20-10 ms, and 6 (20% ) had ≤10 ms. The mean serum ferritin pre DFX therapy of all cases was 3859.8 ± 1690.70 ng/mL (1066 – 6725 ng/mL) and mean cardiac T2* was 23.8±15.2 ms (6.24-69.2 ms). After 12 to 18 months of DFX therapy on a mean dose of 33 mg/kg/day, the mean serum ferritin was 2693.4 ±1831.5 ng/mL (drop by 30.2%, P<0.001) and mean cardiac T2* was 24.2±12.9 ms (increase of 1.6 %, P=0.87). Percentage change in cardiac iron was greater in high risk (24.8%) and intermediate risk (33.4%) patients than low risk patients (8.4%), though these values were not statistically significant. LVEF was 62.0 (±7.0%) before treatment and changed to 58.9 (± 4.8%) after 18 months of therapy but the values remained within normal range and this change was not significant (P=0.061). Adverse effect of DFX included diarrhea, maculopapular skin rash and transient proteinuria that necessitated temporary stoppage of medication. Conclusion: Deferasirox monotherapy has a good safety profile and effectively chelates total body iron. It is also a good myocardial iron chelator, more efficacious in moderate to severe cardiac iron overloaded patients.

Evaluation of Cardiac Iron Load by Cardiac Magnetic Resonance in Thalassemia.

Objective: To quantify myocardial iron stores by Cardiac Magnetic Resonance (CMR) . Design: Prospective cohort study. Setting: Thalassemia center in a teaching hospital. Participants: 60 transfusion dependant thalassemia major patients and 10 controls during 2008-2009. Methods: MRI T2* for cardiac iron load and cardiac functions was performed on a 1.5 Tesla Siemens Sonata machine using the thalassemia tools software. Ejection fraction (EF) was measured using standard CMR sequence and EF <56% considered as cardiac dysfunction. Quantification of iron deposition was categorized as T2* <10 milliseconds (ms) as high risk, 10-20 ms as intermediate risk and >20 ms as low risk. Simultaneous liver iron T2* values were categorized into normal i.e. >6.3 ms, mild iron overload 6.3 - 2.7 ms , moderate iron overload 2.7- 1.4 ms and severe iron overload <1.4 ms. Pretransfusion serum ferritin levels were simultaneously determined. Data was analyzed by paired and unpaired t test of mean. Results: Of 60 patients, 50% had no cardiac siderosis; 33.3% had mild to moderate and while 16.7% had severe cardiac siderosis . In contrast, only 8.3% had normal liver iron values, 55.7% had mild to moderate and 36% had severe iron stores. The mean serum ferritin of all 60 cases was 3528.6 ± 1958.6 ng/mL. There was a statistically significant difference in the mean cardiac T2* of patients (23.45 ± 13.4 ms) as compared to controls (32.67 ± 2.68 ms) (P<0.01). Conclusions: Thalassemia patients had significantly higher cardiac iron stores as compared to controls. Serum ferritin and liver iron values did not correlate with cardiac iron values. Three of 10 patients <10 years showed evidence of myocardial siderosis.

Vertical Transmission of HIV-An Update.

One of the greatest successes in AIDS research to date has by far been the discovery of successful interventions that interrupt the transmission of HIV from mother to child. It is however important to note that these successes have occurred largely in countries with great resources and the least burden of perinatal transmission of HIV. In the developing world wherein currently 95% of vertical transmission of HIV occurs, it is highly condemnable that still every minute an infected infant is said to be born in spite of the fact that vertical transmission is largely preventable, mainly because translating knowledge into practice is not always possible or feasible; This has led to a continuous growing numbers of children with HIV, thereby making pediatric HIV a looming problem rapidly draining the already burdened health care system of these countries. It is the need of the hour to appropriately address the challenges to achieve zero percent transmission of HIV from an infected mother to her child thereby giving a hope for an AIDS-free new generation worldwide.

Evaluation of osteopathy in thalassemia by bone mineral densitometry and biochemical indices.

Objective To evaluate osteopathy in thalassemia by bone mineral densitometry (BMD) and biochemical indices. Methods Prospective review analysis with no follow up from 2006 to 2007 of 42 regularly transfused thalassemics aged 10–25 years (27 boys, 15 girls) was done. Anthropometry, pubertal stage and symptomatology were noted. Urinary C–terminal cross–linked telopeptide of type–1 collagen (Crosslaps) by ELISA; serum 25–OH vitamin D and osteocalcin by RIA; parathyroid hormone (PTH) and ferritin by chemiluminescence and IGF–1 by Enzyme immunoassay were evaluated. Dual Energy X-ray Absorptiometry (DEXA) of lumbar spine and femur was done on Lunar prodigy system. Data was entered and analyzed using the SPSS for Windows software. Mean comparisons were done by ANOVA 1 and data was compared using Chi–square test and p value<0.05 was taken as significant. Results Of 42 patients, 81% had osteoporosis by Z–score of DEXA. Urinary crosslaps was high in 55%; 36% had increased osteocalcin; 62% had low vitamin D levels; 38% had high parathyroid levels and IGF–1 was low in 52%. Mean serum ferritin level was 5344±2855 ng/dl. There was statistical significance (p=0.046) between chronological age and BMD. All 42 cases were divided into two groups: Group–1 (Normal DEXA), Group–2 (Abnormal DEXA) and analysis of biochemical indices between two groups showed no significant difference in any of the biochemical parameters. Conclusion This study revealed majority of thalassemics with inadequate chelation have bone resorption with advancing chronological age and BMD should be evaluated regularly for early diagnosis to prevent morbidity.

L-carnitine in Beta Thalassemia.

This study was conducted to determine L-carnitine levels in regularly transfused and chelated beta thalassemia patients (n=40; mean age, 17.5±5.0 years).Ten age matched controls were also studied. The mean L-carnitine level in thalassemic patients was 23.71±7.3μM as compared to control 29.26±2.37μM (P<0.0001). Mean Carnitine was significantly lower (P=0.037) in those with ferritin greater than 2000ng/dL (22.80±6.97μM) in comparison to those with ferritin less than 2000ng/ dL (30.1±7.77μM). Although Carnitine levels in non vegetarians was higher (26.91 ±8.4μM) than in vegetarians (22.34±6.55μM), this difference was not statistically significant (P=0.072). We conclude that L-carnitine levels were found to be lower in thalassemics as compared to age matched controls.

Prevention of mother-to-child transmission of HIV--an overview.

With the human immunodeficiency virus (HIV) epidemic showing a shift towards women and young people, the increasing seroprevalence among women will result in an increase in the mother-to-child transmission of HIV. The vast majority of HIV-positive children worldwide acquire the infection through vertical transmission. The discovery of successful interventions that interrupt this transmission has been one of the greatest successes in AIDS research. The transmission of HIV from an infected mother to her child can be reduced to less than 2 peer cent by intensive interventions in the antenatal, intranatal and postnatal periods. To achieve this low rate, primary prevention of HIV infection in parents-to-be, early identification of seropositivity in pregnant women, prevention of unwanted pregnancies, prevention of mother-to-child transmission of HIV by appropriate antiretroviral therapy, special interventions in maternal management during labour, appropriate care and follow up of the newborn, all play an important role. However, these approaches are not always possible in developing countries wherein currently 95 per cent of vertical transmission occurs. Several questions and challenges remain. These include choice, availability, affordability, duration, long-term safety of optimal antiretroviral agents to be used during pregnancy and early neonatal life and the issue of transmission via breastfeeds in situations where alternatives to breastfeeding are not available. The challenge is to find the most cost-effective and feasible intervention to achieve zero per cent transmission of HIV from an infected mother to her child.