When a synonymous mutation breaks the silence in a thalassaemia patient.

Synonymous mutations were considered to lack functional roles in human diseases; however, distinguishing deleterious synonymous mutations from benign ones is still a challenge. In this article, we identified a deleterious synonymous mutation ß-codon 16 (C>T). HBB: c.51C>T, in compound heterozygous form with known ß-thalassaemia mutation patients who clinically presented as non-transfusion-dependent thalassaemia (NTDT). A total of 9 families with 11 compound heterozygous index cases were reported. In the heterozygous state, codon 16 (C>T) mutation results in borderline HbA2 (3.18 ± 0.36%) and slightly reduced RBC indices (RBCs: 4.73 ± 0.75 × 106 /µL, Hb: 12.26 ± 2.60 g/dL, MCV: 79.48 ± 8.40 fL, MCH: 25.95 ± 4.15 pg). The compound heterozygous patients showed elevated HbA2 (5.98 ± 1.17%) and HbF (12.75 ± 7.51%) and presented clinically as NTDT with a mean Hb of 6.95 ± 1.29 g/dL. Many of them were dependent on few transfusions and had mild splenomegaly. Of the 11 patients, 5 (45.4%) were treated with hydroxyurea. This study highlights the clinical significance of synonymous mutation, when inherited with other ß-thalassaemia mutations leading to the phenotype of NTDT. Thus, the study would help to improve screening protocols for ß-thalassaemia carriers, which will ultimately improve the prevention programme.

Impact of functional IL-18 polymorphisms on genetic predisposition and diverse clinical manifestations of the disease in Indian SLE patients.

Several studies have demonstrated associations between interleukin-18 polymorphisms and risk of systemic lupus erythematosus in different populations except one of Indian origin. We therefore investigated for the influence of interleukin-18 (-1297T/C, -607A/C, -137G/C; + 105A/C) polymorphisms on genetic susceptibility and clinical expression of the disease in Indian systemic lupus erythematosus patients. A total of 200 systemic lupus erythematosus patients and 201 controls were recruited. Genotyping of interleukin-18 polymorphisms were performed by polymerase chain reaction-restriction fragment length polymorphism. Serum interleukin-18 levels were measured by enzyme-linked immunosorbent assay. Interleukin-18 (-1297T/C; -137G/C) polymorphisms showed significant association with genetic susceptibility to the disease in our systemic lupus erythematosus cohort. Stratification analysis revealed -1297CC and -1297C associated with renal involvement (odds ratio = 3.4, correcting p value = 0.0207), (odds ratio = 2.0, correcting p value = 0.0054) respectively. Additionally, -1297C allele frequency was significantly increased in patients with anti-nucleosome antibody (odds ratio = 2.1, correcting p value = 0.0301). Haplotype analysis showed CC haplotype strongly associated with serositis (odds ratio = 9.1, correcting p values = 0.0009) and neurologic involvement (odds ratio = 9.3, correcting p value = 0.0018). We reported a 2.7-fold increase in serum interleukin-18 levels in patients (511.5 ± 242.3 pg/ml) compared to controls (189.4 ± 80.8 pg/ml) ( p < 0.0001). Furthermore, interleukin-18 levels were positively correlated with disease activity ( r = 0.548, p = 0.0001) and renal involvement in the patients with lupus nephritis ( r = 0.569, p < 0.0001). In summary, interleukin-18 polymorphisms elucidated in this study appear to confer genetic susceptibility to the disease and are associated with renal, serositis and neurologic involvement in Indian systemic lupus erythematosus patients.

Role of MMP-7 in the pathogenesis of systemic lupus erythematosus (SLE).

Systemic lupus erythematosus (SLE) is a clinically heterogeneous chronic, inflammatory autoimmune disorder. The association of MMP-7 and disease severity is still unclear. A total of 150 SLE patients and matched healthy controls were recruited for this study. Disease activity was scored according to SLEDAI (98 active and 52 inactive disease). Mean serum MMP-7 levels were significantly higher in SLE patients than controls ( p < 0.001). Patients with active disease showed higher levels (16.24 ± 6.2 ng/ml) as against inactive disease (10.50 ± 3.97 ng/ml) ( p ≤ 0.0001). Mean MMP-7 mRNA expression was significantly higher in patients (RQ = 3.16 ± 0.93) as compared to controls (RQ = 2.21 ± 0.89, p = 0.006). A positive correlation between MMP-7 levels, mRNA expression and SLEDAI score was observed ( r = 0.563, r = 0.427). The MMP-7 -181 G allele was found to be significantly higher among SLE patients ( p < 0.0001). A significant association was noted between MMP-7 -181 A/G +G/G genotypes with renal ( p = 0.0027) and CNS ( p = 0.0031) manifestations and anti-dsDNA autoantibodies ( p = 0.0312). Serum MMP-7 levels and mRNA expression were elevated in advanced stages of SLE, indicating that MMP-7 is associated with disease activity in SLE.

Do high sensitivity C-reactive protein and serum interleukin-6 levels correlate with disease activity in systemic lupus erythematosuspatients?

INTRODUCTION: Systemic Lupus Erythematosus (SLE) is an inflammatory autoimmune disease where an interplay between acute phase proteins and cytokines are involved in disease activation. AIM AND OBJECTIVES: This case control study was performed to investigate interrelationship between high sensitivity C-reactive proteins (hs-CRP), Interleukin-6 (IL-6) levels and disease activity among SLE patients. MATERIALS AND METHODS: One hundred forty one clinically diagnosed SLE cases were included and disease activity was noted by SLE Disease Activity Index (SLEDAI). Serum IL-6 levels were measure by cytokine multiplex assay. Serum hs-CRP, C3 and C4 levels were measure by nephelometer. The Pearson correlation test was used for correlation between hs-CRP, Il-6 and SLEDAI. RESULTS: Based on SLEDAI, 126 patients (89.4 %) had active disease and 15 patients (10.6%) had inactive disease. Mean hs-CRP levels in SLE patients were significantly higher (12.1+ 11.5 mg/L) than controls (2.41+ 1.37 mg/L) (P < 0.0001). Hs-CRP levels among active SLE were significantly higher (13.5+ 11.4 mg/L) as compared with inactive SLE (4.4 + 2.9 mg/L) (P=0.0002). Similarly, IL-6 levels in SLE patients were significantly higher among active SLE (26.9 + 15.5 pg/ml) as compared with inactive SLE (13.9+ 10.2 pg/ml) (P=0.0001). An inverse correlation between Il-6 and hemoglobin levels between active and inactive SLE was noted (r=-0.46, P <0.0001). CONCLUSION: This study suggests a good correlation between hs-CRP, IL-6 and SLE disease activity indicating their direct involvement in inflammatory conditions associated with disease.

COMT Val158Met genotype is associated with fluctuations in working memory performance: converging evidence from behavioural and single-trial P3b measures.

Intra-subject variability in reaction times (ISV) is a promising endophenotype for several psychiatric conditions, but its neural underpinnings are not yet established. Converging evidence from neuroimaging, molecular genetics, and psychopharmacology suggests that ISV could index catecholaminergically-mediated neural noise. The fine-grained temporal resolution of electroencephalography is ideal for investigating ISV, but only if potential neural correlates of ISV can be assessed in single trials. Based on evidence that ISV is associated with dopaminergic functioning, we apply a recently developed method of single-trial P3b analysis to investigate the association of COMT Val(158)Met genotype with measures of ISV on the behavioural and neural levels at different working memory loads. Greater number of Met alleles was associated with poorer and more intra-individually variable performance on the tasks, and greater latency jitter in single-trial P3bs. These converging results at the behavioural and neurophysiological levels confirm previous observations that prefrontal dopamine availability is associated with stability and accuracy of cognitive performance. Together with previous studies, these data imply pleiotropic cognitive effects of COMT genotype.

The methods and outcomes of cultural adaptations of psychological treatments for depressive disorders: a systematic review.

BACKGROUND: Cultural adaptations of evidence-based psychological treatments (PTs) are important to enhance their universal applicability. The aim of this study was to review systematically the literature on adaptations of PTs for depressive disorders for ethnic minorities in Western countries and for any population in non-Western countries to describe the process, extent and nature of the adaptations and the effectiveness of the adapted treatments. METHOD: Controlled trials were identified using database searches, key informants, previous reviews and reference lists. Data on the process and details of the adaptations were analyzed using qualitative methods and meta-analysis was used to assess treatment effectiveness. RESULTS: Twenty studies were included in this review, of which 16 were included in the meta-analysis. The process of adaptation was reported in two-thirds of the studies. Most adaptations were found in the dimensions of language, context and therapist delivering the treatment. The meta-analysis revealed a statistically significant benefit in favor of the adapted treatment [standardized mean difference (SMD) -0.72, 95% confidence interval (CI) -0.94 to -0.49]. CONCLUSIONS: Cultural adaptations of PTs follow a systematic procedure and lead primarily to adaptations in the implementation of the treatments rather than their content. Such PTs are effective in the treatment of depressive disorders in populations other than those for whom they were originally developed.

Detection of fetal mutations causing hemoglobinopathies by non-invasive prenatal diagnosis from maternal plasma.

BACKGROUND: Prenatal diagnosis of hemoglobinopathies enables couples at risk to have a healthy child. Currently used fetal sampling procedures are invasive with some risk of miscarriage. A non-invasive approach to obtain fetal deoxyribonucleic acid (DNA) for diagnosis would eliminate this risk. AIM: To develop and evaluate a non-invasive prenatal diagnostic approach for hemoglobinopathies using cell-free fetal DNA circulating in the maternal plasma. SETTINGS AND DESIGN: Couples referred to us for prenatal diagnosis of hemoglobinopathies where the maternal and paternal mutations were different were included in the study. MATERIALS AND METHODS: Maternal peripheral blood was collected at different periods of gestation before the invasive fetal sampling procedure was done. The blood was centrifuged to isolate the plasma and prepare DNA. A size separation approach was used to isolate fetal DNA. Nested polymerase chain reaction (PCR)-based protocols were developed for detection of the presence or absence of the paternal mutation. RESULTS AND CONCLUSIONS: There were 30 couples where the parental mutations were different. Of these, in 14 cases the paternal mutation was absent and in 16 cases it was present in the fetus. Using cell-free fetal DNA from maternal plasma, the absence of the paternal mutation was accurately determined in 12 of the 14 cases and the presence of the paternal mutation was correctly identified in 12 of the 16 cases. Thus, this non-invasive approach gave comparable results to those obtained by the conventional invasive fetal sampling methods in 24 cases giving an accuracy of 80.0%. Although the nested PCR approach enabled amplification of small quantities of cell-free DNA from maternal plasma at different periods of gestation after size separation to eliminate the more abundant maternal DNA, an accurate diagnosis of the presence or absence of the paternal mutation in the fetus was not possible in all cases to make it clinically applicable.

Participatory asset mapping and photovoice interviews to scope cultural and community resources to reduce alcohol harm in Chitwan, Nepal.

AIMS: To scope the breadth of existing cultural and community assets and how alcohol drinkers and community health workers perceived them in relation to reducing alcohol-related harm. METHODS: The study was conducted in Chitwan, south-central Nepal, which has considerable alcohol problems. Participatory asset mapping was conducted using field notes, photography, and through engaging with communities to explore how community assets affect alcohol consumption. Semi-structured photovoice interviews were conducted with harmful/hazardous drinkers (AUDIT score 8 to 19) and community health workers. Purposive and snowball sampling were used to recruit participants. During interviews, participants used their photographs to reflect on how community assets influenced alcohol use. Thematic framework analysis was used to analyse the data. RESULTS: We recruited 12 harmful/hazardous drinkers (3 females) and 6 health workers (2 females). The mean AUDIT score of the former was 12.17 (SD ±2.86). Thematic analysis of the photovoice interviews produced three themes: 'influences and impact of families and communities'; 'culture and spirituality'; and 'nature and the environment'. The community mapping produced five assets that promoted alcohol consumption: (1) availability; (2) advertising; (3) negative attitudes towards users; (4) festivals/gatherings; and (5) illiteracy/poverty. Six assets that discouraged consumption were: (1) legislation restricting use; (2) community organisations; (3) cultural/spiritual sites; (4) healthcare facilities; (5) family and communities; and (6) women's community groups. Those from certain ethnic groups consumed more alcohol, experienced more family discord, or felt stigmatised due to their drinking. Assets 'festivals/gatherings' and 'negative attitudes toward users' and the theme 'family and communities' concerned with relationships and community activities were perceived to both promote and reduce alcohol use. CONCLUSIONS: This study provides new insight into a variety of cultural and community assets that promote and reduce alcohol use. The study identifies new possibilities to build on visual participatory and arts-based methods that have potential to be effectively implemented at scale.

Invasive & non-invasive approaches for prenatal diagnosis of haemoglobinopathies: experiences from India.

The thalassaemias and sickle cell disease are the commonest monogenic disorders in India. There are an estimated 7500 - 12,000 babies with ß-thalassaemia major born every year in the country. While the overall prevalence of carriers in different States varies from 1.5 to 4 per cent, recent work has shown considerable variations in frequencies even within States. Thus, micromapping would help to determine the true burden of the disease. Although screening in antenatal clinics is being done at many centres, only 15-20 per cent of pregnant women register in antenatal clinics in public hospitals in the first trimester of pregnancy. There are only a handful of centres in major cities in this vast country where prenatal diagnosis is done. There is considerable molecular heterogeneity with 64 mutations identified, of which 6 to 7 common mutations account for 80-90 per cent of mutant alleles. First trimester foetal diagnosis is done by chorionic villus sampling (CVS) and DNA analysis using reverse dot blot hybridization, amplification refractory mutation system (ARMS) and DNA sequencing. Second trimester diagnosis is done by cordocentesis and foetal blood analysis on HPLC at a few centres. Our experience on prenatal diagnosis of haemoglobinopathies in 2221 pregnancies has shown that >90 per cent of couples were referred for prenatal diagnosis of ß-thalassaemia after having one or more affected children while about 35 per cent of couples were referred for prenatal diagnosis of sickle cell disorders prospectively. There is a clear need for more data from India on non-invasive approaches for prenatal diagnosis.

Five alpha globin chain variants identified during screening for haemoglobinopathies.

BACKGROUND: This study was undertaken to analyse cases of microcytosis, and/or haemolytic anaemia where an unusual peak on HPLC or an abnormal electrophoretic mobility in isolation or along with common beta-globin gene defects was found, and to identify the molecular abnormality in them. PATIENTS AND METHODS: Investigations included a complete blood count, HPLC analysis, cellulose acetate electrophoresis (pH 8.9), heat stability test and DNA sequencing. RESULTS: Five alpha chain variants were identified. This is the first report of Hb Jackson and Hb O Indonesia in the Indian population. The presence of Hb J Meerut along with Hb E and Hb J Paris I with heterozygous beta-thalassaemia are uncommon associations. Hb Sun Prairie would have remained undetected in the heterozygous state. The presence of a homozygous child in the family helped to identify this variant. CONCLUSIONS: This study emphasizes the need to undertake systematic investigations while screening for the beta haemoglobinopathies to identify rare alpha chain variants in a population.

Expression of the matrix metalloproteinases MMP-2 and MMP-9 and their inhibitors TIMP-1 and TIMP-2 in systemic lupus erythematosus patients.

BACKGROUND: The study aimed to look at alterations in expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) and their potential use as biomarkers in the pathogensis of SLE. METHODS: SLE patients (n = 41) and healthy controls (n = 50) were recruited. Quantitative RT-PCR/ELISA assays were performed for expression of MMP and TIMP mRNA in whole blood and PBMC; and corresponding serum protein levels. Intracellular levels of MMP-2 and MMP-9 proteins were analysed by flow cytometry. RESULTS: Based on SLEDAI scores patients were grouped into active (SLEDAI ≥ 10) and inactive cases (SLEDAI < 10). In active cases, MMP-2 expression significantly increased and TIMP-2 expression was decreased (p < 0.0001) both at serum secretion (p = 0.0003) and mRNA (p < 0.0001) levels as compared to inactive cases. MMP-9 and TIMP-1 showed significantly reduced serum secretion and mRNA expression (p < 0.0001) in active cases as compared to inactive cases. Intracellular concentration of MMP-9 was reported to be higher in neutrophils, while MMP-2 was mainly found in lymphocytes of SLE patients as compared to controls. MMP/TIMP ratio profile was altered as SLE disease progresses. INTERPRETATION & CONCLUSIONS: Findings suggest disturbed MMP and TIMP levels have a role in the pathogenesis of SLE.

Spectrum of novel mutations in the human PKLR gene in pyruvate kinase-deficient Indian patients with heterogeneous clinical phenotypes.

Eighteen unrelated pyruvate kinase (PK)-deficient Indian patients were identified in the past 4 years with varied clinical phenotypes ranging from a mild chronic haemolytic anaemia to a severe transfusion-dependent disorder. We identified 17 different mutations in the PKLR gene among the 36 mutated alleles. Ten novel mutations were identified: 427G>A, 499C>A, 1072G>A, 1180G>T, 1216G>A, 1220A>G, 644delG, IVS5 (+20) C>A, IVS9 (+44) C>T, and IVS9 (+93) A>C. A severe syndrome was commonly associated with some mutations, 992A>G, 1436G>A, 1220A>G, 644delG and IVS9 (+93) A>C, in the PKLR gene. Molecular graphics analysis of human red blood cell PK (RPK), based on the crystal structure of human PK, shows that mutations located near the substrate or fructose 1,6-diphosphate binding site may change the conformation of the active site, resulting in very low PK activity and severe clinical symptoms. The mutations target distinct regions of RPK structure, including domain interfaces and catalytic and allosteric sites. In particular, the 1216G>A and 1219G>A mutations significantly affect the interdomain interaction because they are located near the catalytic site in the A/B interface domains. The most frequent mutations in the Indian population appear to be 1436G>A (19.44%), followed by 1456C>T (16.66%) and 992A>G (16.66%). This is the first study to correlate the clinical profile with the molecular defects causing PK deficiency from India where 10 novel mutations that produce non-spherocytic haemolytic anaemia were identified.

Palliative care and symptom relief for people affected by multidrug-resistant tuberculosis.

The World Health Organization (WHO) defines palliative care as the prevention and relief of the physical, psychological, social and spiritual suffering of adults and children with life-threatening illnesses and psycho-social support for their families. Palliative care and symptom relief (PCSR) also addresses suffering in nonlife-threatening situations such as after cure. PCSR should never be considered a substitute for tuberculosis (TB) prevention and treatment, but should be accessible by everyone in need. PCSR can reduce suffering and improve quality of life of patients with end-stage chronic illnesses while reducing costs for health care systems and providing financial risk protection for patients' families. It also may help enable patients to adhere to long and noxious treatments and thereby reduce mortality and help protect public health. Basic PCSR can be taught easily to TB specialists as well as primary care clinicians and delivered in hospitals, clinics or patients' homes combined with infection control. For these reasons, integration of PCSR into multidrug-resistant (MDR) and extensively drug-resistant TB (XDR-TB) treatment programs is medically and morally imperative. We propose an essential package of PCSR for people with M/XDR-TB that includes a set of safe, effective and inexpensive medicines and equipment, social supports for patients and caregivers living in extreme poverty, and necessary human resources. The package aligns with WHO guidance on programmatic management of drug-resistant (DR) TB and should be universally accessible by people affected by M/XDR-TB. We also describe the ethical practice of PCSR for people with M/XDR-TB and identify needed areas of research in PCSR for people with M/XDR-TB.

The Effectiveness of Intravenous Dexmedetomidine on Perioperative Hemodynamics, Analgesic Requirement, and Side Effects Profile in Patients Undergoing Laparoscopic Surgery Under General Anesthesia.

BACKGROUND: There is an upward surge in the use of laparoscopic surgeries due to various advantages when compared to open surgeries. Major advantages are, due to small incisions which are cosmetically acceptable and most of them are now daycare procedures. Problem of economic burden and hospital bed occupancy has been overcome with laparoscopic surgeries. All these advantages are not free from disadvantages, as hemodynamic changes such as hypertension; tachycardia and other surgical-related complications are commonly observed intraoperatively. Dexmedetomidine is one of the α2 agonist drugs which acts at both supraspinal and spinal level and modulate the transmission of nociceptive signals in the central nervous system. The basic effect of dexmedetomidine on the cardiovascular system is to decrease the heart rate and systemic vascular resistance with additional feature of opioid sparing effect. This drug has become an ideal adjuvant during general anesthesia, especially when stress is expected. Hence, the drug was studied in laparoscopic surgeries. AIMS AND OBJECTIVES: (a) To study the effect of dexmedetomidine on hemodynamic parameters during perioperative period in patients undergoing laparoscopic surgery. (b) To study the postoperative sedation score and analgesic requirement. (c) To study the side effect profile of dexmedetomidine. SETTINGS AND DESIGN: Randomized double blind controlled trial. SUBJECTS AND METHODS: After obtaining the Institutional Ethical Clearance, the study was conducted. Forty patients of American Society of Anesthesiologists Class I and II were enrolled in this randomized study. The patients were randomly divided into two groups; group normal saline (NS) and group dexmedetomidine. Patient received either NS or dexmedetomidine in group NS and group dexmedetomidine, respectively, depending upon the allocation. The infusion rate was adjusted according to; loading dose (1 µg/kg) over 10 min and maintenance dose (0.5 µg/kg/h) and perioperative hemodynamics was recorded. Routine general anesthesia was administered in all the patients with conventional technique without deviating from institutional protocols. Postoperatively, Rasmsay sedation score, time taken for request of first analgesic dose, and side effects if any were recorded. STATISTICAL ANALYSIS USED: The categorical factors are represented by the number and frequency (%) of cases. The continuous variables are represented by measures of central frequency and standard deviation. The statistical analysis was done by using unpaired t-test and Chi-square. P < 0.05 was considered statistically significant. RESULTS: Significant hemodynamic changes are observed in NS group during laryngoscopy, intubation, during pneumoperitoneum formation, and during extubation. Hemodynamic stress response in dexmedetomidine group was significantly attenuated. Analgesic requirement during postoperative 24 h were much less in dexmedetomidine group when compared to NS group. No significant side effects were noted except for bradycardia; which was observed in two cases of dexmedetomidine group. CONCLUSION: Dexmedetomidine infusion in the dose of 1 µg/kg body weight as bolus over 10 min and 0.5 µg/kg/h intraoperatively as maintenance dose controlled the hemodynamic stress response in patients undergoing laparoscopic surgery. Use of dexmedetomidine extends the pain free period postoperatively and thereby reducing total analgesic requirement. Thus, dexmedetomidine can be utilized as an ideal anesthetic adjuvant during laparoscopic surgeries.

Pleiotropic Roles of Metalloproteinases in Hematological Malignancies: an Update.

Controlled remodeling of the extracellular matrix (ECM) is essential for cell growth, invasion and metastasis. Matrix metalloproteinases (MMPs) are a family of secreted, zincdependent endopeptidases capable of degradation of ECM components. The expression and activity of MMPs in a variety of human cancers have been intensively studied. They play important roles at different steps of malignant tumor formation and have central significance in embryogenesis, tissue remodeling, inflammation, angiogenesis and metastasis. However, increasing evidence demonstrates that MMPs are involved earlier in tumorigenesis. Recent studies also suggest that MMPs play complex roles in tumor progression. MMPs and membrane type (MT)MMPs are potentially significant therapeutic targets in many cancers, so that designing of specific MMP inhibitors would be helpful for clinical trials. Here, we review the pleiotropic roles of the MMP system in hematological malignancies invitro and invivo models.

Delta globin gene variations leading to reduction in HbA2 levels.

INTRODUCTION: Mutations in the δ-globin gene are not pathogenically relevant, but co-inheritance of δ-globin variants along with ß-globin gene defects can mask the diagnosis of ß-thalassaemia trait. METHODS: Routine haematological parameters were carried out. Molecular analysis of ß-globin gene mutations was carried out by CRDB, ARMS and DNA sequencing. δ- globin gene analysis was carried out by DNA sequencing. RESULTS: In this case study, we report a ß-thalassaemia trait (IVS 1-5G→C) (HBB:c.92 + 5G→C) with HbA2 of 1% showing the presence of δ-globin gene variant HbA2 St. George CD 81 (C→T) (HBD:c.244C→T). A similar observation was reported in another unrelated patient who showed near absence of HbA2 level in HPLC. He showed a presence of δ-globin gene mutation HbA2 Saurashtra CD 100(C→T) (HBD: c.301C→T) and a single 3.7 kb deletion in the α-globin gene. CONCLUSION: In the countries, where ß-thalassaemia is prevalent, an awareness and detection of different δ-globin gene mutations is important, as complex interactions between these haemoglobinopathies can lead to the misdiagnosis of ß-thalassaemia carriers.

Molecular understanding of Indian untransfused thalassemia intermedia.

BACKGROUND: The term thalassemia intermedia describe a form of thalassemia of intermediate severity, between the major transfusion-dependent forms of the disease and the symptomless carrier states. The phenotypic diversity of ß-thalassemia results from its underlying genetic diversity. The wide clinical variability of these conditions leads to major difficulties in their management. The molecular basis of thalassemia intermedia is very heterogeneous. The clinical and hematological course of ß-thalassemia intermedia is influenced by a number of genetic factors. METHODS AND RESULTS: The main aim of the study was to evaluate the effect of globin and nonglobin genetic modifiers on clinical severity of the disease. The study group consisted of 66 homozygous patients with ß-thalassemia [40 transfusion-dependent thalassemia (TDT), 26 nontransfusion-dependent thalassemia (NTDT)]. Hepatosplenomegaly was pronounced in the NTDT group. The presence of associated α-thalassemia was significantly higher in untransfused patients (P < 0.05). The milder ß-thalassemia mutations, such as Cap site +1 (A → C), -88 (C → T), and -87 (C → G), were observed mainly in the NTDT group (9.61%) as against patients with TDT (1.25%). The cis-DNA haplotypes, motifs, or polymorphisms around the gamma-globin genes [(AT)x (T)y motif (38.4%), XmnI (76.92%)and the Aγ-δ intergenic region haplotype T (73.07%) and Pre Gγ globin gene haplotype TAG (46.15%)] contributed significantly in amelioration of the disease severity. CONCLUSION: Our study emphasizes the complexity of genetic interactions that underlie the phenotype of ß-thalassemia and highlights the importance of epistatic factors and the regulation of HbF production in ß-thalassemia syndromes.

Dexmedetomidine with low-dose ketamine for cataract surgery under peribulbar block in a patient with Huntington's chorea.

Huntington's chorea (HC) is a rare hereditary disorder of the nervous system. It is inherited as an autosomal dominant disorder and is characterized by progressive chorea, dementia, and psychiatric disturbances. There are only a few case reports regarding the anesthetic management of a patient with HC and the best anesthetic technique is yet to be established for those patients which are at higher risk of perioperative complications. We report the anesthetic management of a 64-year-old patient with HC admitted for cataract surgery.