Cardiac Changes and Their Reversal Following Curative Surgery in Pheochromocytoma: PheoCard Prospective Cohort Study.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are catecholamine producing tumors of chromaffin cell origin, known to cause varied cardiovascular manifestations from hypertension to myocardial infarction. This study sought to objectively evaluate the cardiac changes in PPGL patients and their reversal following curative surgery. METHODS: The PheoCard study was registered in ClinicalTrials.gov (NCT05082311) and involved 35 consecutive PPGL patients managed as per standard protocol involving alpha blockade followed by curative surgery. They underwent detailed cardiac evaluation using 2D-echocardiography and speckle tracking echocardiography at the time of diagnosis, 7-10 days after alpha blockade, and at 7 days, 3 months, and 6 months after surgical removal. Age- and gender-matched essential hypertensives and healthy individuals (10 in each group) served as two control groups. RESULTS: Patients with PPGLs had significantly higher mean blood pressure, left ventricle end-diastolic dimension and volume (LVEDD, LVEDV), left ventricle end-systolic volume (LVESV), septal wall thickness, LV hypertrophy, lower mean LV ejection fraction (LVEF), early diastolic mitral annular velocity (E/A), decreased amplitude of LV longitudinal strain, and increased circumferential strain (p < 0.001) when compared with the control groups at baseline. After alpha blockade, there was marked reduction in the mean LVEDD, LVEDV, LVESV, and normalization of E/A ratio (p < 0.001) in the PPGL patients. Following curative surgery (normalization of fractionated urinary metanephrines at 7-10 days post-operatively), there was early improvement in all echocardiographic parameters and it continued to improve even at 6 months after surgery. There was marked improvement in the global longitudinal strain as seen on serial speckle tracking echocardiography with recovery of most of the segments of LV depicting the reversal of subclinical endocardial dysfunction (p < 0.001). CONCLUSION: PPGL patients despite normal systolic function have subclinical LV diastolic dysfunction which is reversed after curative surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT05082311.

Pre-Operative Selective vs Non-Selective α-Blockade in Pheochromocytoma-Paraganglioma Patients Undergoing Surgery: A Meta-Analysis.

The main objective of this systematic review and meta-analysis was to review, assess and report on the studies that have evaluated selective alpha blockade (SAB) vs. non-selective alpha blockade (NSAB) therapy in patients undergoing surgery for pheochromocytomas and paragangliomas (PPGL). We performed a systematic search of electronic databases. A meta-analysis was conducted to examine the effectiveness of the two blockades. RevMan 5.3 was used for the meta-analysis. Of the eight articles that met the inclusion criteria, there was only one randomized control trial. Meta-analysis showed that there was no significant difference between the groups SAB and NSAB with regard to intra-operative systolic blood pressure (SBP) >160 mm Hg (relative risk (RR) 0.95 [95% CI 0.57, 1.56] P = 0·83) and intra-operative vasopressor requirement (RR 1.10 [95% CI 0.96, 1.26] P = 0·16). Meta-analysis revealed that there was a significant difference between the groups (SAB vs NSAB) with respect to post-operative vasopressor requirement (RR 1.66 [95% CI 1.0, 2.74] P = 0·05). There was no significant difference between the groups with respect to post-operative complications (RR 0.84 [95% CI 0.58, 1.22] P = 0·36). In conclusion, as patients blocked selectively may have a higher incidence of vasodilator requirement intra-operatively, NSAB offers some haemodynamic advantage over SAB. However, NSAB's real clinical benefit cannot be ascertained with the current studies as this difference did not result in any significant advantage over SAB with regard to morbidity or mortality.

Natural Orifice Endoscopic Thyroidectomy via Transoral Vestibular Approach (TOVA): Single Surgeon Experience from North India.

The transoral vestibular approach (TOVA) is the shortest route for endoscopic thyroidectomy (ET) to approach the thyroid and is a totally scar free procedure, hence it has a clear cosmetic advantage not only over conventional open thyroid surgery but also over other remote access approaches for ET like axilla, breast and chest wall approaches. The aim of this study was to evaluate the feasibility, safety and our initial outcomes of TOVA and highlight the advantages of 3D endoscopic equipment in remote access thyroid surgery. We reviewed our prospectively maintained database who underwent ET. 42 patients who fulfilled the stringent inclusion criteria were offered TOVA. We have used novel Trans-vestibular approach with 3D technology for endoscopic thyroid surgery in all cases. Clinico-demographic profile, investigations, operative details, histopathology and postoperative complications and follow-up data were analyzed by using statistical analysis with SPSS19.00 version. Out of 203 ET operated during study period, 42 (20.69%) patients were operated through TOVA. Hemithyroidectomy were performed in all the patients. There were 3 men and 39 women (M:F = 1:13). Mean tumor size was 3.54 ± 1.17 cm. All patients were euthyroid. All patient had cytological diagnosis of Bethesda category II-IV and all underwent hemithyroidectomy. Mean operation time was 107.71 ± 17.60 min and post-operative length of hospital stay was 2.90 ± 1.28 days. Besides magnification, 3D endoscopy provided excellent depth perception which helped in precise dissection in the restricted space and aided in identification and preservation of the two most vital structures i.e. recurrent laryngeal nerve and parathyroid glands. As most of our patients present with larger goitres, not many patients desirous of ET can be offered TOVA. This novel TOVA has fairly stringent inclusion criteria, however it is the only approach which offers completely scarless endoscopic thyroidectomy and should be offered to eligible patients desirous of ET.

Assessment of iodine nutrition of schoolchildren in Gonda, India, indicates improvement and effectivity of salt iodisation.

OBJECTIVE: To study the total goitre rate (TGR), urinary iodine concentration (UIC) and salt iodine content among schoolchildren in a previously endemic area for severe iodine deficiency disorder (IDD). DESIGN: Cross-sectional epidemiological study. SETTING: The study was carried out in the Gonda district (sub-Himalayan region) of North India. PARTICIPANTS: Nine hundred and seventy-seven schoolchildren (6-12 years) were studied for parameters such as height, weight, UIC and salt iodine content. Thyroid volume (TV) was measured by ultrasonography to estimate TGR. RESULTS: The overall TGR in the study population was 2·8 % (95 % CI 1·8, 3·8). No significant difference in TGR was observed between boys and girls (3·5 % v. 1·9 %, P = 0·2). There was a non-significant trend of increasing TGR with age (P = 0·05). Median UIC was 157·1 µg/l (interquartile range: 94·5-244·9). At the time of the study, 97 % of salt sample were iodised and nearly 86 % of salt samples had iodine content higher than or equal to 15 part per million. Overall, TGR was significantly lower (2·8 % v. 31·0 %, P < 0·001), and median UIC was significantly higher (157·1 v. 100·0 µg/l, P < 0·05) than that reported in the same area in 2009. CONCLUSIONS: A marked improvement was seen in overall iodine nutrition in the Gonda district after three and a half decades of Universal Salt Iodisation (USI). To sustainably control IDD, USI and other programmes, such as health education, must be continuously implemented along with putting mechanisms to monitor the programme at regular intervals in place.

Care of inflammatory bowel disease patients during coronavirus disease-19 pandemic using digital health-care technology.

Background and Aim: Although telemedicine is an option for the care of inflammatory bowel disease (IBD) patients during the Coronavirus Disease (COVID)-19 pandemic, its feasibility and acceptability data are scant. Data on the frequency of COVID-19 among patients with IBD, quality of life (QOL), access to health care, psychological stress, and anxiety during the COVID-19 pandemic are scant. Methods: Video/audio consultation for IBD patients was undertaken after a web-based appointment, and data on acceptability, IBD control, Hospital Anxiety Depression Scale (HADS), and World Health Organization Quality of Life questionnaire (WHOQOL-Bref) were obtained electronically. IBD patients were assessed for COVID-19 symptoms or contact history and tested using reverse transcriptase polymerase chain reaction (RT-PCR) on naso- oro-pharyngeal swabs, and data were compared with 16,317 non-IBD controls. Results: Teleconsultation was feasible and acceptable. IBD patients had COVID-19 as frequently as non-IBD controls despite immunosuppressive therapy, possibly due to their awareness and preventive practices. Although the physical, psychological, and social QOL scores during the COVID-19 pandemic were comparable to the prepandemic period, the environmental scores were worse. Psychological tension and interference with work due to pain were lower during the pandemic, which might be influenced by the control of the disease. Conclusions: Teleconsultation is a feasible and acceptable alternative for IBD patients. They had COVID-19 as frequently as non-IBD controls despite a high frequency of immunosuppressive treatment, possibly due to their awareness of the disease and preventive practices. The QOL scores (except the environmental domains) and psychological issues were quite comparable or even better during the COVID-19 pandemic than earlier.

Uncertainty quantification based cloud parameterization sensitivity analysis in the NCAR community atmosphere model.

Using uncertainty quantification techniques, we carry out a sensitivity analysis of a large number (17) of parameters used in the NCAR CAM5 cloud parameterization schemes. The LLNL PSUADE software is used to identify the most sensitive parameters by performing sensitivity analysis. Using Morris One-At-a-Time (MOAT) method, we find that the simulations of global annual mean total precipitation, convective, large-scale precipitation, cloud fractions (total, low, mid, and high), shortwave cloud forcing, longwave cloud forcing, sensible heat flux, and latent heat flux are very sensitive to the threshold-relative-humidity-for-stratiform-low-clouds ([Formula: see text] and the auto-conversion-size-threshold-for-ice-to-snow [Formula: see text] The seasonal and regime specific dependence of some parameters in the simulation of precipitation is also found for the global monsoons and storm track regions. Through sensitivity analysis, we find that the Somali jet strength and the tropical easterly jet associated with the south Asian summer monsoon (SASM) show a systematic dependence on [Formula: see text] and [Formula: see text]. The timing of the withdrawal of SASM over India shows a monotonic increase (delayed withdrawal) with an increase in [Formula: see text]. Overall, we find that [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] are the most sensitive cloud parameters and thus are of high priority in the model tuning process, in order to reduce uncertainty in the simulation of past, present, and future climate.

Fungating Breast Cancer: Experience in Low and Middle Income Country.

Fungating breast cancer (FBC) is a rare entity in developed nations. But this occurrence is not uncommon in our country. The aim of this study was to review clinico-pathologic profile and outcomes of FBC in a developing country. This retrospective study consisted of patients with FBC managed at our institute (Jan 2005-Dec 2015). Clinico-pathologic profile, management details, and outcomes were analyzed. The Kaplan-Meier method was used to determine overall survival (OS). Log-rank test was performed to compare survival in various subgroups. Seventy-nine patients were detected to have FBC constituting 3.3% of all breast cancers and 24.8% of those having T4b lesions. Mean age of the patients was 55 + 11 years. Ninety-six percent were women and 67% belonged to rural areas. A total of 75% women were postmenopausal. Mean duration of lump was 16 + 11 months. The mean tumor size was 8+ 2 cm. Eighty-seven percent had axillary lymph node involvement and 42% distant metastases. Fifty-eight percent (n = 46) patients had stage III and 42% (n = 33) stage had IV tumors. Hormone receptor (HR) positivity was noted in 44% (n = 35) and HER2/neu overexpression in 39% (n = 31) tumors, whereas 32% (n = 25) were triple negative. Overall, 95% (n = 75) of patients received chemotherapy, 91% (n = 72) patients underwent mastectomy, and 76% (n = 60) loco-regional radiotherapy. Median duration of follow-up was 40 (2-93) months. Median survival was 36 months, and 5-year OS was 40%. Except for stage (53% vs 22%, p = 0.005), no other factor influenced OS. Multimodality therapy in FBS results in good symptom palliation and comparable survival to stage III and IV patients without fungating tumors.

Low-cost Fluorescein as an Alternative to Radio-colloid for Sentinel Lymph Node Biopsy-a Prospective Validation Study in Early Breast Cancer.

BACKGROUND: Sentinel lymph node biopsy (SLNB) using radio-pharmaceutical (RP) and a blue dye is gold standard for axillary staging in clinically node-negative early breast cancer. High costs and limited availability of RP and/or gamma probe are major deterrents in performing SLNB in developing countries. Fluorescence-guided SLNB can obviate the need for RP and gamma probe. Fluorescein is an inexpensive fluorescent lymphatic tracer. In this study, we compared SLN identification rate (SLN-IR) and false negative rates (FNR) of fluorescein-guided SLNB and radio-guided SLNB using 99mTc-Sulfur-colloid, in isolation, or in combination with methylene blue dye (MBD). METHODS: Sixty-five cN0 early and large operable breast cancer patients underwent validation SLNB using fluorescein (and blue LED light), 99mTc-Sulfur-colloid (and gamma probe) and MBD. Inj Fluorescein 4% was injected, 1 ml each peri-tumoral and sub-areolar five minutes before axillary incision. Axillary dissection was performed irrespective of SLNB histology. The SLN-IR and FNR with various tracers and their combinations were compared. RESULTS: The mean number of SLNs identified was 3.5 ± 1.8 (range 1-6). The SLN-IR using RP alone was 94%, fluorescein alone was 92%, and MBD alone was 82%. The SLN-IR using fluorescein plus MBD combination was 95.4%, compared to 97% using MBD plus RP combination. FNR was 6.3% using fluorescein plus MBD, as well as RP plus MBD combinations. CONCLUSIONS: SLN-IR of > 90% and SLN-FNR of < 10% using fluorescein plus MBD combination are in acceptable range, and are comparable to that of RP plus MBD combination. Fluorescein can replace RP for performing SLNB, in combination with MBD.

Surgical Management of Primary Hyperparathyroidism in the Era of Focused Parathyroidectomy: A Study in Tertiary Referral Centre of North India.

BACKGROUND: Despite the benefits of focused parathyroidectomy (FPTx), few studies have questioned its durability with lower long-term cure rates than bilateral or conventional parathyroidectomy (CPTx). The objective of this study is to bring out the information on the type of surgical management versus cure rate, recurrence, and role of intra-operative parathyroid hormone (IOPTH) level monitoring of PHPT patients. MATERIAL AND METHODS: This was a retrospective study of all PHPT patients treated at our center based on operative approach (CPTx vs FPTx) or use of IOPTH. Treatment failure was divided into persistent or recurrent disease, based on documentation of hypercalcemia in combination with an inappropriate PTH within 6 months or more of surgery, respectively. RESULTS: Overall, 50.78% patients underwent CPTx and 49.32% FPTx. 29 FPTx were converted to CPTx. Intention to treat analysis between CPTx and FPTx showed that the persistence rate was not statistically different at 2.54% and 4%, respectively (P = 0.98). Furthermore, when the persistence rate was scrutinized by a treatment received (TR) instead of ITT analysis, the persistence rate was higher for the patients who underwent TR-CPTX than for the patients subjected to TR-FPTX (3.22% vs 1.08%) but not significant statistically. We further analyzed the outcome of FPTx with IOPTH (n = 213) and FPTx without IOPTH (n = 28). The outcome did not differ between two groups statistically. CONCLUSION: FPTx yields a similar success rate as compared to CPTx even in symptomatic PHPT patients and can be performed safely even without intra-opeartive adjunct IOPTH in selected patients.

Indian Summer Monsoon Simulations: Usefulness of Increasing Horizontal Resolution, Manual Tuning, and Semi-Automatic Tuning in Reducing Present-Day Model Biases.

Coupled Global Climate Models (CGCMs) of the Coupled Model Intercomparison Project Phase 5 (CMIP5) are unable to resolve the spatial and temporal characteristics of the South Asian Monsoon satisfactorily. A CGCM with the capability to reliably project the global as well as the regional climatic features would be a valuable tool for scientists and policymakers. Analysis of 28 CMIP5 models highlights varying degree of biases in precipitation and 2 m surface air temperature (T2m) over south Asia, and the Community Earth System Model (CESM) developed at the National Center for Atmospheric Research is found to be one of the best performing models. However, like all other CMIP5 models, CESM also has some inherent model biases. Using CESM, it is found that the precipitation and T2M biases reduce with increase in the model horizontal resolution from 2° to 0.5°. Further, a few deep convective parameters in the Zhang-McFarlane convection scheme are tuned for 2° and 1° model resolutions using both manual and semi-automatic model tuning methods. Comparing results from the two tuning methods we find that the performance of the manually tuned model is better than that of the semi-automated one.

Clinico-Pathological Profile of Anaplastic Thyroid Carcinoma in an Endemic Goiter Area.

INTRODUCTION: Anaplastic thyroid cancers (ATCs) usually present in the sixth to seventh decades of life and little is known about the disease in young patients. The aim was to analyze the clinicopathological characteristics diagnosed with ATC in an iodine-deficient area. MATERIAL AND METHODS: The medical records of 100 patients diagnosed with ATC at a tertiary care hospital between 1991 and 2013 were reviewed. RESULTS: The mean age of patient was 58 years. About 34 patients were ≤50 years. The common presentation was that of a rapidly growing fixed and hard mass (64%). Due to rapid expansion, 27% patients experienced severe pain. About one-third presented as sudden enlargement of pre-existing goiter over few weeks. The median duration of symptoms before diagnosis was 3 months. About 41% presented with lymph node enlargement and 31% with distant metastasis. The diagnosis was established with fine-needle aspiration or core biopsy. Histopathology was available in 32 patients and showed four major patterns: spindle cell (9), giant cell (7), epithelioid (5), squamoid (1), mixed type in 10 patients. Eight patients presenting with stridor required emergency tracheostomy for airway control. Total thyroidectomy with or without lymph node dissection was possible in 21 patients. Patients received radiotherapy with or without chemotherapy. Median overall survival was 3 months. Overall survival was significantly better in patients receiving some form of treatment. CONCLUSION: ATC in endemic goiter areas presents at an earlier age. One-third of ATC is due to anaplastic transformation of pre-existing goiter and majority of the patients refuse treatment due to dismal outcome.

Helicobacter pylori infection in dyspeptic patients in an industrial belt of India.

The present study is done to study different aspects of Helicobacter pylori (H. pylori) such as its prevalence, association with upper gastrointestinal pathology, diagnosis and treatment outcome. Gastric antral biopsy and serology for H. pylori was done for all dyspeptic patients. Histopathology, gram stain and biopsy urease test was done from the gastric biopsy specimen. The prevalence of H. pylori infection was 58.8%. The sensitivity, specificity, positive and negative predictive value for histopathology was 96.9%, 100%, 100% and 95.8%, respectively; for biopsy urease test 80.4%, 100%, 100% and 78.2%, respectively; for gram stain 85.6%, 97.1%, 97.6% and 82.5%, respectively, and for serology 94.8%, 77.9%, 86% and 91.4%, respectively. Mostly peptic ulcer and duodenitis cases followed by chronic active gastritis were associated with H. pylori infection. Repeat biopsy revealed eradication of H. pylori in 90.7% cases. In dyspeptic patients, endoscopic biopsy not only detects H. pylori infection, but also reveals different gastric pathologies.

Pathogenesis of cerebral malaria: new diagnostic tools, biomarkers, and therapeutic approaches.

Cerebral malaria is a severe neuropathological complication of Plasmodium falciparum infection. It results in high mortality and post-recovery neuro-cognitive disorders in children, even after appropriate treatment with effective anti-parasitic drugs. While the complete landscape of the pathogenesis of cerebral malaria still remains to be elucidated, numerous innovative approaches have been developed in recent years in order to improve the early detection of this neurological syndrome and, subsequently, the clinical care of affected patients. In this review, we briefly summarize the current understanding of cerebral malaria pathogenesis, compile the array of new biomarkers and tools available for diagnosis and research, and describe the emerging therapeutic approaches to tackle this pathology effectively.

Investigating the Pathogenesis of Severe Malaria: A Multidisciplinary and Cross-Geographical Approach.

More than a century after the discovery of Plasmodium spp. parasites, the pathogenesis of severe malaria is still not well understood. The majority of malaria cases are caused by Plasmodium falciparum and Plasmodium vivax, which differ in virulence, red blood cell tropism, cytoadhesion of infected erythrocytes, and dormant liver hypnozoite stages. Cerebral malaria coma is one of the most severe manifestations of P. falciparum infection. Insights into its complex pathophysiology are emerging through a combination of autopsy, neuroimaging, parasite binding, and endothelial characterizations. Nevertheless, important questions remain regarding why some patients develop life-threatening conditions while the majority of P. falciparum-infected individuals do not, and why clinical presentations differ between children and adults. For P. vivax, there is renewed recognition of severe malaria, but an understanding of the factors influencing disease severity is limited and remains an important research topic. Shedding light on the underlying disease mechanisms will be necessary to implement effective diagnostic tools for identifying and classifying severe malaria syndromes and developing new therapeutic approaches for severe disease. This review highlights progress and outstanding questions in severe malaria pathophysiology and summarizes key areas of pathogenesis research within the International Centers of Excellence for Malaria Research program.

Microvascular obstruction and endothelial activation are independently associated with the clinical manifestations of severe falciparum malaria in adults: an observational study.

BACKGROUND: Microvascular obstruction and endothelial dysfunction have both been linked to tissue hypoperfusion in falciparum malaria, but their relative contributions to the disease's pathogenesis and outcome are unknown. METHODS: Microvascular blood flow was quantified in adults with severe falciparum malaria on their admission to hospital; plasma biomarkers of endothelial function were measured simultaneously. The relationship between these indices and the patients' clinical findings and in-hospital course was examined. RESULTS: Microvascular obstruction was observed in 119/142 (84 %) patients; a median (interquartile range (IQR)) of 14.9 % (6.6-34.9 %) of capillaries were obstructed in patients that died versus 8.3 % (1.7-26.6 %) in survivors (P = 0.039). The proportion of obstructed capillaries correlated with the estimated parasite biomass (rs = 0.25, P = 0.004) and with plasma lactate (rs = 0.38, P <0.0001), the strongest predictor of death in the series. Plasma angiopoietin-2 (Ang-2) concentrations were markedly elevated suggesting widespread endothelial activation; the median (IQR) Ang-2 concentration was 21.9 ng/mL (13.4-29.4 ng/mL) in patients that died versus 14.9 ng/mL (9.8-29.3 ng/mL) in survivors (P = 0.035). Ang-2 concentrations correlated with estimated parasite biomass (rs = 0.35, P <0.001) and plasma lactate (rs = 0.37, P <0.0001). Microvascular obstruction and Ang-2 concentrations were not significantly correlated with each other (rs = 0.17, P = 0.06), but were independently associated with plasma lactate (P <0.001 and P = 0.002, respectively). CONCLUSIONS: Microvascular obstruction and systemic endothelial activation are independently associated with plasma lactate, the strongest predictor of death in adults with falciparum malaria. This supports the hypothesis that the two processes make an independent contribution to the pathogenesis and clinical manifestations of the disease.

The clinical implications of thrombocytopenia in adults with severe falciparum malaria: a retrospective analysis.

BACKGROUND: Thrombocytopenia is a common finding in adults with severe falciparum malaria, but its clinical and prognostic utility is incompletely defined. METHODS: Clinical and laboratory data from 647 adults with severe falciparum malaria were analysed retrospectively to determine the relationship between a patient's platelet count on admission to hospital and their subsequent clinical course. RESULTS: On admission, 614 patients (94.9%) were thrombocytopenic (platelet count <150 × 10(9)/L) and 328 (50.7%) had a platelet count <50 × 10(9)/L. The admission platelet count was inversely correlated with parasite biomass (estimated from plasma PfHRP2 concentrations, rs = -0.28, P = 0.003), the degree of microvascular sequestration (measured with orthogonal polarizing spectral imaging, rs = -0.31, P = 0.001) and disease severity (the number of World Health Organization severity criteria satisfied by the patient, rs = -0.21, P <0.001). Platelet counts were lower on admission in the patients who died (median: 30 (interquartile range 22 to 52) × 10(9)/L versus 50 (34 to 78) × 10(9)/L in survivors; P <0.001), but did not predict outcome independently from other established laboratory and clinical prognostic indices. The 39 patients (6%) with profound thrombocytopenia (platelet count <20 × 10(9)/L) were more likely to die (odds ratio: 5.00, 95% confidence interval: 2.56 to 9.75) than patients with higher platelet counts, but these high-risk patients could be identified more rapidly with simple bedside clinical assessment. The admission platelet count did not reliably identify the 50 patients (7.7%) with major bleeding during the study. CONCLUSIONS: Thrombocytopenia is a marker of disease severity in adults with falciparum malaria, but has limited utility in prognostication, triage and management.

Interferon-γ (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-α receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations.

Pro-inflammatory cytokines IFNγ and IFNα function through their cellular receptors IFNγR1 and IFNαR1, respectively to mediate immune processes during malaria infection. A total of 21 SNPs, 2 ins/del polymorphisms and a microsatellite repeat, selected on the basis of their reported association with infectious diseases including malaria in world populations, were analysed for association with Plasmodium falciparum malaria susceptibility in a case-control study with adult patients and ethnically-matched controls drawn from a disease meso- to hyperendemic and a nonendemic region of India. Among the five IFNG SNPs tested, an intron 3 and a 3'UTR SNP associated with disease in the endemic region. In addition, large (CA)n repeats of IFNG intron 1 associated with protection from severe malaria in the endemic region (severe vs. control, odds ratio=0.21, 95% CI=0.08-0.52, P=1.3 × 10(-4)). The TA11CAG haplotype (rs2069705 T/C, rs2430561 A/T, rs3138557 (CA)n, rs2069718 T/C, rs2069727 A/G, rs2069728 G/A) carrying a short CA11 repeat also exhibited very strong association with severe malaria, particularly in the endemic region (severe vs. control, OR=14.56, 95% CI=3.39-85.81, P=3 × 10(-5)). One SNP each from the IFNA8 and IFNA17 of IFNA gene cluster had a protective effect in the non-endemic region but not in the endemic region. A promoter and an intron 2 SNP of IFNAR1 were risk factors for disease and the IFNAR1 haplotype GCCAGG (rs2843710 C/G, rs2850015 C/T, +6993 C/T, rs2243594 A/G, rs1012335 G/C, rs2257167 G/C) carrying both the risk alleles strikingly associated with disease manifestation in the endemic region (severe vs. control, OR=27.14, 95% CI=3.12-1254, P=2 × 10(-5); non-severe vs. control, OR=61.87, 95% CI=10.08-2521, P=1 × 10(-8)). The data indicates dissimilar contribution of cytokine and cytokine receptor variants to disease in populations residing in areas of differential malaria endemicity.

Magnetic resonance imaging during life: the key to unlock cerebral malaria pathogenesis?

Understanding the mechanisms underlying the pathophysiology of cerebral malaria in patients with Plasmodium falciparum infection is necessary to implement new curative interventions. While autopsy-based studies shed some light on several pathological events that are believed to be crucial in the development of this neurologic syndrome, their investigative potential is limited and has not allowed the identification of causes of death in patients who succumb to it. This can only be achieved by comparing features between patients who die from cerebral malaria and those who survive. In this review, several alternative approaches recently developed to facilitate the comparison of specific parameters between fatal, non-fatal cerebral malaria and uncomplicated malaria patients are described, as well as their limitations. The emergence of neuroimaging as a revolutionary tool in identifying critical structural and functional modifications of the brain during cerebral malaria is discussed and highly promising areas of clinical research using magnetic resonance imaging are highlighted.