Ferroportin (SLC40A1) gene in thalassemic patients of Indian descent.
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Alleles↗
Biomedical subjects
M Pradhan
Publications and source records attributed to M Pradhan.
The spectrum of renal tubular acidosis in paediatric Sjögren syndrome.
OBJECTIVES: Renal tubular acidosis (RTA) is a well-recognized extraglandular complication of adult Sjögren syndrome (SS) but has been reported only rarely in paediatric SS. We wished to describe the natural history of RTA in paediatric SS. METHODS: We performed a chart and literature review. Inclusion criteria were primary or secondary SS with onset before 18 yr of age, complicated by RTA before 18 yr of age. RESULTS: Twelve cases were identified: two from chart review and 10 from the literature. RTA was mostly associated with primary SS. RTA was detected at the onset of SS or up to 9 yr later. The clinical spectrum ranged from nearly silent to life-threatening, with plasma pH and serum potassium as low as 7.0 and 1.2 mEq/l, respectively. Hypokalaemia was present in 92%. Half the patients presented with profound weakness or paralysis, most likely from hypokalaemia. Proximal, distal and mixed RTA were detected, reflecting a diffuse 'tubulopathy' from interstitial nephritis, which was the predominant histopathological finding. Diabetes insipidus was the most frequent renal comorbidity. The RTA stabilized in 82% of the cases and resolved in one case. Only one patient had long-term unstable RTA. CONCLUSIONS: RTA is an under-recognized complication of paediatric SS. It can be life-threatening in the acute phase but generally has a good long-term renal outcome. SS should be considered in the older child with otherwise unexplained RTA. Likewise, RTA should be excluded in children and adolescents with SS who develop weakness, fatigue or growth failure. Early recognition would reduce long-term complications such as growth failure.
Acidosis, Renal Tubular↗
Hemoglobin E-beta thalassemia: factors affecting phenotype.
The phenotype of E-beta-thalassemia is affected by several genetic factors. The aim of this study was to analyze severity of E-beta-thalassemia and correlate with HbE, HbF, E/F ratios, beta-mutation and Xmn I polymorphism. Thirty cases of E-beta-thalassemia (23 with childhood onset) were studied. HbE levels were quantitated by HPLC. Xmn1 polymorphism and beta-mutations were studied by PCR-RFLP and ARMS respectively. Commonest features were pallor (100%), splenomegaly (74%), and hepatomegaly (65%), 43% (10/23) were on regular transfusions at diagnosis. One case presented with paraplegia. Patients heterozygous for Xmn I polymorphism (+/-) had later onset (>3 yrs) compared to homozygous (-/-) absence (0.5-2.8 yrs). Most (69.6%) showed beta-mutation IVS 1-5 (G-->C). Negative correlation was found between age of onset and HbE. Thus, presentation is similar to previously reported Thai cases. Heterozygosity of Xmn I polymorphism also delays disease onset. Early diagnosis facilitates appropriate management and prenatal diagnosis.
Child↗
Spectrum of holoprosencephaly.
OBJECTIVE: To conduct a clinical study of holoprosencephaly (HPE). METHOD: Thirteen cases of HPE were studied regarding their clinical features, family history, and prenatal and imaging studies. Chromosomal analysis was done whenever fresh sample was available. RESULTS: Six cases were antenatally detected by ultrasound; four cases were stillborn. Three cases were identified by neuroimaging done a part of evaluation of developmental delay or cleft lip. Eleven of them had facial anomalies characteristics of HPE. Two of these had subtle facial features and microcephaly. Karyotype was abnormal in 2 of 7 cases studied. CONCLUSION: Most of the cases of HPE present antenatally or at birth. Milder forms like lobar and semilobar can present as developmental delay during infancy. Facial anomalies are usually associated with HPE. Chromosomal study of the case and clinical examination of the parents is essential for providing information regarding risk of recurrence to the family.
Abnormalities, Multiple↗
High frequency of hepatitis B virus infection in patients with beta-thalassemia receiving multiple transfusions.
BACKGROUND AND OBJECTIVES: Hepatitis B virus (HBV) may occasionally be transmitted through transfusion of blood units that are hepatitis B surface antigen (HBsAg) negative but HBV DNA positive. Children with beta-thalassemia are particularly susceptible to HBV because they receive multiple blood transfusions. These children have high infection rates despite vaccination against HBV. Post-vaccination infections may be a result of viruses harbouring surface (S)-gene mutations (e.g. G587A) in a region critical for reactivity to antibody to hepatitis B surface antigen (anti-HBs). The true prevalence of HBV in individuals with beta-thalassemia has not been studied previously. PATIENTS AND METHODS: Seventy patients with beta-thalassemia (median age 6 years; range 8 months to 22 years; 49 male), who had received seven to 623 (median 61) units of blood each and three doses (10/20 micro g) of HBV vaccine (Engerix B) before presentation to us, were included in the study; 50 of the 70 patients had received transfusions prior to vaccination. Enzyme-linked immunoassay for serological markers [HBsAg, antibody to hepatitis B core antigen (anti-HBc) and quantitative anti-HBs] and polymerase chain reaction (PCR) followed by Southern hybridization for molecular detection of hepatitis B, was performed on all samples. The PCR-amplified product was cloned, sequenced and the nucleotide and deduced amino acid sequences for the HBV S and polymerase (P) genes were analysed for mutations. RESULTS: Four of 70 (5.7%) individuals with beta-thalassemia were HBsAg positive and 14 (20%) were anti-HBc positive. The prevalence of serological markers increased with number of transfusions (P < 0.01). Of 70 patients, 53 (75.7%) had an anti-HBs titre of > 10 IU/l following vaccination and 17 (24.3%) were non-responders (< 10 IU/l); 22 (31.4%) of the 70 were DNA positive. The frequency of HBV infection in beta-thalassemia was similar in vaccine responders and non-responders. The virus was of subtype ayw (genotype D) in the five DNA-positive samples in which a 388-nucleotide region of the S gene was sequenced. Mutations occurred at 13 positions in the S gene and at 10 positions in the P gene. Hydrophobicity plots revealed differences in amino acid regions 117-165 and 195-211. Some of these amino acid substitutions coincided with the putative cytotoxic T-lymphocyte epitopes of both S and P proteins. CONCLUSIONS: A high frequency of HBV infection was seen using molecular methods in thalassemic patients. The frequency of infection was similar in vaccine responders and non-responders. A number of mutations were observed in the S gene, which could have implications for viral replication as well as virus-host cell interaction.
Adolescent↗
Setting priorities for patient safety.
BACKGROUND: Current "flags" for adverse events (AEs) are biased towards those with serious outcomes, potentially leading to failure to address mundane common problems. AIM: To provide a basis for setting priorities to improve patient safety by ranking adverse events by resource consumption as well as by outcome. This was done by classifying a set of AEs, according to how they may be prevented, into "Principal Natural Categories" (PNCs). SETTING: AEs associated with a representative sample of admissions to Australian acute care hospitals. DESIGN: AEs were classified into PNCs which were ranked by overall frequency, an index of resource consumption (a function of mean extended hospital stay and the number of cases in each PNC), and severity of outcome. RESULTS: The 1712 AEs analysed fell into 581 PNCs; only 28% had more than two cases. Most resource use (60%) was by AEs which led to minor disabilities, 36% was by those which led to major disabilities, and 4% by those associated with death. Most of the events with serious outcomes fell into fewer than 50 PNCs; only seven of these PNCs had more than six cases resulting in serious outcomes. CONCLUSIONS: If interventions for AEs are triggered only by serious outcomes by, for example, using recommended risk scoring methods, most problems would not be addressed, particularly the large number of mundane problems which consume the majority of resources. Both serious and mundane problems should be addressed. Most types of events occur too infrequently to be characterised at a hospital level and require large scale (preferably national) collections of incidents and events.
Australia↗
Computer simulations of lymph node metastasis for optimizing the pathologic examination of sentinel lymph nodes in patients with breast carcinoma.
BACKGROUND: Many empiric protocols are used to detect metastases in sentinel lymph nodes (SLNs), but comparison of the efficacy of these methods is impractical because tissue is lost in processing, making reassessment with another policy difficult. Consequently, performance indicators of this test are largely unknown. DESIGN: The authors retrospectively examined 112 SLNs removed from 89 patients with breast carcinoma treated at the authors' institution and used the histologic data to devise a mathematic model of a SLN with Matlab modeling software. The authors simulated examination of this computer-generated (virtual) lymph node according to several macroscopic and histologic sampling protocols and for each protocol assessed the probability of detecting micrometastases of specified sizes. The authors used published costing figures to estimate the cost of the policies. RESULTS: Direct comparison of 6 sectioning strategies currently in use by pathology laboratories showed the chances of detecting a 500-microm metastasis ranged from 20% to 75%. Four of the 6 protocols had a less than 30% chance of detecting metastases of this size. The detection rate of smaller metastases was poorer. Cost was not a good discriminator because some policies were more efficient than others. CONCLUSIONS: The detection of metastases is highly dependent on the methods used to look for them. The authors' simulations suggest that commonly used methods of examining lymph nodes have high false-negative rates, particularly for small metastases. There is an urgent need for pathologists and clinicians to agree on the minimum size of SLN metastases that will be sought by histology and set standard methods for examining these lymph nodes.
Breast Neoplasms↗
The intersection of health informatics and evidence-based medicine: computer-based systems to assist clinicians.
Evidence-based medicine and health informatics may assist clinicians contend with the current barriers to the integration of evidence-based "best practice" into typical healthcare settings. Computer-based decision support systems can improve the process of care, but whether they improve patient outcomes in a cost-effective manner is uncertain.
Decision Making, Computer-Assisted↗
Wegener granulomatosis--an atypical case.
An unusual sequence of the clinical manifestations of microvascular disease is described in a 15 year-old girl. She initially presented with acute renal failure caused by a crescentic glomerulonephritis associated with positive tests for MPO-ANCA. Eighteen months later she had pulmonary hemorrhage and respiratory failure. An open lung biopsy showed granulomas that were diagnostic for Wegener granulomatosis. We discuss the diagnostic dilemmas faced in attempts to distinguish infective causes of pulmonary granulomas, such as tuberculosis or fungi, from granulomas associated with vasculitis, in a patient previously treated with immunosuppressive therapy.
Adolescent↗
Geographic and ethnic distribution of beta-thalassemia mutations in Uttar Pradesh, India.
We have studied the geographic and ethnic distribution of mutations in 376 subjects who were carriers of beta-thalassemia, and identified the mutations in 365 chromosomes. The majority of the beta-thalassemia carriers were of Uttar Pradesh (India) origin. Their pattern of mutations differed from the other states of India and from those families who had migrated from Pakistan. The frequency of the IVS-I-5 (G-->C) and 619 bp deletion mutations were 64.3 and 2.5%, respectively, among families originating from Uttar Pradesh, compared to a prevalence of 37.5 and 27.5%, respectively in the population of Pakistani immigrants. Of the 10 common Asian Indian mutations, only eight were observed in subjects studied from different parts of India. By use of the amplification refractory mutation system along with DNA sequencing techniques, the mutations were successfully identified in 97.1% of subjects, while 11 cases (2.9%) still remain to be characterized by single strand conformation polymorphism and sequencing analyses. The application of this knowledge has facilitated the successful implementation of the program of genetic counseling and prenatal diagnosis of beta-thalassemia, thus helping to avoid the birth of an affected child in India.
DNA Mutational Analysis↗
Pachygyria/hypogenitalism: A monogenic syndrome.
We describe the clinical and neuroimaging findings of two severely retarded boys born to consanguineous parents. This appears to be a monogenic condition of abnormal neuronal migration associated with hypogenitalism. Reports of other monogenic syndromes of neuronal migration abnormalities are reviewed.
Cell Movement↗
Protein interactions of Src homology 2 (SH2) domain-containing inositol phosphatase (SHIP): association with Shc displaces SHIP from FcgammaRIIb in B cells.
Our recent studies revealed that the inositol phosphatase Src homology 2 (SH2) domain-containing inositol phosphatase (SHIP) is phosphorylated and associated with Shc exclusively under negative signaling conditions in B cells, which is due to recruitment of the SHIP SH2 domain to the FcgammaRIIb. In addition, we reported that SHIP-Shc interaction involves both SHIP SH2 and Shc phosphotyrosine binding domains. These findings reveal a paradox in which the single SH2 domain of SHIP is simultaneously engaged to two different proteins: Shc and FcgammaRIIb. To resolve this paradox, we examined the protein interactions of SHIP. Our results demonstrated that isolated FcgammaRIIb contains SHIP but not Shc; likewise, Shc isolates contain SHIP but not FcgammaRIIb. In contrast, SHIP isolates contain both proteins, revealing two separate pools of SHIP: one bound to FcgammaRIIb and one bound to Shc. Kinetic studies reveal rapid SHIP association with FcgammaRIIb but slower and more transient association with Shc. Affinity measurements using a recombinant SHIP SH2 domain and phosphopeptides derived from FcgammaRIIb (corresponding to Y273) and Shc (corresponding to Y317) revealed an approximately equal rate of binding but a 10-fold faster dissociation rate for FcgammaRIIb compared with Shc phosphopeptide and yielding in an affinity of 2.1 microM for FcgammaRIIb and 0.26 microM for Shc. These findings are consistent with a model in which SHIP transiently associates with FcgammaRIIb to promote SHIP phosphorylation, whereupon SHIP binds to Shc and dissociates from FcgammaRIIb.
Adaptor Proteins, Signal Transducing↗
Iniencephaly: a report of 19 cases.
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Abnormalities, Multiple↗
The role of pharmacists in HIV/STD prevention: evaluation of an STD syndromic management intervention in Nepal.
OBJECTIVE: To evaluate the effects of a pilot sexually transmitted disease (STD) syndromic case management training for pharmacists in Nepal on STD drug dispensing behavior, HIV/STD prevention communication, and condom promotion and sales. METHODS: Pre- and post-intervention interviews with samples of 160 pharmacists were conducted utilizing the simulated client method to collect data on pharmacists' response to men reporting urethral discharge. In order to assess the long-term effects, a sub-sample of 38 pharmacists trained 7-9 months before the follow-up survey was analysed separately. RESULTS: There were no significant differences in the percentages of pharmacists who suggested taking medications, dispensed medications, or referred clients to a physician. The proportion of pharmacists who recommended an injection declined from 27% to 14%. Prior to the intervention, only one pharmacist (0.8%) dispensed the correct drugs and regimen for the syndromic treatment of urethritis. This increased to 45% immediately following the training. In a sub-sample of pharmacists who were interviewed 7-9 months after the training, the correct drugs and regimen were dispensed by 26%. The proportion of pharmacists who recommended to clients to have their sex partners treated increased from 5% to 21%. Although the proportion of pharmacists who suggested condom use increased from 14% to 24%, the proportion of pharmacists actually selling a condom or giving advice on HIV testing remained low and unchanged pre- and post-intervention. Over one-third of pharmacists mentioned HIV or AIDS in their interactions with clients, compared to 9% prior to the intervention. CONCLUSIONS: The findings suggest that STD services provided by pharmacists can be significantly improved through a short-term training intervention, although the improvements are modest and probably time-limited. Interventions must be more intensive and combined with regular follow-ups if they are to meet their desired goals of improving STD treatment in a pharmacy setting.
Anti-Infective Agents↗
Activation-induced bi-dentate interaction of SHIP and Shc in B lymphocytes.
SHIP is a SH2 domain-containing inositol polyphosphatase that is selectively tyrosine phosphorylated and associated with the adapter protein Shc in B lymphocytes upon co-crosslinking surface immunoglobulin and Fc gamma RIIB1. We previously observed that this stimulation condition is associated with a reduction in the interaction of Grb2 with phosphorylated Shc, an enhanced interaction of Shc with SHIP, and a block in the Ras signaling pathway. We proposed that the SH2 domain of SHIP competes with Grb2 in binding to phospho-Shc, resulting in a block in Ras signaling. To test this model, we examined the mode of SHIP-Shc interaction. Using recombinant Shc and SHIP interaction domains and purified Shc and SHIP phosphopeptides, we show that the interaction is bi-dentate such that the SH2 domain of SHIP recognizes phosphorylated Y317 and doubly-phosphorylated Y239/Y240 of Shc and the Shc PTB domain recognizes phosphorylated NPxpY motifs within SHIP. We observed no role for the Shc SH2 domain in the interaction. These findings are consistent with our earlier model that SHIP and Grb2 compete for binding to phospho-Shc and support the notion that, in addition to the hydrolysis of inositol phosphates and phospholipids, SHIP contributes to anti-proliferative biochemistry by blocking protein-protein interactions.
Adaptor Proteins, Signal Transducing↗
Nitrites and L-citrulline levels in copper intrauterine device users.
The mechanism of copper in limiting intrauterine infections in intrauterine device (Cu IUD) users is poorly understood. Copper ions may enhance the release of reactive oxygen radicals, which in turn decrease the release of reactive nitrogen intermediates (RNI). RNI are known to have bactericidal effect. The present study compares the levels of RNI prior to Cu-T insertion and at different post-insertion intervals up to 12 weeks. The decrease in RNI was evident by one week and continued until 12 weeks. Therefore, the bactericidal effect of copper in IUD is via reactive oxygen intermediates. The superoxide anion inactivates this active intermediate nitric oxide. Therefore, excess of superoxide radical will markedly shorten the half-life of nitric oxide but will not prevent its conversion to nitrites and nitrates.
Citrulline↗
Negative signaling in B cells: SHIP Grbs Shc.
Negative signaling in B cells is initiated by co-crosslinking of the antigen receptor and the Fcy receptor, resulting in cessation of B-cell signaling events and, in turn, inhibiting B-cell proliferation and antibody secretion. Here, a competitive role is proposed for SHIP in blocking the interaction of Shc with the Grb2-Sos complex of proteins that lead to Ras activation in B cells.
Allergy and Immunology↗
Recruitment and phosphorylation of SH2-containing inositol phosphatase and Shc to the B-cell Fc gamma immunoreceptor tyrosine-based inhibition motif peptide motif.
Recently, we and others have demonstrated that negative signaling in B cells selectively induces the tyrosine phosphorylation of a novel inositol polyphosphate phosphatase, p145SHIP. In this study, we present data indicating that p145SHIP binds directly a phosphorylated motif, immunoreceptor tyrosine-based inhibition motif (ITIM), present in the cytoplasmic domain of Fc gammaRIIB1. Using recombinant SH2 domains, we show that binding is mediated via the Src homology region 2 (SH2)-containing inositol phosphatase (SHIP) SH2 domain. SHIP also bound to a phosphopeptide derived from CD22, raising the possibility that SHIP contributes to negative signaling by this receptor as well as Fc gammaRIIB1. The association of SHIP with the ITIM phosphopeptide was activation independent, while coassociation with Shc was activation dependent. Furthermore, experiments with Fc gammaRIIB1-deficient B cells demonstrated a genetic requirement for expression of Fc gammaRIIB1 in the induction of SHIP phosphorylation and its interaction with Shc. Based on these results, we propose a model of negative signaling in which co-cross-linking of surface immunoglobulin and Fc gammaRIIB1 results in sequential tyrosine phosphorylation of the ITIM, recruitment and phosphorylation of p145SHIP, and subsequent binding of Shc.
Animals↗