Idiopathic Myelofibrosis in an Infant

Idiopathic Myelofibrosis (MF) is an extremely rare condition in children. It has a very variable clinical spectrum. Cases of secondary myelofibrosis associated with Vitamin D deficiency and Systemic Lupus Erythematosus have been reported from India .In this case report, the authors describe clinical signs, laboratory findings and histologic features in a 6 month old infant with Idiopathic myelofibrosis.     

The impact of dermatology in premier medicine journals

In the past 15 years, research in dermatology has significantly increased. Dermatology-related contributions in premier medical journals such as The New England Journal of Medicine (NEJM) and The Journal of the American Medical Association (JAMA) are the representation of our field in the medical world. To analyze this representation, incidence of dermatology-related contributions in NEJM and JAMA during 3 separate years (during a 15-year period) was calculated.     

Expression of apoptosis regulators Bcl-2 and Bax in childhood acute lymphoblastic leukemia

Twenty-five children (19 M:6 F) with newly diagnosed ALL with median age of 5.5 years (1 month-12 years) were enrolled in the study. Apoptosis regulator proteins bcl-2 and bax were measured in all patients using alkaline phosphatase anti-alkaline phosphatase method. Twenty-one patients were positive for bcl-2 and 23 cases for Bax, although expression levels varied. Patients who presented with splenomegaly or hepatomegaly < 5 cm expressed significantly higher levels of bcl-2 and bax protein expression. Neither of age ( < or >10 years), sex, generalized lymphadenopathy, WBC ( < or >50,000/mul) or FAB subtype was associated with high levels of bcl-2 or bax protein expression. Patients with higher mean hemoglobin levels (p = 0.009), high blast % in bone marrow (p = 0.02), immature immunophenotype (p = 0.001) exhibited signifxicantly higher bcl-2 levels. Bcl-2/bax ratio correlated inversely with TLC at presentation (p = 0.022; r = - 0.456) and in B-lineage leukemic cells as compared to T-lineage cells (p = 0.002). Bcl-2/bax ratio did not correlate with any other variable measured. Bcl-2 and bax protein co-express in ALL and high bcl-2/bax ratio correlates with good prognosis features.     

Recurrent Pregnancy Loss and Apolipoprotein E Gene Polymorphisms: A Case–Control Study from North India

Citation Agarwal M, Parveen F, Faridi RM, Phadke SR, Das V, Agrawal S. Recurrent pregnancy loss and apolipoprotein E gene polymorphisms: a case–control study from North India. Am J Reprod Immunol 2010; 64: 172–178 Problem The role of apolipoprotein E gene polymorphisms in the etiology of recurrent pregnancy loss (RPL) is not clearly understood. We evaluated this polymorphism in unexplained pregnancy losses among North Indian women. Method of study In a retrospective case–control study, 200 well‐characterized RPL cases were examined for their APO‐E genotypes based on restriction fragment length polymorphism analysis of PCR‐amplified fragments including amino acid positions 112 and 158. The observed genotypes were compared with those obtained from an equal number of ethnically matched negative controls. Results We found similar APO‐E genotypes and E2, E3, and E4 allele frequency distribution among RPL patients and controls. The allele frequencies obtained in patients and controls respectively were as follows: E2 = 7.5% and 9.0% (P = 0.52; OR = 0.81; 95%CI = 0.49–1.35), E3 = 89.7% and 90% (P = 1.00; OR = 0.97; 95%CI = 0.61–1.54), and E4 = 2.8% and 1% (P = 0.12; OR = 2.79; 95%CI = 0.88–8.86). Conclusions Our data did not support the association of APO‐E gene polymorphisms with recurrent pregnancy loss as reported by some of the previous studies. We endorse adequate characterization of RPL cases, inclusion of appropriate negative controls, and adequate sample size prior to addressing such studies.     

A protective role for the fifth complement component (c5) in allergic airway disease

RATIONALE: Reports from our laboratory, as well as those from others, have documented the importance of complement activation, the C3a anaphylatoxin, and its receptor, C3aR, in promoting Th2 effector functions in a mouse model of bronchopulmonary allergy. Although deficiency in the fifth complement component (C5) has been linked to enhanced airway hyperresponsiveness in mice, the contribution of C5 to other major biological hallmarks of asthma has not been evaluated. OBJECTIVE: Accordingly, congenic C5-sufficient and C5-deficient mice were subjected to a mouse model of bronchopulmonary allergy to assess the impact of C5 on pulmonary inflammation and Th2 effector functions in experimental asthma. METHODS AND MAIN RESULTS: In contrast to observations reported for C3- and C3aR-deficient animals, C5-deficient mice exhibited significantly increased airway hyperresponsiveness relative to wild-type congenic control mice after antigen challenge. Moreover, challenged C5-deficient mice had a 3.4-fold and 2.7-fold increase in the levels of airway eosinophils and lung interleukin (IL)-4-producing cells, respectively, compared with challenged wild-type mice. Consistent with the numbers of IL-4-producing cells, C5-deficient mice also had increased bronchoalveolar lavage levels of the Th2 cytokines IL-5 and IL-13 and elevated serum levels of total and antigen-specific IgE. CONCLUSIONS: These data indicate that C5 plays an important protective role in allergic lung disease by suppressing inflammatory responses and Th2 effector functions observed in this experimental model. The protection provided by the presence of C5 is likely mediated by C5a, suggesting that C5a may play a significant role in tempering inflammation in Th2-driven diseases such as asthma.     

What is the impact of physician communication and patient understanding in the management of headache?

Migraine is a common and debilitating condition. Despite the burden of disease and increasing availability of effective treatment, migraine management is unsatisfactory. Evidence in other chronic conditions indicates that effective physician communication results in better patient understanding and health outcomes.     

Antral Inflammatory Cells,Gastric Emptying,and Electrogastrography in Pediatric Functional Dyspepsia

The aims of the current study were to determine the activation states of antral eosinophils and mast cells and to evaluate the interactions of antral inflammatory cells with gastric emptying and electrogastrography (EGG) in 30 pediatric patients with functional dyspepsia. Eosinophil degranulation was moderate in 42% and extensive in 54% of patients. Mast cell degranulation was >50% in 81% of patients. Elevated mast cell density was associated with slower one hour gastric emptying and increased preprandial dysrhythmia. Mast cell density correlated with the preprandial percentage tachygastria. CD3+ cell density correlated with the preprandial percentage tachygastria also, but only in patients with increased eosinophil density. In conclusion, antral eosinophils and mast cells are significantly activated in pediatric functional dyspepsia. Mast cell density is associated with delayed gastric emptying and preprandial dysrhythmia, suggesting that there may be an interaction between antral inflammation and gastric electromechanical dysfunction in the pathophysiology of pediatric functional dyspepsia.     

Anti-vascular endothelial growth factor treatment normalizes tuberculosis granuloma vasculature and improves small molecule delivery

Tuberculosis (TB) causes almost 2 million deaths annually, and an increasing number of patients are resistant to existing therapies. Patients who have TB require lengthy chemotherapy, possibly because of poor penetration of antibiotics into granulomas where the bacilli reside. Granulomas are morphologically similar to solid cancerous tumors in that they contain hypoxic microenvironments and can be highly fibrotic. Here, we show that TB-infected rabbits have impaired small molecule distribution into these disease sites due to a functionally abnormal vasculature, with a low-molecular-weight tracer accumulating only in peripheral regions of granulomatous lesions. Granuloma-associated vessels are morphologically and spatially heterogeneous, with poor vessel pericyte coverage in both human and experimental rabbit TB granulomas. Moreover, we found enhanced VEGF expression in both species. In tumors, antiangiogenic, specifically anti-VEGF, treatments can “normalize” their vasculature, reducing hypoxia and creating a window of opportunity for concurrent chemotherapy; thus, we investigated vessel normalization in rabbit TB granulomas. Treatment of TB-infected rabbits with the anti-VEGF antibody bevacizumab significantly decreased the total number of vessels while normalizing those vessels that remained. As a result, hypoxic fractions of these granulomas were reduced and small molecule tracer delivery was increased. These findings demonstrate that bevacizumab treatment promotes vascular normalization, improves small molecule delivery, and decreases hypoxia in TB granulomas, thereby providing a potential avenue to improve delivery and efficacy of current treatment regimens.As one of the most prevalent infectious diseases in the world today, Mycobacterium tuberculosis (MTB) infects roughly one-third of the global population, resulting in 2 million deaths annually (1). Although current treatment regimens are largely successful in curing the disease (2), they require 6–8 mo of treatment with up to four agents (3), and multidrug-resistant bacterial strains have emerged and proliferated (4). Resistance to front-line therapies necessitates treatment with up to five or six second-line agents that are poorly tolerated, and treatment success is only achieved in 40–70% of patients (5). Failure to cure drug-resistant disease leads to acquisition of further resistance with a progressively poorer prognosis for these patients, thus fueling an emerging epidemic of drug-resistant disease that threatens to overwhelm fragile health care systems in developing countries (6).When infected with the tuberculosis (TB) bacilli, the body triggers an immune response that walls off the bacteria in dense cellular masses known as granulomas, or tubercular lesions (7). These abnormal tissue structures, which can vary in size within the same host, are surrounded by fibrous cuffs that serve to contain the MTB bacilli (7, 8). Recent studies have demonstrated a wide variation in the spatial distribution of drugs within TB granulomas, with very few agents able to penetrate the central regions (9). This differential ability of drugs to penetrate TB granulomas has been incorporated into modern TB drug development programs as a criterion for optimizing lead molecules and selecting efficacious combinations (10). However, the mechanisms that contribute to this differential penetration of drugs are not fully understood, and novel strategies to improve TB drug delivery and efficacy are urgently needed.Following infection with MTB, pulmonary granulomas form in humans and develop heterogeneous microenvironments, often featuring hypoxia (i.e., low levels of oxygen) and central necrosis, which are recapitulated in nonhuman primate and rabbit models of the disease (11). Large lesions appear to develop their own vasculature, presumably allowing them to continue to grow (7). However, the morphological and functional characteristics of granuloma-associated vessels are largely unknown. In solid tumors, cancer cells can form similar dense tissue masses with abnormal associated vasculature. The physiological abnormalities that characterize tumor vessels have been investigated extensively (12, 13). For example, hypoxia, a common feature in solid tumors, stimulates the overproduction of proangiogenic factors, such as VEGF. Proangiogenic factors enhance the formation of new immature, tortuous, and hyperpermeable vessels (12, 14), often with excess endothelial cells, a lack of associated pericytes (i.e., perivascular cells), and uneven basement membranes (15–17). These atypical features result in an impaired blood flow that further compromises delivery of drugs and oxygen (13). Hypoxia also causes immunosuppression, inflammation, and fibrosis, and it can also confer resistance to many drugs (18). Here, we propose that TB granulomas share many characteristics with solid tumors, namely, that they are associated with abnormal and dysfunctional vasculature that can impair the delivery of small molecules, such as oxygen and antibiotics.Because VEGF is a critical growth factor required for new blood vessel formation (16), anti-VEGF agents were originally developed to block tumor growth by inhibiting blood vessel formation (19). However, bevacizumab, a humanized monoclonal antibody developed to neutralize human VEGF, failed to improve survival benefit as a monotherapy but conferred survival benefit only in combination with chemotherapy or immunotherapy (18). A potential explanation for the success of combined therapies is that bevacizumab “normalizes” the abnormal vasculature of tumors, resulting in improved delivery of concurrently administered anticancer drugs, as well as alleviation of hypoxia (13, 15, 18, 20, 21). However, this strategy has not been tested in a TB disease model. In this study we show, for the first time to our knowledge, in a rabbit model of TB that treatment with bevacizumab normalizes granuloma vasculature, reduces hypoxia, and enhances small molecule delivery during a “window of normalization,” a transient effect observed in tumors (15, 20). Because anti-VEGF drugs have been approved for both malignant and nonmalignant diseases (18), our findings could be rapidly tested in the clinic to enhance TB treatment, shorten treatment duration, and avert the development of treatment resistance.