Can decreasing smoking prevalence reduce leukemia mortality?

Previous studies have demonstrated a modest association between smoking and leukemia particularly for myeloid disorders. Our objective was to examine whether changing trends in cigarette smoking prevalence nationally and within selected states parallel similar trends in mortality from leukemia. Trends in national smoking rates were correlated with trends in leukemia mortality rates obtained from the Centers for Disease Control and Prevention and the Surveillance Epidemiology and End Results registry, respectively. State-specific correlations were assessed from 1984 to 2004 using smoking prevalence data from the Behavioral Risk Factor Surveillance System and leukemia mortality data from National Vital Statistics System. Correlations were computed using the Spearman rank correlation coefficient. Leukemia mortality decreased overall in the United States in parallel with decreased smoking. Analyzed on a state-specific basis, leukemia mortality decreased in states where smoking rates declined markedly but remained unchanged where smoking prevalences were relatively stable. The findings suggest that declining rates of leukemia mortality are associated with changing patterns of smoking behavior.     

Birth order and the severity of illness in schizophrenia

A proposed risk factor for schizophrenia is materno-foetal incompatibility. We tested the hypothesis that, in multiply affected families, later born children would exhibit a more severe form of schizophrenia than their older siblings. The effect of birth order on (1) severity of the worst ever episode of illness; (2) deterioration from premorbid level of functioning; (3) age of onset; (4) response to medication; and (5) illness course, was assessed in 150 sibling pairs with schizophrenia and schizoaffective disorder. We found that later birth order reduced the likelihood of regaining the premorbid level of functioning after an acute episode and was also associated with an earlier age of presentation. This study lends some support to the hypothesis that later birth order results in a more severe form of the disorder, although there are other possible explanations for our findings. Further work is needed to explore the possibility of maternal-foetal genotype incompatibility as a risk factor for schizophrenia.     

The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice

Autophagy is the principal cellular pathway for degradation of long-lived proteins and organelles and regulates cell fate in response to stress. Recently, autophagy has been implicated in neurodegeneration, but whether it is detrimental or protective remains unclear. Here we report that beclin 1, a protein with a key role in autophagy, was decreased in affected brain regions of patients with Alzheimer disease (AD) early in the disease process. Heterozygous deletion of beclin 1 (Becn1) in mice decreased neuronal autophagy and resulted in neurodegeneration and disruption of lysosomes. In transgenic mice that express human amyloid precursor protein (APP), a model for AD, genetic reduction of Becn1 expression increased intraneuronal amyloid beta (Abeta) accumulation, extracellular Abeta deposition, and neurodegeneration and caused microglial changes and profound neuronal ultrastructural abnormalities. Administration of a lentiviral vector expressing beclin 1 reduced both intracellular and extracellular amyloid pathology in APP transgenic mice. We conclude that beclin 1 deficiency disrupts neuronal autophagy, modulates APP metabolism, and promotes neurodegeneration in mice and that increasing beclin 1 levels may have therapeutic potential in AD.     

Recent advances in the pharmacotherapy of chronic anal fissure: an update

Surgical sphincterotomy reduces anal tone and sphincter spasm and promotes ulcer healing. Because the surgery is associated with the side effect of faecal incontinence, pharmacological agents to treat chronic anal fissure have been explored recently. Glyceryl trinitrate (GTN) ointment (0.2%) has an efficacy of up to 68% in healing chronic anal fissure, but it is associated with headache as the major and most common side effect. Though botulinum toxin injected into the anal sphincter healed over 80% of chronic anal fissures, it is more invasive and expensive than GTN therapy. Diltiazem ointment achieved healing of chronic anal fissure comparable to 0.2% GTN ointment but was associated with fewer side effects. Other drugs that have been tried are lidocaine, the alpha-adrenergic antagonist indoramin, and the potassium channel opener minoxidil.     

An fMRI framework for identifying statistical differences in blood oxygenated level dependent response levels: a brain injury demonstration

OBJECTIVE: The general concept surrounding fMRI data analysis for decision support is leveraging previously hidden knowledge from publicly available metadata sources with a high degree of precision. METHODS AND MATERIALS: Normalized fMRI scans are used to calculate cumulative voxel intensity curves for every subject in the dataset that fits chosen demographic criteria. The voxel intensity curve has a direct linear relationship to the subject's neuronal activity. In the case of head trauma, a subject's voxel intensity curve would be statistically compared to the weighted average curve for every subject in dataset that is demographically similar. If the new subject's neuronal activity falls below the threshold for their demographic group, the brain injury detection (BID) system would then pinpoint the areas of deficiency based on Broadmann's cortical areas. ANALYSIS: The analysis presented in this paper indicates that statistical differences among demographic groups exist in BOLD fMRI responses. CONCLUSION: Useful knowledge can in fact be leveraged from mining stockpiled fMRI data without the need for unique human identifiers. The BID system offers the radiologist a statistically based decision support for brain injury.     

A Randomized Clinical Trial of Levonorgestrel Intrauterine System with or without Metformin for Treatment of Endometrial Hyperplasia without Atypia in Indian Women

Background: Endometrial cancer is the second most frequent genital malignancy in women, which is showing a constant rise all over world. Endometrial hyperplasia is the precursor of endometrial cancer. Levonorgestrel intrauterine system is the first line management in patients with endometrial hyperplasia without atypia. Metformin has shown to reverse endometrial hyperplasia, but its effectiveness and safety in endometrial hyperplasia is uncertain. Objective: To compare the efficacy in terms of histopathological response, clinical response and safety at the end of 6 months in patients with endometrial hyperplasia without atypia managed with levonorgestrel intrauterine system alone versus patients managed with levonorgestrel intrauterine system plus metformin. Methods: The randomized control trial was conducted on 51 cases of endometrial hyperplasia without atypia. Twenty-five subjects were prescribed metformin 500mg twice daily with levonorgestrel intrauterine system and 26 subjects, with levonorgestrel intrauterine system only for 6 months. At the end of 6 months, endometrial sampling was performed for histopathological response. Results: Clinical response was observed in 23 of 25 subjects in metformin group and 22 of 24 in levonorgestrel only group. The metformin group responded significantly with amenorrhea (p= 0.0053), while levonorgestrel only group responded with regular cycles (p=0.027). At the end of study, of 46 subjects available for histopathological evaluation, 100% subjects in metformin group and 95.45% in levonorgestrel only group (p=0.47826) showed complete response. The metformin group had a significant reduction in body mass index at end of study [P = 0∙023, 95% confidence interval (-1.7802, -0.1418)]. Conclusion: No significant difference in regression of endometrial hyperplasia was observed on adjunctive use of metformin but a significant reduction in BMI was observed. Use of metformin in obese patients may improve the treatment response.     

Ancient dynamin segments capture early stages of host–mitochondrial integration

Eukaryotic cells use dynamins—mechano-chemical GTPases—to drive the division of endosymbiotic organelles. Here we probe early steps of mitochondrial and chloroplast endosymbiosis by tracing the evolution of dynamins. We develop a parsimony-based phylogenetic method for protein sequence reconstruction, with deep time resolution. Using this, we demonstrate that dynamins diversify through the punctuated transformation of sequence segments on the scale of secondary-structural elements. We find examples of segments that have remained essentially unchanged from the 1.8-billion-y-old last eukaryotic common ancestor to the present day. Stitching these together, we reconstruct three ancestral dynamins: The first is nearly identical to the ubiquitous mitochondrial division dynamins of extant eukaryotes, the second is partially preserved in the myxovirus-resistance-like dynamins of metazoans, and the third gives rise to the cytokinetic dynamins of amoebozoans and plants and to chloroplast division dynamins. The reconstructed sequences, combined with evolutionary models and published functional data, suggest that the ancestral mitochondrial division dynamin also mediated vesicle scission. This bifunctional protein duplicated into specialized mitochondrial and vesicle variants at least three independent times—in alveolates, green algae, and the ancestor of fungi and metazoans—accompanied by the loss of the ancient prokaryotic mitochondrial division protein FtsZ. Remarkably, many extant species that retain FtsZ also retain the predicted ancestral bifunctional dynamin. The mitochondrial division apparatus of such organisms, including amoebozoans, red algae, and stramenopiles, seems preserved in a near-primordial form.Eukaryotes arose through the acquisition of mitochondria by an archaeal host cell about 2 billion y ago (1, 2), a watershed moment in the evolution of the modern compartmentalized cell plan (3). A second transformative endosymbiotic event, the acquisition of a cyanobacterium by a eukaryotic host to form chloroplasts, gave rise to the photosynthetic eukaryotic lineages (4). As the endosymbionts became integrated with their hosts, their growth and division became regulated by host–cellular machinery (5). Proteins of the dynamin superfamily were central to this process: Mitochondria and chloroplasts originally divided using a constricting ring of the prokaryotic cytoskeletal protein FtsZ, but dynamins have been recruited to these roles in all extant eukaryotes (6, 7). By reconstructing the evolutionary history of dynamins, we can probe the process of endosymbiont integration.The dynamin superfamily is diverse (8, 9), and different dynamin variants remodel membranes at different cellular locations (Table S1 and primary references therein). A major class of dynamins is essential for mitochondrial and peroxisomal division. Another large group drives the scission of clathrin-coated vesicles in organisms such as fungi and alveolates. A related group, the so-called “classical” dynamins that drive clathrin-coated vesicle scission in metazoans and land plants, contains a membrane-targeted pleckstrin homology (PH) domain. Members of the phragmoplastin class of dynamins participate in cell plate formation in land plants. The myxovirus-resistance-like dynamins are implicated in antiviral activity in vertebrates. A truncated dynamin variant is involved in cytokinesis in amoebozoans and plants, as well as in chloroplast fission in photosynthetic lineages; another truncated variant drives mitochondrial inner membrane fusion in fungi and metazoans. Finally, mitofusins and the related bacterial dynamin-like proteins (BDLPs) are potentially ancient members of the dynamin superfamily (10); these are excluded from our study because they are highly diverged at the sequence level.Here we present the most comprehensive analysis of dynamin evolution yet reported, including thousands of functionally diverse dynamins from hundreds of broadly sampled eukaryotic species. We reconstruct the series of events that led from the primordial dynamins of the 1.8-billion-y-old last eukaryotic common ancestor (LECA) (11) to the great variety of present-day dynamins. The outcome is a nuanced picture of protein diversification, mirroring key events in the evolution of eukaryotes themselves and shedding light on the earliest stages of endosymbiont integration.     

p19ARF is a critical mediator of both cellular senescence and an innate immune response associated with MYC inactivation in mouse model of acute leukemia

MYC-induced T-ALL exhibit oncogene addiction. Addiction to MYC is a consequence of both cell-autonomous mechanisms, such as proliferative arrest, cellular senescence, and apoptosis, as well as non-cell autonomous mechanisms, such as shutdown of angiogenesis, and recruitment of immune effectors. Here, we show, using transgenic mouse models of MYC-induced T-ALL, that the loss of either p19ARF or p53 abrogates the ability of MYC inactivation to induce sustained tumor regression. Loss of p53 or p19ARF, influenced the ability of MYC inactivation to elicit the shutdown of angiogenesis; however the loss of p19ARF, but not p53, impeded cellular senescence, as measured by SA-beta-galactosidase staining, increased expression of p16INK4A, and specific histone modifications. Moreover, comparative gene expression analysis suggested that a multitude of genes involved in the innate immune response were expressed in p19ARF wild-type, but not null, tumors upon MYC inactivation. Indeed, the loss of p19ARF, but not p53, impeded the in situ recruitment of macrophages to the tumor microenvironment. Finally, p19ARF null-associated gene signature prognosticated relapse-free survival in human patients with ALL. Therefore, p19ARF appears to be important to regulating cellular senescence and innate immune response that may contribute to the therapeutic response of ALL.     

Incidental detection of hyperfunctioning thyroid cancer metastases in patients presenting with thyrotoxicosis

Thyrotoxicosis due to functioning metastases from thyroid cancer is rare. It also presents a therapeutic challenge, as both the metastatic cancer and thyrotoxicosis need to be treated. We present here two cases of thyrotoxicosis which on a routine (99m)Tc-pertechnetate thyroid scan showed extrathyroidal foci of uptake. Two patients who initially presented with thyrotoxicosis underwent a routine thyroid scan. Abnormal uptake in the shoulder was incidentally noted, which prompted us to do a whole body pertechnetate scan in the same sitting, which revealed extensive hyperfunctioning metastases in the lungs and bones. We also discuss the 'Flip Flop' phenomenon in thyroid cancer, which was seen in our case. This report emphasizes the importance of evaluating the abnormal foci of uptake seen on a routine thyroid scan.     

Stem cells for reproductive medicine

The generation of various pluripotent stem cell lines provides a new route to investigate developmental process of germ cell and embryo development, which until now was difficult to access in the human. In the future these cells may be used for new therapies in reproductive medicine. This brief review outlines the development of germ cells and their pluripotent capabilities, how embryonic and germline stem cells can mimic developmental processes in vitro and generate gamete and trophoblast phenotypes for research and potential treatments.