Adverse childhood experiences and substance misuse in young people in India: results from the multisite cVEDA cohort.

BACKGROUND: Adverse childhood experiences (ACEs) increases vulnerability to externalising disorders such as substance misuse. The study aims to determine the prevalence of ACEs and its association with substance misuse. METHODS: Data from the Consortium on Vulnerability to Externalising Disorders and Addictions (cVEDA) in India was used (n = 9010). ACEs were evaluated using the World Health Organisation (WHO) Adverse Childhood Experiences International Questionnaire whilst substance misuse was assessed using the WHO Alcohol, Smoking and Substance Involvement Screening Test. A random-effects, two-stage individual patient data meta-analysis explained the associations between ACEs and substance misuse with adjustments for confounders such as sex and family structure. RESULTS: 1 in 2 participants reported child maltreatment ACEs and family level ACEs. Except for sexual abuse, males report more of every individual childhood adversity and are more likely to report misusing substances compared with females (87.3% vs. 12.7%). In adolescents, family level ACEs (adj OR 4.2, 95% CI 1.5-11.7) and collective level ACEs (adj OR 6.6, 95% CI 1.4-31.1) show associations with substance misuse whilst in young adults, child level ACEs such as maltreatment show similar strong associations (adj OR 2.0, 95% CI 1.1-3.5). CONCLUSION: ACEs such as abuse and domestic violence are strongly associated with substance misuse, most commonly tobacco, in adolescent and young adult males in India. The results suggest enhancing current ACE resilience programmes and 'trauma-informed' approaches to tackling longer-term impact of ACEs in India. FUNDING: Newton Bhabha Grant jointly funded by the Medical Research Council, UK (MR/N000390/1) and the Indian Council of Medical Research (ICMR/MRC-UK/3/M/2015-NCD-I).

Predicting the minimum liquid surface tension activity of pseudomonads expressing biosurfactants.

UNLABELLED: Bacteria produce a variety of biosurfactants capable of significantly reducing liquid (aqueous) surface tension (γ) with a range of biological roles and biotechnological uses. To determine the lowest achievable surface tension (γMin ), we tested a diverse collection of Pseudomonas-like isolates from contaminated soil and activated sludge and identified those expressing biosurfactants by drop-collapse assay. Liquid surface tension-reducing ability was quantitatively determined by tensiometry, with 57 isolates found to significantly lower culture supernatant surface tensions to 24·5-49·1 mN m(-1) . Differences in biosurfactant behaviour determined by foaming, emulsion and oil-displacement assays were also observed amongst isolates producing surface tensions of 25-27 mN m(-1) , suggesting that a range of structurally diverse biosurfactants were being expressed. Individual distribution identification (IDI) analysis was used to identify the theoretical probability distribution that best fitted the surface tension data, which predicted a γMin of 24·24 mN m(-1) . This was in agreement with predictions based on earlier work of published mixed bacterial spp. data, suggesting a fundamental limit to the ability of bacterial biosurfactants to reduce surface tensions in aqueous systems. This implies a biological restriction on the synthesis and export of these agents or a physical-chemical restriction on their functioning once produced. SIGNIFICANCE AND IMPACT OF THE STUDY: Numerous surveys of biosurfactant-producing bacteria have been conducted, but only recently has an attempt been made to predict the minimum liquid surface tension these surface-active agents can achieve. Here, we determine a theoretical minimum of 24 mN m(-1) by statistical analysis of tensiometry data, suggesting a fundamental limit for biosurfactant activity in bacterial cultures incubated under standard growth conditions. This raises a challenge to our understanding of biosurfactant expression, secretion and function, as well as being of interest to biotechnology where they are used in an increasingly wide range of applications.

Discontinuity of the incudo-stapedial joint within a fully aerated middle ear and mastoid on computed tomography: A clinico-radiological study of its aetiology and clinical consequence.

AIM: To investigate the aetiology and clinical consequences of incudo-stapedial (IS) discontinuity when it is demonstrated on computed tomography (CT) within a fully aerated middle ear and mastoid. METHODS AND MATERIALS: Patients with CT evidence of IS discontinuity within a fully aerated middle ear and mastoid were prospectively identified. Clinical history, otoscopic findings, audiometry, and CT data were evaluated. Predefined criteria were used to determine the likely aetiology of IS discontinuity, whether it was diagnosed prior to the CT study, and the clinical consequences in terms of degree of conductive hearing loss and requirement for surgical correction. The range of CT appearances was evaluated. RESULTS: The IS discontinuity in 34/36 ears was felt to be due to incus erosion secondary to chronic otitis, on the basis of clinical history and otoscopic findings. The IS discontinuity was rarely evident prior to CT with long-process deficiency being identified in only 5/36 cases. The mean air bone gap was only 22.5 dB. The ossicular defect was surgically addressed in only four cases. The incus deficiency was confined to the lower-third on CT in 19/36 cases. CONCLUSION: When IS discontinuity is demonstrated within a fully aerated middle ear and mastoid, the most likely aetiology is of acquired incus erosion due to chronic otitis media. The IS discontinuity on CT is usually not evident otoscopically. It usually results in only mild conductive hearing loss and the ossicular discontinuity was rarely surgically addressed in the present series.

Therapeutic potential of computer to cerebral cortex implantable devices.

In this article, an overview of some of the latest developments in the field of cerebral cortex to computer interfacing (CCCI) is given. This is posed in the more general context of Brain-Computer Interfaces in order to assess advantages and disadvantages. The emphasis is clearly placed on practical studies that have been undertaken and reported on, as opposed to those speculated, simulated or proposed as future projects. Related areas are discussed briefly only in the context of their contribution to the studies being undertaken. The area of focus is notably the use of invasive implant technology, where a connection is made directly with the cerebral cortex and/or nervous system. Tests and experimentation which do not involve human subjects are invariably carried out a priori to indicate the eventual possibilities before human subjects are themselves involved. Some of the more pertinent animal studies from this area are discussed. The paper goes on to describe human experimentation, in which neural implants have linked the human nervous system bidirectionally with technology and the internet. A view is taken as to the prospects for the future for CCCI, in terms of its broad therapeutic role.

Mycosis fungoides: subcutaneous and visceral tumors, orbital involvement, and ophthalmoplegia.

A patient with advanced severe mycosis fungoides presented several unusual features, including prominent lesions of the palate and tongue and an orbital tumor with exophthalmos and ophthalmoplegia. A hitherto undescribed feature was the development of multiple, massive subcutaneous tumors unrelated to the dermis or to lymph nodes, and large tumors in the connective tissues of the buttock, flank, and retroperitoneum. The usual sites of extracutaneous dissemination of mycosis fungoides--lymph nodes, spleen, liver, lungs, and blood--were not demonstrably involved. This may be a new pattern of dissemination for this disease. Of practical importance is the immediate and complete relief of exophthalmos and ophthalmoplegia that was obtained with emergency radiotherapy.

Hairy-cell leukemia: induction of complete remission with pentostatin (2'-deoxycoformycin).

Two men with advanced but previously untreated B cell hairy-cell leukemia were treated with low doses of pentostatin (2'-deoxycoformycin) in intermittent courses. There was prompt clearance of hairy cells from the blood, regression of splenomegaly and lymphadenopathy, and correction of anemia, thrombocytopenia, and granulocytopenia. Side effects were tolerable and myelosuppression was not observed. Both patients achieved complete remission documented by bone marrow aspiration and biopsy and radionuclide scans of liver and spleen. They remain in complete remission nine and six months, respectively, after their last treatment. Pentostatin (Warner-Lambert, Ann Arbor, Mich) is highly active in hairy-cell leukemia and merits more extensive evaluation in this disease. A woman with hairy-cell leukemia has begun treatment with pentostatin, and at ten weeks there is disappearance of gross splenomegaly and clearance of hairy cells from the blood. Bone marrow studies have not yet been repeated.

Pentostatin induces durable remissions in hairy cell leukemia.

Fifty patients with hairy cell leukemia were treated with pentostatin (2'-deoxycoformycin; dCF) for a median of 3 months; 32 (64%) patients achieved complete remission (CR), and 10 (20%) patients achieved partial remission (PR), for an overall response rate of 84%. After reaching maximal response, no maintenance therapy was administered. The median duration of follow-up is now 39 months, and only four of 32 patients in CR and two of 10 patients in PR have relapsed. dCF therapy produces durable long-term, disease-free survival in patients with hairy cell leukemia.

Defining the Q-site of Escherichia coli fumarate reductase by site-directed mutagenesis, fluorescence quench titrations and EPR spectroscopy.

We have used fluorescence quench titrations, EPR spectroscopy and steady-state kinetics to study the effects of site-directed mutants of FrdB, FrdC and FrdD on the proximal menaquinol (MQH(2)) binding site (Q(P)) of Escherichia coli fumarate reductase (FrdABCD) in cytoplasmic membrane preparations. Fluorescence quench (FQ) titrations with the fluorophore and MQH(2) analog 2-n-heptyl-4-hydroxyquinoline-N-oxide (HOQNO) indicate that the Q(P) site is defined by residues from FrdB, FrdC and FrdD. In FQ titrations, wild-type FrdABCD binds HOQNO with an apparent K(d) of 2.5 nM, and the following mutations significantly increase this value: FrdB-T205H (K(d) = 39 nM); FrdB-V207C (K(d) = 20 nM); FrdC-E29L (K(d) = 25 nM); FrdC-W86R (no detectable binding); and FrdD-H80K (K(d) = 20 nM). In all titrations performed, data were fitted to a monophasic binding equation, indicating that no additional high-affinity HOQNO binding sites exist in FrdABCD. In all cases where HOQNO binding is detectable by FQ titration, it can also be observed by EPR spectroscopy. Steady-state kinetic studies of fumarate-dependent quinol oxidation indicate that there is a correlation between effects on HOQNO binding and effects on the observed K(m) and k(cat) values, except in the FrdC-E29L mutant, in which HOQNO binding is observed, but no enzyme turnover is detected. In this case, EPR studies indicate that the lack of activity arises because the enzyme can only remove one electron from reduced MQH(2), resulting in it being trapped in a form with a bound menasemiquinone radical anion. Overall, the data support a model for FrdABCD in which there is a single redox-active and dissociable Q-site.

The treatment of hairy cell leukemia with 2'-deoxycoformycin: results in India and in the United States.

We treated 11 patients (nine men and two women) with hairy cell leukemia with low doses of pentostatin (2'-deoxycoformycin). As of January 1987, 10 patients (91%) were in complete remission (CR) and one (9%) was in partial remission. Thus, the overall response rate was 100%. Maintenance therapy was not given once CR was attained, but no patient in CR relapsed: remission durations were from 40+ to 9+ months. For hairy cell leukemia, pentostatin is a better treatment than splenectomy and probably is superior to interferon, but further studies are needed to better define its role in this disease.

Inferior vena cava obstruction. A complication of prostate cancer.

Inferior vena cava (IVC) obstruction, manifested as bilateral, asymmetric, asymptomatic, pitting leg edema and scrotal swelling, developed in two patients with advanced prostatic cancer. Radiological confirmation was obtained in both patients. Inferior vena cava obstruction was the initial manifestation of disease progression and occurred in patients who were ambulatory without evidence of congestive heart failure or concurrent estrogen therapy. Early IVC contrast study is indicated in similar patients in whom asymptomatic bilateral leg edema of obscure origin develops.

Percutaneous management of pulmonary metastases arising from colorectal cancer; a systematic review.

BACKGROUND: Radiofrequency ablation (RFA) is a well-established treatment modality for colorectal hepatic metastases, the success of which has prompted its use to treat other lesions such as colorectal pulmonary metastases (CRPM). Our aim was to perform a systematic review of the evidence and to assess the safety and effectiveness of ablative techniques in the management of CRPM. METHOD: A literature search was performed using PubMed, Embase, Cochrane Library, CINAHL and Google scholar databases to identify studies, which analysed ablative techniques and their effectiveness in the management of CRPM. The primary outcome measures were overall survival, local recurrence rates and disease free survival. Secondary outcome measures were complication (major/minor), chest drain insertion rates and follow up duration. RESULTS: Eight studies were included in the review with a total of 903 patients and all of which used RFA for ablation. Mortality from ablation was <1% with overall survival ranging from 31 to 67 months. 1, 3 and 5 year survival ranges of 84-95%, 35-72% and 20-54% respectively. Local progression following ablation ranged from 9 to 21%. Major complication rates were noted in 0.5%-8% of patients with minor complications ranging between 7% and 33%. 23% of patients required chest drain insertion post procedure. CONCLUSION: s: RFA is a safe and effective technique for the management of CRPM. However, in the absence of large randomised controlled trials it is unclear where RFA should sit in the treatment algorithm for patients with CRPM.

The role of pentostatin (2'-deoxycoformycin, dCF) in the management of lymphoproliferative malignancies.

Laboratory and clinical data relating to the use of 2'-deoxycoformycin in human disease are reviewed. Pentostatin is an inhibitor of adenosine deaminase, an enzyme that is important for purine metabolism, but more than one mechanism may be involved in its cytotoxic action. Early studies with dCF employed large doses and for the most part were conducted in patients with acute lymphocytic leukaemia: responses were brief and relatively few, and severe renal, hepatic, and central nervous system toxicity were encountered, leading to temporary abandonment of clinical trials. More recently, it has been shown that dCF is effective in much smaller doses, with considerably less toxicity. It has proved to be more effective in low-grade lymphoid malignancies (chronic leukaemias, indolent lymphomas) than in more undifferentiated neoplasms (acute leukaemias, lymphoblastic and immunoblastic lymphomas), and is outstandingly effective in hairy cell leukaemia, both as initial therapy and after failure of splenectomy and interferon. Pentostatin is profoundly immunosuppressive: generally this is considered a disadvantage but its potential therapeutic exploitation merits investigation. Despite extensive knowledge of its biochemical effects, the optimal dose regimen of dCF and the value of combining it with purine antagonists remain to be defined.

Glucocorticoids and insulin sensitivity: dissociation of insulin's metabolic and vascular actions.

Insulin sensitivity in tissues such as a skeletal muscle and fat is closely correlated with insulin action in the vasculature, but the mechanism underlying this is unclear. We investigated the effect of dexamethasone on insulin-stimulated glucose disposal and vasodilation in healthy males to test the hypothesis that a reduction in glucose disposal would be accompanied by a reduction in insulin action in the vasculature. We performed a double-blind, placebo-controlled, cross-over trial comparing insulin sensitivity (measured by the euglycemic hyperinsulinemic clamp) and vascular insulin action (measured by small vessel wire myography) in young healthy males allocated to placebo or 1 mg dexamethasone twice daily for 6 d, each in random order. Six days of dexamethasone therapy was associated with a 30% (95% confidence interval, 19.1-40.0%) fall in insulin sensitivity. Despite this, there was no difference in insulin-mediated vasodilation between phases. Dexamethasone had no effect on circulating markers of endothelial function, such as D-dimer, von Willebrand factor, and tissue plasminogen activator. By short-term exposure to high dose dexamethasone we were able to differentially affect the metabolic and vascular actions of insulin. This implies that, using this model, there is physiological uncoupling of the effects of insulin in different tissues.

Clinical manifestations of chronic granulocytic leukemia.

CGL is a highly specific disease that is defined by strict hematologic parameters that include a pathognomonic differential leukocyte count. Usually CGL is accompanied by the presence, in bone marrow cells, of the Ph chromosome, the first chromosomal anomaly to be regularly associated with a human neoplastic disease. CGL is predominantly a disease of the productive middle years of life, which maximizes its adverse impact on family life and family economics. The disease is of worldwide distribution and there is a slight male preponderance. The disease is characterized by an initial chronic phase when it behaves as a differentiated neoplasm and responds very well to simple, nonintensive therapy. After a variable interval, CGL undergoes metamorphosis to a refractory phase that responds poorly or sometimes not at all to therapy, even when this is intensive. At the stage of metamorphosis a great variety of clinical and hematologic pictures occur, and CGL may mimic a myeloproliferative disease, a myelodysplasia, a subacute leukemia, AML, or ALL. The old concept of an abrupt, explosive transition from the chronic phase to a so-called blastic crisis is incorrect: this rarely occurs and in most patients who are carefully followed, CGL is observed to undergo two or more stepwise evolutions, eg, from chronic phase to an accelerated myeloproliferative phase to a phase that resembles AML. Many patients with CGL conform to an established pattern of clinical features. There is a history of insidious symptoms of anemia and of splenomegaly. The physical signs are those of pallor and marked splenomegaly, while the hematologic findings are of moderate anemia, moderate thrombocytosis, and a marked granulocytic leukocytosis with a specific differential count. The radiologic findings are typically normal. Diagnostic difficulty seldom arises with this classic presentation. The patient who is detected at an early stage of CGL may lack the history, physical signs, and fully developed hematologic picture of CGL. Before the availability of cytogenetic studies, the diagnosis could only be established with confidence by observing the patient until the typical features of the disease emerged. Also considered are the less frequent but important atypical presentations of CGL. The symptoms and complaints, findings on examination, complications and hematologic findings may depart from the typical case in a bewildering variety of ways, so that the diagnosis may be difficult, indeed, CGL is generally not the initial diagnosis that is made. When the patient with CGL has received treatment, it is usual for he or she to become asymptomatic, with no abnormal physical signs.(ABSTRACT TRUNCATED AT 400 WORDS)

Non-Hodgkin's lymphoma in the older person: a review.

OBJECTIVE: To study the epidemiology of non-Hodgkin's Lymphoma (NHL) in the older person and to explore treatment strategies for older persons with NHL. DESIGN: Review of the English literature. MEASUREMENTS: Incidence of NHL in patients of different ages; prevalence of NHL of different grades and stages in persons of different ages; and response to treatment, disease free survival, and survival, for patients of different ages. RESULTS: The incidence of NHL in the aged has increased approximately 80% since 1970, and approximately one-half of the 40,000 annual new cases occur in persons aged 60 and older in the USA. The 2-4 phenoxy pesticides may be partly responsible for this increment. The treatment of low grade lymphoma is mostly palliative and well tolerated by the aged. Age may have an adverse effect on the prognosis of intermediate grade lymphomas, and the prevalence of poor prognostic factors and comorbidity increases with age. Among persons aged 65-75, the complete response rate (CRR) of intermediate grade NHL to chemotherapy is approximately 50%, and approximately one-third of complete responders remain alive and free of disease 5 years from diagnosis. Among those aged 75 and older, the CRR to chemotherapy is approximately 40%, and the median duration of response is 16 months. Strategies aimed to ameliorate treatment-related toxicity include lower doses of chemotherapy, choice of drugs better tolerated by older individuals, and prevention of chemotherapy-induced toxicity. CONCLUSIONS: NHL are an increasingly common problem for older persons. Approximately 80% of older patients with low grade lymphomas and 40%-50% of those with intermediate grade lymphomas may benefit from chemotherapy. Individualized treatment, based on life expectancy and comorbidity, is the key to effective management.

Acute lymphoblastic leukemia of Burkitt's type (L-3 ALL) lacking surface immunoglobulin and the 8;14 translocation.

A 25-year-old man developed acute lymphoblastic leukemia, morphologically of Burkitt's type (L3-ALL, F.A.B. classification) but with immunologic and cytogenetic features not previously reported. The leukemic blasts were B1+, CALLA+, OKT3-, and OKT11-. Surface immunoglobulin and cytoplasmic IgM were not detected, but cytoplasmic IgG lambda was present. Karyotypic analysis of 20 metaphases was normal at presentation but abnormal after relapse. At that time, the predominant karyotype was 47XY, 1q-, 7q-, 12p-, M1. This case illustrates the following: (1) Burkitt cell morphology may accompany some uncommon pre-B-cell lymphoblastic leukemias, and (2) rearrangements involving chromosomes 14, 2 or 22 may not be found in all cases of L-3 ALL.

Neutrophil alkaline phosphatase score in chronic granulocytic leukaemia: effects of splenectomy and antileukaemic drugs.

Staining with naphthol AS phosphate and Fast Blue BB salt has been used for the estimation of neutrophil alkaline phosphatase (NAP) scores in patients with chronic granulocytic leukaemia (CGL). The very low scores found at diagnosis rise when the disease is treated, and there is some inverse correlation between the NAP score and the absolute neutrophil count. Patients treated intensively developed high NAP scores. Elective splenectomy performed during the chronic phase of CGL is followed by a pronounced but transient neutrophilia and a concurrent striking rise in the NAP score. Similar changes were observed in patients without CGL who underwent splenectomy. These observations can be explained by assuming that newly formed neutrophils in CGL have a normal content of NAP but are rapidly sequestered in non-circulating extramedullary pools, whereas the circulating neutrophil with a typically low NAP content is a relatively aged cell which has lost enzyme activity. In subjects with or without CGL, removal of the spleen, a major site of such pooling, temporarily permits the circulation of newly formed neutrophils but eventually other organs assume the sequestering functions of the spleen. Thus the aberrations of NAP score seen in CGL might be attributable not to an intrinsic cellular defect but to an exaggeration of the granulocyte storage phenomena which also occur in subjects without CGL.

Megakaryoblastic transformation of chronic granulocytic leukaemia. An electron microscopy and cytochemial study.

Morphological, cytochemical, and ultrastructural electron microscopic (EM) studies were performed on blood and bone-marrow cells of case of Ph1-positive chronic ganulocytic leukaemia in megakaryocytic acute transformation. The entire leukaemic cell population was found to consist and of megakaryoblasts and megakaryocytes. Intermediate stages of maturation between blasts and micromegakaryocytes were observed at EM level.

A pharmacoeconomic evaluation of the use of dexrazoxane in preventing anthracycline-induced cardiotoxicity in patients with stage IIIB or IV metastatic breast cancer.

A Markov model was developed to determine the cost of treating patients with stage IIIB or IV metastatic breast cancer with 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) and dexrazoxane (administered after six courses of FAC) versus FAC alone. The primary end point in our economic study was cost per cardiac event avoided. Cost per life-year saved was also calculated, even though the survival advantage needs to be confirmed in follow-up studies. The model incorporated the direct medical costs of treating patients with chemotherapy, as well as the costs associated with treatment of any cardiac events that occurred. Data were collected for this analysis from several sources, including completed clinical trials on FAC plus dexrazoxane versus FAC plus placebo (obtained from two patient groups randomized at different time points), a panel of three oncologists, and a panel of three cardiologists. Analyses showed that therapy with dexrazoxane costs $5661.77 per cardiac event prevented. Sensitivity analyses on model variables were performed and showed that the basic results of the model did not change when parameters were varied. The clinical efficacy and cost-effectiveness of dexrazoxane as shown by the results of the current study encourage further investigation of the uses of dexrazoxane in other populations and against other comparators.

Chronic granulocytic leukemia.

This article reviews the definition, etiology, epidemiology, cytogenetics, and diagnosis of chronic granulocytic leukemia (CGL). There is detailed consideration of clinical and laboratory findings, the natural history of CGL, and the selection of therapy at different stages of the disease. The roles of bone marrow transplantation and of newer experimental therapeutic approaches are discussed.