Effect of interleukin 1 on human thymocytes and purified human T cells.

Human Interleukin 1 (IL-1) purified by molecular weight fractionation, isoelectric focusing, and gel electrophoresis has been tested on human thymocytes and highly purified human T cells. IL-1 prepared in this manner could not support the long-term growth of T cells yet would augment lectin-stimulated mitogenesis. The IL-1 preparations were shown to possess the lectin-augmenting activity at dilutions containing less than 1 ng of the measurable protein. These data are in agreement with the model that IL-1 stimulates production of IL-2 from lectin-stimulated lymphocytes.

Radiotherapy: Basic Concepts and Recent Advances.

Radiation therapy (RT) is a clinical modality dealing with the use of ionizing radiations to treat malignant neoplasias (and occasionally benign diseases). Since its inception, the goal of RT has been to cure cancer locally without excessive side effects. The most important factors affecting the results of RT are the tumor type, its location and regional extent, the anatomic area of involvement and the geometric accuracy with which a calculated radiation dose is delivered. Although higher doses of radiation can produce better tumor control, the dosage which can be given is limited by the possibility of normal tissue damage. Approximately 60-65% of all cancer patients require RT as the sole treatment modality and / or in combination with surgery or chemotherapeutic drugs. There is a huge gap between demand and supply of radiotherapy facilities and infrastructure. Most of the oncocentres are located in urban areas in private sector and are beyond the reach of the common man.

Blood transfusion and ischaemic outcomes according to anemia and bleeding in patients with non-ST-segment elevation acute coronary syndromes: Insights from the TAO randomized clinical trial.

BACKGROUND: The benefits and risks of blood transfusion in patients with acute myocardial infarction who are anemic or who experience bleeding are debated. We sought to study the association between blood transfusion and ischemic outcomes according to haemoglobin nadir and bleeding status in patients with NST-elevation myocardial infarction (NSTEMI). METHODS: The TAO trial randomized patients with NSTEMI and coronary angiogram scheduled within 72h to heparin plus eptifibatide versus otamixaban. After exclusion of patients who underwent coronary artery bypass surgery, patients were categorized according to transfusion status considering transfusion as a time-varying covariate. The primary ischemic outcome was the composite of all-cause death or MI within 180 days of randomization. Subgroup analyses were performed according to pre-transfusion hemoglobin nadir and bleeding status. RESULTS: 12,547 patients were enrolled. Among these, blood transfusion was used in 489 (3.9%) patients. Patients who received transfusion had a higher rate of death or MI (29.9% vs. 8.1%, p<0.01). This excess risk persisted after adjustment on GRACE score and nadir of hemoglobin (HR 3.36 95%CI 2.63-4.29 p<0.01). Subgroup analyses showed that blood transfusion was associated with a higher risk in patients without overt bleeding (adjusted HR 6.25 vs. 2.85; p-interaction 0.001) as well as in those with hemoglobin nadir > 9.0 g/dl (HR 4.01; p-interaction<0.0001). CONCLUSION: In patients with NSTEMI, blood transfusion was associated with an overall increased risk of ischaemic events. However, this was mainly driven by patients without overt bleeding and those hemoglobin nadir > 9.0g/dl. This suggests possible harm of transfusion in those groups.

Voriconazole plus terbinafine combination antifungal therapy for invasive Lomentospora prolificans infections: analysis of 41 patients from the FungiScope® registry 2008-2019.

OBJECTIVES: Lomentospora prolificans is an emerging cause of serious invasive fungal infections. Optimal treatment of these infections is unknown, although voriconazole-containing treatment regimens are considered the treatment of choice. The objective of this study was to evaluate the role of combination antifungal therapy for L. prolificans infections. METHODS: We performed a retrospective review of medical records of patients with invasive L. prolificans infection diagnosed between 1 January 2008 and 9 September 2019 that were documented in the FungiScope® registry of rare invasive fungal infections. We compared clinical outcomes between antifungal treatment strategies. RESULTS: Over the study period, 41 individuals with invasive L. prolificans infection from eight different countries were documented in the FungiScope® registry. Overall, 17/40 (43%) had treatment response/stable disease and 21/40 (53%) had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was associated with increased 28-day survival (15/24 survived versus 4/16 receiving monotherapy; p 0.027) and the combination voriconazole plus terbinafine trended to be associated with higher rates of treatment success (10/16, 63%, 95% CI 35%-85%) compared with other antifungal treatment regimens (7/24, 29%, 95% CI 13%-51%, p 0.053). In Kaplan-Meier survival analysis there was a higher survival probability in individuals receiving the voriconazole/terbinafine combination compared with other antifungal regimens (median survival 150 days versus 17 days). CONCLUSIONS: While overall mortality was high, combination antifungal treatment, and in particular combination therapy with voriconazole plus terbinafine may be associated with improved treatment outcomes compared with other antifungal regimens for the treatment of invasive L. prolificans infections.

Diabetes Mellitus in India: The Modern Scourge.

India has a high prevalence of diabetes mellitus and the numbers are increasing at an alarming rate. In India alone, diabetes is expected to increase from 40.6 million in 2006 to 79.4 million by 2030. Studies have shown that the prevalence of diabetes in urban Indian adults is about 12.1%, the onset of which is about a decade earlier than their western counterparts and the prevalence of Type 2 diabetes is 4-6 times higher in urban than in rural areas. The risk factors peculiar for developing diabetes among Indians include high familial aggregation, central obesity, insulin resistance and life style changes due to urbanization. Screening for gestational diabetes and impaired glucose tolerance among pregnant women provides a scope for primary prevention of the disease in mothers as well as in their children. The problems of obesity and impaired glucose tolerance (IGT) (important predisposing factors) are not confined to adults alone but children are also increasingly getting affected. Most long standing macro and micro vascular complications are also more common among Indian diabetics as compared to other races and ethnic groups. A strong familial clustering of diabetic nephropathy among Indian Type 2 diabetics has also been noted. Clustering of cardiovascular risk factor like Syndrome X is common among urban Indians. The rising incidence of diabetes and its complications are going to pose a grave health care burden on our country. Timely effective interventions/measures and screening tests for complications at the time of diagnosis becomes imperative not only for early detection, but also to prevent progression to end stage disease. Screening for gestational diabetes among pregnant women would also go a long way in primary prevention of the disease. Life style changes/interventions and drugs like rosiglitazone are the current strategies that can prevent and/or delay the onset of diabetes. Simple interventional strategies like "Eat less, Eat on time and Walk more" can go a long way in preventing these chronic disorders among present as well as in the future generations.

Bioshock: Biotechnology and Bioterrorism.

In the recent past, the threat of a global bioterrorist attack has increased dramatically. In addition to the already existing microorganisms and techniques, the recent explosion in biotechnology has considerably added to the arsenal of the bioterrorist. Molecular technologies are now available which can be used by committed bioterrorist groups to manipulate and modify microorganisms so as to make them increasingly infectious, virulent or treatment resistant for causing maximum casualties. Infectious diseases which are likely to be used as bioweapons are Anthrax, Botulism, Plague, Smallpox and Brucella. Molecular techniques like immunoassays and nucleic acid amplification are now available to detect bioattacks. This article discusses the threat of bioterrorism. It also evaluates the molecular diagnostic methods and the future of early containment of a bioterrorist attack using molecular techniques.

Prevalence and Correlates of Injecting with Visitors from the United States Among People Who Inject Drugs in Tijuana, Mexico.

Cross-border infectious disease transmission is a concern related to drug tourism from the U.S. to Mexico. We assessed this risk among people who inject drugs (PWID) in Tijuana, Mexico. We measured the prevalence and identified correlates of injecting with PWID visiting from the U.S. among PWID in Tijuana using univariable and multivariable logistic regression. Of 727 participants, 18.5% injected during the past 6 months in Mexico with U.S. PWID described mostly as friends (63%) or acquaintances (26%). Injecting with U.S. PWID was independently associated with higher education [adjusted odds ratio (aOR) = 1.13/year], deportation from the U.S. (aOR = 1.70), younger age at first injection (aOR = 0.96/year), more lifetime overdoses (aOR = 1.08), and, in the past 6 months, backloading (aOR = 4.00), syringe confiscation by the police (aOR = 3.02) and paying for sex (aOR = 2.98; all p-values < 0.05). Nearly one-fifth of PWID in Tijuana recently injected with U.S. PWID, and their reported risk behaviors could facilitate cross-border disease transmission.

Management of malaria: recent trends.

In the present day scenario of resurgence of infectious diseases, malaria compounded with problems of multi drug resistance, assumes paramount importance. A combination of artemisinine derivatives with other effective anti-malarial drug remains the most effective form of treatment against the falciparum malaria which is most lethal form of disease. Oral chloroquin in the dose of 25 mg base/kg over 48 hours is effective in infections due to P. vivax, P. ovale P. malariae and chloroquine sensitive P. Falciparum. For chloroquine resistant P. vivax and multidrug resistant falciparum malaria, a combination of Quinine with doxycycline or clindamycin for 5-7 days, Quinine with singlt dose sulfadoxine-pyrimethamine combination. Mefloquine with artemeter or artesunate for 3 days, artesunate with doxycycline or clindamycin for 7 days and Otovaquin with proguanil for 3 days have been found to be effective. Primiquin as a hypnozoticide for 5-10 days is mandatory for preventing relapse in cases of P. vivax, P. Ovale and P. malariae. Death due to complicated malaria can be as high as 75% if case diagnosis is delayed or the patient arrives late. The artemisinine based rectal suppositories can be very effective in home/village setting in patients who can not be given oral anti malarial, though not yet approved for use in our country. In ICU settings, properly administered loading dose of quinine has proved to be effective and safe in almost all therapeutic trials including our study on Indian patients. Frequent blood glucose monitoring is mandatory. Parentral artemisinine with oral mefloquine is an effective alternative to quinine based therapy. The cerebral malaria management in the ICU setting includes monitoring fluid and electrolyte balance so as to maintain a CVP of 5 cm of water and pulmonary arterial occlusive pressure at less than 15 mm of mercury. In renal failure haemofiltration is ideal. Mefloquine is safe in second and third trimester of pregnancy. Exchange transfusion, haemopheresis and plasmapheresis are new techniques in the treatment of gravely ill patients with PF malaria especially when parasitemia exceeds 10%.

Transient stimulation of the c-Jun-NH2-terminal kinase/activator protein 1 pathway and inhibition of extracellular signal-regulated kinase are early effects in paclitaxel-mediated apoptosis in human B lymphoblasts.

We demonstrate here that paclitaxel exposure to RPMI-1788 B lymphoblasts caused a dose- and time-dependent increase in nuclear factor activator protein 1 (AP-1) DNA binding activity. The basal DNA binding activities of nuclear factors NF-kappaB and Ets were not affected by paclitaxel. Consistent with these biochemical events, paclitaxel stimulated AP-1-dependent chloramphenicol acetyltransferase (CAT) reporter gene transcription in vivo, as directed from a tetradecanoyl phorbol acetate-inducible promoter. AP-1 binding activity of nuclear extracts isolated from paclitaxel treated cells was reduced following immunodepletion with antibodies directed against individual Jun family proteins, whereas anti-cFos, anti-Fra1, and anti-FosB antibodies were not inhibitory. Paclitaxel caused a rapid and transient increase in c-Jun NH2-terminal kinase (JNK) activity, a proposed mediator of stress activation pathways. By contrast, exposure to paclitaxel produced a transient reduction in the extracellular signal-regulated mitogen-activated protein kinase 2 (ERK2) activity, a proposed mediator of growth factor-stimulated proliferation pathways. Transient activation of the c-Jun-NH2-terminal kinase/AP-1 pathway, together with down-regulation of ERK2 activity, may be a key event in the early response of RPMI-1788 B lymphoblasts to paclitaxel exposure.

Validation of the GeneXpert® CT/NG Assay for use with Male Pharyngeal and Rectal Swabs.

OBJECTIVES: The GeneXpert® CT/NG (Cepheid, Sunnyvale, CA) assay is a point-of-care (POC) molecular diagnostic assay designed to rapidly test for the presence of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC). However, the test is only approved for vaginal swabs, urine, and endocervical swabs. Here, we performed an evaluation of the GeneXpert® CT/NG assay to detect the presence of CT and GC on male pharyngeal and rectal swabs. METHODS: Men who have sex with men participating in an HIV and Sexually Transmitted Infection (STI) screening program providing consent were enrolled into the study. Participants were asked to self-collect two pharyngeal and two rectal swabs. One set was tested on site using GeneXpert® and the other was sent to a reference lab for molecular testing using the APTIMA® system (Hologic, San Diego, CA). RESULTS: A total of 570 swabs were collected from 144 patients. GeneXpert® detected 13/15 rectal swabs testing CT positive by the APTIMA® assay (relative sensitivity=88.2%), 1/2 pharyngeal swabs testing CT positive (relative sensitivity=50%), and 7/9 pharyngeal swabs testing NG positive (relative sensitivity =77.8%). No discordance was observed for rectal NG swabs. CONCLUSIONS: Although less sensitive than the APTIMA® assay for the molecular detection of NG and CT, GeneXpert®'s potential as a rapid POC diagnostic still make it a viable diagnostic test for STI screening. Molecular POC diagnostics, such as this, will allow more thorough screening of at risk individuals, and enhance the ability of clinics to provide same-day diagnosis and treatment.

Prognostic significance of thrombocytopenia during hirudin and heparin therapy in acute coronary syndrome without ST elevation: Organization to Assess Strategies for Ischemic Syndromes (OASIS-2)study.

BACKGROUND: The development of thrombocytopenia in acute coronary syndromes (ACS) appears to be associated with adverse clinical outcomes. Unfractionated heparin is a recognized cause of thrombocytopenia, but the incidence, predictors, and prognostic significance of thrombocytopenia during hirudin therapy in ACS have not been reported. METHODS AND RESULTS: Patients with ACS without ST elevation were randomized in a double-blind manner to receive a 72-hour intravenous infusion of unfractionated heparin or hirudin. Platelet counts were measured at baseline and within 24 hours of completion of study drug. The overall incidence of thrombocytopenia (<100x10(9)/L) was 1% and was similar in unfractionated heparin- and hirudin-treated patients (P:=0.42). Thrombocytopenia during study drug infusion was an independent predictor of 7-day outcomes, including death (OR, 6.7; 95% CI, 1.9 to 25); the composite of death, myocardial infarction, and recurrent ischemia (OR, 2.0; 95% CI, 1.0 to 1.5); revascularization (OR, 4.0; 95% CI, 2.2 to 7.1); and major bleeding (OR, 8.3; 95% CI, 3.4 to 17.7). Among patients who developed thrombocytopenia, hirudin (OR, 5.4; 95% CI, 2.6 to 11.3) but not unfractionated heparin (OR, 2.0; 95% CI, 0.3 to 14.4) therapy was associated with a significantly increased risk of major bleeding. CONCLUSIONS: Early-onset thrombocytopenia in patients with ACS without ST elevation is strongly associated with adverse clinical outcomes, including death, ischemic events, and bleeding. The excess of major bleeding in hirudin-treated patients who develop thrombocytopenia suggests that thrombocytopenia may contribute to the increased risk of bleeding observed with hirudin.

Stroke in relation to cardiac procedures in patients with non-ST-elevation acute coronary syndrome: a study involving >18 000 patients.

BACKGROUND: There are few published data on risk factors for stroke in patients with non-ST-elevation acute coronary syndrome (ACS). We investigated prognostic factors for stroke in 2 large cohorts of patients from the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry (8010) and the OASIS-2 trial (10 141). METHODS AND RESULTS: A total of 18 151 patients with non-ST-elevation ACS were enrolled in the OASIS program. Data from these 2 studies were pooled (a test for heterogeneity was nonsignificant, P=0.34). Overall, 238 patients (1.3%) had a stroke over a 6-month follow-up. Those who experienced stroke had a 4-fold increase in 6-month mortality (27.0% versus 6.3%, P<0.001). A Cox multivariate regression analysis identified CABG surgery as the most important predictor of stroke (hazard ratio [HR], 4.6), followed by history of stroke (HR, 2.3), diabetes mellitus (HR, 1.7), older age (HR, 1.6 per 10-year increase), higher heart rate (HR, 1.1 per 10-bpm increase), and on-site catheterization facility (HR, 1.4). There was no significant excess in stroke in patients undergoing percutaneous coronary intervention (P=0.21). Patients who underwent early CABG surgery were at a substantially increased risk compared with those who had later CABG (3.3% versus 1.6%; HR, 2.1; P=0.003) or who had no surgery (3.3% versus 1.1%; HR, 3.95; P=0.0001). CONCLUSIONS: In this large cohort of patients with ACS, stroke was an uncommon but serious event associated with high mortality. The performance of early CABG surgery was a powerful independent predictor of stroke.

Impact of right ventricular involvement on mortality and morbidity in patients with inferior myocardial infarction.

OBJECTIVES: We sought to evaluate the prognostic impact of right ventricular (RV) myocardial involvement in patients with inferior myocardial infarction (MI). BACKGROUND: There is uncertainty regarding the risk of major complications in patients with inferior MI complicated by RV myocardial involvement. Whether these complications are related to RV myocardial involvement itself or simply to the extent of infarction involving the left ventricle (LV) is also unknown. METHODS: We examined the incidence of death and mechanical and electrical complications in patients with (n = 491) and without (n = 638) RV myocardial involvement and in patients with anterior MI (n = 971) in an analysis from the Collaborative Organization for RheothRx Evaluation (CORE) trial. Left ventricular infarct size was assessed by technetium-99m-sestamibi single-photon emission computed tomography and peak creatine kinase, and LV function was assessed by radionuclide angiography. We also performed a meta-analysis in which we pooled the results of our study with previous smaller studies addressing the same question. RESULTS: Six-month mortality was 7.8% in inferior MI compared with 13.2% in anterior MI. Among patients with inferior MI, serious arrhythmias were significantly more common in patients with RV myocardial involvement who also had a trend toward higher mortality, pump failure and mechanical complications. However, this was not associated with a difference in LV infarct size or function. A meta-analysis of six studies (n = 1,198) confirmed that RV myocardial involvement was associated with an increased risk of death (odds ratio [OR] 3.2, 95% confidence interval [CI] 2.4 to 4.1), shock (OR 3.2, 95% CI 2.4 to 3.5), ventricular tachycardia or fibrillation (OR 2.7, 95% CI 2.1 to 3.5) and atrioventricular block (OR 3.4, 95% CI 2.7 to 4.2). CONCLUSIONS: Patients with inferior MI who also have RV myocardial involvement are at increased risk of death, shock and arrhythmias. This increased risk is related to the presence of RV myocardial involvement itself rather than the extent of LV myocardial damage.

Avian Flu - A Bird's Eye View.

Influenza A (H5N1) virus infects a variety of animals, birds and humans. Present ongoing epidemic of this deadly virus in poultry livestock and humans has had major economic and health repercussions. It causes a wide spectrum of clinical features in human beings ranging from mild respiratory tract infection to a fatal pneumonia leading to multi organ system failure. Diagnosis is mainly clinical, aided by lab features like lymphopaenia and non-specific chest X-ray findings. Diagnostic tests are being evolved for rapid and specific diagnosis. Management is mainly symptomatic. Newer and effective antivirals, i.e. amantadine, zanamivir etc are also being tried.

Diagnostic significance of pleural fluid eosinophilia during initial thoracocentesis.

A prospective study of pleural fluid eosinophilia (PFE) during initial thoracocentesis in 162 patients of pleural effusion was undertaken to determine its value in establishing an etiological diagnosis. Eighteen of the 162 cases showed pleural fluid eosinophilia (PFE), twelve could not be labelled with any definitive etiology even after extensive investigations, four belonged to the para-pneumonic group and resolved with treatment. Of the 32 patients with malignancy, PFE was seen in a single case of pleural mesothelioma. None of the patients with tuberculosis, empyema, systemic lupus erythematosus or amoebiasis had PFE. These findings suggest that PFE seen at initial thoracocentesis favours a benign diagnosis, with a rare chance of malignancy. Tuberculosis is unlikely in such patients.

Distal spinal muscular atrophy.

Spinal muscular atrophies (SMA) are clinically heterogenous group of motor system disorders characterised by progressive pure lower motor neuron involvement. The distal form of SMA is an extremely rare disorder, which presents in the adults and has a relatively slow progression with almost no effect on the patients' life-span. Differential diagnosis of this syndrome include other forms of neuromuscular disorders with peroneal muscular atrophy like hereditary motor sensory neuropathy (HMSN) and distal myopathies, which need exclusion before confirming this rare entity. We present a young male with this disorder and briefly discuss the theoretical aspects.

Multigated radionuclide ventriculography during in-hospital phase of acute myocardial infarction.

Global and regional left ventricular performance was assessed by multigated radionuclide technique in thirty patients sustaining acute myocardial infarction on two occasions during in-hospital phase. Thirteen (76.5%) of the seventeen patients with anterior infarction had depressed initial left ventricular ejection fraction compared with seven (53.8%) of the thirteen patients with inferior infarction. From initial to discharge study, change in ejection fraction was statistically insignificant in either group of infarctions. All except three (10%) patients had regional wall motion abnormality on initial evaluation with little subsequent alteration. Our data demonstrates that ejection fraction changes variably during the course of illness, and location of infarction has profound effect upon degree of left ventricular dysfunction. Assessment by non-invasive radionuclide technique may have prognostic implications.

Normokalaemic periodic paralysis as the presenting manifestation of hyperthyroidism.

We report a 50 year old male admitted with complaints of episodic weakness. During the attack of paralysis there was no hypokalaemia. There were no clinical signs of thyrotoxicosis, but since thyroid function tests revealed hyperthyroidism, he was treated as a case of thyrotoxic periodic paralysis, with no recurrence of symptoms over 6 months.

The changed clinical spectrum of malaria due to drug resistance.

The clinical spectrum of 14 cases of Plasmodium falciparum malaria (PF) who received empirical treatment and suffered from initial prolonged mild illness culminating into severe complicated malaria are presented. The empirical treatment (ET) consisted of adequate doses of chloroquine in 9, chloroquine with pyrimethamine-sulphadoxine combination in 3 and pyrimethamine-sulphadoxine alone in 2 cases. Moderate fever and weakness persisted for 7 to 28 days leading to anaemia and progressive hepatosplenomegaly in all patients. Other clinical features noticed included jaundice in 5, sudden shock with pulmonary oedema in 4, cerebral malaria and renal failure in 3 each and multiorgan in 4 cases. Subsequent investigations revealed PF rings in 9 cases, mixed PF and vivax infection in 3 and PF gametocytaemia only in 2 patients. Seven patients received quinine, 4 quinine with doxycycline and 3 were given quinine followed by injection artemether. Exchange transfusion was carried out in two cases. Four patients died. The empirical treatment with first line antimalarials alters the clinical profile of resistant PF, makes it milder temporarily, delays in confirming the diagnosis and leads to high mortality. There is urgent need for more diligent early workup for these patients who linger on with moderate pyrexia, progressive hepatosplenomegaly, anaemia and jaundice after ET till better diagnostic methods are available to avoid the prolonged illness and high mortality.

Experience on loading dose--quinine therapy in cerebral malaria.

Twelve cases of cerebral malaria due to plasmodium falciparum, treated with loading dose of quinine (20 mg/kg salt in 500 ml of 5% glucose infused IV in 4 hrs) are compared with eleven age and sex matched cases treated with conventional dose of 10 mg/kg. The parasite clearance rate was significantly faster in loading dose group. There was no difference in recovery time: the interval between the initiation of treatment to full recovery of consciousness in both groups. One patient had pretreatment hypoglycaemia and two cases in the conventional dose group developed hypoglycaemia during therapy. One patient died in conventional dose group due to multi-organ failure. Two litres blood exchange transfusion was also tried for this case. Mild cinchonism occurred in two cases after loading dose while this was observed only in one case in conventional dose group. There was no significant hypotension or ECG changes in any patient. Loading dose of quinine seems to be well tolerated and may clear parasitaemia faster in case of malaria due to Plasmodium falciparum (PF).