Antibody-drug conjugate as targeted therapeutics against hepatocellular carcinoma: preclinical studies and clinical relevance.

An antibody-drug conjugate (ADC) is an advanced chemotherapeutic option with immense promises in treating many tumor. They are designed to selectively attack and kill neoplastic cells with minimal toxicity to normal tissues. ADCs are complex engineered immunoconjugates that comprise a monoclonal antibody for site-directed delivery and cytotoxic payload for targeted destruction of malignant cells. Therefore, it enables the reduction of off-target toxicities and enhances the therapeutic index of the drug. Hepatocellular carcinoma (HCC) is a solid tumor that shows high heterogeneity of molecular phenotypes and is considered the second most common cause of cancer-related death. Studies show enormous potential for ADCs targeting GPC3 and CD24 and other tumor-associated antigens in HCC with their high, selective expression and show potential outputs in preclinical evaluations. The review mainly highlights the preclinical evaluation of different antigen-targeted ADCs such as MetFab-DOX, Anti-c-Met IgG-OXA, Anti CD 24, ANC-HN-01, G7mab-DOX, hYP7-DCand hYP7-PC, Anti-CD147 ILs-DOX and AC133-vcMMAF against hepatocellular carcinoma and its future relevance.

Application of an electrocardiography device (iECG) for heart rhythm analysis after exercise in Thoroughbred horses.

AliveCor is a smartphone electrocardiography device (iECG) providing automated heart rate (HR) and rhythm determination. Atrial fibrillation (AF) in horses often is paroxysmal and rapid ECG acquisition is needed for diagnostic confirmation. iECGs were collected post-race from 15 horses with AF and 64 horses in sinus rhythm (SR). Results of manual assessment were compared to 3 commercial algorithms for HR and rhythm. Agreement between manually derived HR (HRM ) and HR derived by the AliveECG Vet (HRVET ) and Kardia version-1 (KV1 HR) and Kardia advanced (KADV HR) algorithms was quantified by the Bland-Altman limits of agreement test. Agreement between manual rhythm classification and KV1 and KADV algorithms for AF and SR was calculated by the Kappa statistical coefficient. The agreement (bias, 95% limits), between HRM and HRVET was 7.1 BPM (-29 to 43) in AF and -4.2 BPM (-38 to 30) in SR, between HRM and KV1 HR, was -0.3 BPM (-31 to 30) in AF and 0.2 BPM (-3 to 4) in SR, and between HRM and KADV HR was 7.0 BPM (-29 to 43) in AF and 0.2 BPM (-3.9 to 4.2) in SR. Agreement between manual rhythm classification and KV1 was 0.36 (0.13-0.59), and KADV was 0.84 (0.68-0.99). Sensitivity and specificity for identification of AF and SR of the KV1 algorithm were 60, 100% and 83, 100%, respectively, and of KADV was 87, 100% and 93, 100% respectively. The Kardia algorithms improved precision for HR determination in SR but not AF. The advanced algorithm accurately distinguished between AF and SR. The iECG is suitable for recording episodes of AF following exercise.

Heritability estimates of atrial fibrillation in Thoroughbred racehorses in Hong Kong and Australia.

INTRODUCTION: Atrial fibrillation (AF) is the most common performance-limiting arrhythmia of racehorses. A genetic contribution has been suggested in Standardbred racehorses but has not been investigated in Thoroughbreds. The objective of this study was to determine the heritability of AF in Thoroughbred racehorses. ANIMALS, MATERIALS AND METHODS: Horses racing between 2007 and 2019 in Hong Kong and Australia that had AF detected postrace via auscultation (n = 463 cases) were compared with five randomly selected racing contemporaries (n = 2,315 controls). The ASReml-R programme was used to fit an animal model to the AF data to estimate heritability using the entire data set and a subset of horses (n = 106 cases) that had electrocardiographic confirmation of AF. Variance components were estimated assuming AF was normally distributed and on the logit-transformed scale. The risk of producing AF-affected offspring was calculated using Fisher's exact test for stallions that sired ≥10 individuals in the case-control population. RESULTS: Heritability on the underlying scale was 0.064 ± 0.04 (logit animal) and 0.071 ± 0.04 (normal animal) for the entire population and 0.065 ± 0.097 (logit animal) and 0.058 ± 0.11 (normal animal) for electrocardiographic-confirmed AF cases. Of 71 stallions that sired ≥10 individuals, three were more likely to produce affected offspring (odds ratio: 4.05-7.57; p < 0.01). Age (p = 0.991), sex (p = 0.830), and year of birth (p = 0.547) did not contribute to expression. CONCLUSIONS: Although some stallions were overrepresented amongst affected horses, the heritability of AF in this population of Thoroughbreds was low. Environmental and individual factors contributing to AF development require further investigation.

Plasma HMGB-1 and Nucleosome Concentrations in Horses with Colic and Healthy Horses.

BACKGROUND: Acute gastrointestinal disease occurs commonly in horses. Novel biomarkers might improve the understanding of SIRS and aid diagnosis and determination of prognosis. HYPOTHESES: Increased plasma concentrations of the biomarkers HMGB-1 and nucleosomes are associated with severity of gastrointestinal lesions in horses; concentrations of these biomarkers will be greater in horses with lesions more likely to cause SIRS; and will provide additional information compared with standard biomarkers fibrinogen and SAA. ANIMALS: Thirty horses with gastrointestinal disease, 22 healthy horses. METHODS: Prospective study. Plasma samples taken on admission were used for measurement of HMGB-1, nucleosomes, fibrinogen, and SAA. Values were compared between healthy horses and those with gastrointestinal disease, and between horses with gastrointestinal disease grouped by lesion type (inflammatory, strangulating, and nonstrangulating). Correlations between biomarkers were assessed. RESULTS: Plasma concentrations of all biomarkers were significantly higher in horses with gastrointestinal disease compared to healthy horses (P ≤ .001). HMGB-1 and nucleosomes were significantly higher in inflammatory and strangulating groups compared to healthy horses (3.5-fold and 5.4-fold increases, respectively, for HMGB-1 (P < .05) and 4.8-fold and 5.6-fold increases for nucleosomes (P < .05)), but concentrations in the group with nonstrangulating disease did not differ from healthy horses. There was significant correlation between HMGB-1 and nucleosomes (Spearman's r = 0.623; P < .001), and fibrinogen and SAA (Spearman's r = 0.801; P < .001) but not between other biomarkers. CONCLUSIONS AND CLINICAL IMPORTANCE: High mobility group box-1 and nucleosomes might have use as biomarkers for horses with gastrointestinal disease. Further studies are required to determine kinetics and prognostic value of serial measurements of these biomarkers in horses.

Design, development and optimization of oral colon targeted drug delivery system of azathioprine using biodegradable polymers.

The present study was aimed at designing a microflora triggered colon targeted drug delivery system (MCDDS) based on swellable polysaccharide, Sterculia gum in combination with biodegradable polymers with a view to specifically deliver azathioprine in the colonic region for the treatment of IBD with reduced systemic toxicity. The microflora degradation properties of Sterculia gum was investigated in rat caecal phosphate buffer medium. The polysaccharide tablet cores were coated to different film thicknesses with blends of Eudragit RLPO and chitosan and overcoated with Eudragit L00 to provide acid and intestinal resistance. Swelling and drug release studies were carried out in simulated gastric fluid, SGF (pH 1.2), simulated intestinal fluid, SIF (pH 6.8) and simulated colonic fluid, SCF (pH 7.4 under anaerobic environment), respectively. Drug release study in SCF revealed that swelling force of the Sterculia gum could concurrently drive the drug out of the polysaccharide core due to the rupture of the chitosan/Eudargit coating in microflora activated environment. The degradation of chitosan was the rate-limiting factor for drug release in the colon. Drug release from the MCDDS was directly proportional to the concentration of the pore former (chitosan), but inversely related to the Eudragit RLPO coating thickness.

Serum cardiac troponin I concentrations in horses with cardiac disease.

OBJECTIVES: To measure the cardiac troponin I (cTnI) concentration in horses and determine whether it could be used in the diagnosis of myocardial disease, as well as determining the association between cTnI and survival. DESIGN: Prospective, observational study. PROCEDURE: Physical examination, echocardiography, telemetric electrocardiography and postmortem were used to diagnose cardiac disease. Diagnoses were grouped as myocardial disease, structural heart disease or lone arrhythmia. Blood samples were collected at admission for cTnI analysis and the results were compared with those for 18 healthy horses. RESULTS: In total, 49 horses were admitted with cardiac disease. Elevated cTnI concentration (>0.03 ng/mL) was observed in a greater proportion of horses with myocardial disease (7/7), compared with healthy horses (0/18; P < 0.0001), horses with structural heart disease (7/25; P = 0.001), and horses with a lone arrhythmia (2/17; P = 0.0001). The median cTnI concentration for horses with myocardial disease was 17.5 ng/mL (range 0.78-49.87 ng/mL), which was higher than in the healthy horses (0.01 ng/mL, range 0.01-0.03 ng/mL; P < 0.0001). Of the 49 horses with cardiac disease, the median cTnI concentration for non-survivors (0.28 ng/mL, range 0.01-49.87 ng/mL) was higher than for survivors (0.01 ng/mL, range 0.01-30.31 ng/mL; P = 0.0035). However, the proportion of surviving horses with an elevated cTnI (10/39, 26%) was not significantly different from the proportion of non-surviving horses with an elevated cTnI (6/10, 60%; P = 0.060). CONCLUSIONS: cTnI is elevated in horses with myocardial disease and elevated to a lesser degree in some horses with structural heart disease or lone arrhythmias. The association between cTnI concentration and survival was not clear.

Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: phase I results of the Indian Council of Medical Research-INdia DIABetes (ICMR-INDIAB) study.

AIMS/HYPOTHESIS: This study reports the results of the first phase of a national study to determine the prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in India. METHODS: A total of 363 primary sampling units (188 urban, 175 rural), in three states (Tamilnadu, Maharashtra and Jharkhand) and one union territory (Chandigarh) of India were sampled using a stratified multistage sampling design to survey individuals aged ≥ 20 years. The prevalence rates of diabetes and prediabetes were assessed by measurement of fasting and 2 h post glucose load capillary blood glucose. RESULTS: Of the 16,607 individuals selected for the study, 14,277 (86%) participated, of whom 13,055 gave blood samples. The weighted prevalence of diabetes (both known and newly diagnosed) was 10.4% in Tamilnadu, 8.4% in Maharashtra, 5.3% in Jharkhand, and 13.6% in Chandigarh. The prevalences of prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were 8.3%, 12.8%, 8.1% and 14.6% respectively. Multiple logistic regression analysis showed that age, male sex, family history of diabetes, urban residence, abdominal obesity, generalised obesity, hypertension and income status were significantly associated with diabetes. Significant risk factors for prediabetes were age, family history of diabetes, abdominal obesity, hypertension and income status. CONCLUSIONS/INTERPRETATIONS: We estimate that, in 2011, Maharashtra will have 6 million individuals with diabetes and 9.2 million with prediabetes, Tamilnadu will have 4.8 million with diabetes and 3.9 million with prediabetes, Jharkhand will have 0.96 million with diabetes and 1.5 million with prediabetes, and Chandigarh will have 0.12 million with diabetes and 0.13 million with prediabetes. Projections for the whole of India would be 62.4 million people with diabetes and 77.2 million people with prediabetes.

Acute myeloid leukaemia (M6B: pure acute erythroid leukaemia) in a Thoroughbred foal.

A 10-week-old Thoroughbred filly was referred for anaemia of 4 weeks' duration. Haematology revealed severe anaemia and panleucopenia. Cytological examination of bone marrow smears revealed a myeloid to erythroid ratio <0.02:1 (reference range 0.5-2.4:1.0) and an abundance of erythroid precursor cells. The erythroid cell population included rubriblasts, prorubricytes and rubricytes, with only scant numbers of metarubricytes present. There were numerous mitotic erythroid cells, some of which were atypical and megaloblastic. These cytomorphological changes are consistent with pure acute erythroid leukaemia. No treatment was instituted and the filly died three days after presentation. This case illustrates the need to consider both haematology and bone marrow findings to establish a diagnosis of pure erythroid leukaemia. To our knowledge, there is no documented case of acute myeloproliferative disease in horses involving cells of erythroid lineage, but this condition should be considered a differential diagnosis for horses presenting with anaemia.

Activin A as a novel biomarker of equine inflammatory abdominal disease: preliminary findings.

This study evaluated the inflammatory mediator activin A in horses with acute abdominal disease and compared this putative novel biomarker with serum amyloid A (SAA). Thirty-three adult horses referred for evaluation of acute abdominal disease were grouped into three lesion categories, non-strangulating, strangulating or inflammatory. Eleven healthy adult horses served as controls. Serum activin-A was significantly increased in animals with inflammatory or strangulating lesions compared with controls. Horses with non-strangulating, strangulating or inflammatory lesions had significantly elevated SAA concentrations. Activin A, along with other biomarkers, may be useful in monitoring inflammation in cases of acute abdominal disease in horses. Further validation is warranted to determine the utility of this biomarker in evaluating the effectiveness of novel anti-inflammatory treatments for equine colic and endotoxaemia.

Reproductive efficiency of Thoroughbred and Standardbred horses in north-east Victoria.

OBJECTIVE: To evaluate the reproductive efficiency of horse farms in north-east Victoria and identify aspects of management to be targeted for improving reproductive efficiency. DESIGN: Retrospective study. PROCEDURE: Records from seven Thoroughbred (TB) and four Standardbred (STB) studs in north-east Victoria from 1990 to 2001 were reviewed; 8813 cycles in 4455 mares were analysed. TB mares were inseminated by natural mating, whereas STB mares (89%) were artificially inseminated. RESULTS: The overall early pregnancy rate per cycle was 68.8% for TB mares and for STB mares, 68.3%. Multiple pregnancy per cycle was more frequent in TB (8.3%) than in STB (4.6%) mares (P < 0.001). Early embryonic death occurred in 7.1% of TB and 7.5% of STB pregnancies. TB mares had fewer inseminations per cycle (1.03) than STB mares (1.43) (P < 0.001). There was a significantly lower proportion of barren reproductive status within the TB than the STB mares. Pregnancy rate per cycle among stallions ranged from 48% to 79%. CONCLUSIONS: On-farm pregnancy rates in both breeds were higher than previously reported and likely reflect improvements in reproductive management. The disparity between breeds in the inseminations per cycle and proportion of barren mares exposed the differing structures of the two industries, and presents a target for improving the reproductive efficiency in STBs. The difference between breeds in the multiple pregnancy rate per cycle likely reflects the higher ovulation rate of TB mares. The variability in pregnancy rate per cycle between the 22 stallions was associated with differences in individual inherent fertility and the quality of stallion management.

Formulation, development, and optimization of immediate release nateglinide tablets by factorial design.

In the present study, selection of superdisintegrants among sodium starch glycolate, cross povidone, Starch-1500 and cross carmellose sodium (CCS) was carried out for development of immediate release nateglinide tablets (NTG). A 3(2) full factorial design was used to investigate the influence of two independent variables, i.e., amount of selected superdisintegrants and hardness of the tablets, on two dependent variables, i.e., disintegration time and percentage of drug release at 30 min (DR(0.5h)). The results revealed that CCS was the best superdisintegrant for the development of immediate release tablets of NTG. The sign of the coefficient of the polynomial equation signified that the disintegration time was decreased and DR(0.5h) was increased by decreasing the hardness of the tablets as well as by increasing the concentration of CCS in the tablets. A checkpoint batch of the tablets was prepared by changing the value of independent variables within the range used in the preparation of factorial batches of tablets to check the validity of the evolved optimized mathematical model. Stability studies of optimized formulations indicated that there was no significant change in the physical parameters, disintegration time, and percentage of drug release of tablets. The systematic formulation approach helped to understand the effect of formulation processing variables.

Design and development of anthropometric device for the standardization of sizes of knee-ankle-foot orthoses.

An anthropometric device (AD) was designed and developed to collect data on foot and knee of locomotor disabled people. The aim was to standardize the sizes of knee-ankle-foot orthoses (KAFOs) in a standard modular form so that they can be mass produced to cater for fitting to a large number of locomotor disabled people. The anthropometric data collected on large numbers of locomotor disabled people were processed, with the help of a computer programme, to arrive at standard sizes for three modules, i.e. a foot plate (seven sizes), knee pieces (six sizes) and a lateral upright in a universal size. These modules were produced by plastic injection moulding and compression moulding processes using glass-reinforced polypropylene. KAFOs were assembled and fitted to locomotor disabled people. Feedback obtained was encouraging and this vindicated the concept, design and utility of the AD.

Evaluation of Antioxidant Potential of Kaempferia rotunda Linn.

The plant Kaempferia rotunda Linn. has been explored for its anti oxidant potential in the present study. The antioxidant property was assessed by lipid peroxidation markers such as malonaldehyde (MDA) and 4-hydroxyl-2-nonenal (4-HNE). The lipid peroxidation byproducts are highly toxic and responsible for various diseases like myocardial infarction, diabetes mellitus, hepatic injury, atherosclerosis, rheumatoid arthritis and cancer. The chemical constituents of the plant were critically and qualitatively analyzed to confirm the presence of flavonoids and phenolic derivatives. Hence our objective has been designed to evaluate the antioxidant effect of Kaempferia rotunda linn. and its contribution to control the lipid peroxidation.

Aneurysmal deformity of the basal interventricular septum secondary to impinging turbulent transprosthetic eccentric flow jets.

Cases of aneurysm of basal muscular interventricular septum are very uncommon. This report describes a rare case of a young man in which aneurysmal deformity was an incidental finding during follow-up after thrombolysis of the obstructed mitral prosthesis.

M-shaped doppler signal across ventricular septal defect: potential implications for estimation of right ventricuilar systolic pressure.

An 8-year-old child suffering from ventricular septal defect and severe valvular pulmonary stenosis was evaluated by echo-Doppler technique and cardiac catheterization. A peak instantaneous transventricular systolic gradient of 64 mmHg was recorded across the ventricular septal defect with an interesting M-shaped spectral pattern. However, cardiac catheterization revealed a peak-to-peak non-simultaneous gradient between the right and the left ventricle of only 14 mmHg. This discrepancy along with its implications are discussed in this report.

Pharmacological properties of a protease from ficus hispiad linn.

A sulphydryl plant protease present in the latex of Ficus hispida Linn affects hatematological values in mice. The isolated protease was found to increase clotting time and erythrocyte sedimentation rate while haemoglobin conten, RBC count and WBC count were decreased in a dose dependent manner. Ointment containing 1.0% (w/w) hispidain in washable ointment base showed good wound healing property in mice. The protease also possesses mild anti inflammatory activity.

Impact of HIV/AIDS on the national economy of India.

BACKGROUND INFORMATION: Human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) is a major public health problem in India. In general, it affects mainly young people who are at their most productive part of life. Despite initial fears that AIDS will be disastrous for the economy, recent experience and estimations have shown that there is a need for reappraisal of its economic impact on society. RESEARCH QUESTION: From the viewpoint of the society of India, what is the total cost and equivalent annual cost of HIV infections for the period 1986-1995 (10 years) in India? METHODS: Type of analysis: Cost-descriptive based on predictive modelling cohort analysis using human capital approach. A discount rate of 5% was used. The cost of HIV infections include (i) loss of productivity among HIV patients due to sickness and death, (ii) productivity loss due to caregivers of AIDS patients, and (iii) cost of management of AIDS patients. To estimate the loss of productivity due to premature death attributable to AIDS, a life table approach using two cohorts, one with and one without HIV/AIDS infection at assumed rates was used. The demographic data of 1991 census were used. The difference in the person-years lived in the two scenarios gave the person-years lost due to HIV/AIDS. This was calculated separately for rural and urban areas. To convert this to monetary terms, national per capita income for 1992-93 of Rs. 5529 was used. The data on the days of inpatient care and the cost of management of AIDS patients were based on currently available data and 'expert opinion'. We analysed, using three different sets of assumptions for determination, the low, medium and high estimates of the impact of HIV/AIDS in India. Some of the costs were not included in the present analysis: (i) use of antiviral AZT, (ii) cost of retraining of new workforce, (iii) cost of strengthening of health care system, (iv) cost of research and development, (v) cost of communication activities, (vi) cost of prevention of vertical transmission, and (vii) the intangible cost of pain and suffering to the patients and their families. RESULTS: The total cumulative number of HIV-infected persons in India until 1995 was estimated to be 1.5 million (low estimate), 2.5 million (medium estimate) and 4.5 million (high estimate). The estimated total annual cost (in billion Rupees) of HIV/AIDS in India under low, medium and high assumptions was 6.73, 20.16 and 59.19, respectively. Cost of treatment of AIDS and loss in productivity were the two major components of the cost. CONCLUSIONS: The estimated annual cost of HIV/AIDS appears to be about 1% of the GDP of India if based on high assumptions. However, as mentioned earlier, all costs of HIV have not been taken into account. Its significance has to be assessed in the context of annual growth of GDP (3.5%) and cost of other major diseases in India.