Investigation into in silico and in vitro approaches for inhibitors targeting MCM10 in Leishmania donovani: a comprehensive study.

Visceral Leishmaniasis (VL), the second neglected tropical disease caused by various Leishmania species, presents a significant public health challenge due to limited treatment options and the absence of vaccines. The agent responsible for visceral leishmaniasis, also referred to as "black fever" in India, is Leishmania donovani. This study focuses on L. donovani Minichromosome maintenance 10 (LdMcm10), a crucial protein in the DNA replication machinery, as a potential therapeutic target in Leishmania therapy using in silico and in vitro approaches. We employed bioinformatics tools, molecular docking, and molecular dynamics simulations to predict potential inhibitors against the target protein. The research revealed that the target protein lacks homologues in the host, emphasizing its potential as a drug target. Ligands from the DrugBank database were screened against LdMcm10 using PyRx software. The top three compounds, namely suramin, vapreotide, and pasireotide, exhibiting the best docking scores, underwent further investigation through molecular dynamic simulation and in vitro analysis. The observed structural dynamics suggested that LdMcm10-ligand complexes maintained consistent binding throughout the 300 ns simulation period, with minimal variations in their backbone. These findings suggest that these three compounds hold promise as potential lead compounds for developing new drugs against leishmaniasis. In vitro experiments also demonstrated a dose-dependent reduction in L. donovani viability for suramin, vapreotide, and pasireotide, with computed IC50 values providing quantitative metrics of their anti-leishmanial efficacy. The research offers a comprehensive understanding of LdMcm10 as a drug target and provides a foundation for further investigations and clinical exploration, ultimately advancing drug discovery strategies for leishmaniasis treatment.

Hemodynamics: Strangers to Lung-kidney Crosstalk in ARDS?

How to cite this article: Magoon R, Sharma AG, Yadav N, Choupoo NS. Hemodynamics: Strangers to Lung-kidney Crosstalk in ARDS? Indian J Crit Care Med 2024;28(2):177-178.

Functional ß-mannooligosaccharides: Sources, enzymatic production and application as prebiotics.

One of the emerging non-digestible oligosaccharide prebiotics is ß-mannooligosaccharides (ß-MOS). ß-MOS are ß-mannan derived oligosaccharides, they are selectively fermented by gut microbiota, promoting the growth of beneficial microorganisms (probiotics), whereas the growth of enteric pathogens remains unaffected or gets inhibited in their presence, along with production of metabolites such as short-chain fatty acids. ß-MOS also exhibit several other bioactive properties and health-promoting effects. Production of ß-MOS using the enzymes such as ß-mannanases is the most effective and eco-friendly approach. For the application of ß-MOS on a large scale, their production needs to be standardized using low-cost substrates, efficient enzymes and optimization of the production conditions. Moreover, for their application, detailed in-vivo and clinical studies are required. For this, a thorough information of various studies in this regard is needed. The current review provides a comprehensive account of the enzymatic production of ß-MOS along with an evaluation of their prebiotic and other bioactive properties. Their characterization, structural-functional relationship and in-vivo studies have also been summarized. Research gaps and future prospects have also been discussed, which will help in conducting further research for the commercialization of ß-MOS as prebiotics, functional food ingredients and therapeutic agents.

Comparison of Ultrasound Examination and Fiberoptic Laryngoscopy for Confirmation of Laryngeal Mask Airway Placement.

OBJECTIVES: 1) To compare ultrasound (US) examination and fiberoptic laryngoscopy (FOL) for confirmation of laryngeal mask airway (LMA) placement. 2) To evaluate the necessity for reinsertion of LMA based on FOL. METHODS: This prospective observational study included 100 adult patients of American Society of Anesthesiologists (ASA) Grade I and II, undergoing elective surgery under General Anesthesia requiring Proseal LMA™ placement as an airway device. LMA placement was first confirmed by clinical tests. Clinically acceptable patients were further assessed by US and categorized as acceptable (US-A) or unacceptable (US-U) and again by FOL as (FOL-A and FOL-U). Categorical variables presented in number, percentage (%), and continuous variables presented as mean ± SD and median. Inter-rater kappa agreement was used to find out the strength of agreement of acceptability between FOL and US. RESULTS: The LMA placement was clinically acceptable in 82% of patients on first attempt. FOL had 63% (FOL-A) acceptable LMA placement as compared with US examination which had 56% (US-A). In 85% of patients, US and FOL findings were in good agreement with each other for LMA placement (κ = 0.690 and P < .05). In all patients of FOL of unacceptable (FOL-U) category (37%), LMA was replaced with endotracheal tube. CONCLUSION: US provides a safe, non-invasive, and real-time dynamic assessment with 85% diagnostic accuracy for confirmation of LMA placement as compared with FOL.

Epidemic prevalence information on social networks can mediate emergent collective outcomes in voluntary vaccine schemes.

The effectiveness of a mass vaccination program can engender its own undoing if individuals choose to not get vaccinated believing that they are already protected by herd immunity. This would appear to be the optimal decision for an individual, based on a strategic appraisal of her costs and benefits, even though she would be vulnerable during subsequent outbreaks if the majority of the population argues in this manner. We investigate how voluntary vaccination can nevertheless emerge in a social network of rational agents, who make informed decisions whether to be vaccinated, integrated with a model of epidemic dynamics. The information available to each agent includes the prevalence of the disease in their local network neighborhood and/or globally in the population, as well as the fraction of their neighbors that are protected against the disease. Crucially, the payoffs governing the decision of agents vary with disease prevalence, resulting in the vaccine uptake behavior changing in response to contagion spreading. The collective behavior of the agents responding to local prevalence can lead to a significant reduction in the final epidemic size, particularly for less contagious diseases having low basic reproduction number [Formula: see text]. Near the epidemic threshold ([Formula: see text]) the use of local prevalence information can result in divergent responses in the final vaccine coverage. Our results suggest that heterogeneity in the risk perception resulting from the spatio-temporal evolution of an epidemic differentially affects agents' payoffs, which is a critical determinant of the success of voluntary vaccination schemes.

Environmental & occupational exposure & female reproductive dysfunction.

All individuals are exposed to certain chemical, physical, biological, environmental as well as occupational factors. The data pertaining to role of these factors on female reproduction are scanty as compared to male. The available data suggest the adverse effects of certain toxicants, viz., metals such as lead, cadmium and mercury, pesticides such as bis(4-chlorophenyl)-1,1,1-trichloroethane and organic solvent such as benzene, toluene and ionizing radiation on the female reproductive system affecting directly the organ system or impacting in directly through hormonal impairments, molecular alterations, oxidative stress and DNA methylation impairing fertility as well as pregnancy and its outcomes. Thus, there is a need for awareness and prevention programme about the adverse effects of these factors and deterioration of female reproductive health, pregnancy outcome and offspring development as some of these chemicals might affect the developing foetus at very low doses by endocrine disruptive mechanism.

Nuclear grade and necrosis predict prognosis in malignant epithelioid pleural mesothelioma: a multi-institutional study.

A recently described nuclear grading system predicted survival in patients with epithelioid malignant pleural mesothelioma. The current study was undertaken to validate the grading system and to identify additional prognostic factors. We analyzed cases of epithelioid malignant pleural mesothelioma from 17 institutions across the globe from 1998 to 2014. Nuclear grade was computed combining nuclear atypia and mitotic count into a grade of I-III using the published system. Nuclear grade was assessed by one pathologist for three institutions, the remaining were scored independently. The presence or absence of necrosis and predominant growth pattern were also evaluated. Two additional scoring systems were evaluated, one combining nuclear grade and necrosis and the other mitotic count and necrosis. Median overall survival was the primary endpoint. A total of 776 cases were identified including 301 (39%) nuclear grade I tumors, 354 (45%) grade II tumors and 121 (16%) grade III tumors. The overall survival was 16 months, and correlated independently with age (P=0.006), sex (0.015), necrosis (0.030), mitotic count (0.001), nuclear atypia (0.009), nuclear grade (<0.0001), and mitosis and necrosis score (<0.0001). The addition of necrosis to nuclear grade further stratified overall survival, allowing classification of epithelioid malignant pleural mesothelioma into four distinct prognostic groups: nuclear grade I tumors without necrosis (29 months), nuclear grade I tumors with necrosis and grade II tumors without necrosis (16 months), nuclear grade II tumors with necrosis (10 months) and nuclear grade III tumors (8 months). The mitosis-necrosis score stratified patients by survival, but not as well as the combination of necrosis and nuclear grade. This study confirms that nuclear grade predicts survival in epithelioid malignant pleural mesothelioma, identifies necrosis as factor that further stratifies overall survival, and validates the grading system across multiple institutions and among both biopsy and resection specimens. An alternative scoring system, the mitosis-necrosis score is also proposed.

Comparison of Awareness of Patient Parameters between Two Groups of Caregivers in Intensive Care Unit.

AIM OF THE STUDY: The overlap in the scope of duties performed by two core groups of Intensive Care Unit caregivers, the doctors and nurses may lead to gaps in awareness of patient-related parameters among them. Our study tested the hypothesis that there is no difference in the awareness of patient-related parameters between the two study groups (doctors and nurses). MATERIALS AND METHODS: A questionnaire-based study, incorporating various aspects of a patient's medical care was designed. Pro forma for 100 patients was filled by doctors and nurses divided into two groups of 100 each (50 junior residents [JRs] and 50 senior residents [SRs] in the doctors' group). Statistical analysis of categorical data was done by Chi-squared test and interval data by t-test. A subgroup analysis was done for comparison between nurses SRs and JRs as independent groups. P < 0.05 was considered statistically significant. RESULTS: There was no statistically significant difference between the two groups (doctors and nurses) in terms of percentage of correct responses in the questionnaire (P = 0.655). A highly significant difference between the knowledge of SRs and nurses was found with a P = 0.0001. P < 0.0001 was calculated for the SRs versus JRs which was highly significant. CONCLUSIONS: As a group, doctors (SRs and JRs) did not reflect any difference in awareness of patient-related parameters when compared to nurses. However, SRs were more knowledgeable about the patient-related parameters when compared independently with the JRs and the nurses.

Monitoring of pesticide residues in human blood from Punjab, India.

In the present study, the current levels of pesticide residues were studied in the human populace of Punjab state. A total of 111 human blood samples were analyzed by gas chromatography and pesticide residues were detected in 35 % of the blood sample(s). Residues of alpha-hexachlorocyclohexane (α-HCH), beta-hexachlorocyclohexane (ß-HCH), p,p'-dichlorodiphenyldichloroethane (p,p' DDD), p,p' dichlorodiphenyldichloroethylene (p,p' DDE), p,p' dichlorodiphenyldichloroethane (p,p' DDT), ß-endosulfan, monocrotophos, profenophos and phosalone were found in human blood samples with mean levels of 1.11, 5.89, 0.51, 3.88, 0.39, 34.90, 0.79, 0.39 and 6.76 ng ml(-1), respectively, with ß-endosulfan as a leading pesticide residue. A paradigm shift in the pattern of the pesticide usage was observed with a shift from organochlorine pesticides to organophosphates.

Monitoring of pesticide residues in human breast milk from Punjab, India and its correlation with health associated parameters.

This study was undertaken to determine the present status of pesticide residues in breast milk from Punjab. A total of 127 breast milk samples were analyzed and pesticide residues were detected in 25 % of the milk samples. Residues of cyfluthrin, fenvalerate, cypermethrin, profenophos, γ-HCH, ß-HCH, chlorpyriphos, monocrotophos, p,p' DDE and phosalone were detected with mean levels of 63.04, 11.69, 3.63, 2.66, 2.64, 2.29, 1.91, 1.63, 0.56 and 0.29 ng g(-1), respectively. Cyfluthrin was leading pesticide detected in breast milk contributing 31.28 % to the total residue load. It was observed that the residue levels were decreasing with increase in parity and age of mother and cyfluthrin had highest mean concentration of 90.63 ng g(-1) in the first parity and 21.11 ng g(-1) in youngest age group. Residue levels were higher in urban population than the rural population although, statistically non-significant difference was found between the two (p > 0.05).

Aluminum phosphide (celphos) poisoning in children: A 5-year experience in a tertiary care hospital from northern India.

BACKGROUND: Aluminum phosphide (ALP) (celphos) is an agricultural pesticide commonly implicated in poisoning. Literature pertaining to the clinical manifestations and treatment outcome of its poisoning among children is limited. MATERIALS AND METHODS: A retrospective chart review was conducted of the medical records of 30 children aged less than 14 years admitted to pediatric intensive care unit (PICU) of a tertiary care hospital in northern India. Demographic, clinical, and laboratory parameters were recorded. The outcome was categorized into "survivors" and "nonsurvivors." RESULTS: The Mean (SD) age of the enrolled children [19 males (63.3%)] was 8.55 (3.07) years. Among the 30 children, 14 (46.67%) were nonsurvivors and the rest 16 (53.33%) were survivors. Nonsurvivors had ingested significantly higher doses of ALP (P < 0.001), and showed higher time lag to PICU transfer (P 0.031), presence of abnormal radiological findings on chest skiagram (P = 0.007), and a higher Pediatric Risk of Mortality (PRISM) III score (P < 0.001) at admission. Use of magnesium sulfate was associated significantly with survival [odds ratio (OR) (95% CI): 0.11 (0.02-0.66); P 0.016]. CONCLUSION: The present study highlights that survival among children with ALP poisoning is predicted by dose of ALP ingestion, time lag to medical attention, and higher PRISM score at admission. Use of magnesium sulfate could be associated with better survival among them.

Identification of molecular interactions of pesticides with keratinase for their potential to inhibit keratin biodegradation.

The recalcitrant, fibrous protein keratin is found in the outermost layer of vertebrate skin, feathers, hair, horn, and hooves. Approximately, 10 million tons of keratin wastes are produced annually worldwide, of which around 8.5 million tons are from feather wastes. The biodegradation of keratin has been a challenge due to the lack of understanding of biological parameters that modulate the process. Few soil-borne microbes are capable of producing keratinase enzyme which has the potential to degrade the hard keratin. However, various pesticides are abundantly used for the management of poultry farms and reports suggest the presence of the pesticide residues in feather. Hence, it was hypothesized that pesticides would interact with the substrate-binding or allosteric sites of the keratinase enzyme and interferes with the keratin-degradation process. In the present study, molecular interactions of 20 selected pesticides with the keratinase enzyme were analyzed by performing molecular docking. In blind docking, 14 out of 20 pesticides showed higher inhibitory potential than the known inhibitor phenylmethylsulfonyl flouride, all of which exhibited higher inhibitory potential in site-specific docking. The stability and strength of the protein complexes formed by the top best potential pesticides namely fluralaner, teflubenzuron, cyhalothrin, and cyfluthrin has been further validated by molecular dynamic simulation studies. The present study is the first report for the preliminary investigation of the keratinase-inhibitory potential of pesticides and highlights the plausible role of these pesticides in hindering the biological process of keratin degradation and thereby their contribution in environmental pollution. Graphical abstract: Illustration depicting the hypothesis, experimental procedure, and the resultant keratinase-inhibitory potential of selected pesticides.

Burden of COVID-19 pandemic on tuberculosis hospitalisation patterns at a tertiary care hospital in Rajasthan, India: a retrospective analysis.

OBJECTIVE: This study aimed to investigate the burden of the COVID-19 pandemic on tuberculosis (TB) trends, patient demographics, disease types and hospitalisation duration within the Respiratory Medicine Department over three distinct phases: pre-COVID-19, COVID-19 and post-COVID-19. DESIGN: Retrospective analysis using electronic medical records of patients with TB admitted between June 2018 and June 2023 was done to explore the impact of COVID-19 on patients with TB. The study employed a meticulous segmentation into pre-COVID-19, COVID-19 and post-COVID-19 eras. SETTING: National Institute of Medical Science Hospital in Jaipur, Rajasthan, India. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome includes patients admitted to the Respiratory Medicine Department of the hospital and secondary outcome involves the duration of hospital stay. RESULTS: The study encompassed 1845 subjects across the three eras, revealing a reduction in TB incidence during the post-COVID-19 era compared with the pre-COVID-19 period (p<0.01). Substantial demographic shifts were observed, with 5.2% decline in TB incidence among males in the post-COVID-19 era (n=529) compared with the pre-COVID-19 era (n=606). Despite the decrease, overall TB incidence remained significantly higher in males (n=1460) than females (n=385), with consistently elevated rates in rural (65.8%) as compared with the urban areas (34.2%). Extended hospital stays were noted in the post-COVID-19 era compared with the pre-COVID-19 era (p<0.01). CONCLUSION: The study underscores the influence of the COVID-19 pandemic on the TB landscape and hospitalisation dynamics. Notably, patient burden of TB declined during the COVID-19 era, with a decline in the post-COVID-19 era compared with the pre-COVID-19 era. Prolonged hospitalisation in the post-COVID-19 period indicates the need for adaptive healthcare strategies and the formulation of public health policies in a post-pandemic context. These findings contribute to a comprehensive understanding of the evolving TB scenario, emphasising the necessity for tailored healthcare approaches in the aftermath of a global health crisis.

Micro-Solvation of Propofol in Propylene Glycol-Water Binary Mixtures: Molecular Dynamics Simulation Studies.

The water microstructure around propofol plays a crucial role in controlling their solubility in the binary mixture. The unusual nature of such a water microstructure can influence both translational and reorientational dynamics, as well as the water hydrogen bond network near propofol. We have carried out all-atom molecular dynamics simulations of five different compositions of the propylene glycol (PG)/water binary mixture containing propofol (PFL) molecules to investigate the differential behavior of water microsolvation shells around propofol, which is likely to control the propofol solubility. It is evident from the simulation snapshots for various compositions that the PG at high molecular ratio favors the water cluster and extended chainlike network that percolates within the PG matrix, where the propofol is in the dispersed state. We estimated that the radial distribution function indicates higher ordered water microstructure around propofol for high PG content, as compared to the lower PG content in the PG/water mixture. So, the hydrophilic PG regulates the stability of the water micronetwork around propofol and its solubility in the binary mixture. We observed that the translational and rotational mobility of water belonging to the propofol microsolvation shell is hindered for high PG content and relaxed toward the low PG molecular ratio in the PG/water mixture. It has been noticed that the structural relaxation of the hydrogen bond formed between the propofol and the water molecules present in the propofol microsolvation shell for all five compositions is found to be slower for high PG content and becomes faster on the way to low PG content in the mixture. Simultaneously, we calculated the intermittent residence time correlation function of the water molecules belonging to the microsolvation shell around the propofol for five different compositions and found a faster short time decay followed up with long time components. Again, the origin of such long time decay is primarily from the structural relaxation of the microsolvation shell around the propofol, where the high PG content shows the slower structural relaxation that turns faster as the PG content approaches to the other end of the compositions. So, our studies showed that the slower structural relaxation of the microsolvation shell around propofol for a high PG molecular ratio in the PG/water mixture correlate well with the extensive ordering of the water microstructure and restricted water mobility and facilitates the dissolution process of propofol in the binary mixture.

HER-2 pulsed dendritic cell vaccine can eliminate HER-2 expression and impact ductal carcinoma in situ.

BACKGROUND: HER-2/neu overexpression plays a critical role in breast cancer development, and its expression in ductal carcinoma in situ (DCIS) is associated with development of invasive breast cancer. A vaccine targeting HER-2/neu expression in DCIS may initiate immunity against invasive cancer. METHODS: A HER-2/neu dendritic cell vaccine was administered to 27 patients with HER-2/neu-overexpressing DCIS. The HER-2/neu vaccine was administered before surgical resection, and pre- and postvaccination analysis was conducted to assess clinical results. RESULTS: At surgery, 5 of 27 (18.5%) vaccinated subjects had no evidence of remaining disease, whereas among 22 subjects with residual DCIS, HER-2/neu expression was eradicated in 11 (50%). When comparing estrogen receptor (ER)(neg) with ER(pos) DCIS lesions, vaccination was more effective in hormone-independent DCIS. After vaccination, no residual DCIS was found in 40% of ER(neg) subjects compared with 5.9% in ER(pos) subjects. Sustained HER-2/neu expression was found in 10% of ER(neg) subjects compared with 47.1% in ER(pos) subjects (P = .04). Postvaccination phenotypes were significantly different between ER(pos) and ER(neg) subjects (P = .01), with 7 of 16 (43.8%) initially presenting with ER(pos) HER-2/neu(pos) luminal B phenotype finishing with the ER(pos) HER-2/neu(neg) luminal A phenotype, and 3 of 6 (50%) with the ER(neg) HER-2/neu(pos) phenotype changing to the ER(neg) HER-2/neu(neg) phenotype. CONCLUSIONS: Results suggest that vaccination against HER-2/neu is safe and well tolerated and induces decline and/or eradication of HER-2/neu expression. These findings warrant further exploration of HER-2/neu vaccination in estrogen-independent breast cancer and highlight the need to target additional tumor-associated antigens and pathways.

Occupational and environmental mercury exposure and human reproductive health - a review.

Mercury is a toxic heavy metal. Humans are exposed to mercury through several sources including environmental, occupational, contaminated food and water and from mercury-containing dental amalgam. Mercury exposure is known to harm the nervous system profoundly, and have a negative impact on digestive and immune systems, and other organs. To review and discuss the effect of mercury exposure through environmental or occupational routes on human reproduction, pregnancy, and its outcome. Published information about the potential toxic effects of mercury on human reproduction were collected and summarized. Literature was identified by systematic search using relevant keywords. Literature review revealed a number of negative impacts of mercury on human reproduction. These included effects on semen quality, including reduced sperm count, motility, and changes in morphology that may reduce fertility potential. There may also be an effect in changing reproductive hormone levels. Mercury exposure might also affect pregnancy but the data concerning mercury effects on female reproduction are limited except for some data about mercury exposure and poor pregnancy outcomes. Available data indicate that mercury exposure may have a toxicity effect on reproductive potential, especially in males. Prenatal mercury exposure may affect pregnancy or its outcome and this appears to be dependent upon dose, duration, and timing of exposure. Nutritional status of exposed individual might also influence the impact of mercury.

Clinical and laboratory profile of patients with presumptive clinical diagnosis of acute bacterial meningitis and its short-term complications.

Background: Worldwide, one million cases of bacterial meningitis are estimated to occur and 200,000 of them die annually. Case fatality rates vary with age at the time of illness and the species of bacterium causing infection. In view of variable clinical features and complication rates in various studies, the present study was planned to assess the clinical and laboratory profile of patients with acute bacterial meningitis and analyze the therapeutic response and short-term sequelae. Materials: This study was conducted in the department of pediatrics at Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences (PGIMS), Rohtak. A total of 50 pediatric patients with signs and symptoms of acute bacterial meningitis who satisfied the inclusion or selection criteria were enrolled in the study. Appropriate statistical tests were applied for analysis and trial registry was done with PGIMS. Results: In the present study, slightly more males (54%) were found than females (46%). The sequelae and mortality were 33.3%, 26.1% and 7.4%, 8.7% in males and females, respectively. There were higher chances of sequelae or mortality in males as compared to females (OR 1.289, 95% CI 0.073-6.11, P > 0.05). Predominant cells were polymorphonuclear (PMN) cells except in >120 months age group where both PMN (50%) and mononuclear (50%) cells were equally visualized. Mean CSF protein was slightly higher in 2-24 months age group. Conclusion: We compared the group with sequelae with the group with no sequelae and found neurological deficit (P < 0.01), and presence of complications (P < 0.01) were significantly associated with sequelae.

The significance of HER-2/neu receptor positivity and immunophenotype in ductal carcinoma in situ with early invasive disease.

INTRODUCTION: Biologic markers that predict development of invasive breast cancer (IBC) in patients diagnosed with ductal carcinoma in situ (DCIS) are needed to improve personalized therapy. In this study, we examined the incidence of early IBC in DCIS subgroups defined by immunophenotype. METHODS: Clinical and histologic materials of 143 patients with radiographically suggesting DCIS without obvious evidence of IBC were reviewed. All patients underwent initial biopsy followed by short-term subsequent resection. The presence of IBC, histopathologic features of DCIS and IBC, when present, and their estrogen receptor (ER), progesterone receptor (PR), and HER2 phenotypes were evaluated. RESULTS: Early IBC was identified on initial biopsy in 6 (4%) and subsequent resection in 24 (17%) patients. HER2 positivity in DCIS was the dominant factor associated with IBC. There was also a significant association between ER/PR/HER2+ DCIS and the presence of IBC. The ER/PR/HER2+ DCIS appeared to be the most unstable precursor, because of the highest invasion rate and frequent association with a discordant phenotype. CONCLUSIONS: HER2 positivity and ER/PR/HER2 phenotype may be used to identify DCIS patients at higher risk of harboring or potentially developing IBC. Strategies targeting HER2 in DCIS may be of potential benefit in preventing IBC in patients with DCIS.

Surface modified dendrimers: synthesis and characterization for cancer targeted drug delivery.

Dendrimers represents a highly branched three-dimensional structure that provides a high degree of surface functionality and versatility. PAMAM dendrimers are used as well-defined nanocontainers to conjugate, complex or encapsulate therapeutic drugs or imaging moieties. Star-burst [PAMAM] dendrimers represent a superior carrier platform for drug delivery. The present study was aimed at synthesis of a surface modified dendrimer for cancer targeted drug delivery system. For this 4.0 G PAMAM dendrimer was conjugated with Gallic acid [GA] and characterized through UV, IR, ¹H NMR and mass spectroscopy. Cytotoxicity study of dendrimer conjugate was carried out against MCF-7 cell line using MTT assay. The study revealed that the conjugate is active against MCF-7 cell line and might act synergistically with anti-cancer drug and gallic acid-dendrimer conjugate might be a promising nano-platform for cancer targeting and cancer diagnosis.

Spatial segregation and cooperation in radially expanding microbial colonies under antibiotic stress.

Antibiotic resistance in microbial communities reflects a combination of processes operating at different scales. In this work, we investigate the spatiotemporal dynamics of bacterial colonies comprised of drug-resistant and drug-sensitive cells undergoing range expansion under antibiotic stress. Using the opportunistic pathogen Enterococcus faecalis with plasmid-encoded ß-lactamase, we track colony expansion dynamics and visualize spatial patterns in fluorescently labeled populations exposed to antibiotics. We find that the radial expansion rate of mixed communities is approximately constant over a wide range of drug concentrations and initial population compositions. Imaging of the final populations shows that resistance to ampicillin is cooperative, with sensitive cells surviving in the presence of resistant cells at otherwise lethal concentrations. The populations exhibit a diverse range of spatial segregation patterns that depend on drug concentration and initial conditions. Mathematical models indicate that the observed dynamics are consistent with global cooperation, despite the fact that ß-lactamase remains cell-associated. Experiments confirm that resistant colonies provide a protective effect to sensitive cells on length scales multiple times the size of a single colony, and populations seeded with (on average) no more than a single resistant cell can produce mixed communities in the presence of the drug. While biophysical models of drug degradation suggest that individual resistant cells offer only short-range protection to neighboring cells, we show that long-range protection may arise from synergistic effects of multiple resistant cells, providing surprisingly large protection zones even at small population fractions.