Human Medical Conditions Research Articles

Synthesis of L-methionine-loaded chitosan nanoparticles for controlled release and their in vitro and in vivo evaluation

Therapeutically popular controlled release-enabling technology has forayed into the nutrition sector. Polymer coated forms of L-methionine used in soy protein diets, and its intermediate metabolite, S-adenosyl-L-methionine, used in myriad of medical conditions have proved more efficacious over (highly catabolized) free forms. In this premier study, L-methionine-loaded chitosan nanoparticles (M-NPs) were synthesized using ionic gelation method and their efficacy was evaluated. Biophysical characterization of the NPs was done using a Nanopartica SZ 100 analyser, transmission electron microscopy, and Fourier transform infrared spectroscopy. The M-NPs were spherical and smooth and 218.9 ± 7.4 nm in size and in vitro testing confirmed the controlled release of methionine. A 60-days feeding trial in L. rohita fish fingerlings was conducted. A basal diet suboptimal (0.85%) in methionine was provided with one of the supplements as under: none (control), 0.8% chitosan NPs (0.8% NPs), 1.2% L-methionine (1.2% M) (crystalline free form), 0.6% M-NPs and 1.2% M-NPs. While the addition of 0.6% M-NPs to the basal diet complemented towards meeting the established dietary requirement and resulted in significantly highest (P < 0.05) growth and protein efficiency and sero-immunological test scores (serum total protein, serum globulin, serum albumin: globulin ratio, phagocytic respiratory burst/NBT reduction and lysozyme activity), 1.2% supplementation in either form (free or nano), for being 0.85% excess, was counterproductive. Liver transaminases and dehydrogenases corroborated enhanced growth. It was inferred that part of the methionine requirement in nano form (M-NPs) can confer intended performance and health benefits in animals relying on plant proteins-based diets limiting in this essential amino acid. The study also paves the way for exploring chitosan NPs-based sustained delivery of amino acids in human medical conditions.

How “old age” was withdrawn as a diagnosis from ICD-11

The classification of the causes of death and diseases dates back to the 18th century. The International Statistical Institute adopted the first international classification of diseases in 1893. After 1948, WHO assumed responsibility for publishing the International Classification of Diseases (ICD) as a global, multilingual catalogue of known human diseases, medical conditions, and mental health disorders, to standardise disease diagnosis. The 11th revision (ICD-11) was launched on Jan 1, 2022. The ICD is a platform for systematic statistical data collection, which are analysed and interpreted to compare causes of mortality and morbidity in different countries or regions of the world over time.

Betelvine (Piper betle L.): A comprehensive insight into its ethnopharmacology, phytochemistry, and pharmacological, biomedical and therapeutic attributes.

Piper betle L. (synonym: Piper betel Blanco), or betel vine, an economically and medicinally important cash crop, belongs to the family Piperaceae, often known as the green gold. The plant can be found all over the world and is cultivatedprimarily in South East Asian countries for its beautiful glossy heart‐shaped leaves, which are chewed or consumed as betelquidand widely used in Chinese and Indian folk medicine, as carminative, stimulant,astringent, against parasitic worms, conjunctivitis, rheumatism, wound, etc., andis also used for religious purposes. Hydroxychavicol is the most important bioactive compound among the wide range of phytoconstituents found in essential oil and extracts. The pharmacological attributes of P. betle are antiproliferation, anticancer, neuropharmacological, analgesic, antioxidant, antiulcerogenic, hepatoprotective, antifertility, antibacterial, antifungal and many more. Immense attention has been paid to nanoformulations and their applications. The application of P. betle did not show cytotoxicity in preclinical experiments, suggesting that it could serve as a promising therapeutic candidate for different diseases. The present review comprehensively summarizes the botanical description, geographical distribution, economic value and cultivation, ethnobotanical uses, preclinical pharmacological properties with insights of toxicological, clinical efficacy, and safety of P. betle. The findings suggest that P. betle represents an orally active and safe natural agent that exhibits great therapeutic potential for managing various human medical conditions. However, further research is needed to elucidate its underlying molecular mechanisms of action, clinical aspects, structure–activity relationships, bioavailability and synergistic interactions with other drugs.

CRISPER/Cas in Plant Natural Product Research: Therapeutics as Anticancer and other Drug Candidates and Recent Patents.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR- associated9 (Cas9) endonuclease system is a facile, highly efficient and selective site-directed mutagenesis tool for RNA-guided genome-editing. CRISPR/Cas9 genome-editing strategy uses designed guide-RNAs that recognizes a 3 base-pair protospacer adjacent motif (PAM) sequence in the target-DNA. CRISPR/Cas-editing tools have mainly been employed in crop plants in relation to yield and stress tolerance. However, the immense potential of this technology has not yet been fully utilized in medicinal plants in deciphering or modulating secondary metabolic pathways producing therapeutically active phytochemicals against cancer and other diseases. The present review elucidates the use of CRISPR-Cas9 as a promising genome-editing tool in plants and plant-derived natural products with anticancer and other therapeutic applications. It also includes recent patents on the therapeutic applications of CRISPR-CAS systems implicated to cancer and other human medical conditions. Popular search engines, such as PubMed, Scopus, Google Scholar, Google Patents, Medline, ScienceDirect, SpringerLink, EMBASE, Mendeley, etc., were searched in order to retrieve literature using relevant keywords viz. CRISPER/Cas, plant natural product research, anticancer, therapeutics, etc., either singly or in various combinations. Retrieved citations and further cross-referencing among the literature have resulted in a total number of 71 publications and 3 patents are being cited in this work. Information presented in this review aims to support further biotechnological and clinical strategies to be carried using CRISPER/ Cas mediated optimization of plant natural products against cancer and an array of other human medical conditions. Off late, knock-in and knock-out, point mutation, controlled tuning of gene-expression and targeted mutagenesis have enabled the versatile CRISPR/Cas-editing device to engineer medicinal plants' genomes. In addition, by combining CRISPR/Cas-editing tool with next-generation sequencing (NGS) and various tools of system biology, many medicinal plants have been engineered genetically to optimize the production of valuable bioactive compounds of industrial significance.

The Use of Essential Oils in Traditional Chinese Veterinary Medicine: Small Animal Practice

Essential oils (EO) have been used for medicinal purposes since ancient times. Advancing to the present day, these aromatic plant-based compounds are proving to effectively treat human medical conditions as well as promote physical and mental health in maintenance programs and are supported by a growing body of scientific literature. The EO’s have a long history associated with traditional Chinese medicine (TCM) and exhibit the TCM functions characteristic of the Five Elements, Yin and Yang and Channel affinity. The use of EO’s is growing in veterinary medicine and similar to humans, they can be administered by several routes which include inhalation (water based diffusers, nebulizers), topical (diluted, undiluted) and ingestion. It is important for safe use in domestic animals to be attentive to species differences, purity of the product, route of administration and concentration of the EO. This therapy is predominately used as an adjunct to both conventional medicine and traditional Chinese veterinary medicine (TCVM) therapy and allows increased treatment flexibility and efficacy for a variety of veterinary medical conditions.

Phytochemical constituents, biological activities, and health-promoting effects of the genus Origanum.

Origanum species are mostly distributed around the Mediterranean, Euro-Siberian, and Iran-Siberian regions. Since time immemorial, the genus has popularly been used in Southern Europe, as well as on the American continent as a spice now known all over the world under the name "oregano" or "pizza-spice." Origanum plants are also employed to prepare bitter tinctures, wines, vermouths, beer, and kvass. The major components of Origanum essential oil are various terpenes, phenols, phenolic acids, and flavonoids with predominant occurrence of carvacrol and thymol (with reasonable amounts of p-cymen and -terpinene) or of terpinene-4-ol, linalool, and sabinene hydrate. Many species of Origanum genus are used to treat kidney, digestive, nervous, and respiratory disorders, spasms, sore throat, diabetes, lean menstruation, hypertension, cold, insomnia, toothache, headache, epilepsy, urinary tract infections, etc. Origanum essential oil showed potent bioactivities owing to its major constituents' carvacrol, thymol, and monoterpenes. Several preclinical studies evidenced its pharmacological potential as antiproliferative or anticancer, antidiabetic, antihyperlipidemic, anti-obesity, renoprotective, antiinflammatory, vasoprotective, cardioprotective, antinociceptive, insecticidal, and hepatoprotective properties. Its nanotechnological applications as a promising pharmaceutical in order to enhance the solubility, physicochemical stability, and the accumulation rate of its essential oils have been investigated. However, Origanum has been reported causing angioedema, perioral dermatitis, allergic reaction, inhibition of platelet aggregation, hypoglycemia, and abortion. Conclusive evidences are still required for its clinical applications against human medical conditions. Toxicity analyses and risk assessment will aid to its safe and efficacious application. In addition, elaborate structure-activity studies are needed to explore the potential use of Origanum-derived phytochemicals as promising drug candidates.

A case of morphological anomalies in Amblyomma americanum (Acari: Ixodidae) collected from nature

We describe a case of morphological anomalies in Amblyomma americanum, a medically important species associated with several human diseases and medical conditions. Based on morphological characters using dichotomous morphological keys, high-resolution light microscopy, and scanning electron microscopy imaging, the tick was identified as Am. americanum nymph exhibiting various morphological anomalies including ectromely associate with asymmetry, olygomely (lack) of the fourth left leg, and schizomely (bifurcation of palpus) on the right side. We believe this is the first report of the presence of several spontaneous anomalies in one Am. americanum specimen. Morphological identity of the specimen was corroborated by DNA sequencing of the mitochondrial 16S region. We discuss recent reports of morphological anomalies in ixodid ticks and emphasize the significance of additional studies of teratology in medically important tick species and its potential implications.

The Role of Prenatal Melatonin in the Regulation of Childhood Obesity.

There is a growing awareness that pregnancy can set the foundations for an array of diverse medical conditions in the offspring, including obesity. A wide assortment of factors, including genetic, epigenetic, lifestyle, and diet can influence foetal outcomes. This article reviews the role of melatonin in the prenatal modulation of offspring obesity. A growing number of studies show that many prenatal risk factors for poor foetal metabolic outcomes, including gestational diabetes and night-shift work, are associated with a decrease in pineal gland-derived melatonin and associated alterations in the circadian rhythm. An important aspect of circadian melatonin’s effects is mediated via the circadian gene, BMAL1, including in the regulation of mitochondrial metabolism and the mitochondrial melatoninergic pathway. Alterations in the regulation of mitochondrial metabolic shifts between glycolysis and oxidative phosphorylation in immune and glia cells seem crucial to a host of human medical conditions, including in the development of obesity and the association of obesity with the risk of other medical conditions. The gut microbiome is another important hub in the pathoetiology and pathophysiology of many medical conditions, with negative consequences mediated by a decrease in the short-chain fatty acid, butyrate. The effects of butyrate are partly mediated via an increase in the melatoninergic pathway, indicating interactions of the gut microbiome with melatonin. Some of the effects of melatonin seem mediated via the alpha 7 nicotinic receptor, whilst both melatonin and butyrate may regulate obesity through the opioidergic system. Oxytocin, a recently recognized inhibitor of obesity, may also be acting via the opioidergic system. The early developmental regulation of these processes and factors by melatonin are crucial to the development of obesity and many diverse comorbidities.

Adenylate Kinase: A Ubiquitous Enzyme Correlated with Medical Conditions.

Adenylate kinase is a small, usually monomeric, enzyme found in every living thing due to its crucial role in energetic metabolism. This paper outlines the most relevant data about adenylate kinases isoforms, and the connection between dysregulation or mutation of human adenylate kinase and medical conditions. The following datadases were consulted: National Centre for Biotechnology Information, Protein Data Bank, and Mouse Genomic Informatics. The SmartBLAST tool, EMBOSS Needle Program, and Clustal Omega Program were used to analyze the best protein match, and to perform pairwise sequence alignment and multiple sequence alignment. Human adenylate kinase genes are located on different chromosomes, six of them being on the chromosomes 1 and 9. The adenylate kinases' intracellular localization and organ distribution explain their dysregulation in many diseases. The cytosolic isoenzyme 1 and the mitochondrial isoenzyme 2 are the main adenylate kinases that are integrated in the vast network of inflammatory modulators. The cytosolic isoenzyme 5 is correlated with limbic encephalitis and Leu673Pro mutation of the isoenzyme 7 leads to primary male infertility due to impairment of the ciliary function. The impairment of the mitochondrial isoenzymes 2 and 4 is demonstrated in neuroblastoma or glioma. The adenylate kinases are disease modifier that can assess the risk of diseases where oxidative stress plays a crucial role in pathogenesis like metabolic syndrome or neurodegenerative diseases. Because adenylate kinases has ATP as substrate, they are integrated in the global network of energetic process of any organism therefore are valid target for new pharmaceutical compounds.

Strategies to decrease oxidative stress biomarker levels in human medical conditions: A meta-analysis on 8-iso-prostaglandin F2α

The widespread detection of elevated oxidative stress levels in many medical conditions has led to numerous efforts to design interventions to reduce its effects. Efforts have been wide-ranging, from dietary changes to administration of antioxidants, supplements, e.g., omega-3-fatty acids, and many medications. However, there is still no systemic assessment of the efficacy of treatments for oxidative stress reduction across a variety of medical conditions.The goal of this meta-analysis is, by combining multiple studies, to quantitate the change in the levels of the popular oxidative stress biomarker 8-iso-prostaglandin F2α (8-iso-PGF2α) after a variety of treatment strategies in human populations.Nearly 350 unique publications with 180 distinct strategies were included in the analysis. For each strategy, the difference between pre- or placebo and post-treatment levels calculated using Hedges’ g value of effect. In general, administration of antibiotics, antihyperlipidemic agents, or changes in lifestyle (g = − 0.63, − 0.54, and 0.56) had the largest effect. Administration of supplements, antioxidants, or changes in diet (g = − 0.09, − 0.28, − 0.12) had small quantitative effects. To fully interpret the effectiveness of these treatments, comparisons to the increase in g value for each medical condition is required. For example, antioxidants in populations with coronary artery disease (CAD) reduce the 8-iso-PGF2α levels by g = − 0.34 ± 0.1, which is quantitatively considered a small effect. However, CAD populations, in comparison to healthy populations, have an increase in 8-iso-PGF2α levels by g = 0.38 ± 0.04; therefore, the overall reduction of 8-iso-PGF2α levels is ≈ 90% by this treatment in this specific medical condition.In conclusion, 8-iso-PGF2α levels can be reduced not only by antioxidants but by many other strategies. Not all strategies are equally effective at reducing 8-iso-PGF2α levels. In addition, the effectiveness of any strategy can be assessed only in relation to the medical condition investigated.

Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study

SummaryBackgroundMiddle East respiratory syndrome (MERS) is a severe respiratory illness with an overall mortality of 35%. There is no licensed or proven treatment. Passive immunotherapy approaches are being developed to prevent and treat several human medical conditions where alternative therapeutic options are absent. We report the safety of a fully human polyclonal IgG antibody (SAB-301) produced from the hyperimmune plasma of transchromosomic cattle immunised with a MERS coronavirus vaccine.MethodsWe did a phase 1 double-blind, placebo-controlled, single-dose escalation trial at the National Institutes of Health Clinical Center. We recruited healthy participants aged 18–60 years who had normal laboratory parameters at enrolment, a body-mass index of 19–32 kg/m2, and a creatinine clearance of 70 mL/min or more, and who did not have any chronic medical problems that required daily oral medications, a positive rheumatoid factor (≥15 IU/mL), IgA deficiency (<7 mg/dL), or history of allergy to intravenous immunoglobulin or human blood products. Participants were randomly assigned by a computer-generated table, made by a masked pharmacist, to one of six cohorts (containing between three and ten participants each). Cohorts 1 and 2 had three participants, randomly assigned 2:1 to receive active drug SAB-301 versus normal saline placebo; cohorts 3 and 4 had six participants randomised 2:1; and cohorts 5 and 6 had ten participants, randomised 4:1. Participants received 1 mg/kg, 2·5 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, or 50 mg/kg of SAB-301, or equivalent volume placebo (saline control), on day 0, and were followed up by clinical, laboratory, and pharmacokinetic assessments on days 1, 3, 7, 21, 42, and 90. The primary outcome was safety, and immunogenicity was a secondary outcome. We analysed the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02788188.FindingsBetween June 2, 2016, and Jan 4, 2017, we screened 43 participants, of whom 38 were eligible and randomly assigned to receive SAB-301 (n=28) or placebo (n=10). 97 adverse events were reported: 64 adverse events occurred in 23 (82%) of 28 participants receiving SAB-301 (mean 2·3 adverse events per participant). 33 adverse events occurred in all ten participants receiving placebo (mean 3·3 adverse events per participant). The most common adverse events were headache (n=6 [21%] in participants who received SAB-301 and n=2 [20%] in those receiving placebo), albuminuria (n=5 [18%] vs n=2 [20%]), myalgia (n=3 [11%] vs n=1 [10%]), increased creatine kinase (n=3 [11%] vs 1 [10%]), and common cold (n=3 [11%] vs n=2 [20%]). There was one serious adverse event (hospital admission for suicide attempt) in one participant who received 50 mg/kg of SAB-301. The area under the concentration–time curve (AUC) in the 50 mg/kg dose (27 498 μg × days per mL) is comparable to the AUC that was associated with efficacy in a preclinical model.InterpretationSingle infusions of SAB-301 up to 50 mg/kg appear to be safe and well tolerated in healthy participants. Human immunoglobulin derived from transchromosomic cattle could offer a new platform technology to produce fully human polyclonal IgG antibodies for other medical conditions.FundingNational Institute of Allergy and Infectious Diseases, National Institutes of Health, and Biomedical Advanced Research and Development Authority.

Potential damaging mutation in LRP5 from genome sequencing of the first reported chimpanzee with the Chiari malformation

The genus Pan is the closest related to humans (Homo sapiens) and it includes two species: Pan troglodytes (chimpanzees) and Pan paniscus (bonobos). Different characteristics, some of biomedical aspect, separate them from us. For instance, some common human medical conditions are rare in chimpanzees (menopause, Alzheimer disease) although it is unclear to which extent longevity plays an active role in these differences. However, both humans and chimpanzees present similar pathologies, thus, understanding traits in chimpanzees can help unravel the molecular basis of human conditions. Here, we sequenced the genome of Nico, a central chimpanzee diagnosed with a particular biomedical condition, the Chiari malformation. We performed a variant calling analysis comparing his genome to 25 whole genomes from healthy individuals (bonobos and chimpanzees), and after predicting the effects of the genetic variants, we looked for genes within the OMIM database. We found a novel, private, predicted as damaging mutation in Nico in LRP5, a gene related to bone density alteration pathologies, and we suggest a link between this mutation and his Chiari malformation as previously shown in humans. Our results reinforce the idea that a comparison between humans and chimpanzees can be established in this genetic frame of common diseases.

Long-distance connections in the Copper Age: New evidence from the Alpine Iceman's copper axe.

25 years after the discovery in the Ötztal Italian Alps, the 5,300-year-old mummy keeps providing key information on human biological and medical conditions, aspects of everyday life and societal organization in the Copper Age. The hand axe found with the body of the Alpine Iceman is one of the rare copper objects that is firmly dated to the early Copper Age because of the radiocarbon dating of the axe wooden shaft. Here we report the measurement of the lead isotope ratios of the copper blade. The results unambiguously indicate that the source of the metal is the ore-rich area of Southern Tuscany, despite ample evidence that Alpine copper ore sources were known and exploited at the time. The experimental results are discussed within the framework of all the available coeval archaeometallurgical data in Central-Southern Europe: they show that the Alps were a neat cultural barrier separating distinct metal circuits. The direct evidence of raw metal or object movement between Central Italy and the Alps is surprising and provides a new perspective on long-distance relocation of goods and relationships between the early Copper Age cultures in the area. The result is in line with the recent investigations re-evaluating the timing and extent of copper production in Central Italy in the 4th millennium BC.

A web-based knowledge management system integrating Western and Traditional Chinese Medicine for relational medical diagnosis.

This article presents the design of a web-based knowledge management system as a training and research tool for the exploration of key relationships between Western and Traditional Chinese Medicine, in order to facilitate relational medical diagnosis integrating these mainstream healing modalities. The main goal of this system is to facilitate decision-making processes, while developing skills and creating new medical knowledge. Traditional Chinese Medicine can be considered as an ancient relational knowledge-based approach, focusing on balancing interrelated human functions to reach a healthy state. Western Medicine focuses on specialties and body systems and has achieved advanced methods to evaluate the impact of a health disorder on the body functions. Identifying key relationships between Traditional Chinese and Western Medicine opens new approaches for health care practices and can increase the understanding of human medical conditions. Our knowledge management system was designed from initial datasets of symptoms, known diagnosis and treatments, collected from both medicines. The datasets were subjected to process-oriented analysis, hierarchical knowledge representation and relational database interconnection. Web technology was implemented to develop a user-friendly interface, for easy navigation, training and research. Our system was prototyped with a case study on chronic prostatitis. This trial presented the system's capability for users to learn the correlation approach, connecting knowledge in Western and Traditional Chinese Medicine by querying the database, mapping validated medical information, accessing complementary information from official sites, and creating new knowledge as part of the learning process. By addressing the challenging tasks of data acquisition and modeling, organization, storage and transfer, the proposed web-based knowledge management system is presented as a tool for users in medical training and research to explore, learn and update relational information for the practice of integrated medical diagnosis. This proposal in education has the potential to enable further creation of medical knowledge from both Traditional Chinese and Western Medicine for improved care providing. The presented system positively improves the information visualization, learning process and knowledge sharing, for training and development of new skills for diagnosis and treatment, and a better understanding of medical diseases.

Concise Review: Embryonic Stem Cells Derived by Somatic Cell Nuclear Transfer: A Horse in the Race?

Embryonic stem cells (ESC) hold promise for the treatment of human medical conditions but are allogeneic. Here, we consider the differences between autologous pluripotent stem cells produced by nuclear transfer (NT-ESCs) and transcription factor-mediated, induced pluripotent stem cells (iPSCs) that impact the desirability of each of these cell types for clinical use. The derivation of NT-ESCs is more cumbersome and requires donor oocytes; however, the use of oocyte cytoplasm as the source of reprogramming factors is linked to a key advantage of NT-ESCs-the ability to replace mutant mitochondrial DNA in a patient cell (due to either age or inherited disease) with healthy donor mitochondria from an oocyte. Moreover, in epigenomic and transcriptomic comparisons between isogenic iPSCs and NT-ESCs, the latter produced cells that more closely resemble bona fide ESCs derived from fertilized embryos. Thus, although NT-ESCs are more difficult to generate than iPSCs, the ability of somatic cell nuclear transfer to replace aged or diseased mitochondria and the closer epigenomic and transcriptomic similarity between NT-ESCs and bona fide ESCs may make NT-ESCs superior for future applications in regenerative medicine. Stem Cells 2017;35:26-34.

MiRNA molecular profiles in human medical conditions: connecting lung cancer and lung development phenomena.

MiRNAs are endogenous, single stranded ~22-nucleotide non-coding RNAs (ncRNAs) which are transcribed by RNA polymerase II and mediate negative post-transcriptional gene regulation through binding to 3'untranslated regions (UTR), possibly open reading frames (ORFs) or 5'UTRs of target mRNAs. MiRNAs are involved in the normal physiology of eukaryotic cells, so dysregulation may be associated with diseases like cancer, and neurodegenerative, heart and other disorders. Among all cancers, lung cancer, with high incidence and mortality worldwide, is classified into two main groups: non-small cell lung cancer and small cell lung cancer. Recent promising studies suggest that gene expression profiles and miRNA signatures could be a useful step in a noninvasive, low-cost and repeatable screening process of lung cancer. Similarly, every stage of lung development during fetal life is associated with specific miRNAs. Since lung development and lung cancer phenomena share the same physiological, biological and molecular processes like cell proliferation, development and shared mRNA or expression regulation pathways, and according to data adopted from various studies, they may have partially shared miRNA signature. Thus, focusing on lung cancer in relation to lung development in miRNA studies might provide clues for lung cancer diagnosis and prognosis.

Representation and Practical Accomplishment in the Laboratory: When is an Animal Model Good-enough?

Biomedical science is dependent on standardised rodents. These lab-rats and lab-mice are different from their wild cousins. Interest in the genetic basis of a variety of phenotypes has meant that lab-rodents have been bred over many decades as resources for experimental science. We focus on the use of lab-rodents as animal models in the study of single-gene human medical conditions. The animals’ status as models is not a given. Scientists calibrate animals against the medical phenomena which they are intended to represent. In turn, human medical conditions and the patients who manifest them have to be calibrated against the rodent models. The creation of animal models and their interpretation is, therefore, part of the practical work of biomedical scientists and their adjustment is a key aspect in determining when the model is good-enough.

Nanotube Action between Human Mesothelial Cells Reveals Novel Aspects of Inflammatory Responses

A well-known role of human peritoneal mesothelial cells (HPMCs), the resident cells of the peritoneal cavity, is the generation of an immune response during peritonitis by activation of T-cells via antigen presentation. Recent findings have shown that intercellular nanotubes (NTs) mediate functional connectivity between various cell types including immune cells - such as T-cells, natural killer (NK) cells or macrophages - by facilitating a spectrum of long range cell-cell interactions. Although of medical interest, the relevance of NT-related findings for human medical conditions and treatment, e.g. in relation to inflammatory processes, remains elusive, particularly due to a lack of appropriate in vivo data. Here, we show for the first time that primary cultures of patient derived HPMCs are functionally connected via membranous nanotubes. NT formation appears to be actin cytoskeleton dependent, mediated by the action of filopodia. Importantly, significant variances in NT numbers between different donors as a consequence of pathophysiological alterations were observable. Furthermore, we show that TNF-α induces nanotube formation and demonstrate a strong correlation of NT connectivity in accordance with the cellular cholesterol level and distribution, pointing to a complex involvement of NTs in inflammatory processes with potential impact for clinical treatment.

Overlooking Subvisible Particles in Therapeutic Protein Products: Gaps That May Compromise Product Quality

Therapeutic protein products provide unique and effective treatments for numerous human diseases and medical conditions. In many cases, these treatments are used chronically to slow disease progression, reduce morbidity and/or to replace essential proteins that are not produced endogenously in patients. Therefore, any factor that reduces or eliminates the effectiveness of the treatment can lead to patient suffering and even death. One means by which efficacy of therapeutic proteins can be compromised is by an immune response, resulting in antibody-mediated neutralization of the protein’s activity or alterations in bioavailability. 1. Kessler M. Goldsmith D. Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21: 9-12 Crossref PubMed Scopus (177) Google Scholar , 2. Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1104) Google Scholar For example, in the case of treatment of hemophilia A, neutralizing antibodies to Factor VIII can cause life-threatening bleeding episodes, resulting in significant morbidity and necessitating treatment with a prolonged course of a tolerance-inducing therapy to reverse immunity. 3. Hooks W.K. Urgent inhibitor issues: Targets for expanded research. Haemophilia. 2006; 12: 107-113 PubMed Google Scholar , 4. Reipert B.M. van den Helden P.M. Schwartz H.-P. Hausl C. Mechanisms of action of immune tolerance induction against factor VIII in patients with cogenital haemophilia A and factor VIII inhibitors. Br J Haemophilia. 2007; 136: 12-25 Crossref PubMed Scopus (86) Google Scholar In other cases, drug-induced antibodies to a therapeutic version of an endogenous protein can cross-react with and neutralize the patient’s endogenous protein. If the endogenous protein serves a nonredundant biological function, such an immune response can have devastating results. For example, pure red cell aplasia can result from neutralizing antibodies to epoetin alpha. 1. Kessler M. Goldsmith D. Schellekens H. Immunogenicity of biopharmaceuticals. Nephrol Dial Transplant. 2006; 21: 9-12 Crossref PubMed Scopus (177) Google Scholar , 2. Rosenberg A.S. Effects of protein aggregates: An immunologic perspective. AAPS J. 2006; 8: E501-E507 Crossref PubMed Scopus (1104) Google Scholar

Liposomal Drug Delivery: Recent Patents and Emerging Opportunities

It is challenging to develop innovative, as well as commercially viable, lipid-based drug delivery systems for the treatment of cancer because of the breadth of existing intellectual property that limits freedom-to-operate. For example, novel compositions can be described in which a new chemical entity is associated with a lipid based carrier, but if the loading method or components of the lipid compositions are proprietary then the ability to develop novel compositions will require access to the appropriate intellectual property. We believe it is useful to present a review of the patent literature describing novel liposomal drug delivery systems given by parenteral administration to humans for the treatment of serious medical conditions such as cancer. This review is intended to: (i) identify and describe novel approaches that have recently been protected by US or international patents and patent applications, and; (ii) identify founding technology in the field which is recently off-patent, thus presenting emerging opportunities for the development of new therapeutic options for patients. Issued patents, and selected patent applications, having publication dates in 2005 or 2006 were retrieved from searches of the US, European, German, Japanese, INPADOC and WIPO PCT databases. Liposomal delivery systems patented for systemic administration in the treatment of human medical conditions were reviewed in detail.