Expanding the Arsenal Against Huntington's Disease-Herbal Drugs and Their Nanoformulations

Huntington’s disease (HD) is an autosomal fatal genetic disease in which degeneration of neuronal cells occurs in the central nervous system (CNS). Commonly used therapeutics are cludemonoamine depletors, antipsychotics, antidepressants, and tranquilizers. However, these drugs cannot prevent the psychotic, cognitive, and behavioral dysfunctions associated with HD. In addition to this, their chronic use is limited by their long-term side effects. Herbal drugs offer a plausible alternative to this and have shown substantial therapeutic effects against HD. Moreover, their safety profile is better in terms of side effects. However, due to limited drug solubility and permeability to reach the target site, herbal drugs have not been able to reach the stage of clinical exploration. In recent years, the paradigm of research has been shifted towards the development of herbal drugs based nanoformulations that can enhance their bioavailability and blood-brain barrier permeability. The present review covers the pathophysiology of HD, available biomarkers, phytomedicines explored against HD, ongoing clinical trials on herbal drugs exclusively for treating HD and their nanocarriers, along with their potential neuroprotective effects.     

Regulation of mammalian siderophore 2,5-DHBA in the innate immune response to infection

Competition for iron influences host–pathogen interactions. Pathogens secrete small iron-binding moieties, siderophores, to acquire host iron. In response, the host secretes siderophore-binding proteins, such as lipocalin 24p3, which limit siderophore-mediated iron import into bacteria. Mammals produce 2,5-dihydroxy benzoic acid, a compound that resembles a bacterial siderophore. Our data suggest that bacteria use both mammalian and bacterial siderophores. In support of this idea, supplementation with mammalian siderophore enhances bacterial growth in vitro. In addition, mice lacking the mammalian siderophore resist E. coli infection. Finally, we show that the host responds to infection by suppressing siderophore synthesis while up-regulating lipocalin 24p3 expression via TLR signaling. Thus, reciprocal regulation of 24p3 and mammalian siderophore is a protective mechanism limiting microbial access to iron.The growth and metabolism of many pathogenic microbes is exquisitely iron sensitive (Schaible and Kaufmann, 2004). Mammals have evolved a defense mechanism to sequester iron that permits host cells to maintain access to iron while preventing invading microbes from acquiring the metal (Ganz, 2009; Cassat and Skaar, 2013). Iron is predominantly intracellular or tightly bound to proteins. Invading pathogens therefore obtain iron from their host by secreting small, iron-binding siderophores, which remove iron from host protein–iron complexes due to their higher affinity for iron (Miethke and Marahiel, 2007). In parallel, mammals have evolved siderophore-binding proteins as components of the innate immune system, e.g., 24p3 (Flo et al., 2004). 24p3 is a member of the lipocalin family of proteins that transport a variety of ligands (Flower, 2000). 24p3 binds small hydrophobic molecules, the siderophores (Goetz et al., 2002). By binding iron-laden bacterial siderophores, 24p3 participates in innate host defense (Flo et al., 2004; Berger et al., 2006; Saiga et al., 2008). 24p3 expression in innate immunity is highly induced in response to stimulation by TLR2, TLR4, and TLR5 agonists (Flo et al., 2004; Saiga et al., 2008; Van Maele et al., 2010). 24p3 is also one of the secondary granule proteins of neutrophils (Kjeldsen et al., 1993). Therefore, the 24p3 released upon neutrophil degranulation, complements 24p3 secreted by TLR stimulated macrophages, epithelial cells and liver opposing salvage of host iron by bacterial siderophores (Borregaard and Cowland, 2006).24p3 specifically binds catecholate or mixed phenolate type siderophores (Holmes et al., 2005). The ability of 24p3 to curtail the growth of bacteria is limited to those species that depend on catecholes and mixed phenolates for iron acquisition (Berger et al., 2006, Flo et al., 2004; Saiga et al., 2008). Strains of E. coli and Staphylococcus aureus have modified siderophores that evade capture by 24p3 (Fischbach et al., 2006). Moreover, pathogenic strains of E. coli secrete multiple siderophores (Henderson et al., 2009). Although 24p3 is highly induced by infection with these bacteria, secreted 24p3 may not be able to sequester the multiple siderophores excreted by these bacteria because its binding pocket is selective for catecholes (Holmes et al., 2005; Reigstad et al., 2007). Interestingly, 24p3 is also highly induced by E. coli infection of C3H/HeJ mice that harbor a mutation in TLR4 (Reigstad et al., 2007). Despite high levels of 24p3, these mice succumb to E. coli infection; the effect of 24p3 on E. coli growth in C3H/HeJ mice is insignificant (Hagberg et al., 1985). As stated above, 24p3 is a secondary granule protein in neutrophils, which is critical for motility and chemotaxis (Rathore et al., 2011; Schroll et al., 2012; Liu et al., 2013). 24p3 deficiency confers enhanced sensitivity upon mice to a variety of pathogens independent of their ability to secrete siderophores (Liu et al., 2013). These studies suggest that additional mechanisms may be in place that synergize with 24p3 to counter bacterial hijacking of iron.Mammalian-derived 24p3 also captures iron indicating the existence of siderophore-like molecules (Yang et al., 2003). In addition, older studies have suggested the existence of low-molecular weight iron binding compounds or siderophore-like molecules that are capable of binding iron and that stimulate proliferation of bacteria (Fernandez-Pol, 1978; Jones et al., 1980). However, these molecules were not implicated in iron carrier function of 24p3. Using 24p3 as bait we recently identified a siderophore in mammalian cells that facilitates iron loading onto 24p3 (Devireddy et al., 2010). The mammalian siderophore, 2,5-dihydroxy benzoic acid (2,5-DHBA) is chemically similar to 2,3-DHBA, the iron-binding moiety of E. coli enterobactin (Raymond et al., 2003). One of the short chain dehydrogenases (SDR) family of reductases, 3-OH butyrate dehydrogenase-2 (Bdh2), a homologue of bacterial EntA, catalyzes a rate-limiting step in the 2,5-dihydroxy benzoic acid (DHBA) biosynthetic pathway (Devireddy et al., 2010).However, the role of the mammalian siderophore in innate immunity is not clear. Due to its similarity to bacterial siderophore, we hypothesized that the mammalian siderophore promotes bacterial growth. We now show that the mammalian siderophore augments bacterial growth and can rescue a growth deficit conferred by the absence of the E. coli siderophore, enterobactin. To counter bacterial coopting of the mammalian siderophore, the host responds by suppressing mammalian siderophore biosynthesis. Thus, negative regulation of the mammalian siderophore provides an ingenious strategy to withhold iron from invading pathogens. Of note, mammalian siderophore-deficient mice resist pathogenic E. coli. In addition to decreasing mammalian siderophore the host responds by secreting 24p3 to sequester iron-laden bacterial siderophores. Thus, reciprocal regulation of 24p3 and the mammalian siderophore restricts the growth of invading pathogens.     

Carbapenem resistant Gram-negative bacteremia in an Indian intensive care unit: A review of the clinical profile and treatment outcome of 50 patients

Background:

Growing antimicrobial resistance and limited therapeutic options to treat carbapenem-resistant bacteremia prompted us to evaluate the clinical outcomes associated with healthcare-associated bacteremia.

Methods:

This was a retrospective observational study of carbapenem-resistant Gram-negative bacteremia performed at a tertiary care facility in Chennai, India between May 2011 and May 2012.

Results:

In our study, patients had mean 11.76 days of intensive care unit (ICU) care and mean time to onset of bacteremia was 6.4 days after admission. The commonest organism was Klebsiella pneumoniae (44%). Patients with combination treatment had lower mortality (44.8%) compared with colistin monotherapy (66.6%); (P = 0.35).

Conclusion:

Carbapenem resistant bacteremia is a late onset infection in patients with antibiotic exposure in the ICU and carries a 30 days mortality of 60%; K. pneumoniae is the most common organism at our center. Two drug combinations appear to carry a lower mortality compared with monotherapy.     

Comparison of corneal endothelial cell loss during manual small-incision cataract surgery using viscoelastic-assisted nucleus removal versus continuous balanced salt solution plus technique - Randomized controlled trial

Purpose:The purpose of this study was to compare and analyze the endothelial cell loss during manual small-incision cataract surgery (MSICS) using the viscoelastic-assisted nucleus removal versus basal salt solution plus technique.Methods:This was a prospective randomized trial of 204 patients who underwent MSICS using viscoelastic-assisted nucleus removal (Group 1- OVD) versus basal salt solution plus technique (Group 2- BSS) at a tertiary eye care hospital in North India from January 2018 to 2021. Of these 204 patients, 103 (50.5%) and 101 (49.5%) were allocated to Group 1 and 2, respectively. The parameters assessed were detailed history, demographics, and anterior and posterior segment details. Visual acuity, intraocular pressure (IOP), keratometry, pachymetry, and endothelial cell density were evaluated preoperatively and postoperatively on day 1 and 30.Results:The mean age of the patients was 64.5 ± 8.2 years (range 48–82 years). There were 129 (63.2%) males and 75 (36.8%) females. The mean LogMAR visual acuity for both groups on day 1 (Group 1- 0.3 ± 0.1, Group 2- 0.5 ± 0.2) and day 30 (Group 1- 0.1 ± 0.2, Group 2- 0.1 ± 0.1) was statistically significant (P < 0.001), and the mean IOP value showed a statistically significant value (P < 0.009) on day 1 in Group 2 (15.0 ± 2.4 mmHg) and on day 30 (P < 0.001) in both the groups (Group 1- 13.6 ± 1.8 mmHg, Group 2- 13.5 ± 2 mmHg). The horizontal and vertical k values also showed a statistically significant difference on day 1 and day 30 (P < 0.001). The mean percentage change of central corneal thickness (CCT) in Group 1 was 17.7% and in Group 2 was 17.4% on day 1, and it was 1.1% on day 30 in both the groups, which was statistically significant (P < 0.001) compared to preoperative values. The percentage change in endothelial cell density on day 1 was 9% in Group 1 and 4.6% in Group 2, which was statistically significant (P < 0.001). On day 30, it was 9.7% and 4.8%, respectively, which was statistically significant (P < 0.001).Conclusion:Our study highlights statistically significant endothelial cell loss with viscoelastic-assisted nuclear delivery compared to BSS-assisted nuclear delivery during MSICS in a short follow-up of 1 month. The CCT values showed a slight increase, and the keratometry and IOP were unaffected compared to the preoperative parameters in both the groups.     

A Simple Method of Positioning the Iris Disk on a Custom-Made Ocular Prosthesis. A Clinical Report

We report two cases of ocular prosthesis fabrication that make use of a transparent graph grid for positioning the iris disk. The custom‐made ocular prostheses achieved intimate contact with the tissue bed enabling ideal fit. As asymmetry may result in a squint‐eyed appearance, proper positioning of the iris disk in the scleral wax pattern is vital to fabricating the custom‐made artificial eye. The position of the iris disk in the custom‐made ocular prosthesis was in symmetry with that of the natural eye, restoring esthetics of the patient.     

Paraplegia treated with blood transfusion

Extramedullary hematopoiesis is a compensatory response in patients with thalassemia and other chronic anemia and can result in compressive myelopathy, if untreated. Two young adults with history of thalassemia presented with symptoms of spinal cord compression. Presence of extramedullary hematopoiesis was confirmed by magnetic resonance imaging. Both the patients were treated with blood hypertransfusion and showed improvement clinically and radiologically. Although there are various options in the management of such condition, including decompression surgery and radiation treatment, hypertransfusion can be very effective even in severe compression of the spinal cord. Hypertransfusion should be tried as the first line of management in patients with thalassemia presenting with compressive myelopathy to decrease the bulk of extramedullary hematopoietic tissue.