Deep Brain Stimulation for Parkinson's Disease-the Developing World's Perspective.

Background: Deep brain stimulation (DBS) is the most widely used device-assisted therapy in patients with moderately advanced stages of Parkinson's disease (PD) experiencing motor complications. Only a minority of eligible patients get the opportunity to undergo DBS in the developing world. Objectives: To examine the proportion and characteristics of patients with motor complications of PD who are willing for DBS and who undergo surgery. Methods: Patients with motor complications of PD eligible for DBS over a five-year study period (2016-2020) were included. The demographic, clinical and socio-economic characteristics and information on their status in 2021 were collected and analyzed. Results: Among 1017 patients, 223 had motor symptoms qualifying for DBS and follow-up information available. Only 78 (35%) opted for surgery. The willing patients had higher socioeconomic status, were older and had longer duration of PD and motor complications, more freezing of gait, cognitive symptoms, and neuropsychiatric disturbances. 37 of them were found unfit during pre-operative work-up; only 41 (18%) with motor complications were finally taken up for DBS. Age, duration or severity of motor symptoms did not differ between patients who were finally selected for surgery and those who were not. Conclusions: Less than one-fifth of our patients with motor complications of PD finally underwent DBS. The patients appeared to wait till the late stages of PD, before making a decision on availing surgical treatment. The delay resulted in nearly half of them being found unfit in pre-operative work-up. Our findings may enable clinicians to counsel eligible patients more efficiently.

The structure of the neurotoxin palytoxin determined by MicroED.

Palytoxin (PTX) is a potent neurotoxin found in marine animals that can cause serious symptoms such as muscle contractions, haemolysis of red blood cells and potassium leakage. Despite years of research, very little is known about the mechanism of PTX. However, recent advances in the field of cryoEM, specifically the use of microcrystal electron diffraction (MicroED), have allowed us to determine the structure of PTX. It was discovered that PTX folds into a hairpin motif and is able to bind to the extracellular gate of Na,K-ATPase, which is responsible for maintaining the electrochemical gradient across the plasma membrane. These findings, along with molecular docking simulations, have provided important insights into the mechanism of PTX and can potentially aid in the development of molecular agents for treating cases of PTX exposure.

MicroED in drug discovery.

The cryo-electron microscopy (cryo-EM) method microcrystal electron diffraction (MicroED) was initially described in 2013 and has recently gained attention as an emerging technique for research in drug discovery. As compared to other methods in structural biology, MicroED provides many advantages deriving from the use of nanocrystalline material for the investigations. Here, we review the recent advancements in the field of MicroED and show important examples of small molecule, peptide and protein structures that has contributed to the current development of this method as an important tool for drug discovery.

The interplay of stress and electrocortical reactivity to reward in the prospective prediction of depression symptoms during COVID-19.

Rates of depression have increased during the novel coronavirus disease 2019 (COVID-19) pandemic, potentially due to associated stress exposure. However, it remains unclear which individuals are most susceptible. Electrocortical markers of reward processing, such as the reward positivity (RewP), are implicated in depression risk and may provide insights into who is most vulnerable to stress during the COVID-19 pandemic. The current study examined whether pre-pandemic neural correlates of reward reactivity (i.e., RewP) moderated the impact of social and financial stress on changes in youth and mother depression symptoms pre-to-post pandemic onset. Youth (n = 45) and mothers (n = 45) in the current sample were recruited prior to the COVID-19 pandemic as part of a larger study. RewP was assessed pre-pandemic, and depression symptoms were assessed pre- and post-pandemic onset for both youth and mothers. Additionally, social and financial chronic stress severity was assessed post-pandemic onset using a modified version of the UCLA Life Stress Interview. Financial stress was associated with prospective increases in depression for youth exhibiting blunted RewP at baseline. Similarly, family stress was associated with prospective increases in depression symptoms for mothers exhibiting blunted RewP at baseline. Findings suggest reduced reward responsiveness at the neural level may predispose both youth and mothers to future depression symptoms when exposed to higher levels of stress in the context of a pandemic.

Clinicobiochemical Parameters and Predictors of Liver Disease in Hospitalized Asian Indian Pregnant Women in a Tertiary Care Center in Northern India.

Introduction  During pregnancy, liver dysfunction is more frequent than expected and may require specialized care. For the early diagnosis, it is important to determine if changes in liver physiology may develop into liver disease. Liver disease during pregnancy may require intervention from a hepatologist for adequate monitoring of mother-fetus health outcomes. This study was aimed to evaluate the clinical profile and predictors of maternal mortality in patients with liver diseases among Asian-Indian-females. Methods We conducted a prospective, open-label, consecutive all-comers study of 2,663 pregnant Asian Indian women admitted in the hospital, which included 92 with liver dysfunction. The medical aspects of the pregnancy were then followed prospectively with laboratory and clinical data during the hospital stay and analyzed. The current study was approved by the Institutional Ethical Committee. Results We found that 92 out of 2,663 patients had liver dysfunction with a prevalence of 3.45%. Fifty-four (58.7%) patients had icterus followed by fever in 23 (25.0%), hypertension in 22 (23.9%), central nervous system manifestations in 21 (22.8%), abdominal pain in 19 (20.6%), vomiting in 19 (20.6%), and pruritus in six (6.5%). Predictors of maternal mortality were icterus (p = 0.04), hepatomegaly (p = 0.04), presenting serum-bilirubin greater than 10 milligram% (mg%) (p = 0.008). The most common etiology was acute viral hepatitis (45.6%), followed by a hypertensive disorder of pregnancy (29.3%), acute fatty liver of pregnancy (1.1%), cholestatic jaundice (9.8%), hyperemesis gravidarum (2.2%), septicemic hepatitis (3.3%), dengue immunoglobulin M (IgM), and plasmodium vivax malaria antigen positive in (2.2%) each. Four patients (4.3%) were leptospira IgM reactive and had co-infection with hepatitis E virus. There was one patient (1.1%) with underlying chronic liver disease. Idiopathic liver disease was present in 5.4% of patients. Conclusion Liver disease is relatively common in Indian pregnant women. It is associated with high maternal and perinatal mortality, even in a tertiary referral center. When managing pregnancy in a tertiary care center, for adequate follow-up of the disease and to prevent adverse consequences for mother and child, it is important to discard liver alterations early. For this purpose, liver disease during pregnancy needs early diagnosis for proper management. Furthermore, it is difficult to manage patients with preexisting liver disease, and it may require specialized intervention from a hepatologist and a gastroenterologist.

Analogues of the Herbicide, N-Hydroxy-N-isopropyloxamate, Inhibit Mycobacterium tuberculosis Ketol-Acid Reductoisomerase and Their Prodrugs Are Promising Anti-TB Drug Leads.

New drugs to treat tuberculosis (TB) are urgently needed to combat the increase in resistance observed among the current first-line and second-line treatments. Here, we propose ketol-acid reductoisomerase (KARI) as a target for anti-TB drug discovery. Twenty-two analogues of IpOHA, an inhibitor of plant KARI, were evaluated as antimycobacterial agents. The strongest inhibitor of Mycobacterium tuberculosis (Mt) KARI has a Ki value of 19.7 nM, fivefold more potent than IpOHA (Ki = 97.7 nM). This and four other potent analogues are slow- and tight-binding inhibitors of MtKARI. Three compounds were cocrystallized with Staphylococcus aureus KARI and yielded crystals that diffracted to 1.6-2.0 Å resolution. Prodrugs of these compounds possess antimycobacterial activity against H37Rv, a virulent strain of human TB, with the most active compound having an MIC90 of 2.32 ± 0.04 µM. This compound demonstrates a very favorable selectivity window and represents a highly promising lead as an anti-TB agent.

Optimal Antibiotic Duration for Bloodstream Infections Secondary to Intraabdominal Infection.

BACKGROUND: Bloodstream infections (BSIs) secondary to intraabdominal infections (IAIs) are common in the intensive care unit (ICU). The Surgical Infection Society guidelines recommend treatment duration after achieving source control in patients with secondary bacteremia; however, literature supporting this recommendation is limited. The purpose of this study was to compare outcomes in patients who received shorter versus extended duration of antibiotics for bacteremia secondary to IAI. MATERIALS AND METHODS: A retrospective cohort analysis was conducted in adult surgical ICU patients (n = 42) with BSIs and source control procedure(s) for IAI. The primary outcome was recurrent IAI. Secondary outcomes included surgical site infections (SSIs), Clostridium difficile infections (CDIs), secondary fungal infections, and in-hospital mortality. RESULTS: Forty-two patients met inclusion criteria and were divided into groups according to antimicrobial duration; 12 patients received <7 d, and 30 patients received >7 d of antibiotics. There were no differences in baseline characteristics between the two cohorts except for the presence of sepsis [4/12 (33.3%) versus 27/30 (90.0%); P = 0.001]. Thirty-one percent (13/42) of all organisms isolated from blood cultures were gram-negative bacteria, 12/42 (28.6%) were MDROs, and 2/42 (4.8%) patients experienced a culture mismatch in which cultured bacteria were not susceptible to empiric antibiotic therapy. Rates of recurrent IAI were similar between the two cohorts [1/12 (8.3%) versus 4/30 (13.3%), P = 0.554]. CONCLUSIONS: Among surgical ICU patients with BSI secondary to IAI, cessation of antibiotic therapy within 7 d of source control was not associated with an increased incidence of recurrent IAI.

Discovery of a Pyrimidinedione Derivative with Potent Inhibitory Activity against Mycobacterium tuberculosis Ketol-Acid Reductoisomerase.

New drugs aimed at novel targets are urgently needed to combat the increasing rate of drug-resistant tuberculosis (TB). Herein, the National Cancer Institute Developmental Therapeutic Program (NCI-DTP) chemical library was screened against a promising new target, ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid (BCAA) biosynthesis pathway. From this library, 6-hydroxy-2-methylthiazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione (NSC116565) was identified as a potent time-dependent inhibitor of Mycobacterium tuberculosis (Mt) KARI with a Ki of 95.4 nm. Isothermal titration calorimetry studies showed that this inhibitor bound to MtKARI in the presence and absence of the cofactor, nicotinamide adenine dinucleotide phosphate (NADPH), which was confirmed by crystal structures of the compound in complex with closely related Staphylococcus aureus KARI. It is also shown that NSC116565 inhibits the growth of H37Ra and H37Rv strains of Mt with MIC50 values of 2.93 and 6.06 µm, respectively. These results further validate KARI as a TB drug target and show that NSC116565 is a promising lead for anti-TB drug development.

Discovery, Synthesis and Evaluation of a Ketol-Acid Reductoisomerase Inhibitor.

Ketol-acid reductoisomerase (KARI), the second enzyme in the branched-chain amino acid biosynthesis pathway, is a potential drug target for bacterial infections including Mycobacterium tuberculosis. Here, we have screened the Medicines for Malaria Venture Pathogen Box against purified M. tuberculosis (Mt) KARI and identified two compounds that have Ki values below 200 nm. In Mt cell susceptibility assays one of these compounds exhibited an IC50 value of 0.8 µm. Co-crystallization of this compound, 3-((methylsulfonyl)methyl)-2H-benzo[b][1,4]oxazin-2-one (MMV553002), in complex with Staphylococcus aureus KARI, which has 56 % identity with Mt KARI, NADPH and Mg2+ yielded a structure to 1.72 Šresolution. However, only a hydrolyzed product of the inhibitor (i.e. 3-(methylsulfonyl)-2-oxopropanic acid, missing the 2-aminophenol attachment) is observed in the active site. Surprisingly, Mt cell susceptibility assays showed that the 2-aminophenol product is largely responsible for the anti-TB activity of the parent compound. Thus, 3-(methylsulfonyl)-2-oxopropanic acid was identified as a potent KARI inhibitor that could be further explored as a potential biocidal agent and we have shown 2-aminophenol, as an anti-TB drug lead, especially given it has low toxicity against human cells. The study highlights that careful analysis of broad screening assays is required to correctly interpret cell-based activity data.

New Drugs Approved in 2019.

In 2019, the US Food and Drug Administration (FDA) approved 48 novel drugs. Thirty of the 48 (62.5%) novel drug approvals were reviewed and approved through an expedited review pathway while 20 of the 48 (41.7%) were approved for treatment of a rare disease. This review includes a summary of the novel drugs approved by the FDA in 2019.

A new flatland buddy as toxic gas scavenger: A first principles study.

Recently predicted and grown new single element two dimensional (2D) material borophene gathered tremendous research interest due to its structural, electronic and other properties. Using first principles based dispersion corrected density functional calculations, we have studied interaction of two toxic gases phosgene (COCl2) and carbon monoxide (CO) with borophene to understand the role of borophene as biosensor and carriers in drug delivery. The sensing behaviour of borophene towards COCl2 and CO has been studied by calculating the binding energy and electronic density of states (DOS). The change in the band structure, DOS, charge density and work function (WF) upon adsorption of gas molecules further confirms the sensing properties of borophene towards these molecules. The binding energy for COCl2 and CO molecules on borophene is -0.306 eV and -0.15 eV respectively which indicates that the COCl2 is adsorbed more favourably than CO over borophene. The WF is enhanced by 0.193 eV and 0.051 eV after the adsorption of COCl2 and CO over borophene. Short recovery time of 148 ns and 37 ns for COCl2 and CO has been predicted. These findings show that the borophene can be used as nanosensor to detect COCl2 and CO.

Crystal Structures of Staphylococcus aureus Ketol-Acid Reductoisomerase in Complex with Two Transition State Analogues that Have Biocidal Activity.

Ketol-acid reductoisomerase (KARI) is an NAD(P)H and Mg2+ -dependent enzyme of the branched-chain amino acid (BCAA) biosynthesis pathway. Here, the first crystal structures of Staphylococcus aureus (Sa) KARI in complex with two transition state analogues, cyclopropane-1,1-dicarboxylate (CPD) and N-isopropyloxalyl hydroxamate (IpOHA) are reported. These compounds bind competitively and in multi-dentate manner to KARI with Ki values of 2.73 µm and 7.9 nm, respectively; however, IpOHA binds slowly to the enzyme. Interestingly, intact IpOHA is present in only ≈25 % of binding sites, whereas its deoxygenated form is present in the remaining sites. This deoxy form of IpOHA binds rapidly to Sa KARI, but with much weaker affinity (Ki =21 µm). Thus, our data pinpoint the origin of the slow binding mechanism of IpOHA. Furthermore, we propose that CPD mimics the early stage of the catalytic reaction (preceding the reduction step), whereas IpOHA mimics the late stage (after the reduction took place). These structural insights will guide strategies to design potent and rapidly binding derivatives of these compounds for the development of novel biocides.

Student engagement and perceptions of stigmatizing views in a mental health-focused collegiate organization.

INTRODUCTION: While often unintentional, stigma associated with mental health remains prevalent among health care professionals and is implicated in treatment disparities between patients with and without mental disorders. Pharmacists and pharmacy students have also been previously described as prone to discomfort interacting with this population. The purpose of this study was to evaluate stigma, student involvement in mental health activities, and student interest in psychiatric pharmacy. METHODS: An anonymous, voluntary online survey was open to all student chapters in a mental health-focused professional organization. Sixty-five students from 19 chapters participated in the survey after consent was obtained. Stigma and social distance survey items were adapted from previously validated instruments. Descriptive statistics were used and correlations were investigated using Spearman rank correlation. RESULTS: Results indicated that students had overall low stigma but more negative views related to disclosure of one's own illness or to more personal interactions. Level of involvement was unrelated to level of stigma, and perceived impact by nonleadership activities was associated with lower stigma (P = .016). Shadowing pharmacists and community service were frequently reported as most influential on student perceptions of mental health (23% and 26%, respectively). DISCUSSION: Students involved in a mental health-focused organization had overall positive perceptions toward mental illness. Student engagement in specific opportunities at any level may be more influential than total number of activities participated in. Students have a strong interest in pursuing extracurricular activities in mental health and perceive interactions with patient contact as the most influential on their attitudes.

Role of l-Arginine in Oligohydramnios.

BACKGROUND: Oligohydramnios is a known obstetric complication which is associated with operative interferences and perinatal morbidity and mortality. l-arginine is a precursor of nitric oxide and may play a role in local vasodilatation. Administration of l-arginine has been suggested to improve amniotic fluid index (AFI) in oligohydramnios. AIMS AND OBJECTIVES: To study the effect of l-arginine in optimizing fetal outcome in cases of oligohydramnios. MATERIALS AND METHODS: A retrospective study was conducted at Dr L H Hiranandani hospital consisting of 100 antenatal patients diagnosed with oligohydramnios [AFI < 8 cm] remote from term. Patients were evaluated for all antenatal risk factors and were started on l-arginine sachets (3 g, 3 sachets a day). The treatment was continued till an adequate improvement in liquor was noted. However, patients were considered for delivery if the liquor remained <5. Further, mean increase in AFI, intervention delivery interval, and neonatal outcome were studied. RESULTS: The mean gestational age at the time of recruitment was 32.3 weeks. The mean AFI noted was 5.421 cm. These patients were delivered at 35 ± 1.1 weeks, and thus, pregnancy could be prolonged by 2.4 ± 1.1 weeks. The mean AFI at the end of therapeutic intervention was 8.753, and thus, an AFI increase of 3.332 cm could be obtained. There was no significant neonatal morbidity in these patients. Significant improvement in liquor volume was obtained in these patients after intervention with l-arginine sachets. CONCLUSION: l-arginine supplementation is promising in improving volume of amniotic fluid in cases of oligohydramnios and prolonging pregnancy by a mean of 2.4 weeks, allowing fetal lung maturation thus benefiting the neonatal outcome.

Interaction of FGF-2 with IGF-1 and BDNF in stimulating Akt, ERK, and neuronal survival in hippocampal cultures.

The significance of multiple growth factors acting on individual neurons in the central nervous system is presently unclear. Cultured hippocampal neurons were used in the present study to compare the neurotrophic actions of fibroblast growth factor-2 (FGF-2) with the better characterized growth factors, insulin-like growth factor (IGF)-1 and brain-derived neurotrophic factor (BDNF). Additionally, cultures were utilized to identify possible interactions between FGF-2 and the other growth factors. Activation of the ERK and Akt pro-survival pathways, as well as neuronal survival itself, were studied. The maximal magnitude of Akt activation stimulated by FGF-2 was found to be similar to that stimulated by IGF-1 and BDNF. In contrast, IGF-1 was less effective at inducing ERK activation than were BDNF and FGF-2. All three agents were found to promote survival of neurons cultured under serum-free, low-insulin conditions, with FGF-2 surprisingly being significantly more effective than the other two peptides. Co-treatment with maximal concentrations of either IGF-1 or BDNF enhanced FGF-2-stimulated Akt and ERK activation. However, no enhancement of survival beyond that stimulated by FGF-2 was observed with co-treatment. These findings suggest that FGF-2 may play an important role in promoting the survival of hippocampal neurons. Additionally, an interesting dissociation was identified between the positive interaction of FGF-2 with both IGF-1 and BDNF in activating Akt and ERK, and the lack of enhancement of FGF-2-induced neuroprotection.