Development of a Novel Lead that Targets M. tuberculosis Polyketide Synthase 13.

Widespread resistance to first-line TB drugs is a major problem that will likely only be resolved through the development of new drugs with novel mechanisms of action. We have used structure-guided methods to develop a lead molecule that targets the thioesterase activity of polyketide synthase Pks13, an essential enzyme that forms mycolic acids, required for the cell wall of Mycobacterium tuberculosis. Our lead, TAM16, is a benzofuran class inhibitor of Pks13 with highly potent in vitro bactericidal activity against drug-susceptible and drug-resistant clinical isolates of M. tuberculosis. In multiple mouse models of TB infection, TAM16 showed in vivo efficacy equal to the first-line TB drug isoniazid, both as a monotherapy and in combination therapy with rifampicin. TAM16 has excellent pharmacological and safety profiles, and the frequency of resistance for TAM16 is ∼100-fold lower than INH, suggesting that it can be developed as a new antitubercular aimed at the acute infection. PAPERCLIP.

Does achieving clinically important thresholds after first shoulder arthroplasty predict similar outcomes of the contralateral shoulder?

BACKGROUND: Patients are increasingly undergoing bilateral total shoulder arthroplasty (TSA). At present, it is unknown whether success after the first TSA is predictive of success after contralateral TSA. We aimed to determine whether exceeding clinically important thresholds of success after primary TSA predicts similar outcomes for subsequent contralateral TSA. METHODS: We performed a retrospective review of a prospectively collected shoulder arthroplasty database for patients undergoing bilateral primary anatomic (aTSA) or reverse (rTSA) total shoulder arthroplasty since January 2000 with preoperative and 2- or 3-year clinical follow-up. Our primary outcome was whether exceeding clinically important thresholds in the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score for the first TSA was predictive of similar success of the contralateral TSA; thresholds for the ASES score were adopted from prior literature and included the minimal clinically important difference (MCID), the substantial clinical benefit (SCB), 30% of maximal possible improvement (MPI), and the patient acceptable symptomatic state (PASS). The PASS is defined as the highest level of symptom beyond which patients consider themselves well, which may be a better indicator of a patient's quality of life. To determine whether exceeding clinically important thresholds was independently predictive of similar success after second contralateral TSA, we performed multivariable logistic regression adjusted for age at second surgery, sex, BMI, and type of first and second TSA. RESULTS: Of the 134 patients identified that underwent bilateral shoulder arthroplasty, 65 (49%) had bilateral rTSAs, 45 (34%) had bilateral aTSAs, 21 (16%) underwent aTSA/rTSA, and 3 (2%) underwent rTSA/aTSA. On multivariable logistic regression, exceeding clinically important thresholds after first TSA was not associated with greater odds of achieving thresholds after second TSA when success was evaluated by the MCID, SCB, and 30% MPI. In contrast, exceeding the PASS after first TSA was associated with 5.9 times greater odds (95% confidence interval 2.5-14.4, P < .001) of exceeding the PASS after second TSA. Overall, patients who exceeded the PASS after first TSA exceeded the PASS after second TSA at a higher rate (71% vs. 29%, P < .001); this difference persisted when stratified by type of prosthesis for first and second TSA. CONCLUSIONS: Patients who achieve the ASES score PASS after first TSA have greater odds of achieving the PASS for the contralateral shoulder regardless of prostheses type.

Establishing the diagnosis of radial tunnel syndrome: a systematic review of published clinical series.

PURPOSE: Radial tunnel syndrome (RTS) is a controversial diagnosis due to non-specific exam findings and frequent absence of positive electromyography (EMG) and nerve conduction study (NCS) findings. The purpose of this study was to identify the methods used to diagnose RTS in the literature. METHODS: We queried PubMed, Embase, Web of Science, and Cochrane databases per PRISMA guidelines. Extracted data included article and patient characteristics, diagnostic assessments utilized and their respective findings, and treatments. Objective data were summarized descriptively. The relationship between reported diagnostic findings (i.e., physical exam and diagnostic tests) and treatments was assessed via a descriptive synthesis. RESULTS: Our review included 13 studies and 391 upper extremities. All studies utilized physical exam in diagnosing RTS; most commonly, patients had tenderness over the radial tunnel (381/391, 97%). Preoperative EMG/NCS was reported by 11/13 studies, with abnormal findings in 8.9% (29/327) of upper extremities. Steroid and/or lidocaine injection for presumed lateral epicondylitis was reported by 9/13 studies (46/295 upper extremities, 16%), with RTS being diagnosed after patients received little to no relief. It was also common to inject the radial tunnel to make the diagnosis (218/295, 74%). The most common reported intraoperative finding was narrowing of the PIN (38/137, 28%). The intraoperative compressive site most commonly reported was the arcade of Frohse (142/306, 46%). CONCLUSIONS: There is substantial heterogeneity in modalities used to diagnose RTS and the reported definition of RTS. This, in conjunction with many patients having concomitant lateral epicondylitis, makes it difficult to compare treatment outcomes for RTS. LEVEL OF EVIDENCE: Level III. Systematic review of retrospective and prospective cohort studies.

Tuberculosis treatment outcomes and patient support groups, southern India.

Objective: To assess treatment outcomes in tuberculosis patients participating in support group meetings in five districts of Karnataka and Telangana states in southern India. Methods: Tuberculosis patients from five selected districts who began treatment in 2019 were offered regular monthly support group meetings, with a focus on patients in urban slum areas with risk factors for adverse outcomes. We tracked the patients' participation in these meetings and extracted treatment outcomes from the Nikshay national tuberculosis database for the same patients in 2021. We compared treatment outcomes based on attendance of the support groups meetings. Findings: Of 30 706 tuberculosis patients who started treatment in 2019, 3651 (11.9%) attended support groups meetings. Of patients who attended at least one support meeting, 94.1% (3426/3639) had successful treatment outcomes versus 88.2% (23 745/26 922) of patients who did not attend meetings (adjusted odds ratio, aOR: 2.44; 95% confidence interval, CI: 2.10-2.82). The odds of successful treatment outcomes were higher in meeting participants than non-participants for all variables examined including: age ≥ 60 years (aOR: 3.19; 95% CI: 2.26-4.51); female sex (aOR: 3.33; 95% CI: 2.46-4.50); diabetes comorbidity (aOR: 3.03; 95% CI: 1.91-4.81); human immunodeficiency virus infection (aOR: 3.73; 95% CI: 1.76-7.93); tuberculosis retreatment (aOR: 1.69; 1.22-2.33); and drug-resistant tuberculosis (aOR: 1.93; 95% CI: 1.21-3.09). Conclusion: Participation in support groups for tuberculosis patients was significantly associated with successful tuberculosis treatment outcomes, especially among high-risk groups. Expanding access to support groups could improve tuberculosis treatment outcomes at the population level.

Carbofuran pesticide toxicity to the eye.

Pesticide exposure to eyes is a major source of ocular morbidities in adults and children all over the world. Carbofuran (CF), N-methyl carbamate, pesticide is most widely used as an insecticide, nematicide, and acaricide in agriculture, forestry, and gardening. Contact or ingestion of carbofuran causes high morbidity and mortality in humans and pets. Pesticides are absorbed in the eye faster than other organs of the body and damage ocular tissues very quickly. Carbofuran exposure to eye causes blurred vision, pain, loss of coordination, anti-cholinesterase activities, weakness, sweating, nausea and vomiting, abdominal pain, endocrine, reproductive, and cytotoxic effects in humans depending on amount and duration of exposure. Pesticide exposure to eye injures cornea, conjunctiva, lens, retina, and optic nerve and leads to abnormal ocular movement and vision impairment. Additionally, anticholinesterase pesticides like carbofuran are known to cause salivation, lacrimation, urination, and defecation (SLUD). Carbofuran and its two major metabolites (3-hydroxycarbofuran and 3-ketocarbofuran) are reversible inhibitors of acetylcholinesterase (AChE) which regulates acetylcholine (ACh), a neurohumoral chemical that plays an important role in corneal wound healing. The corneal epithelium contains high levels of ACh whose accumulation by AChE inhibition after CF exposure overstimulates muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs). Hyper stimulation of mAChRs in the eye causes miosis (excessive constriction of the pupil), dacryorrhea (excessive flow of tears), or chromodacryorrhea (red tears). Recent studies reported alteration of autophagy mechanism in human cornea in vitro and ex vivo post carbofuran exposure. This review describes carbofuran toxicity to the eye with special emphasis on corneal morbidities and blindness.

Lactic acid bacteria in the functional food industry: biotechnological properties and potential applications.

With the growing demand for functional foods having better nutraceutical properties, lactic acid bacteria (LAB) has become an important industrial microorganism. LAB play a significant role in the functional food industry by exhibiting probiotic properties and has the ability to produce various biologically active metabolites such as γ-aminobutyric acid (GABA), exopolysaccharides (EPSs), conjugated linoleic acid (CLA), bacteriocins, reuterin and reutericyclin, which provides enhanced nutraceutical properties to the final food products. LAB are also known to produce several specific enzymes essential for producing substrate-derived bioactive compounds, such as polyphenols, bioactive peptides, inulin-type fructans and ß-glucans, fatty acids, and polyols. These compounds exhibit many health benefits, including better mineral absorption, oxidative stress protection, blood glucose and cholesterol-lowering properties, prevention of gastrointestinal tract infections and improved cardiovascular function. Further, metabolically engineered LAB have been widely used for the nutritive enhancement of different food products and the application of CRISPR-Cas9 holds tremendous potential for the engineering of food cultures. This review provides an overview of the use of LAB as probiotics, its application in producing fermented foods and nutraceutical products, and its health benefits on the host.

Chronic Inhalation Exposure to Antimony Trioxide Exacerbates the MAPK Signaling in Alveolar Bronchiolar Carcinomas in B6C3F1/N Mice.

Antimony trioxide (AT) is used as a flame retardant in fabrics and plastics. Occupational exposure in miners and smelters is mainly through inhalation and dermal contact. Chronic inhalation exposure to AT particulates in B6C3F1/N mice and Wistar Han rats resulted in increased incidences and tumor multiplicities of alveolar/bronchiolar carcinomas (ABCs). In this study, we demonstrated Kras (43%) and Egfr (46%) hotspot mutations in mouse lung tumors (n = 80) and only Egfr (50%) mutations in rat lung tumors (n = 26). Interestingly, there were no differences in the incidences of these mutations in ABCs from rats and mice at exposure concentrations that did and did not exceed the pulmonary overload threshold. There was increased expression of p44/42 mitogen-activated protein kinase (MAPK) (Erk1/2) protein in ABCs harboring mutations in Kras and/or Egfr, confirming the activation of MAPK signaling. Transcriptomic analysis indicated significant alterations in MAPK signaling such as ephrin receptor signaling and signaling by Rho-family GTPases in AT-exposed ABCs. In addition, there was significant overlap between transcriptomic data from mouse ABCs due to AT exposure and human pulmonary adenocarcinoma data. Collectively, these data suggest chronic AT exposure exacerbates MAPK signaling in ABCs and, thus, may be translationally relevant to human lung cancers.

Study Design and Analysis in Hand Surgery Research: Tips for Success.

Hand surgeons are constantly faced with evaluation of new evidence to identify best practices in clinical care. However, even the most rigorous study designs have limitations due to biases, generalizability, and other flaws. Here, we highlight seven common aspects of study design and analysis that should be considered by hand surgeons when interpreting findings. The evaluation of these practices can optimize the peer-review process and assess the value of evidence to be incorporated into clinical practice.

Two-year outcomes of the reverse humeral reconstruction prosthesis.

BACKGROUND: Extensive proximal humeral bone loss in the setting of shoulder arthroplasty represents a difficult challenge for the treating surgeon. Achieving adequate fixation with standard humeral prostheses can be problematic. Allograft-prosthetic composites are a viable solution for this problem; however, high rates of complications have been reported. Modular proximal humeral replacement systems are another potential solution, but there is a paucity of outcome data on these implants. This study reports the 2-year minimum follow-up outcomes and complications of a single system reverse proximal humeral reconstruction prosthesis (RHRP) for patients with extensive proximal humeral bone loss. METHODS: We retrospectively reviewed all patients with minimum 2-year follow-up who underwent implantation of an RHRP for either (1) failed shoulder arthroplasty or (2) proximal humerus fracture with severe bone loss (Pharos 2 and 3) and/or sequelae thereof. Forty-four patients met inclusion criteria (average age 68.3 ± 13.1 years). The average follow-up was 36.2 ± 12.4 months. Demographic information, operative data, and complications were recorded. Pre- and postoperative range of motion (ROM), pain, and outcome scores were assessed and compared to the minimal clinically important difference (MCID) and substantial clinical benefit (SCB) for primary rTSA where available. RESULTS: Of the 44 RHRPs evaluated, 93% (n = 39) had undergone prior surgery and 70% (n = 30) were performed for failed arthroplasty. ROM improved significantly in abduction by 22° (P = .006) and forward elevation by 28° (P = .003). Average pain on a daily basis and pain at worst improved significantly, by 2.0 points (P < .001) and 2.7 points (P < .001), respectively. Mean Simple Shoulder Test score improved by 3.2 (P < .001), Constant score by 10.9 (P = .030), American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score by 29.7 (P < .001), University of California, Los Angeles (UCLA), score by 10.6 (P < .001), and Shoulder Pain and Disability Index score by 37.4 (P < .001). A majority of patients achieved the MCID for all outcome measures assessed (56%-81%). The SCB was exceeded by half of patients for forward elevation and the Constant score (50%), and exceeded by the majority of patients for the ASES score (58%) and UCLA score (58%). The complication rate was 28%; the most common complication was dislocation requiring closed reduction. Notably, there were no occurrences of humeral loosening requiring revision surgery. DISCUSSION: These data demonstrate that the RHRP resulted in significant improvements in ROM, pain, and patient-reported outcome measures, without the risk of early humeral component loosening. RHRP represents another potential solution for shoulder arthroplasty surgeons when addressing extensive proximal humerus bone loss.

The association between humeral lengthening and clinical outcomes after reverse shoulder arthroplasty: a systematic review and meta-analysis.

BACKGROUND: The purpose of this study was to evaluate the relationship between humeral lengthening and clinical outcomes after reverse shoulder arthroplasty (RSA) with stratification based on measurement method and implant design. METHODS: This systematic review was performed using PRISMA-P guidelines. PubMed/Medline, Cochrane Trials, and Embase were queried for articles evaluating the relationship between humeral lengthening and clinical outcomes inclusive of range of motion (ROM), strength, outcome scores, and pertinent complications (acromial and scapular spine fractures, nerve injury) after RSA. The relationship between humeral lengthening and clinical outcomes was reported descriptively overall and stratified by measurement method and implant design (globally medialized vs. lateralized). A positive association was defined as increased humeral lengthening being associated with greater ROM, outcome scores, or a greater incidence of complications, whereas a negative association denoted that increased humeral lengthening was associated with poorer ROM, outcome scores, or a lower incidence of complications. Meta-analysis was performed to compare humeral lengthening between patients with and without fractures of the acromion or scapular spine. RESULTS: Twenty-two studies were included. Humeral lengthening was assessed as the acromiohumeral distance (AHD), the distance from the acromion to the greater tuberosity (AGT), the acromion to the deltoid tuberosity (ADT), and the acromion to the distal humerus (ADH). Of 11 studies that assessed forward elevation, a positive association with humeral lengthening was found in 6, a negative association was found in 1, and 4 studies reported no association. Of studies assessing internal rotation (n = 9), external rotation (n = 7), and abduction (n = 4), all either identified a positive or lack of association with humeral lengthening. Studies assessing outcome scores (n = 11) found either a positive (n = 5) or no (n = 6) association with humeral lengthening. Of the studies that assessed fractures of the acromion and/or scapular spine (n = 6), 2 identified a positive association with humeral lengthening, 1 identified a negative association, and 3 identified no association. The single study that assessed the incidence of nerve injury identified a positive association with humeral lengthening. Meta-analysis was possible for AGT (n = 2) and AHD (n = 2); greater humeral lengthening was found in patients with fractures for studies using the AGT (mean difference 4.5 mm, 95% CI 0.7-8.3) but not the AHD. Limited study inclusion and heterogeneity prohibited identification of trends based on method of measuring humeral lengthening and implant design. CONCLUSION: The relationship between humeral lengthening and clinical outcomes after RSA remains unclear and requires future investigation using a standardized assessment method.

Effect of ultraviolet radiation on immature stages of Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus mosquitoes.

Background & objectives: Understanding the influence of ultraviolet light on organisms is important for examining the hazards of exposure to ultraviolet (UV) light. However, little is known about the biological toxicity of ultraviolet light against mosquitoes, which are regularly exposed to UV light. This study was planned to determine the impact of UV radiation on different aquatic stages of Aedes aegypti, Anopheles stephensi and Culex quinquefaciatus mosquitoes. Methods: We exposed I/II instar larvae, III/IV instar larvae and pupae of Ae. aegypti, An. stephensi and Cx. quinquefaciatus mosquitoes to UV radiation of 253 nm wavelength in a closed chamber of 30×30 cm. The exposure was done for different time intervals viz. 1, 2, 3, 4 minutes and so on. Development of larvae/pupae to adult stage was monitored daily and mortality, if any, was recorded. Results: Development of I/II instar larvae of Ae. aegypti and Cx. quinquefasciatus to pupal stage was unsuccessful at an exposure time of one minute while only 1.7% pupation occurred in I/II instar larvae of Ae. aegypti upon similar exposure. When III/IV stage larvae were exposed to UV light, pupal development occurred only at 30seconds and one-minute exposure in An. stephensi and Cx. quinquefaciatus but in Ae. aegypti, no pupation occurred with one-minute exposure. With four-minute UV exposure of pupae, no adult emerged in Ae. aegypti; 33.3% adult emerged in An. stephensi and 66.7% adult emerged in Cx. quinquefaciatus. Interpretation & conclusion: Our results show that UV radiation results in developmental arrest of Ae. aegypti, An. stephensi and Cx. quinquefaciatus mosquitoes.

Efficacy of TurmiZn, a Metallic Complex of Curcuminoids-Tetrahydrocurcumin and Zinc on Bioavailability, Antioxidant, and Cytokine Modulation Capability.

Complexes of curcumin with metals have shown much-improved stability, solubility, antioxidant capability, and efficacy when compared to curcumin. The present research investigates the relative bioavailability, antioxidant, and ability to inhibit inflammatory cytokine production of a curcuminoid metal chelation complex of tetrahydrocurcumin-zinc-curcuminoid termed TurmiZn. In vitro uptake assay using pig intestinal epithelial cells showed that TurmiZn has an ~3-fold increase (p ≤ 0.01) in uptake compared to curcumin and a ~2-fold increase (p ≤ 0.01) over tetrahydrocurcumin (THC). In a chicken model, an oral 1-g dose of TurmiZn showed a ~2.5-fold increase of a specific metabolite peak compared to curcumin (p = 0.004) and a ~3-fold increase compared to THC (p = 0.001). Oral doses (5 g/Kg) of TurmiZn in rats also showed the presence of curcumin and THC metabolites in plasma, indicating bioavailability across cell membranes in animals. Determination of the antioxidant activity by a 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) radical scavenging assay indicated that TurmiZn was about 13x better (p ≤ 0.0001) than curcumin and about 4X better (p ≤ 0.0001) than THC, in reducing free radicals. In vitro experiments further showed significant (p ≤ 0.01) reductions of lipopolysaccharide (LPS)-induced proinflammatory cytokines such as interleukin (IL) IL-6, IL-8, IL-15, IL-18, and tumor necrosis factor (TNF)-alpha, while showing a significant (p ≤ 0.01) increase of granulocyte-macrophage colony-stimulating factor (GM-CSF) in dog kidney cells. In vivo cytokine modulations were also observed when TurmiZn was fed for 6 weeks to newborn chickens. TurmiZn reduced IL-1 and IL-6, but significantly reduced (p ≤ 0.01) IL-10 levels while there was a concurrent significant (p = 0.02) increase in interferon gamma compared to controls. Overall, these results indicate that TurmiZn has better bioavailability and antioxidant capability than curcumin or THC and has the ability to significantly modulate cytokine levels. Thus, TurmiZn could be an excellent candidate for a novel ingredient that can be incorporated into food and supplements to help overall health during the aging process.

Glenoid component placement accuracy in total shoulder arthroplasty with preoperative planning and standard instrumentation is not influenced by supero-inferior glenoid erosion.

PURPOSE: Accurate glenoid component placement in total shoulder arthroplasty (TSA) remains challenging even with preoperative planning, especially for variable glenoid erosion patterns in the coronal plane. METHODS: We retrospectively reviewed 170 primary TSAs in which preoperative planning software was used. After registration of intraoperative bony landmarks, surgeons were blinded to the navigation screen and attempted to implement their plan by simulating placement of a central-axis guide pin: 230 screenshots of simulated guide pin placement were included (aTSA = 66, rTSA = 164). Displacement, error in version and inclination, and overall malposition from the preoperatively-planned target point were stratified by the Favard classification describing superior-inferior glenoid wear: E0 (n = 89); E1 (n = 81); E2 (n = 29); E3(n = 29); E4(n = 2). Malposition was considered > 10° for version/inclination errors or > 4 mm displacement from the starting point. RESULTS: Mean displacement error was 3.5 ± 2.7 mm (aTSA = 2.7 ± 2.3 mm, rTSA = 3.8 ± 2.9 mm), version error was 5.7 ± 4.7° (aTSA = 5.8 ± 4.4°, rTSA = 5.7 ± 4.8°), inclination error was 7.1 ± 5.6 (aTSA = 4.8 ± 4.8°, rTSA = 8.1 ± 5.7°), and malposition rate was 53% (aTSA = 38%, rTSA = 59%). When compared by Favard classification, there were no differences in any measure; when stratified by TSA type, version error differed for rTSAs (P = .038), with E1 having the greatest version error (6.9 ± 5.2°) and E3 the least (4.2 ± 3.4°). When comparing glenoids without wear (E0) and glenoids with superior wear (E2 and E3), the only difference was greater version error in glenoids without wear (6.0 ± 4.9° vs. 4.6 ± 3.7°, P = .041). CONCLUSIONS: Glenoid malposition did not differ based on coronal glenoid morphology. Although, malposition was relatively high, suggesting surgeons should consider alternate techniques beyond preoperative planning and standard instrumentation in TSA. LEVEL OF EVIDENCE III: Retrospective Cohort Study.

Stem Region of tRNA Genes Favors Transition Substitution Towards Keto Bases in Bacteria.

Transversion and transition mutations have variable effects on the stability of RNA secondary structure considering that the former destabilizes the double helix geometry to a greater extent by introducing purine:purine (R:R) or pyrimidine:pyrimidine (Y:Y) base pairs. Therefore, transversion frequency is likely to be lower than that of transition in the secondary structure regions of RNA genes. Here, we performed an analysis of transition and transversion frequencies in tRNA genes defined well with secondary structure and compared with the intergenic regions in five bacterial species namely Escherichia coli, Klebsiella pneumoniae, Salmonella enterica, Staphylococcus aureus and Streptococcus pneumoniae using a large genome sequence data set. In general, the transversion frequency was observed to be lower than that of transition in both tRNA genes and intergenic regions. The transition to transversion ratio was observed to be greater in tRNA genes than that in the intergenic regions in all the five bacteria that we studied. Interestingly, the intraspecies base substitution analysis in tRNA genes revealed that non-compensatory substitutions were more frequent than compensatory substitutions in the stem region. Further, transition to transversion ratio in the loop region was observed to be significantly lesser than that among the non-compensatory substitutions in the stem region. This indicated that the transversion is more deleterious than transition in the stem regions. In addition, substitutions from amino bases (A/C) to keto bases (G/T) were also observed to be more than the reverse substitutions in the stem region. Substitution from amino bases to keto bases are likely to facilitate the stable G:U pairing unlike the reverse substitution that facilitates the unstable A:C pairing in the stem region of tRNA. This work provides additional support that the secondary structure of tRNA molecule is what drives the different substitutions in its gene sequence.

Yap1-Scribble polarization is required for hematopoietic stem cell division and fate.

Yap1 and its paralogue Taz largely control epithelial tissue growth. We have identified that hematopoietic stem cell (HSC) fitness response to stress depends on Yap1 and Taz. Deletion of Yap1 and Taz induces a loss of HSC quiescence, symmetric self-renewal ability, and renders HSC more vulnerable to serial myeloablative 5-fluorouracil treatment. This effect depends on the predominant cytosolic polarization of Yap1 through a PDZ domain-mediated interaction with the scaffold Scribble. Scribble and Yap1 coordinate to control cytoplasmic Cdc42 activity and HSC fate determination in vivo. Deletion of Scribble disrupts Yap1 copolarization with Cdc42 and decreases Cdc42 activity, resulting in increased self-renewing HSC with competitive reconstitution advantages. These data suggest that Scribble/Yap1 copolarization is indispensable for Cdc42-dependent activity on HSC asymmetric division and fate. The combined loss of Scribble, Yap1, and Taz results in transcriptional upregulation of Rac-specific guanine nucleotide exchange factors, Rac activation, and HSC fitness restoration. Scribble links Cdc42 and the cytosolic functions of the Hippo signaling cascade in HSC fate determination.

Taurine and N-Bromotaurine in Topical Treatment of Psoriasis.

Psoriasis is a chronic skin auto-inflammatory and systemic disorder. Novel treatments are needed to solve a plethora of cases refractory to current treatment regimens. N-bromotaurine (TauNH-Br), a natural taurine oxidizing derivative produced by inflammatory cells, has anti-inflammatory, antiproliferative, and antimicrobial properties. This evidence prompted us to use TauNH-Br as a local agent for treatment of therapy-refractory psoriasis. Two pustular-plaque psoriasis cases, unresponsive to systemic and local treatments, one with localized lesions and one with generalized lesions, were selected. Both applications primarily indicated a sufficient curative activity of 1% TauNH-Br in psoriasis lesions. Moreover, TauNH-Br co-administration with taurine and a novel olive oil formulation cut in half the time needed for TauNH-Br alone to cause the same regression of equivalent psoriasis plaque lesions in the same patient. Importantly, all adverse effects of TauNH-Br (erythema, itching, bleeding) could be minimized by the combination therapy. Periods of 2-7 weeks to achieve almost complete regression with this formulation were remarkably short as compared to conventional treatment regimens that both patients had followed previously. Of note, there was no relapse within 3 months of monitoring. Combination formulations containing TauNH-Br and olive oil could become an advantageous topical medication for treatment of psoriasis.

Transient enhancement of p53 activity protects from radiation-induced gastrointestinal toxicity.

Gastrointestinal (GI) syndrome is a serious side effect and dose-limiting toxicity observed in patients undergoing lower-abdominal radiotherapy. Previous mouse studies show that p53 gene dosage determines susceptibility to GI syndrome development. However, the translational relevance of p53 activity has not been addressed. Here, we used a knock-in mouse in which the p53-Mdm2 negative feedback loop is genetically disrupted. These mice retain biallelic p53 and thus, normal basal p53 levels and activity. However, due to the lack of p53-mediated Mdm2 transcription, irradiated Mdm2P2/P2 mice exhibit enhanced acute p53 activity, which protects them from GI failure. Intestinal crypt cells residing in the +4 and higher positions exhibit decreased apoptosis, increased p21 expression, and hyperproliferation to reinstate intestinal integrity. Correspondingly, pharmacological augmentation of p53 activity in wild-type mice with an Mdm2 inhibitor protects against GI toxicity without affecting therapeutic outcome. Our results suggest that transient disruption of the p53-Mdm2 interaction to enhance p53 activity could be a viable prophylactic strategy for alleviating GI syndrome in patients undergoing radiotherapy.

How to Shoot and Edit High-Quality Surgical Videos for Hand and Upper Extremity Surgery.

A surgical video can improve patient care, surgical education, as well as scientific presentations and publications. Previous authors have outlined a basic understanding of how to produce high-quality surgical videos. With continuous technological improvements in video-filming hardware and editing software, multiple options for producing high-quality surgical videos are available. This article described important aspects of filming and editing videos to create a video that the surgeon can watch before performing the procedure. The authors reviewed camera terminology, including resolution, optical and digital zoom, shutter speed, and frame rate, as well as equipment options or setup for recording high-quality surgical videos. We provided information regarding computer requirements and editing on Windows and Macintosh operating systems, optimizing educational value for the viewer.

Insecticide susceptibility status of malaria vectors in Himachal Pradesh, India.

BACKGROUND & OBJECTIVES: The state of Himachal Pradesh is one of the hilly forested states of India. Warming of climate has been evidenced in the state due to the ongoing climate change which may cause the upsurge/introduction of mosquito-borne diseases. To curb disease transmission, an effective vector control strategy will be required. METHODS: Insecticide susceptibility status of available malaria vectors was determined using the standard WHO method in six districts Kangra, Una, Mandi, Bilaspur, Solan and Mandi of the state. An. culicifacies and An. fluviatilis were tested against DDT (4%), malathion (5%) and deltamethrin (0.05%) using WHO insecticide susceptibility kits. RESULTS: Overall, An. culicifacies was found resistant to DDT in all the six districts, susceptible to malathion in all districts except Bilaspur and Solan where it showed possible resistance. It was susceptible to deltamethrin in all the study districts. An. fluviatilis was resistant to DDT and susceptible to malathion and deltamethrin in Kangra and Una districts. INTERPRETATION & CONCLUSION: At present, indoor residual spraying (IRS) is not being undertaken in Himachal Pradesh. However, with the information generated through the present study, the state government can plan evidence-based IRS at least for focal spray in limited foci reporting malaria incidence.

Laboratory evaluation of the efficacy of boric acid containing toxic sugar baits against Anopheles culicifacies, An. stephensi and Aedes aegypti mosquitoes.

BACKGROUND & OBJECTIVES: Attractive toxic sugar baits (ATSB) is a novel tool which employs mosquito sugar feeding behaviour to kill them. The potential of ATSB against mosquito vectors has been demonstrated in limited scope around the world including Israel, some of the African countries and USA. But their efficacy against mosquito vectors of India is yet to be ascertained. Therefore, current study was planned to evaluate the efficacy of TSB (without attractant) against two important malaria vectors Anopheles culicifacies and An. stephensi along with major dengue vector Aedes aegypti. METHODS: TSB solution was prepared by dissolving different concentrations of boric acid in glucose and tested against each of the mosquito species. Another experiment was done by spraying this boric acid sugar solution on to Calendula officinalis plant. It served as a sole source of mosquito feed and mortality of mosquitoes was counted after 24 hours. RESULTS: The TSB resulted in 100% mortality of Ae. aegypti and An. stephensi at 4% concentration of boric acid while in An. culicifacies 100% mortality was achieved at 3% concentration TSB solution. TSB solution with 2% boric acid, resulted in 99.1% mortality in An. culicifacies while ~95 % mortality of An. stephensi and Ae. aegypti. When TSB solution with 2% boric acid was sprayed on plant, ~89-94% mortality was observed in both An. stephensi and An. culicifacies. INTERPRETATION & CONCLUSION: Based on the results, boric acid based toxic sugar bait solution could be a promising tool for vector control. Further studies are needed to find out its toxicity of TSB against non-target organisms and residual efficacy in field trials in different ecotypes.