Monkeypox outbreak 2022: What we know so far and its potential drug targets and management strategies

Monkeypox is a rare zoonotic disease caused by infection with the monkeypox virus. The disease can result in flu-like symptoms, fever, and a persistent rash. The disease is currently spreading throughout the world and prevention and treatment efforts are being intensified. Although there is no treatment that has been specifically approved for monkeypox virus infection, infected patients may benefit from using certain antiviral medications that are typically prescribed for the treatment of smallpox. The drugs are tecovirimat, brincidofovir, and cidofovir, all of which are currently in short supply due to the spread of the monkeypox virus. Resistance is also a concern, as widespread replication of the monkeypox virus can lead to mutations that produce monkeypox viruses that are resistant to the currently available treatments. This article discusses monkeypox disease, potential drug targets, and management strategies to overcome monkeypox disease. With the discovery of new drugs, it is hoped that the problem of insufficient drugs will be resolved, and it is not anticipated that drug resistance will become a major issue in the near future.     

Screening for depression in African-Caribbean elders

BACKGROUND: There are increasing numbers of older African-Caribbeans in the UK. Primary care staff often feel less confident about diagnosing depression in this group. Screening instruments may assist in making diagnoses in cross-cultural consultations. OBJECTIVE: We aimed to determine the sensitivity and specificity of screening instruments for depression in older African-Caribbean people in Manchester, UK. METHODS: We carried out a two-stage study to compare three screening instruments for depression (Geriatric Depression Scale, Brief Assessment Schedule Depression Cards, Caribbean Culture Specific Screen), with a computerized diagnostic interview for mental health disorders in older adults (Geriatric Mental State). The study was set in inner-city Manchester. The subjects were community-resident African-Caribbeans aged 60 years and over; 227 subjects were approached. Of the 160 people screened, 130 agreed to diagnostic interview. The main outcome measures were Spearman correlation coefficients; these were calculated between each screening instrument and the diagnostic interview. Receiver-operating characteristic (ROC) curve analysis was used to determine appropriate sensitivity and specificity for each instrument. RESULTS: The results for the largest subgroup, the Jamaicans (n = 96/130), demonstrated highly significant correlations between screening instruments and diagnostic interview (P < 0.001). Each instrument had a high sensitivity: Brief Assessment Schedule depression cards (cut-off > or =6; sensitivity 90.9% (95% CI 58.8-99.8), specificity 82.1% (95% CI 74.0-90.3)), Caribbean Culture Specific Screen (cut-off > or =6; sensitivity 90.9% (95% CI 58.8-99.8), specificity 74.1% (95% CI 64.8-83.4)), and Geriatric Depression Scale (cut-off > or =4; sensitivity 100% (95% CI 97.1-100), specificity 69.1% (95% CI 59.6-79.2)). CONCLUSIONS: These screening instruments demonstrate high sensitivity levels, if an appropriate cut-off point is used. The culture-specific instrument did not perform better than the traditional instruments. Health professionals should approach the consultation in a culturally sensitive manner and use the validated instrument they are most familiar with.     

Naphthylphthalamic acid associates with and inhibits PIN auxin transporters

N-1-naphthylphthalamic acid (NPA) is a key inhibitor of directional (polar) transport of the hormone auxin in plants. For decades, it has been a pivotal tool in elucidating the unique polar auxin transport-based processes underlying plant growth and development. Its exact mode of action has long been sought after and is still being debated, with prevailing mechanistic schemes describing only indirect connections between NPA and the main transporters responsible for directional transport, namely PIN auxin exporters. Here we present data supporting a model in which NPA associates with PINs in a more direct manner than hitherto postulated. We show that NPA inhibits PIN activity in a heterologous oocyte system and that expression of NPA-sensitive PINs in plant, yeast, and oocyte membranes leads to specific saturable NPA binding. We thus propose that PINs are a bona fide NPA target. This offers a straightforward molecular basis for NPA inhibition of PIN-dependent auxin transport and a logical parsimonious explanation for the known physiological effects of NPA on plant growth, as well as an alternative hypothesis to interpret past and future results. We also introduce PIN dimerization and describe an effect of NPA on this, suggesting that NPA binding could be exploited to gain insights into structural aspects of PINs related to their transport mechanism.

Many aspects of plant growth are controlled by the hormone auxin. A distinct feature of auxin is that its hormonal action requires it to be actively transported between cells and ultimately throughout the whole plant in a controlled directional or polarized manner, a process known as polar auxin transport (PAT). The ability of plants to perform PAT is ascribed to the auxin export activity of PIN transporters (1). Plasma membrane PINs can be restricted to a specific side of cells (2), and when this polarity is maintained in continuous plant cell files, the combined activity of identically localized PINs results in auxin flowing in that direction (3). This lays the vectorial foundations for PAT to create local auxin gradients and plant-wide PAT streams that are critical for auxin action and normal plant growth (4, 5).Synthetic PAT inhibitors such as N-1-naphthylphthalamic acid (NPA) were initially developed as herbicides and then subsequently exploited by researchers to identify and characterize the unique PAT-based mechanisms that drive plant development (6). Having been used for over six decades, the question as to how NPA actually inhibits PAT has been keenly pursued. Several putative modes of action have been proposed, but the topic remains to date not fully or satisfactorily resolved (6).Early studies established NPA binding with high affinity to membrane-integral components of plant membranes (7–10). With the later discovery of pin1 mutants bearing their distinct bare inflorescences reminiscent of NPA-treated plants (11), followed by identification of the PIN gene family and gradual confirmation that PINs were NPA-sensitive auxin transporters that mediated PAT (1–5), it was apparent that the physiological and genetic evidence overwhelmingly linked NPA to inhibition of PIN activity (6). However, direct molecular association of NPA with PINs has never been reported (6). Instead, a substantial body of data has accumulated suggesting that the NPA target is not PIN itself, but rather other proteins or complexes that either actively coparticipate in PAT or are indirectly involved in control of PAT components (6, 12). Members of the B-family of ABC transporters, such as ABCB1 and ABCB19, showed high-affinity NPA binding and NPA-sensitive auxin export (1, 12–15), thus leading to proposals that they may either physically interact with PINs, or functionally interact such that their nonpolar auxin export activity contributes to PAT and/or to regulation of PINs (12, 16). In these scenarios, PIN/PAT would be rendered vulnerable to the NPA sensitivity of ABCB. However, these schemes are not yet fully resolved, are not fully consistent with key genetic and physiological data (6), and are particularly obfuscated by ABCB1/19 functioning both interactively and independently from PINs (1, 12, 15–20), with ABCB-PIN interaction occurring in an as-yet-unclarified manner (15, 18).A further twist in assigning ABCBs as the main NPA target is their regulation by their chaperone TWD1/FKBP42 (14, 16), with TWD1 itself also being an NPA-binding protein (14, 17). NPA interferes with this regulation and affects TWD1-ABCB interaction, but curiously NPA cannot bind stably to the ABCB-TWD1 complex (14, 17). As TWD1 has also been implicated in NPA-sensitive actin-based PIN trafficking (17), this has led to a model proposing that TWD1 could mediate the NPA sensitivities of both ABCB and PINs, thus presenting TWD1 as a modulator of PAT (17, 21). In an analogous scheme in some plant species, CYPA immunophilins such as tomato DGT, which are functionally similar to TWD1/FKBP42, are suggested to replace TWD1 in modulating auxin transporters and transducing NPA effects to PINs (12, 21).Similar to TWD1, BIG/TIR3 has also been associated with NPA and PIN trafficking (22). Given the undisputed role of trafficking in controlling PIN polarity (5), these reported effects warrant attention, although they are inconsistent with other reports that NPA perturbs neither vesicular trafficking nor actin dynamics in conditions where auxin transport is inhibited (23, 24). Together with trafficking, phosphorylation is another key modulator of PIN polarity as well as activity (5), so it is not surprising to find hypotheses suggesting that NPA could interfere with critical phosphorylation events (6), particularly as PID, a kinase crucial for PIN trafficking and activation, has also been connected to ABCB function and TWD1/ABCB/NPA interactions (25). Others propose that NPA may mimic natural compounds in their capacity as endogenous regulators of PAT, with plant flavonoids being suspected candidates (6, 26). Since flavonoids can compete with or inhibit ATP-binding in mammalian kinases and ABC transporters (27, 28), and as flavonoids can bind to and inhibit PID (25), a phosphorylation-based NPA mode of action would overlap with this hypothesis and poses the question whether NPA acts similarly as an ATP mimic.With these many potential NPA-affected pathways, there is a need to distinguish between low- and high-affinity NPA targets and possible secondary effects due to prolonged PAT inhibition. Current consensus is that low concentrations of NPA (<10 µM) cause direct inhibition of auxin transporters in PAT (21) and the consequent physiological effects seen in planta (IC₅₀ 0.1 to 10 µM) (7, 9, 19, 23, 29). This is associated with high-affinity binding to membranes (K_d 0.01 to 0.1 µM) (7, 8) and the inhibition of PIN/ABCB activity in short-term auxin transport assays (1, 14, 18, 20, 23). In contrast, NPA is thought to affect trafficking (21, 30) and other non-PAT processes (31) when used at higher doses (50 to 200 µM NPA), presumably via binding to its lower-affinity targets, although excessive NPA exposure may also have fast-acting toxic side effects (23). As the in vitro affinity of TWD1 for NPA is surprisingly low (K_d ∼100 µM) (17), the TWD1-mediated NPA effects on PIN/PAT are thought to be of the low-affinity type and linked to trafficking perturbations (17, 21). However, as NPA is always externally applied to plants or cells, it is not clear how or where the drug distributes or accumulates, and thus there may be discrepancies between actual and reported/apparent effective concentrations, as might be the case for TWD1 (17). Finally, NPA also binds with low affinity to inhibit APM1, an aminopeptidase implicated in auxin-related plant growth, but as with trafficking effects, this low-affinity NPA interaction is not connected to direct regulation of PAT (31).Thus, the available data proffer various indirect mechanisms that could lead to NPA inhibition of PIN-mediated PAT, but the proposed schemes have complicating aspects and struggle at times to satisfactorily explain the prime effects of NPA. Here we propose an alternative simpler scenario involving a more direct link between NPA and PINs that would resolve some of these currently outstanding issues. We present evidence from heterologous transport assays, classical in situ membrane binding, and oligomerization studies which collectively suggest that NPA can interact directly in a high-affinity manner with PINs, leading to conformational or structural effects and inhibition of auxin export activity.     

Effect of storage time on metabolite profile and alpha-glucosidase inhibitory activity of Cosmos caudatus leaves – GCMS based metabolomics approach

Cosmos caudatus, which is a commonly consumed vegetable in Malaysia, is locally known as “Ulam Raja”. It is a local Malaysian herb traditionally used as a food and medicinal herb to treat several maladies. Its bioactive or nutritional constituents consist of a wide range of metabolites, including glucosinolates, phenolics, amino acids, organic acids, and sugars. However, many of these metabolites are not stable and easily degraded or modified during storage. In order to investigate the metabolomics changes occurring during post-harvest storage, C. caudatus samples were subjected to seven different storage times (0 hours, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, and 12 hours) at room temperature. As the model experiment, the metabolites identified by gas chromatography-mass spectrometry (GC-MS) were correlated with α-glucosidase inhibitory activity analyzed with multivariate data analysis (MVDA) to find out the variation among samples and metabolites contributing to the activity. Orthogonal partial least squares (OPLS) analysis was applied to investigate the metabolomics changes. A profound chemical alteration, both in primary and secondary metabolites, was observed. The α-tocopherol, catechin, cyclohexen-1-carboxylic acid, benzoic acid, myo-inositol, stigmasterol, and lycopenecompoundswerefoundtobethediscriminatingmetabolitesatearlystorage;however, sugars such as sucrose, α-d-galactopyranose, and turanose were detected, which was attributed to the discriminating metabolites for late storage. The result shows that the MVDA method is a promising technique to identify biomarker compounds relative to storage at different times.     

Expression of iron absorption genes in mouse large intestine

OBJECTIVE: The large intestine has been reported to have a capacity for iron absorption and expresses genes for iron absorption normally found in the duodenum. The importance and function of these genes in the large intestine are not understood. We therefore investigated the cellular localization and regulation of expression of these genes in mouse caecum and colon. MATERIAL AND METHODS: Gene expression was measured by real-time PCR using RNA extracted from iron-deficient and hypoxic mouse large intestine, compared to controls. Protein localization and regulation were measured by immunohistochemistry using frozen sections of the large intestine from the same mice. RESULTS: Dcytb (duodenal ferric reductase) was expressed at very low levels in the large intestine, compared to the duodenum, while Ireg1 and DMT1 were expressed at significant levels in the large intestine and were increased in iron-deficient caecum, proximal and distal colon, with the most significant increases seen in the distal colon. Hypoxia increased Ireg1 expression in the proximal colon. Immunohistochemistry detected significant levels of only IREG1, which was localized to the basolateral membrane of colonic epithelial cells. CONCLUSIONS: Iron absorption genes were expressed at lower levels in mouse caecum and colon than in the duodenum. They are regulated by body iron requirements. Colonic epithelial cells express basolateral IREG1in the same fashion as in the duodenum and this protein could regulate colonic epithelial cell iron levels.     

Effect of propranolol vs prednisolone vs propranolol with prednisolone in the management of infantile hemangioma: A randomized controlled study

Aims and Objectives

The purpose of this study was to compare the efficacy of orally administered propranolol versus prednisolone versus both in the treatment of potentially disfiguring or functionally threatening infantile hemangiomas.

Material and Methods

A prospective study of 30 patients aged 1 week–8 months was randomized into three equal groups. These were as follows: A, propranolol (2–3 mg/kg/d); B, prednisolone (1–4 mg/kg/d); and C, receiving both for a minimum duration of 3 months. Dimensions, color, consistency, ultrasonography, photographic documentation based on Visual Analogue Scale (VAS) were recorded before and periodically after starting treatment. A minimum 75% improvement was considered as success with no regrowth up to 1 month of stopping treatment.

Results

Mean initial response time (days) in A (4.1 ± 3.3 SD) and C (4.7 ± 3.4SD) was significantly lower than B (9.78 ± 7.8SD) (p < 0.047). Significant change in consistency was noted very early in A (24 hours) compared to B and C (8 days). VAS results are as follows: (a) color fading—significant reduction in A within 48 hours compared to B and C (p = 0.025), (b) flattening—more significant and earlier in A and C than B (p < 0.05), and (c) mean reduction in size: significant in A and C at 3 months (p = 0.005, p = 0.005), 6 months (p = 0.005, p = 0.008), 12 months (p = 0.005, p = 0.008), and 18 months (p = 0.02, p = 0.04), whereas in B, it was seen only at 6 months (p = 0.008).

Conclusions

Propranolol had a consistent, rapid therapeutic effect compared to prednisolone. A combination of the two had a comparable but not higher efficacy than propranolol alone. Prednisolone was associated with a higher number of complications, thereby decreasing patient compliance.     

颅内动脉瘤栓塞后并发脑缺血的原因分析

1 临床资料我们总结2004-02/2004-06在第四军医大学唐都医院神经外科住院行栓塞治疗颅内动脉瘤患者27(男12,女15)例,年龄32～72岁.