Synthesis and biological evaluation of Halogen-Substituted novel α-Ketoamides as potential protein aggregation modulators in Alzheimer's disease.

The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aß) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from ß,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aß aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aß aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10-6 cm/s. In addition to its Aß inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aß induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23's interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.

Virtual screening and molecular dynamics investigations using natural compounds against autotaxin for the treatment of chronic pain.

Chronic pain is a common and debilitating condition with a huge social and economic burden worldwide. Currently, available drugs in clinics are not adequately effective and possess a variety of severe side effects leading to treatment withdrawal and poor quality of life. Recent findings highlight the potential role of autotaxin (ATX) as a promising novel target for chronic pain management, extending beyond its previously established involvement in arthritis and other neurological disorders, such as Alzheimer's disease. In the present study, we used a virtual screening strategy by targeting ATX against commercially available natural compounds (enamine- phenotypic screening library) to identify the potential inhibitors for the treatment of chronic pain. After initial identification using molecular docking based virtual screening, molecular mechanics (MM/GBSA), ADMET profiling and molecular dynamics simulation were performed to verify top hits. The computational screening resulted in the identification of fifteen top scoring structurally diverse hits that have free energy of binding (ΔG) values in the range of -25.792 (for compound Enamine_1850) to -74.722 Kcal/mol (for compound Enamine_1687). Moreover, the top-scoring hits have favourable ADME properties as calculated using in-silico algorithms. Additionally, the molecular dynamics simulation revealed the stable nature of protein-ligand interaction and provided information about amino acid residues involved in binding. This study led to the identification of potential autotaxin inhibitors with favourable pharmacokinetic properties. Identified hits may further be investigated for their safety and efficacy potential using in-vitro and in-vivo models of chronic pain.Communicated by Ramaswamy H. Sarma.

Dermorphin [D-Arg2, Lys4] (1-4) Amide Alleviates Frostbite-Induced Pain by Regulating TRP Channel-Mediated Microglial Activation and Neuroinflammation.

Cold injury or frostbite is a common medical condition that causes serious clinical complications including sensory abnormalities and chronic pain ultimately affecting overall well-being. Opioids are the first-choice drug for the treatment of frostbite-induced chronic pain; however, their notable side effects, including sedation, motor incoordination, respiratory depression, and drug addiction, present substantial obstacle to their clinical utility. To address this challenge, we have exploited peripheral mu-opioid receptors as potential target for the treatment of frostbite-induced chronic pain. In this study, we investigated the effect of dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a peripheral mu-opioid receptor agonist, on frostbite injury and hypersensitivity induced by deep freeze magnet exposure in rats. Animals with frostbite injury displayed significant hypersensitivity to mechanical, thermal, and cold stimuli which was significant ameliorated on treatment with different doses of DALDA (1, 3, and 10 mg/kg) and ibuprofen (100 mg/kg). Further, molecular biology investigations unveiled heightened oxido-nitrosative stress, coupled with a notable upregulation in the expression of TRP channels (TRPA1, TRPV1, and TRPM8), glial cell activation, and neuroinflammation (TNF-α, IL-1ß) in the sciatic nerve, dorsal root ganglion (DRG), and spinal cord of frostbite-injured rats. Treatment with DALDA leads to substantial reduction in TRP channels, microglial activation, and suppression of the inflammatory cascade in the ipsilateral L4-L5 DRG and spinal cord of rats. Overall, findings from the present study suggest that activation of peripheral mu-opioid receptors mitigates chronic pain in rats by modulating the expression of TRP channels and suppressing glial cell activation and neuroinflammation.

Development and validation of clinically Mimicable model of frostbite injury-induced chronic pain.

Frostbite, a debilitating condition, significantly affects the well-being of military veterans and high-altitude residents, causing severe clinical complications such as chronic pain that markedly impacts overall quality of life. There has been a notable increase in the development of pre-clinical models for studying frostbite injury, but their suitability for pain evaluation remains limited. The major hurdle in the development of novel therapeutics for the treatment of frostbite-induced chronic pain is the unavailability of well-established preclinical models. In this study, we employed deep-frozen magnets to induce frostbite injury and conducted validation for chronic pain through assessments of face, predictive, and mechanistic validity. Behavioral assays demonstrated that frostbite injury exhibited significant mechanical, thermal & cold hypersensitivity in rats. Further, molecular analysis indicated that frostbite injury triggered the activation of TRP channels (TRPA1, TRPV1 and TRPM8), microgliosis, and neuroinflammation in the dorsal root ganglion (DRG) and spinal cord of rats. Notably, NR2B protein expressions were significantly upregulated in the DRG of injured rats, while no changes were observed in spinal NR2B expressions. Furthermore, the administration of ibuprofen (25, 50, and 100 mg/kg, i.p.) resulted in a significant improvement in behavioral, biochemical, and molecular alterations in frostbite-injured rats. Overall, results suggested that established frostbite model effectively recapitulates face, pharmacological, and mechanistic validity, highlighting its potential for screening future treatment modalities and exploring the intricate mechanisms associated with frostbite-induced chronic pain.

Peripheral mu-opioid receptor activation by dermorphin [D-Arg2, Lys4] (1-4) amide alleviates behavioral and neurobiological aberrations in rat model of chemotherapy-induced neuropathic pain.

Paclitaxel, a frequently utilized chemotherapeutic agent, often gives rise to severe and distressing sensory neuropathy in patients undergoing chemotherapy. Unfortunately, current therapeutics for chemotherapy-induced neuropathic pain (CINP) demonstrate limited effectiveness and are burdened with the potential for central side effects such as sedation, respiratory depression, cognitive impairment, and addiction, posing substantial clinical challenges. In light of these limitations, present study is designed to investigate the therapeutic potential of Dermorphin [D-Arg2, Lys4] (1-4) amide (DALDA), a preferential peripherally acting mu-opioid receptor agonist, in rat model of CINP. The primary objective was to assess the analgesic properties of DALDA and elucidate the underlying mechanisms governing its therapeutic activity. Our findings revealed that DALDA treatment significantly ameliorated paclitaxel-induced evoked and spontaneous ongoing pain in rats without causing drug addiction and other central side effects. Molecular analyses further unveiled that paclitaxel administration resulted in increased expression of TRP channels, NR2B, voltage-gated sodium channels (VGSCs) and neuroinflammatory markers in both the dorsal root ganglion (DRG) and the spinal cord (L4-L5 region) of rats. DALDA treatment significantly downregulated ion channels (TRPs, VGSCs) and NR2B expressions, concomitant with the inhibition of microglial activation, resulting in the suppression of oxido-nitrosative stress and neuroinflammatory cascade. Findings from the current study suggests that peripheral mu-opioid receptors may offer a potential target for the treatment of patients suffering from CINP, offering new avenues for improved pain relief while minimizing central side effects.

Glucose regulation by newly synthesized boronic acid functionalized molecules as dipeptidyl peptidase IV inhibitor: a potential compound for therapeutic intervention in hyperglycaemia.

Management of type 2 diabetes mellitus (T2DM) using dipeptidyl peptidase IV (DPP IV) inhibitors is gaining precedence as this enzyme plays an indispensable role in cleaving and inactivating peptides, such as glucagon-like peptide-1 (GLP-1), incretin hormones, and glucose-dependent insulinotropic polypeptide (GIP). There are several DPP IV inhibitors used to treat T2DM, but limited by side effects such as disturbed GIT, flu-like symptoms, etc. Thus, there is an urgent need for the development of novel and better DPP IV inhibitors for the management of the same. In the present study, we investigated the effect of new boronic acid-based thiazole compounds as DPP IV inhibitors. We used substituted anilines that were progressively modified through a multi-step synthesis and then chemically characterised. These molecules have good binding affinity and molecular interactions at the active site of the DPP IV enzyme. Two boronic acid-based molecules, i.e. PC06R58 and PC06R108, were used for the assessment of their in-vitro enzymatic activities. Both molecules (PC06108 and PC06R58) exhibited potent uncompetitive DPP IV enzyme inhibition at two different concentrations of 90.9 and 15.6 nM, respectively, compared to sitagliptin having an IC50 of 17.3 nM. Furthermore, the oral glucose tolerance test suggested significantly reduced blood glucose levels at 20 mg/kg of the body weight upon administration of PC06R58 and PC06R108 molecules in rats after glucose ingestion (2 g/kg of the body weight). The compounds showed satisfactory DPP IV inhibition. Furthermore, DPP IV inhibitory activity and acceptable pre-ADME/Tox profile indicate it is a lead compound in this novel class of DPP IV inhibitors.Communicated by Ramaswamy H. Sarma.

Bergenin ameliorates chemotherapy-induced neuropathic pain in rats by modulating TRPA1/TRPV1/NR2B signalling.

Chemotherapy-induced neuropathic pain (CINP) is one of the most prominent and incapacitating complication associated with chemotherapeutic regimens. The exact mechanisms underlying CINP are not fully understood yet, which hampers the development of effective therapeutics. The current study has been designed to investigate the effect of bergenin on CINP and dissect the underlying cellular and molecular mechanisms. Behavioural responsiveness assays were conducted in rats before and after CINP induction and at different time points post-bergenin treatment. We also measured alterations in tight junction proteins, pro-inflammatory cytokines, microglia activity, transient receptor potential (TRP) channels (TRPV1, TRPA1 and TRPM8) and N-methyl-D-aspartate receptor subtype 2 (NR2B) in dorsal root ganglion (DRG) and spinal tissues of neuropathic rats. Bergenin treatment leads to a significant and dose-dependent reduction in evoked and spontaneous ongoing pain without causing central side effects in neuropathic rats. Furthermore, treatment with bergenin and gabapentin did not affect the baseline pain threshold in healthy, non-chemotherapy-treated rats, as evaluated through tail-flick and tail-clip assays. Chemotherapy administration leads to a significant activation of TRP channels, concurrent with microglial activation, disruption of spinal cord tight junction proteins, and subsequent infiltration of pro-inflammatory cytokines, as well as NR2B activation. Notably, bergenin treatment effectively reversed all of these alterations, with the exception of TRPM8, in both the DRG and spinal cord of neuropathic rats. Findings from the present study suggests that bergenin mitigates neuropathic pain by modulating the TRPA1/TRPV1/NR2B signalling and presents a promising therapeutic avenue for the treatment of chemotherapy-induced neuropathic pain.

Loperamide, a peripheral Mu-Opioid receptor agonist, attenuates chemotherapy-induced neuropathic pain in rats.

Opioids are employed in the management of chemotherapy-induced neuropathic pain (CINP) when other pain management approaches have failed and proven ineffective. However, their use in CINP is generally considered as a second-line or adjunctive therapy owing to their central side effects and development of tolerance with their long-term usage. Targeting peripheral sites may offer several advantages over the conventional CNS-based approaches as peripheral targets modulate pain signals at their source, thereby relieving pain with higher specificity, efficacy and minimizing adverse effects associated with off-site CNS actions. Therefore, present study was designed with an aim to investigate the effect of loperamide, a peripherally acting mu-opioid receptor agonist, on paclitaxel-induced neuropathic pain in rats and elucidate its underlying mechanism. Loperamide treatment significantly attenuated mechanical, and cold hypersensitivity and produced significant place preference behaviour in neuropathic rats indicating its potential to treat both evoked and spontaneous pain. More importantly, loperamide treatment in naïve rats did not produce place preference to drug-paired chamber pointing towards its non-addictive analgesic potential. Further, molecular investigations revealed increased expression of ion channels such as TRPA1, TRPM8; voltage-gated sodium channels (VGSCs) and neuroinflammatory markers in the dorsal root ganglion (DRG) and lumbar (L4-L5) spinal cord of neuropathic rats, which was significantly downregulated upon loperamide treatment. These findings collectively suggest that activation of peripheral mu-opioid receptors contributes to the amelioration of both evoked and spontaneous pain in neuropathic rats by downregulating TRP channels and VGSCs along with suppression of oxido-nitrosative stress and neuroinflammatory cascade.

Unusually high clarithromycin resistance in Mycobacterium abscessus subsp. abscessus isolated from human gastric epithelium.

Mycobacterium abscessus subsp. abscessus is a rapidly growing facultative intracellular pathogen that usually infects human lung and skin epithelium. Recently, we and another group have shown that it also has the potential to colonize human gastric epithelium, but its significance with respect to gastric diseases remains unclear. Although Helicobacter pylori still remains the only definite gastric pathogen, recent studies have shown that M. abscessus subsp. abscessus also has the potential to colonize human gastric epithelium. M. abscessus subsp. abscessus is known to exhibit multidrug resistance and clarithromycin has been used as the drug of choice. We aimed to determine the clarithromycin resistance profile of 117 (74 rough and 43 smooth) gastric M. abscessus subsp. abscessus strains and to detect the point mutations in rrl and erm (41) genes conferring the resistance. Our data showed 79.48% (19 smooth and 74 rough) of M. abscessus subsp. abscessus strains were resistant to clarithromycin (MIC90 ≤ 512 µg/mL), while 20.51% (24 smooth) were susceptible (MIC90 ≤ 8 µg/mL). Nucleotide sequence analysis of the rrl gene with reference strains of M. abscessus subsp. abscessus did not show any mutation that is relevant to the clarithromycin resistance. However, analysis of erm (41) gene showed that M. abscessus subsp. abscessus strains, which were susceptible to clarithromycin had C, C, G, and C at their nucleotide positions 28, 159, 238, and 330, respectively, while the resistant strains showed T, T, A, and A at the same positions. Based on antibiogram and sequence analysis data we recommend further studies involving genomic analysis to identify the other genes involved in high clarithromycin resistance in gastric M. abscessus subsp. abscessus along with the mechanisms involved.

Disentangling the enigmatic role of ephrin signaling in chronic pain: Moving towards future anti-pain therapeutics.

Chronic pain is a common and debilitating condition with a huge social and economic burden worldwide. Currently, available drugs in clinics are not adequately effective and possess a variety of severe side effects leading to treatment withdrawal and poor quality of life. The ongoing search for new therapeutics with minimal side effects for chronic pain management remains a high research priority. Erythropoietin-producing human hepatocellular carcinoma cell receptor (Eph) is a tyrosine kinase receptor that is involved in neurodegenerative disorders, including pain. The Eph receptor interacts with several molecular switches, such as N methyl d-aspartate receptor (NMDAR), mitogen-activated protein kinase (MAPK), calpain 1, caspase 3, protein kinase a (PKA), and protein kinase Cy (PKCy), which in turn regulates pathophysiology of chronic pain. Here we highlight the emerging evidence of the Ephs/ephrin system as a possible near-future therapeutic target for the treatment of chronic pain and discuss the various mechanism of its involvement. We critically analyse the present status of Eph receptor system and conclude that extrapolating the pharmacological and genetic approaches using a strong therapeutic development framework could serve as next-generation analgesics for the management of chronic pain.

Unlocking the potential of TRPV1 based siRNA therapeutics for the treatment of chemotherapy-induced neuropathic pain.

Chemotherapy-induced neuropathic pain (CINP) is among the most common clinical complications associated with the use of anti-cancer drugs. CINP occurs in nearly 68.1% of the cancer patients receiving chemotherapeutic drugs. Most of the clinically available analgesics are ineffective in the case of CINP patients as the pathological mechanisms involved with different chemotherapeutic drugs are distinct from each other. CINP triggers the somatosensory nervous system, increases the neuronal firing and activation of nociceptive mediators including transient receptor protein vanilloid 1 (TRPV1). TRPV1 is widely present in the peripheral nociceptive nerve cells and it has been reported that the higher expression of TRPV1 in DRGs serves a critical role in the potentiation of CINP. The therapeutic glory of TRPV1 is well recognized in clinics which gives a promising insight into the treatment of pain. But the adverse effects associated with some of the antagonists directed the scientists towards RNA interference (RNAi), a tool to silence gene expression. Thus, ongoing research is focused on developing small interfering RNA (siRNA)-based therapeutics targeting TRPV1. In this review, we have discussed the involvement of TRPV1 in the nociceptive signaling associated with CINP and targeting this nociceptor, using siRNA will potentially arm us with effective therapeutic interventions for the clinical management of CINP.

Natural Products and some Semi-synthetic Analogues as Potential TRPV1 Ligands for Attenuating Neuropathic Pain.

Natural products and leads inspired by them have acted as a probe for successful drug discovery for many decades. Pain is an obnoxious sensory and emotional experience associated with potential tissue damage. It affects the quality of life of patients to a greater extent. Despite the availability of several agents targeting TRP receptors, none of them can proficiently alleviate neuropathic pain. TRPV1 is a prospective target for treating neuropathic pain as it is recognized to modulate the pain circuitry at the periphery and the central level. In this review, we have discussed several natural molecules, such as Capsaicinoids, Capsinoids, Piperine, Eugenol, Scutigeral, Ginsenosides, Cinnamaldehyde, Camphor, Shogaol, Gingerols, Zingerone, Allicin, Evodiamine, Allylisothiocyanate, Cannabidiol, Ricinoleic acid, Isovelleral, Capsazepine, Thapsigargin, Pellitorine, Yohimbine, Curcumin and some semi-synthetic analogues that activate TRPV1 channels and consequently, can be further harnessed for the treatment of neuropathic pain.

Multifarious Targets and Recent Developments in the Therapeutics for the Management of Bone Cancer Pain.

Bone cancer pain (BCP) is a distinct pain state showing characteristics of both neuropathic and inflammatory pain. On average, almost 46% of cancer patients exhibit BCP with numbers flaring up to as high as 76% for terminally ill patients. Patients suffering from BCP experience a compromised quality of life, and the unavailability of effective therapeutics makes this a more devastating condition. In every individual cancer patient, the pain is driven by different mechanisms at different sites. The mechanisms behind the manifestation of BCP are very complex and poorly understood, which creates a substantial barrier to drug development. Nevertheless, some of the key mechanisms involved have been identified and are being explored further to develop targeted molecules. Developing a multitarget approach might be beneficial in this case as the underlying mechanism is not fixed and usually a number of these pathways are simultaneously dysregulated. In this review, we have discussed the role of recently identified novel modulators and mechanisms involved in the development of BCP. They include ion channels and receptors involved in sensing alteration of temperature and acidic microenvironment, immune system activation, sodium channels, endothelins, protease-activated receptors, neurotrophins, motor proteins mediated trafficking of glutamate receptor, and some bone-specific mechanisms. Apart from this, we have also discussed some of the novel approaches under preclinical and clinical development for the treatment of bone cancer pain.

Episymbiotic Saccharibacteria suppresses gingival inflammation and bone loss in mice through host bacterial modulation.

Saccharibacteria (TM7) are obligate epibionts living on the surface of their host bacteria and are strongly correlated with dysbiotic microbiomes during periodontitis and other inflammatory diseases, suggesting they are putative pathogens. However, due to the recalcitrance of TM7 cultivation, causal research to investigate their role in inflammatory diseases is lacking. Here, we isolated multiple TM7 species on their host bacteria from periodontitis patients. These TM7 species reduce inflammation and consequential bone loss by modulating host bacterial pathogenicity in a mouse ligature-induced periodontitis model. Two host bacterial functions involved in collagen binding and utilization of eukaryotic sialic acid are required for inducing bone loss and are altered by TM7 association. This TM7-mediated downregulation of host bacterial pathogenicity is shown for multiple TM7/host bacteria pairs, suggesting that, in contrast to their suspected pathogenic role, TM7 could protect mammalian hosts from inflammatory damage induced by their host bacteria.

Helicobacter pylori in Human Stomach: The Inconsistencies in Clinical Outcomes and the Probable Causes.

Pathogenic potentials of the gastric pathogen, Helicobacter pylori, have been proposed, evaluated, and confirmed by many laboratories for nearly 4 decades since its serendipitous discovery in 1983 by Barry James Marshall and John Robin Warren. Helicobacter pylori is the first bacterium to be categorized as a definite carcinogen by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO). Half of the world's population carries H. pylori, which may be responsible for severe gastric diseases like peptic ulcer and gastric cancer. These two gastric diseases take more than a million lives every year. However, the role of H. pylori as sole pathogen in gastric diseases is heavily debated and remained controversial. It is still not convincingly understood, why most (80-90%) H. pylori infected individuals remain asymptomatic, while some (10-20%) develop such severe gastric diseases. Moreover, several reports indicated that colonization of H. pylori has positive and negative associations with several other gastrointestinal (GI) and non-GI diseases. In this review, we have discussed the state of the art knowledge on "H. pylori factors" and several "other factors," which have been claimed to have links with severe gastric and duodenal diseases. We conclude that H. pylori infection alone does not satisfy the "necessary and sufficient" condition for developing aggressive clinical outcomes. Rather, the cumulative effect of a number of factors like the virulence proteins of H. pylori, local geography and climate, genetic background and immunity of the host, gastric and intestinal microbiota, and dietary habit and history of medicine usage together determine whether the H. pylori infected person will remain asymptomatic or will develop one of the severe gastric diseases.

Posterior hip dislocation associated with concomitant ipsilateral femoral head and shaft fractures: an unusual combination of injuries.

The combination of posterior hip dislocation with an ipsilateral femoral head and shaft fractures is unusual. While cases of concomitant fractures of femoral head and shaft have been previously reported, the treatment of such injuries is challenging. Presence of an associated hip dislocation further complicates the matter. A timely diagnosis and treatment are crucial to have a good outcome.We are presenting the case of a 20-year-old man who sustained a traumatic posterior hip dislocation with ipsilateral femoral shaft and femur head fractures. After reducing the hip, we fixed the femoral shaft with a retrograde femur nail and the femoral head by the trochanteric flip approach in the same sitting. The patient returned to his pre-injury occupation after 4 months. He has been doing well until his last follow-up, 1 year after the surgery, thus emphasising the utility of following basic principles of trauma management in the management of unusual injuries.

Low Bifidobacterium Abundance in the Lower Gut Microbiota Is Associated With Helicobacter pylori-Related Gastric Ulcer and Gastric Cancer.

Helicobacter pylori infection in stomach leads to gastric cancer, gastric ulcer, and duodenal ulcer. More than 1 million people die each year due to these diseases, but why most H. pylori-infected individuals remain asymptomatic while a certain proportion develops such severe gastric diseases remained an enigma. Several studies indicated that gastric and intestinal microbiota may play a critical role in the development of the H. pylori-associated diseases. However, no specific microbe in the gastric or intestinal microbiota has been clearly linked to H. pylori infection and related gastric diseases. Here, we studied H. pylori infection, its virulence genes, the intestinal microbiota, and the clinical status of Trivandrum residents (N = 375) in southwestern India by standard H. pylori culture, PCR genotype, Sanger sequencing, and microbiome analyses using Illumina Miseq and Nanopore GridION. Our analyses revealed that gastric colonization by virulent H. pylori strains (vacAs1i1m1cagA+) is necessary but not sufficient for developing these diseases. Conversely, distinct microbial pools exist in the lower gut of the H. pylori-infected vs. H. pylori-non-infected individuals. Bifidobacterium (belonging to the phylum Actinobacteria) and Bacteroides (belonging to the phylum Bacteroidetes) were present in lower relative abundance for the H. pylori+ group than the H. pylori- group (p < 0.05). On the contrary, for the H. pylori+ group, genus Dialister (bacteria belonging to the phylum Firmicutes) and genus Prevotella (bacteria belonging to the phylum Bacteroidetes) were present in higher abundance compared to the H. pylori- group (p < 0.05). Notably, those who carried H. pylori in the stomach and had developed aggressive gastric diseases also had extremely low relative abundance (p < 0.05) of several Bifidobacterium species (e.g., B. adolescentis, B. longum) in the lower gut suggesting a protective role of Bifidobacterium. Our results show the link between lower gastrointestinal microbes and upper gastrointestinal diseases. Moreover, the results are important for developing effective probiotic and early prognosis of severe gastric diseases.

Comparison of functional outcomes among subtypes of Fraser's type â ¡ floating knee.

PURPOSE: The poor prognosis in patients with floating knee injuries is mainly contributed to articular involvement (Fraser's type Ⅱ). This study aims to evaluate and compare the functional outcomes among different Fraser's type Ⅱ floating knee injuries after surgical management. METHODS: Twenty-seven patients with Fraser's type Ⅱ floating knee injuries (54 fractures) between September 2014 and December 2015 were enrolled prospectively in this study and were distributed according to Fraser's floating knee classification into three different groups as type ⅡA (ipsilateral femoral shaft and tibial intra-articular involvement, n = 11), type ⅡB (ipsilateral tibial shaft and femoral intra-articular involvement, n = 9) and type ⅡC (both femoral and tibial intra-articular involvement, n = 7). The differences among the groups were evaluated and compared. The functional outcomes of these injuries at one year were analyzed using Knee Injury and Osteoarthritis Outcome Score (KOOS) which covers 5 subscales of pain, other symptoms, activities of daily living, sports and recreation, and quality of life. The result was also compared with standardized age-sex matched healthy population using paired samples t-test. RESULTS: All the patients were male, and the injury mechanism was solely roadside accident. The mean age was 29.8 years and injury severity score 17.9 (comparable in all the three groups). Most injuries were observed on the right side (20 cases, 74.1%). Based on paired samples t-test, the KOOS score of patients with Fraser's type ⅡA was found to be better than that of type ⅡB and type ⅡC. Compared with the reference age-sex matched control group, patients with Fraser's type ⅡB and ⅡC fractures had significantly lower mean score in all KOOS subscales (all p < 0.01). However, Fraser's type ⅡA only revealed significant difference regarding the subscales of activities of daily living (p < 0.0001), sports and recreation (p < 0.0001), and quality of life (p < 0.0001). CONCLUSION: The results of this study show that patients with Fraser's type ⅡA fractures had a better functional outcome as compared to those with type ⅡB and ⅡC fractures. This might be due to the open intra-articular involvement of the distal femur of the latter two fracture types.

Unilateral carpal tunnel syndrome: an unusual presentation of nodular fasciitis.

Nodular fasciitis is a benign, self-limiting proliferative disorder of fibroblast of uncertain aetiology, occurs frequently in the forearm. Nodular fasciitis in hand inducing carpal tunnel syndrome is exceptional. There are four cases of non-intraneural nodular fasciitis causing peripheral neuropathy that has been reported previously. We present the case of a 38-year-old man with features of unilateral carpal tunnel syndrome. Decompression of the median nerve performed subsequently along with excision of the lesion in a piecemeal fashion. Histopathological and immunohistochemical findings were consistent with nodular fasciitis. There were complete resolution of symptoms and no sign of recurrence at the end of 1 year after surgery.

Kienböck's disease: Where do we stand?

Avascular necrosis of the lunate, commonly known as Kienböck's disease is a disorder that can lead to carpal collapse and the need for surgeries, which can stabilize the wrist. There are different associations with the disease but the exact etiology is unknown. Kienböck's disease is believed to result from mechanical and vascular factors in genetically predisposed individuals. The newer classification based on advanced wrist arthroscopy and MRI help in a better understanding of the disease, early diagnosis, and treatment. A review of recent literature regarding newer treatment options has shown good results in the early stages of osteonecrosis. This article intends to review an update on the etiopathogenesis, classification, and the current advanced treatment options.