Online ISSN: 2515-8260

Keywords : Inflammation

Evaluating a herbal formulation for particulate matter induced lung tissue degeneration in wistar rat

Pooja Sharma, Era Upadhyay

European Journal of Molecular & Clinical Medicine, 2023, Volume 10, Issue 2, Pages 1472-1477

Particulate Matter (PM) is the biggest challenge for human health as the lungs shows its deleterious impacts even in early pathogenesis. It is imperative to treat the lung tissues with effective and with minimum side effects of the medicine. This study is carried out to evaluate a herbal formulation which included eight plant samples ‘Angelica archangelica (leaf), Dioscorea bulbifera (Root), Fagopyrum dibotrys (Root), Myrtus communis Linn (Leaf), Nasturtum offcinalea  (whole Plant), Perilla frutescens (Leaf and Seed), Catharanthus roseus (Whole Plant) and Solanum xanthocarpum (Root). The therapeutic actions were observed against particulate matter concentrations (artificially generated PM exposure) induced lungs tissue degeneration at various dose 100, 200 and 400 mg/kilogram in wistar albino rats for 30 days. Blood sample collected terminally on 30th day has been gone through the hematology test. All surviving animals have been euthanized by high dose of anaesthetics and subjected to a lung necropsy examination at the end of the treatment period Differential cell count in blood have been analysed.  As well as in Bronchoalveolar lavage fluid (BALF) also. That has been reduced progressively in all test groups (<0.05, <0.01, <0.001). Histopathology of the lungs reflected inflammatory changes, deform alveolar space, edema and condense of the intra-bronchial wall. In the induced control group and in the treatment group @ doses of 100, 200, and 400 mg/kilogram progressive reduced inflammation alveolar space, and edema. The results showed that the formulation was found therapeutic active against degenerated lung tissue induced by particulate matter in wistar albino rats most effective at a dose of 400 mg/kilogram during 30 days.

Cannabinoids in Inflammatory Modulation of Allergic Respiratory Disorders and its Pharmacotherapeutic Approaches to central Respiratory disorders

Aruna Gundluru, Debanjan Mitra, Dr. K.S.Bhosale, Dr. Ashish Kumar Jha, Ganesh Suresh Tolsarwad

European Journal of Molecular & Clinical Medicine, 2023, Volume 10, Issue 1, Pages 2548-2554

The study has clearly provided an idea of anti inflammatory responses of Cannabinoids against respiratory disorders. In that case, asthma can be considered as one of the major diseases and most of the individuals have been suffering from it. In that case, “human endocannabinoid system” can be considered as one of the complicated structures that are mainly responsible for producing signals. Therefore, the entire system of ECS includes ligand, enzymes, synthesis process and degradation. Cannabinoids can be obtained from the plant Cannabis Sativa plant. On the other hand, cannabinoids have the anti-inflammatory properties which can exacerbate the activation of CB2 signalling pathways. The study also demonstrates the derivative substances of cannabinoids has involved the inflammation process and also focuses on the immune responses. In this study, there were mainly two types of receptors mentioned and both of them belong from the G protein family. CB2 cells mainly activate and release proinflammatory mediators, which mainly act on the respiratory inflammation and also help in reducing the impact. In contrast, the activation of CB1 receptors directly impacts the bronchial nerve endings and it can be taken as a positive aspect for treating asthma.

Role of Hypoxia on Periodontal Health

Prateek Choudhury, Dr. Dhirendra Kumar Singh, Natasha Sahu, Saismita Sahoo, Dr. Subhalaxmi Baral

European Journal of Molecular & Clinical Medicine, 2023, Volume 10, Issue 1, Pages 487-499

The opportunistic Gram-negative anaerobic bacteria at the tooth-supporting system cause human periodontitis which is a persistent inflammatory disease. The anaerobic bacteria that reside there interact with the host's inflammatory responses to create a low-oxygen or hypoxic environment within the gingivitis-affected sulcus or periodontal pocket. To help tissues adapt to fluctuations in oxygen availability caused by pathology or natural occurrences, an oxygen-sensing mechanism within each cell and within each tissue is required, as well as its proper management. In this review article, the biological significance of hypoxia  with regard to periodontal/oral cellular growth, epithelial barrier function, periodontal inflammation, and immunology has been described briefly. 

A Case Report on Eosinophilic Cholecystitis with Frozen Calot’s Triangle – A Rare Inflammatory Etiology Affecting Gallbladder

Dr. Sreedevi B.V .

European Journal of Molecular & Clinical Medicine, 2023, Volume 10, Issue 2, Pages 70-73

Eosinophilic cholecystitis is regarded as ther are presentation of gallbladder infection that has similar presentation as acute cholecystitis. It presents with symptoms similar to that of cholecystitis with infiltration of excessive esnophils within the gallbladder. Eosinophilic cholecystitis can occur alone or most of the times in combination with eosinophilic inflammation gastrointestinal tract and rarely associated with inflammation of airway


Mr. Mangi Lal Choudhary, Dr. S.S. Sisodia

European Journal of Molecular & Clinical Medicine, 2022, Volume 9, Issue 9, Pages 377-392

The PI3K/Akt pathway, which is abnormally activated in the phosphatidylinositol 3-kinase (PI3K) malignancies and essential for many cellular functions, promotes the growth and development of tumours. It may be possible to fully understand the role of this pathway by looking at its upstream and downstream nodes. The development of new cancer drugs may benefit from techniques that target the pathway's primary constituents in light of mounting evidence.
Therefore, approaches combining pathway inhibitors and additional cancer therapies may be able to address the therapeutic conundrum. In this review, we cover the functions of the PI3K/Akt pathway in different cancer phenotypes, a status report on several PI3K/Akt inhibitors, and an introduction to combination therapies that combine signalling inhibitors with traditional cancer treatments. The evidence presented here demonstrates that the most successful approach to treating cancer involves cascade inhibitors of the PI3K/Akt signalling pathway, either alone or in conjunction with other medicines.

Effect of Citrullus colocynthis extract on reduction in pain and inflamation

Anil Kamboj, Vipin Saini

European Journal of Molecular & Clinical Medicine, 2022, Volume 9, Issue 7, Pages 6128-6133

The use of medicinal plants in treatment has been very common nowdays. Colocynth, Scientifically kwon as Citrullus colocynthis is used to reduce pain and inflammation in traditional medicine. C. colocynthis are already reported as rich source of different phytochemical constituents and responsible for many pharmacological applications. The aim of present study is to evaluate the effects of acetone extract of Colocynth fruit (AECC) on pain and inflammatory mediators at doses of 100 mg/kg, 200mg/kg, 400mg/kg by using tail flick and formaline induced pain methods. Our observations indicated that C. colocynthis fruit acetone extract can reduce pain and inflammation and we can use this plant as analgesic and anti inflammatory agent in the future.

Effects of Carvedilol and Bisoprolol on Inflammation and Oxidative Damage in Patients with Chronic Heart Failure

J. Jacob Justin, Sabu Augustine

European Journal of Molecular & Clinical Medicine, 2022, Volume 9, Issue 7, Pages 478-485

Background: Inflammation and oxidative stress contribute to persistent heart failure (CHF). Bisoprolol is better than carvedilol at protecting CHF patients' myocardium, according to our earlier clinical trial. Low high-sensitivity cardiac troponin T showed this (hsTnT).
Materials and Methods: From the 87 people who took part in the trial, 48 (26 in the bisoprolol group and 22 in the carvedilol group) were included in this study because they had measurements of derivatives of reactive oxygen metabolites (d-ROMs) as an indicator of oxidative stress at the beginning and end of the trial.
Results: High-sensitivity C-reactive protein (hsCRP), a marker of inflammation, went down in both groups, but the drop in the bisoprolol group was bigger than the drop in the carvedilol group. Both groups also had a drop in d-ROMs, but the drop in the bisoprolol group was not as big as the drop in the carvedilol group. The change in hsTnT was linked to the change in hsCRP for all 48 patients (R = 0.467, p = 0.003).
Conclusion: Bisoprolol might be better than carvedilol at reducing inflammation, but carvedilol might be better at reducing oxidative stress than bisoprolol. Patients with CHF could benefit from the right use of bisoprolol or carvedilol based on their own pathophysiology.

Nepafenac punctal plugs delivery system- potency in inflammation following cataract surgery

Samia Rahman

European Journal of Molecular & Clinical Medicine, 2022, Volume 9, Issue 4, Pages 1420-1424

Aim: The purpose of this study was to determine the safety and effectiveness of a nepafenac punctal plug delivery system (N-PPDS) after cataract surgery.
Methods: The investigation was carried out in a single Indian clinical setting. It is a single-center, randomised, parallel-arm, double-masked, prospective pilot research. Thirty-eight participants (aged 22 and higher) with predicted postcataract correctable distant vision of 20/30 or better and lower puncta enabling dilatation up to 1.0 mm were included in the study (N-PPDS group). All of the eyes had standard unilateral cataract surgery with intraocular lens implantation. Postoperative ocular discomfort and inflammation were used as primary and secondary efficacy measures, respectively.
Results: The experimental N-PPDS group had 38 patients, while the control group included 18 individuals. The N-PPDS group had a substantially greater proportion of pain-free patients (22/32 [69%] after 3 days, P =.038; and 24/36 [67%] at 7 days, P =.018). The N-PPDS group had a larger percentage of pain-free patients (15/29 [52 percent]) at all visits (P =.001). At 7 days, the N-PPDS group had good anterior chamber cell scores (patients with no anterior chamber cells: 18/36 [50%]; P =.034). At 14 days, the plug retention rate was 98 percent (55/56).
Conclusion: Adverse events associated with the punctal plug therapy occurred in 1 case of the N-PPDS group involving placement. The N-PPDS was shown to be both safe and effective in the treatment of ocular discomfort and inflammation following cataract surgery.

Haematological parameters in type 2 diabetes mellitus, controlled and uncontrolled

Akhouri Sukrit Prakash

European Journal of Molecular & Clinical Medicine, 2022, Volume 9, Issue 3, Pages 10078-10084

Aims: To compare HbA1c levels with inflammatory markers that include a neutrophilto-
lymphocyte ratio (NLR) and monocyteto-lymphocyte ratio (MLR) in controlled and
uncontrolled diabetics.
Materials and methods: Two hundred type 2 diabetes mellitus (T2DM) patients were
separated into two groups of managed (HbA1c 7%) diabetics. HbA1c (glycated
haemoglobin) levels, leukocyte count (WBC), haemoglobin (Hb), hematocrit (Hct), red
blood cell distribution width (RDW), neutrophils, lymphocytes, and monocytes were all
measured using recent laboratory data. The laboratory results were used to determine
the NLR and MLR.
Results:Controlled diabetics had a mean age of 58.30 years, while uncontrolled diabetics
had a mean age of 55.62 years. The mean NLR in diabetics with and without diabetes
was 2.61 and 4.88, respectively. The distinction was discovered to be statistically
significant (p < 0.05). The mean MLR in diabetics with and without diabetes was 0.2
and 0.24, respectively, however the difference was not statistically significant (p > 0.05).
The data showed a modest positive connection between HbA1c levels and the
haematological indices, but it was statistically insignificant.
Conclusion: The study found a substantial difference in NLR between diabetics who
were well-controlled and those who were not. Although only a slight positive connection
was detected between glycated Hb levels and the haematological indices, the results
revealed a substantial difference in NLR between the two groups. This demonstrates
that these ratios have the potential to be used as inflammatory indicators in T2DM.

C - Reactive Protein In children with Allergic Asthma

Laxmi Chourasiya, Dr. Jaya Jain, Dr. Ashutosh Jain

European Journal of Molecular & Clinical Medicine, 2022, Volume 9, Issue 3, Pages 151-155

Background:Asthma is characterized by chronic inflammation of upper and lower
airways. Allergic diseases like allergic asthma, allergic rhinitis is increasing worldwide.
C-reactive protein is a marker of inflammation and infection. A positive relationship of
inflammation has been shown between raised CRP levels in allergic asthma.
Aims and Objective: The study aims to evaluate high sensitivity CRP levels in allergic
asthma cases and in controls.
Materials and Methods:The study was carried out in the Department of Biochemistry at
Index Medical College Hospital and Research Centre, Indore Madhya Pradesh. The
study was done on 80 males and females subjects of the age group 6 to 18 years. Forty
males and female children suffering from allergic asthma attending the Ear, Nose and
Throat outpatient department of IMCHRC, Indore were taken as the case. Forty
healthy males and female children were taken as controls after careful selection as per
inclusion and exclusion criteria. CRP was done by latex enhanced
tubidometericimmunoassay (CRP kit).
Results:The levels of CRP were significantly higher in allergic asthma cases (P<0.001)as
compared to controls (0.001).
Conclusion:The results of the present study indicate that the concentration of CRP was
increased in asthma cases as compared to the controls.In allergic asthma there
isincreased inflammation of upper and lower airways and so the levels of CRP are

Assessment of the role of procalcitonin in the management of severe surgical patients with sepsis

Dr. Ashutosh Singh, Dr. MA Reshamwala, Dr. Kartikeya Sharma

European Journal of Molecular & Clinical Medicine, 2022, Volume 9, Issue 2, Pages 1394-1397

Background: The assessment of procalcitonin not only provides valuable information about the diagnosis but is also useful in the selection of the corresponding antibiotics for the management of sepsis. The studies related to this procalcitonin role are comparatively sparse.
Objective: The present study was undertaken to observe the role of procalcitonin in the management of severe surgical patients with sepsis.
Materials and methods: A total of 50 patients diagnosed with sepsis and aged more than 18 years including both males and females were part of the study after obtaining the written, voluntary informed consent. Unwilling participants were excluded from the study. Patients with any severe complications were also excluded from the study.
Results: Results were presented in Tables no 1 and 2. Table no 1 presents the gender distribution of the participants. The majority of the participants were males with 56% and females were 44%. Table no 2 presents the levels of procalcitonin levels in the participants. The majority of the participants have excessive levels of procalcitonin levels. That is procalcitonin was more than 10ng/ml in 40 patients which means nearly 80 percent of the patients have excessive levels of procalcitonin. This will testify to the importance of procalcitonin in the diagnosis of sepsis.
Conclusion: Significantly higher levels of procalcitonin levels were observed in the patients with sepsis. The study results testify to the diagnostic value of the procalcitonin. The study recommends further detailed studies in this area to support the procalcitonin in the diagnosis of sepsis.

To Study Association Between the Levels of Oxidative Stress Markers and Pulmonary Hypertension in Patients with Chronic Obstructive Pulmonary Disease at a Tertiary Care Hospital

Shinde Shivprasad, Karpe Sonal Prabhakar, Meshram Priti, Pundpal Gurudas Sadanand

European Journal of Molecular & Clinical Medicine, 2022, Volume 9, Issue 3, Pages 5782-5788

Introduction: Chronic obstructive pulmonary disease (COPD) is a disease state
characterized by airflow limitation that is not fully reversible. An increased
inflammatory response in the lungs plays a central role in the pathogenesis of COPD.
Oxidative stress and systemic inflammation are co-dependent processes. Pulmonary
hypertension is a common complication of chronic obstructive pulmonary disease
(COPD). The present study is an attempt to study the various markers of oxidative
stress in COPD and their co relation with pulmonary hypertensionusing 2D ECHO
Materials and Methods: The present study enrolled 100 participants, 50 of them
diagnosed cases of COPD and the remaining 50 as control. Apart from the chest X ray,
routine blood investigations, sputum AFB examination and PFT, 6-minute walk test
(6MWT), 2D Echo and levels of above mentioned oxidative and inflammatory markers
were done of the patients. Pulmonary hypertension diagnosed based on the
Transthoracic 2D – ECHO by TR jet method – presence of mPAP more than 25 mmHg
considered as the criteria for defining pulmonary hypertension. As far as the
quantitative data was concerned, comparison between the 2 groups was done using
unpaired t test, and for the qualitative data appropriate data was used.


Dr.Pradip Butale, Dr. Syed Waseem, Dr. BalawantKove

European Journal of Molecular & Clinical Medicine, 2021, Volume 8, Issue 4, Pages 1149-1158

Background: Chronic colitis, regardless of type, is defined histologically by chronic
inflammation, mainly plasmacytosis, in the lamina propria. Specific diagnosis of chronic
colitides in biopsies can be challenging for practicing pathologists. The present research was
undertaken to study complete clinico-pathology of chronic colitis, pathological pattern and
spectrum of colitis, also study correlation of colonoscopy and histopathology of these
lesions.Method:This study was a retrospective and prospective analysis of 187 cases
ofhistopathologicallyproven colitis on colonic biopsies over a period of 5 years from June 2015
to May 2020. Results:Majority of specimen were rectal biopsies (57.22%) followed by mapping
biopsies (34.22%). Of 85 cases where both colonoscopy and histopathology diagnosis was
available, 61 (71.76%) colonoscopy diagnosis were consistent with histopathology. Among 187
cases, 107 were inflammatory bowel disease (57.22%), they were further sub classified as
ulcerative colitis (UC) (96.26%), Crohn’s (0.93%) and indeterminate colitis (2.8%). Cases of
UC had features of basal plasmacytosis (97.19%), crypt distortion (93.45%), crypt loss
(70.09%) and goblet cell depletion.48cases diagnosed as non-specific colitis. Infectious colitis
comprised 8.56% of total colitis cases. It included tuberculosis 4 (2.14%), CMV colitis
2(1.07%) and 5.35% cases of acute self-limiting colitis. 5(2.67%) cases were diagnosed as
lymphocytic colitis and 2 cases showed focal active colitis. Also, found single case of
eosinophilic colitis and radiation proctitis each.Conclusion:Good clinico-pathological
correlation helps to reduce number of cases diagnosed as non-specific colitis. To improve the
detection rate of microscopic colitis, it is important to take multiple biopsies from normal
looking colon on colonoscopy.

Design And Development Of Herbal Tablet Containing Ethanolic Extract Of Diplocyclos Palmatus (L.) Jeffry. For The Treatment Of Inflammation

Paras Gupta; Alok Mukerjee; Anil K. Singh; Bhupesh K. Verma; Sumeet Dwivedi

European Journal of Molecular & Clinical Medicine, 2020, Volume 7, Issue 9, Pages 443-452

Diplocyclos palmatus (L.) Jeffry. commony known as Shivlingi belongs to family Cucurbitaceae had been widely used for its reported biological activities in indigenous system of medicine. The present investigation was designed to develop herbal tablet containing ethanolic extract of leaves of Diplocyclos palmatus (L.) Jeffry. for the treatment of inflammation. The developed herbal tablet was evaluated as per IP. Hence, present investigation established pharmacological evidences to support the folklore claim that Diplocyclos palmatus (l.) Jeffry. is used as anti-inflammatory agent.

Carbon Nanotubes In Treatment Of Arthritis: An Overview

Manvendra Singh; Pallavi Nayak; Vijay Mishra

European Journal of Molecular & Clinical Medicine, 2020, Volume 7, Issue 7, Pages 4366-4372

Arthritis is a type of joint dysfunction that includes one or more joint inflammation like rheumatoid or psoriatic arthritis, and associated autoimmune disorders. The biggest concern about arthritis is that the discomfort is always persistent and may be confined to the injured joint due to swelling that happens throughout the joint, trauma to the joint induced by illness, regular wear and tear, muscle strains triggered by vigorous action toward hard sore joints and exhaustion, which in effect contributes to inflexibility, immobility and muscle weakening. Carbon nanotubes with unusual physicochemical properties (cell membrane penetration, large surface area and drug payload, biocompatibility, simple surface alteration, photoluminescence properties and non-immunogenicity) are employed to conquer the challenges of inflammation.

A Review Study On Relationship Among Covid-19 And Inflammation

Mr.Ponnazhagan .; Dr.Amarendiran .

European Journal of Molecular & Clinical Medicine, 2020, Volume 7, Issue 7, Pages 5440-5444

In reality, numerous research works have begun to report the metabolic function of COVID-19 shifts. Characteristically characterised are I decline in low-density (LDL-c) and high-density (HDL-c) cholesterol lipoproteins, (later proportionate with the gravity of the symptoms), and (ii) a mild rise in the populating T-assistance cell populations (CD3+T, CD4+T) and (iii) CD8+T lymphopenia. Further, in seriously ill patients the overall counts of White Blood Cells (WBC) is considerably higher, with a macrophage activation syndrome that was supported by the existence of the bronchoalveolar monocyte recruitment chemokines.

The Dynamics of C-reactive Protein Associated with Nutritional Status Changes in Kidney Failure Patients at Initiation and After 3 Months of Dialysis

Trina Primalia Irawanti; Haerani Rasyid; Syakib Bakri; Hasyim Kasim; Andi Makbul Aman; Fabiola Maureen Shinta Adam; Nur Ahmad Tabri; Arifin Seweng

European Journal of Molecular & Clinical Medicine, 2020, Volume 7, Issue 8, Pages 152-159

Among kidney failure patients, especially those on dialysis, malnutrition is associated with poor outcomes. Malnutrition is a multifactorial process, including inflammation, which can be measured by C-reactive protein (CRP). The objective is to evaluate the dynamics of CRP associated with nutritional status changes in kidney failure patients at initiation and after 3 months of dialysis. A prospective cohort study using a consecutive sampling method consisting of 40 kidney failure patients who received initial dialysis at Dr. Wahidin Sudirohusodo Hospital, Makassar, Indonesia from January-March 2020. Nutritional status was evaluated with Subjective Global Assessment (SGA), and CRP was measured at the initial dialysis and after 3 months. All subjects received nutritional education at the beginning. Nutritional status was defined as well-nourished (WN, SGA A) and malnourished (MN, SGA B and C), then classified into 4 groups denoting nutritional changes: Group 1 (WN to WN), Group 2 (MN to WN), Group 3 (WN to MN), and Group 4 (MN to MN). ANOVA, paired t-test, and chi-square test (significance p<0.05) were used for statistical analyses. Subject’s mean age was 50.5±14.8 years old; 52.5% were male. Diabetes and obstructive nephropathy were the most frequent underlying diseases, both had a prevalence of 35%. At initiation, the prevalence of malnutrition was 77.5%; after 3 months, it was 70%. The highest proportion of Group 4 were female (62.5%) and those with diabetes (45.9%). Among all subjects, mean CRP decreased (9.4±32.3 mg/dL) after 3 months. While mean CRP based on nutritional changes, Group 2 had the highest reduction (18.8±26.8 mg/dL), and Group 3, CRP increased (17.5±17.0 mg/dL). C-reactive protein is negatively associated with nutritional status changes in kidney failure patients after 3 months of dialysis. Malnutrition was higher in female subjects and those with diabetes.

Recent updates on Cyclin-Dependent Kinase 8 for targeted cancer therapy

Mr. Mangi Lal Choudhary, Dr. S.S. Sisodia .

European Journal of Molecular & Clinical Medicine, 2020, Volume 7, Issue 8, Pages 6088-6109

Cyclin-structured kinase 8 (CDK8) performs a essential function in regulating transcription both via its affiliation with the Mediator complicated or via way of means of phosphorylating transcription factors. Myriads of genetic and biochemical research have establishedCDK8 as a key oncogenic driving force in lots of cancers. Specifically, CDK8- mediated activation of oncogenic Wnt-β-catenin signaling, transcription of estrogen-inducible genes, and suppression of exceptional enhancer-related genes contributes to oncogenesis in colorectal, breast, and hematological malignancies, respectively. However, at the same time as maximum studies helps the function of CDK8 as an oncogene, different paintings has raised the opportunity of its opposite function. The various organic features of CDK8 and its apparently context-precise roles in distinct forms of cancers have spurred a fantastic quantity of hobby and possibly an excellent greater quantity of controversy withinside the improvement of CDK8 inhibitors as ability most cancers healing agents. Herein, we overview the ultra-modern panorama of CDK8 biology and its involvement in carcinogenesis. We dissect contemporary efforts in coming across CDK8inhibitors and try to offer an outlook on the destiny of CDK8-focused most cancers therapies.


FarhatYaasmeenSadiqueBasha .; Rajeshkumar. S; SS Raj

European Journal of Molecular & Clinical Medicine, 2020, Volume 7, Issue 1, Pages 1839-1843

Inflammation is a natural immune process caused by physiological disturbance in the body. The characteristic signs of inflammation are redness, heat, swelling, pain and loss of function. This whole process is a protection mechanism produced by the body following any injury.
But sometimes this also ends up harming the body. For such times drugs are needed to suppress this condition, they are called anti inflammatory drugs. NSAIDs are the widely used drugs of choice. Examples are aspirin, diclofenac, mefenamic acid etc. But the prolonged use of these drugs is also known to produce side effects. Many plants are said to contain phytoconstituents that possess anti inflammatory activity. Since plants are natural, easily available and produce little to no side effects, they are believed to be a safer source of cures or drugs.
The aim of this review is to determine the state of knowledge on medicinal plants and their antiinflammatory activity. This review discusses how plants may be used in medicine for their anti inflammatory activity.