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Early Phase of Diabetes Mellitus May Just Be a Reversible İnsufficiency of Pancreas Against Excess Fat Tissue

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Research Article | DOI: https://doi.org/10.31579/2690-1919/588

Early Phase of Diabetes Mellitus May Just Be a Reversible İnsufficiency of Pancreas Against Excess Fat Tissue

  • Mehmet Rami Helvaci 1*
  • Esma Helvaci 2
  • Emine Helvaci 2
  • Yusuf Aydin 1
  • Leyla Yilmaz Aydin 3
  • Alper Sevinc 1
  • Celaletdin Camci 1
  • Abdulrazak Abyad 4
  • Lesley Pocock 5

1Specialist of Internal Medicine, MD, Turkey.

2Manager of Writing and Statistics, Turkey.

3Specialist of Pulmonary Medicine, MD, Turkey.

4Middle-East Academy for Medicine of Aging, MD, Lebanon.

5Medi-WORLD International, Australia.

*Corresponding Author: Mehmet Rami Helvaci, Specialist of Internal Medicine, MD, Turkey.

Citation: Mehmet R. Helvaci, Esma Helvaci, Emine Helvaci, Yusuf Aydin, Leyla Y. Aydin, et al, (2026), Early Phase of Diabetes Mellitus May Just Be a Reversible İnsufficiency of Pancreas Against Excess Fat Tissue, J Clinical Research and Reports, 23(1); DOI:10.31579/2690-1919/588

Copyright: © 2026, Mehmet Rami Helvaci. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: 10 December 2025 | Accepted: 23 December 2025 | Published: 02 January 2026

Keywords: sickle cell diseases; early diabetes mellitus; excess fat tissue; acarbose; metformin

Abstract

Background: Excess fat tissue may be a reversible etiology of early diabetes mellitus (DM).

Methods: Sickle cell diseases (SCD) patients were studied.

Results: We studied 222 males and 212 females (30.8 vs 30.3 years of age, p>0.05, respectively). Smoking (23.8% vs 6.1%, p<0.001), alcohol (4.9% vs 0.4%, p<0.001), transfused red blood cells (RBC) in their lives (48.1 vs 28.5 units, p=0.000), disseminated teeth losses (5.4% vs 1.4%, p<0.001), ileus (7.2% vs 1.4%, p<0.001), stroke (12.1% vs 7.5%, p<0.05), chronic renal disease (CRD) (9.9% vs 6.1%, p<0.05), cirrhosis (8.1% vs 1.8%, p<0.001), chronic obstructive pulmonary disease (25.2% vs 7.0%, p<0.001), coronary heart disease (18.0% vs 13.2%, p<0.05), leg ulcers (19.8% vs 7.0%, p<0.001), and clubbing (14.8% vs 6.6%, p<0.001) were all higher in males.

Conclusion: As a prototype of accelerated atherosclerosis, hardened RBC-induced capillary endothelial cell damage terminates with end-organ deficiencies in early decades in SCD. Although atherosclerotic endpoints are so common, we detected no case of DM probably due to lower excess fat. As the most common cause of CRD, DM may be a reversible insufficiency of pancreas against excess fat tissue in early phases. Increased blood and insulin needs of excess fat in contrast to decreased blood supply of excess tissue and pancreas both due to excess pressure on vasculature, externally and atherosclerosis, internally may be important in DM. Acarbose and metformin are safe, cheap, oral, long-term used, and effective drugs for excess fat which may be curative in early phases of DM before development of other atherosclerotic endpoints.

Introduction

Chronic endothelial damage starting at birth may be the most common cause of early aging and shortened survival by means of the atherosclerotic endpoints in the body [1]. Much higher blood pressures (BP) of the arterial system may be the strongest accelerating factor via the repeated injuries on vascular endothelium. Probably, whole afferent vasculature including capillaries are mainly involved in the catastrophic process. Thus, venosclerosis is not a significant health problem in medicine. Due to the chronic endothelial damage, inflammation, and fibrosis, vascular walls thicken, their lumens narrow, and they lose their elastic natures, which terminally reduce blood supply to the end-organs, and increase systolic and decrease diastolic BP further. Some of the well-known accelerating factors of the inflammatory process are physical inactivity, emotional stress, animal-rich diet, smoking, alcohol, excess fat tissue, chronic inflammation, prolonged infection, and cancers for the development of atherosclerotic endpoints including obesity, hypertension (HT), diabetes mellitus (DM), chronic renal disease (CRD), coronary heart disease (CHD), cirrhosis, chronic obstructive pulmonary disease (COPDA), peripheric artery disease (PAD), stroke, abdominal angina, osteoporosis, dementia, early aging, and shortened survival [2, 3]. Although early withdrawal of the accelerating factors can delay the atherosclerotic endpoints, the endothelial changes can not be reversed, completely due to fibrotic natures. The accelerating factor and atherosclerotic endpoints have been researched under the titles of metabolic syndrome, aging syndrome, and accelerated endothelial damage syndrome in the literature, extensively [4-6]. Similarly, sickle cell diseases (SCD) are highly catastrophic process on vascular endothelial cells initiating at birth and terminating with an accelerated atherosclerosis-induced end-organ deficiencies even at childhood [7, 8]. Hemoglobin S causes loss of elastic and biconcave disc shaped structures of red blood cells (RBC). Loss of elasticity instead of shape may be the major problem since the sickling is rare in peripheric blood samples of patients with associated thalassemia minors (TM), and survival is not affected in hereditary spherocytosis or elliptocytosis. Loss of elasticity is present during whole lifespan, but exaggerated with inflammation, infection, cancer, surgery, and emotional stress. The hardened RBC-induced chronic endothelial damage, inflammation, and fibrosis terminate with tissue hypoxia all over the body [9]. As a difference from other causes of chronic endothelial damage, SCD keep vascular endothelium particularly at the capillary level since the capillary system is the main distributor of the hardened RBC into the body [10, 11]. The hardened RBC-induced chronic endothelial damage builds up an accelerated atherosclerosis in much earlier decades. Vascular narrowing and obstructions-induced tissue ischemia and end-organ insufficiencies are the terminal consequences, so the mean life expectancy is decreased 30 years or more in the SCD because we have patients with the age of 96 years without the SCD but just with the age of 59 years with the SCD (8).

Material and methods

The study was performed in the Medical Faculty of the Mustafa Kemal University between March 2007 and June 2016. All patients with the SCD were included. SCD are diagnosed with the hemoglobin electrophoresis performed via high performance liquid chromatography (HPLC). Smoking, alcohol, acute painful crises per year, transfused units of RBC in their lifespans, leg ulcers, stroke, surgeries, deep venous thrombosis (DVT), epilepsy, and priapism were searched in all cases. Cases with a history of one pack-year and one drink-year were accepted as smoker and drinkers, respectively. A physical examination was performed by the Same Internist, and patients with disseminated teeth losses (<20>

Results

We included 222 males and 212 females with similar mean ages (30.8 vs 30.3 years, p>0.05, respectively) into the study, and there was no patient above the age of 59 years. Associated TM were detected with similar prevalences in both genders (72.5% vs 67.9%, p>0.05, respectively). Smoking (23.8% vs 6.1%) and alcohol (4.9% vs 0.4%) were both higher in males (p<0>Table 1). Transfused units of RBC in their lives (48.1 vs 28.5, p=0.000), disseminated teeth losses (5.4% vs 1.4%, p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>Table 2). On the other hand, the mean ages of the atherosclerotic endpoints were shown in Table 3.

VariablesMales with the SCD*p-valueFemales with the SCD
Prevalence51.1% (222)Ns†48.8% (212)
Mean age (year)30.8 ± 10.0 (5-58)Ns30.3 ± 9.9 (8-59)
Associated TM‡72.5% (161)Ns67.9% (144)
Smoking23.8% (53)<0>6.1% (13)
Alcoholism4.9% (11)<0>0.4% (1)

*Sickle cell diseases   †Nonsignificant (p>0.05)   ‡Thalassemia minors

Table 1: Characteristic features of the study patients

VariablesMales with the SCD*p-valueFemales with the SCD
Painful crises per year5.0 ± 7.1 (0-36)Ns†4.9 ± 8.6 (0-52)
Transfused units of RBC‡48.1 ± 61.8 (0-434)0.00028.5 ± 35.8 (0-206)
Disseminated teeth losses (<20>5.4% (12)<0>1.4% (3)
CHD§18.0% (40)<0>13.2% (28)
Cirrhosis8.1% (18)<0>1.8% (4)
COPD¶25.2% (56)<0>7.0% (15)
Ileus7.2% (16)<0>1.4% (3)
Leg ulcers19.8% (44)<0>7.0% (15)
Digital clubbing14.8% (33)<0>6.6% (14)
CRD**9.9% (22)<0>6.1% (13)
Stroke12.1% (27)<0>7.5% (16)
PHT***12.6% (28)Ns11.7% (25)
Autosplenectomy50.4% (112)Ns53.3% (113)
DVT**** and/or varices and/or telangiectasias9.0% (20)Ns6.6% (14)
Rheumatic heart disease6.7% (15)Ns5.6% (12)
Avascular necrosis of bones24.3% (54)Ns25.4% (54)
Sickle cell retinopathy0.9% (2)Ns0.9% (2)
Epilepsy2.7% (6)Ns2.3% (5)
ACS*****2.7% (6)Ns3.7% (8)
Mortality7.6% (17)Ns6.6% (14)
Mean age of mortality (year)30.2 ± 8.4 (19-50)Ns33.3 ± 9.2 (19-47)

*Sickle cell diseases   †Nonsignificant (p>0.05)   ‡Red blood cells   §Coronary heart disease   ¶Chronic obstructive pulmonary disease   **Chronic renal disease   ***Pulmonary hypertension   ****Deep venous thrombosis   *****Acute chest syndrome

Table 2: Associated pathologies of the study patients

VariablesMean age (year)
Ileus29.8 ± 9.8 (18-53)
Hepatomegaly30.2 ± 9.5 (5-59)
ACS*30.3 ± 10.0 (5-59)
Sickle cell retinopathy31.5 ± 10.8 (21-46)
Rheumatic heart disease31.9 ± 8.4 (20-49)
Autosplenectomy32.5 ± 9.5 (15-59)
Disseminated teeth losses (<20>32.6 ± 12.7 (11-58)
Avascular necrosis of bones32.8 ± 9.8 (13-58)
Epilepsy33.2 ± 11.6 (18-54)
Priapism33.4 ± 7.9 (18-51)
Left lobe hypertrophy of the liver33.4 ± 10.7 (19-56)
Stroke33.5 ± 11.9 (9-58)
COPD†33.6 ± 9.2 (13-58)
PHT‡34.0 ± 10.0 (18-56)
Leg ulcers35.3 ± 8.8 (17-58)
Digital clubbing35.4 ± 10.7 (18-56)
CHD§35.7 ± 10.8 (17-59)
DVT¶ and/or varices and/or telangiectasias37.0 ± 8.4 (17-50)
Cirrhosis37.0 ± 11.5 (19-56)
CRD**39.4 ± 9.7 (19-59)

*Acute chest syndrome   †Chronic obstructive pulmonary disease   ‡Pulmonary hypertension   §Coronary heart disease   ¶Deep venous thrombosis   **Chronic renal disease

Table 3: Mean ages of endpoints of the sickle cell diseases

Discussion

Excess fat tissue may be the most common cause of vasculitis, aging, and death. It causes both excess pressure on the vasculature, externally and an exaggerated atherosclerosis, internally in addition to the increased blood and insulin requirements of the excess tissue. DM may just be an atherosclerotic endpoint of excess fat tissue in whole body rather than the pancreas alone. Although all kinds of the atherosclerotic endpoints are common with the SCD, we have detected no case of DM, probably due to the lower body mass indexes (BMI) (10). The BMI were 20.7 vs 24.9 kg/m2 in the SCD and control groups, respectively with the mean age of 28.6 years (p= 0.000 for both) (10). The heights were similar in both groups (166.1 vs 168.5 cm, respectively, p>0.05) which may powerfully indicate that the body height is determined, genetically (10). Similarly, just 20% of elderly have DM, but 55% of patients with DM are obese. So excess fat tissue may be more harmfull than smoking, alcohol, or chronic inflammatory or infectious processes for atherosclerosis. Excess fat tissue leads to a chronic and low-grade inflammation on vascular endothelium, and risk of death from all causes increases parallel to its severity [19]. The low-grade chronic inflammation may also cause genetic changes on the endothelial cells, and the systemic atherosclerotic process may even decrease clearance of malignant cells by the natural killers [20]. The chronic inflammatory process is characterized by lipid-induced injury, invasion of macrophages, proliferation of smooth muscle cells, endothelial dysfunction, and increased atherogenicity [21, 22]. Excess fat tissue is considered as a strong factor for controlling of C-reactive protein (CRP) since the excess tissue produces biologically active leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, and adiponectin-like cytokines [23, 24]. On the other hand, excess fat tissue will also aggravate myocardial hypertrophy and decrease cardiac compliance further. Fasting plasma glucose (FPG) and serum cholesterol increased and high density lipoproteins (HDL) decreased parallel to the severity of BMI [25]. Similarly, CHD and stroke increased parallel to the severity of BMI [26]. Eventually, the risk of death from all causes increased parallel to the severity of excess fat tissue in all age groups, and people with underweight may even have lower biological ages and longer overall survival [27]. Similarly, calorie restriction prolongs survival and retards age-related chronic sicknesses [28]. So the term of excess weight should be replaced with the excess fat tissue because there are nearly 19 kg of excess fat even between lower and upper borders of normal weight in adults.

Smoking may be the second most common cause of vasculitis all over the world. It causes a systemic inflammation on vascular endothelium terminating with atherosclerotic endpoints in early decades [29]. Its atherosclerotic effect is the most obvious in the Buerger’s disease and COPD [30]. Buerger’s disease is an obliterative vasculitis in the small and medium-sized arteries and veins, and it has never been reported in the absence of smoking. Its characteristic features are chemical toxicity, inflammation, fibrosis, and narrowing and occlusions of arteries and veins. Claudication is the most significant symptom with a severe pain in feet and hands caused by insufficient blood supply, particularly by walking in the feet. It may also radiate to central areas in advanced cases. Numbness or tingling of the limbs is also common. Skin ulcerations and gangrene of fingers or toes are the terminal endpoints. Similar to the venous ulcers, diabetic ulcers, leg ulcers of the SCD, digital clubbing, onychomycosis, and delayed wound and fracture healings of the lower extremities, pooling of blood due to the gravity may be the main cause of Buerger's disease, particularly in the lower extremities. Several narrowing and occlusions of the arm and legs are diagnostic in the angiogram. Skin biopsies may be risky, because a poorly perfused area will not heal, completely. Although most patients are heavy smokers, the limited smoking history of some patients may support the hypothesis that Buerger's disease may be an autoimmune reaction triggered by some constituent of tobacco. Although the only treatment way is complete cessation of smoking, the already developed narrowing and occlusions are irreversible. Due to the well-known role of inflammation, anti-inflammatory dose of aspirin in addition to the low-dose warfarin may even be life threatening by preventing microvascular infarctions. On the other hand, FPG and HDL may be negative whereas triglycerides, low density lipoproteins (LDL), erythrocyte sedimentation rate, and CRP positive acute phase reactants (APR) in smokers [31]. Similarly, smoking was associated with the lower BMI due to the systemic inflammatory effects [32, 33]. An increased heart rate was detected just after smoking even at rest [34]. Nicotine supplied by patch after smoking cessation decreased caloric intake in a dose-related manner [35]. Nicotine may lengthen intermeal time, and decrease amount of meal eaten [36]. Smoking may be associated with a postcessation weight gain, but the risk is the highest during the first year, and decreases with the following years [37]. Although the CHD was detected with similar prevalences in both genders, prevalences of smoking and COPD were higher in males against the higher white coat hypertension, BMI, LDL, triglycerides, HT, and DM in females [38]. The risk of myocardial infarction is increased three-fold in men and six-fold in women with smoking probably due to the higher BMI in women [39]. Chemical toxicity of smoking can affect all organ systems. For example, it is usually associated with depression, irritable bowel syndrome (IBS), chronic gastritis, hemorrhoids, and urolithiasis with several possible mechanisms [40]. First of all, smoking may also have some anxiolytic properties. Secondly, smoking-induced vascular inflammation may disturb epithelial absorption and excretion in the gastrointestinal (GI) and genitourinary (GU) tracts [41]. Thirdly, diarrheal losses-induced urinary changes may cause urolithiasis [42]. Fourthly, smoking-induced sympathetic nervous system activation may cause motility problems in the GI and GU tracts terminating with IBS and urolithiasis. Finally, immunosuppression secondary to smoking may terminate with the GI and GU tract infections and urolithiasis since some types of bacteria can provoke urinary supersaturation, and modify the environment to form crystal deposits. Actually, 10% of urinary stones are struvite stones which are built by magnesium ammonium phosphate produced by the urease producing bacteria. As a result, urolithiasis was higher in the IBS patients (17.9% vs 11.6%, p<0>

DM is the most common cause of blindness, non-traumatic amputation, and renal dialysis in adults. As the most common cause of CRD, DM may just be an atherosclerotic endpoint affecting the pancreas, too. Increased blood and insulin requirements of the excess fat tissue in contrast to the decreased blood supply of the excess tissue and pancreas due to excess pressure on the vasculature, externally and atherosclerosis, internally may be the underlying mechanisms in the development of DM. For example, excess fat tissue in the liver and pancreas are called as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic fatty pancreas disease (NAFPD). They are usually accepted as components of the metabolic syndrome. NAFLD progresses to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Blocking triglycerides secretion, subcellular lipid sequestration, lipolysis deficiency, enhanced lipogenesis, gluconeogenesis defects, or inhibition of fatty acid oxidation may be some of the development mechanisms [44]. NAFLD may just be an atherosclerotic process, and strongly associated with an accelerated atherosclerotic process not only in the liver instead all over the body. For example, NAFLD is seen in one-third of cases with hepatitis B virus-related chronic liver disease [45]. Similarly, higher fatty liver ratios were observed in children with non-Hodgkin lymphomas [46]. The liver density on contrast abdominopelvic CT of colorectal cancer patients was low that is consistent with the NAFLD [47]. As one of the APR, serum thrombopoietin levels increased in the NAFLD [48]. Although serum levels of oxidizing agents including nitrate and advanced oxidation protein products increased, serum nitrite did not adequately increase as an antioxidant agent in the NAFLD [49]. As a result, NAFLD is associated with an impaired carotid intima-media thickness (IMT) and flow-mediated dilation which are considered as early markers of systemic atherosclerosis [50]. Carotid IMT was correlated with the BMI (p<0>p= 0.001), and grade 2-3 NAFLD (p<0>p<0>

Acute painful crises are nearly pathognomonic for the SCD. Although some authors reported that pain itself may not be life threatening directly, infections, medical or surgical emergencies, or emotional stresses are the most common precipitating factors of the crises [65]. The increased basal metabolic rate during such stresses aggravates the sickling and capillary endothelial cell damage, inflammation, and edema terminating with tissue hypoxia and end-organ deficiencies. So the risk of mortality is much higher during the crises. Actually, each crisis may complicate with the following crises by leaving significant sequelaes on the capillary endothelial system in whole body. After a period of time, the sequelaes may terminate with end-organ failures and sudden death with an acute painful crisis that may even be silent, clinically. Similarly, after a 20-year experience on such patients, the deaths seem sudden and unexpected events in the SCD. Unfortunately, most of the deaths develop just after the hospital admission, and majority of them are patients without hydroxyurea therapy [66, 67]. Rapid RBC supports are usually life-saving for such patients, although preparation of RBC units for transfusion usually takes time. Beside that RBC supports in emergencies become much more difficult in terminal cases due to the repeated transfusions-induced blood group mismatch. Actually, transfusion of each unit of RBC complicates the following transfusions by means of the blood subgroup mismacth. Due to the significant efficacy of hydroxyurea therapy, RBC transfusions should be preserved just for acute stresses and emergencies [66-68]. According to our experiences, simple and repeated transfusions are superior to RBC exchange [69, 70]. First of all, preparation of one or two units of RBC suspensions in each time rather than preparation of six units or higher provides time to clinicians by preventing sudden death of such high-risk patients. Secondly, transfusions of one or two units of RBC suspensions in each time decrease the severity of pain, and relax the patients and their relatives since RBC transfusions probably have the strongest analgesic effects during such crises [71]. Actually, the decreased severity of pain by transfusions also indicates the decreased severity of inflammation in whole body. Thirdly, transfusions of lesser units of RBC suspensions by means of the simple transfusions will decrease transfusion-related complications including infections, iron overload, and blood group mismatch. Fourthly, transfusions of RBC suspensions in the secondary health centers prevent deaths developed during the transport to the tertiary centers for the exchange. Terminally, cost of the simple transfusions on insurance system is much lower than the exchange which needs trained staff and additional devices. On the other hand, pain is the result of complex and poorly understood interactions between RBC, WBC, platelets (PLT), and endothelial cells, yet. Probably, leukocytosis contributes to the pathogenesis by releasing cytotoxic enzymes. The adverse effects of WBC on vascular endothelium are of particular interest for atherosclerotic endpoints. For example, leukocytosis even in the absence of any infection was an independent predictor of the severity of the SCD [72], and it was associated with the risk of stroke [73]. Disseminated tissue hypoxia, releasing of inflammatory mediators, bone infarctions, and activation of afferent nerves may take role in the pathophysiology of the intolerable pain. Due to the severity of pain, narcotic analgesics are usually required [74], but simple RBC transfusions are effective both to relieve pain and to prevent sudden deaths which may develop due to the end-organ failures on atherosclerotic background of the SCD.

Hydroxyurea is the life-saving drug for the SCD. It interferes with the cell division by blocking the formation of deoxyribonucleotides by means of inhibition of ribonucleotide reductase. The deoxyribonucleotides are the building blocks of DNA. Hydroxyurea mainly affects hyperproliferating cells. Although the action way of hydroxyurea is thought to be the increase in gamma-globin synthesis for fetal hemoglobin (Hb F), its main action may be the suppression of leukocytosis and thrombocytosis by blocking the DNA synthesis [75, 76]. Due to the same action way, hydroxyurea is also used in moderate and severe psoriasis to suppress hyperproliferating skin cells. As in the viral hepatitis cases, although presence of a continuous damage of sickle cells on the capillary endothelium, the severity of catastrophic process is probably exaggerated by the patients’ own WBC and PLT. So suppression of proliferation of them can limit the endothelial cells damage-induced edema, ischemia, and infarctions ]77]. Similarly, Hb F levels in hydroxyurea users did not differ from their pretreatment levels [78]. The Multicenter Study of Hydroxyurea (MSH) studied 299 severely affected adults with the SCA, and compared the results of patients treated with hydroxyurea or placebo [79]. The study particularly researched effects of hydroxyurea on painful crises, ACS, and requirement of blood transfusion. The outcomes were so overwhelming in the favour of hydroxyurea group that the study was terminated after 22 months, and hydroxyurea was initiated for all patients. The MSH also demonstrated that patients treated with hydroxyurea had a 44?crease in hospitalizations [79]. In multivariable analyses, there was a strong and independent association of lower neutrophil counts with the lower crisis rates [79]. But this study was performed just in severe SCA cases alone, and the rate of painful crises was decreased from 4.5 to 2.5, annually [79]. Whereas we used all subtypes of the SCD with all clinical severity, and the rate of painful crises was decreased from 10.3 to 1.7, annually (p<0>p<0>

Aspirin is a member of nonsteroidal anti-inflammatory drugs (NSAID). Although aspirin has similar anti-inflammatory effects with the other NSAID, it also suppresses the normal functions of PLT, irreversibly. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the cyclooxygenase (COX) enzyme. Aspirin inactivates the COX enzyme, irreversibly, which is required for the synthesis of prostaglandins (PG) and thromboxanes (TX). PG are the locally produced hormones with some diverse effects, including the transmission of pain into the brain and modulation of the hypothalamic thermostat and inflammation. TX are responsible for the aggregation of PLT to form blood clots. Low-dose aspirin irreversibly blocks the formation of TXA2 in the PLT, producing an inhibitory effect on the PLT aggregation during whole lifespan of the affected PLT (8-9 days). Since PLT do not have nucleus and DNA, they are unable to synthesize new COX enzyme anymore. But aspirin has no effect on the blood viscosity. The antithrombotic property is useful to reduce the risks of myocardial infarction, transient ischemic attack, and stroke [82]. Low-dose of aspirin is effective to prevent the second myocardial infarction, too [83]. Aspirin may also be effective in prevention of colorectal cancers [84]. On the other hand, aspirin has some side effects including gastric ulcers, gastric bleeding, worsening of asthma, and Reye syndrome in childhood and adolescence. Due to the risk of Reye syndrome, the US Food and Drug Administration recommends that aspirin should not be prescribed for febrile patients under the age of 12 years [85], and it was only recommended for Kawasaki disease [86]. Reye syndrome is a rapidly worsening brain disease [86]. The first detailed description of Reye syndrome was in 1963 by an Australian pathologist, Douglas Reye [87]. The syndrome mostly affects children, but it can only affect fewer than one in a million children, annually [87]. Symptoms of Reye syndrome may include personality changes, confusion, seizures, and loss of consciousness [86]. Although the liver toxicity and enlargement typically occurs in most cases, jaundice is usually not seen [86]. Although the death occurs in 20-40% of affected cases, about one third of survivors get a significant degree of brain damage [86]. It usually starts just after recovery from a viral infection, such as influenza or chicken pox. About 90% of children are associated with an aspirin use [87, 88]. Inborn errors of metabolism are also the other risk factors, and the genetic testing for inborn errors of metabolism became available in developed countries in the 1980s [86]. When aspirin use was withdrawn for children in the US and UK in the 1980s, a decrease of more than 90% in rates of Reye syndrome was seen [87]. Due to the low risk of Reye syndrome but higher risk of death, aspirin should be added into 

sfunctional cardiac atria. It is commonly used to prevent DVT and pulmonary embolism, and against stroke in atrial fibrillation (AF), valvular heart disease, and artificial heart valves. It is additionally used following ST-segment elevation myocardial infarction and orthopedic surgeries. Initiation regimens are simple, safe, and suitable to be used in the ambulatory settings [90]. It should be initiated with a 5 mg dose, or 2 to 4 mg in the elderlies. In the protocol of low-dose warfarin, the target international normalised ratio (INR) is between 2.0 and 2.5, whereas in the protocol of standard-dose warfarin, the target INR is between 2.5 and 3.5 (91). Simple discontinuation of the drug for five days is enough to reverse the effect, and causes INR to drop below 1.5 [92]. Its effects can be reversed with phytomenadione (vitamin K1), fresh frozen plasma, or prothrombin complex concentrate, rapidly. Warfarin decreases blood clotting by blocking vitamin K epoxide reductase, an ezyme that reactivates vitamin K1. Without sufficient active vitamin K1, abilities of clotting factors II, VII, IX, and X are decreased. The abilities of anticlotting protein C and S are also inhibited, but to a lesser degree. A few days are required for full effect which is lasting up to five days. The consensus agrees that current self-testing and management devices are effective providing outcomes possibly better than achieved, clinically. The risk of severe bleeding is just 1-3%, annually, and the severest ones are those involving the central nervous system [92, 93]. The risk is particularly increased once the INR exceeds 4.5 [93]. The risk of bleeding is increased further when warfarin is combined with antiplatelet drugs such as clopidogrel or aspirin [94]. Thirteen publications from 11 cohorts including more than 48.500 patients with more than 11.600 warfarin users were included in the meta-analysis in which warfarin resulted with a lower risk of ischemic stroke (p= 0.004) and mortality (p<0>p>0.05) in patients with AF and non-end-stage CRD (95). Warfarin is associated with significant reductions in ischemic stroke even in patients with warfarin-associated intracranial hemorrhage (ICH), and recurrent ICH occured in 6.7% of warfarin users and 7.7% of the others (p>0.05) [96]. On the other hand, patients with cerebral venous thrombosis (CVT) anticoagulated either with warfarin or dabigatran had lower risk of recurrent venous thrombotic events (VTE), and the risks of bleeding were similar in both regimens [97]. Additionally, an INR value of 1.5 achieved with an average daily dose of 4.6 mg warfarin, has resulted with no increase in the number of men ever reporting minor bleeding episodes [98]. Non-rheumatic AF increases the risk of stroke, presumably from atrial thromboemboli, and long-term use of low-dose warfarin is highly effective and safe with a reduction of 86% in the risk of stroke (p= 0.0022) [99]. The mortality rate was markedly lower in the warfarin group, too (p= 0.005) [99]. The frequencies of bleedings that required hospitalization or transfusions were similar in both groups (p>0.05) [99]. Additionally, very-low-dose warfarin was safe and effective for prevention of thromboembolism in metastatic breast cancer in which the average daily dose was 2.6 mg, and the mean INR value was 1.5 [100]. On the other hand, new oral anticoagulants had a favourable risk-benefit profile with significant reductions in stroke, ICH, and mortality, and with similar major bleedings as for warfarin, but increased GI bleeding [101]. Interestingly, rivaroxaban and low-dose apixaban were associated with increased risks of all cause mortality compared with warfarin [102]. The mortality rates were 4.1%, 3.7%, and 3.6% per year in the warfarin, 110 mg of dabigatran, and 150 mg of dabigatran groups, respectively (p>0.05 for both) with AF [103]. Eventually, infection, inflammation, medical or surgical emergency, and emotional stress-induced increased basal metabolic rate accelerates sickling, and an exaggerated capillary endothelial edema-induced myocardial infarction or stroke may cause sudden deaths [104]. So anti-inflammatory dose of aspirin plus low-dose warfarin may be the other life-saving regimen to prevent atherosclerotic endpoints even at childhood in SCD [105].

COPD is the third leading cause of death in human being [106]. Aging, smoking, alcohol, male gender, excess fat tissue, chronic inflammation, prolonged infection, and cancers may be the main causes. Atherosclerotic effects of smoking may be the most obvious in the COPD and Buerger’s disease, probably due to the higher concentrations of toxic substances in the lungs and pooling of blood in the extremities. After smoking, excess fat tissue may be the second common cause of COPD due to the excess fat tissue-induced atherosclerotic endpoints all over the body. Since an estimated 25-45% of patients with the COPD have never smoked [107]. Regular alcohol consumption may be the third leading cause of the systemic accelerated atherosclerotic process and COPD, since COPD was one of the most common diagnoses in alcohol dependence [108]. Furthermore, 30-day readmission rates were higher in the COPD patients with alcoholism [109]. Probably an accelerated atherosclerotic process is the main structural background of functional changes that are characteristics of the COPD. The inflammatory process of vascular endothelial cells is exaggerated by release of various chemicals by inflammatory cells, and it terminates with an advanced fibrosis, atherosclerosis, and pulmonary losses. COPD may actually be the pulmonary endpoint of the systemic atherosclerotic process. Beside the accelerated atherosclerotic process of the pulmonary vasculature, there are several reports about coexistence of associated endothelial inflammation all over the body in COPD [110]. For instance, there may be close relationships between COPD, CHD, PAD, and stroke [111]. Furthermore, two-third of mortality cases were caused by cardiovascular diseases and lung cancers in the COPD, and the CHD was the most common cause in a multicenter study of 5.887 smokers [112]. When hospitalizations were researched, the most common causes were the cardiovascular diseases, again [112]. In another study, 27% of mortality cases were due to the cardiovascular diseases in the moderate and severe COPD [113]. Finally, COPD may also be an atherosclerotic endpoint of SCD [106].

Leg ulcers are seen in 10% to 20% of the SCD, and its prevalence increases with aging, male gender, and SCA [114, 115]. The leg ulcers have an intractable nature, and around 97% of them relapse in a period of one year [114]. Similar to Buerger's disease, the leg ulcers occur in the distal segments of the body with a lesser collateral blood flow [114]. The hardened RBC-induced chronic endothelial damage, inflammation, edema, and fibrosis at the capillaries may be the chief causes [115]. Prolonged exposure to the hardened bodies due to the pooling of blood in the lower extremities may also explain the leg but not arm ulcers in the SCD. The hardened RBC-induced venous insufficiencies may also accelerate the process by pooling of causative bodies in the legs, and vice versa. Pooling of blood may also be important for the development of venous ulcers, diabetic ulcers, Buerger’s disease, digital clubbing, and onychomycosis in the lower extremities. Furthermore, pooling of blood may be the cause of delayed wound and fracture healings in the lower extremities. Smoking and alcohol probably have some additional atherosclerotic effects on the leg ulcers in males. Hydroxyurea is the first drug that was approved by Food and Drug Administration in the SCD [116]. It is an oral, cheap, safe, and effective drug that blocks cell division by suppressing formation of deoxyribonucleotides which are the building blocks of DNA [11. Its main action may be the suppression of hyperproliferative WBC and PLT in the SCD [117]. Although presence of a continuous damage of hardened RBC on vascular endothelial cells, severity of the destructive process is probably exaggerated by the immune system. Similarly, lower WBC counts were associated with lower crisis rates, and if a tissue infarct occurs, lower WBC counts may decrease severity of tissue damage and pain [78]. Prolonged resolution of leg ulcers with hydroxyurea may also suggest that the ulcers may be secondary to increased WBC and PLT counts-induced exaggerated capillary endothelial cell edema.

Clubbing is characterized by the increased normal angle of 165° between nailbed and fold, increased convexity of the nail fold, and thickening of thewhole distal finger [118]. Although the exact cause and significance is unknown, the chronic tissue hypoxia is highly suspected [119]. In the previous study, only 40% of clubbing cases turned out to have significant underlying diseases while 60% remained well over the subsequent years (18). But according to our experiences, clubbing is frequently associated with the pulmonary, cardiac, renal and hepatic diseases, and smoking those are characterized with chronic tissue hypoxia (5). As an explanation for that hyothesis, lungs, heart, kidneys, and liver are closely related organs which affect their functions in a short period of time. On the other hand, clubbing is also common in the SCD with a prevalence of 10.8% in the present study, too. It probably shows chronic tissue hypoxia caused by disseminated endothelial damage, edema, and fibrosis, particularly at the capillary level in the SCD. Beside the effects of SCD, smoking, alcohol, cirrhosis, CRD, CHD, and COPD, the higher digital clubbing in males (14.8% vs 6.6%, p<0>

CRD is increasing which can be explained by prolonged survival and increased prevalence of excess fat in human being, too [120]. Aging, animal-rich diet, excess fat tissue, smoking, alcohol, chronic inflammatory or infectious process, and cancers may be the major causes of the renal endothelial inflammation, too. The inflammatory process is enhanced by release of various chemicals by lymphocytes to repair the damaged endothelial cells of the renal arteriols. Due to the continuous irritation of the vascular endothelial cells, prominent changes develop in the architecture of the renal tissues with advanced atherosclerosis, tissue hypoxia, and infarcts [121]. Excess fat tissue-induced hyperglycemia, dyslipidemia, elevated BP, and insulin resistance can cause tissue inflammation and immune cell activation [122]. Age (p= 0.04), high-sensitivity CRP (p= 0.01), mean arterial BP (p= 0.003), and DM (p= 0.02) had significant correlations with the CIMT [120]. Increased renal tubular sodium reabsorption, impaired pressure natriuresis, volume expansion due to the activations of sympathetic nervous system and renin-angiotensin system, and physical compression of kidneys by visceral fat tissue may be some mechanisms of the increased BP with excess fat tissue [123]. Excess fat tissue also causes renal vasodilation and glomerular hyperfiltration which initially serve as compensatory mechanisms to maintain sodium balance due to the increased tubular reabsorption [123]. However, along with the increased BP, these changes cause a hemodynamic burden on the kidneys in long term that causes chronic endothelial damage [124]. With prolonged excess fat tissue, there are increased urinary protein excretion, loss of nephron function, and exacerbated HT. With the development of dyslipidemia and DM, CRD progresses more easily [123]. The systemic inflammatory effects of smoking on endothelial cells is also important in the CRD [125]. Although the presence of some opposite reports [125]. alcohol can give harm to the renal vascular endothelium, too. Chronic inflammatory or infectious processes may also terminate with atherosclerotic endpoints in kidneys [124]. There are close relationships between CRD and other atherosclerotic endpoints (126, 127). The most common causes of death were CHD and stroke in CRD, again [128]. The hardened RBC-induced capillary endothelial damage may be the major cause of CRD in SCD, again P129].

Stroke is the other terminal cause of death, together with the CHD, and it develops as an acute thromboembolic event on the chronic atherosclerotic background. Aging, male gender, smoking, alcohol, excess fat tissue, chronic inflammatory or infectious process, cancer, and emotional stress may be the major causes. Stroke is also a common atherosclerotic endpoint of the SCD (130). Similar to the leg ulcers, stroke is particularly higher in cases with the SCA and higher WBC counts [131]. Sickling-induced capillary endothelial damage, activations of WBC, PLT, and coagulation system, and hemolysis may terminate with chronic capillary endothelial damage, edema, and fibrosis [132]. Stroke may not have a macrovascular origin, and an acute onset diffuse capillary endothelial edema may be more important in the SCD. Thus permanent neurological deficits are rare with stroke in the SCD. Infection, inflammation, medical or surgical emergency, and emotional stress may cause by increasing basal metabolic rate and sickling. Low risk of stroke with hydroxyurea can also suggest that a significant proportion is developed due to the increased WBC and PLT counts-induced an acute capillary endothelial edema P133].

Acarbose is a pseudotetrasaccharide produced as a natural microbial product of Actinoplanes strain SE 50. It binds to oligosaccharide binding site of alpha-glucosidase enzymes in the brush border of the small intestinal mucosa with a dose-dependent manner, reversibly and competitively. It inhibits glycoamylase, sucrase, maltase, dextranase, and pancreatic alpha-amylase. It has little affinity for isomaltase but does not have any effect on beta-glucosidases such as lactase. By this way, it delays the intestinal hydrolysis of oligo- and disaccharides mainly in the upper half of the small intestine. As a result, the absorption of monosaccharides is delayed, and transport into the circulation is interrupted. Its effects may prolong up to 5 hours. The suppression of alpha-glucosidases is persistent with long-term use. Its usage results with carbohydrates appearing in the colon where bacterial fermentation occurs, and causes flatulence, loose stool, and abdominal discomfort [134]. If started with a lower dosage and titrated slowly, side effects are tolerable [135]. Long-term use increases colonic bacterial mass that of lactobacteria in particular. The finally impaired carbohydrate absorption, increased bacterial carbohydrate fermentation, and fecal acidification mimic effects of lactulose in portosystemic encephalopathy. So acarbose has a favourable therapeutic profile for the long-term use even in cirrhosis. Similarly, observed changes in bacterial flora and decreased stool pH and beta-hydroxybutyrate may be associated with anti-proliferative effects on the epithelial cells of colon that may potentially decrease carcinogenesis. After oral administration, less than 2% of the unchanged drug enters into the circulation. Therefore there is no need for dosage adjustment in mild renal insufficiency. After a high carbohydrate meal, acarbose lowers the postprandial rise in blood glucose by 20% and secondarily FPG by 15% P136]. The initial improvement in blood glucose tends to be modest, but efficacy steadily improves with the long-term use. Its beneficial effects on serum lipids were also seen with a dose-dependent manner [136], because dietary carbohydrates are key precursors of lipogenesis, and insulin plays a central role for postprandial lipid metabolism. Carbohydrate-induced postprandial triglycerides synthesis is reduced for several hours, so acarbose lowers plasma triglycerides levels [136]. The same beneficial effect is also seen in non-diabetic patients with hypertriglyceridemia, and acarbose reduced LDL significantly, and HDL remained as unchanged in hyperinsulinemic and overweight patients with impaired glucose tolerance (IGT) [137]. Significantly elevated ursocholic acids in the stool appear to be the additive endpoint of a decreased rate of absorption and increased intestinal motility due to the changes of intestinal flora. Acarbose may lower LDL via increased fecal bifido bacteria and biliary acids. Acarbose together with insulin was identified to be associated with a greater improvement in the oxidative stress and inflammation in DM [138]. Probably, acarbose improves release of glucagon-like peptide-1, inhibits PLT activation, increases epithelial nitrous oxide synthase activity and nitrous oxide concentrations, promotes weight loss, decreases BP, and eventually prevents endothelial dysfunction [136]. So it prevents atherosclerotic endpoints of excess fat tissue even in the absence of IGT or DM [139, 140]. Although some authors reported as opposite [141], it should be used as the first-line antidiabetic agent. Based on more than 40 years of use, numerous studies did not show any significant side effect or toxicity [142]. Although 25.9% of patients stopped metformin due to excessive anorexia [143], only 10.6% stopped acarbose due to an excessive flatulence or loose stool [144].

Metformin is a biguanide, and it is not metabolized, and 90% of absorbed drug is eliminated as unchanged in the urine. Plasma protein binding is negligible, so the drug is dialyzable. According to literature, antihyperglycemic effect of metformin is largely caused by inhibition of hepatic gluconeogenesis, increased insulin-mediated glucose disposal, inhibition of fatty acid oxidation, and reduction of intestinal glucose absorption [145, 146]. Precise mechanism of intracellular action of metformin remains as unknown. Interestingly, 25.9% of patients stopped metformin due to the excessively lost appetite [143]. Additionally, 14.1% of patients with overweight or obesity in the metformin group rose either to normal weight or overweight group by weight loss without a diet regimen [143]. According to our opinion, the major effect of metformin is an inhibition of appetite. Similar results indicating the beneficial effects on the BMI, BP, FPG, and lipids were also reported [147,148]. Probably the major component of the metabolic syndrome may be the excess fat tissue. So treatment of excess fat tissue with acarbose plus metformin will probably prevent not only IGT or DM but also the other atherosclerotic endpoints.

As a conclusion, hardened RBC-induced capillary endothelial cell damage terminates with end-organ deficiencies in early decades in the SCD. Although atherosclerotic endpoints are so common, we detected no case of DM probably due to lower excess fat tissue. As the most common cause of CRD, DM may be a reversible insufficiency of pancreas against excess fat tissue in early phases. Increased blood and insulin needs of excess fat tissue in contrast to decreased blood supply of excess tissue and pancreas both due to excess pressure on vasculature, externally and atherosclerosis, internally may be important in the development of DM. Acarbose and metformin are safe, cheap, oral, long-term used, and effective drugs for loss of excess fat tissue which may even be curative in early phases of DM before development of other atherosclerotic endpoints.

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner

My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.

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Lin-Show Chin

My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.

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Sonila Qirko

My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.

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Luiz Sellmann

I would like to offer my testimony in the support. I have received through the peer review process and support the editorial office where they are to support young authors like me, encourage them to publish their work in your esteemed journals, and globalize and share knowledge globally. I really appreciate your journal, peer review, and editorial office.

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Zhao Jia

Dear Agrippa Hilda- Editorial Coordinator of Journal of Neuroscience and Neurological Surgery, "The peer review process was very quick and of high quality, which can also be seen in the articles in the journal. The collaboration with the editorial office was very good."

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Thomas Urban

I would like to express my sincere gratitude for the support and efficiency provided by the editorial office throughout the publication process of my article, “Delayed Vulvar Metastases from Rectal Carcinoma: A Case Report.” I greatly appreciate the assistance and guidance I received from your team, which made the entire process smooth and efficient. The peer review process was thorough and constructive, contributing to the overall quality of the final article. I am very grateful for the high level of professionalism and commitment shown by the editorial staff, and I look forward to maintaining a long-term collaboration with the International Journal of Clinical Case Reports and Reviews.

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Cristina Berriozabal

To Dear Erin Aust, I would like to express my heartfelt appreciation for the opportunity to have my work published in this esteemed journal. The entire publication process was smooth and well-organized, and I am extremely satisfied with the final result. The Editorial Team demonstrated the utmost professionalism, providing prompt and insightful feedback throughout the review process. Their clear communication and constructive suggestions were invaluable in enhancing my manuscript, and their meticulous attention to detail and dedication to quality are truly commendable. Additionally, the support from the Editorial Office was exceptional. From the initial submission to the final publication, I was guided through every step of the process with great care and professionalism. The team's responsiveness and assistance made the entire experience both easy and stress-free. I am also deeply impressed by the quality and reputation of the journal. It is an honor to have my research featured in such a respected publication, and I am confident that it will make a meaningful contribution to the field.

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Dr Tewodros Kassahun Tarekegn

"I am grateful for the opportunity of contributing to [International Journal of Clinical Case Reports and Reviews] and for the rigorous review process that enhances the quality of research published in your esteemed journal. I sincerely appreciate the time and effort of your team who have dedicatedly helped me in improvising changes and modifying my manuscript. The insightful comments and constructive feedback provided have been invaluable in refining and strengthening my work".

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Dr Shweta Tiwari

I thank the ‘Journal of Clinical Research and Reports’ for accepting this article for publication. This is a rigorously peer reviewed journal which is on all major global scientific data bases. I note the review process was prompt, thorough and professionally critical. It gave us an insight into a number of important scientific/statistical issues. The review prompted us to review the relevant literature again and look at the limitations of the study. The peer reviewers were open, clear in the instructions and the editorial team was very prompt in their communication. This journal certainly publishes quality research articles. I would recommend the journal for any future publications.

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Dr Farooq Wandroo

Dear Jessica Magne, with gratitude for the joint work. Fast process of receiving and processing the submitted scientific materials in “Clinical Cardiology and Cardiovascular Interventions”. High level of competence of the editors with clear and correct recommendations and ideas for enriching the article.

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Dr Anyuta Ivanova

We found the peer review process quick and positive in its input. The support from the editorial officer has been very agile, always with the intention of improving the article and taking into account our subsequent corrections.

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Dr David Vinyes

My article, titled 'No Way Out of the Smartphone Epidemic Without Considering the Insights of Brain Research,' has been republished in the International Journal of Clinical Case Reports and Reviews. The review process was seamless and professional, with the editors being both friendly and supportive. I am deeply grateful for their efforts.

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Gertraud Teuchert-Noodt

To Dear Erin Aust – Editorial Coordinator of Journal of General Medicine and Clinical Practice! I declare that I am absolutely satisfied with your work carried out with great competence in following the manuscript during the various stages from its receipt, during the revision process to the final acceptance for publication. Thank Prof. Elvira Farina

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Dr Elvira Farina

Dear Jessica, and the super professional team of the ‘Clinical Cardiology and Cardiovascular Interventions’ I am sincerely grateful to the coordinated work of the journal team for the no problem with the submission of my manuscript: “Cardiometabolic Disorders in A Pregnant Woman with Severe Preeclampsia on the Background of Morbid Obesity (Case Report).” The review process by 5 experts was fast, and the comments were professional, which made it more specific and academic, and the process of publication and presentation of the article was excellent. I recommend that my colleagues publish articles in this journal, and I am interested in further scientific cooperation. Sincerely and best wishes, Dr. Oleg Golyanovskiy.

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Dr Oleg Golyanovski

Dear Ashley Rosa, Editorial Coordinator of the journal - Psychology and Mental Health Care. " The process of obtaining publication of my article in the Psychology and Mental Health Journal was positive in all areas. The peer review process resulted in a number of valuable comments, the editorial process was collaborative and timely, and the quality of this journal has been quickly noticed, resulting in alternative journals contacting me to publish with them." Warm regards, Susan Anne Smith, PhD. Australian Breastfeeding Association.

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Dr Susan Anne Smith

Dear Jessica Magne, Editorial Coordinator, Clinical Cardiology and Cardiovascular Interventions, Auctores Publishing LLC. I appreciate the journal (JCCI) editorial office support, the entire team leads were always ready to help, not only on technical front but also on thorough process. Also, I should thank dear reviewers’ attention to detail and creative approach to teach me and bring new insights by their comments. Surely, more discussions and introduction of other hemodynamic devices would provide better prevention and management of shock states. Your efforts and dedication in presenting educational materials in this journal are commendable. Best wishes from, Farahnaz Fallahian.

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Dr Farahnaz Fallahian

Dear Maria Emerson, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews, Auctores Publishing LLC. I am delighted to have published our manuscript, "Acute Colonic Pseudo-Obstruction (ACPO): A rare but serious complication following caesarean section." I want to thank the editorial team, especially Maria Emerson, for their prompt review of the manuscript, quick responses to queries, and overall support. Yours sincerely Dr. Victor Olagundoye.

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Dr Victor Olagundoye

Dear Ashley Rosa, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews. Many thanks for publishing this manuscript after I lost confidence the editors were most helpful, more than other journals Best wishes from, Susan Anne Smith, PhD. Australian Breastfeeding Association.

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Dr Susan Anne Smith

Dear Agrippa Hilda, Editorial Coordinator, Journal of Neuroscience and Neurological Surgery. The entire process including article submission, review, revision, and publication was extremely easy. The journal editor was prompt and helpful, and the reviewers contributed to the quality of the paper. Thank you so much! Eric Nussbaum, MD

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Dr Eric S Nussbaum

Dr Hala Al Shaikh This is to acknowledge that the peer review process for the article ’ A Novel Gnrh1 Gene Mutation in Four Omani Male Siblings, Presentation and Management ’ sent to the International Journal of Clinical Case Reports and Reviews was quick and smooth. The editorial office was prompt with easy communication.

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Hala Al Shaikh

Dear Erin Aust, Editorial Coordinator, Journal of General Medicine and Clinical Practice. We are pleased to share our experience with the “Journal of General Medicine and Clinical Practice”, following the successful publication of our article. The peer review process was thorough and constructive, helping to improve the clarity and quality of the manuscript. We are especially thankful to Ms. Erin Aust, the Editorial Coordinator, for her prompt communication and continuous support throughout the process. Her professionalism ensured a smooth and efficient publication experience. The journal upholds high editorial standards, and we highly recommend it to fellow researchers seeking a credible platform for their work. Best wishes By, Dr. Rakhi Mishra.

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Dr Rakhi Mishra

Dear Jessica Magne, Editorial Coordinator, Clinical Cardiology and Cardiovascular Interventions, Auctores Publishing LLC. The peer review process of the journal of Clinical Cardiology and Cardiovascular Interventions was excellent and fast, as was the support of the editorial office and the quality of the journal. Kind regards Walter F. Riesen Prof. Dr. Dr. h.c. Walter F. Riesen.

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Dr Walter F Riesen

Dear Ashley Rosa, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews, Auctores Publishing LLC. Thank you for publishing our article, Exploring Clozapine's Efficacy in Managing Aggression: A Multiple Single-Case Study in Forensic Psychiatry in the international journal of clinical case reports and reviews. We found the peer review process very professional and efficient. The comments were constructive, and the whole process was efficient. On behalf of the co-authors, I would like to thank you for publishing this article. With regards, Dr. Jelle R. Lettinga.

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Dr Jelle Lettinga

Dear Clarissa Eric, Editorial Coordinator, Journal of Clinical Case Reports and Studies, I would like to express my deep admiration for the exceptional professionalism demonstrated by your journal. I am thoroughly impressed by the speed of the editorial process, the substantive and insightful reviews, and the meticulous preparation of the manuscript for publication. Additionally, I greatly appreciate the courteous and immediate responses from your editorial office to all my inquiries. Best Regards, Dariusz Ziora

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Dariusz Ziora

Dear Chrystine Mejia, Editorial Coordinator, Journal of Neurodegeneration and Neurorehabilitation, Auctores Publishing LLC, We would like to thank the editorial team for the smooth and high-quality communication leading up to the publication of our article in the Journal of Neurodegeneration and Neurorehabilitation. The reviewers have extensive knowledge in the field, and their relevant questions helped to add value to our publication. Kind regards, Dr. Ravi Shrivastava.

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Dr Ravi Shrivastava

Dear Clarissa Eric, Editorial Coordinator, Journal of Clinical Case Reports and Studies, Auctores Publishing LLC, USA Office: +1-(302)-520-2644. I would like to express my sincere appreciation for the efficient and professional handling of my case report by the ‘Journal of Clinical Case Reports and Studies’. The peer review process was not only fast but also highly constructive—the reviewers’ comments were clear, relevant, and greatly helped me improve the quality and clarity of my manuscript. I also received excellent support from the editorial office throughout the process. Communication was smooth and timely, and I felt well guided at every stage, from submission to publication. The overall quality and rigor of the journal are truly commendable. I am pleased to have published my work with Journal of Clinical Case Reports and Studies, and I look forward to future opportunities for collaboration. Sincerely, Aline Tollet, UCLouvain.

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Dr Aline Tollet

Dear Ms. Mayra Duenas, Editorial Coordinator, International Journal of Clinical Case Reports and Reviews. “The International Journal of Clinical Case Reports and Reviews represented the “ideal house” to share with the research community a first experience with the use of the Simeox device for speech rehabilitation. High scientific reputation and attractive website communication were first determinants for the selection of this Journal, and the following submission process exceeded expectations: fast but highly professional peer review, great support by the editorial office, elegant graphic layout. Exactly what a dynamic research team - also composed by allied professionals - needs!" From, Chiara Beccaluva, PT - Italy.

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Dr Chiara Giuseppina Beccaluva

Dear Maria Emerson, Editorial Coordinator, we have deeply appreciated the professionalism demonstrated by the International Journal of Clinical Case Reports and Reviews. The reviewers have extensive knowledge of our field and have been very efficient and fast in supporting the process. I am really looking forward to further collaboration. Thanks. Best regards, Dr. Claudio Ligresti

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Dr Claudio Ligresti

Dear Chrystine Mejia, Editorial Coordinator, Journal of Neurodegeneration and Neurorehabilitation. “The peer review process was efficient and constructive, and the editorial office provided excellent communication and support throughout. The journal ensures scientific rigor and high editorial standards, while also offering a smooth and timely publication process. We sincerely appreciate the work of the editorial team in facilitating the dissemination of innovative approaches such as the Bonori Method.” Best regards, Dr. Matteo Bonori.

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Dr Matteo Bonori

I recommend without hesitation submitting relevant papers on medical decision making to the International Journal of Clinical Case Reports and Reviews. I am very grateful to the editorial staff. Maria Emerson was a pleasure to communicate with. The time from submission to publication was an extremely short 3 weeks. The editorial staff submitted the paper to three reviewers. Two of the reviewers commented positively on the value of publishing the paper. The editorial staff quickly recognized the third reviewer’s comments as an unjust attempt to reject the paper. I revised the paper as recommended by the first two reviewers.

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Edouard Kujawski

Dear Maria Emerson, Editorial Coordinator, Journal of Clinical Research and Reports. Thank you for publishing our case report: "Clinical Case of Effective Fetal Stem Cells Treatment in a Patient with Autism Spectrum Disorder" within the "Journal of Clinical Research and Reports" being submitted by the team of EmCell doctors from Kyiv, Ukraine. We much appreciate a professional and transparent peer-review process from Auctores. All research Doctors are so grateful to your Editorial Office and Auctores Publishing support! I amiably wish our article publication maintained a top quality of your International Scientific Journal. My best wishes for a prosperity of the Journal of Clinical Research and Reports. Hope our scientific relationship and cooperation will remain long lasting. Thank you very much indeed. Kind regards, Dr. Andriy Sinelnyk Cell Therapy Center EmCell

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Dr Andriy Sinelnyk

Dear Editorial Team, Clinical Cardiology and Cardiovascular Interventions. It was truly a rewarding experience to work with the journal “Clinical Cardiology and Cardiovascular Interventions”. The peer review process was insightful and encouraging, helping us refine our work to a higher standard. The editorial office offered exceptional support with prompt and thoughtful communication. I highly value the journal’s role in promoting scientific advancement and am honored to be part of it. Best regards, Meng-Jou Lee, MD, Department of Anesthesiology, National Taiwan University Hospital.

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Dr Meng-JouLe

Dear Editorial Team, Journal-Clinical Cardiology and Cardiovascular Interventions, “Publishing my article with Clinical Cardiology and Cardiovascular Interventions has been a highly positive experience. The peer-review process was rigorous yet supportive, offering valuable feedback that strengthened my work. The editorial team demonstrated exceptional professionalism, prompt communication, and a genuine commitment to maintaining the highest scientific standards. I am very pleased with the publication quality and proud to be associated with such a reputable journal.” Warm regards, Dr. Mahmoud Kamal Moustafa Ahmed

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Mahmoud Kamal Moustafa Ahmed

Dear Maria Emerson, Editorial Coordinator of ‘International Journal of Clinical Case Reports and Reviews’, I appreciate the opportunity to publish my article with your journal. The editorial office provided clear communication during the submission and review process, and I found the overall experience professional and constructive. Best regards, Elena Salvatore.

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Dr Elena Salvatore

Dear Mayra Duenas, Editorial Coordinator of ‘International Journal of Clinical Case Reports and Reviews Herewith I confirm an optimal peer review process and a great support of the editorial office of the present journal

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Christoph Maurer

Dear Editorial Team, Clinical Cardiology and Cardiovascular Interventions. I am really grateful for the peers review; their feedback gave me the opportunity to reflect on the message and impact of my work and to ameliorate the article. The editors did a great job in addition by encouraging me to continue with the process of publishing.

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Baciulescu Laura

Dear Cecilia Lilly, Editorial Coordinator, Endocrinology and Disorders, Thank you so much for your quick response regarding reviewing and all process till publishing our manuscript entitled: Prevalence of Pre-Diabetes and its Associated Risk Factors Among Nile College Students, Sudan. Best regards, Dr Mamoun Magzoub.

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Dr Mamoun Magzoub

International Journal of Clinical Case Reports and Reviews is a high quality journal that has a clear and concise submission process. The peer review process was comprehensive and constructive. Support from the editorial office was excellent, since the administrative staff were responsive. The journal provides a fast and timely publication timeline.

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Joel Yat Seng Wong

Dear Maria Emerson, Editorial Coordinator of International Journal of Clinical Case Reports and Reviews, What distinguishes International Journal of Clinical Case Report and Review is not only the scientific rigor of its publications, but the intellectual climate in which research is evaluated. The submission process is refreshingly free of unnecessary formal barriers and bureaucratic rituals that often complicate academic publishing without adding real value. The peer-review system is demanding yet constructive, guided by genuine scientific dialogue rather than hierarchical or authoritarian attitudes. Reviewers act as collaborators in improving the manuscript, not as gatekeepers imposing arbitrary standards. This journal offers a rare balance: high methodological standards combined with a respectful, transparent, and supportive editorial approach. In an era where publishing can feel more burdensome than research itself, this platform restores the original purpose of peer review — to refine ideas, not to obstruct them Prof. Perlat Kapisyzi, FCCP PULMONOLOGIST AND THORACIC IMAGING.

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Dr Perlat Kapisyzi

Dear Grace Pierce, International Journal of Clinical Case Reports and Reviews I appreciate the opportunity to review for Auctore Journal, as the overall editorial process was smooth, transparent and professionally managed. This journal maintains high scientific standards and ensures timely communications with authors, which is truly commendable. I would like to express my special thanks to editor Grace Pierce for his constant guidance, promt responses, and supportive coordination throughout the review process. I am also greatful to Eleanor Bailey from the finance department for her clear communication and efficient handling of all administrative matters. Overall, my experience with Auctore Journal has been highly positive and rewarding. Best regards, Sabita sinha

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Sabita sinha

Dear Mayra Duenas, Editorial Coordinator of the journal IJCCR, I write here a little on my experience as an author submitting to the International Journal of Clinical Case Reports and Reviews (IJCCR). This was my first submission to IJCCR and my manuscript was inherently an outsider’s effort. It attempted to broadly identify and then make some sense of life’s under-appreciated mysteries. I initially had responded to a request for possible submissions. I then contacted IJCCR with a tentative topic for a manuscript. They quickly got back with an approval for the submission, but with a particular requirement that it be medically relevant. I then put together a manuscript and submitted it. After the usual back-and-forth over forms and formality, the manuscript was sent off for reviews. Within 2 weeks I got back 4 reviews which were both helpful and also surprising. Surprising in that the topic was somewhat foreign to medical literature. My subsequent updates in response to the reviewer comments went smoothly and in short order I had a series of proofs to evaluate. All in all, the whole publication process seemed outstanding. It was both helpful in terms of the paper’s content and also in terms of its efficient and friendly communications. Thank you all very much. Sincerely, Ted Christopher, Rochester, NY.

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Dr Ted Christopher