bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating Estrogen Metabolites and Risk of Breast Cancer among Postmenopausal Women in the Nurses’ Health Study
Authors: Brantley Kristen D. , Ziegler Regina G. , Craft Neal E. , Hankinson Susan E. , Eliassen A. Heather
Published: August 2024

Background:

Estradiol and estrone are well-established risk factors for postmenopausal breast cancer. Experimental evidence suggests that specific estrogen metabolites, produced via irreversible hydroxylation of estrone and estradiol at position 2 or 16, may independently influence carcinogenesis.

Methods:

We performed a nested case–control study of breast cancer (328 breast cancer cases; 639 controls) among postmenopausal women within the Nurses’ Health Study to examine the role of estrogens and estrogen metabolites (jointly referred to as EM). Plasma concentrations of each EM (unconjugated + conjugated forms) were measured by LC-MS/MS. Multivariable conditional logistic regression, adjusting for breast cancer risk factors, estimated relative risks (RR) and 95% confidence intervals of breast cancer across quintiles of individual EM, EM pathways, and pathway ratios. Associations by estrogen receptor (ER) and progesterone receptor (PR) status were analyzed by unconditional logistic regression.

Results:

Estradiol and estrone were strongly associated with increased breast cancer risk [estradiol: RRQ5 vs. Q1 (95% confidence interval) = 2.64 (1.64–4.26); estrone: 2.78 (1.74–4.45); both P-trends <0.001]. The 2-hydroxylation pathway was strongly associated with risk [RRQ5 vs. Q1 = 3.09 (1.81–5.27); P-trend <0.001] and remained so after adjusting for unconjugated estradiol [RRQ5 vs. Q1 = 2.23 (1.25–3.96); P-trend = 0.01]. Although the 16-hydroxylation pathway was modestly associated with risk [RRQ5 vs. Q1 = 1.62 (1.03–2.54); P-trend = 0.01], the association was attenuated after unconjugated estradiol adjustment [RRQ5 vs. Q1 = 1.24 (0.77–1.99); P-trend = 0.19]. Similar positive associations with the 2-pathway and 16-pathway were observed for ER+/PR+ and ER−/PR− tumors.

Conclusion:

In this cohort of postmenopausal women, 2-hydroxylation of estrone and estradiol was associated with increased breast cancer risk, independent of unconjugated estradiol.

Impact:

These results highlight the need to revisit the role of estrogen metabolism in breast cancer etiology and prevention.
Phase II Clinical Chemoprevention Trial of Weekly Erlotinib before Bladder Cancer Surgery
Authors: Downs Tracy M. , Bailey Howard H. , Lozar Taja , Schmitz Natalie S. , Green Heather , Scarlett Cameron O. , Havighurst Thomas C. , Twaroski Kyleigh , DeShong Katina , Wollmer Barbara , Bivalacqua Trinity J. , Saltzstein Daniel R. , Shore Neal , Kim KyungMann , Huang Wei , Ricke William A. , Barroilhet Lisa , House Margaret , Parnes Howard L. , Messing Edward
Published: August 2024

We performed a clinical trial in patients with non–muscle-invasive (NMI) urothelial cancer randomized (2:1) to the EGFR tyrosine kinase inhibitor erlotinib or placebo (either orally once weekly × 3 doses prior to scheduled surgery) to assess for a difference in EGFR phosphorylation in tumor-adjacent normal urothelium <24 hours post–study dose and tolerance of weekly erlotinib therapy. Thirty-seven volunteers (6 female/31 male; mean age 70; 35 White/2 non-White) with confirmed or suspected NMI urothelial cancer were enrolled into either erlotinib (n = 24; 900 mg-13, 600 mg-11) or placebo (n = 13). IHC assessment of phosphorylated and total EGFR in tumor-adjacent normal urothelium (20 erlotinib and 9 placebo subjects) or tumor (21 erlotinib and 11 placebo subjects) at study end showed no significant difference between those receiving erlotinib or placebo. This was also true for other assessed tissue biomarkers (phosphorylated ERK, ERK, E-cadherin, p53, and Ki67). Adverse events were more common, in a dose-related fashion, in participants receiving erlotinib, e.g., 38% experienced grade 1 with rare grade 2 diarrhea and skin toxicity versus 8% in placebo. Clinically insignificant but statistically significant (P = 0.001) elevations in serum total bilirubin and creatinine were observed in participants receiving erlotinib. Serum erlotinib and metabolite concentrations (OSI-420) confirmed compliance in all subjects receiving erlotinib and did not significantly differ between the 600 and 900 mg doses. Despite compelling preclinical and clinical data for targeted EGFR inhibition in bladder cancer prevention, these data do not support the use of weekly erlotinib therapy to prevent progression of NMI bladder cancer.

Prevention Relevance: We evaluated the potential of erlotinib in preventing cancer by performing a randomized, double-blind, placebo-controlled trial of weekly erlotinib therapy in participants undergoing surgical removal of suspected noninvasive bladder neoplasia. Weekly erlotinib therapy was tolerated with common grade 1 to 2 toxicities but without evidence of beneficial effect upon urothelial tissue.

See related Spotlight, p. 7
Medicinal plants used in the treatment of diabetes in Morocco
Authors: Bnouham Mohamed , Legssyer Abdelkhaleq , Mekhfi Hassane , Ziyyat Abderrahim
Published: August 2024

The present review shows a listing of medicinal plants used in phytotherapy of diabetes and those
experimentally studied as hypoglycaemic in Morocco. The review is presented as 3 tables. The first one
includes the taxonomic classification of the plant, the popular names in Morocco, the parts used, the
mode of preparation and the other medicinal uses and toxicity. The second table summarises the
experiments done by Moroccan researchers to confirm the hypoglycemic activity of the medicinal
plants. It also describes the methodology used, and the magnitude of the hypoglycemic activity. The
third table lists the toxicological studies carried out with plants reported to be toxic. The large number
of plants described in this review (94 species belonging to 38 families) demonstrated the prevalence of
phytotherapy in Morocco. The plant families which contained the most commonly used species for their
antidiabetic effects are: Compositae (18 species), Lamiaceae (14 sp.), Leguminosae (8 sp.), Liliaceae (5
sp.), Apiaceae (5 sp.), and Graminae (4 sp.). Among these medicinal plants, 17 are toxic, the most
known being: Daphne gnidium, Nerium oleander, Ferula communis, Peganum harmala and Citrullus
colocynthis.
Starvation and the development of the metabolic syndrome
Authors: Savona-Ventura C. , Zammit K. , Vella S.
Published: August 2024

A number of studies have associated the adult-onset disease state of Metabolic Syndrome with either a low or a high birth
weight. This has been correlated to alterations in the intrauterine milieu causing changes in pancreatic and hypothalamic
development. This study was designed to test for a possible link between the nutritional deprivation which occurred during
the Second World War in Malta to an increased risk of gestational carbohydrate metabolism abnormalities. The study
confirmed that women who were born during the war were statistically more likely to have infants with a higher mean birth
weight than their counterparts born before and after the war. (Int J Diabetes Metab 15: 1-3, 2007)
Non-enzymatic glycosylation reaction contributes to a rise of blood glucose in alloxan-induced diabetic rats
Authors: Zhang Zhicai , Cui Feng-Jie
Published: August 2024

Non-enzymatic glycosylation reaction, which proceeded at an accelerated rate in diabetes, directly caused sharp diminution of
total haemoglobin due to glycosylated proteins including haemoglobin digested by macrophages. The diminution contributed
to hypoxia of tissue that repressed the enzymatic activities in the respiratory chain as well as in the tri-carboxylic acid cycle
(TCA) and Embden-Meyerhof-Parnas (EMP) pathways. It was postulated that non-enzymatic glycosylation reaction
accelerated the rise of blood glucose. The theory was further proven by the hypoglycaemic activities of the extract from
Tremella aurantialba broth (TBE). TBE inhibited the formation of advanced glycosylation end-products (AGEs) in vitro (IC50
=1.7 mg/ml) and in vivo. TBE, when given in vitro, increased the concentration of total haemoglobin and supply of oxygen,
enhanced respiration of tissue, decreased the levels of NADH, speeded up catabolism of glucose and finally generated
significant anti-hyperglycaemic and hypoglycaemic effect on alloxan-induced diabetic rats. In addition it elevated plasma
insulin level. Oral administration of TBE (100 mg/Kg bw) once a day for 4 weeks resulted in significant reduction in the
plasma levels of glucose, fructosamine and the ratio of glycosylated haemoglobin to total haemoglobin. Moreover, oral
administration of TBE increased the total haemoglobin and plasma insulin levels and enhanced some key enzymatic activities
of EMP, TCA pathways and respiratory chain in the blood of diabetic rats compared with control. (Int J Diabetes Metab 15:
52-59, 2007)
The efficacy and safety of rosiglitazone with concurrent sulphonylurea therapy in subjects with type 2 diabetes mellitus in Nigeria
Authors: Onyemelukwe G.C. , Wokoma S.S. , Ohwovoriole A.E. , Bakari A.G.
Published: August 2024

An open label study was conducted to asses the efficacy and safety of rosiglitazone when administered concurrently with
sulphonylurea compounds. Sixty-three type 2 diabetic patients were enrolled in the study in three different centres across
Nigeria, Zaria in the north, Lagos in the southwest and Port Harcourt in the southeast. Nigeria is a large country with multiethnic
groups. Subjects were randomly divided into two treatment groups; one on only sulphonylurea and the other on
rosiglitazone (4 mg daily) for 26 weeks in addition to the current dose of sulphonylurea. Fifty-two subjects (82.5%)
completed the study. The addition of rosiglitazone to sulphonylurea therapy resulted in more steady control of fasting plasma
glucose (FPG) over time, higher mean change in FPG from baseline and higher proportion of subjects recording HBA1C
value of <7.5. There were no significant adverse events attributable to rosiglitazone therapy during the 26 weeks of therapy. It
is concluded that the addition of rosiglitazone to sulphonylurea treatment is safe and has a synergistic effect in controlling
glycaemia in type 2 diabetic patients. (Int J Diabetes Metab 15:62-67, 2007)
The association of TGF-β1, angiotensin II and oxidative stress with diabetic nephropathy in type 2 diabetic patients
Authors: El-mesallamy H.O. , Gad M.Z. , Sallam A.M.
Published: August 2024

Diabetic nephropathy (DN) is a severe complication of diabetes which may progress to end-stage renal disease (ESRD). Chronic hyperglycemia is considered as the major initiator of DN, either by creation of oxidative stress or by induction of growth factors and cytokines. Moreover, dyslipidemia plays a role in DN progression. The aim of our study was to examine the changes in lipid profile, malondialdehyde (MDA), transforming growth factor-β1 (TGF-β1) and angiotensin II (Ang II) levels in type 2 diabetic patients associated with kidney disease. Diabetic microalbuminuric (n=25) and macroalbuminuric (n=15) patients showed significantly higher levels of blood glucose, glycated hemoglobin (HbA1c), triglycerides (TG), total cholesterol (TC), MDA, TGF-β1 and Ang II than either diabetic normoalbuminuric (n=14) or control (n=16) subjects. In the microalbuminuric and macroalbuminuric diabetic groups, albumin excretion rate (AER) was positively correlated with MDA (r=0.448, p<0.01), TGF-β1 (r=0.81, p<0.01) and Ang II (r=0.772, p<0.01). Additionally, MDA correlated with TGF-β1 (r=0.625, p<0.01) and Ang II (r=0.428, p<0.01). In conclusion, dyslipidemia, oxidative stress, and increased TGF-β1 and Ang II are associated with DN in type 2 diabetic patients.
Effects of isotretinoin on bone turnover markers and bone mineral density in women with acne vulgaris and vitamin D deficiency: a preliminary study.
Authors: Saadi H. , Afandi B. , Houssami L. , Saleh N. , Mohamadiyeh M. , Benedict S.
Published: August 2024

The prolonged use of retinoids is associated with changes in bone turnover markers and toxic skeletal effects. Although the effect of short-term oral isotretinoin therapy on bone loss is not well established, caution is recommended when it is used in patients with metabolic bone disease. We examined prospectively the effect of short-term oral isotretinoin therapy on bone turnover markers and bone mineral density (BMD) in women affected by severe acne and vitamin D deficiency. Serum bone Tartrate-resistant Acid Phosphatase (TRACP), bone specific alkaline phosphatase (Bone ALP), calcium, phosphorus, parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D] were measured in 10 women at baseline, 6 weeks, and end of isotretinoin treatment. BMD was measured in 5 subjects at baseline and end of treatment. Mean serum 25(OH)D at baseline was 16.3  7.5 nmol/L. Mean TRACP and Bone ALP increased at end of treatment but this was only statistically significant for TRACP (1.18, 1.13, 1.64 U/L; P<0.001). Mean calcium decreased slightly at end of treatment but no significant changes occurred in PTH, 25(OH)D and phosphorus. BMD decreased in all studied patients at the femur (range -2.5 to -7.6%), and in all but one patient at the lumbar spine (range +3.2 to -6.8%). Mean BMD decreased at all measured sites but this was statistically significant only for the femur (-5.3  1.9%; P=0.002). Our preliminary study suggests that short-term oral isotretinoin therapy in women with vitamin D deficiency is likely associated with increased bone resorption and decreased BMD. Correction of vitamin D deficiency may be necessary before starting isotretinoin therapy.
A survey amongst Complementary Alternative Medicine (CAM) users with type 2 diabetes
Authors: Huri Hasniza Zaman , Lian Grace Tan Poh , Hussain Samsinah , Pendek Rokiah , Widodo Riyanto Teguh
Published: August 2024

This survey studied the different types of Complementary Alternative Medicine (CAM) usage, the reasons of CAM usage and the out-of-pocket expenditure incurred by CAM users with Type 2 diabetes. Methods: This was a descriptive, cross-sectional survey that involved 132 Type 2 diabetes patients. Results: A total of 30.2% of the patients used dietary supplements, followed by traditional Chinese medicine (TCM) (25.1%) and traditional Malay medicine (17.9%). Two main reasons for using CAM include: the need of patients for more control of their diabetes and also dissatisfaction with conventional medicine. More than half of the patients spent around USD 7.2 to USD 13.9 per month on CAM as an out-of-pocket expenditure. Less than 20% of the patients consult their physicians before using CAM. About 57% of patients stated that their diabetes control did not show any improvement or worsen after CAM usage. Conclusion: CAM was widely used among Type 2 diabetics as an adjunct to their conventional therapy. More than half of the patients found that CAM did not give improvement nor worsens their diabetes control. CAM was one of the alternative treatments considered by Type 2 diabetes patients in complement with the conventional treatment for their diabetes control.
Lack of correlation between serum alanine amino transferrase and abdominal ultrasound in the diagnosis non alcoholic fatty liver disease in type 2 diabetes
Authors: Fallatah Hind I. , Akbar Hisham O.
Published: August 2024

Non alcoholic fatty liver disease (NAFLD) and type II diabetes (DM II) are increasingly recognized. Screening of DM II patients for NAFLD includes serum alanine amino transferase (ALT) and abdominal ultrasound (US). A retrospective cohort study was used to examine the sensitivity of serum ALT in the diagnosis of NAFLD in type 2 DM patients when compared to abdominal ultrasound and to determine the predictive factors of serum ALT in type 2 DM patients. Patient's age, sex, and history of hypertension (HTN), hyperlipidemia, height and weight were obtained from type 2 DM patients attending Out-patient Clinics. The body mass index (BMI) was also measured. Then retrospectively, we collected results of liver function tests, fasting lipids and abdominal US. Out of the 72 patients (30 males, 42 females; mean age: 58.49), 38.9% had hyperlipidemia, 59.7 % had HNT. The mean BMI was 29.97. Females were more obese and morbidly obese compared to males (p  0.001). 69 patients had normal serum ALT. Mean serum ALT for males was 39.29 U/L (95% CI 33.5-45.07) and the value for females was 30.9U/L (95% CI 33.55-36.2). The difference between the values in male and females was statistically significant (p  0.033). The serum ALT in type 2 DM obese and morbidly obese patients was significantly (p  0.034) higher than that of normal and overweight patients. 55.6% had NAFLD by US. ALT was not different in patients with US diagnosed NFLD from those without. HTN significantly increased the risk for NAFLD (p  0.018). In conclusion, serum ALT correlates poorly with abdominal US in the diagnosis of NAFLD in type 2 diabetic patients. Sex and BMI significantly influence serum ALT in type 2 DM patients.
Twelve-week resistance training decreases myostatin level and improves insulin sensitivity in overweight-obese women
Authors: Saremi Abbas Saremi , Parastesh Mohammad
Published: August 2024

Myostatin is a secreted protein that acts as a potent inhibitor of skeletal muscle growth. Inactivation of myostatin increases muscle mass and decreases insulin resistance. The aim of this study was to determine if the improvement in insulin resistance after resistance training is associated with a decline in serum levels of myostatin. A sample of 19 obese-overweight women (age= 23.2±3.4 yr, body mass index= 29.18±1.72 kg/m2) were assigned to resistance training (n= 10) and control (n= 9) groups. Resistance training was performed 3 times weekly for 12 weeks. Body composition, metabolic parameters, and myostatin were measured prior to and after the intervention. Insulin resistance improved significantly after 12wk of resistance training (P<0.05), but without changes in adiposity parameter such as body weight, body mass index, fat percent and waist circumference (p>0.05). Also, following the resistance training, muscle strength and lean body mass were significantly increased (P<0.05). Concurrently, myostatin concentration significantly decreased in response to resistance training (P<0.05). In conclusion, 12-wk resistance training program increases insulin sensitivity in obese-overweight women, and this improvement was associated with decreased myostatin levels but is independent of measurable changes in body fat. These data suggest that resistance training-induced alterations in myostatin levels may have a role in resistance training-induced insulin sensitivity improvement.
Gender associated differences in diet and anthropometric measures in Cape Breton Caucasians with well-controlled type 2 diabetes
Authors: Barre Douglas E. , Mizier-Barre Kazimiera A. , Griscti Odette , Hafez Kevin
Published: August 2024

Diet and anthropometic measures are important indicators of risk of various complications in type 2 diabetics. The purpose was to assess the hypothesis that there would be gender differences in anthropometric measures and dietary intakes for energy and energy-yielding nutrients including oleic acid in the study population of well-controlled (HbA1c < 8 %) Caucasian type 2 diabetics. Males (n=18) and females (n = 14) participated. Subjects came in for two visits each 3 months apart. Males differed from females only in height (m) (1.72 + 0.02 vs 1.59 ± 0.01), hip circumference (cm) (103.0 ± 1.4 vs 117.8 ± 3.9), waist to hip ratio (0.99 ± 0.01 vs 0.87 ± 0.01 and waist to height ratio (0.591 ± 0.010 vs 0.640 ± 0.018). Despite a higher intake for total calories in males and similar intakes for the energy yielding nutrients including oleic acid in the study population of type 2 diabetics, males and females had similar weights and waist circumferences while males had greater waist to hip ratios, lesser waist to height ratios and very a strong trend toward lesser BMI. Females are further away from recommended anthropometric targets and as such appear to be at greater risk of complications from type 2 diabetes.
Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder in Huntington Disease Patient with Improvement in Neuropsychiatric and Movement Symptoms: A Case Report
Authors: Rahn Cheyenne , Peterson Kris , Lamb Elizabeth
Published: August 2024

Introduction: Huntington disease (HD) is a progressive disorder characterized by significant neurodegeneration that results in severe neuropsychiatric symptoms and disordered movement. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive treatment that has been used in major depressive disorder (MDD) with great success. Case Presentation: We present a case of a patient with newly diagnosed HD, persistent MDD with suicidal ideation, and generalized anxiety disorder who was treated with rTMS and had sustained significant improvement of her mood disorder with additional improvement of her movement disorder. Conclusion: This result brings into question the use of rTMS to treat MDD and chorea in patients with HD, especially early in its course.
Impact of Selective Reporting of Antibiotic Susceptibility Test Results on Antibiotic Use in Patients with Bloodstream Infection with Streptococcus pneumoniae
Authors: Geismann Florian , Brueckner Kathleen , Pfeifer Michael , Salzberger Bernd , Bauernfeind Stilla , Hitzenbichler Florian , Simon Michaela , Caplunik-Pratsch Aila , Schneider-Brachert Wulf , Wiest Clemens , Hinterberger Thilo , Ruegamer Tamara , Mohr Arno
Published: August 2024

Introduction: Invasive pneumococcal disease is a major cause of morbidity and mortality in infectious diseases. Selective reporting of antibiotic susceptibility test results might lead to a tailored antibiotic therapy and could therefore be an important antibiotic stewardship program intervention. The aim of this study was to analyse whether a switch to selective reporting of antibiotic test results leads to a more focused antibiotic therapy in patients with a bloodstream infection with Streptococcus pneumoniae. Methods: This study was performed as a retrospective cohort study at the University Hospital Regensburg, Germany. All blood cultures positive for Streptococcus pneumoniae between 2006 and 2021 were analysed. In 2014, a switch to selective reporting of antibiotic susceptibility test results omitting sensitivity results for agents not recommended was introduced. Results: Twenty-four hours after final antibiotic susceptibility test results were available, 20.9% before (BI) versus 15.4% after implementation (AI) of selective reporting of antibiotic test results received a narrow-spectrum penicillin, while only 2.3% BI versus 5.8% AI received a narrow-spectrum penicillin from the beginning. Conclusion: Selective reporting of antibiotic susceptibility test results without further antimicrobial stewardship interventions did not lead to a higher use of a narrow-spectrum penicillin in this study.
Mixed Neuroendocrine-Non-Neuroendocrine Neoplasms of the Rectum: A Case Report
Authors: Verdasca Filipa Ribeiro , Ferreira Rita , Montenegro Alexandra , Mendes José Leão , Furtado Ivánia , Escaleira Rui , Fernandes Válter , Seladas Marta , Cristovão Miguel , da Luz Ricardo , Guerreiro Inês
Published: August 2024

Introduction: Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNEN) represent roughly 1–2% of all colorectal malignancies. Given the rareness and heterogeneity of these mixed tumors, recognition and accurate diagnosis remain a challenge. In the absence of established guidelines, they are treated according to the standard of care for pure neuroendocrine carcinomas or adenocarcinomas from similar sites of origin. Case Presentation: We herein report a case of a rectal MiNEN in a 55-year-old male. He underwent colonoscopy for rectal bleeding and mucus emission, which revealed a vegetating lesion located approximately 8 cm from the anal verge, corresponding to a moderately differentiated low-grade adenocarcinoma of the rectum. Computed tomography scan and magnetic resonance imaging uncovered the presence of lung, lymph node, and subcutaneous implant metastases. The biopsy of the cutaneous implant showed neuroendocrine carcinoma Ki-67 90%. The patient underwent systemic chemotherapy. Conclusion: High-grade MiNEN tumors are the most commonly encountered in clinical practice and have an aggressive biological behavior. Little is known about the genetic drivers of this neoplasm and its pathogenesis remains controversial. Clinical and pathological awareness of this rare entity is a key step to design future targeted therapies and improve treatment options. The aim of this case report is to further our understanding regarding the clinical presentation, radiological features, pathology, management, and prognosis of MiNEN.
Severe Hepatitis Complicating Olmesartan Enteropathy: A Case Report
Authors: Tan Ruyi , Abasszade Joshua Haron , Dhillon Hardesh , Kuan Chih Chien , Worland Thomas , Tabatabai Shireen
Published: August 2024

Introduction: Olmesartan, an angiotensin II receptor antagonist, is associated with an uncommon complication of enteropathy that presents insidiously, usually months to years after initial commencement of anti-hypertensive therapy which can be dose-dependent. It has a variable spectrum of clinical presentation but commonly presents as a moderate to severe malabsorptive process with potential severe complications related to poor end-organ perfusion. Lymphocytic gastritis and microscopic colitis are often noted in patients presenting with olmesartan-induced enteropathy; however, hepatic involvement has been less frequently observed. Case Presentation: We illustrate a case of a 43-year-old female presenting with 2 weeks of profuse non-bloody diarrhea in the context of olmesartan enteropathy which was complicated by an acute severe ischemic and enteropathic hepatopathy. Conclusion: Our case prompts clinicians to maintain a high index of suspicion in cases presenting with a seronegative enteropathy and concurrent acute liver injury while on olmesartan therapy. Cessation of olmesartan therapy resulted in prompt resolution of diarrheal symptoms and normalization of the acute transaminitis on subsequent three-week follow-up.
Differential Effect of JAK1/2 and TYK2 Inhibitors on Type III Interferon Induced Antiviral Defence in Human Intestinal Epithelial Cells
Authors: Castro Martha A. , Ringqvist Emma E. , Parajuli Anirudra , Stone Virginia M. , Flodström-Tullberg Malin
Published: August 2024

Introduction: Many cytokines, acting via Janus kinase (JAK)/tyrosine kinase 2 (TYK2)/signal transducer and activator of transcription (STAT) signalling pathways, are critical mediators of pathology in immune-mediated inflammatory diseases (IMIDs). Therefore, drugs that inhibit JAKs and TYKs (JAKis) have gained traction as effective treatment options for IMIDs. However, a common side effect of JAKis is increased risk of viral infection. Type I and III interferon (IFN) signal via JAK1 and TYK2. Type III IFNs protect mucosal membranes, including the intestinal barrier, from viral infection and type I IFNs prevent systemic viral spread. Methods: The human cell lines Caco-2 and HT-29 were used to investigate the impact of currently approved JAKis, baricitinib (JAK1/2 inhibitor) and deucravacitinib (TYK2 inhibitor), on type I and III IFN signalling and antiviral defence of intestinal epithelial cells (IECs). Results: Using concentrations commonly used for in vitro studies on IFNs, we found that attenuation of IFN-mediated antiviral defence in IECs is a mechanism that could contribute to the increased risk of viral infections associated with JAKis. However, when we examined clinically relevant drug concentrations, we found that while both drugs blocked the type I IFN response, type III IFN-induced antiviral immunity was less affected during TYK2 inhibition (deucravacitinib) compared to JAK1/2 inhibition (baricitinib). Conclusions: Our studies suggest that in treating diseases associated with excessive cytokine production (e.g., type I IFNs, interleukin (IL)-6, and IL-23), a TYK2 inhibitor may be preferable over a JAK1/2 inhibitor. This preference arises as the TYK2 inhibitor can effectively block the activity of proinflammatory and tissue-damaging cytokines (e.g., type I IFNs), while having less negative impact on the intestine’s ability to respond to type III IFN, thereby enabling it to enter an antiviral state.
Ruyi Zhenbao Tablet and Baimai Ointment Therapy in Acute Ischemic Stroke: A Study Protocol for a Multi-Center, Randomized, Double-blinded, and Parallel-Controlled Trial
Authors: Qin Xinzuo , Huang Liyuan , Zhang Haiyue , Wang Zijian , Wu Xiao , Mingji Cuomu , Wan Qi , Song Haiqing , Song Juexian
Published: August 2024

Introduction: Stroke is characterized by high incidence, recurrence rate, and mortality. Patients with acute ischemic stroke (AIS) who are ineligible for acute revascularization therapy require more effective medication treatments. A previous clinical study showed that Ruyi Zhenbao tablets and Baimai ointments might be effective against AIS; however, high-quality clinical evidence supporting their application in AIS is lacking. To explore the efficacy of the two classic Tibetan medicines in the treatment of AIS, a randomized clinical trial will be conducted in patients with AIS who are not eligible for thrombolytic treatment. Methods: A prospective, randomized, multiple-center, double-blinded, placebo-controlled, and parallel-group trial will be conducted. We shall randomize 480 eligible participants to either the intervention or the control group. The distribution ratio of each group will be 1:1:1:1, including 120 patients each in the dual-medication group, the Baimai ointment group, the Ruyi Zhenbao tablet group, and the placebo group. Participants will be treated with medication for 8 weeks, and they will receive three follow-up visits: at 4 weeks (D29), 8 weeks (D56), and 90 days (D90) after commencing treatment. The primary outcome will be D90 change in the simplified Fugl-Meyer score from baseline to posttreatment. The secondary outcomes are as follows: D29 change of simplified Fugl-Meyer score from baseline to posttreatment; proportion of participants whose D29 NIHSS scores decreased by four or more points from baseline D90 proportion of subjects with mRS score of 0–2 (inclusive); D90 proportion of subjects with Barthel index score ≥95; D90 incidence of cardiovascular and cerebrovascular events. Safety endpoint includes mortality within 90 days; proportion of subjects with adverse events/serious adverse events within 90 days. Conclusion: This research protocol lays a solid groundwork for its practical execution. This study is poised to serve as a reference for other Tibetan medicine researchers, contributing to the reduction of stroke-related expenditures globally and, in turn, benefiting a broader population of stroke patients.
Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia: A Blanked Out Pulmonary Neuroendocrine Tumor
Authors: Swied Muhammed Yaman , Azhar Waqas , Alkhabaz Anas , Zaidi Fawwad
Published: August 2024

Introduction: Lung neuroendocrine tumors (NETs) are a rare type of pulmonary tumor and represent approximately 2% of all lung cancers. The prevalence of lung NETs is increasing, which may be due to improved diagnostic techniques for asymptomatic tumors. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare and underdiagnosed disease that falls under the spectrum of NETs. Case Presentation: We presented a case of a 59-year-old male who presented with severe coughing spells, flushing, and diarrhea. His computed tomography scan showed innumerable pulmonary nodules and irregular nodular opacities throughout the lungs. He underwent a left upper lobe wedge resection and was eventually diagnosed with neuroendocrine tumorlets via immunohistochemical stains. He was started on a trial of octreotide and reported significant improvement in symptoms after 1 month. Conclusion: DIPNECH is a rare preinvasive lesion characterized by the abnormal proliferation of pulmonary neuroendocrine cells. Patients with DIPNECH can present initially with respiratory symptoms, while other cases are discovered incidentally during the workup of different conditions. Definitive diagnosis of DIPNECH requires histopathological examination of lung tissue. There is limited evidence on DIPNECH management, and an individualized approach is currently advised.
Two Cases of Increased Gastrointestinal Polyps in Familial Adenomatous Polyposis following Antiacid Agent Intake
Authors: Urabe Yuji , Ishikawa Hideki , Ishikawa Akira , Ishiguro Shingo , Ishibashi Kazuki , Arihiro Koji , Mutoh Michihiro , Oka Shiro
Published: August 2024

Introduction: Familial adenomatous polyposis (FAP), a hereditary disorder of the gastrointestinal tract, is an autosomal dominant inherited condition caused by germline mutations in the adenomatous polyposis coli (APC) gene. It is characterized by the development of hundreds to thousands of colorectal adenomatous polyps, which, if left untreated, can eventually develop into colorectal carcinomas. Representative extracolonic tumors in FAP include multiple duodenal adenomas and desmoid tumors. Moreover, multiple fundic gland polyps are frequently identified in the stomachs of patients with FAP. Case Presentation: Herein, we report the two cases. A 52-year-old woman who underwent total colectomy for FAP, and pancreatoduodenectomy was initiated on esomeprazole for the treatment of anastomotic erosion. Esophagogastroduodenoscopy performed 42 months later showed an increased number and size of gastric fundic gland polyps, which subsequently decreased after replacing esomeprazole with ranitidine. Similarly, a 39-year-old woman with FAP was initiated on vonoprazan for the treatment of reflux symptoms. Esophagogastroduodenoscopy and colonoscopy performed 14 months later indicated an increase in the number of gastric fundic gland polyps and colorectal polyps, which subsequently decreased after vonoprazan discontinuation. In these two cases, the increase and decrease in the number and size of fundic gland polyps and colon adenoma were associated with serum gastrin levels. Conclusion: Gastric fundic gland polyps and colon polyps may rapidly increase in number and size due to increased gastrin levels induced by proton pump inhibitor/potassium-competitive acid blocker use. Hence, these drugs should be prescribed with caution.
A Rapid Development of Post-Colonoscopy Appendicitis within Twelve Hours: A Case Report
Authors: Prince Sean-Patrick , Huang Qitan , Dayto Denisse Camille , Sephien Andrew , Patel Varun , Chandrupatla Sreekanth
Published: August 2024

Introduction: Colon cancer has seen a steady decline in incidence due to increased colonoscopy use. We can assume that this increased use, results in a higher incidence of post-colonoscopy complications such postpolypectomy syndrome, perforation and post-colonoscopy appendicitis (PCA). In this report, we present a case of PCA presenting to the emergency department within 12 h of a screening colonoscopy. Case Presentation: Our patient, a 77-year-old male, underwent an uncomplicated screening colonoscopy and was discharged home after briefly being monitored without any complaints. Later that day, the patient presented to the emergency department complaining of acute generalized abdominal pain. On presentation, the patient was found to be hypertensive and febrile with a distended abdomen with right lower quadrant tenderness on examination. Laboratory investigations noted an elevated white blood cell count with no evidence of acute appendicitis or focal inflammatory changes on contrast-enhanced abdominal and pelvic computer tomography. The patient was subsequently admitted and developed worsening right lower quadrant abdominal pain and distention overnight. Due to this worsening clinical condition, the decision was made to proceed with a diagnostic laparoscopy. After frank pus was found laparoscopically around the cecum and appendix, it was then converted to an exploratory laparotomy. Subsequently, a perforated gangrenous appendix was found with an erythematous and indurated cecum. Conclusion: Major complications of colonoscopy can include perforation and/or post-colonoscopy bleeding which have been shown to have a respective incidence of 0.21% and 0.1%. With the anticipated rise in the number of colonoscopies, much rarer complications such as PCA with an incidence of less than 0.05% will be seen more frequently. Due to its nonspecific presentation, it is necessary for providers to consider PCA as an important differential for all patients presenting with abdominal pain after a colonoscopy.
Self-Recording of Eye Movements in Amyotrophic Lateral Sclerosis Patients Using a Smartphone Eye-Tracking App
Authors: Barahim Bastani Pouya , Saber Tehrani Ali S. , Badihian Shervin , Rieiro Hector , Rastall David , Farrell Nathan , Parker Max , Otero-Millan Jorge , Hassoon Ahmed , Newman-Toker David , Clawson Lora L. , Uchil Alpa , Riley Kristen , Zeiler Steven R.
Published: August 2024

Introduction: Amyotrophic lateral sclerosis (ALS) can affect various eye movements, making eye tracking a potential means for disease monitoring. In this study, we evaluated the feasibility of ALS patients self-recording their eye movements using the “EyePhone,” a smartphone eye-tracking application. Methods: We prospectively enrolled ten participants and provided them with an iPhone equipped with the EyePhone app and a PowerPoint presentation with step-by-step recording instructions. The goal was for the participants to record their eye movements (saccades and smooth pursuit) without the help of the study team. Afterward, a trained physician administered the same tests using video-oculography (VOG) goggles and asked the participants to complete a questionnaire regarding their self-recording experience. Results: All participants successfully completed the self-recording process without assistance from the study team. Questionnaire data indicated that participants viewed self-recording with EyePhone favorably, considering it easy and comfortable. Moreover, 70% indicated that they prefer self-recording to being recorded by VOG goggles. Conclusion: With proper instruction, ALS patients can effectively use the EyePhone to record their eye movements, potentially even in a home environment. These results demonstrate the potential for smartphone eye-tracking technology as a viable and self-administered tool for monitoring disease progression in ALS, reducing the need for frequent clinic visits.
Peritonitis in Peritoneal Dialysis: When to Consider Acute Pancreatitis? Case Report and Mini-Review
Authors: Schietzel Simeon , Rippin Wagner Sarah Jane , Nigg Calanca Luzia
Published: August 2024

Introduction: Acute pancreatitis is an infrequent but challenging cause of peritonitis in peritoneal dialysis (PD). Presentation is often indistinguishable from infectious peritonitis, interpretation of pancreatic enzymes is not straight-forward, and multiple etiologies need to be considered. Case Presentation: A 74-year-old PD patient presented with cloudy dialysate and subtle symptoms of malaise and abdominal pain. WBC was 26,000/µL, CRP was 250 mg/L, and dialysis effluent contained 1,047 leucocytes/μL (90% polymorphs). Infectious peritonitis was presumed, and antibiotic treatment started. However, dialysate cultures remained negative, effluent leucocyte count remained high, and clinical condition deteriorated. Abdominal ultrasound was unremarkable (pancreas not visible). Acute pancreatitis was diagnosed by elevated lipase level (serum: 628 U/L, dialysis fluid: 15 U/L) and CT scan. Disentangling etiological factors was challenging. The patient had gallstones, consumed alcoholic beverages, was recently on doxycycline and dialyzed with icodextrin. In addition, PD treatment itself may have been a contributory factor. Antibiotic therapy was stopped, and PD was temporarily suspended. Systemic and effluent markers of inflammation took 4 weeks to normalize. The patient did not regain his usual state of health until several weeks after discharge. Follow-up CT scan showed considerable pancreatic sequelae. Conclusion: Acute pancreatitis is an important cause of PD peritonitis. Negative dialysate cultures and unsatisfactory clinical response should trigger evaluation for acute pancreatitis and its multiple potential causes, including PD treatment itself. Serum lipase levels >3 times ULN and elevated dialysis fluid lipase can be expected. Timely performance of imaging is advisable. Prognosis can be poor, and close monitoring is recommended.
A Case of Nonagenarian Gastric Anisakiasis with Atypical Presentation
Authors: Arai Toshio , Saito Seisuke , Kinebuchi Takahiro , Nishikawa Koji , Morishima Yasuyuki , Sugiyama Hiromu
Published: August 2024

Introduction: Anisakiasis is a parasitic disease caused by larvae from anisakid nematodes. In recent years, there has been an increase in cases of anisakiasis, a relatively uncommon medical condition. Case Presentation: A 93-year-old woman with chronic heart failure developed hives and nausea 6 h after eating silver flounder sashimi, leading to suspicion of fish allergy. Despite treatment, symptoms persisted and progressed to abdominal pain. An upper gastrointestinal endoscopy revealed an Anisakis larva in her stomach, an unusual finding given her age. After endoscopic removal of the living worm, the patient’s symptoms were relieved. Conclusion: A case of atypical anisakiasis in a 93-year-old patient was demonstrated. This case underscores the importance of considering atypical presentations in clinical decision-making.
Characteristics of Epithelioid Trophoblastic Tumor: Endoscopic and Magnetic Resonance Imaging Findings
Authors: Idegami Daiki , Amano Tsukuru , Torii Hiroko , Tsuji Shunichiro , Urabe Mamoru , Murakami Takashi
Published: August 2024

Introduction: Epithelioid endothelial tumor (ETT) is an extremely rare tumor that typically occurs in women of reproductive age. The diagnosis tends to be delayed because it often necessitates a total hysterectomy. Therefore, it is important to understand ETT macroscopic and imaging findings. Here, we report a case of ETT with detailed macroscopic and imaging findings. Case Presentation: A 39-year-old woman with positive pregnancy test results was admitted to a nearby hospital. No gestational sac was found in the uterus, and magnetic resonance imaging (MRI) revealed a cystic mass of approximately 7 cm that extended continuously from the anterior wall of the lower uterine segment into the pelvic cavity. She underwent laparoscopic and hysteroscopic surgeries for a ruptured cervical pregnancy. Pathology of the specimens obtained from this surgery did not allow for the diagnosis of ETT. Two months after the surgery, as the serum human chorionic gonadotropin β subunit (β-HCG) level did not decrease, she was diagnosed with low-grade gestational trophoblastic neoplasia, leading to the administration of chemotherapy. After three regimens of chemotherapy over 9 months, her β-HCG level decreased but did not reach normal levels. Ultimately, a total hysterectomy was performed. The pathological diagnosis was mixed ETT and choriocarcinoma. A literature review revealed several cases similar to ours. Conclusion: ETT in the lower uterus often perforates the myometrium and forms cystic lesions in the retroperitoneal space or subserosa. The MRI and laparoscopic/hysteroscopic findings in this case may have contributed to the early diagnosis of ETT.
Cancer of Unknown Primary: When Imaging, Pathology, and Molecular Biology Do Not Match
Authors: Juarez-Vignon Whaley Juan Jose , Pophali Prateek , Chornenkyy Yevgen , Peters Mary Linton
Published: August 2024

Introduction: Cancers of unknown primary are aggressive and rare malignancies with a complex diagnosis and management. Here we present a case in which imaging, pathology, and molecular biology did not match for a specific tumor site and the importance of a multidisciplinary team for these complicated cases. Case Presentation: A man in his 70s with strong smoking history under workup for suspicion of metastatic lung cancer underwent lung mass biopsy. Immunohistochemical stains corresponded to hepatocellular/cholangiocarcinoma or germ cell tumor; however, dedicated liver and testicular studies including imaging and iscochrome 12p FISH were negative. Additionally, somatic variant profiling was not specific for any malignancy nor targetable variants. Given the pattern of disease, risk factors, and patient history, the patient received treatment for lung adenocarcinoma (carboplatin, pemetrexed, and pembrolizumab). The patient had a drastic improvement in dyspnea, weight gain, and was able to return to work. Conclusion: This report describes a case in which immunohistochemistry and molecular profiling did not identify the tissue of origin and highlights the importance of a multidisciplinary team to reach a diagnosis and guide treatment without delaying patient care in patients with these diagnoses.
Cyclosporine A Protects Podocytes by Regulating Transgelin in Adriamycin-Induced Podocyte Injury
Authors: Li Xiaoyan , Ding Fangrui , Zhang Xiaoyan , Li Xuejuan , Ding Jie
Published: August 2024

Introduction: The calcineurin inhibitor cyclosporine A (CsA) has been shown to effectively reduce proteinuria. However, its precise mechanism is still not fully understood. Our previous study showed that CsA reduced proteinuria by directly stabilizing the foot process (FP) cytoskeletal structure via cofilin-1, suggesting that synaptopodin, a podocyte-specific actin protein, is not the sole target of CsA in podocytes. Methods: In this study, we established an adriamycin (ADR)-induced nephropathy rat model and a cultured podocyte injury model. We employed Western blotting and immunofluorescence techniques to assess the expression and distribution of transgelin, Krüppel-like factor-4 (KLF-4), nephrin, and synaptopodin. Results: We observed a significant increase in proteinuria levels accompanied by loss of normal FP structure in the ADR-induced nephropathy rat model. The levels of the actin cross-linking protein transgelin were increased significantly, while those of the podocyte-specific molecules nephrin and synaptopodin were decreased in vivo. Treatment with CsA effectively reduced proteinuria while restoring FP effacement stability in ADR-induced nephropathy models and restoring the expression of transgelin, nephrin, and synaptopodin both in vivo and in vitro. Furthermore, CsA treatment dose-dependently decreased transgelin levels while significantly increasing KLF-4 expression in injured podocytes. In addition, CsA failed to downregulate transgelin when KLF-4 was specifically knocked down. Conclusion: Our findings suggest that CsA protects against podocyte injury by downregulating abnormally high levels of transgelin via upregulation of KLF-4 expression.