Flea-Borne Typhus Presenting with Acalculous Cholecystitis and Severe Anemia.

Background: Flea-borne typhus (FBT), an uncommon illness in the United States, typically presents as a high continuous fever with commonly associated symptoms including headache, myalgias, and rashes on the trunk and extremities. Patients infected with FBT may also present with atypical symptoms. As such, the combination of its relatively low incidence in the United States coupled with its variability in associated symptoms poses a diagnostic challenge for clinicians; early empiric treatment with doxycycline is warranted prior to a definitive diagnosis to reduce the risk of damage to vital organs. Case Report. This case describes a 54-year-old male who presented to an emergency room in Houston, Texas, with one week of constant right upper quadrant abdominal pain and fevers up to 40°C. The patient was initially diagnosed with Grade III severe acute cholangitis after abdominal ultrasound revealed gallbladder sludge and wall thickening without ductal dilatation, but a subsequent endoscopic retrograde cholangiopancreatography was unremarkable. Following intermittent fevers and worsening anemia, the patient was started on oral doxycycline for atypical infection, and an infectious disease workup subsequently returned a positive titer for Rickettsia typhi. He experienced rapid symptomatic and clinical improvement, and the patient was discharged home with a final diagnosis of flea-borne typhus. Conclusion: Albeit uncommon, the presentation of this patient's symptoms and final diagnosis of flea-borne typhus demonstrates the importance of (1) keeping atypical infections such as FBT in the differential diagnosis and (2) beginning empiric treatment to prevent damage to vital organs if suspicion of FBT is high.

Undue Influence from the Family in Declining COVID-19 Vaccination and Treatment for the Elderly Patient.

This paper examines a patient with borderline mental capacity, where the healthcare team is conflicted about how to proceed. This case demonstrates the complicated intersection between undue influence and mental capacity, allowing us to explore how the law is applied in clinical practice. Patients have the right to decline or accept medical treatments offered to them. In Singapore, family members perceive a right to be involved in the decision-making process for sick and elderly patients. Elderly patients, dependent on mainly family members for care and support, sometimes submit to their overbearing influence resulting in decisions that fail to protect the patients' own best interests. However, the clinicians' own well-intentioned influence, driven by a desire for the best medical outcome can also be undue, and neither influence should seek to be a substitution for the patient's decision. Following Re BKR [2015] SGCA 26, we are now obliged to examine how mental capacity can be affected by undue influence. A lack of capacity can be found when a patient fails to appreciate the presence of undue influence or is susceptible to undue influence due to their mental impairment causing their will to be overborne. This then paves the way for the health care team to decide based on best interests, because the patient is determined to be lacking in mental capacity.

Hypereosinophilic syndrome presenting with gastrointestinal manifestations.

Hypereosinophilic syndrome (HES) is a spectrum of diseases characterised by an elevated eosinophilic count causing end-organ damage. Differential diagnoses of hypereosinophilia are vast and include drug hypersensitivities, allergies, infections, cancers, autoimmune disorders and rare eosinophilic syndromes. Herein, we describe a case of a patient presenting with gastrointestinal (GI) symptoms including progressive dysphagia, abdominal distension, vomiting, diarrhoea and abdominal pain with significant peripheral eosinophilia who was found to have an overlap HES involving the GI tract. This patient's eosinophilia was rapidly corrected with intravenous methylprednisolone, and the patient experienced gradual resolution of clinical symptoms with maintenance oral prednisone. Due to the rarity and diverse presentation of HES, there are few large, longitudinal studies that describe disease progression and inform treatment guidelines. This case demonstrates the difficulty in designing a treatment regimen for these patients and emphasises the clinical need for improved understanding of HES.

Torticollis in infants with neonatal abstinence syndrome.

OBJECTIVE: To report the incidence of torticollis diagnosed in infants treated for neonatal abstinence syndrome (NAS) and compare neonates with and without torticollis. STUDY DESIGN: This prospective cohort study reports on infants examined at 1-4 months of age. Numerous obstetrical/newborn factors and other drugs used during gestation were compared. RESULTS: Of 501 neonates treated for NAS, 421 (84%) were seen for follow-up. Of these, 105 (24.9%) were diagnosed with torticollis. The only significant obstetrical/newborn factor identified was a lower rate if the parents were the primary caregiver after hospital discharge. Of the 105 cases, 88 (84%) were right-sided and 17 (16%) were left-sided. CONCLUSIONS: These data demonstrate that torticollis is a common diagnosis in infants examined at 1-4 months of age after being treated for NAS with a predilection for this to be right-sided. The etiology for this is uncertain, but newborns treated for NAS need close follow-up post discharge.

Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum.

OBJECTIVE: The glands of the stomach body and antral mucosa contain a complex compendium of cell lineages. In lower mammals, the distribution of oxyntic glands and antral glands define the anatomical regions within the stomach. We examined in detail the distribution of the full range of cell lineages within the human stomach. DESIGN: We determined the distribution of gastric gland cell lineages with specific immunocytochemical markers in entire stomach specimens from three non-obese organ donors. RESULTS: The anatomical body and antrum of the human stomach were defined by the presence of ghrelin and gastrin cells, respectively. Concentrations of somatostatin cells were observed in the proximal stomach. Parietal cells were seen in all glands of the body of the stomach as well as in over 50% of antral glands. MIST1 expressing chief cells were predominantly observed in the body although individual glands of the antrum also showed MIST1 expressing chief cells. While classically described antral glands were observed with gastrin cells and deep antral mucous cells without any parietal cells, we also observed a substantial population of mixed type glands containing both parietal cells and G cells throughout the antrum. CONCLUSIONS: Enteroendocrine cells show distinct patterns of localisation in the human stomach. The existence of antral glands with mixed cell lineages indicates that human antral glands may be functionally chimeric with glands assembled from multiple distinct stem cell populations.

Human epididymis protein 4 is up-regulated in gastric and pancreatic adenocarcinomas.

Upper gastrointestinal neoplasia in the esophagus, stomach, and pancreas is associated with the formation of preneoplastic metaplasias. We have previously reported the up-regulation of human epididymis protein 4 (HE4) in all metaplasias in the stomach of humans and mice. We have now sought to evaluate the expression of HE4 in metaplasias/preneoplastic precursors and cancers of the human stomach, pancreas, and esophagus. Tissue microarrays for gastric cancers, pancreatic cancers, and esophageal adenocarcinoma were stained with antibodies against HE4. Immunostaining was quantified by digital imaging, and the results were evaluated to assess the expression in metaplasias, the expression in cancer pathological subtypes, and the effects of expression on survival in patients with cancer. In patients with gastric cancer from Korea, HE4 was detected in 74% of intestinal and 90% of diffuse cancers, whereas in a gastric cancer cohort from Johns Hopkins, HE4 was detected in 74% of intestinal-type and 92% of diffuse cancers. Nevertheless, in both cohorts, there was no impact of HE4 expression on overall survival. In the esophagus, we observed the expression of HE4 in scattered endocrine cells within Barrett esophagus samples, but Barrett columnar metaplasias and HE4 were detected in only 2% of esophageal adenocarcinomas. Finally, in the pancreas, HE4 expression was not observed in pancreatic intraepithelial neoplasia lesions, but 46.8% of pancreatic adenocarcinomas expressed HE4. Still, we did not observe any influence of HE4 expression on survival. The results suggest that HE4 is up-regulated during gastric and pancreatic carcinogenesis.

Gastric tumor development in Smad3-deficient mice initiates from forestomach/glandular transition zone along the lesser curvature.

SMAD proteins are downstream effectors of the TGF-ß signaling pathway. Smad3-null mice develop colorectal cancer by 6 months of age. In this study, we have examined whether the loss of Smad3 promotes gastric neoplasia in mice. The stomachs of Smad3⁻/⁻ mice were compared with age-matched Smad3 heterozygous and wild-type mice. E-cadherin, Ki-67, phosphoSTAT3, and TFF2/SP expression was analyzed by immunohistochemisty. The short hairpin RNA (ShRNA)-mediated knockdown of Smad3 in AGS and MKN28 cells was also performed. In addition, we examined alterations in DCLK1-expressing cells. Smad3⁻/⁻ mouse stomachs at 6 months of age revealed the presence of exophytic growths along the lesser curvature in the proximal fundus. Six-month-old Smad3⁻/⁻ mouse stomachs showed metaplastic columnar glands initiating from the transition zone junction between the forestomach and the glandular epithelium along the lesser curvature. Ten-month-old Smad3⁻/⁻ mice all exhibited invasive gastric neoplastic changes with increased Ki-67, phosphoSTAT3 expression, and aberrant cytosolic E-cadherin staining in papillary glands within the invading submucosal gland. The shRNA-mediated knockdown of Smad3 in AGS and MKN28 cells promoted the expression of phosphoSTAT3. DCLK1-expressing cells, which also stained for the tuft cell marker acetylated-α-tubulin, were observed in 10-month-old Smad3⁻/⁻ mice within tumors and in fundic invasive lesions. In conclusion, Smad3-null mice develop gastric tumors in the fundus, which arise from the junction between the forestomach and the glandular epithelium and progress to prominent invasive tumors over time. Smad3-null mice represent a novel model of fundic gastric tumor initiated from forestomach/glandular transition zone along the lesser curvature.

Spasmolytic polypeptide-expressing metaplasia (SPEM) in the gastric oxyntic mucosa does not arise from Lgr5-expressing cells.

OBJECTIVE: Metaplastic lineages in the oxyntic mucosa of the stomach are critical preneoplastic precursors of gastric cancer. Recent studies have demonstrated that spasmolytic polypeptide-expressing metaplasia (SPEM) in the mouse oxyntic mucosa arises from transdifferentiation of mature gastric chief cells. Other investigations of intestinal progenitor cells have shown that cells demonstrating transcriptional activity for leucine-rich repeat containing G-protein-coupled receptor 5 (Lgr5) in the intestine, colon and gastric antrum function as adult stem cells. We have now investigated whether cells demonstrating Lgr5 transcriptional activity in the oxyntic mucosa of mice might be responsible for development of metaplasia. DESIGN: Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice were used to examine the distribution of Lgr5 transcriptionally active cells in the normal oxyntic mucosa as well as after treatment with DMP-777 or L-635 to induce acute SPEM. Lineage mapping was performed to determine if Lgr5-expressing cells gave rise to SPEM. RESULTS: Cells expressing transcriptional activity for Lgr5 in the oxyntic mucosa were present as scattered rare cells only along the lesser curvature of the stomach. These cells also stained for markers of chief cells (intrinsic factor and pepsinogen) but never showed any staining for proliferative markers (Ki-67). In Lgr5-EGFP-IRES-Cre(ERT2/+);Rosa26R mice induced with tamoxifen, treatment with either DMP-777 or L-635 to induce acute oxyntic atrophy caused induction of SPEM, but no lineage mapping into SPEM from Lgr5-expressing cells was observed. CONCLUSION: The results indicate that, while chief cells with Lgr5 transcriptional activity are present along the lesser curvature of the gastric oxyntic mucosa, they are not responsible for production of metaplasia.

Mature chief cells are cryptic progenitors for metaplasia in the stomach.

BACKGROUND & AIMS: Gastric cancer evolves in the setting of a pathologic mucosal milieu characterized by both loss of acid-secreting parietal cells and mucous cell metaplasias. Indeed, mucous cell metaplasia is considered the critical preneoplastic lesion for gastric cancer. Previous investigations have shown that infection of mice with Helicobacter felis or induction of acute parietal cell loss with the drug DMP-777 leads to the emergence of a type of metaplasia designated spasmolytic polypeptide-expressing metaplasia (SPEM). We have hypothesized that SPEM arises from proliferating cells in gland bases, either from a cryptic progenitor cell or by transdifferentiation of mature chief cells. METHODS: Taking advantage of the chief cell-restricted expression of Mist1-Cre-ER(T2), we used lineage mapping to examine whether SPEM lineages were derived from chief cells in 3 independent models of induction by DMP-777 treatment, L-635 treatment, or H felis infection. RESULTS: Treatment of mice with L-635 for 3 days led to rapid parietal cell loss, induction of a prominent inflammatory infiltrate, and emergence of SPEM. In all 3 models, SPEM developed, at least in part, from transdifferentiation of chief cells. We further found that acute parietal cell loss in the setting of inflammation (L-635 treatment) led to more rapid induction and expansion of SPEM derived from transdifferentiation of chief cells. CONCLUSIONS: These studies provide direct evidence by lineage tracing that SPEM evolves from differentiated chief cells. Thus, mature gastric chief cells have the ability to act as cryptic progenitors and reacquire proliferative capacity within the context of mucosal injury and inflammation.

Relationship of ethnic origin, gender, and age to blood creatine kinase levels.

BACKGROUND: Creatine kinase is expressed at high levels in muscle, where it plays a central role in energy metabolism. Highly elevated creatine kinase levels in blood may indicate muscle trauma or disease. However, it is known that baseline creatine kinase levels are higher in African Americans than in whites and that they are higher in men than in women. This analysis explores the relationship of ethnic origin, gender, and age to baseline blood creatine kinase levels in a large group of adults with hypercholesterolemia. METHODS: Data from the screening phases of 4 North American trials of statins, which included large numbers of specific racial/ethnic populations, were combined for analysis. The pooled population (N=11,346) included 2760 African Americans, 3301 whites, 2930 Hispanics, and 2355 South Asians. RESULTS: Creatine kinase levels varied according to ethnic origin, gender, and age. African American participants had higher median creatine kinase levels than did individuals of the 3 other ethnicities. Within each ethnic group, men had higher median creatine kinase levels than women: African Americans, 135 versus 73 U/L; whites, 64 versus 42 U/L; Hispanics, 69 versus 48 U/L; and South Asians, 74 versus 50 U/L. An age-dependent decrease in creatine kinase levels was noted among men, but no such trend was seen among women. The median creatine kinase levels for younger African American men exceeded the standard upper limit of normal. CONCLUSION: Physicians should use caution when interpreting creatine kinase levels that seem elevated, particularly when treating African American patients and younger men.

Clinical commentary: Reaching new targets in monotherapy and combination therapy.

Cardiovascular disease remains the most common cause of death in the United States. There has, however, been a decline in the age-adjusted death rate for coronary heart disease. This decline may be due, in part, to more aggressive treatment guidelines for treating cardiovascular risk factors, such as hypertension, diabetes, and dyslipidemia. The 2004 update to the National Cholesterol Education Program guidelines have recommended lower low-density lipoprotein cholesterol goals in high-risk patients. Based on the new targets for low-density lipoprotein cholesterol, clinicians will need more efficacious lipid-lowering therapies and improved options for combination therapy. Statin and statin-based combinations have been the mainstays of therapy during the last several years, and as statin utilization increases in the United States, more high-risk patients become exposed to potential statin intolerance. This commentary reviews statin-sparing combinations and use of cholesterol-absorption inhibitors.

Comparison of efficacy and safety of rosuvastatin versus atorvastatin in African-American patients in a six-week trial.

The lipid-modifying effects of statin therapy in hypercholesterolemic African-Americans have not been well characterized. This study compared the efficacy and safety of rosuvastatin and atorvastatin treatment for 6 weeks in hypercholesterolemic African-American adults. In the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial (4522US/0002), 774 adult African-Americans with low-density lipoprotein cholesterol > or = 160 and < or = 300 mg/dl and triglycerides < 400 mg/dl were randomized to receive open-label rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg for 6 weeks. At week 6, significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B concentrations, as well as lipoprotein and apolipoprotein ratios, were seen with rosuvastatin versus milligram-equivalent atorvastatin doses (analysis of variance with Bonferroni-adjusted critical p < 0.017 for all comparisons). Rosuvastatin 10 mg also increased high-density lipoprotein cholesterol significantly more than atorvastatin 20 mg (p < 0.017). Although statistical comparisons were not performed, larger proportions of rosuvastatin-treated patients than atorvastatin-treated patients achieved National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. The median high-sensitivity C-reactive protein levels were significantly reduced statistically from baseline with rosuvastatin 20 mg and atorvastatin 20 mg among all patients and with rosuvastatin 10 and 20 mg and atorvastatin 20 mg in those patients with a baseline C-reactive protein level > 2.0 mg/L. The 2 study medications were well tolerated during the 6-week study period. In conclusion, rosuvastatin 10 and 20 mg improved the overall lipid profile of hypercholesterolemic African-Americans better than did milligram-equivalent doses of atorvastatin.

Complementary therapy to target LDL cholesterol: the role of the ezetimibe/simvastatin combination.

Cardiovascular (CV) disease remains the number 1 cause of death in the USA. Nonetheless, there has been a decline in the age-adjusted death rate for coronary heart disease (CHD) which may be due to more aggressive treatment guidelines for treating CV risk factors, such as hypertension, diabetes, and dyslipidemia. The recent update to the National Cholesterol Education Program (NCEP) guidelines have recommended lower low-density lipoprotein cholesterol (LDL-C) goals in high-risk patients. Based on the new targets for LDL-C, clinicians will need more efficacious lipid-lowering therapies. One of these newer therapies is the combination of ezetimibe and simvastatin. This article reviews the implications of the updated guidelines and discusses the efficacy and safety of ezetimibe/simvastatin for lowering LDL-C.

Lipid-lowering: can ezetimibe help close the treatment gap?

Most patients who should be on lipid-lowering therapy are not receiving it, and most patients who are receiving it are not reaching their appropriate low-density lipoprotein (LDL) goals. This is in part because physicians and patients fear side effects of statins and other lipid-lowering agents. Ezetimibe (Zetia), a new lipid-lowering drug, may help physicians close this "treatment gap" in more patients, especially in combination with a statin.