Dental Considerations and Precautions Associated with Oral Excisional Biopsy on a Patient with Cushing's Syndrome (Hypercortisolism).

Chronic exposure to endogenous and exogenous glucocorticoids will cause CS. Endogenous CS is uncommon, with an annual incidence of 0.2-5 individuals per million. Endogenous causes could be 1. adrenocorticotropic hormone (ACTH) dependent or 2. ACTH independent. The use of exogenous glucocorticoids to manage chronic autoimmune or inflammatory diseases is the most common cause of CS and results in iatrogenic CS. Cushing disease is caused by excess ACTH production by a pituitary tumor. CS's clinical manifestations in the head and neck region include a moon-shaped face, acne flares, and hirsutism.

A Patient with Addison Disease (Primary Adrenal Insufficiency) Presenting for Surgical Extraction of Third Molars.

The local prevalence of primary adrenal insufficiency (PAI) depends on various factors such as genetics, environment, and timely disease diagnosis. PAI is uncommon, and the prevalence is reported to be 2 per 10,000 population. PAI is commonly caused by an autoimmune process that destroys the adrenal gland, resulting in the loss of glucocorticoid and mineralocorticoid secretion from the adrenal cortex. The lack of cortisol results in impaired glucose/fat/protein metabolism, hypotension, increased adrenocorticotropic hormone secretion, impaired fluid excretion, and hyperpigmentation. PAI has a female predominance and is commonly seen in ages 20 to 50 years but can occur at any age.

Impacted Wisdom Teeth Removal on a Patient with Primary Hypothyroidism (Hashimoto Disease).

Thyroid gland dysfunctions can adversely affect patients' systemic health and well-being. Thyroid disease is the most common endocrine disorder. Recognizing early signs and symptoms of hypothyroidism is crucial in the early diagnosis of hypothyroidism. Oral health care providers must obtain comprehensive medical records from patients with hypothyroidism before dental treatments.

Implant Placement in a Patient with Thyromegaly Associated with Graves Disease.

Oral health care providers should obtain comprehensive medical records from patients with hyperthyroidism before dental treatments. Graves disease is the most common cause of hyperthyroidism. Untreated hyperthyroidism can lead to dangerous adverse effects, such as coma or death. Recognizing early signs and symptoms of hyperthyroidism is crucial in reducing complications.

Mandibular Jaw Lesion Excisional Biopsy on a Patient with Hyperparathyroidism (Primary).

Most of the primary hyperparathyroidism is due to adenomas in the parathyroid glands. Hypercalcemia is more common in primary hyperparathyroidism. Hyperparathyroidism may be asymptomatic and detected incidentally as part of a routine serological evaluation. Oral health care providers should recognize distinct changes in the jawbone associated with primary and secondary hyperparathyroidism.

Pharmacokinetics comparison of vardenafil as administered by an intranasal spray formulation vs a 10-mg oral tablet.

BACKGROUND: Oral vardenafil (VDF) tablet is an effective treatment for erectile dysfunction (ED), but intranasal administration with a suitable formulation can lead to a faster onset of action and offer more convenient planning for ED treatment. AIM: The primary purpose of the present pilot clinical study was to determine whether intranasal VDF with an alcohol-based formulation can result in more "user-friendly pharmacokinetics" as compared with oral tablet administration. METHODS: This single-dose randomized crossover study was conducted in 12 healthy young volunteers receiving VDF as a 10-mg oral tablet or 3.38-mg intranasal spray. Multiple blood concentrations were obtained, and VDF concentrations were determined with a liquid chromatography-tandem mass spectrometry assay. Pharmacokinetic parameters following each treatment were compared and adverse events assessed. OUTCOMES: Pharmacokinetic parameters were obtained: apparent elimination rate constant, elimination half-life, peak concentration, peak time, total area under the curve, and relative bioavailability. RESULTS: Although mean apparent elimination rate constant, elimination half-life, peak concentration, and total area under the curve were similar between intranasal and oral administration, the median peak time from intranasal was much shorter (10 vs 58 minutes, P < .001, Mann-Whitney U test). The variability of the pharmacokinetic parameters was also less with intranasal than oral administration. The relative bioavailability of intranasal to oral was 1.67. Intranasal VDF caused transient but tolerable local nasal reactions in 50% of subjects. Other adverse events (eg, headache) were similar between the treatments. The incidence of adverse events was, however, significantly less in the second treatment after initial exposure to VDF. No serious adverse events were noted. CLINICAL IMPLICATIONS: Intranasal VDF potentially offers a more timely and lower dose for the treatment of ED in patients who can tolerate the transient local adverse reactions. STRENGTHS AND LIMITATIONS: The strength of this study is its randomized crossover design. Because the study was conducted in 12 healthy young subjects, the results may not reflect those observed in elderly patients who may be likely taking VDF for ED. Nevertheless, the changes of pharmacokinetic parameters in the present study are likely a reflection of the differences between intranasal and oral administration of the formulations. CONCLUSION: Our study indicated that the present VDF formulation, when administered intranasally, can achieve a more rapid but similar plasma concentration with only about one-third dose when compared with the oral administration.

Prevalence of Hypertension and Related Characteristics: Perspectives from an Outpatient Podiatric Medical Clinic.

BACKGROUND: Hypertension is a highly prevalent condition in the general population, conferring a high risk of significant morbidity and mortality. Associated with the condition are many well-characterized controllable and noncontrollable risk factors. This study aimed to identify the prevalence of hypertension in the outpatient podiatric medical clinic setting and to determine the relevance of hypertension risk factors in this setting. METHODS: A survey tool was created to characterize relevant risk factors, and systolic and diastolic blood pressures were recorded. Descriptive statistics were generated after conclusion of enrollment. Analysis was also performed to determine the relationship between individual risk factors and systolic blood pressure. RESULTS: Of the 176 patients, 56 (31.8%) had an incidentally high blood pressure at intake, including 18.5% of patients without a known history of hypertension and 38.5% with a known history of hypertension. Three risk factors were found to be significantly associated with increasing systolic blood pressure: weight (P = .022), stress level (P = .017), and presence of renal artery stenosis (P = .021). There was also a near-statistically significant inverse relationship between systolic blood pressure and amount of time spent exercising (P = .068). CONCLUSIONS: Overall, a relatively high prevalence of incidental hypertension was identified, including among patients not previously diagnosed as having hypertension. Consideration of risk factors and awareness of the prevalence of the condition can be useful for practitioners, even as they manage presenting podiatric medical concerns. Future investigations may consider interventional or preventive strategies in the outpatient clinic setting.

Effects of Oral Liposomal Glutathione in Altering the Immune Responses Against Mycobacterium tuberculosis and the Mycobacterium bovis BCG Strain in Individuals With Type 2 Diabetes.

The World Health Organization (WHO) has identified type 2 diabetes (T2DM) as a neglected, important, and re-emerging risk factor for tuberculosis (TB), especially in low and middle-income countries where TB is endemic. In this clinical trial study, oral liposomal glutathione supplementation (L-GSH) or placebo was given to individuals with T2DM to investigate the therapeutic effects of L-GSH supplementation. We report that L-GSH supplementation for 3 months in people with T2DM was able to reduce the levels of oxidative stress in all blood components and prevent depletion of glutathione (GSH) in this population known to be GSH deficient. Additionally, L-GSH supplementation significantly reduced the burden of intracellular mycobacteria within in vitro granulomas generated from peripheral blood mononuclear cells (PBMCs) of T2DM subjects. L-GSH supplementation also increased the levels of Th1-associated cytokines, IFN-γ, TNF-α, and IL-2 and decreased levels of IL-6 and IL-10. In conclusion our studies indicate that oral L-GSH supplementation in individuals with T2DM for three months was able to maintain the levels of GSH, reduce oxidative stress, and diminish mycobacterial burden within in vitro generated granulomas of diabetics. L-GSH supplementation for 3 months in diabetics was also able to modulate the levels of various cytokines.

Everolimus-induced effector mechanism in macrophages and survivability of Erdman, CDC1551 and HN878 strains of Mycobacterium tuberculosis infection.

With a disease as widespread and destructive as tuberculosis, more effective drugs and healthcare strategies, in addition to the current antibiotics regimen, are crucial for the enhanced well-being of millions of people suffering from the disease. Host-directed therapy is a new and emerging concept in treating chronic infectious diseases, such as tuberculosis. Repurposing of anti-cancer drugs, such as everolimus, may be an effective way to supplement the standard antibiotic treatment. Individuals with type 2 diabetes are increasingly susceptible to co-morbidities and co-infections including Mycobacterium tuberculosis, the causative agent of tuberculosis. We demonstrated in this study that in vitro everolimus treatment of granulomas from individuals with type 2 diabetes caused significant reduction in the viability of Mycobacterium tuberculosis.Further investigations revealed the effects of everolimus in targeting foamy macrophages, a macrophage phenotype that forms around granulomas, and is characterized by a higher lipid accumulation inside the cells. These foamy macrophages are thought to harbor dormant bacilli, which are potential sources of disease reactivation. Therefore, blocking foamy macrophage formation would help better killing of intracellular bacteria. Here, we report the potential of everolimus treatment to downregulate lipid content within the foamy macrophages of in vitro granulomas, thus leading to a potential decrease in the number of foamy macrophages and a more robust response to Mycobacterium tuberculosis.

The Effects of Oral Liposomal Glutathione and In Vitro Everolimus in Altering the Immune Responses against Mycobacterium bovis BCG Strain in Individuals with Type 2 Diabetes.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tb) still remains a devastating infectious disease in the world. There has been a daunting increase in the incidence of Type 2 Diabetes Mellitus (T2DM) worldwide. T2DM patients are three times more vulnerable to M. tb infection compared to healthy individuals. TB-T2DM coincidence is a challenge for global health control. Despite some progress in the research, M. tb still has unexplored characteristics in successfully evading host defenses. The lengthy duration of treatment, the emergence of multi-drug-resistant strains and extensive-drug-resistant strains of M. tb have made TB treatment very challenging. Previously, we have tested the antimycobacterial effects of everolimus within in vitro granulomas generated from immune cells derived from peripheral blood of healthy subjects. However, the effectiveness of everolimus treatment against mycobacterial infection in individuals with T2DM is unknown. Furthermore, the effectiveness of the combination of in vivo glutathione (GSH) supplementation in individuals with T2DM along with in vitro treatment of isolated immune cells with everolimus against mycobacterial infection has never been tested. Therefore, we postulated that liposomal glutathione (L-GSH) and everolimus would offer great hope for developing adjunctive therapy for mycobacterial infection. L-GSH or placebo was administered to T2DM individuals orally for three months. Study subjects' blood was drawn pre- and post-L-GSH/or placebo supplementation, where Peripheral Blood Mononuclear Cells (PBMCs) were isolated from whole blood to conduct in vitro studies with everolimus. We found that in vitro treatment with everolimus, an mTOR (membrane target of rapamycin) inhibitor, significantly reduced intracellular M. bovis BCG infection alone and in conjunction with L-GSH supplementation. Furthermore, we found L-GSH supplementation coupled with in vitro everolimus treatment produced a greater effect in inhibiting the growth of intracellular Mycobacterium bovis BCG, than with the everolimus treatment alone. We also demonstrated the functions of L-GSH along with in vitro everolimus treatment in modulating the levels of cytokines such as IFN-γ, TNF-α, and IL-2 and IL-6, in favor of improving control of the mycobacterial infection. In summary, in vitro everolimus-treatment alone and in combination with oral L-GSH supplementation for three months in individuals with T2DM, was able to increase the levels of T-helper type 1 (Th1) cytokines IFN-γ, TNF-α, and IL-2 as well as enhance the abilities of granulomas from individuals with T2DM to improve control of a mycobacterial infection.

Investigating the Use of Denosumab in the Treatment of Acute Charcot Neuroarthropathy.

Charcot neuroarthropathy is a devastating condition, most commonly affecting poorly controlled diabetic patients with peripheral neuropathy. Pharmacological options for the condition are currently limited. The purpose of this study was to investigate the potential of Prolia® (denosumab) as a safe and feasible option in the treatment of acute Charcot neuroarthropathy. A total of 7 consecutive subjects were enrolled and followed for 1 year. Subjects received a single one-time injection of denosumab 60 mg. Subjects also received standard of care treatment, which included total contact casting, restricted weightbearing status, and biweekly office visits until normalization of the skin temperature gradient. Overall, the pharmaceutical treatment was generally well-tolerated. One subject developed a diabetic foot infection with cellulitis of the contralateral lower extremity, which occurred following the 6-month follow-up visit and which resolved with oral antibiotics One subject identified transient muscle pain in the same upper extremity which received the injection. Subjects were found to exit the acute phase of the condition at an average of 52.00 ± 17.89 days after their injection, which was defined by normalization of skin temperature to within 2°C of the contralateral foot. Treatment of acute Charcot neuroarthropathy with denosumab was well-tolerated in this open-label, pilot study. The clinical outcomes suggest that the medication may be efficacious, though a larger sample size would be needed to confirm these preliminary results. An adequately-powered, randomized, controlled study may be an appropriate follow-up.

The association of pulmonary fibrosis with diabetes mellitus.

The association between diabetes and pulmonary fibrosis is not well understood. This large study demonstrates that the prevalence of pulmonary fibrosis is lower in diabetic decedents compared to nondiabetic decedents. https://bit.ly/3gNgjeU.

Characteristics and Outcomes of Patients With and Without Type 2 Diabetes Mellitus and Pulmonary Sepsis.

PURPOSE: To date, studies have provided conflicting results regarding the impact of type 2 diabetes mellitus (DM) on sepsis-related outcomes. Our objective is to understand the impact of type 2 DM in bacterial pneumonia and sepsis-related intensive care unit (ICU) outcomes. METHODS: Retrospective study using Multiparameter Intelligent Monitoring in Intensive Care III database. We included 1698 unique patients admitted with sepsis secondary to bacterial pneumonia to the ICU within the time period of 2001 to 2012. RESULTS: The type 2 DM group had an increased incidence of acute kidney injury (67.9% vs 58.1%, P < .01) and need for dialysis compared to the non-DM group. There was no difference in mortality, microbiology, other organ failure, or hospital length of stay between the type 2 DM and non-DM group. Lower admission blood glucose was associated with increased mortality in patients with type 2 DM (49% at ≤120 mg/dL, 35.1% at 121-180 mg/dL, and 32.1% at >180 mg/dL) but not in non-DM patients. Conversely, higher mean glucose during the hospital stay was associated with increased mortality in non-DM patients (24.7% at ≤120 mg/dL, 45.1% at 121-180 mg/dL, and 73.0% at >180 mg/dL) but not in patients with type 2 DM. CONCLUSIONS: Our findings demonstrated that type 2 DM does not increase the overall mortality. Our findings of increased mortality in both type 2 DM patients with lower admission glucose, and non-DM patients with higher mean glucose during the hospital stay needs to be further evaluated. Future studies in regards to this could lead to personalized glucose treatment goals for patients.

The preclinical candidate indole-2-carboxamide improves immune responses to Mycobacterium tuberculosis infection in healthy subjects and individuals with type 2 diabetes.

A novel group of agents known as the indole-2-carboxamides (often referred to as indoleamides) have been shown to demonstrate high antimycobacterial activity. Studies have demonstrated that the best indoleamides possess desirable ADME/Tox properties, with less adverse effects and increased efficacy against both MDR-TB (multi-drug resistant TB) and XDR-TB (extensively drug-resistant TB). The primary mechanism of killing Mycobacterium tuberculosis (Mtb) by indoleamides is by disrupting the function of the essential mycolic acid transporter MmpL3 protein (Mycobacterial membrane protein Large 3). Therefore, targeting this essential mycobacterial transporter by small molecules opens new possibility for the development of novel and effective anti-TB agents. In the present study, we characterized the effects of indoleamides in altering the viability of Mtb in an in vitro granuloma model using immune cells derived from healthy subjects and those with type 2 diabetes mellitus (T2DM). Our results indicate that treatment with the best indoleamide 3 resulted in a significant reduction in the viability of Mtb in both THP-1 macrophages as well as in granulomas derived from healthy individuals and subjects with T2DM. Graphical Abstract.

Flavonoid Mixture Inhibits Mycobacterium tuberculosis Survival and Infectivity.

BACKGROUND: Flavonoids have been shown to exert anti-pathogenic potential, but few studies have investigated their effects on Mycobacterium tuberculosis (Mtb) infectivity. We hypothesized that a flavonoid mixture would have a favorable influence on cell death and the resolution of Mtb infection in THP-1 macrophages and in granulomas derived from both healthy participants and those with type 2 diabetes mellitus (T2DM). METHODS: THP-1 macrophages, and in vitro granulomas from healthy participants (N = 8) and individuals with T2DM (N = 5) were infected with Mtb. A mixed flavonoid supplement (MFS) at a concentration of 0.69 mg per ml was added as treatment to Mtb infected THP-1 macrophages and granulomas for 8 to 15 days. RESULTS: MFS treatment significantly reduced the intracellular Mtb survival, increased cell density, aggregation, and granuloma formation, and increased glutathione (GSH) levels. IL-12 and IFN-γ levels tended to be higher and IL-10 lower when Mtb infected THP-1 macrophages and granulomas obtained from healthy subjects were treated with MFS compared to control. CONCLUSIONS: MFS treatment exerted a strong influence against Mtb infectivity in THP-1 macrophages and in granulomas including antimycobacterial effects, GSH enrichment, cytokine regulation, and augmented granuloma formation. Our data support the strategy of increased flavonoid intake for managing tuberculosis.

The Synergistic Effects of the Glutathione Precursor, NAC and First-Line Antibiotics in the Granulomatous Response Against Mycobacterium tuberculosis.

Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.

Effects of ReadiSorb L-GSH in Altering Granulomatous Responses against Mycobacterium tuberculosis Infection.

Mycobacterium tuberculosis (M. tb), a rod-shaped acid-fast bacterium, is the causative agent of tuberculosis (TB). TB remains one of the leading causes of morbidity and mortality worldwide. Additionally, approximately one-third of the world's population has latent tuberculosis infection (LTBI) as a result of the body's primary mechanism of defense against M. tb infection, the formation of a granuloma. A granuloma is the aggregation of immune cells that encapsulate the bacteria to keep them localized to prevent further infection and thus the bacteria become quiescent. However, if an individual becomes immunocompromised, they become more susceptible to M. tb, which may lead to bacterial reactivation and an active infection, because the host is no longer able to generate adequate immune responses. In this study, we examined liposomal glutathione's (L-GSH) effectiveness in promoting the formation of solid, stable granulomas. We assessed this ability by generating in vitro human granulomas constructed from peripheral blood mononuclear cells (PBMCs) that were derived from healthy subjects and testing their granulomatous effector responses against both M. bovis bacille Calmette-Guérin (BCG) and the highly virulent Erdman strain of M. tb. Additionally, we measured the survival and immune characteristics of the Erdman strain of M. tb in THP-1 originated macrophages as well as in vitro granulomas generated from individuals from type 2 diabetes (T2DM). Our results demonstrate that L-GSH treatment can decrease the intracellular survival of both BCG and virulent M. tb, as well as downregulate the levels of overexpressed proinflammatory cytokines delegated from the granulomas derived from not only healthy subjects but also individuals with T2DM.

Complement 3 Receptor Expression in Individuals with Type 2 Diabetes.

BACKGROUND: According to the World Health Organization, as of 2014 9% of the world's adult population is affected by diabetes. Uncontrolled diabetes is a pro-inflammatory process that increases generation of reactive oxygen species (ROS). METHODS: The production of ROS leads to a chronic increase in oxidative stress which results in an increased susceptibility to infections. Individuals with type 2 diabetes mellitus (T2DM) are highly susceptible to Mycobacterium tuberculosis (M. tb) infection. Previous research has demonstrated that glutathione (GSH) plays an important role in the control of M. tb infection. Recent studies have demonstrated that phagocytosis of M.tb is diminished in patients with T2DM. Phagocytosis in macrophages is thought to be mediated in part by complement protein 3b (C3b)-complement protein receptor 3b (C3R) interactions. Since C3b production is not diminished in patients with T2DM we propose that C3R production is reduced and is the cause for impaired macrophage phagocytosis as well as IL-12 and IFN-γ signaling. CONCLUSION: This study utilizes a quantitative PCR (qPCR), demonstrating decreased transcription of C3R mRNA in patients with T2DM as compared to non-diabetics.

Investigating the causes for decreased levels of glutathione in individuals with type II diabetes.

Tuberculosis (TB) remains an eminent global burden with one third of the world's population latently infected with Mycobacterium tuberculosis (M. tb). Individuals with compromised immune systems are especially vulnerable to M. tb infection. In fact, individuals with Type 2 Diabetes Mellitus (T2DM) are two to three times more susceptible to TB than those without T2DM. In this study, we report that individuals with T2DM have lower levels of glutathione (GSH) due to compromised levels of GSH synthesis and metabolism enzymes. Transforming growth factor beta (TGF-ß), a cytokine that is known to decrease the expression of the catalytic subunit of glutamine-cysteine ligase (GCLC) was found in increased levels in the plasma samples from individuals with T2DM, explaining the possible underlying mechanism that is responsible for decreased levels of GSH in individuals with T2DM. Moreover, increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17) were observed in plasma samples isolated from individuals with T2DM. Increased levels of IL-6 and IL-17 was accompanied by enhanced production of free radicals further indicating an alternative mechanism for the decreased levels of GSH in individuals with T2DM. Augmenting the levels of GSH in macrophages isolated from individuals with T2DM resulted in improved control of M. tb infection. Furthermore, cytokines that are responsible for controlling M. tb infection at the cellular and granuloma level such as tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin-2 (IL-2), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), were found to be compromised in plasma samples isolated from individuals with T2DM. On the other hand, interleukin-10 (IL-10), an immunosuppressive cytokine was increased in plasma samples isolated from individuals with T2DM. Overall, these findings suggest that lower levels of GSH in individuals with T2DM lead to their increased susceptibility to M. tb infection.