Approach to the Patient With Type 2 Diabetes Requiring Add-On Medication.

In the last 20 years, the number of approved agents and agent classes for management of type 2 diabetes has expanded significantly. This more robust armamentarium affords us the opportunity to utilize drugs with complementary modes of action to address progressive hyperglycemia as insulin secretion declines over time. Furthermore, some of these agents provide additional benefits, such as weight loss, prevention of major adverse cardiac events (MACE), and protection against declining renal function. This dramatic increase of treatment options has led to complex published treatment advice which may be challenging for the busy clinician. A critical element in medication selection is awareness of the hemoglobin A1c (HbA1c)-lowering potency of the agent being considered, and the distance of the patient's HbA1c level from the individualized goal. Other important factors in choosing medication as diabetes progresses include the recognition that there is a diminishing return of glucose-lowering efficacy as add-on agents are introduced, and that the extent of benefit for cardiac and renal protection is not fully understood. In addition, the availability of newer non-insulin agents may distract the clinician from utilizing insulin, the most potent agent available. The goal of this article is to provide a straightforward approach to add-on medication in the treatment of type 2 diabetes, recognizing the limits of polypharmacy and the importance of employing agents best suited to achieving treatment targets. Proposed is a practical tool which provides stepwise guidance, utilizing available data on medication efficacy, while allowing flexibility based on clinician and patient preference.

Multisystem Progeroid Syndrome With Lipodystrophy, Cardiomyopathy, and Nephropathy Due to an LMNA p.R349W Variant.

BACKGROUND: Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. METHODS: We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. RESULTS: Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. CONCLUSIONS: The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.

Everyday objects and spaces: How they afford resilience in diabetes routines.

Thirty million Americans currently have diabetes, and a substantial portion do not reach the goals of clinical treatment. This is in part due to the complex barriers to effective self-care faced by people with diabetes. This study uses a patient work perspective, focusing on the everyday, lived experience of managing diabetes. Our primary research goal was to explore how the work of self-care is embedded in the other routines of everyday living. We found that everyday objects and spaces were instrumental in the incorporation of diabetes work into daily routines. Objects anchored diabetes tasks by linking illness-specific artifacts to space and time (e.g. a morning routine), and by enabling the performance on diabetes tasks while on the move in either planned or unplanned ways.

Approach to the Patient With Thyrotoxicosis Using Telemedicine.

CONTEXT: The potential for endocrine care via telemedicine has been recognized since the early 2000s when clinical outcome data demonstrated improvements in glycemic control with telemedicine. The widespread use of telemedicine during the COVID-19 pandemic has pushed telemedicine beyond diabetes care and into clinical areas with a paucity of published data. The evaluation and treatment of thyrotoxicosis heavily relies on laboratory assessment and imaging with physical exam playing a role to help differentiate the etiology and assess the severity of thyrotoxicosis. CASE DESCRIPTION: We describe a patient presenting for evaluation of new thyrotoxicosis via telemedicine, and describe modifications to consider for thorough, safe evaluation via telemedicine. CONCLUSION: Telemedicine may be an ideal way to assess and treat patients with thyrotoxicosis who are not able to physically attend a visit with an endocrinologist but still have access to a laboratory for blood draws. Potential challenges include access to imaging and high-volume surgeons if needed. Clinical and economic outcomes of telemedicine care of thyrotoxicosis should be studied so that standards of care for endocrine telemedicine can be established.

Clinical Excellence in Endocrinology.

CONTEXT: Clinical endocrinology is a field driven largely by numerical parameters. To achieve outstanding patient care, however, the clinical endocrinologist must employ a range of skills which can collectively be called "clinical excellence." While there is extensive published guidance regarding appropriate medical management and outcomes for endocrine patients, there has been no consensus definition of excellence in the field, nor any recommendation as to how excellence can be achieved. EVIDENCE ACQUISITION: Literature review, review of websites of professional societies, clinical organizations, and government agencies. EVIDENCE SYNTHESIS AND RECOMMENDATIONS: After review of endocrine clinical outcomes guidelines and published descriptions of clinical excellence generally, key aspects of clinical excellence in endocrinology were derived: the ability to work in teams, communication and interpersonal skills, skillful negotiation of the health care system, and a strong knowledge base and scholarly approach. Examples of how these skills drive superior outcomes for patients are discussed. CONCLUSIONS: Clinical excellence in endocrinology is necessary to optimize care for endocrine patients. A definition of clinical excellence should be adopted by professional societies and medical institutions and its importance in patient care recognized and emphasized. Efforts should be undertaken in the context of endocrine fellowship training and faculty development to foster the skills inherent in clinical excellence.

Ectopic ACTH Production Leading to Diagnosis of Underlying Medullary Thyroid Carcinoma.

Medullary thyroid carcinoma (MTC) has been described as a source of ectopic ACTH secretion in patients with Cushing's syndrome. This is an infrequent association, occurring in less than 1% of MTC cases. Among these, it is even more unusual for an initial diagnosis of hypercortisolism to lead to the discovery of underlying MTC. Here we present a case of a patient with weakness, diarrhea, and hypokalemia who was found first to have Cushing's syndrome and later diagnosed with metastatic MTC. The patient was treated initially with oral agents to control his hypercortisolism, then with an etomidate infusion after experiencing intestinal perforation. He also received vandetanib therapy targeting his underlying malignancy, as this has been shown to reverse clinical signs of Cushing's syndrome in patients with MTC and subsequent ectopic ACTH secretion. Bilateral adrenalectomy was ultimately required. Medullary thyroid carcinoma should be considered in patients presenting with Cushing's syndrome due to ectopic ACTH secretion, and a multimodality treatment approach is often required.

Continuing improvement in type 2 diabetes care through performance-based evaluations.

AIMS: The timely evidence-based care of type 2 diabetes mellitus (T2DM) is imperative for achieving and maintaining glycemic control, reducing complications, and changing the paradigm of this epidemic. Based largely on results from earlier performance improvement (PI) activities, we conducted a continuing medical education (CME)-certified PI activity to foster improved adherence to guideline recommendations and current evidence for the care of patients with T2DM. METHODS: Participants engaged in a 3-stage process of self-assessment, goal setting, and reassessment. RESULTS: A total of 64 clinicians completed the entire PI process, abstracting data from 1600 patient charts before and after a period of self-improvement. After the intervention, clinicians were more likely to assess patients for disease-related complications and provide counseling on proper nutrition, exercise, and smoking cessation. Patients with A1C, blood pressure (BP), and low-density lipoprotein cholesterol (LDL-C) values above goal (defined as A1C ≥7, BP ≥130/80 mm Hg, and LDL-C >100 g/dL) were more likely to receive treatment modifications compared with baseline clinician performance. Significant changes observed in patient outcomes included improved mean A1C values (baseline 7.5% vs postintervention 7.3%; P = .027), decreased likelihood of BP at or above 130/80 mm Hg (baseline 37% vs postintervention 30%; P < .001), and decreased likelihood of LDL-C above 100 g/dL (baseline 33% vs postintervention, 27%; P < .001). CONCLUSIONS: Significant changes in clinician performance of key quality measures were reported in patients with T2DM after a PI CME activity improved adherence to evidence-based recommendations of care.

Analysis of global gene expression changes in human bronchial epithelial cells exposed to spores of the allergenic fungus, Alternaria alternata.

Exposure and sensitivity to ubiquitous airborne fungi such as Alternaria alternata have long been implicated in the development, onset, and exacerbation of chronic allergic airway disorders. This present study is the first to investigate global changes in host gene expression during the interaction of cultured human bronchial epithelial cells and live Alternaria spores. In in vitro experiments human bronchial epithelial cells (BEAS-2B) were exposed to spores or media alone for 24 h. RNA was collected from three biological replicates per treatment and was used to assess changes in gene expression patterns using Affymetrix Human Genome U133 Plus 2.0 Arrays. In cells treated with Alternaria spores compared to controls, 613 probe sets representing 460 individual genes were found differentially expressed (p ≤ 0.05). In this set of 460 statistically significant, differentially expressed genes, 397 genes were found to be up-regulated and 63 were down-regulated. Of these 397 up-regulated genes, 156 genes were found to be up-regulated ≥2 fold. Interestingly, none of the 63 down-regulated genes were found differentially expressed at ≤-2 fold. Differentially expressed genes were identified following statistical analysis and subsequently used for pathway and network evaluation. Interestingly, many cytokine and chemokine immune response genes were up-regulated with a particular emphasis on interferon-inducible genes. Genes involved in cell death, retinoic acid signaling, and TLR3 response pathways were also significantly up-regulated. Many of the differentially up-regulated genes have been shown in other systems to be associated with innate immunity, inflammation and/or allergic airway diseases. This study now provides substantial information for further investigating specific genes and innate immune system pathways activated by Alternaria in the context of allergic airway diseases.

Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial.

Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over baseline. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors.

Human breast development.

This review presents an atlas of the histology of the normal physiological states of the human breast including prenatal, prepubertal, and pubertal development, adult resting gland, pregnancy, lactation, and postinvolution. The aim is to produce a pictorial overview of the main stages in development and the common findings in the adult that are considered to be within the range of normality. Unlike inbred strains of animals, in humans it is clear that the chronology of ductal and lobular development is not predictable, either in the fetus, the infant, the peripubertal breast, or the adult. This is probably due to the individual variation in hormone levels both in utero and after birth. For many of the developmental time points there are very little data available. In this review we indicate the current state of knowledge of human breast development and some of the main similarities and differences with the rodent, the main animal model. The major phases of growth and development are described and accompanied by photographs that are representative of each stage. Stress is placed on terminology as there is confusion in the literature. This article is written as an accessory to the companion review on breast cancer.

Lumbar spinal fusion using recombinant human bone morphogenetic protein in the canine. A comparison of three dosages and two carriers.

STUDY DESIGN: A randomized, prospective and controlled animal study. OBJECTIVE: To evaluate lumbar spinal fusion using recombinant human bone morphogenetic protein 2 in a canine model. SUMMARY OF BACKGROUND DATA: Spinal fusion using autogenous bone grafting is associated with donor site morbidity and a nonunion rate of 5% to 35%. The use of recombinant human bone morphogenetic protein 2 as a bone graft substitute would eliminate donor site morbidity and perhaps augment the rate of successful fusion. METHODS: Mature beagles underwent bilateral paraspinal exposure at L4-L5, followed by transverse process decortication and randomization into one of six groups using differing doses of recombinant human bone morphogenetic protein 2 implanted using either a Type I collagen carrier or a polylactic acid carrier. Two control groups were used: one group without recombinant human bone morphogenetic protein 2 and another group using autogenous rib graft alone. RESULTS: Groups treated with recombinant human bone morphogenetic protein 2 demonstrated complete fusion in all animals. Animals treated with collagen carrier alone (no recombinant human bone morphogenetic protein 2) demonstrated complete absence of fusion. Successful fusion occurred in one of three canines in the autogenous bone graft group. Fusion masses in the recombinant human bone morphogenetic protein 2 treatment groups were significantly larger in size at 3 months than in the autogenous bone graft group. The collagen carrier was more biocompatible and biodegradable because residual polylactic acid carrier was seen with adjacent multinucleated giant cells. There was no evidence of spinal canal or nerve root encroachment in the recombinant human bone morphogenetic protein 2 treatment groups. CONCLUSIONS: The use of recombinant human bone morphogenetic protein 2 implanted using a Type I collagen carrier resulted in 100% fusion without adverse effects.

Safety of recombinant human bone morphogenetic protein-2 after spinal laminectomy in the dog.

STUDY DESIGN: This was a randomized, blinded trial of the safety of the application of recombinant human bone morphogenetic protein (rhBMP)-2 or autologous bone graft onto a laminectomy defect of the dog in the presence or absence of a dural membrane puncture. OBJECTIVE: To test the safety of rhBMP-2 in an application in which direct contact of the material with neural tissue occurs. SUMMARY OF BACKGROUND DATA: Application of rhBMP-2 in laboratory animals stimulates local bone formation to effect spinal fusion and healing of segmental bone defects. The use of rhBMP-2 as a bone graft substitute in spinal fusion would eliminate donor site morbidity and may augment the rate of successful fusion. Because rhBMP-2 may unintentionally come in contact with neural tissue, the consequences of such a safety issue must be addressed in an animal model before human trials. METHODS: Twenty skeletally mature beagles underwent spinal exposure followed by bilateral laminectomy at L5. In half of the dogs, a puncture wound was made to the dura with the expression of cerebrospinal fluid at the site of the puncture. In randomly selected animals, the exposed dural elements received either autologous bone graft with the bone removed from the laminectomy site or an implant of the rhBMP-2 device. The animals was observed for 12 weeks with periodic clinical examinations and monthly computed tomographic scans. RESULTS: There was no clinical, radiographic, or histologic evidence of neurologic abnormalities in these animals. The rhBMP-2 stimulated bone growth in the laminectomy defect and came into direct contact with the dural membrane. There was no evidence of abnormal mineralization within the thecal sac or in the spinal cord itself. CONCLUSIONS: The rhBMP-2 implant stimulated bone formation in the laminectomy site. Neither autologous bone, rhBMP-2, nor the dural puncture had deleterious consequences for the animals.

Effects of cold acclimation and central opioid processes on thermoregulation in rats.

Two experiments, using centrally administered [D-Ala2-MePhe4-Gly(ol)5]enkephalin (DAMGO), a selective mu-opioid agonist, assessed the thermoregulatory consequences of cold acclimation. Experiment 1 assessed whether cold acclimation influenced DAMGO hyperthermia at room temperature. Sialo-adenectomized rats were implanted with ICV cannulae and IP Mini-Mitters. After 3 weeks of exposure to 5 degrees C (cold acclimation) or 22 degrees C (non-cold acclimation) rats were pretreated with IP naltrexone HCl (2 mg/kg b.wt.) or vehicle (0.15 M saline) and later administered a 5-microliters ICV injection of 0.15 M saline, 0.1, or 1.0 microgram DAMGO. Cold acclimation exerted little effect on core temperature but potentiated DAMGO hyperthermia in a dose-dependent, naltrexone-reversible, activity-independent manner. Experiment 2 assessed the effect these same manipulations exerted on operant escape from a convective source of mild heat (37 degrees C). Duration of heat escape increased with cold acclimation in a naltrexone-resistant manner, yet was not influenced by DAMGO in either non-cold-acclimated or cold-acclimated rats. These findings suggest that two central adaptations occur with cold acclimation: A non-mu-opioid process that increases heat sensitivity and a mu-opioid process that potentiates hyperthermia but fails to alter heat escape due to mu-opioid-mediated analgesia.

Activity of penciclovir in antiviral assays against herpes simplex virus.

The effect of penciclovir and acyclovir on the replication of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) strains was determined in MRC-5 cells infected with 0.01 pfu/cell and exposed to the drugs for 72 h to allow multiple cycles of replication. Penciclovir was significantly more active than acyclovir against three strains of HSV-1 and three strains of HSV-2 at 1 mg/L (P = 0.009), 3 mg/L (P < 0.001) and 10 mg/L (P = 0.001). Further comparisons between the compounds were made in MRC-5 cells infected with HSV-1 strain SC16 using four different antiviral assays namely, the 24 h virus yield reduction assay, plaque reduction assay, viral antigen inhibition assay, and a viral DNA inhibition assay, to determine the relative merits of each. Penciclovir and acyclovir shared similar activities in the plaque reduction assay (with 50% effective concentrations, EC50, being 0.8 and 0.6 mg/L, respectively) and in the viral antigen inhibition assay (EC50s. 0.6 and 0.7 mg/L, respectively). The EC50 of penciclovir in the 24 h viral DNA inhibition assay was 0.01 mg/L compared with 0.06 mg/L of acyclovir. In the 24 h virus yield reduction assay in which MRC-5 cells were infected with 0.3 pfu/cell, penciclovir was more active than acyclovir with 99% effective concentrations of 0.6 mg/L and 1.1 mg/L, respectively. The activity of penciclovir in the 24 h virus yield reduction and antigen inhibition assays was inversely related to the multiplicity of infection, whereas this had considerably less effect on the inhibition of viral DNA synthesis. These results suggest that famciclovir, which is the oral form of penciclovir, will be at least as effective as acyclovir in treating infections caused by HSV-1 and HSV-2.

Comparison of a DNA probe assay with the plaque reduction assay for measuring the sensitivity of herpes simplex virus and varicella-zoster virus to penciclovir and acyclovir.

A DNA probe assay was compared with the plaque reduction assay to determine the sensitivity of clinical isolates of herpes simplex virus (HSV) and varicella-zoster virus (VZV) to penciclovir and acyclovir in MRC-5 cells. In both assays, penciclovir and acyclovir shared comparable activity against cell-free virus (CFV) preparations of VZV and herpes simplex virus type 1 (HSV-1) isolates, whilst acyclovir was significantly more active than penciclovir against herpes simplex virus type 2 (HSV-2) isolates in both the DNA probe assay (P < or = 0.01) and the plaque reduction assay (P < or = 0.01). However, the 50% effective concentrations (EC50s) were generally lower in the DNA probe assay and the correlation between the plaque reduction and DNA probe assays was poor for either compound. Six acyclovir-resistant strains of HSV-1 derived in cell culture were also tested for susceptibility to penciclovir and acyclovir, in the DNA probe and plaque reduction assays. The relative susceptibilities of these strains were comparable, for example, one ACV-resistant strain was susceptible to penciclovir in both assays. Further comparisons of the assay methods were made using cell-associated VZV (CAV). As with CFV the EC50s were significantly lower in the DNA probe assay than the plaque reduction assay for penciclovir (P < or = 0.01) and acyclovir (P < or = 0.01). In the DNA probe assay there was no significant difference in the EC50s for either penciclovir or acyclovir when comparing CAV with CFV. However, in the plaque reduction assay the EC50s for CAV were significantly higher than those for CFV for both penciclovir (P < or = 0.01) and acyclovir (P < or = 0.01). Overall the DNA probe assay is objective, does not require prior titration of isolates and provides opportunities for automation. It is more suitable for sensitivity testing of large numbers of clinical isolates than the well-established plaque reduction assay.