First Ever Documented Total Calcaneus Replacement with 3D Printed Metallic Implant for Chronic Osteomyelitis after a Calcaneal Fracture in a Young, Healthy Individual—A Literature Review and Preliminary Case Report

Osteomyelitis of the calcaneus can be a limb threatening diagnosis, which is typically treated with antibiotic therapy with or without partial resection of the bone. Extensive infection of the bone commonly results in limb amputation via transtibial or transfemoral amputation, which can increase morbidity and mortality. This case report involves a 29-year-old male who sustained bilateral calcaneal fracture after a fall, who developed osteomyelitis of the right calcaneus after being treated with internal/external fixation and antibiotic therapy. In order to preserve the limb total calcaneal replacement with 3D printed implant was done.

Diabetes Mellitus: Disorder of Cellular Dysfunction Due to Lack of Entry into Cell of Glucose. The Most Efficient Fuel for Cellular Function*

Background: Diabetes Mellitus is established to be a chronic hyperglycemic disorder secondary to altered glucose metabolism. Alternatively, hyperglycemia may be one of several manifestations in subjects with type 1 and type 2 diabetes Mellitus. Most tissues require insulin for entry of glucose, exceptions being red blood cells, renal medulla and nervous system. Hyperglycemia in intravascular compartment and other extra cellular milieu may be attributed to impaired glucose entry into endothelial cells of the vessel wall and cells in other tissues due to absence of insulin in type 1 and both insulin resistance and decline in insulin secretion in type 2 Diabetes. Objective: Hypothesis is proposed that Diabetes mellitus is a disorder of cellular dysfunction due to lack of entry of glucose, the most efficient fuel. Literature review was conducted to establish the perspective. Results: Declines in both phases of insulin secretion are induced by lack of glucose entry into pancreatic beta cells. Hyperglycemia is perpetuated by increased hepatic glucose production caused by sustained hyperglucagonemia secondary to lack of glucose entry into the pancreatic alpha cells. Moreover, decline in insulin secretion by beta cells and rise in glucagon release by alpha cells are enhanced by fall in GLP1 and GIP caused by dysfunction of L cells and K cells secondary to lack of glucose entry in both types of diabetes. Increased prevalence of infections and thromboembolic events may be attributed to dysfunction of leukocytes and platelets due to impaired glucose entry. Finally, alterations in metabolemics including Adiponectin, TNF alpha, Plasminogen inhibitor factor 1, Homocysteine, CRP, Lipids etc. as well as dysfunction of several organs in both types of diabetes may also be attributed to the lack of glucose entry into specific cells. Hypothesis is validated by improvement in metabolemics and organ function on facilitation of glucose entry into cells by insulin administration and/or improvement in insulin sensitivity. Conclusion: Diabetes mellitus is a disorder manifesting dysfunction involving almost all organs and cells induced by lack of entry of glucose, the most efficient substrate for cellular function.

How low do we fall to lower hemoglobin A1c? SGLT2 inhibitors: Effective drugs or expensive toxins!

SGLT2 inhibitors improve hyperglycemia with a decline in body weight and blood pressure, the outcomes touted to be of major importance in management of type 2 diabetes. However, the efficacy in lowering glycemia is very modest and imparts an undue cost burden on patients. Moreover, the declines in body weight and blood pressure are slight at best and orthostatic hypotension and its manifestations including syncope at worst, are all secondary to dehydration and probable total body electrolyte depletion caused by polyuria and nocturia as anticipated and established consequences of glycolsuria induced by SGLT2 inhibitors via their mechanism of action. Moreover, frequent adverse effects including impaired renal function as expressed by rises in serum creatinine and urea nitrogen, hyperkalemia and recurrent genitourinary infections are certainly likely to lead to the decline in quality of life. Finally, a rise in LDL cholesterol accompanied by increased serum viscosity secondary to dehydration may compromise cardiovascular safety as well. Thus, use of these expensive agents with modest efficacy and with established significant pathologic side effects escalating costs even further and unknown long term safety may be contradictory to the tenets of ethical medical practice established by “Hippocratic oath”. Recent approval of SGLT2 inhibitors by regulatory agencies in Europe and USA for treatment of hyperglycemia in type 2 diabetes is therefore surprising and disheartening.

Hyperhidrosis of Central Hypogonadism Leading to Diagnosis of Shapiro Syndrome: Temperature Dysregulation, Hypothermia and Agenesis of the Corpus Callosum

Background: Central or hypothalamic hypogonadism as an initial manifestation of Shapiro Syndrome has not been described in the literature. Herein, we report first case in which initial presentation of central hypogonadism led to a confirmed diagnosis of Shapiro Syndrome during a casual evaluation of hypothalamic pituitary anatomy with MRI of brain. Case presentation: 53 year old Caucasian man was documented to manifest Central or hypogonadotropic hypogonadism following evaluation of excessive sweating episodes, lack of libido and erectile dysfunction for a duration of several years. Brain MRI performed for assessment of the etiology documented no pituitary abnormality. Instead agenesis of Corpus Callosum was noted. The subject had been hospitalized on many occasions at this and several other medical centers with hypothermia or hyperthermia without a documentation of a definite cause. Therefore, the diagnosis of Shapiro Syndrome was made. Conclusion: This report is the first documentation of subject manifesting central, more likely to be hypothalamic rather than hypogonadotropic hypogonadism in conjunction with Shapiro Syndrome.

Marked Improvement in Glycemic Control with Exenatide on Addition to Metformin, Sulfonylurea and Insulin Glargine in Type 2 Diabetes Mellitus, a Real World Experience

Background: The major effect of Exenatide is attributed to lowering of post-prandial glycemia, whereas insulin glargine mainly improves fasting glycemia [FPG]. Objective: Therefore, we assessed effect of Exenatide administration at 6 months and for at 1 year on glycemic control, lipids, body weight [BW], daily insulin dose and hypoglycemic events. Methods: Records of 164 subjects, 126 men and 38 women administered Exenatide between January 2011 and December 2013 are included in this report. Exenatide was initiated at 5 mcg subcutaneously twice daily [BID] in obese subjects, BMI > 30 kg/m2, with C-peptide > 1 ng/d, and HbA1c 7.5% - 9.5%, while receiving daily metformin 2000 mg, Sulfonylurea Glimepiride 8 mg and insulin Glargine [GLAR]. Exclusion criteria were creatinine > 1.5 mg/dL and liver enzymes > 2.5 times upper limit of normal. Indices of glycemic control include fasting plasma glucose levels and HbA1c. Lipids include serum concentrations of total, LDL and HDL cholesterol. Other endpoints are body weight, daily insulin dose and number of hypoglycemic events per patient during 4 weeks prior to initiation of Exenatide, at 6 months and 1 year of therapy. Results: In 37 subjects, Exenatide was discontinued within 1 - 3 weeks;29 due to onset of nausea and vomiting. Seven of these also complained of abdominal pain and in these, serum amylase and lipase were elevated indicating presence of acute pancreatitis. One subject discontinued because of chest pain. Fasting plasma Glucose remained unchanged following Exenatide administration. However, HbA1c declined significantly denoting improvement in overall glycemic control without significant changes in body weight, daily insulin dose and hypoglycemic events. Lipid panel improved as well. Conclusion: Exenatide may be an appropriate adjuvant option in obese subjects with Type 2 diabetes mellitus with lack of desirable glycemic control while receiving therapy with Metformin, Glimepiride, and insulin Glargine. Moreover, improvement in glycemic control is likely to be secondary to lowering of post prandial hyperglycemia induced by Exenatide.

Sulfonylurea Glimepiride: A Proven Cost Effective, Safe and Reliable War Horse in Combating Hyperglycemia in Type 2 Diabetes

Recently, a debate has been raised regarding the place and the role of sulfonylureas (SU) amongst the armamentarium of drugs available for treatment of hyperglycemia in subjects with type 2 diabetes mellitus. With the advent of new drugs, SUs are being relegated and denigrated by some authorities contrary to present recommendations by various organizations e.g. American Diabetes Association, European Association for the Study of Diabetes and International Diabetes Federation. In this article, the advantages of SUs over the new agents in terms of their well established and proven better efficacy as well as their short term and long term (over 50 years) safety based on extensive literature data are documented. Moreover, lower costs of SUs render them to be far more cost effective when compared to new agents and therefore make them affordable in many regions of the world. Additionally, SUs are probably the initial drugs of choice in lean subjects with prediabetes and type 2 diabetes because they are the most effective secretogogues and major pathophysiologic mechanism of altered glucose metabolism in lean subjects is the decline in insulin secretion and not rising insulin resistance. Furthermore, SUs are also the most cost effective 2nd line agents in obese subjects with type 2 diabetes on lapse of glycemic control while receiving metformin. Finally, with progression of the disorder, the most cost effective combination of 2 oral agents in conjunction with basal insulin remains to be metformin and SUs. Many studies have documented a significantly greater extra pancreatic effect of glimepiride in comparison to other SUs probably because of its unique property in enhancing insulin sensitivity in conjunction with its ability to stimulate both 1st and 2nd phase insulin secretion. These characteristics may contribute to its greater efficacy with lesser hypoglycemia when compared with other SUs. Lack of hypoglycemic effect of metabolites of glimepiride may also be responsible for lesser hypoglycaemia. Moreover, metabolism of glimepiride performed partially by the liver and partially by the kidneys may render it suitable and adaptable to be administered safely in subjects with hepatic or renal dysfunctional as well as elderly. Finally, the documentation of its pleiotropic effects in lowering of cardiovascular surrogate markers, improving thrombotic milleau by reducing platelet aggregation factors along with improvement in glycemic control and its preferential binding to SU receptors on the pancreatic beta cells rather than myocardium may be responsible for providing better cardiovascular outcomes in comparison to other SUS and thus make it a better choice amongst SUs in subjects with or without presence of cardiovascular disease. Additionally, once daily administration because of lasting efficacy for 24 hours based on its half life is likely to enhance compliance on the part of patients and assist in attaining and maintaining desirable glycemic control. Therefore, SUs still deserve to be major players in management of hyperglycemia in subjects with type 2 diabetes mellitus and glimepiride may be the best choice amongst SUs because of its long term record regarding efficacy and safety in diverge population of subjects with type 2 diabetes mellitus.

Selective Pituitary Resistance to Thyroid Hormone: Clinical Hyperthyroidism with High TSH on Levothyroxine Administration in I-131 Ablated “Graves Disease”

Resistance to Thyroid Hormone (RTH) is a rare form of hormone resistance secondary to changes in the genes encoding thyroid hormone receptors. The two subtypes, Pituitary RTH (PRTH) and Generalized RTH (GRTH), cause clinically distinguishable patient presentations. In PRTH, typically only the pituitary gland is resistant to thyroid hormone (TH) while the rest of the body maintains sensitivity. Selective pituitary resistance to thyroid hormone results in dysregulation of thyroid hormone homeostasis with clinical presentation as either euthyroid or hyperthyroidism. PRTH is characterized by elevated thyroid hormone levels with an elevated or inappropriately normal TSH concentration. Herein we describe a case report of a 70-year-old woman who complained of weight loss of over 35 lbs., palpitations, jitters, hair loss, diarrhea, fatigue, muscle weakness, etc. over 6 months, thus, indicating the presence of iatrogenic hyperthyroidism while receiving levothyroxine 175 ug daily prescribed by her primary care provider because of a reported history of “Graves disease” treated by radioactive iodine ablation of the thyroid several years ago. The daily dose of levothyroxine had been increased gradually at an interval of 3 months over a year because of persistent elevation of serum TSH level. Laboratory tests revealed markedly elevated Free T4, Free T3 and TSH levels, along with low concentrations of all lipid fractions, serum creatinine and urea nitrogen levels, indicating TSH induced hyperthyroidism or PRTH. Further testing documented a mutation of thyroid hormone receptor beta gene 2 confirming presence of PRTH. We believe that the initial diagnosis of Graves Disease was erroneous and I-131 ablation further confounded and missed the diagnosis of PRTH. Thus, the purpose of this report is to report a patient with PRTH and describe potential pitfalls in diagnosis and management of this rare disorder.

Low Reverse T3: A Reliable, Sensitive and Specific in Diagnosis of Central Hypothyroidism*

Background: Low free T4 and normal/low TSH concentrations are often noted in clinical practice and denote presence of “Euthyroid Sick Syndrome” or Central Hypothyroidism. However, accurate diagnosis is difficult even with determination of free T3 being low/normal in both. Repeated determination of these tests may help differentiate between these disorders. Objective: Evaluation of reverse T3 to differentiate between “Euthyroid Sick Syndrome” and Central Hypothyroidism. Subjects and Methods: Free T3 and Reverse T3 were determined as “add on” tests using previously drawn blood samples of 78 consecutive adults showing low free T4, 0.80 ± 0.02 and low/normal TSH, 1.29 ± 0.40 [normal ranges, 0.89 - 1.70 mcg/dl;0.45 - 4.67 uU/ml]. Free T4, free T3, TSH and reverse T3 levels were also determined in age-matched 35 healthy volunteers and reassessed in study group. Statistical analyses for comparisons were conducted between groups. All data are reported as Mean ± SEM. Results: Reverse T3 established two distinct groups: 1) subnormal concentrations, 8.31 ± 0.52 [range, 11 - 14 ng/dl];2) supernormal levels;32 ± 4 [normal Range 12 - 26]. Free T3 concentrations were subnormal or normal, 1.6 - 2.9 [normal range, 2.3 - 4.2 ng/ml] in individuals amongst both groups. On reassessment after 3 - 6 weeks, free T4, free T3, TSH and reverse T3 normalized in group with normal or elevated reverse T3 indicating recovery from “Euthyroid Sick Syndrome” whereas free T4 and reverse T3 remained subnormal in the other group suggesting presence of Central Hypothyroidism. Conclusion: Reverse T3 is a reliable laboratory test differentiating between Central Hypothyroidism and “Euthyroid Sick Syndrome” in subjects with low free T4 and low/normal TSH levels.