Romesh Khardori

FIBROUS DISEASE OF THE BREAST, THYROIDITIS, AND CHEIROARTHROPATHY IN TYPE I DIABETES MELLITUS

Fibrous breast lumps were noted in 12 women with longstanding type I diabetes mellitus who had multiple diabetic complications including cheiroarthropathy (11 of 12). 5 of the 12 women also had thyroid microsomal antibodies (greater than 1:1000). The coexistence of cheiroarthropathy and fibrosis of the breasts raises the possibility of a common link related to the connective-tissue abnormalities observed in diabetes. Although autoimmunity may also be a factor, HLA histocompatibility typing did not indicate that these patients formed a distinct subgroup of type I diabetics.

Influence of TRPV1 on diabetes-induced alterations in thermal pain sensitivity.

A common complication associated with diabetes is painful or painless diabetic peripheral neuropathy (DPN). The mechanisms and determinants responsible for these peripheral neuropathies are poorly understood. Using both streptozotocin (STZ)-induced and transgene-mediated murine models of type 1 diabetes (T1D), we demonstrate that Transient Receptor Potential Vanilloid 1 (TRPV1) expression varies with the neuropathic phenotype. We have found that both STZ- and transgene-mediated T1D are associated with two distinct phases of thermal pain sensitivity that parallel changes in TRPV1 as determined by paw withdrawal latency (PWL). An early phase of hyperalgesia and a late phase of hypoalgesia are evident. TRPV1-mediated whole cell currents are larger and smaller in dorsal root ganglion (DRG) neurons collected from hyperalgesic and hypoalgesic mice. Resiniferatoxin (RTX) binding, a measure of TRPV1 expression is increased and decreased in DRG and paw skin of hyperalgesic and hypoalgesic mice, respectively. Immunohistochemical labeling of spinal cord lamina I and II, dorsal root ganglion (DRG), and paw skin from hyperalgesic and hypoalgesic mice reveal increased and decreased TRPV1 expression, respectively. A role for TRPV1 in thermal DPN is further suggested by the failure of STZ treatment to influence thermal nociception in TRPV1 deficient mice. These findings demonstrate that altered TRPV1 expression and function contribute to diabetes-induced changes in thermal perception.

Clinical and molecular studies in a unique family with autosomal dominant limb-girdle muscular dystrophy and Paget disease of bone

Purpose: To characterize the clinical features and perform linkage analysis of candidate loci in a large Illinois family with autosomal dominant limb-girdle muscular dystrophy (LGMD) and Paget disease of bone (PDB).Methods: The family includes 11 affected individuals (8 M, 3 F). Clinical, biochemical and radiologic evaluations were performed to delineate clinical features of the disorder. Linkage analysis with polymorphic markers was performed for previously identified LGMD, PDB and cardiomyopathy loci.Results: Onset of PDB is early, at a mean age of 35 y, with classic distribution involving the spine, pelvis, and skull. Muscle weakness and atrophy is progressive with mildly elevated to normal creatine phosphokinase levels. Muscle biopsy in the oldest male revealed vacuolated fibers, however, in others revealed nonspecific myopathy. Affected individuals die from progressive muscle weakness, and respiratory and cardiac failure in their 40s-60s. Linkage analysis excluded autosomal dominant and recessive LGMD, PDB, and cardiomyopathy loci.Conclusion: Autosomal dominant LGMD associated with PDB is an unusual disorder. Linkage analysis indicates a unique locus in this family.

Hyperosmolar hyperglycemic nonketotic syndrome: Report of 22 cases and brief review

In a series of 22 patients with the hyperosmolar hyperglycemic nonketotic syndrome managed during a five-year period in a community hospital setting, 21 patients were known to be diabetic and only six patients were in coma. The overall mortality was 36.3 percent, and seven of the eight deaths were explained by associated nonmetabolic causes. In this study, hyperosmolarity was not related to coma or to final outcome of treatment. Patients were managed with relatively small amounts of fluid, and the type of fluid used did not influence the final outcome.

Gender difference in cytoprotection induced by estrogen on female and male bovine aortic endothelial cells

Before menopause, women have a lower risk of cardiovascular diseases than men. Studies attribute this gender difference to estrogenic protection in the female cardiovascular system. We have demonstrated that 17β-estradiol (E2) protects female bovine aortic endothelial cells against oxidative injury, probably through the induction of antioxidant enzyme activities. In this study, we examined whether E2 confers a differential protection on male and female cells. Bovine aortic endothelial cells from both genders were preconditioned for 24 h with E2 (1 nM to 10 µM), and their resistance to paraquat (1 mM, 3 h), a superoxide generator, was measured using an MTT assay. In contrast to the protection observed in female bovine aortic endothelial cells, there was no protective effect by E2 on male bovine aortic endothelial cells at physiologic concentrations. However, E2 at 1–10 µM attenuated paraquat’s toxicity in both male and female cells, probably through its direct antioxidant activity. E2 at 1 nM increased in female, but not in male, cells the activities of super-oxide dismutase, catalase, glutathione peroxidase, and glutathione reductase, which was associated with decreased levels of reactive oxygen species during subsequent paraquat exposure. This suggests that antioxidant enzyme induction plays some role in E2-augmented oxidative resistance in female endothelial cells.

Electrocardiographic finding simulating acute myocardial infarction in a compound metabolic aberration

A patient with hypokalemic metabolic alkalosis, hypophosphatemia, and hypomagnesemia/hypocalcemia is described. Electrocardiography demonstrated the pattern of acute anterior myocardial infarction. Further evaluation revealed that the patient had not actually had the acute myocardial infarction and that the electrocardiographic change was a mere simulation. The possible role of hypomagnesemia in the pathogenesis of the electrocardiographic change and the interrelation between the metabolic disturbances noted are discussed.

Transient Ischemic Attack and Nephrotic Syndrome: Case Report and Review of Literature

Thrombotic complications in patients with nephrotic syndrome are attributed to a hypercoagulable state. Venous thrombosis is common, but arterial thrombosis occurs less frequently in adult nephrotic patients. We report a case of recurrent transient ischemic attacks as an initial manifestation of nephrotic syndrome due to early-stage membranous glomerulonephritis, review the literature for similar cases, and briefly discuss this potentially life-threatening condition. We observed that transient ischemic attack or ischemic stroke could be the initial manifestation of nephrotic syndrome. Our observation may serve as reminder to consider nephrotic syndrome as a possible contributor when evaluating patients with transient ischemic attacks with no other discernable clues. A high index of suspicion alone avoids the unnecessary withholding of prophylaxis or treatment that can be life saving.

Lymphocytic interstitial pneumonitis in autoimmune thyroid disease

Four patients are described who were found to have autoimmune thyroid disease associated with lymphocytic interstitial pneumonitis. The patients were not receiving any medications known to cause lymphocytic interstitial pneumonitis. Their response to steroid therapy and the relapse of their clinical symptoms after steroid withdrawal support an underlying immunologic dysfunction. It is proposed that lymphocytic interstitial pneumonitis may be yet another manifestation of immune dysfunction in autoimmune thyroid disease.

Usefulness of MC-540 fluorescent dye as probe versus scanning electron microscopy for assessing membrane changes

The effect of primaquine enantiomers on cell membranes of glucose-6-phosphate (G-6PD)-deficient erythrocytes was studied in vitro. Staining with merocyanine (Mc-540) showed that exposure to primaquine enantiomers produces significant fluorescence in G-6PD-deficient erythrocytes, indicating marked drug-induced alterations in membrane fluidity. Scanning electron microscopy (SEM) studies confirmed that primaquine enantiomers altered membrane morphology (by producing stomatocytes) in both normal and G-6PD-deficient cells. The concentration-dependent effect, however, was more pronounced with MC-540, a lipophylic dye, than with SEM (an expensive technique).

Immunotherapy in Clinical Medicine

Active Immunotherapy in the form of pre-exposure primary and secondary (booster) vaccination has made the most significant impact on the current state of human health and longevity by preventing childhood and adult infectious diseases. The current availability of a vaccine (HPV vaccine) that prevents a number of cancers by inducing an immune response to a virus has opened up the field of preventive cancer vaccines. Passive immunotherapy using preformed antibodies and modulation of cytokine cascade by agonists and antagonists has added to the therapeutic armamentarium for diseases involving many organ systems. A brief overview of the history and current status of immunotherapy is presented in the first article. The next 10 articles review in detail the current status of immunological therapies in various diseases. The major focus of these articles is on clinically available immunotherapies. However, all the authors have included information on investigational and evolving immunotherapies. Such therapies for potentially fatal acute infectious disease caused by resistant pathogens are the need of the hour considering that no novel antimicrobial agents are in the pipeline. Even if such novel agents did become available, microbes developing resistance to antimicrobial agents are by now an expectation rather than news. It seems that understanding and utilizing physiology will be the most lasting intervention against pathology of human disease. That being the case, broadening and deepening of basic science curricula during medical school and graduate training should be a priority for educators and policy-makers. Simply teaching about a list of currently prevalent diseases in a superficial manner is likely feeding them today without concern for tomorrow. We find one of Osler’s quotes most appropriate in this context: “We are easily misled by our experience and not only are the reactions (of patients) themselves variable, but we, the doctors, are so fallible, ever beset with the common and fatal facility of reaching conclusions from superficial observations, and constantly misled by the ease with which our mind fall into the ruts of one or two experiences.”