Identification of a G-Protein Subunit-α11 Gain-of-Function Mutation, Val340Met, in a Family With Autosomal Dominant Hypocalcemia Type 2 (ADH2).

Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia, inappropriately low serum parathyroid hormone concentrations and hypercalciuria. ADH is genetically heterogeneous with ADH type 1 (ADH1), the predominant form, being caused by germline gain-of-function mutations of the G-protein coupled calcium-sensing receptor (CaSR), and ADH2 caused by germline gain-of-function mutations of G-protein subunit α-11 (Gα11 ). To date Gα11 mutations causing ADH2 have been reported in only five probands. We investigated a multigenerational nonconsanguineous family, from Iran, with ADH and keratoconus which are not known to be associated, for causative mutations by whole-exome sequencing in two individuals with hypoparathyroidism, of whom one also had keratoconus, followed by cosegregation analysis of variants. This identified a novel heterozygous germline Val340Met Gα11 mutation in both individuals, and this was also present in the other two relatives with hypocalcemia that were tested. Three-dimensional modeling revealed the Val340Met mutation to likely alter the conformation of the C-terminal α5 helix, which may affect G-protein coupled receptor binding and G-protein activation. In vitro functional expression of wild-type (Val340) and mutant (Met340) Gα11 proteins in HEK293 cells stably expressing the CaSR, demonstrated that the intracellular calcium responses following stimulation with extracellular calcium, of the mutant Met340 Gα11 led to a leftward shift of the concentration-response curve with a significantly (p < 0.0001) reduced mean half-maximal concentration (EC50 ) value of 2.44 mM (95% CI, 2.31 to 2.77 mM) when compared to the wild-type EC50 of 3.14 mM (95% CI, 3.03 to 3.26 mM), consistent with a gain-of-function mutation. A novel His403Gln variant in transforming growth factor, beta-induced (TGFBI), that may be causing keratoconus was also identified, indicating likely digenic inheritance of keratoconus and ADH2 in this family. In conclusion, our identification of a novel germline gain-of-function Gα11 mutation, Val340Met, causing ADH2 demonstrates the importance of the Gα11 C-terminal region for G-protein function and CaSR signal transduction. © 2016 American Society for Bone and Mineral Research.

Hyperglycemia in Diabetic Patients in General Medicine Wards: No independent correlation with In- and Out-Of-Hospital Mortality.

BACKGROUND: Admission glucose levels correlate with clinical outcome in patients with type 2 diabetes mellitus (T2DM) hospitalized in general medicine wards. OBJECTIVE: To investigate whether in-hospital hyperglycemia alone, and after adjustment for age, gender and lipidemia, correlates with in- and out-of-hospital mortality. METHODS: Capillary glucose, serum lipids and diagnoses at discharge among patients with T2DM hospitalized in the general medical wards of our hospital were documented. Correlation with in- and out-of-hospital mortality was determined through uni- and multivariate analyses. RESULTS: Of the 4607 patients included in the study 22% died while hospitalized. From a median of five capillary glucose tests obtained per patient, average capillary glucose level was significantly lower in those who survived than in those who died (174 ± 64 vs. 180 ± 65 mg/dl, P = 0.005). Overall, blood cholesterol was higher in those who survived than in those who died (P < 0.001). Multivariate analysis, however, including age, gender, lipidemia and glycemia, showed that only age and male gender correlated with mortality. CONCLUSIONS: Hyperglycemia was associated with increased in- and out-of-hospital mortality on univariate analysis. However, it was not an independent risk factor when corrected for age, gender and hyperlipidemia.

Characterization of Patients who were Mechanically Ventilated in General Medicine Wards.

BACKGROUND: In Israel, where the "Do not resuscitate code" and "advanced directives" are not yet universally practiced, physicians are frequently 'forced' to mechanically ventilate patients despite an upfront unfavorable prognosis. Due to the shortage of intensive care unit (ICU) beds, patients are mostly hospitalized in general medicine wards. OBJECTIVES: To differentiate between patients with particularly grim prognoses and those with good prognoses, in order to inform the potential decision-making process regarding whether or not to offer aggressive medical care. METHODS: This retrospective study included all mechanically ventilated patients hospitalized exclusively in one of the six general internal medicine wards at the Assaf Harofeh Medical Center during 2009-2010. Demographic and ventilation-related data, laboratory values and main medical diagnoses were correlated to in-hospital mortality. RESULTS: The study group comprised 437 patients with a median age of 83 years. Mortality was 72%. Initiation of mechanical ventilation out of the hospital or in the emergency room improved outcome. Age, anemia, leukocytosis and renal failure correlated negatively to outcome. In-hospital mortality was 80% in patients after in-hospital resuscitation, 90% in patients ventilated due to infections, but 50% in patients ventilated for cardiac or respiratory failure. CONCLUSIONS: The prognosis of mechanically ventilated patients can be foreseen, which could help in deciding whether aggressive life support would be in the interest of the patient.

Decreased nocturnal glucose variability in non-diabetic patients with sleep apnea: a pilot study.

BACKGROUND: Obstructive sleep apnea has been sho be associated with impaired glucose metabolism and overt diabetes mellitus. However, the effect of hypoxic episodes on nocturnal glucose regulation in non-diabetic patients is unknown. OBJECTIVES: To investigate the effect of hypoxemia and nocturnal glucose homeosatsis in non-diabetic patients with sleep apnea. METHODS: Seven non-diabetic patients with moderate to severe sleep apnea were connected to a continuous glucose-monitoring sensor while undergoing overnight polysomnography. Mean SpO2 and percentage of time spent at SpO2 90% were recorded. The correlation between mean glucose levels, the difference between consecutive mean glucose measurements (glucose variability) and the corresponding oxygen saturation variables were determined in each patient during REM and non-REM sleep. RESULTS: No consistent correlation was found forthe individual patient between oxygen saturation variables and glucose levels during sleep. However, a lower mean SpO2 correlated with decreased glucose variability during sleep (r = 0.79, P = 0.034). This effect was primarily evident during REM sleep in patients with significant, compared to those with mild, oxygen desaturations during sleep (> 30% vs. < 10% of sleeping tim spent with SpO2 < 90%) (P = 0.03). CONCLUSIONS: Severe nocturnal hypoxemia in non-diabetic patients with moderate to severe sleep apnea might affect glucose regulation primarily during REM sleep.

Incidence of malignancies in patients with diabetes mellitus and correlation with treatment modalities in a large Israeli health maintenance organization: a historical cohort study.

It has been hypothesized that incidence of and mortality from several malignancies are increased among diabetic patients. Whether certain treatment modalities, including use of metformin, sulfonylureas, or insulins, affect cancer incidence or mortality and whether use of long-acting insulin analogues glargine and detemir may increase cancer incidence more than traditional human insulins are debated. The objective was to investigate the association between specific glucose-lowering agents and cancer incidence in diabetic members of an Israeli health maintenance organization. We studied a cohort of 36,342 diabetic patients aged at least 18 years with no history of cancer or treatment with insulin as of January 1, 2003. For the period from January 2003 to December 2007, we searched pharmacy records for purchases of glucose-lowering agents, including metformin, sulfonylureas, human insulin, and analogue insulins. Incident cancer diagnoses were identified from the health maintenance organization cancer registry. We studied the association of cancer incidence with the use of specific glucose-lowering agents, controlling for age, sex, and baseline glycohemoglobin measurement. Cancer was diagnosed in 6% of the study cohort during 164,652 person-years of follow-up time. Cancer incidence increased with age and varied with medication purchasing patterns. On multivariate analysis, age (hazard ratio [HR], 1.049; confidence interval [CI], 1.045-1.052), male sex (HR, 1.16; CI, 1.065-1.264), and number of insulin purchases (HR, 1.007; CI, 1.001-1.012) were significantly associated with increased cancer risk, whereas number of metformin purchases was associated with reduced cancer risk (HR, 0.996; CI, 0.994-0.998). Male sex, age, and human insulin purchases were associated with increased cancer incidence, whereas metformin purchases were associated with decreased cancer risk. There was a trend for increased cancer incidence associated with use of long-acting insulin analogues, but the number of long-acting insulin analogue users was too small for risk estimates to be conclusive.

Institutional glucometrics to determine glucose control as practiced by general medicine wards.

BACKGROUND: It is currently recommended that capillary glucose levels of non-critically ill hospitalized diabetic patients be maintained at between 140 and 180 mg/dl. Implementation of these recommendations and evaluation of their effectiveness require that data regarding the glucose control of these hospitalized patients be accessible. OBJECTIVE: To analyze glucose control and monitoring of all diabetic patients hospitalized in the general medicine wards of our medical center. METHODS: Capillary glucose measurements of all diabetic patients hospitalized in our departments of medicine between June and December 2008 were recorded by a central computerized institutional glucometer. Median glucose values and frequency of daily glucose checks per patient were analyzed in the internal medicine wards. RESULTS: We evaluated 14,366 capillary measurements from 2475 patients; 43% were taken before breakfast and 25% before dinner. A median of one daily determination per patient was obtained. This number increased 1.4-fold in patients with hyperglycemia >200 mg/dl and 2.5-fold in patients with hypoglycemia. Seventy-five percent of the recorded glucose values were within the recommended target range, with a median daily level of 161 mg/dl and median fasting glucose of 142 mg/dl. A significant variance was found between wards. CONCLUSIONS: The frequency of capillary glucose measurements in diabetic patients hospitalized in general medicine wards was low; most capillary glucose values, however, were within the recommended target range. The optimal monitoring of glucose in these patients remains to be determined.

Feasibility and safety of multiple daily insulin injections in general medicine wards.

AIM: Intravenous insulin improves clinical outcome in patients hospitalized in intensive care units. Whether glucose control with multiple daily subcutaneous insulin injections (MDI) is beneficial in patients hospitalized in general medical wards is unknown. We tested the feasibility, safety and efficacy of glucose control with MDI in diabetic patients hospitalized in a general medicine ward. METHODS: Eighty-eight adults with diabetes mellitus were studied in an internal medicine department. All patients were treated with subcutaneous pre-meal insulin analogue and Glargin insulin. A conservative and an intensified protocol was tested. RESULTS: Mean daily glucose levels decreased in the conservatively treated patients from 275+/-71 mg/dl at day 1 to 197.0+/-60 mg/dl at day 4 of hospitalization p=0.0001 and in the intensified protocol to 191+/-38 mg/dl already on day 1 remaining stable throughout the hospitalization. A mean daily glucose <180 mg% was reached by day 2 in 48% of patients in the intensified and in 32% in the conservative groups. Only one serious event of hypoglycemia was noted in the intensified group. CONCLUSION: Intensive insulin treatment with MDI is feasible, safe and efficacious in general medicine wards.

Heparanase, galectin-3, and tissue factor mRNA are expressed in benign neoplasms of the thyroid.

OBJECTIVE: Heparanase, galectin-3, and tissue factor (TF) are overexpressed in solid malignant thyroid tumors. We studied their expression in multinodular goiters (MNGs). DESIGN AND METHODS: Thyroid tissue specimens from 15 MNGs were obtained during surgery. mRNA expression for galectin-3, heparanase, and TF was assessed by RT-PCR. RESULTS: Isolated expressions of heparanase and galectin- 3 mRNA were expressed in 2 and 4 of the 15 MNGs, respectively; 8/15 MNGs were positive for both heparanase and galectin-3. TF mRNA was found in all MNG specimens. CONCLUSION: Galectin-3, heparanase, and TF RNA expression is prevalent in MNGs. Further studies will be needed to determine the prognostic significance of these findings.