Hypoglycemia in diabetes

Iatrogenic hypoglycemia causes recurrent morbidity in most people with type 1 diabetes and many with type 2 diabetes, and it is sometimes fatal. The barrier of hypoglycemia generally precludes maintenance of euglycemia over a lifetime of diabetes and thus precludes full realization of euglycemia's long-term benefits. While the clinical presentation is often characteristic, particularly for the experienced individual with diabetes, the neurogenic and neuroglycopenic symptoms of hypoglycemia are nonspecific and relatively insensitive; therefore, many episodes are not recognized. Hypoglycemia can result from exogenous or endogenous insulin excess alone. However, iatrogenic hypoglycemia is typically the result of the interplay of absolute or relative insulin excess and compromised glucose counterregulation in type 1 and advanced type 2 diabetes. Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia. In insulin-deficient diabetes (exogenous) insulin levels do not decrease as glucose levels fall, and the combination of deficient glucagon and epinephrine responses causes defective glucose counterregulation. Reduced sympathoadrenal responses cause hypoglycemia unawareness. The concept of hypoglycemia-associated autonomic failure in diabetes posits that recent antecedent hypoglycemia causes both defective glucose counterregulation and hypoglycemia unawareness. By shifting glycemic thresholds for the sympathoadrenal (including epinephrine) and the resulting neurogenic responses to lower plasma glucose concentrations, antecedent hypoglycemia leads to a vicious cycle of recurrent hypoglycemia and further impairment of glucose counterregulation. Thus, short-term avoidance of hypoglycemia reverses hypoglycemia unawareness in most affected patients. The clinical approach to minimizing hypoglycemia while improving glycemic control includes 1) addressing the issue, 2) applying the principles of aggressive glycemic therapy, including flexible and individualized drug regimens, and 3) considering the risk factors for iatrogenic hypoglycemia. The latter include factors that result in absolute or relative insulin excess: drug dose, timing, and type; patterns of food ingestion and exercise; interactions with alcohol and other drugs; and altered sensitivity to or clearance of insulin. They also include factors that are clinical surrogates of compromised glucose counterregulation: endogenous insulin deficiency; history of severe hypoglycemia, hypoglycemia unawareness, or both; and aggressive glycemic therapy per se, as evidenced by lower HbA(1c) levels, lower glycemic goals, or both. In a patient with hypoglycemia unawareness (which implies recurrent hypoglycemia) a 2- to 3-week period of scrupulous avoidance of hypoglycemia is advisable. Pending the prevention and cure of diabetes or the development of methods that provide glucose-regulated insulin replacement or secretion, we need to learn to replace insulin in a much more physiological fashion, to prevent, correct, or compensate for compromised glucose counterregulation, or both if we are to achieve near-euglycemia safely in most people with diabetes.     

Estimation of planetary boundary layer height using Suomi NPP-CrIS soundings

The study estimates planetary boundary layer height (PBLH) using temperature and humidity profiles from Cross-Track Infrared Sounder (CrIS) onboard Suomi National Polar-Orbiting Operational Environmental Satellite System Preparatory Project (SNPP). PBLH is estimated using six different methods and also using an integrated approach. PBLH estimated from SNNP-CrIS soundings by the integrated approach is compared with the PBLH values estimated using atmospheric profiles from radiosonde ascents and Constellation Observing System for Meteorology Ionosphere and Climate-radio occultation (COSMIC-RO) measurements. Analysis shows reasonable agreement of PBLH values from SNPP-CrIS soundings with those from radiosonde measurements and COSMIC-RO retrievals, thus revealing the capability of atmospheric profiles from SNNP-CrIS for the characterization of planetary boundary layer (PBL) with excellent spatial resolution and coverage. PBLH from SNNP-CrIS soundings are observed to be overestimated by around 336 m compared to the estimates from radiosonde ascends and is partly attributed to the difference in time of observations and coarse vertical resolution of the SNPP-CrIS-derived profiles. Compared to the estimates from SNPP-CrIS soundings, PBLH values from COSMIC-RO profiles are overestimated by around 596 m. Estimates from SNPP-CrIS soundings, through the integrated approach, are further used to examine the spatial and seasonal variations of PBLH over the Indian landmass. PBLH is observed highest in pre-monsoon and lowest in winter over most of the regions. Due to rainfall and associated changes in lower atmosphere and surface characteristics, PBLH is observed shallow during monsoon.     

Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein.

Our group has previously demonstrated that oxidized phospholipids in mildly oxidized LDL (MM-LDL) produced by oxidation with lipoxygenase, iron, or cocultures of artery wall cells increase monocyte-endothelial interactions and this sequence of events is blocked by HDL. To obtain further insight into the mechanism by which HDL abolishes the activity of MM-LDL we investigated the effect of the HDL-associated ester hydrolase paraoxonase (PON). Treatment of MM-LDL with purified PON significantly reduced the ability of MM-LDL to induce monocyte-endothelial interactions. Inactivation of PON by pretreating HDL with heat or EDTA reduced the ability of HDL to inhibit LDL modification. HPLC analysis of phospholipids isolated from MM-LDL before and after treatment with purified PON showed that the 270 nm absorbance of phospholipids was decreased, while no effect was observed on 235 nm absorbance. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and specific fractions of Ox-PAPC isolated by HPLC induced the same monocyte-endothelial interactions as did MM-LDL. Biologically active and inactive HPLC fractions of Ox-PAPC were compared by fast atom bombardment-mass spectrometry which revealed that active fractions possessed ions with a mass to charge [correction of change] ratio greater than native PAPC by multiples of 16 D suggesting the addition of 3 and 4 oxygen atoms to PAPC. Comparison of Ox-PAPC by fast atom bombardment-mass spectrometry before and after PON treatment showed that PON destroyed these multi-oxygenated molecules found in biologically active fractions of Ox-PAPC. These results suggest that PON in HDL may protect against the induction of inflammatory responses in artery wall cells by destroying biologically active lipids in mildly oxidized LDL.     

Estimation of serum anticollagen and the antibodies against chondrocyte membrane fraction: their clinical diagnostic significance in osteoarthritis

The serum anticollagen antibodies to collagen types II, IX, and XI, as well as the antibody level to chondrocyte membrane extract were investigated in patients suffering from severe osteoarthritis (n = 86) in comparison with patients free of primary arthritis (n = 33) and with control healthy patients (n = 44), respectively. Isolation and purification of cartilage antigens and their relevance to ELISA reaction have been outlined. Although the method for anticollagen antibodies to types IX and XI was more sensitive than that of type II, its sensitivity was very low (52%). The determination of the specific IgG fraction by affinity chromatography seemed to be more sensitive: in osteoarthritic patients the percentage of the "arthritogen" IgG rose to 10% of the total IgG. The determination of antibody level against chondrocyte membrane extract was adapted to human diagnostic purposes. In osteoarthritic patients the serum antibody level was significantly higher than in healthy controls. The specificity of this new test was proved by the facts that: (a) only the collagen-binding fraction of the membrane extract reacts with the patient's sera; (b) the ELISA reaction could be totally inhibited by the antigen; (c) patients suffering from noninflammatory joint diseases were characterized by low antibody levels.     

Somatosensory evoked potentials following tibial nerve stimulation. Method and normal values in relation to physical variables

Somatosensory evoked potentials were recorded in 40 healthy subjects (age: 22-63 years) with gluteal, lumbar, cervical and cortical surface electrodes after stimulation of the tibial nerve. Normal latency values were established in relationship to height and also for the amplitudes of the different components; the latencies of the cortical P40, N50 and P60 were significantly dependent on height, the latency of the cervical N33, the lumbar N22 and the gluteal Ng were dependent on the distance (stimulation--to recording point). The central conduction time showed no dependence on back length. Age dependence (in relation to normal height) was found only in the case of cortical P60.     

Further analysis of mutant thiolase protein in fibroblasts from a Japanese boy with 3-ketothiolase deficiency.

We examined the mutant protein of mitochondrial acetoacetyl-CoA thiolase (mutant T2) in fibroblasts from a Japanese boy with 3-ketothiolase deficiency. The molecular size of the mutant T2 protein, determined by pulse labeling and SDS/PAGE, was intermediate between the mature subunit and the precursor of T2. To characterize the mutant T2 protein, pulse-labeling and rhodamine 6G inhibition of mitochondrial transport in fibroblasts, cell-free translation experiments, and family studies by thiolase assay, immunoblotting, and pulse-labeling were carried out. The mutant T2 was detectable as early as a 10-min pulse. The probable precursor of the mutant T2 was not detectable in either the rhodamine 6G inhibition or cell-free translation experiments. In the parents, the K+ ion dependency of acetoacetyl-CoA thiolase activity was low and the T2 bands in immunoblots were faint. It would thus appear that the parents are heterozygotes of this disease. In pulse-labeling, only a band for the mutant T2 was detected in the patient and a single band for the normal mature subunit of T2 in the father; both bands were detected in the mother. These findings suggested that the mutant T2 in the patient was inherited from the mother, and that the expression of another mutant allele of the father may be either abolished or scanty.     

Associations of multiple chronic health conditions with active life expectancy in the United States

Purpose: To estimate associations of eight common health conditions with life expectancy (LE) and disabled life expectancy (DLE), the percentage of life disabled in an activity of daily living. Methods: Data from the Panel Study of Income Dynamics represented Americans ages 55+ (1999–2011, n?=?2118, mean baseline age 63.3, 19?447 person-years). We estimated probabilities of death and disability with multinomial logistic Markov models adjusted for age, sex, race/ethnicity and education. We used the probabilities to create large populations with microsimulations, each individual having a known monthly disability status, age 55 through death. We calculated LE and DLE for the populations, repeating each microsimulation 100 times for confidence intervals. Results: Nearly half (48.8%) of the participants had two or more conditions, 24.7% had three or more, 11.5% had four or more. Having any one condition significantly reduced LE. For example, white women lived to age 87.3 (95% confidence interval 86.5–88.1) with no conditions, 75.8 (70.9–80.7) with heart disease. Multiple conditions did not further reduce LE but often increased DLE, which for white women was 12.2% (11.1–13.2) with no conditions, 39.1% (28.3–49.8) with heart disease and 47.0% (46.9–47.1) with heart disease, diabetes and hypertension. Conclusion: The increasing prevalence of multiple chronic conditions may substantially increase disability.

• Implications for Rehabilitation

• The growing number of individuals with multiple chronic conditions will greatly increase the prevalence of disability in later life.

• It is important for rehabilitation science, practice and policy to address this emerging epidemiological transition.

• Rehabilitation is especially important for people with pre-diabetes, developing heart disease or early stages of other cardiovascular-related diseases as avoiding the development of multiple chronic diseases through increased activity may greatly reduce disability and mortality.

     

Human carbonic anhydrase I concentration in erythrocytes during pregnancy and the menstrual cycle

Carbonic anhydrase I (HCAI) concentrations were measured in erythrocytes (RBC) taken from nine women at intervals throughout their pregnancies and from thirteen normal women during the menstrual cycle. No significant changes in RBC HCAI concentrations were found in any instance. Small changes which were found in RBC HCAI concentrations were within experimental error and did not correlate with any other measured parameter. Changes in RBC HCAI concentrations in six men over a four-week period were of similar order to that found in the thirteen normal women over a similar length of time.