The α-MSH analogue AP214 attenuates rise in pulmonary pressure and fall in ejection fraction in lipopolysaccharide-induced systemic inflammatory response syndrome in pigs

Background: The effect of an α‐melanocyte stimulating hormone (α‐MSH) analogue (AP214) on experimentally endotoxin‐induced systemic inflammatory response syndrome (SIRS) was studied, because α‐MSH in rodent models has shown promise in attenuating inflammatory response markers and associated organ damage in SIRS. SIRS is associated with considerable morbidity and mortality. Consequently, new treatment modalities are still warranted to address the different aspects of the pathophysiological process. Methods: SIRS was induced by lipopolysaccharide (LPS) (Escherichia coli endotoxin) infusion in anaesthetized Danish Landrace pigs (20–25 kg). The pigs received an α‐MSH analogue (AP214) or saline as a bolus at the initiation of the LPS infusion. The hemodynamic response was registered as well as echocardiographic indices of left ventricular function. Results: The cardiovascular response was recorded together with echocardiographic indices of left ventricular function in control and in intervention animals. AP214 reduced the early peak in pulmonary pressure and pulmonary vascular resistance by approximately 33%. Furthermore, AP214 prevented the decline in left ventricular fractional shortening as observed in the control group. Mean change and standard deviation in fractional shortening (ΔFS) in control group: ‐ 7·3 (4·7), AP214 (low dose): 0·9 (8·2) and AP214 (high dose) 4·1 (6·0), P < 0·05 for both intervention groups versus control. Conclusions: In the porcine model, the peak increase in pulmonary pressure was attenuated, and the LPS‐induced decline in left ventricular function was prevented.     

Elevation of serum type IV collagen-degrading enzyme in hepatocellular carcinoma with metastasis

The activity of serum type IV collagen-degrading enzyme was measured in 21 patients with hepatocellular carcinoma, and the changes in the enzyme activity were investigated with respect to metastasis. The activity of serum type IV collagen-degrading enzyme did not increase until tumor invasion to the portal vein and intrahepatic metastasis were clearly detected ultrasonographically. Activities did not increase during the observation period in patients whose tumor grew slowly and did not invade the portal vein. Thus, the enzyme activity increases in relation to the metastasis of hepatocellular carcinoma and may be useful to detect ongoing metastases.     

Nonlinear (amplified) relationship between nuclear occupancy by triiodothyronine and the appearance rate of hepatic alpha-glycerophosphate dehydrogenase and malic enzyme in the rat.

Three separate approaches were applied to examine the general relationship between R, the rate of induction of specific enzymes (mitochondrial alpha-glycero-phosphate dehydrogenase and cytosolic malic enzyme) and q, the fractional nuclear occupancy by triiodothyronine in male Sprague-Dawley rats. Daily 200-microgram injections of triiodothyronine per 10u g body wt for 7 days resulted in saturation of the hepatic nuclear sites and the achievement of an apparent new steady state of enzyme levels. The increase achieved over base-line hypothyroid levels was then compared with the increment over hypothyroid base line characteristic of intact euthyroid animals with 47% of nuclear sites occupied. The maximal theoretical reate of steady-state enzyme induction could be protected on the basis of the observed maximal increase in enzyme activity observed 1 day after the injection of graded doses of hormone and lambda, the known fractional rate of enzyme dissipation. The 24-h dose-response studies were used to generate R as a continuous function of q, both in hypothyroid as well as in euthyroid animals. This approach involved the numerical solution of an ordinary differential equation describing the rate of change of enzyme as a function of R, which was assumed to be uniquely related to q. Results of these analyses indicated that the ratio of the maximal rate of induction of enzyme at full occupancy to the rate of induction under euthyroid conditions assumes a value between 9.0 and 19.5, depending on the precise analytic and experimental approach applied. This value is far in excess of the theoretical ratio 2.13 which on would anticipate if R were linearly related to q and 47% of the nuclear sites occupied under physiological conditions. Thus, the signal for enzyme induction appears to undergo progressjive amplification with increasing nuclear occupancy. Moreover, the curve describing the relationship between R and q appears highly nonlinear throughout (concave upwards). Although the molecular mechanism responsible for amplification is unknown, recognition of this phenomenon may be helpful in understanding tissue effects of thyroid hormone excess. Moreover, the analytic technique for determining R as a function of q may be of general applicability in studying hormonal response systems under nonsteady-state conditions.     

Newly diagnosed human immunodeficiency virus after sepsis-like reaction of trimethoprim-sulfamethoxazole

A rare sepsis-like hypersensitivity reaction has been observed in persons with human immunodeficiency virus (HIV) after exposure to trimethoprim-sulfamethoxazole. This reaction most commonly occurs on rechallenge with the drug and is manifested by a syndrome resembling bacterial sepsis. The mechanism of this unusual reaction remains unclear. We describe the first case in which this severe hypersensitivity reaction was the initial manifestation of HIV.     

A clinical sickness score for the critically ill in Central Africa

Scoring systems provide a means for comparing results, ensuring consistent standards and evaluating changes in therapy. The APACHE II system depends partly on the results of laboratory tests which are not normally available in Central Africa. The aim of this study was to develop a scoring system based only on clinical observations. Six hundred and twenty-four consecutive admissions to the intensive care unit (ICU) were allocated a clinical sickness score (CSS) according to pulse rate, blood pressure, respiration rate, urine output, Glasgow Coma Scale, temperature and age. CSS was significantly associated with outcome, there being no significant difference between actual and predicted outcomes calculated by logistic regression analysis. There was a significant difference between mean scores for survivors and non-survivors in all diagnostic groups except diabetes. The proportional change in score from admission was also significantly associated with outcome on each subsequent day in ICU. The CSS provides an objective measure of illness severity for critically ill patients in Africa.     

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.