Secretory leukocyte protease inhibitor regulates nerve reflex-mediated skin barrier function in psoriasis.

BACKGROUND: Secretory leukocyte protease inhibitor (SLPI), a ~12 kDa protein is an important regulator of innate and adaptive immunity and a component of tissue regenerative programmes. SLPI expression is markedly elevated in chronically inflamed skin, including that of individuals suffering from psoriasis. However, the role of SLPI in these diseases remains elusive. OBJECTIVES: The poor understanding of the early stages of the development of psoriasis is a major obstacle to successful intervention in the skin pathology. We hypothesized that SLPI and peripheral nerves that might be activated early in the progression of the disease likely form a functional relationship to maintain skin barrier homeostasis and respond to a variety of threats. METHODS: We used skin biopsies of healthy donors and individuals with psoriasis to show expression pattern of SLPI. A role of SLPI in psoriasis was mechanistically assessed using SLPI-deficient mice and an imiquimod (IMQ)-induced experimental model of psoriasis. RESULTS: We show that mice lacking SLPI had exaggerated skin alterations that extended beyond the treatment site in an imiquimod-induced psoriasis. The spatiotemporally distinct skin responses in SLPI-deficient mice, compared to their wild-type littermates, resulted from a compromised skin barrier function that manifested itself in heightened transepidermal water loss through the larger skin area surrounding the IMQ-challenged skin. The increased pathogenic skin changes in the absence of SLPI were reversible through pharmacological treatment that blocks a nerve-reflex arc. CONCLUSIONS: Together, these data indicate that SLPI plays a protective role in psoriasis through preventing skin dryness, inherent in the pathogenesis of psoriasis and that this SLPI action depends on neuronal input operating in a reflex manner. These findings reveal a previously unrecognized mechanism that maintains cutaneous homeostasis, which involves a crosstalk between the nervous system and a protein anatomically poised to fortify the epidermal permeability barrier.

Cardiac arrest secondary to acute coronary syndrome: a 4-year observational study of patient characteristics and outcomes.

BACKGROUND: Cardiac arrest due to ischaemia is frequently the first manifestation of cardiovascular disease. We sought to describe the characteristics and outcomes of patients admitted to the Intensive Care Unit (ICU) with a diagnosis of cardiac arrest secondary to acute coronary syndrome (ACS). METHODS: We performed a retrospective analysis of patients admitted to the intensive care unit over a 4 year period. Baseline demographic characteristics, the use of therapeutic hypothermia, rates of percutaneous coronary intervention, co-morbidities and baseline left ventricular function were all documented. Outcomes included Glasgow Coma Scale (GCS) at time of discharge from the ICU, survival to hospital discharge, 6 months survival and left ventricular function at 6 months. RESULTS: We identified 31 admissions to the ICU following cardiac arrest due to ACS during the study period. 71 % of patients survived to hospital discharge and all of these were still alive at 6 months. 65 % had good neurological function (GCS > 13) when discharged from ICU. Mean left ventricular ejection fraction remained stable at 6 months. CONCLUSIONS: A significant proportion of patients admitted to the intensive care unit with a diagnosis of cardiac arrest secondary to acute coronary syndrome survive to hospital discharge with meaningful recovery in neurological and cardiac function.

Targeted temperature management in cardiovascular disease complicated by cardiac arrest.

PURPOSE: The majority of cardiac arrests occur due to cardiovascular etiology. Targeted temperature management (TTM) (32-34 °C) is a part of the standard post arrest care. We hypothesized that lower body temperature may lead to reduced cardiac metabolic demand and potentially have a beneficial effect on myocardial function. METHODS: We performed a retrospective study on patients admitted to the intensive care unit following cardiac arrest secondary to cardiovascular etiology over a 9 year period. We assessed the impact of TTM on neurological and cardiac outcomes. RESULTS: There were 57 patients in the cohort; 21 patients in the TTM group and 36 in the non-TTM group. Demographic characteristics were similar in both groups-the majority of patients (86 vs 80 %, respectively) were males in their 60s. Neurological outcomes were similar; 24 % of patients died during the ICU admission in the TTM group vs 18 % in the non-TTM group. Mean GCS on admission to the ICU was 4 vs 7, respectively, and 11 at discharge in both groups. Majority of patients recovered good neurological function (GCS ≥ 13)-57 % in the TTM group vs 64 % in the non-TTM group. The change in left ventricular function over a 6 month follow up period was significantly better in patients who received targeted temperature management-mean change of +4.4 vs -3.3 %, respectively. This proved to be statistically significant (p = 0.02). CONCLUSIONS: The study demonstrates a possible beneficial effect of TTM on long-term cardiac function, when instituted following cardiac arrest.

Effect of triiodothyronine (T3) excess on fatty acid metabolism in the soleus muscle from endurance-trained rats.

We studied whether short-term administration of triiodothyronine (T3) for the last 3 days of endurance training would influence the rate of uptake of palmitic acid (PA) as well as metabolism in rat soleus muscle, in vitro. Training per se did not affect the rate of PA uptake by the soleus; however, an excess of T3 increased the rate of this process at 1.5 mmol/L PA, as well as the rate that at which PA was incorporated into intramuscular triacylglycerols (TG). The rate of TG synthesis in trained euthyroid rats was reduced after exercise (1.5 mmol/L PA). The rate of PA oxidation in all of the trained rats immediately after exercise was enhanced by comparison with the sedentary values. Hyperthyroidism additionally increased the rate of this process at 1.5 mmol/L PA. After a recovery period, the rate of PA oxidation returned to the control values in both the euthyroid and the hyperthyroid groups. Examination of the high-energy phosphate levels indicated that elevated PA oxidation after exercise-training in euthyroid rats was associated with stable ATP levels and increased ADP and AMP levels, thus reducing energy cellular potential (ECP). In the hyperthyroid rats, levels of ADP and AMP were increased in the sedentary as well as the exercise-trained rats. ECP levels were high as a result of high levels of ATP and decreased levels of ADP and AMP in hyperthyroid rats after the recovery period. In conclusion, short-term hyperthyroidism accelerates PA utilization in well-trained soleus muscle.

The journey of mesothelioma: from postmortem to FNA.

A 73-year-old man, non-smoker presented with an 8-week history of left-sided chest pain and shortness of breath on exertion. He had no significant medical history. He worked in construction for 40 years, but denied definite asbestos exposure. His initial chest X-ray demonstrated a large left-sided pleural effusion. Subsequent CT thorax revealed circumferential thickening of the pleura with associated pleural plaques and calcification. A provisional diagnosis of mesothelioma was made. Initial ultrasound-guided thoracocentesis revealed a transudate with negative cytology. In addition, thoracoscopy and CT-guided pleural biopsy failed to obtain a definitive diagnosis. A surgical biopsy was planned, but at the time of admission, the patient developed unilateral neck swelling. Ultrasound-guided fine-needle aspiration (FNA) and core biopsies of the lymph node were diagnostic for pleural mesothelioma. Treatment with palliative chemotherapy was planned, but the patient's clinical status rapidly deteriorated and he passed away prior to the beginning of therapy.

Fasting increases palmitic acid incorporation into rat hind-limb intramuscular acylglycerols while short-term cold exposure has no effect.

The aim of the study was to investigate the palmitic acid incorporation into intramuscular acylglycerols in perfused hind-limb skeletal muscles of different fibre types in rats either fasted for 48 h or exposed to cold (6 °C) for 12 h. Hind-limb preparations of fasted and cold exposed rats were perfused with buffers containing tritium labelled and cold palmitic acid. Palmitic acid incorporation into intracellular lipid pools in the soleus, plantaris, red and white gastrocnemius and red and white quadriceps was measured. It was found that fasting increased approximately 2-fold palmitic acid incorporation in all muscles examined regardless of the fibre type composition of the muscle. On the other hand, exposure to cold had no effect on the palmitic acid incorporation into intramuscular acylglycerols regardless the muscle fibre type. The increased incorporation of palmitic acid into acylglycerols in fasted animals is in line with data showing that 48 h fasting stimulates the expression of plasma membrane proteins putatively facilitating fatty acid uptake. It appears that although 12 h cold exposure increases the use of fatty acids as energy substrates it does not alter the incorporation of palmitic acid into intramuscular acylglycerols in the perfused rat hind-limb.

Palmitic acid incorporation into intramuscular acylglycerols depends on both total and unbound to albumin palmitic acid concentration.

Palmitic acid incorporation into the intramuscular acylglycerols in rat skeletal muscles of different fiber types was investigated at various total and unbound to albumin concentrations by means of the hind-limb perfusion technique. It was found that at simultaneously increasing total and unbound to albumin palmitic acid concentrations in the perfusion medium the incorporation of palmitic acid into acylglycerols increased. However, when the concentration of palmitic acid not bound to albumin was kept constant and the total palmitic acid concentration was increased, the incorporation also increased although markedly less than under former conditions. The increase was most apparent in the muscles composed of slow-twitch oxidative and fast-twitch oxidative-glycolytic fibers where fatty acid uptake is the greatest. These findings suggest that fatty acid incorporation into intramuscular acylglycerols depends not only on the unbound to albumin fatty acid concentration but also, to some extent, on the total fatty acid concentration.

Time course of changes in lipoprotein lipase activity in rat skeletal muscles during denervation-reinnervation.

The effects of denervation-reinnervation after sciatic nerve crush on the activity of extracellular and intracellular lipoprotein lipase (LPL) were examined in the soleus and red portion of gastrocnemius muscles. The activity of both LPL fractions was decreased in the two muscles within 24 h after the nerve crush and remained reduced for up to 2 wk. During the reinnervation period, LPL activity was still reduced in the soleus and started to increase only on the 40th day. In the red gastrocnemius, LPL activity increased progressively with reinnervation, exceeding control values on the 30th day post-crush. The LPL activity in the soleus from the contralateral to denervated hindlimb was also affected, being increased on the postoperation day and then gradually decreased during the following days. In conclusion, the time course of changes in muscle LPL activity after nerve crush confirmed the predominant role of nerve conduction in controlling muscle potential to take up free fatty acids derived from the plasma triacylglycerols. However, other factors, such as muscle fiber composition and the fiber transformation, should also be considered in this aspect of the denervation-reinnervation process. Moreover, it was found that denervation of muscles from one hindlimb may influence LPL activity in muscles from the contralateral leg.

Palmitic acid uptake by the rat soleus muscle in vitro.

Abstract: The rate of fatty acid uptake, oxidation, and deposition in skeletal muscles in relation to total and unbound to albumin fatty acids concentration in the medium were investigated in the incubated rat soleus muscle. An immunohistochemical technique was applied to demonstrate whether the albumin-bound fatty acid complex from the medium penetrates well within all areas of the muscle strips. It was found that the percentage of incorporation of palmitic acid into intramuscular lipids was fairly constant, independently of the fatty acid concentration in the medium, and amounted to 63-72% for triacylglycerols, 7-12% for diacylglycerols-monoacylglycerols, and 19-26% for phospholipids. Both palmitic acid incorporation into the muscle triacylglycerol stores and its oxidation to CO2 closely correlated with an increase in both total and unbound to albumin fatty acid concentrations in the incubation medium. Under conditions of increased total but constant unbound to albumin palmitic acid concentrations, the incorporation of palmitic acid into triacylglycerols and its oxidation to CO2 were also increased, but to a lower extent. This supports the hypothesis that the cellular fatty acid metabolism depends not only on the availability of fatty acids unbound to albumin, but also on the availability of fatty acids complexed to albumin.

[A case of chloroquine-resistant tropical malaria from eastern Africa (Kenya)]. / Ein Fall von chloroquinresistenter Malaria tropica aus Ostafrika (Kenia).

A case of chloroquine-resistant falciparum malaria in a non-immune Swiss tourist is described. The infection was acquired in Kenya in spite of regular chloroquine prophylaxis with therapeutic serum levels. The isolated plasmodia showed marked in vitro resistance to chloroquine and sensitivity to mefloquine and pyrimethamine.

Regulatory role of humoral factors released by macrophages in reactivity of rat lymphocytes in vitro. III. Humoral factors released by lymph node macrophages regulating lymphocyte response to PHA.

Lymph node macrophages, derived from normal rats, generated in vitro factors enhancing or suppressing syngeneic lymph node lymphocyte stimulation in response to PHA and reconstituting the PHA-dependent response of lymphocytes deprived of native macrophages. The occurrence of one of the opposite activities depended on the degree of lymphocyte stimulation by PHA. Moreover, the expression of suppressing or stimulating effect no lymphocyte response to PHA of the same supernatants, changed twice with their dilution, (suppression leads to enhancement leads to suppression) suggesting the existence of two distinct factors: suppressing and enhancing.

The influence of PGE1 and db-cAMP on permeability of lysosomal membranes of rat lymphocytes in the in vitro histamine test.

An attempt was made to develop as in vitro model of inflammation which would allow the study of the inflammatory process on the subcellular level and on the influence of PGE1 and db-cAMP on permeability of lysosomal membranes of liver lymphocytes. The results showed that the in vitro histamine test permits evaluation of early changes in the lysosomal membranes. Drugs such as acetylsalicylic acid, hydrocortisone, as well as PGE1 and db-cAMP exerted a stabilizing influence on the lysosomal membranes of rat lymphocytes.

The regulatory role of macrophage factors on rat lymphocyte reactivity.

The sensitized peritoneal rat macrophages released in vitro soluble factors stimulating and transforming normal syngenic lymphocytes into the cytotoxic cells with nonspecific activity. Normal peritoneal macrophages released factors stimulating a low spontaneous synthesis of DNA in lymph node lymphocytes or suppressing a high spontaneous synthesis of DNA in native and cortisone-resistant thymocytes. Normal lymph node macrophages in addition to factors suppressing the spontaneous synthesis of DNA in native and cortisone-resistant thymocytes also release factors enhancing or depressing the response of lymphocytes to PHA; the revealing of one of the opposite activities was dependent on the rate of lymphocyte stimulation with PHA. The factors released by lymph node macrophages could also reconstitute the reactivity of lymphocytes depleted of adherent cells to PHA.