Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure

CONTEXT: Primary IGF deficiency (IGFD) describes the condition in which serum concentrations of IGF-I are low in the face of normal to elevated GH production. Because IGF-I, which circulates as part of a ternary complex with IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS), mediates the growth-promoting effects of GH, IGFD is associated with severe growth failure in humans. OBJECTIVE: We investigated a case of IGFD in which serum IGF-I and IGFBP-3 were abnormally low, yet growth failure was modest (-2.1 sd score at 15.5 yr of age). RESULTS: The young male subject, from a consanguineous pedigree, had a postnatal growth profile consistently below the third percentile. The subject had a normal fasting GH level of 3.7 muU/ml and normal serum GH binding protein level (1258 pmol/liter; normal range 431-1892 pmol/liter), but serum IGF-I and IGFBP-3 were profoundly reduced (-5.8 and -7.2 sd score, respectively, at age 12.3 yr), even through puberty. A novel homozygous missense mutation was subsequently identified in the ALS gene, which resulted in severe deficiency of serum ALS (undetectable). CONCLUSIONS: ALS is critical for maintaining normal serum concentrations of IGF-I and IGFBP-3, most likely by prolonging the half-lives of both proteins. ALS deficiency can be associated with moderate growth failure, but in this patient, the onset and progression of puberty appear to be normal. Altogether the results support a modest role for the ternary complex in the regulation of stature.     

Risk factors for symptomatic stone recurrence after transpapillary laser lithotripsy for difficult bile duct stones using a laser with a stone recognition system

BACKGROUND: Laser-induced shock-wave lithotripsy (LISL) is successfully used for the treatment of difficult bile duct stones. The aim of this study was to assess the long-term risk for a symptomatic bile duct stone recurrence after LISL and to detect risk factors predicting recurrence. METHODS: Between 1993 and 2001, 80 patients with difficult bile duct stones were successfully treated by intracorporeal LISL through the papilla of Vater. Seventy-one of these patients [median age, 65.8 years; 51 women (71.8%)] were followed for a median (range) period of 58 (1-114) months. RESULTS: Eleven patients (15.5%) had a symptomatic stone recurrence. The median (range) period between laser lithotripsy and recurrence was 40 (5-85) months. The presence of a bile duct stenosis (P=0.032) and a body-mass index below 25 (P=0.025) were significantly associated with an increased risk for stone recurrence. A gallbladder in situ, the presence of gallbladder stones, dilation of the bile duct, or a peripapillary diverticulum was not associated with stone recurrence. CONCLUSIONS: The presence of a bile duct stenosis is significantly related to bile duct stone recurrence after treatment with LISL. The impact of the body mass index on stone recurrence is interesting. The gallbladder status did not predict stone recurrence in our study.     

Heat Stress is Associated with Reduced Health Status in Pulmonary Arterial Hypertension: A Prospective Study Cohort

Background

Summer heat waves with temperature extremes are becoming more frequent with growing numbers in morbidity and mortality in patients with respiratory diseases. The aim of this study was to evaluate the ramifications of heat stress (temperature >25 °C) on the health status of patients with pulmonary arterial hypertension (PAH).

Methods

Fifteen patients with PAH (mean age = 66.7 ± 5.2 years) continuously wore an accelerometer from April 1 to September 30, 2011, and their daily step count was recorded. In addition, patients kept a diary to record data on seven standardized questions regarding their daily symptoms. Echocardiography, 6-minute walk test, NTproBNP, and Modified Medical Research Council Scale (MMRC) were assessed at baseline and at the end of the study after 6 months.

Results

On heat-stress days, patients showed significantly more symptoms and lower total steps/day compared to thermal comfort days (3,995 ± 2,013 steps/day vs. 5,567 ± 2,434 steps/day, respectively; P < 0.001). There was a significant negative correlation between total steps/day and Temp_max (R = ?0.47; P < 0.001) and humidity (R = ?0.34; P < 0.001). A significant positive correlation was found between daily symptoms and Temp_max (R = +0.79; P < 0.001) and humidity (R = +0.23; P < 0.001).

Conclusions

Heat stress is associated with a compromised clinical status in patients with PAH. Adaptation strategies must be implemented to prevent heart-related morbidity, including therapeutic adjustments and adequate room cooling in the patient’s home and at the hospital.     

Effect of home mechanical ventilation on inspiratory muscle strength in COPD

BACKGROUND: The mechanism responsible for chronic hypercapnic respiratory failure (HRF) in patients with COPD remains unclear. In this study, we tested the hypothesis that chronic HRF in patients with COPD is associated with low-frequency fatigue (LFF) of the diaphragm. METHODS: To test this hypothesis, we measured the twitch transdiaphragmatic pressure (Tw Pdi) elicited by stimulation of the phrenic nerves in 25 patients with chronic HRF (mean [+/- SD] Paco(2), 55.2 +/- 5.2 mm Hg) due to COPD before and 2 months after the initiation of noninvasive mechanical ventilation (NIV) [pressure-cycled ventilation with inspiratory positive airway pressure of 19.0 +/- 2.5 cm H(2)O]. We reasoned that had LFF been present, Tw Pdi should rise after effective NIV. RESULTS: The treatment compliance with NIV was good (median of machine usage was 7.1 h per night). Paco(2) decreased from 55.2 +/- 5.2 to 48.8 +/- 5.9 mm Hg (p < 0.001), and Pao(2) increased from 53.1 +/- 5.9 to 57.7 +/- 7.0 mm Hg (p = 0.007). Mean Tw Pdi at baseline was 11.1 +/- 6.6 cm H(2)O and after treatment was 11.7 +/- 7.2 cm H(2)O (not significant). Also, maximal static inspiratory mouth pressure did not change significantly (44.3 +/- 15.9 cm H(2)O vs 46.5 +/- 19.7 cm H(2)O). CONCLUSION: LFF of the diaphragm does not accompany chronic HRF in patients with COPD.     

Bile salt-induced apoptosis involves NADPH oxidase isoform activation

BACKGROUND & AIMS: Hydrophobic bile salts trigger a rapid oxidative stress response as an upstream event of CD95 activation and hepatocyte apoptosis. METHODS: The underlying mechanisms were studied by Western blot, immunocytochemistry, protein knockdown, and fluorescence resonance energy transfer microscopy in rat hepatocytes and human hepatoma cell line 7 (Huh7). RESULTS: The rapid oxidative stress formation in response to taurolithocholate-3-sulfate (TLCS) was inhibited by diphenyleneiodonium, apocynin, and neopterin, suggestive for the involvement of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. TLCS induced a rapid serine phosphorylation of the regulatory subunit p47phox, which was sensitive to inhibition of sphingomyelinase and protein kinase Czeta (PKCzeta). Inhibitors of p47phox phosphorylation and p47phox protein knockdown abolished the TLCS-induced oxidative stress response and blunted subsequent CD95 activation. Consequences of TLCS-induced oxidative stress were c-Jun-N-terminal kinase activation and Yes-dependent activation of the epidermal growth factor receptor (EGFR), followed by EGFR-catalyzed CD95 tyrosine phosphorylation, formation of the death-inducing signaling complex, and execution of apoptosis. As shown by fluorescence resonance energy transfer experiments in Huh7 cells, TLCS induced a c-Jun-N-terminal kinase-dependent EGFR/CD95 association in the cytosol and trafficking of this protein complex to the plasma membrane. Inhibition of EGFR tyrosine kinase activity by AG1478 allowed for cytosolic EGFR/CD95 association, but prevented targeting of the EGFR/CD95 complex to the plasma membrane. Both processes, and TLCS-induced Yes and EGFR activation, were sensitive to inhibition of sphingomyelinase, PKCzeta, or NADPH oxidases. CONCLUSIONS: The data suggest that hydrophobic bile salts activate NADPH oxidase isoforms with the resulting oxidative stress response triggering activation of the CD95 system and apoptosis.     

Acute aortic syndromes: aortic dissections, penetrating aortic ulcers and intramural aortic hematomas

Acute aortic syndromes, including dissections, intramural hematomas and penetrating aortic ulcers, are a catastrophic clinical entity that are relatively uncommon. A high index of clinical suspicion along with proper imaging modalities are critical in making a prompt and accurate diagnosis for immediate management and to improve survival of the patient.     

Functional rescue of defective mutant connexons by pairing with wild-type connexons

We have compared the functional and structural integrity of gap junction channels assembled from a Cx45 truncation mutant with those of gap junction channels assembled from wild-type (wt) Cx45 and Cx43. These channel-forming proteins are constitutively expressed in HeLa cells. The truncation mutant lacks the last 26 amino acids of the COOH-terminus, including nine serine phosphorylation sites that are associated with regulatory processes of these channels. We determined the presence of gap junction plaques in these cells with the immunogold freeze fracture technique, which showed that plaque formation is similar in all the clones investigated. Junctional permeability was probed with calcein transfer and flow cytometry analyses and junctional conductance was measured in cell pairs with double whole-cell patch-clamp techniques. For homotypic pairing only the truncated mutant did not form permeable channels. However, coupling was restored for heterotypic channels (pairing wtCx45- or wtCx43- with mutant-connexons), whose junctional communication was not different from that of the homotypic channels. Our results indicate that the presence of gap junction plaques does not warrant functional coupling and that heterotypic trCx45/wtCx45 channels can be regulated by the intact wtCx45 connexons. This dominant-positive effect is also operative when wtCx43 are paired with trCx45 connexons.     

Acute changes in neuromuscular excitability after exhaustive whole body vibration exercise as compared to exhaustion by squatting exercise

The effects of hard squatting exercise with (VbX+) and without (VbX-) vibration on neuromuscular function were tested in 19 healthy young volunteers. Before and after the exercise, three different tests were performed: maximum serial jumping for 30 s, electromyography during isometric knee extension at 70% of the maximum voluntary torque, and the quantitative analysis of the patellar tendon reflex. Between VbX+ and VbX- values, there was no difference found under baseline conditions. Time to exhaustion was significantly shorter in VbX+ than in VbX- (349 +/- 338 s versus 515 +/- 338 s), but blood lactate (5.49 +/- 2.73 mmol l-1 versus 5.00 +/- 2.26 mmol l-1) and subjectively perceived exertion (rate of perceived exertion values 18.1 +/- 1.2 versus 18.6 +/- 1.6) at the termination of exercise indicate comparable levels of fatigue. After the exercise, comparable effects were observed on jump height, ground contact time, and isometric torque. The vastus lateralis mean frequency during isometric torque, however, was higher after VbX+ than after VbX-. Likewise, the tendon reflex amplitude was significantly greater after VbX+ than after VbX- (4.34 +/- 3.63 Nm versus 1.68 +/- 1.32 Nm). It is followed that in exercise unto comparable degrees of exhaustion and muscular fatigue, superimposed 26 Hz vibration appears to elicit an alteration in neuromuscular recruitment patterns, which apparently enhance neuromuscular excitability. Possibly, this effect may be exploited for the design of future training regimes.     

Oxygen uptake during whole-body vibration exercise: comparison with squatting as a slow voluntary movement

In this study we investigated metabolic power during whole-body vibration exercise (VbX) compared to mild resistance exercise. Specific oxygen consumption ( ) and subjectively perceived exertion (rating of perceived exertion, RPE; Borg scale) were assessed in 12 young healthy subjects (8 female and 4 male). The outcome parameters were assessed during the last minute of a 3-min exercise bout, which consisted of either (1) simple standing, (2) squatting in cycles of 6 s to 90° knee flexion, and (3) squatting as before with an additional load of 40% of the subject's body weight (35% in females). Exercise types 1–3 were performed with (VbX+) and without (VbX–) platform vibration at a frequency of 26 Hz and an amplitude of 6 mm. Compared to the VbX– condition, the specific was increased with vibration by 4.5 ml·min^–1·kg^–1. Likewise, squatting and the additional load were factors that further increased . Corresponding changes were observed in RPE. There was a correlation between VbX– and VbX+ values for exercise types 1–3 (r=0.90). The correlation coefficient between squat/no-squat values (r=0.70 without and r=0.71 with the additional load) was significantly lower than that for VbX–/VbX+. Variation in specific was significantly higher in the squatting paradigm than with vibration. It is concluded that the increased metabolic power observed in association with VbX is due to muscular activity. It is likely that this muscular activity is easier to control between individuals than is simple squatting. Electronic Publication