Laparoscopy in transplantation.

BACKGROUND: Solid-organ transplantation has become the treatment of choice for patients with end-stage renal disease, end-stage liver failure, and some patients with type 1 diabetes mellitus. Similarly, surgical expertise and mechanical improvements have led to significant advances in laparoscopic surgery. Laparoscopic interventions are sometimes not pursued in transplant recipients due to the lack of strong supporting evidence for the use of laparoscopic techniques in these patients. METHODS: Using an extensive literature search, we review herein the available data on the utility of laparoscopic interventions in transplant recipients, with particular attention to the risks and benefits, indications, and contraindications for this complex patient population. RESULTS: Although randomized trials are few, multiple case reports indicate that many transplant recipients have benefited from laparoscopic interventions. CONCLUSION: The well-known benefits of laparoscopy could be extended to transplant recipients.     

Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo.

Targeted silencing of disease-associated genes by synthetic short interfering RNA (siRNA) holds considerable promise as a novel therapeutic strategy. However, unmodified siRNA can be potent triggers of the innate immune response, particularly when associated with delivery vehicles that facilitate intracellular uptake. This represents a significant barrier to the therapeutic development of siRNA due to toxicity and off-target gene effects associated with this inflammatory response. Here we show that immune stimulation by synthetic siRNA can be completely abrogated by selective incorporation of 2'-O-methyl (2'OMe) uridine or guanosine nucleosides into one strand of the siRNA duplex. These noninflammatory siRNA, containing less than 20% modified nucleotides, can be readily generated without disrupting their gene-silencing activity. We show that, coupled with an effective systemic delivery vehicle, 2'OMe-modified siRNA targeting apolipoprotein B (apoB) can mediate potent silencing of its target mRNA, causing significant decreases in serum apoB and cholesterol. This is achieved at therapeutically viable siRNA doses without cytokine induction, toxicity, or off-target effects associated with the use of unmodified siRNA. This approach to siRNA design and delivery should prove widely applicable and represents an important step in advancing synthetic siRNA into a broad range of therapeutic areas.     

Delayed and persistent suppression of bronchoconstriction by trypsin in the airway lumen.

Mucosal trypsin, a protease-activated receptor (PAR) stimulant, may have an endogenous bronchoprotective role on airway smooth muscle. To test this possibility the effects of lumenal trypsin on airway tone in segments of pig bronchus were tested. Bronchial segments from pigs were mounted in an organ chamber containing Kreb's solution. Contractions were assessed from isovolumetric lumen pressure induced by acetylcholine (ACh) or carbachol added to the adventitia. Trypsin, added to the airway lumen (300 microg x mL(-1)), had no immediate effect on smooth muscle tone but suppressed ACh-induced contractions after 60 min, for at least 3 h. Synthetic activating peptides (AP) for PAR1, PAR2 or PAR3 were without effect, but PAR4 AP caused rapid, weak suppression of contractions. Lumenal thrombin was without effect and did not prevent the effects of trypsin. Effects of trypsin were reduced by N(omega)-nitro-L-arginine methyl ester but not indomethacin. Trypsin, thrombin and PAR4 AP released prostaglandin E2. Adventitially, trypsin, thrombin and PAR4 AP (but not PAR2 AP) relaxed carbachol-toned airways after <3 min. The findings of this study show that trypsin causes delayed and persistent bronchoprotection by interacting with airway cells accessible from the lumen. The signalling mechanism may involve nitric oxide synthase but not prostanoids or protease-activated receptors.     

Chronic hepatitis C in patients with persistently normal alanine transaminase levels.

BACKGROUND & AIMS: Many patients with chronic hepatitis C virus (HCV) have persistently normal serum alanine transaminase (ALT) levels. We compared characteristics of chronic hepatitis C patients with patients with normal and elevated ALT levels using data from 3 randomized phase III trials of peginterferon alfa-2a (40 kDa). METHODS: The characteristics of 480 patients with normal ALT values (on >or=3 occasions without any increases in ALT level over a 6- to 18-month period) and 1993 patients with elevated ALT levels were compared. Sixty-eight of the 480 patients with normal ALT levels were randomized to no treatment and monitored for 72 weeks. RESULTS: More patients with normal ALT levels than patients with elevated ALT levels were women (59% vs 32%; P<.01). The serum HCV RNA titer was significantly lower in patients with normal ALT levels (P<.01 vs in patients with elevated ALT levels). Patients with normal ALT levels had significantly lower inflammation and fibrosis scores on liver biopsy examination than patients with elevated ALT levels, but almost two-thirds had portal fibrosis and 10% had bridging fibrosis. No correlation between baseline ALT activity, HCV RNA level, and liver histology was observed in patients with normal ALT levels. During the 72-week follow-up period, ALT activity elevated above the upper limit of normal in 53% of the untreated patients with normal levels of ALT. None became HCV RNA undetectable. CONCLUSIONS: Chronic hepatitis C patients with normal ALT levels should be evaluated in a similar manner as patients with elevated ALT levels because they are at risk for developing significant liver disease. The decision to treat with peginterferon alfa and ribavirin should be based on multiple factors, rather than on ALT levels alone.     

Gram negative aerobic bacillus pneumonia in oral and maxillofacial surgery--a case for comment.

A case illustrating the potentially fatal complication of endogenous Gram Negative Aerobic Bacillus (GNAB) septicaemia secondary to nosocomial pneumonia is presented along with current theories as to its aetiology. The technique of selective decontamination of the digestive tract is designed and advocated to prevent such occurrences; oral and maxillofacial surgeons should be aware of this approach. It may be, however, that by using much simpler manoeuvres such as changes in policy regarding gastric stress ulcer prophylaxis, the already small risk of such an occurrence will be further reduced. Awareness of this condition will allow a higher index of suspicion when presented with catastrophic septic complications on the ITU and aid in more rational planning of antimicrobial therapy.     

SPARC, an extracellular matrix glycoprotein containing the follistatin module, is expressed by astrocytes in synaptic enriched regions of the adult brain

Although extracellular matrix (ECM) glycoproteins play important roles in neural development, their levels are generally believed to decrease in the adult brain. Immunohistochemical analysis indicates that the anti-adhesive ECM glycoprotein SPARC/osteonectin, which contains a follistatin ‘module’, is expressed in the adult rabbit nervous system. In the cerebellum, SPARC is present in Bergmann glia, with a strong signal along their radial fibres. SPARC, while enriched in membrane fractions, is not a transmembrane protein. In the hippocampus, colocalization of SPARC is observed in cells which express the astrocytic marker GFAP. The expression of SPARC by a subset of astrocytes, particularly in synaptic enriched areas, suggests a continuing role for the ECM in the adult brain.     

Human balancing of an inverted pendulum: position control by small, ballistic-like, throw and catch movements

In standing, there are small sways of the body. Our interest is to use an artificial task to illuminate the mechanisms underlying the sways and to account for changes in their size. Using the ankle musculature, subjects balanced a large inverted pendulum. The equilibrium of the pendulum is unstable and quasi-regular sway was observed like that in quiet standing. By giving full attention to minimising sway subjects could systematically reduce pendulum movement. The pendulum position, the torque generated at each ankle and the soleus and tibialis anterior EMGs were recorded. Explanations about how the human inverted pendulum is balanced usually ignore the fact that balance is maintained over a range of angles and not just at one angle. Any resting equilibrium position of the pendulum is unstable and in practice temporary; movement to a different resting equilibrium position can only be accomplished by a biphasic 'throw and catch' pattern of torque and not by an elastic mechanism. Results showed that balance was achieved by the constant repetition of a neurally generated ballistic-like biphasic pattern of torque which can control both position and sway size. A decomposition technique revealed that there was a substantial contribution to changes in torque from intrinsic mechanical ankle stiffness; however, by itself this was insufficient to maintain balance or to control position. Minimisation of sway size was caused by improvement in the accuracy of the anticipatory torque impulses. We hypothesise that examination of centre of mass and centre of pressure data for quiet standing will duplicate these results.