Pro/con debate: Should PaCO2 be tightly controlled in all patients with acute brain injuries?

You are the attending intensivist in a neurointensive care unit caring for a woman five days post-rupture of a cerebral aneurysm (World Federation of Neurological Surgeons Grade 4 and Fisher Grade 3). She is intubated for airway protection and mild hypoxemia related to an aspiration event at the time of aneurysm rupture, but is breathing spontaneously on the ventilator. Your patient is spontaneously hyperventilating with high tidal volumes despite minimal support and has developed significant hypocapnia. She has not yet developed the acute respiratory distress syndrome. You debate whether to tightly control her partial pressure of arterial carbon dioxide, weighing the known risks of acute hypocapnia in other forms of brain injury against the potential loss of clinical neuromonitoring associated with deep sedation and neuromuscular blockade in this patient who is at high risk of delayed ischemia from vasospasm. You are also aware of the potential implications of tidal volume control if this patient were to develop the acute respiratory distress syndrome and the effect of permissive hypercapnia on her intracranial pressure. In this paper we provide a detailed and balanced examination of the issues pertaining to this clinical scenario, including suggestions for clinical management of ventilation, sedation and neuromonitoring. Until more definitive clinical trial evidence is available to guide practice, clinicians are forced to carefully weigh the potential benefits of tight carbon dioxide control against the potential risks in each individual patient based on the clinical issues at hand.     

Organ Correlation in IgG4-Related Diseases

IgG4-related disease (IgG4-RD) is a potentially multiorgan disorder. In this study, clinical and serological features from 132 IgG4-RD patients were compared about organ correlations. Underlying pathologies comprised autoimmune pancreatitis (AIP) in 85 cases, IgG4-related sclerosing cholangitis (IgG4-SC) in 12, IgG4-related sialadenitis (IgG4-SIA) in 56, IgG4-related dacryoadenitis (IgG4-DAC) in 38, IgG4-related lymphadenopathy (IgG4-LYM) in 20, IgG4-related retroperitoneal fibrosis (IgG4-RF) in 19, IgG4-related kidney disease (IgG4-KD) in 6, IgG4-related pseudotumor (IgG4-PT) in 3. Sixty-five patients (49%) had multiple IgG4-RD (two affected organs in 36 patients, three in 19, four in 8, five in 1, and six in 1). Serum IgG4 levels were significantly higher with multiple lesions than with a single lesion (P<0.001). The proportion of association with other IgG4-RD was 42% in AIP, the lowest of all IgG4-RDs. Serum IgG4 level was lower in AIP than in other IgG4-RDs. Frequently associated IgG4-RDs were SIA (25%) and DAC (12%) for AIP; AIP (75%) for IgG4-SC; DAC (57%), AIP (38%) and LYM (27%) for IgG4-SIA; AIP (26%) and LYM (26%) for IgG4-DAC; SIA (75%), DAC (50%) and AIP (45%) for IgG4-LYM; SIA (58%), AIP (42%) and LYM (32%) for IgG4-RF; AIP (100%) and SIA (67%) for IgG4-KID; and DAC (67%) and SIA (67%) for IgG4-PT. Most associated IgG4-RD lesions were diagnosed simultaneously, but IgG4-SIA and IgG4-DAC were sometimes identified before other lesions. About half of IgG4-RD patients had multiple IgG4-RD lesions, and some associations were seen between specific organs.

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Inhibitory neuropeptides and intrinsic inhibitory innervation of descending human colon

The effects of aging on inhibitory neuropeptide concentrations and intrinsic inhibitory innervation of circular muscle were investigated using normal descending colon obtained at surgery. Immunoreactive vasoactive intestinal peptide, peptide histidine-methionine, met⁵-enkephalin, neuropeptide Y, and somatostatin were extracted from specimens of muscularis externa (patient ages: 19–84 years) and measured by radioimmunoassay. Intracellular electrical activity was recorded from strips of circular muscle (patients ages: 49–84 years) using glass microelectrodes; inhibitory junction potentials were evoked by electrical field stimulation. There were no significant differences (t tests:P>0.05) between neuropeptide concentrations in patients<70 years old (N=28) compared to patients70 years old (N=12). However, the amplitude of inhibitory junction potentials declined with increasing patient age (r=–0.58,P=0.02,N=16), with no change in resting membrane potentials (r=0.22;P>0.05). The decline in amplitude in women (r=–0.68,P=0.03,N=9) preceded the decline in men (r=–0.62,P=0.10,N=7). Age-related decline in inhibitory junction potentials could be related to decreased: density of inhibitory nerves, release of inhibitory neurotransmitter, density of binding sites for inhibitory neurotransmitter on smooth muscle, or a combination thereof. Alternatively, this decline might represent a change in interaction of inhibitory neurotransmitter with the smooth muscle membrane, such as a change in coupling of binding site with the potassium channel, decreased number of potassium channels, or altered permeability of the potassium channel.This study was supported in part by the National Institutes of Health (DK 17238 and DK 34988), and by VA Medical Research funds.     

Development of an opinion leader-led HIV prevention intervention among alcohol users in Chennai, India.

In 1999, we began a community-based randomized controlled prevention trial in Chennai, which aims to test the efficacy of HIV prevention messages disseminated through members of an individual's social group called community popular opinion leaders, or CPOLs. We targeted patrons of 100 bars or wine shops in the city of Chennai, India. In this article we report on the process of development of an HIV prevention intervention for wine shop patrons. First, we conducted detailed ethnography to understand social norms and CPOL and social network characteristics, including 41 in-depth interviews among wine shop patrons and gatekeepers. Second, we tailored a generic HIV education training manual to appropriately address the needs of Chennai wine shop patrons. Field-testing involved 16 focus groups with wine shop patrons and 12 sessions of participant observations in wine shops. Finally, we piloted the intervention to determine the appropriateness of the training program and its content among wine shop patrons. Our ethnographic data indicated that wine shops are a common meeting place for men. We were able to identify CPOLs influential in these settings and train them to deliver appropriate prevention messages to their close friends and associates. We found that HIV prevention messages in this population need to dispel misperceptions about HIV transmission, provide strategies and skills to adopt and sustain condom use, and target the role of alcohol in sexual behavior. We outline specific lessons we learned in intervention development in this population.     

Detection of cofilin mRNA by hybridization-sensitive double-stranded fluorescent probes

We have developed hybridization-sensitive fluorescent oligonucleotide probes that, in the presence of quencher strands, undergo efficient fluorescence quenching through the formation of partial DNA/DNA duplexes. In the presence of target RNA, rapid displacement of the quencher strands results in highly enhanced fluorescence.

We have developed hybridization-sensitive fluorescent oligonucleotide probes that, in the presence of quencher strands, undergo efficient fluorescence quenching through the formation of partial DNA/DNA duplexes.

The detection of biomolecules is an important part of any investigation into their biological mechanisms and phenomena. Fluorescence-based methods are particularly useful for providing interpretable signals for various targets (e.g., genes, proteins, small molecules). When nucleic acids are used as probes, they can provide sequence-specific information regarding the binding (through hydrogen bonding) of target nucleic acids. Because of their high sequence-specificity, many fluorescent hybridization probes, including molecular beacons (MBs), have been developed and applied for nucleic acid detection and visualization.^1,2In previous studies, we found that a quencher-free molecular beacon (QF-MB) containing the pyrene-modified nucleoside ^PyU exhibited a high fluorescence enhancement in the presence of trinucleotide repeats, especially for RNA.^3,4 Among various fluorescent nucleobase derivatives, uracil derivatives have been particularly useful for selective detection of specific sequences, taking advantage of changes in photoinduced electron transfer between the fluorophore and the neighboring base.^3–5 To apply such systems to various other target sequences, here we designed fully complementary sequences and incorporated the internal fluorescent nucleoside ^PyU in place of a thymine residue, resulting in a significantly increased fluorescence signal based on strand displacement (Fig. 1). Incorporation of a ^PyU unit in a single strand of the probe sequence and hybridization with a strand partially complementary to the probe strand containing a pyrene unit as a fluorescence quencher can lead to improved discrimination factors.^4,6 Such partially double-stranded probes have several attractive features.Open in a separate windowFig. 1(A) Schematic representation of the strand displacement process developed in this present system. (B) Structures of the internal fluorophore ^PyU.First, the probe sequence does not require an additional sequence in its strand that is not complementary to the target sequence to ensure formation of a secondary structure (e.g., a hairpin). Such additional sequences might interfere with the specific hybridization between the probe and the target sequence. Accordingly, double-stranded fluorescence probes should allow the specific detection of many kinds of targets. Second, the highly quenched initial fluorescence signal, due to the formation of a partial duplex, results in significantly increased fluorescence in the presence of the target; the incorporation of a hybridization-sensitive internal fluorophore provides a stable and sensitive fluorescence signal upon perfect hybridization with the target.Cofilin is a protein that regulates the activity of actin, which is related to the formation of the cytoskeleton in cells. Actin plays a crucial role in the growth and elongation of cells,⁷ especially in neurons and, therefore, in the control of neurotransmission. We designed probe strands complementary to the 3′-untranslated region (3′-UTR) of target cofilin mRNA and synthesized three kinds of 19-mer probe strands (P1–P3) containing one or two ^PyU units in each strand (Fig. 2A and S1, ESI^†). The fluorescence intensities of P1 and P3 increased dramatically after binding with the target RNA T19—by 17.6- and 16.0-fold, respectively. For the probe P2 (in which the ^PyU residue was located close to the 3′-end), however, the fluorescence enhancement was very low: only 1.8-fold (Table S2, ESI^†). We assume that terminal modification of the ^PyU unit in the probe resulted in weak base pairs around the ^PyU residue than did central modification, resulting in a decrease in fluorescence enhancement (Table S3, ESI^†).⁸ Because flanking base pairs around the ^PyU unit are relatively less rigid compared to central base pairs, the microenvironment of ^PyU in the duplex formed from P2 and T19 is different from the central modification. Therefore, the fluorescence intensity did not increase significantly compared to the single-stranded P2. The absorption spectrum of P2 in the presence of T19 exhibited a relatively less intense absorption band than that of the duplex formed from P1 and T19—the latter featured an intense signal corresponding to the high fluorescence intensity (Fig. S1, ESI^†).^9,10 Even though two ^PyU units were incorporated into the single strand P3, its fluorescence enhancement was similar to that of probe P1 containing only one ^PyU unit. Among other examined probe sequences complementary to other parts of 3′-UTR in cofilin mRNA, P6 (containing two ^PyU units) also exhibited fluorescence intensity similar to those of P4 and P5, single-^PyU – containing probes each modified in the central position (Fig. S2, ESI^†). These results suggest that single modification of a ^PyU unit in the probe sequence is more efficient than dual modification, in terms of inducing high fluorescence enhancement with target RNA.Oligonucleotide sequences of probe and target strands