Current use of procedure specific consent forms for laparoscopic cholecystectomy.

Introduction Procedure specific consent forms (PSCFs) have been shown to improve consenting practice for a standardised list of complications. The aim of this study was to assess the current usage and quality of PSCFs in the National Health Service (NHS) for cholecystectomy, specifically comparing the listed complications with those mentioned on the NHS website. Methods A freedom of information request was sent to all NHS trusts asking whether they perform laparoscopic cholecystectomy and whether they have a PSCF for this. A copy of the PSCF was also requested. Complications stated on these forms were compared with those on the NHS Choices website. Results Overall, 162 (88%) of the 185 trusts responded, with 121 of these performing cholecystectomies. Among these, 20 (17%) currently use PSCFs; all provided a copy. Five (25%) of the PSCFs contained all eight risks mentioned on the NHS website. The number of risks listed varied from 4 to 18 per form. Only bile duct injury was listed on every PSCF. The least frequently mentioned complication (45% of forms) was the risk from general anaesthetic. Conclusions This study suggests that too few trusts are using PSCFs and that those PSCFs that are in use contain too little detail on the risks of cholecystectomy. The listed risks and incidences on each PSCF were highly variable. More trusts should begin to use PSCFs during the informed consent process and each PSCF should include a nationally standardised list of potential complications to act as a prompt for discussion (and documentation) of risk.

Pre-made consent for elective inguinal hernia repair: the need for standardisation-a survey of all UK NHS Trusts.

PURPOSE: Elective inguinal hernia repair (IHR) is one of the most commonly performed operations in the UK. As with all procedures, informed consent is essential. Pre-made consent forms have been suggested to improve consenting practice. This study aimed to assess the usage and quality of pre-made hernia-specific consent forms (PCF) in the UK. METHODS: A freedom of information request was sent to all UK NHS Trusts asking: (1) does the trust perform IHRs; (2) do they have a PCF; and (3) to send a copy. Complications lists on received forms were reviewed and compared to those listed on the British Hernia Society (BHS) "patient information" webpage. RESULTS: 157/185 Trusts (85%) responded. 117/157 (75%) perform IHRs; 16/117 (14%) use PCFs. The number of reported risks was variable (range 4-18), as was the content of each form (28 different risks were listed). Quoted percentage risks were inconsistent (e.g. recurrence range < 1-5%). The frequency of each BHS-quoted risk was (open/laparoscopic): Bleeding 62/75%; infection 85/92%; seroma 31/42%; damage to testicular blood supply 69/75%; damage to abdominal contents NA/25%; haematoma 62/67%; venous thromboembolism 54/50%; recurrence 85/83%; chronic pain 77/58%; mesh infection 23/8%. Zero forms contained all BHS-quoted risks. CONCLUSIONS: Whilst the consent form only provides documentation of the consent process, this study suggests that PCFs do not improve the quality of consent as both the type and likelihood of quoted complications were highly variable between Trusts. As follow-up for elective procedures is rare, it is unlikely that this variability reflects actual measured outcomes.

ARHGAP12 Functions as a Developmental Brake on Excitatory Synapse Function.

The molecular mechanisms that promote excitatory synapse development have been extensively studied. However, the molecular events preventing precocious excitatory synapse development so that synapses form at the correct time and place are less well understood. Here, we report the functional characterization of ARHGAP12, a previously uncharacterized Rho GTPase-activating protein (RhoGAP) in the brain. ARHGAP12 is specifically expressed in the CA1 region of the hippocampus, where it localizes to the postsynaptic compartment of excitatory synapses. ARHGAP12 negatively controls spine size via its RhoGAP activity and promotes, by interacting with CIP4, postsynaptic AMPA receptor endocytosis. Arhgap12 knockdown results in precocious maturation of excitatory synapses, as indicated by a reduction in the proportion of silent synapses. Collectively, our data show that ARHGAP12 is a synaptic RhoGAP that regulates excitatory synaptic structure and function during development.

Diffuse large B-cell lymphoma (DLBCL) in the bypassed stomach after obesity surgery.

Laparoscopic Roux-en-Y gastric bypass is the most commonly performed surgical procedure for obesity and, consequently, post-operative patients are increasingly encountered by all specialties. This is a case of a patient presenting with abdominal pain, nausea and fever 9 months following gastric bypass surgery caused by diffuse large B-cell lymphoma (DLBCL) in the bypassed stomach. It demonstrates well that symptoms that may normally be considered 'red-flags' may not be as obvious or specific following an operation. The case also indicates the importance of considering diagnoses unrelated to surgery presenting in the post-operative period (especially when conventional investigation methods are not feasible), and the potential danger of assuming they are due to the operation alone; had this occurred in this patient then a malignancy may have been missed. This is only the second reported case of DLBCL in the bypassed stomach, and the third for lymphoma of any type.

Nasal fracture manipulation: a comparative study of general and local anaesthesia techniques.

Nasal injuries are common conditions treated in either Otolaryngology or Plastic Surgical departments. Manipulation for deformity can be conducted in various ways. The aim of this study is to determine if the anaesthetic technique used for manipulation influences outcomes. Five hundred and fifty-five patients had either local anaesthetic (LA) or general anaesthetic (GA) nasal fracture manipulations in our departments over a 6-year period. Three hundred and twenty-four of these could be contacted and questioned as to subsequent surgical treatments received. Rhinoplasty, septorhinoplasty or septoplasty had been subsequently performed in 3.2% of the GA group and in 17.2% of the LA group (P < 0.0001). We recommend considering this result when treating nasal fractures in conjunction with other important issues of patient preference, financial costs, associated risks, morbidity and facilities available.

Heat stress downregulates FLIP and sensitizes cells to Fas receptor-mediated apoptosis.

The heat shock response and death receptor-mediated apoptosis are both key physiological determinants of cell survival. We found that exposure to a mild heat stress rapidly sensitized Jurkat and HeLa cells to Fas-mediated apoptosis. We further demonstrate that Hsp70 and the mitogen-activated protein kinases, critical molecules involved in both stress-associated and apoptotic responses, are not responsible for the sensitization. Instead, heat stress on its own induced downregulation of FLIP and promoted caspase-8 cleavage without triggering cell death, which might be the cause of the observed sensitization. Since caspase-9 and -3 were not cleaved after heat shock, caspase-8 seemed to be the initial caspase activated in the process. These findings could help understanding the regulation of death receptor signaling during stress, fever, or inflammation.

Tramadol vs. diclofenac for posttonsillectomy analgesia.

OBJECTIVE: To compare the analgesic efficacy of oral tramadol hydrochloride and oral diclofenac sodium for posttonsillectomy pain management. DESIGN: Single-blind (surgeon and research team members), prospective, randomized, controlled clinical trial. PATIENTS AND METHODS: Sixty-four patients 11 years and older undergoing bipolar electrocautery tonsillectomy were randomized to either the oral tramadol or the oral diclofenac postoperative pain group. Patients recorded pain levels twice daily for 14 days using a visual analogue scale. RESULTS: Pain scores for the 14 days were not significantly different between the oral tramadol and oral diclofenac groups. There were no significant differences in the incidence of postoperative hemorrhage and hospital readmission for uncontrolled pain. CONCLUSION: Oral tramadol can deliver the same analgesic efficacy as oral diclofenac for posttonsillectomy pain relief, which might be beneficial for avoiding the adverse effects of nonsteroidal anti-inflammatory drug therapy.

Information about surgery: what does the public want to know?

BACKGROUND: Informed consent has become an important part of medical practice. The aim of the present study was to determine what the public prefers to know before an operation and to establish some order of priority on that information. METHODS: A questionnaire was developed from 12 pieces of information each developed into a statement. There were two sections to the questionnaire. The purpose of the first section was to assess the priority that participants place on each statement of information, and the purpose of the second section was to assess the preference to knowing that statement of information. RESULTS: According to priority the four most important statements were options for treatment; risks ('common'); the operator ('meeting the surgeon'); and surgical technique. The four statements with the highest percentage of 'prefer to know' responses were recovery time; options for treatment; legal rights; and the operator ('meeting the surgeon'). CONCLUSIONS: The present study has identified priorities that the public assign to different aspects of preoperative information. The public has a high degree of desire for this information. The present study gives further insight into what information the public would like surgeons to share with them in preoperative consultations.

Dual roles for c-Jun N-terminal kinase in developmental and stress responses in cerebellar granule neurons.

c-Jun N-terminal kinases (JNKs) typically respond strongly to stress, are implicated in brain development, and are believed to mediate neuronal apoptosis. Surprisingly, however, JNK does not respond characteristically to stress in cultured cerebellar granule (CBG) neurons, a widely exploited CNS model for studies of death and development, despite the regulation of its substrate c-Jun. To understand this anomaly, we characterized JNK regulation in CBG neurons. We find that the specific activity of CBG JNK is elevated considerably above that from neuron-like cell lines (SH-SY5Y, PC12); however, similar elevated activities are found in brain extracts. This activity does not result from cellular stress because the stress-activated protein kinase p38 is not activated. We identify a minor stress-sensitive pool of JNK that translocates with mitogen-activated protein kinase kinase-4 (MKK4) into the nucleus. However, the major pool of total activity is cytoplasmic, residing largely in the neurites, suggesting a non-nuclear role for JNK in neurons. A third JNK pool is colocalized with MKK7 in the nucleus, and specific activities of both increase during neuritogenesis, nuclear JNK activity increasing 10-fold, whereas c-Jun expression and activity decrease. A role for JNK during differentiation is supported by modulation of neuritic architecture after expression of dominant inhibitory regulators of the JNK pathway. Channeling of JNK signaling away from c-Jun during differentiation is consistent with the presence in the nucleus of the JNK/MKK7 scaffold protein JNK-interacting protein, which inhibits JNK-c-Jun interaction. We propose a model in which distinct pools of JNK serve different functions, providing a basis for understanding multifunctional JNK signaling in differentiating neurons.

The mechanism of Ara-C-induced apoptosis of differentiating cerebellar granule neurons.

Neurotoxicity is one of the side-effects of the therapeutically useful antitumour agent, Ara-C (or 1-beta-d-arabinofuranosyl-cytosine, cytarabine). This agent is also reported to induce cell death of cultured neurons. In this study, we show that Ara-C-induced death of differentiating rat cerebellar granule neurons is prevented by cycloheximide at concentrations corresponding to its action in preventing protein synthesis. The death is accompanied by cleavage of the caspase substrate poly ADP ribose polymerase (PARP) and c-Abl-dependent activation of the stress-activated protein kinases c-Jun N-terminal kinase and p38. However, c-Jun levels do not rise and the activation of the stress-activated protein kinases is not required for this form of neuronal death. Cyclin-dependent kinase (cdk) activity and inappropriate cell-cycle re-entry have been implicated in some forms of death in differentiated neurons. Here we show that Ara-C-induced death of cerebellar granule neurons is prevented by an inhibitor of cdk4, whereas inhibition of cdk1, -2 and -5 mimics the death, and non-cdk4/6 cdks are inhibited by Ara-C treatment. Cdk1 and -2 are dramatically down-regulated during neuronal differentiation, and neither Ara-C nor inhibition of these cdks induces death in mature neurons. This mechanism could also play a significant role in the neurotoxicity associated with the therapeutic use of Ara-C, as cdk levels can be upregulated in stressed neurons of adult brain. We propose that the balance between cdk4/6 and cdk1/2/5 activity may determine the survival of early differentiating neurons, and that DNA-damaging agents may induce neuronal death by inhibiting cdk1/2/5 under conditions which require these activities for survival.

Alpha2B-adrenoceptors couple to Ca2+ increase in both endogenous and recombinant expression systems.

The ability of cloned human alpha2B-adrenoceptors heterologously expressed in Sf9 cells and endogenous alpha2B-adrenoceptors in NG 108-15 neuroblastoma x glioma cells to couple to increase of intracellular Ca2+ was studied. Ca2+ increases in NG 108-15 cells were detectable but slight, whereas those in alpha2B-adrenoceptor-expressing Sf9 cells were greater. In the latter, the maximum Ca2+ increase correlated positively, and the EC50-value of noradrenaline negatively, with the receptor expression density. The order of potency of the agonists was D-medetomidine ([D]-4-[5]-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole) > noradrenaline approximately = clonidine > oxymetazoline, with clonidine and UK14,304 (5-bromo-N-[4,5-dihydro-1H-imidazole-2-yl]-6-quinoxalinamine) being weak partial agonists. In Sf9 cells Ca2+ increases consisted of concomitant mobilization from an intracellular store and influx of extracellular Ca2+. In these cells alpha2B-adrenoceptor stimulation also increased the inositol 1,4,5-trisphosphate mass. We conclude that alpha2B-adrenoceptors can couple to intracellular Ca2+ increases which may involve prior activation of phospholipase C.

The effect of a preanaesthetic information booklet on patient understanding and satisfaction.

AIM: To determine if a brief user friendly anaesthetic booklet compliments the anaesthetic service currently provided, in terms of greater patient understanding and satisfaction. METHOD: Two questionnaires were completed by participants in each group, one questionnaire preoperatively and the other postoperatively. The booklet group received the anaesthetic booklet in the mail with their booking card while the control group only received their booking card. RESULTS: Of the 209 eligible, 140 patients consented to and completed the preoperative questionnaire, of whom 53 were in the anaesthetic booklet group and 87 were in the control group. The postoperative questionnaire was completed by 38 and 65 respectively. The anaesthetic booklet group had better understanding of what a premed will do (p < 0.05) and how long after an anaesthetic to wait before driving (p < 0.025). The percentage of correct answers for the more general anaesthetic questions was high and very similar in both groups. There was no significant difference in the satisfaction scores between groups. Satisfaction scores for both groups rose significantly in the postoperative questionnaire when compared with the preoperative questionnaire (p < 0.001). CONCLUSION: The value of the anaesthetic booklet is in providing detailed anaesthetic information to the patient. This will aid the preanaesthetic consultation with the anaesthetist and provide a focus for further discussion about the intended anaesthetic. Patient satisfaction with the anaesthetic service was high in both groups pre- and postoperatively and was not altered by the anaesthetic booklet.

Neurotrophins protect cultured cerebellar granule neurons against the early phase of cell death by a two-component mechanism.

Cerebellar granule neurons cultured with serum develop a mature neuronal phenotype, including stimulus-coupled release of glutamate, and depend on elevated potassium for survival. We find that cells cultured with serum undergo two phases of cell death. By 6 d in vitro, 30-50% of the cells present are dead; after this time the remaining cells die. Elevated potassium prevents only this later phase of death, whereas neurotrophins protect these cells against the early phase of death. Factors that bind p75(NTR) or TNF-R, members of the same receptor family, exhibit voltage-sensitive calcium channel-dependent protection, whereas ligands of expressed Trk receptors show additional calcium channel-independent protection. The cells express TrkB protein and show elevated c-Fos and c-Jun levels in response to BDNF. No TrkA is detected, although p75(NTR) protein is expressed and NGF induces depolarization-dependent elevation of c-Jun levels. In the presence of the protein kinase C inhibitor bisindolylmaleimide, BDNF-induced survival promotion is reduced partially, whereas NGF-induced death is unmasked. Basal survival mechanisms are insensitive to inhibition of PK-C or PI-3 kinase. We conclude that BDNF promotes survival in part via its TrkB receptor, whereas there is an additional pathway promoting survival and elevating c-Jun evoked by both NGF and BDNF via a non-Trk receptor.

Brain derived neurotrophic factor induces a rapid upregulation of synaptophysin and tau proteins via the neurotrophin receptor TrkB in rat cerebellar granule cells.

We have examined the effects of neurotrophins brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) on the expression of the maturation-specific proteins synaptophysin and tau, and the growth-associated protein (GAP)-43 in cerebellar granule cells. We find that BDNF but not NGF rapidly (within 2 h) upregulates levels of synaptophysin, tau and c-Fos correlating with expression of the neurotrophin receptor TrkB. The rapid increase in synaptophysin is not preceded by c-Fos elevation suggesting a post-transcriptional mechanism may be involved. In contrast, no upregulation of GAP-43 levels are seen within this time period. Phorbol ester mimics the effects of BDNF, indicating that protein kinase C (PKC) is either a component of, or feeds into the signalling mechanism. We conclude that BDNF, characterized to be survival promoting early in differentiation of cerebellar granule cells, enhances maturation at a later stage.

Localization of voltage-sensitive Ca2+ fluxes and neuropeptide Y immunoreactivity to varicosities in SH-SY5Y human neuroblastoma cells differentiated by treatment with the protein kinase inhibitor staurosporine.

The distribution of voltage-sensitive elevations of the level of Ca2+ in untreated SH-SY5Y cells and cells that had been induced to differentiate with staurosporine was investigated by monitoring fura-2 fluorescence in cell suspensions, and by using microfluorometry and quantitative fluorescence imaging on cell bodies and on cellular processes. Cell bodies of both types of cells displayed small Ca2+ elevations, which were composed of transient and sustained components. Elevations were partially sensitive to the L- and N-channel blockers nifedipine (1 microM) and omega-conotoxin GVIA (100 nM) respectively. Up to ten times Ca2+ elevations were observed in varicosities of treated cells than in cell bodies of treated and cells. These elevations were insensitive to compounds known to release Ca2+ from intracellular stores. Elevations of Ca2+ were sustained, and they were insensitive to 5 microM nifedipine, 100 nM omega-agatoxin IVA and 100 nM omega-conotoxin GVIA, and partially sensitive to 2 microM omega-conotoxin GVIA, indicating predominance of non-L-type, non-N-type, non-P-type channel activity. The intracellular localization of neuropeptide Y, a marker of differentiation in these cells, was also investigated by fluorescence immunocytochemistry. Varicosities of treated cells displayed marked fluorescence when viewed in a confocal microscope. These findings show that the varicosities of staurosporine-treated cells exhibit some of the functional properties of nerve terminals. The varicosities resemble boutons en passant nerve endings and they seem to express Ca2+ channels different from those in the cell body.

Ethanol specifically inhibits NMDA receptors with affinity for ifenprodil in the low micromolar range in cultured cerebellar granule cells.

The effect of ethanol on the intracellular Ca2+ concentration response to NMDA in rat cerebellar granule cells grown in low or high KCl concentrations has been studied using image analysis. The cells grown in low KCl displayed high sensitivity for glycine. The subtype-selective antagonist ifenprodil inhibited the response with high (in the low micromolar range) and low (in the high micromolar range) potency. Ethanol affected the high-potency component in these cultures. In cells grown in high KCl the glycine sensitivity was lower, and a low potency for ifenprodil (high micromolar) dominated. These cells were not significantly sensitive to ethanol. The results indicate that the component displaying potency for ifenprodil in the low micromolar range with properties of the NR2B subunit is the target for ethanol action on the NMDA receptor.

Coupling of astroglial alpha 2-adrenoreceptors to second messenger pathways.

We have investigated which alpha 2-receptor subtypes are expressed in cultured cortical astroglia, and their coupling to second messengers. Binding assays using [3H]rauwolscine showed a very low number of alpha 2 receptors in the astrocytic cultures. Treatment of cultures with dibutyryl cyclic AMP (dBcAMP) increased significantly the number of receptors. The RNase protection assay was used to investigate which receptor subtype the cells express. The alpha 2B message was expressed at a low level in both treated and untreated cells, the levels of mRNA for the alpha 2A/D subtype were up-regulated significantly in cells treated with dBcAMP and no expression of mRNA for the alpha 2C subtype was detected. The alpha 2 agonist dexmedetomidine inhibited forskolin-induced increases in cyclic AMP both in treated and untreated cultures in a pertussis toxin-dependent manner. This effect was abolished by the alpha 2-receptor antagonist rauwolscine. Selective alpha 2-receptor agonists dexmedetomidine, clonidine, and UK14,304 all increased intracellular calcium only in dBcAMP-treated cells. The antagonist rauwolscine abolished this effect. Ca2+ responses were also seen in the absence of extracellular Ca2+ and they were inhibited by the phospholipase C inhibitor U-73122, suggesting that astroglial alpha 2 receptors are coupled to the inositol phospholipid pathway. We therefore also tested the effect of dexmedetomidine directly on inositol 1,4,5-trisphosphate accumulation. A significant increase was seen that was blocked by the antagonist rauwolscine and, as expected, by U-73122. In short, the results demonstrate that the alpha 2 receptors in astroglia are coupled to multiple second messenger pathways. They are up-regulated in cells treated with dBcAMP, which simultaneously assume a process-bearing morphology. If this morphological change reflects some in vivo process such as reactive gliosis, the up-regulation of alpha 2-receptor expression could mean an adaptive change in astrocytic responses to a common neurotransmitter, noradrenaline.

The calcium response to the excitotoxin kainate is amplified by subsequent reduction of extracellular sodium.

The relation between intracellular and extracellular [Na+] and [Ca2+] and membrane potential during stimulation of non-N-methyl-D-aspartate glutamate receptors has been studied in cerebellar granule cells using the fluorescent indicators SBFI, fura-2 and the bisoxonol membrane potential probe DiBaC4(3). Kainate increased both [Ca2+]i (intracellular [Ca2+]) and [Na+]i (intracellular [Na+]) and depolarized the membrane. This elevation of [Ca2+]i was only partially dependent on the presence of extracellular Na+ at the time of kainate addition. Removal of extracellular Na+ itself had a very minor effect on the [Ca2+]i or membrane potential of unstimulated cells. If extracellular Na+ was removed (in order to reverse the [Na+] gradient) or its concentration reduced during stimulation with kainate, the membrane depolarization recovered as expected. However, the intracellular level of sodium recovered only very slowly and the [Ca2+]i rose sharply, rather than recovering as might be expected on repolarization of depolarized cells possessing voltage sensitive calcium channels. This effect of extracellular [Na+] reduction on [Ca2+]i was mimicked by ouabain, another agent that causes accumulation of [Na+] in cells. These results suggest that Na+/Ca2+ exchange may play a major role in calcium homeostasis in stimulated cells, and that the levels of Na+ inside and outside the cell are critical in determining the effect of receptor stimulation on the intracellular [Ca2+].