The nicotinic acetylcholine (ACh) receptor is the neurotransmitter-gated ion channel responsible for the rapid propagation of electrical signals between cells at the nerve/muscle synapse. We report here the 4.6 A structure of this channel in the closed conformation, determined by electron microscopy of tubular crystals of Torpedo postsynaptic membranes embedded in amorphous ice. The analysis was conducted on images recorded at 4 K with a 300 kV field emission source, by combining data from four helical families of tubes (-16,6; -18,6; -15,7; -17,5), and applying three-dimensional corrections for lattice distortions. The study extends earlier work on the same specimen at 9 A resolution. Several features having functional implications now appear with better definition. The gate of the channel forms a narrow bridge, consisting of no more than one or two rings of side-chains, across the middle portion of the membrane-spanning pore. Tunnels, framed by twisted beta-sheet strands, are resolved in the extracellular wall of the channel connecting the water-filled vestibule to the putative ACh-binding pockets. A set of narrow openings through which ions can flow are resolved between alpha-helical segments forming part of the cytoplasmic wall of the channel. It is suggested that the extracellular tunnels are access routes to the binding pockets for ACh, and that the cytoplasmic openings serve as filters to exclude anions and other impermeant species from the vicinity of the pore. Both transverse pathways are likely to be important in achieving a rapid postsynaptic response.

The rapid expansion of human activities threatens ocean-wide biodiversity. Numerous marine animal populations have declined, yet it remains unclear whether these trends are symptomatic of a chronic accumulation of global marine extinction risk. We present the first systematic analysis of threat for a globally distributed lineage of 1,041 chondrichthyan fishes-sharks, rays, and chimaeras. We estimate that one-quarter are threatened according to IUCN Red List criteria due to overfishing (targeted and incidental). Large-bodied, shallow-water species are at greatest risk and five out of the seven most threatened families are rays. Overall chondrichthyan extinction risk is substantially higher than for most other vertebrates, and only one-third of species are considered safe. Population depletion has occurred throughout the world's ice-free waters, but is particularly prevalent in the Indo-Pacific Biodiversity Triangle and Mediterranean Sea. Improved management of fisheries and trade is urgently needed to avoid extinctions and promote population recovery. DOI: http://dx.doi.org/10.7554/eLife.00590.001.

Recent studies have shown that protein kinase C (PKC) delta is proteolytically activated at the onset of apoptosis induced by DNA-damaging agents, tumor necrosis factor, and anti-Fas antibody. However, the relationship of PKC delta cleavage to induction of apoptosis is unknown. The present studies demonstrate that full-length PKC delta is cleaved at DMQD330N to a catalytically active fragment by the cysteine protease CPP32. The results also demonstrate that overexpression of the catalytic kinase fragment in cells is associated with chromatin condensation, nuclear fragmentation, induction of sub-G1 phase DNA and lethality. By contrast, overexpression of full-length PKC delta or a kinase inactive PKC delta fragment had no detectable effect. The findings suggest that proteolytic activation of PKC delta by a CPP32-like protease contributes to phenotypic changes associated with apoptosis.

The inducer of cbf expression (ICE)-C-repeat binding factor/DRE binding factor1 (CBF/DREB1) transcriptional pathway plays a critical role in modulating cold stress responses in Arabidopsis thaliana. Dissecting crucial upstream regulatory signals or components of the ICE-CBF/DREB1 cascade will enhance our understanding of plant cold-tolerance mechanisms. Here, we show that jasmonate positively regulates plant responses to freezing stress in Arabidopsis. Exogenous application of jasmonate significantly enhanced plant freezing tolerance with or without cold acclimation. By contrast, blocking endogenous jasmonate biosynthesis and signaling rendered plants hypersensitive to freezing stress. Consistent with the positive role of jasmonate in freezing stress, production of endogenous jasmonate was triggered by cold treatment. In addition, cold induction of genes acting in the CBF/DREB1 signaling pathway was upregulated by jasmonate. Further investigation revealed that several jasmonate ZIM-domain (JAZ) proteins, the repressors of jasmonate signaling, physically interact with ICEICEICEICE-CBF/DREB1 pathway to positively regulate Arabidopsis freezing tolerance.

Brown adipose tissue (BAT) can be identified by (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in adult humans. Thirteen healthy male volunteers aged 20-28 years underwent FDG-PET after 2-h cold exposure at 19 °C with light-clothing and intermittently putting their legs on an ice block. When exposed to cold, 6 out of the 13 subjects showed marked FDG uptake into adipose tissue of the supraclavicular and paraspinal regions (BAT-positive group), whereas the remaining seven showed no detectable uptake (BAT-negative group). The BMI and body fat content were similar in the two groups. Under warm conditions at 27 °C, the energy expenditure of the BAT-positive group estimated by indirect calorimetry was 1,446 ± 97 kcal/day, being comparable with that of the BAT-negative group (1,434 ± 246 kcal/day). After cold exposure, the energy expenditure increased markedly by 410 ± 293 (P < 0.05) and slightly by 42 ± 114 kcal/day (P = 0.37) in the BAT-positive and -negative groups, respectively. A positive correlation (P < 0.05) was found between the cold-induced rise in energy expenditure and the BAT activity quantified from FDG uptake. After cold exposure, the skin temperature in the supraclavicular region close to BAT deposits dropped by 0.14 °C in the BAT-positive group, whereas it dropped more markedly (P < 0.01) by 0.60 °C in the BAT-negative group. The skin temperature drop in other regions apart from BAT deposits was similar in the two groups. These results suggest that BAT is involved in cold-induced increases in whole-body energy expenditure, and, thereby, the control of body temperature and adiposity in adult humans.

Small-scale studies have suggested a large inter-individual variation in early postoperative pain after laparoscopic cholecystectomy, emphasizing the need for improved analgesic treatment and valid predictors. We investigated prospectively the association between a preoperative nociceptive stimulus by ice water (cold pressor test), neuroticism, dyspepsia, patient history of biliary symptoms, intraoperative factors, and demographic information in 150 consecutive patients undergoing uncomplicated laparoscopic cholecystectomy for their influence on early postoperative pain. During the first postoperative week patients registered overall pain, incisional, visceral, and shoulder pain on a visual analogue scale and verbal rating scale, and daily analgesic requirements were noted. Throughout the first postoperative week overall pain showed a pronounced inter-individual variability. Incisional pain dominated in incidence and intensity compared with visceral pain, which in turn dominated over shoulder pain. In a multivariate analysis model, preoperative neuroticism, sensitivity to cold pressor-induced pain, and age were identified as independent risk factors for early postoperative pain. Our results suggest that future analgesic studies after laparoscopic cholecystectomy should focus on reduction of incisional pain.

According to current understanding, cytoplasmic events including activation of protease cascades and mitochondrial permeability transition (PT) participate in the control of nuclear apoptosis. However, the relationship between protease activation and PT has remained elusive. When apoptosis is induced by cross-linking of the Fas/APO-1/CD95 receptor, activation of interleukin-1beta converting enzyme (ICE; caspase 1) or ICE-like enzymes precedes the disruption of the mitochondrial inner transmembrane potential (DeltaPsim). In contrast, cytosolic CPP32/ Yama/Apopain/caspase 3 activation, plasma membrane phosphatidyl serine exposure, and nuclear apoptosis only occur in cells in which the DeltaPsim is fully disrupted. Transfection with the cowpox protease inhibitor crmA or culture in the presence of the synthetic ICE-specific inhibitor Ac-YVAD.cmk both prevent the DeltaPsim collapse and subsequent apoptosis. Cytosols from anti-Fas-treated human lymphoma cells accumulate an activity that induces PT in isolated mitochondria in vitro and that is neutralized by crmA or Ac-YVAD.cmk. Recombinant purified ICE suffices to cause isolated mitochondria to undergo PT-like large amplitude swelling and to disrupt their DeltaPsim. In addition, ICE-treated mitochondria release an apoptosis-inducing factor (AIF) that induces apoptotic changes (chromatin condensation and oligonucleosomal DNA fragmentation) in isolated nuclei in vitro. AIF is a protease (or protease activator) that can be inhibited by the broad spectrum apoptosis inhibitor Z-VAD.fmk and that causes the proteolytical activation of CPP32. Although Bcl-2 is a highly efficient inhibitor of mitochondrial alterations (large amplitude swelling + DeltaPsim collapse + release of AIF) induced by prooxidants or cytosols from ceramide-treated cells, it has no effect on the ICE-induced mitochondrial PT and AIF release. These data connect a protease activation pathway with the mitochondrial phase of apoptosis regulation. In addition, they provide a plausible explanation of why Bcl-2 fails to interfere with Fas-triggered apoptosis in most cell types, yet prevents ceramide- and prooxidant-induced apoptosis.

Interleukin-1 beta converting enzyme (ICE) is a mammalian homolog of CED-3, a protein required for programmed cell death in the nematode Caenorhabditis elegans. The activity of ICE can be specifically inhibited by the product of crmA, a cytokine response modifier gene encoded by cowpox virus. Microinjection of the crmA gene into chicken dorsal root ganglion neurons was found to prevent cell death induced by deprivation of nerve growth factor. Thus, ICE is likely to participate in neuronal death in vertebrates.

In a reported gene assay, cationic liposomes containing the cationic lipid 3 beta-(N-(N',N'-dimethylaminoethane)carbamoyl)cholesterol (DC-Chol) and a neural phospholipid dioleoylphosphatidylethanolamine (DOPE) showed high transfection activity. DNA/liposome complex which contained low amount of liposomes could bind to the cell surface but failed to transfect the cells. We have designed a two-step protocol to examine this phenomenon in more detail. A431 human cells were incubated on ice (pulse) with DNA complexed to a low level of cationic liposomes. The cells were washed and incubated at 37 degrees C (chase) with or without free cationic liposomes of various composition (helper liposomes). Only liposomes enriched with DOPE showed helper activity; liposomes containing dioleoylphosphatidylcholine (DOPC), a structural analog of DOPE, had no helper activity. The delivery was inhibited by the lysosomotropic agent chloroquine and was optimal if the helper liposome chase was initiated immediately after the pulse. An endocytosis model of DNA delivery by cationic liposomes is proposed in which the principal function of the chase liposomes is to destabilize the endosome membrane and allow the release of DNA into the cytosol. This model is consistent with the known activity of DOPE to assume non-bilayer structures, hence destabilizing the endosome membrane.

Words, grammar, and phonology are linguistically distinct, yet their neural substrates are difficult to distinguish in macroscopic brain regions. We investigated whether they can be separated in time and space at the circuit level using intracranial electrophysiology (ICE), namely by recording local field potentials from populations of neurons using electrodes implanted in language-related brain regions while people read words verbatim or grammatically inflected them (present/past or singular/plural). Neighboring probes within Broca's area revealed distinct neuronal activity for lexical (approximately 200 milliseconds), grammatical (approximately 320 milliseconds), and phonological (approximately 450 milliseconds) processing, identically for nouns and verbs, in a region activated in the same patients and task in functional magnetic resonance imaging. This suggests that a linguistic processing sequence predicted on computational grounds is implemented in the brain in fine-grained spatiotemporally patterned activity.

This study sought evidence for apoptosis, a form of programmed cell death, in human atheromatous coronary and carotid arteries. Markers for apoptotic cells included in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), genomic DNA electrophoresis, and morphological analysis. Intimal lesions contained more TUNEL+ cells (34 +/- 6%, n = 8) than non-atherosclerotic arterial intima (8 +/- 3%, n = 5, P < 0.05). The tunica media of the diseased arteries had a percentage of TUNEL+ cells (5 +/- 1%) similar to that in the normal vessels (3 +/- 1%, N.S.). Oligonucleosomal DNA fragments were visualized in extracts from 12 atheromatous plaques but in none of 5 non-atherosclerotic vessels. Both smooth muscle cells (SMC) and macrophages, two major cell types in the atherosclerotic intima, bore markers of apoptosis, but with different patterns, as determined by double histochemical labeling for cell types and TUNEL. The TUNEL+ SMC localized mainly in the fibrotic portion of the atheroma, whereas TUNEL+ macrophages clustered near or within the lipid-rich core of the lesion. Atheromatous lesions expressed mRNA encoding interleukin-1 beta-converting enzyme (ICE), a mammalian cell death gene, as demonstrated by reverse transcriptase polymerase chain reaction. Immunohistochemistry revealed that ICE localized in regions of TUNEL+ SMC and macrophages. TUNEL- cells showed little or no immunoreactive ICE. These data point to a role for apoptosis in regulation of cell accumulation during atherogenesis and suggest involvement of ICE in SMC death in fibrous regions of complex atheroma, and in macrophage death in the lipid-rich core of the lesion. Apoptosis of vascular cells in fibrous cap may impede maintenance or repair of the matrix in this region and affect stability of the plaques.

BACKGROUND

The prevalence of jumper's knee across different sports has not been examined, and it is not known if there is a gender difference. Data from surgical case series indicate that there may be a high prevalence in sports with high speed and power demands.

OBJECTIVE

The aim of this study was to estimate the prevalence of jumper's knee in different sports among female and male athletes and to correlate the prevalence to the loading characteristics of the extensor mechanism in these sports.

METHODS

Cross-sectional study; Level of evidence, 4.

METHODS

The authors examined approximately 50 Norwegian male and female athletes at the national elite level from each of the following 9 sports: athletics (male athletes: high jump, 100- and 200-m sprint), basketball (male athletes), ice hockey (male athletes), volleyball (male athletes), orienteering (male athletes), road cycling (male athletes), soccer (male and female athletes), team handball (male and female athletes), and wrestling (male athletes). The examination included an interview on individual characteristics (weight, age, height, and training background), a clinical examination, and self-recorded Victorian Institute of Sport Assessment score from 0 (worst) to 100 (best).

RESULTS

The overall prevalence of current jumper's knee was 14.2% (87 of 613 athletes), with a significant difference between sports with different performance characteristics (range, 0%-45%). In addition, 51 athletes (8%) reported previous symptoms. The prevalence of current symptoms was highest in volleyball (44.6%+/-6.6%) and basketball (31.9%+/-6.8%), whereas there were no cases in cycling or orienteering. The prevalence of current jumper's knee was lower among women (5.6%+/-2.2%) compared with men (13.5%+/-3.0%; chi2 test, P=.042). The duration of symptoms among athletes with current jumper's knee (n=87) was 32+/-25 (standard deviation) months, with a Victorian Institute of Sport Assessment score of 64+/-19.

CONCLUSIONS

The prevalence of jumper's knee is high in sports characterized by high demands on speed and power for the leg extensors. The symptoms are often serious, resulting in long-standing impairment of athletic performance.

Interleukin-1 beta converting enzyme (ICE)-like proteases, which are synthesized as inactive precursors, play a key role in the induction of apoptosis. We now demonstrate that benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethylketone (Z-VAD.FMK), an ICE-like protease inhibitor, inhibits apoptosis by preventing the processing of CPP32 to its active form. These results suggest that novel inhibitors of apoptosis can be developed which prevent processing of proforms of ICE-like proteases.

The cytoskeletal protein non-erythroid alpha-spectrin is well documented as an endogenous calpain substrate, especially under pathophysiological conditions. In cell necrosis (e.g. maitotoxin-treated neuroblastoma SH-SY5Y cells), alpha-spectrin breakdown products (SBDPs) of 150 kDa and 145 kDa were produced by cellular calpains. In contrast, in neuronal cells undergoing apoptosis (cerebellar granule neurons subjected to low potassium and SH-SY5Y cells treated with staurosporine), an additional SBDP of 120 kDa was also observed. The formation of the 120 kDa SBDP was insensitive to calpain inhibitors but was completely blocked by an interleukin 1 beta-converting-enzyme (ICE)-like protease inhibitor, Z-Asp-CH2OC(O)-2,6-dichlorobenzene. Autolytic activation of both calpain and the ICE homologue CPP32 was also observed in apoptotic cells. alpha-Spectrin can also be cleaved in vitro by purified calpains to produce the SBDP doublet of 150/145 kDa and by ICE and ICE homologues [ICH-1, ICH-2 and CPP32(beta)] to produce a 150 kDa SBDP. In addition, CPP32 and ICE also produced a 120 kDa SBDP. Furthermore inhibition of either ICE-like protease(s) or calpain protects both granule neurons and SH-SY5Y cells against apoptosis. Our results suggest that both protease families participate in the expression of neuronal apoptosis.

Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. Here we analyse genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3-6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory.

An imbalance of immunoregulatory factors is believed to contribute to uncontrolled mucosal Th1 cell activation in Crohn's disease (CD). IL-18, a macrophage-like cell-derived cytokine, is involved in Th1 clone development, and IFN-gamma production. Therefore, IL-18 expression was investigated in CD. Whole mucosal intestinal tissue and lamina propria mononuclear cells (LPMC) of 12 CD and 9 ulcerative colitis (UC) patients and 15 non-inflammatory bowel disease (IBD) controls were tested for IL-18 by semiquantitative RT-PCR and Western blot analysis. Transcripts for IL-18 were found in all samples tested. However, increased IL-18 mRNA accumulation was detected in both mucosal and LPMC samples from CD in comparison to UC and controls. In CD, transcripts for IL-18 were more abundant in the mucosal samples taken from involved areas. An 18-kDa band consistent with mature IL-18 was predominantly found in CD mucosal samples. In mucosal samples from non-IBD controls, IL-18 was present as a 24-kDa polypeptide. Consistently, active IL-1beta-converting enzyme (ICE) subunit (p20) was expressed in samples from either CD or UC, whereas, in colonic mucosa from non-IBD controls, ICE was synthesized as precursor (p45) only. To confirm that IL-18 produced in CD tissue was functionally active, CD LPMC were treated with a specific IL-18 antisense oligonucleotide. In these cultures, IL-18 down-regulation was accompanied by a decrease in IFN-gamma expression. In aggregate, our data indicate that IL-18 up-regulation is a feature of CD and suggest that IL-18 may contribute to the local immunoinflammatory response in CD.

The effector arm of the cell-death pathway is composed of cysteine proteases belonging to the ICE/CED-3 family. In metazoan cells these exist as inactive polypeptide precursors (zymogens), each composed of a prodomain, which is cleaved to activate the protease, and a large and small catalytic subunit. The coupling of these 'death' proteases to signalling pathways is probably mediated by adaptor molecules that contain protein-protein interaction motifs such as the death domain. Here we describe such an adaptor molecule, RAIDD, which has an unusual bipartite architecture comprising a carboxy-terminal death domain that binds to the homologous domain in RIP, a serine/threonine kinase component of the death pathway. The amino-terminal domain is surprisingly homologous with the sequence of the prodomain of two ICE/CED-3 family members, human ICH-1 (ref. 5) and Caenorhabditis elegans CED-3 (ref. 6). This similar region mediates the binding of RAIDD to ICH-1 and CED-3, serving as a direct link to the death proteases, indicating that the prodomain may, through homophilic interactions, determine the specificity of binding of ICE/CED-3 zymogens to regulatory adaptor molecules. Finally, alternations in the sequence of the N-terminal domain that are equivalent to inactivating mutations in the C. elegans ced-3 gene prevent homophilic binding, highlighting the potentially primordial nature of this interaction.

Protein tyrosine kinases activate the STAT (signal transducer and activator of transcription) signaling pathway, which can play essential roles in cell differentiation, cell cycle control, and development. However, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon (IFN-gamma) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells. EGF receptor autophosphorylation and mitogen-activated protein kinase activation in response to EGF were similar in both cell lines. The breast cancer cell line MDA-MB-468 exhibited a similar response to A431 cells, i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-gamma treatment. In addition, in a mutant A431 cell line in which STAT activation was abolished, no apoptosis was induced by either EGF or IFN-gamma. We further demonstrated that both EGF and IFN-gamma induced caspase 1 (interleukin-1beta converting enzyme [ICE]) gene expression in a STAT-dependent manner. IFN-gamma was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-gamma in U3A cells into which STAT1 had been reintroduced. Moreover, both EGF-induced apoptosis and IFN-gamma-induced apoptosis were effectively blocked by Z-Val-Ala-Asp-fluoromethylketone (ZVAD) in all the cells tested, and studies from ICE-deficient cells indicated that ICE gene expression was necessary for IFN-gamma-induced apoptosis. We conclude that activation of the STAT signaling pathway can induce apoptosis through the induction of ICE gene expression.

OBJECTIVE

To describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH).

METHODS

Primary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed.

RESULTS

Thirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% +/- 11%) were significantly better than those for younger patients (EFS, 11% +/- 6%; OS, 17% +/- 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy.

CONCLUSIONS

Children presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.

Previous genetic studies of the nematode Caenorhabditis elegans identified three important components of the cell death machinery. CED-3 and CED-4 function to kill cells, whereas CED-9 protects cells from death. Here CED-9 and its mammalian homolog Bcl-xL (a member of the Bcl-2 family of cell death regulators) were both found to interact with and inhibit the function of CED-4. In addition, analysis revealed that CED-4 can simultaneously interact with CED-3 and its mammalian counterparts interleukin-1beta-converting enzyme (ICE) and FLICE. Thus, CED-4 plays a central role in the cell death pathway, biochemically linking CED-9 and the Bcl-2 family to CED-3 and the ICE family of pro-apoptotic cysteine proteases.

OBJECTIVE

Moderate hypothermia decreases ischemic damage in experimental stroke models. This multicenter study was performed to evaluate (1) the safety and feasibility of moderate hypothermia and (2) its potential to reduce intracranial hypertension in acute stroke patients.

METHODS

Fifty prospective patients with cerebral infarction involving at least the complete middle cerebral artery territory treated with moderate hypothermia were evaluated. Hypothermia was induced with the use of cooling blankets as well as alcohol and ice bags within 22+/-9 hours after stroke onset and maintained for 24 to 72 hours; subsequently, patients passively rewarmed over a mean duration of 17 hours. Outcome was assessed at 4 weeks and at 3 months.

RESULTS

Time required for cooling to <33 degrees C varied from 3.5 to 11 hours. The most frequent complications of hypothermic therapy were thrombocytopenia (70%), bradycardia (62%), and pneumonia (48%). Four patients (8%) died during hypothermia as a result of severe coagulopathy, cardiac failure, or uncontrollable intracranial hypertension. An additional 15 patients (30%) died during or after rewarming because of rebound increase in intracranial pressure (ICP) and fatal herniation. A shorter (<16 hours) rewarming period was associated with a more pronounced rise of ICP. Elevated ICP values were significantly reduced under hypothermia. Neurological outcome according to the National Institutes of Health Stroke Scale score 4 weeks after stroke was 29, and Rankin Scale score 3 months after stroke was 2.9.

CONCLUSIONS

Moderate hypothermia is feasible in patients with acute stroke, although it is associated with several side effects. Most deaths occur during rewarming as a result of excessive ICP rise. Our preliminary observation that a longer duration of the rewarming period limits the ICP increase remains to be confirmed in future studies.

During 1999 the issue of rape in South Africa was debated at the highest levels. The epidemiology of rape has become an issue of considerable political importance and sensitivity, with President Mbeki demanding an answer to the question: how much rape is there in South Africa? The purpose of this paper is both to summarise and synthesise the findings of research to provide an overview of the epidemiology of rape of women in South Africa and to show how difficult it is to answer the President's question. The review begins by considering why rape is so difficult to research. Data available shows that rape reported to the police (240 incidents of rape and attempted rape per 100,000 women each year) represents the tip of an ice berg of sexual coercion. Representative community-based surveys have found, for example, that in the 17-48 age group there are 2070 such incidents per 100,000 women per year. Non-consensual sex in marriage and dating relationships is believed to be very common but is usually not well reported in surveys. Forced sexual initiation is reported by almost a third of adolescent girls. In addition coerced consensual sex is a common problem in schools, workplaces and amongst peers. Knowledge of causal and contributory factors influencing the high levels of rape are also discussed. We conclude that the rape statistic for the country is currently elusive but levels of non-consensual and coerced sex are clearly very high. International comparison needs to be approached with caution because most developing countries lack the infrastructure for accurate crime reporting and do not have such a substantial body of survey data.

BACKGROUND

The impact of applying renal ischaemia during nephron-sparing surgery to avoid renal damage in the treated kidney has gained importance in different surgical techniques.

OBJECTIVE

The main objective of the present study is to point out the limit of renal ischaemia times for warm and cold ischaemia approaches. Important results of research on renal ischaemia and different surgical techniques as well as results of clinical studies concerning renal function after renal ischaemia in partial nephrectomy are highlighted.

METHODS

A Medline literature research was performed, combining queries on the keywords nephron-sparing surgery, partial nephrectomy, and ischemia. Links to related articles and cross-reading of citations in related articles were surveyed, as were reviews, letters to editors, and information collected from urologic textbooks. The references formed the basis of this review article, with selection and deletion based on the relevance and importance of the content. In a final step, interactive peer review by the expert panel of coauthors completed the review.

RESULTS

Renal ischaemia research showed an increasing renal damage proportional to ischemic time. Current clinical data support safe ischaemia times, within 20 min of warm ischaemia and up to 2 h of cold ischaemia, to minimise renal ischemic damage. To date, no ischaemia dose-response curve or algorithm is available to predict the risk of acute kidney injury and chronic kidney disease in patients undergoing intraoperative ischaemia. In general, there seems to be a higher risk for comorbidity caused by renal damage in patients suffering from kidney tumour.

CONCLUSIONS

If ischaemia is required, the tumour should be removed within 20 min of warm ischaemia, regardless of surgical approach. Efforts should be made to start immediately with cold ischaemia, if the feasibility within this span of time seems to be jeopardised. Thus, cold ischaemia times up to 2 h can be tolerated by the kidney, depending on the individual method. Nevertheless, cold ischaemia with ice slush should be kept as short as possible--at best within 35 min. In ischemic nephron-sparing surgery, one of the surgeon's main aims should be to avoid loss of renal function. Only after optimal preoperative appraisal and planning can the best postoperative outcomes for renal function be achieved.

The first successful attempt at deep freezing and thawing of the human oocyte is reported. A twin pregnancy was achieved after insemination and replacement in utero. The procedure involved reduction in size of the oocyte/cumulus-oophorus complex, the addition of the cryoprotectant dimethyl sulphoxide as a one-step procedure, slow cooling between -7 degrees C and -36 degrees C after ice nucleation, and rapid freezing to -196 degrees C before storage in liquid nitrogen. Thawing was achieved rapidly by warming in a 37 degrees C water-bath, followed by dilution of dimethyl sulphoxide as a single step. 80% of forty oocytes showed morphological survival after freezing and thawing. Thirty of these were inseminated; 83% retained their capacity to be fertilised, and 60% proceeded to cleavage division.