We have hypothesized that these PGE2 dependent effects on firing rate are due to changes in the inherent electrical properties of VMPO neurons, which are regulated by the activity of specific ionic currents.Physiological and morphological evidence suggests that activation of the ventromedial preoptic area of the hypothalamus (VMPO) is an essential component of an intravenous LPS-dependent fever. In response to the endogenous pyrogen prostaglandin E2 dependent firing rate responses were not the result of changes in resting membrane potential, action potential amplitude and duration, or local synaptic input. However, PGE2 reduced the input resistance of all VMPO neurons, while increasing the excitability of temperature insensitive neurons and decreasing the excitability of warm sensitive neurons. In addition, the majority of temperature insensitive neurons responded to PGE2 with an increase in the rate of rise of the depolarizing prepotential that precedes each action potential. This response to PGE2 was reversed for warm sensitive neurons, in which the prepotential rate of rise decreased.To characterize the electrical properties of VMPO neurons, whole-cell recordings were made in tissue slices from male Sprague-Dawley rats. Our results indicate that PGE2 is having an effect on the ionic currents that regulate firing rate by controlling how fast membrane potential rises to threshold during the prepotential phase of the action potential.We would therefore suggest that PGE This criterion is based on previous studies that indicate a functional difference for neurons which show this degree of inherent thermosensitivity [2 (PGE2), which could shift the thermostatic set-point and alter the activation of thermoregulatory mechanisms [Fever, an elevation in body temperature, is thought to play an adaptive role in the immune system's ability to fight infection . A suggesitivity ,4. In adsitivity . Regardl2 within the hypothalamus [2 producing enzyme cyclooxygenase-2 in the ventromedial preoptic area of the hypothalamus (VMPO) [2 has a selective effect on the firing rates of VMPO neurons, based on thermosensitivity, with PGE2 increasing the firing rates of temperature insensitive neurons and inhibiting the firing rates of warm sensitive neurons [2 directly into the VMPO will produce a fever that can be correlated with an increase in the cellular activation of neurons within the VMPO [In response to stimulation of the immune system, changes in the activity of neurons in specific regions of the PO/AH may be responsible for the adjustment of the thermostatic set-point that results in an elevation in body temperature. Physiologic evidence suggests that in response to endotoxins such as lipopolysaccharide (LPS), this shift in set-point is mediated by the activation of afferent neural pathways or the production of systemic pyrogens, which ultimately leads to the local production of PGEthalamus ,6. Earlythalamus -10. Mores (VMPO) . In addi neurons . Anatomithe VMPO ,14.2 on the firing rates of VMPO neurons has been demonstrated [2 dependent increase in the firing rates of temperature insensitive neurons or decrease in the firing rates of warm sensitive neurons could lead to a hyperthermic shift in the thermostatic set-point and production of a fever [2 regulates the firing rates of VMPO neurons. We have hypothesized that these PGE2 dependent changes in firing rate are not the result of a change in the frequency of synaptic input to these neurons, but a selective effect on specific electrical properties of VMPO neurons. To characterize these responses, whole-cell recordings were made from VMPO neurons in tissue slices from male Sprague-Dawley rats, in response to changes in temperature and PGE2.Using a functional criterion for determining the thermosensitivity of hypothalamic neurons, a clear difference in the effects of PGEnstrated . Based o a fever . Yet, li2 dependent changes in firing rate, electrical activity, and the frequency of synaptic input were determined. The majority of these neurons were classified as temperature insensitive (n = 32). The remaining ten neurons were classified as warm sensitive. With respect to thermosensitivity or responses to PGE2, there was no specific pattern to the distribution of these neurons throughout the VMPO . Of the thirteen temperature insensitive neurons with thermosensitivities of 0.41 – 0.79 impulses·s-1.°C-1, the majority (n = 10) showed little or no change in firing rate in response to PGE2. The firing rates of these neurons did not significantly change from a baseline of 8.4 ±1.21 impulses·s-1 (PGE2 = 8.55 ± 1.24 impulses·s-1 (paired T test, P = 0.38); washout = 8.34 ± 1.24 impulses·s-1). In contrast to the responses of temperature insensitive neurons, the majority (n = 8) of VMPO warm sensitive neurons showed a significant decrease in firing rate during perfusion with PGE2. The firing rates of warm sensitive neurons significantly decreased from 15.28 ± 4.93 impulses·s-1 to 12.35 ± 4.85 impulses·s-1 in response to PGE2 .Using the cellularly invasive procedure of whole cell recording, the PGEng study . In resp2 and was not responsible for PGE2 dependent changes in firing rate.All VMPO neurons recorded in this study had resting membrane potentials of -45.0 ± 1.1 mV (n = 42). There was no significant difference between the resting membrane potentials of temperature insensitive neurons  and warm sensitive neurons . In addition, resting membrane potential did not change in response to PGE2, and the washout period. While the resting membrane potential did not change from a baseline mean of -43.94 mV, firing rate increased 43.4% in response to PGE2, from a mean of 5.11 impulses·s-1 to 7.33 impulses·s-1. The onset of this response occurred several minutes after perfusion with PGE2 had begun and lasted approximately 15 minutes beyond the point when perfusion with PGE2 ended. This was typical of all temperature insensitive neurons which had a significant change in firing rate in response to PGE2. These neurons showed response latencies of 3.5 ± 0.69 minutes and durations that ranged from 7 to 40 minutes before firing rate returned towards the baseline level.The top panels of Figure 2, and the washout period. While the resting membrane potential did not change from a baseline mean of -51.62 mV, the firing rate of this neuron decreased in response to PGE2, from a mean of 10.07 impulses·s-1 to 8.40 impulses·s-1. The onset of this response occurred several minutes after perfusion with PGE2 had begun and lasted approximately 25 minutes beyond the point when perfusion with PGE2 was stopped. Similar changes were recorded for the other warm sensitive neurons that were inhibited by PGE2, which showed response latencies of 3.90 ± 0.95 minutes and durations that ranged from 10 to 25 minutes.The lower panels of Figure 2 dependent changes in firing rate reported in this study and previous extracellular recordings [2. There were also no significant changes in the amplitudes or durations of action potentials recorded from temperature insensitive and warm sensitive neurons in response to PGE2.Throughout the entire length of a recording (46.7 ± 1.8 minutes), the amplitude and duration of action potentials recorded from VMPO neurons slowly decreased by an average of 4.6 mV and 0.16 milliseconds, respectively (n = 42). It is presumed that this was due to minor changes in ionic gradients, resulting from the technique of whole-cell recording. Based on the PGEcordings , these s2 from 367.1 ± 24.5 MΩ. to 339.7 ± 23.7 MΩ . This PGE2 dependent decrease in resistance was independent of thermosensitivity. Figure 2, with a reversal potential at or near the resting membrane potential.The input resistance of VMPO neurons recorded in this study significantly decreased in response to PGE2 dependent changes in the frequency of action potentials (frequency response). However, the majority of VMPO neurons did show PGE2 dependent changes in another characteristic of neuronal excitability, the first spike latency. Temperature insensitive neurons with thermosensitivities ≤ 0.4 impulses·s-1.°C-1showed a significant PGE2 dependent decrease in the first spike latency, from 7.4 ± 1.2 ms during baseline conditions to 5.2 ± 0.6 ms in response to PGE2 , similar to the response of the warm sensitive neuron in Figure 2 = 7.9 ± 1.1 ms (paired T test, P = 0.046); washout = 4.2 ± 0.5 ms). Temperature insensitive neurons with thermal coefficients of 0.41 to 0.79 impulses·s-1.°C-1 showed little change in this measurement of neuronal excitability (n = 8), in response to PGE2 ; washout = 6.8 ± 1.1 ms).During the application of a depolarizing current, VMPO neurons did not show PGE2. In a similar manner to the neuron shown in Figure -1.°C-1 showed a significant increase in the rate of rise of the depolarizing prepotential in response to PGE2 . In contrast, the majority of warm sensitive neurons showed a significant decrease in the rate of rise of the depolarizing prepotential in response to PGE2, similar to the response of the neuron in Figure -1, PGE2 = 0.50 ± 0.08 mV·ms-1; paired T test, P = 0.012). Although small changes in the voltage deflections that occurred at the end of an action potential showed some degree of change in response to PGE2, these changes were inconsistent in both temperature insensitive or warm sensitive neurons. Temperature insensitive neurons with thermosensitivities of 0.41 – 0.79 impulses·s-1.°C-1 did not show a significant change in the rate of rise of the depolarizing prepotential in response to PGE2.In Figure -1.°C-1) or excitatory post synaptic potentials . In response to PGE2, the frequency of synaptic input recorded from VMPO neurons did not change  recorded from VMPO neurons in the localized environment of coronal tissue slices was predominately inhibitory and insensitive to changes in temperature Table . In 92% in vitro recordings from tissue slices have also identified neurons in the PO/AH that lack spontaneously generated activity (silent neurons), are predominantly driven to produce action potentials by synaptic input (EPSP-driven neurons), or produce action potentials in a bursting pattern [As current models for temperature regulation suggest, the integrated responses of hypothalamic warm sensitive neurons and temperature insensitive neurons play an important role achieving and maintaining a discrete set-point for temperature control . While t pattern ,15. Howe2 or other endogenous pyrogens [2 was reported, with temperature insensitive neurons excited by PGE2 and warm sensitive neurons inhibited [-1.°C-1) [in vivo. In the present study, which uses whole-cell recording techniques to record the intracellular properties of VMPO neurons and the same functional criterion for defining warm sensitivity, similar firing rate responses were recorded. As suggested above, either an increase in the firing rates of temperature insensitive neurons or a decrease in the firing rates of warm sensitive neurons could lead to a hyperthermic shift in the thermostatic set-point and a fever.In the generation of a fever, current thermoregulatory models of neural networking suggest that either an increase in the activity of temperature insensitive neurons or the inhibition of warm sensitive neurons would shift the set-point to a more hyperthermic temperature . Throughpyrogens -19. Thisnhibited . In this-1.°C-1) ,15. As t2 responsive neurons showed a significant recovery in firing rate during the washout period, some did not. This lack of complete recovery may have resulted from responses to PGE2 that were considerably long in duration, lasting up to 40 minutes, and minor changes in ionic gradients that can occur over time during whole-cell recordings. As mentioned in the methods, all recordings were closely monitored for any changes that would make them unacceptable.It is also important to note that while the majority of PGE2 on the electrical properties of VMPO neurons, the frequency of localized synaptic input was characterized. In the present study, we were specifically interested in monitoring firing rate responses to PGE2 and characterizing the resulting voltage potential changes . In order to ensure that we did not interrupt the firing rate responses, we did not perform any voltage clamp measurements and did all recordings in current clamp, with current = 0 pA. This prevented any detailed characterization of synaptic potentials, other than frequency. As has been shown in other regions of the PO/AH [2, the frequency of PSPs recorded from most VMPO neurons either did not change or showed an increase. However, PGE2 dependent increases in the frequency of PSPs were not recorded from neurons that showed PGE2 dependent changes in firing rate. This may have resulted from a smaller degree of synaptic influence on firing rate, due to a change in the input resistance [In addition to the direct effects of PGEhe PO/AH , the majsistance . Additio2, regardless of temperature sensitivity or PGE2 dependent changes in firing rate. Since this response had little or no influence on firing rate, we would suggest that decreases in resistance resulted from changes in the activity of multiple currents, which continued to maintain equilibrium at or near the resting membrane potential. While we have also suggested that PGE2 may cause cAMP concentrations to either increase or decrease within these neurons [+ currents and depolarizing Na+ or Ca++ currents may still lead to an increase in conductance that does not result in a change in resting membrane potential. Therefore, although these changes in the input resistance may be an important response to PGE2, they are not directly responsible for PGE2 dependent changes in firing rate.As shown in Figure  neurons ,21, the 2 dependent changes in the excitability of VMPO neurons were recorded. Using two primary measurements of excitability, the frequency response and first spike latency (see: Results & Methods), our recordings indicate that PGE2 selectively increased the excitability of temperature insensitive neurons, while decreasing the excitability of warm sensitive neurons. Although there was no significant PGE2 dependent changes in the frequency responses of VMPO neurons, temperature insensitive neurons showed a significant decrease in first spike latency in response to PGE2  in suprachiasmatic neurons [K, Ca current in posterior hypothalamic neurons [A current in PO/AH neurons [A has been implicated in temperature dependent changes in firing rate, through a mechanism in which the thermally dependent inactivation rate of this current influences the rate of rise of the prepotential that precedes each action potential [2 has a direct effect on the firing rates of VMPO neurons through changes in the prepotential, increasing the rate of rise in temperature insensitive neurons, while decreasing the rate of rise of the prepotential in warm sensitive neurons  and sacrificed by quick decapitation, according to procedures approved by the National Science Foundation and the Animal Care and Use Committee of the College of William and Mary. Following removal of the brain, a tissue block of the hypothalamus was cut using a vibratome into 400 μm thick coronal slices. Two or three slices containing the VMPO were then placed in a recording chamber and allowed to equilibrate for 1–2 hours. Tissue slices were continually perfused with pyrogen free artificial cerebral spinal fluid (aCSF), which consisted of (in mM), 124 NaCl, 26 NaHCO3, 10 glucose, 5 KCl, 2.4 CaCl2, 1.3 MgSO4, and 1.24 KH2PO4. This nutrient medium was oxygenated (95% O2 – 5% CO2), warmed to a stable temperature of ~36°C by a thermoelectric assembly, and allowed to gravity flow into the chamber at 1 – 1.5 ml· min-1 (chamber volume = 1.2 ml) [Anterior hypothalamic tissue slices containing the VMPO were prepared from male Sprague-Dawley rats (100 – 150 grams), which were housed under standard conditions and given food and water  1.2 ml) . A small2, 1 CaCl, having a pH of 7.2 and an osmolarity of approximately 295 mOsmols/liter. As described previously [Tight-seal whole-cell recordings were made using glass microelectrodes with tip inner diameters of ~2 μm (3–5 MΩ), filled with a solution that consisted of (in mM) 130 K-gluconate, 10 EGTA, 2 ATP, 1 MgCleviously , a liqui-1·°C-1) was characterized by plotting firing rate as a function of temperature to determine the regression coefficient (m) of this plot. As in previous studies [-1·°C-1. All other neurons in this study were defined as temperature insensitive.Using a stereomicroscope, the recording electrode was positioned in the VMPO, which encompasses 700 μm of the hypothalamus just rostral to the suprachiasmatic nucleus. It extends laterally 900 μm from the third ventricle and dorsally 500 μm from the ventral brain surface . Once a  studies ,15,35, w2. At a stable temperature (~36°C), the perfusion medium was switched to one containing PGE2 . The duration of exposure to PGE2 ranged from 5 – 15 minutes, with durations of less than 10 minutes occurring only when there was a clear indication of a response. Exposure to PGE2 was followed by perfusion with aCSF for a washout period of at least 10 minutes.After thermosensitivity had been characterized, each neuron was tested for its response to PGE2 had a significant effect on firing rate, one-minute segments of stable activity were digitized for comparison . These segments were collected during baseline conditions (just prior to perfusion with PGE2) at the end of perfusion with PGE2, and at the end of a 10-minute washout period (or when firing rate returned to baseline levels). For each segment, a mean and standard error were calculated (Sigmaplot software, SPSS Inc.). A significant response to PGE2 was determined by comparison to the baseline level using a standard T-test (P ≤ 0.05).To determine if PGE2 were also characterized. As in a previous study [2, and the washout period. To characterize changes in the action potential, an averaged action potential from ten inherently activated action potentials was produced for each of the experimental conditions (sampling rate = 66.7 kHz). Measurements were made of action potential amplitude  and duration . Measurements were also made of the rate of rise of the depolarizing prepotential that precedes each action potential [2 were determined by comparison to baseline using a standard T-test (P ≤ 0.05).Changes in resting membrane potential and the action potential waveform in response to PGEus study , the resotential . For res2 and to insure that recordings remained stable. Large changes that did not return towards baseline levels were a characteristic of a deteriorating recording and marked the end of legitimate data. Input resistance was determined by the slope of a current-voltage plot obtained from a computer generated protocol in which a series of ten current pulses (-10 to -100 pA) were administered [2 were again determined by comparison to baseline using a standard T-test (P ≤ 0.05).Throughout each recording, input resistance and excitability were measured every 5 – 10 minutes to determine changes in response to PGEnistered . In addinistered . The fre2, and the washout period. As in previous whole-cell recordings, individual potentials were identified as rapid changes in membrane potential of at least 1 mV greater than background noise [-1). As with the other measurements, all significant responses to PGE2 were determined by comparison to baseline using a standard T-test (P ≤ 0.05). In addition, the thermosensitivities of EPSPs and IPSPs were characterized by calculating frequency averages (using the same methods as detailed above) at different temperatures (≥ 3°C range) and plotting the results as a function of temperature [The frequencies of synaptic potentials (EPSPs and IPSPs) recorded from each VMPO neuron were determined during baseline conditions, perfusion with PGEnd noise ,20. For perature .Once a recording had been completed, a stereomicroscope was used to visually confirm the location of the recording electrode. The ventral edge of the third ventricle was used as a reference to determine the lateral-medial and dorsal-ventral coordinates. The coronal position was also specified by the depth of the electrode from the surface of the tissue slice. In addition, the side of the brain from which the recording was made was identified by preparing the tissue slices with more lateral tissue on the left. Tissue slices were then removed from the recording chamber, fixed in a 10% formalin solution, and sectioned again to a thickness of 50 μm. Sections were then stained with giemsa to identify specific hypothalamic areas so that the location of each recording within VMPO could be reconfirmed  [38].HJR, carried out the majority of cellular recordings and data analysis. JDG conceived of the study and participated in its design, coordination and completion. Both authors contributed equally to the drafting of this manuscript.


What can we learn about human autoimmune disorders that have a genetic component -- such as systemic lupus erythematosus -- from mouse models? Autoimmune diseases afflict a large segment of the population in Western countries. Many of them have been described, and rheumatoid arthritis, type I diabetes , multiple sclerosis, and systemic lupus erythematosus (SLE) are among the most common. Although tremendous progress has been made in disease management over the last decade, cures for these diseases have not yet been found. Consequently, a large research effort is sustained in this field. In addition, autoimmunity has intrigued basic immunologists since the early realization that the ability to discriminate self from non-self was at the core of the immune system's ability to protect an organism from pathogens while avoiding self-destruction. A failure of this mechanism results in autoimmune reactions that often lead to clinical disease. In spite of massive research efforts, the mechanisms by which autoimmune diseases develop are not clearly understood. Genetic predisposition as well as environmental triggers plays a role, but the identity of these factors has been largely elusive. The identification of the most common genetic and environmental factors that set off autoimmunity may lead to a better understanding of the ensuing pathogenesis, and offers the best hope for improved therapies, and ultimately, cures.So far, animal models have proved the best way to probe the mechanisms of disease in general, and autoimmune diseases in particular. In the past few decades, the mouse has become the model of choice for experimental medicine, and the rat is following close behind. Starting in the early twentieth century at the Jackson Laboratory (Bar Harbor, Maine, United States), the production of inbred strains of mice and the systematic collection and characterization of naturally occurring mutants have created the building blocks on which much of the research using animal models is now based. Inbred strains are collections of genetically identical animals obtained through selective breeding. These strains have provided homogenous experimental groups, with interindividual variability reduced to environmental (and stochastic) factors. In addition, inbred strains have an assortment of distinct phenotypes that have then been exploited as models of human diseases.Since the 1980s, techniques have been developed to manipulate the mouse genome. Specific genes now can be routinely over-expressed as transgenes, or eliminated by gene targeting, which creates a “knockout” . This apInterestingly, the percentage of mouse genes without any homolog currently detectable in the human genome (and vice versa) has been estimated to be less than 1%, a fact that strengthens the validity of mouse models of human diseases. However, one has to be careful in directly applying data obtained from animal models to human diseases. Most human autoimmune diseases show an extremely heterogeneous clinical presentation, which animal models present as simplified versions. A mouse model, as in any reductionist approach, is both inconvenient, because it provides only a partial representation of the real biological complexity underlying the human disease, and advantageous, because it is a more tractable tool with which to probe mechanistic issues. In addition, a number of differences exist between the human and rodent immune systems . Since iNonetheless, animal models are at the core of autoimmune research, and a large body of literature reflects the many advances brought by these models in terms of deciphering disease mechanisms. The relative lack of progress in certain human autoimmune diseases for which an animal model does not exist, such as neuropsychiatric lupus, corroborates the indispensable role played by animal models. Three basic types of animal models have been used in autoimmune research: spontaneous models, induced models, and genetically engineered models. The latter category has been further subdivided into transgenic and knockout strains .Spontaneous models were produced through fortuitous observations of clinical symptoms reminiscent of a given human autoimmune disease developing in a given mouse strain, or in crosses between mouse strains. This happened, for example, with the nonobese diabetic (NOD) mouse, which developed type 1 diabetes, and the hybrid between the New Zealand Black (NZB) and the New Zealand White (NZW) mouse, (NZB × NZW)F1, which developed a lupus-like disease.Unfortunately, spontaneous models are not available for all human autoimmune diseases. Therefore, scientists have created induced models, often by exposing the animals to high doses of a suspected autoantigen at the same time as stimulating the immune system. Interestingly, marked differences exist between strains in their responses to these autoimmune inductions that reflect genetic variation associated with susceptibility to autoimmune diseases. For this reason, induced models have been limited to a small number of strains. For example, experimental autoimmune encephalomyelitis has been widely used as a model of multiple sclerosis. In this model, spinal cord homogenate or a protein derivative such as myelin basic protein is injected with a mixture of potent immunostimulants, most commonly in mice from the SJL strain. Another example of an induced model is collagen-induced arthritis, which has been used to study rheumatoid arthritis. In this model, type II collagen, a joint component, is injected also with immunostimulants, most commonly into mice from the DBA/1 strain.Finally, the ability to turn specific genes on or off, in specific cell types and/or at specific times, has created a plethora of mouse models limited only by the immunologist's imagination. Genes suspected to play a role in the pathogenesis of various autoimmune diseases have been evaluated this way, and those studies have been very informative in mapping out functional pathways that are targeted in these diseases. However, these models have intrinsic problems that have become more apparent in the past few years, and require careful controls to avoid possible misinterpretation. These problems are a result of the fundamental way in which transgenic and knockout strains are produced. When a piece of DNA carrying the gene of interest is injected as a “transgene” into fertilized eggs, it integrates randomly into the genome, and in doing so, potentially modifies the expression of the gene it integrates into. Since all genetic studies have recognized that a large number of genes are involved in autoimmune disease susceptibility, the potential for a transgene to hit one of those susceptibility genes is not negligible. This potentially confounding factor is usually controlled by producing and comparing several independent transgenic lines.More problematic is the interpretation of results obtained with knockout models. A gene is “knocked out” (KO) by homologous recombination of a disrupting piece of DNA within that gene. This genetic manipulation takes place in embryonic stem (ES) cells, which once mutated, are introduced into the inner cavity of a blastocyst (very early mouse embryo), creating chimeric embryos that are put back into female mice that carry the pregnancy to term. After multiple trials (and errors), ES cell lines from the 129 strain and blastocysts from the C57BL/6 (B6) strain have shown themselves to be superior in terms of efficiency and reliability. Consequently, this strain combination is at the origin of the overwhelming majority of knockout strains. Although the chimeric mice are usually backcrossed to B6 to dilute the contribution of the 129 genome, the knockout strains are always a mixture of the two genomes . Most imThe production of autoantibodies and mild antibody-related renal pathology, highly relevant to autoimmune diseases, especially SLE, has been reported independently in four mouse models using the (129 × B6) genetic background . It is gPLoS Biology, Marina Botto and her colleagues have tested this hypothesis by taking one of their knockout models for SLE, the serum amyloid P component deficient mouse (Apcs−/−) (Apcs−/− mice on a (129 × B6) genetic background develop a lupus-like disease, even after repeated backcrosses to B6 , carrying the same 129 region on Chromosome 1, but expressing Apcs. Amazingly, no difference was found between the two strains regarding the production of autoantibodies, clearly eliminating Apcs deficiency as a mechanism for this autoimmune process. Apcs deficiency was however associated with markedly increased renal damage, suggesting that this gene may be involved in preventing pathological consequences of autoantibody production.In this issue of pcs−/−) . This gres to B6 . Serum an humans . As mentIt has been reported anecdotally that the most common outcome of a genetic knockout is a lupus-like disease. Botto and her colleagues may have identified the reason behind this somewhat surprising observation as a spurious consequence of the gene-targeting process. Gene targeting has been an invaluable tool in understanding the mechanisms of immunological diseases, and has still a very important role to play with increasingly sophisticated techniques of selective targeting. The immediate consequence of this work should be an increased scrutiny for appropriate controls, which may include congenic mice carrying the same 129 flanking region, but expressing the targeted gene .The past few years have shown that genetic susceptibility to autoimmune diseases involves a large number of genes with small individual contributions. In spite of this great complexity, advances have been made, and a small but growing number of susceptibility genes have been identified . A commoUsing mouse models has its pitfalls; many differences, both obvious and subtle, exist between mice and humans. Those differences are, however, outweighed by the power of the experimental system offered by the mouse. What the new study of Botto and colleagues reminds us is that the appropriate control is still crucial to meaningful data interpretation. Keeping that in mind, one can predict that many of the keys to human autoimmune diseases are still in the mouse room.


Tuberculosis (TB) is increasing in the world and drug-resistant (DR) disease beckons new treatments.6 IU of recombinant human IFN gamma intramuscularly, daily for one month and then three times per week up to 6 months as adjuvant to the indicated chemotherapy, according to their antibiograms and WHO guidelines. Sputum samples collection for direct smear observation and culture as well as routine clinical and thorax radiography assessments were done monthly.To evaluate the action of interferon (IFN) gamma as immunoadjuvant to chemotherapy on pulmonary DR-TB patients, a pilot, open label clinical trial was carried out in the Cuban reference ward for the management of this disease. The eight subjects existing in the country at the moment received, as in-patients, 1 × 10Sputum smears and cultures became negative for acid-fast-bacilli before three months of treatment in all patients. Lesion size was reduced at the end of 6 months treatment; the lesions disappeared in one case. Clinical improvement was also evident; body mass index increased in general. Interferon gamma was well tolerated. Few adverse events were registered, mostly mild; fever and arthralgias prevailed.These data suggest that IFN gamma is useful and well tolerated as adjunctive therapy in patients with DR-TB. Further controlled clinical trials are encouraged. Mycobacterium tuberculosis. Every year, around 8 – 10 million new cases occur [th cause of death worldwide [Tuberculosis (TB) is not yet a defeated affection. Although controllable at a community level and curable in individuals, its eradication seems distant. At present, at least one third of the World's population, more than 1 500 million individuals are infected with the es occur , and cororldwide . TB reprorldwide . The emeorldwide . Accordiorldwide .Mycobacteria have developed mechanisms to adapt to the noxious intracellular environment. Thus, it can persist, replicate and disseminate, leading to new infectious foci. Resistance emergence depends on several factors such as initial bacillary load, inadequate or incomplete chemotherapy administration, and the patient's immune condition.The infection is mainly transmitted by inhalation of the bacilli coming from respiratory airways infected secretions. Once inhaled, the bacilli are subjected to phagocytosis within the alveolar macrophages, where they can be destroyed. Nevertheless, Chemotherapy is successful in most cases, given that the treatment schedule is thoroughly followed. It is prolonged, costly, and needs to be directly observed. Otherwise it is inadequate to kill all the bacilli and drug resistance emerges. Toxicities are frequent as well .The immunologic approach to TB treatment can be promising since only 10 – 20% of infected people develop the disease and many of them have spontaneous remission . InterfeEnough evidences exist related to IFN gamma action on the macrophages immunoregulatory activity -14]. LacTherefore a pilot clinical study was done with the aim to evaluate IFN gamma effect on drug resistant pulmonary TB patients regarding their clinical, bacteriological and radiological evolutions. The results show that the use of this protein in eight DR-TB patients (four of them MDR) as adjuvant to antibiotics had short and middle-term beneficial effects.An open-label, non-randomized, non-controlled, pilot trial was carried out at the "Benéfico -Jurídico" Hospital, Havana, which is the national reference unit for TB and other respiratory diseases. According to the national TB program, all patients with unfavorable response to treatment are remitted to this center.The study population was constituted by eight Cuban patients, both sexes, more than eighteen years old, with diagnosis of TB without a favorable response to the usual therapy, who gave their written, informed consent to participate. The diagnosis comprised clinical findings such as cough and expectoration, pulmonary lesions at thorax radiography, and positive DR-TB sputum-smear and culture. To confirm drug resistance the Canetti's multiple proportions method  was usedThe previous drug therapy received by the patients included 4 drugs (isoniazid, rifampin, streptomycin, and pyrazinamide) daily during 2 months, then isoniazid and rifampin twice per week for 2 additional months. Since their sputum tests had not become negative at this point they were returned to the 4 drugs regime plus ethambutol daily for 3 months, and finally isoniazid, rifampin, and ethambutol three times per week for 5 months.The trial was done in compliance with the Helsinki Declaration. The protocol was approved by the hospital's Ethics Committee and by the Cuban Regulatory Authority. Data from nineteen historical control cases were obtained from the hospital's archives.®, Heber Biotec, Havana), intramuscularly, daily during 4 weeks and then 3 times per week for the next 20 weeks. Participants stayed as in-patients during the study period. They received anti-TB drugs (WHO schemes) [Patients received 1 000 000 IU of human recombinant IFN gamma (Heberon Gamma Rschemes) , accordiEvaluations were carried out at entry and monthly during IFN gamma treatment. A complete physical examination was done. Sputum samples were taken for acid-fast-bacilli smear and culture, as well as blood samples for hematological counts, globular sedimentation rate, alanine aminotransferase, and creatinin determinations. Thorax radiographies were also recorded. Afterwards, patients were followed up with half-yearly evaluations during one year.Treatment efficacy evaluation included clinical, bacteriological and radiological outcomes. Complete response was defined as total disappearance of all signs and symptoms, negative sputum acid-fast-bacilli smear and culture, and pulmonary lesions improvement at X-ray. Partial response included signs and symptoms decrease, negative sputum smear and culture and stable X-ray lesions. No response consisted in signs and symptoms persistence, positive bacteriological examinations, and lesions stabilization or progression. Safety and tolerability of the IFN gamma treatment were monitored by means of a rigorous control of the adverse events that could be presented.2. Their main symptoms were cough, expectorations, dyspnea, stertors, distal cyanosis, and finger clubbing. Bacteriological tests codification was mostly high and all patients showed active lesions at thorax radiography. Most of them had accelerated globular sedimentation rates (GSR). Anemia or other hematological alterations were not recorded.Eight patients were enrolled in the study. Those were all the pulmonary DR-TB cases in the country during the inclusion period, from December 1999 to February 2002. They had not responded to the usual Directly Observed Treatment Short-course (DOTS) chemotherapy regime. Strain resistance was acquired in all cases. This was well determined since in Cuba all detected cases are screened for resistance on their first isolate. The patients did not have any extra-pulmonary manifestation of the disease. Their demographic and baseline characteristics are shown in Table A rapid favorable evolution was obtained after treatment with IFN gamma Table . ClinicaThe treatment with IFN gamma was safe and well tolerated. Four patients presented at least one adverse event. These events were arthralgias, fever, headache and asthenia. All adverse events were mild, except for one moderate fever, which was efficiently controlled with acetaminophen. Significant differences were not detected in other clinical laboratory tests.After completion or the IFN gamma 6-months treatment the patients continued with the corresponding chemotherapy schedule. Seven of the eight patients remained bacteriologically, clinically and radiologically negative at least twelve months after the treatment with IFN gamma concluded. However, patient number five relapsed six months after the end of IFN therapy. He developed additional resistance to rifampin and ethionamide and a chronic obstructive respiratory disease that contributed negatively to his evolution.Table In spite of the reduced size of the population studied, the results suggest the efficacy of IFN gamma on DR-TB, when used as adjuvant to chemotherapy. All eight patients were considered as complete responders at the end of IFN treatment with disappearance of the disease signs and symptoms, sputum tests conversion, and pulmonary lesions improvement. Bacteriological and radiological improvement correlated with the clinical evolution; BMI increased and manifestations as cough and expectoration did not recur after IFN gamma treatment. Clinical practice demonstrates that these results are very difficult to obtain in such a short period of time with the chemotherapy alone.Any conclusion from this study is also limited by the fact that it was not a controlled trial. This was not possible due to the low incidence of TB (7.6/100,000 inhabitants in 2002)  and DR-TThe fact that four patients received rifampin, according to the strain sensitivity, which is one of the election drugs for the treatment of TB with excellent results in patients treated with DOTS regime, does not diminish the consideration regarding the possible benefit exerted by IFN gamma since these same patients had already not responded to this antibiotic as part of the DOTS. Moreover, one patient recurred after he had finished IFN gamma treatment for 6 months, despite still being under chemotherapy regime. This suggests that in his case a new IFN gamma cycle combined to the antibiotics would have been necessary, but this was not previewed in the protocol. However, only a controlled trial can definitely clarify the role of IFN gamma and second line antibiotics in this kind of patient's improvement.The radiological results demonstrated IFN gamma antifibrotic properties as well. All patients had a reduction in the pulmonary lesions size, while one showed a complete resolution. This effect cannot be attributable to the antibiotics, since it is well known that DR-TB patients only develop radiological improvement long time after sputum smears and culture become negative. In many cases extensive fibrotic lesions never improve, and stay stable for life. This antifibrotic action agrees with that obtained with IFN gamma in idiopathic lung fibrosis  and suggTherapy was well tolerated. It was not necessary to suspend the combined treatment due to adverse events; mostly mild. Adverse events such as arthralgias, fever and headache coincide with those reported for interferons .M. tuberculosis [Mycobacteria. It stimulates macrophages to produce tumor necrosis factor alpha (TNF α), oxygen free radicals and nitric oxide, increase surface display of MHC antigens and Fc receptors, decrease lysosomal pH, and increase the intracellular concentration of some antibiotics [Immunity to TB depends on the development of CD4+ cells- and macrophages-mediated Th1 response. The role of IFN gamma as the main macrophage-activator Th1 cytokine has been clearly established in animal models infected with rculosis ,26,27. Iibiotics -14,28.Regarding its antifibrotic effect, IFN gamma inhibits lung fibroblast proliferation and chemotaxis in a dose dependent manner, and reduces collagen synthesis ,19,29. FOn the other hand, mutations in the IFN gamma gene , or in tMycobacteria [IFN gamma therapy has been shown effective for cerebral tuberculosis caused by a multidrug-resistant strain . The aerbacteria ,39-42.These results can suggest a beneficial effect of IFN gamma when it is used as adjuvant in the treatment of tuberculosis patients that have resistance to standard chemotherapy, and encourage carrying out more extensive, controlled studies. Combination with second-line drugs can reduce the time of treatment, diminishing toxicities and possible relapses; in many cases could reduce the application of recessional surgery. Further controlled clinical trials are needed to confirm these results.Authors IGG, CMVS, and PALS are employees of the Center for Biological Research, which is part of the Center for Genetic Engineering and Biotechnology, Havana network, where IFN gamma is produced. The rest of the authors have no competing interests at all.RSM conceived the study and carried out the bacteriological determinations. IGG participated in the study design and coordinating, and wrote the manuscript draft. NFO, MVQ, MTM, DC, and DMM took care of patient recruitment, management, and follow-up. CMVS participated in the study design and result analysis. PALS took part in the design, results analysis and manuscript writing. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Back to Sleep campaign in the United States, which encouraged parents to use a supine sleeping position for infants.Parental smoking and prone sleep positioning are recognized causal features of Sudden Infant Death. This study quantifies the relationship between prenatal smoking and infant death over the time period of the This retrospective cohort study utilized the Colorado Birth Registry. All singleton, normal birth weight infants born from 1989 to 1998 were identified and linked to the Colorado Infant Death registry. Multivariable logistic regression was used to analyze the relationship between outcomes of interest and prenatal maternal cigarette use. Potential confounders analyzed included infant gender, gestational age, and birth year as well as maternal marital status, ethnicity, pregnancy interval, age, education, and alcohol use.We analyzed 488,918 birth records after excluding 5835 records with missing smoking status. Smokers were more likely to be single, non-Hispanic, less educated, and to report alcohol use while pregnant (p < 0.001). The study included 598 SIDS cases of which 172 occurred in smoke-exposed infants. Smoke exposed infants were 1.9 times (95% CI 1.6 to 2.3) more likely to die of SIDS. The attributed risk associating smoking and SIDS increased during the study period from approximately 50% to 80%. During the entire study period 59% (101/172) of SIDS deaths in smoke-exposed infants were attributed to maternal smoking.Back to Sleep campaign. Mothers should be informed of the 2-fold increased rate of SIDS associated with maternal cigarette consumption.Due to a decreased overall rate of SIDS likely due to changing infant sleep position, the attributed risk associating maternal smoking and SIDS has increased following the  Back to Sleep campaign, has had a major role in reducing SIDS rates. This public health campaign encourages parents to place infants in a supine rather than prone sleeping position. Early studies investigating the effects of supine sleeping revealed significantly reduced SIDS rates [Previous literature has shown a relationship between maternal smoking and the Sudden Infant Death Syndrome (SIDS). Published studies vary in size and methodology but consistently demonstrate a two-fold increased odds of SIDS with both prenatal and postnatal maternal smoking -10, inclDS rates , but smoBack to Sleep campaign in the United States for the ten-year period from 1989 to 1998. We hypothesized that maternal prenatal smoking confers a clinically significant risk of SIDS and that an increased attributed risk of SIDS associated with smoking could be identified in the wake of the supine sleeping campaign.The aim of this study was to confirm the relationship between reported prenatal maternal smoking and SIDS and to examine the effect of sleeping position changes on the attributed risk of SIDS and smoking. The analysis spans the rollout of the Since 1969, the State of Colorado has collected data on multiple items through a birth registry. This registry includes extensive demographic data such as maternal report of the number of cigarettes smoked per day during pregnancy. We used the Colorado Infant Death Registry over a 10-year period (1989–1998) to identify causes of infant death.We conducted a retrospective cohort study utilizing Cochran Mantel-Haenszel univariate analysis of risk factors and multiple logistic regression on the outcomes of infant death, SIDS, and respiratory deaths. We excluded non-singleton births (14978 records), infants born at less than 2500 grams (36779 records), and birth records where a mother's smoking status was unknown (5835 records). Additional records with missing data were coded so as to place the record in the presumed lower risk group: 42 records with unclear marital status were coded as "married," 67 records missing a maternal age were coded as age "18–34 years," 865 records with unclear gestational age were coded as "term" infants, and 4 records missing a gender assignment were coded as "female" in the analysis. Missing data for education (9659 records) and ethnicity (582 records) were coded as such and included in the analysis directly. We linked the birth and death registries using a unique birth number present in both registries. Utilizing multiple logistic regression, we modeled the exposure of interest, maternal smoking, as both a dichotomous and a continuous variable. Other variables analyzed included infant gender and gestational age (less than 37 weeks, 37 weeks or older), as well as maternal marital status, ethnicity, time between pregnancies (less than 12 months or 12 months and greater), maternal age (<18 years, 18 to 34 years, and >34 years), education, and self-reported use of alcohol in pregnancy. In the analyses for SIDS and respiratory causes of death, deaths from other causes were excluded from the analysis.Power to detect a 20% difference in a baseline disease occurrence of 3 per 1000 was calculated at 99% for a population of 500,000. SAS version 8.0 (SAS Institute) on a PC was utilized for statistical analyses. We included the interaction between ethnicity and cigarette use in the modeling and requested the Hosmer-Lemeshow statistic from the model.We compared cases of SIDS (ICD 9 codes 798.0 to 798.9) between cohorts of infants born to mothers who reported prenatal smoking versus mothers who reported no prenatal smoking. Secondary outcomes included total infant mortality and respiratory deaths (ICD 9 codes 033.0 to 033.9 and 460 to 490). We used unadjusted annual rates to calculate the attributable risk of SIDS associated with maternal cigarette consumption.Over the 10-year study period, 1573 infants died, 598 SIDS cases occurred (1.2/1000 live born infants), and 34 infants died due to a respiratory etiology. Table We calculated adjusted odds ratios by analyzing smoking as a dichotomous exposure (mother smoked or did not smoke) and as a continuous variable (number of reported cigarettes per day during the pregnancy). Dichotomous outcomes of reported smoking during pregnancy yielded adjusted odds ratios of 1.9 (95% CI: 1.6 to 2.3) for death due to SIDS, 1.5 (95% CI: 1.3 to 1.7) for infant deaths from all causes, and 3.0 (95% CI: 1.4 to 6.3) for deaths due to respiratory etiologies . Table per cigarette are 1.042 . In this model, consumption of 10 cigarettes per day is associated with a 51% increased odds of SIDS (95% risk limit 35% to 70%). The Hosmer-Lemeshow test statistic was non-significant (p > 0.1948) suggesting adequate model fit.Analyzing cigarette consumption as a continuous variable shows the associated odds 12. In this analysis, 101 infant deaths due to SIDS bear an association with maternal smoking among the exposed cohort of 172 infants. Figure Back to Sleep campaign. In the final year of the analysis, 80% of the SIDS deaths in the smoke-exposed infant cohort are attributed to maternal smoking.Table Back to Sleep public health campaign in the United States, we noted an increasing attributed risk of SIDS with smoking. As a major etiology of SIDS, prone sleeping position, decreased over the study period due to the national educational campaign, the remaining SIDS deaths may now be due to the more isolated effects of tobacco exposure. Due to a decreased overall rate of SIDS, almost 80% of SIDS among smoke-exposed infants now bear a relationship to cigarette smoking.Smoking is deleterious and has negative effects on children born to mothers who smoke -16. We cBack to Sleep campaign in the United States, suggest that up to 30% of SIDS deaths may be attributed to maternal smoking [Taylor and Sanderson, using data prior to the  smoking . We noteOur study cannot establish a causal role for maternal smoking in SIDS. Others have argued for a causal relationship based on prospective data, demonstrable dose-response relationships, and analysis using multiple potential confounders . The cauThe published literature reports a 20% to 30% smoking rate among pregnant women . ApproxiBack to Sleep campaign in the United States and our dataset did not assess whether parents positioned their infants prone or supine. We therefore could not control for this ecological association with SIDS. The very nature of retrospective data creates limitations in that we cannot carefully control the setting in which the data are collected, or the individual collecting the data. Missing data records are a third limitation, although this appears to have not been a major issue with this dataset.This study has several important limitations related to design and the nature of the data set used. Given the rich nature of the Colorado Birth Registry, we controlled for many potential confounding variables, but others may exist. This analysis likely represents an under-estimate of the actual associated risk with prenatal smoking, given that it relies on maternal report of a behavior widely known to be harmful. We suspect that self-report of maternal smoking underestimates the true rate of maternal smoking. Fetal and infant exposure to tobacco smoke occurs in manner ways, including prenatal maternal smoking, prenatal maternal second-hand smoke exposure, and postnatal smoke exposure by one or more care providers in the home. In this study we cannot distinguish among these exposure pathways, which may result in an erroneous under or over estimate of risk. The time period spanned by this study includes the rollout of the Back to Sleep campaign in the United States we examined the increasing attributed risk associating smoking with SIDS. As SIDS rates declined, the attributed risk of SIDS with smoking has increased. In the final year of analysis, we demonstrated a link between 80% of the SIDS deaths and maternal smoking. A major, preventable exposure remains for infants in the United States and providers should redouble counseling efforts toward reducing this exposure.As prone infant sleeping has decreased, other causes of SIDS such as maternal smoking assume increased importance in the effort to protect infants from SIDS. Spanning the rollout of the The author(s) declare that they have no competing interests.MA participated in the study conception, background research, study design, statistical analysis, and drafting of the manuscript. DJ participated in the study conception, study design, and proofreading of the manuscript. HB participated in the study conception, study design, statistical analysis, and proofreading of the manuscript.The pre-publication history for this paper can be accessed here:


Drug industry insiders share their tips on using celebrities to market drugs and diseases Drug industry insiders share their tips on using celebrities to expand markets As the Hispanic world well knows, the word in Spanish for advertising is ‘propaganda’, its meaning derived literally from the propagation of the faith, the antithesis of science's Enlightenment ideals. The old word somehow seems perfect for describing the new world of drug promotion and its growing use of the famous face. Like the catholic cardinals of the 17th century, many of the feted celebrities of the 21st are now engaged in spreading the word. Now, as then, the religion promises miraculous breakthroughs, wonder cures, and sometimes even eternal life. The difference is that this time around, the stars are earning fat fees from the marketing departments of giant pharmaceutical companies. And if the latest revelations from industry insiders are anything to go by, their hefty investments in celebrity selling are well worth it.Oprah and The Today Show. According to celebrity brokers, the star's remuneration package, though always confidential, can range from $20,000 to $2 million.The epicentre of this phenomenon is of course the United States, where companies routinely hire celebrities to attract attention to the latest drugs and the diseases that go with them. Pfizer famously paid presidential hopeful Bob Dole to promote awareness of erectile dysfunction as sildenafil (Viagra) was hitting the market. Wyeth hired supermodel Lauren Hutton to hawk hormone replacement therapy and menopause. GSK contracted football star Ricky Williams to sell social anxiety disorder, helping make paroxetine (Paxil)—briefly—the world's top-selling antidepressant. Even the dead are raising awareness, with the estate of Errol Flynn now enlisted to help promote cardiovascular disease as a household name . The cel‘A partnership between a celebrity and a brand has an intangible sort of magic’, writes a senior marketing executive at Amgen, in an extremely candid piece published recently in an industry trade magazine . Amgen iThe Rosie Show can be better forums for celebrities than straight advertisements, which are governed by regulations. ‘The great advantage over advertising is that the airtime is practically free, and there is no fair balance to worry about’ she writes [Benshoshan then reveals why on-air talk-show appearances on ‘top-tier media venues’ like e writes . The dowe writes .Another recent report from within the industry draws on public opinion survey data to guide drug company marketers on the selection and ‘effective use’ of celebrity spokespersons . The surThe issue of credibility is important, the NexCura Inc. researchers point out, because ‘the credibility rating is used as a surrogate for “buying” behavior’—an intermediate measure of whether the star can persuade people to request the target drug from their doctor. The survey found that Bob Dole was still the most recognisable celebrity marketer with the United States public, but that the skater Dorothy Hamill—currently promoting Merck's arthritis medication rofecoxib (Vioxx)—took the lead in the credibility stakes. Significantly though, almost three-quarters of those surveyed were correctly able to identify Bob Dole with Pfizer's Viagra, despite the fact that the advertisements in which he appeared were ‘unbranded’ ads for erectile dysfunction. The researchers concluded by recommending that drug companies choose a celebrity with personal experience of the target condition; choose someone trustworthy—perhaps a newsreader or sports figure; and choose someone who will promote a single cause or brand rather than multiple ones.Ironically, the NexCura survey also found two-thirds of medical consumers agreed with the proposition that celebrities were ‘just doing it for the money and can't be trusted’.Frasier star Kelsey Grammer and his wife were promoting irritable bowel syndrome on top-rating TV shows, viewers thought the pair were speaking on behalf of an independent foundation. In fact the couple's fee had flowed from GSK, which was at that time preparing the market for alosetron (Lotronex), a controversial new drug that carried modest benefits and severe side effects, including possible death [The first problem here is that the public is often not even informed whether a celebrity is receiving money from a drug company. In the case of TV star Rob Lowe, there was no mandated requirement for him to disclose his link with Amgen when appearing on media shows watched by millions. According to one industry insider familiar with the case, who did not want to be named, ‘it depended if he remembered to say it, and whether he was asked’. The media's failure to disclose relevant conflicts of interest when covering healthcare is well established . When Frle death .Equally as serious is the lack of any formal requirement for stars or media outlets to spell out drug side effects along with benefits when celebrities are pushing products or conditions. Lauren Hutton can be quoted, in magazine articles read by millions of readers, as saying, ‘My No. 1 secret is estrogen’ without any need for her, or the magazine, to list the dangers of the hormone replacement therapy made by her sponsor . But perWhile Prince Charles's companion Camilla Parker Bowles takes no money from drug companies, she did choose to make an important public statement about the bone condition osteoporosis at an international conference funded by Lilly, a company promoting a medication for the condition . CamillaWith pharmaceutical marketing, it is clear that nothing short of a Vatican II-style reform is required, though there are already encouraging signs of change. Scientific journals are slowly disentangling themselves from unhealthy industry influence over what they publish, and public access to clinical trial data is daily a closer reality . However


The shift handover forms an important part of the communication process that takes place twice within the nurses' working day in the gynaecological ward. This paper addresses the topic of implementing a new system of bedside handover, which puts patients central to the whole process of managing care and also addresses some of the shortcomings of the traditional handover system.A force field analysis in terms of the driving forces had shown that there was dissatisfaction with the traditional method of handover which had led to an increase in the number of critical incidents and complaints from patients, relatives and doctors. The restraining forces identified were a fear of accountability, lack of confidence and that this change would lead to more work. A 3 – step planned change model consisting of unfreezing, moving and refreezing was used to guide us through the change process. Resistance to change was managed by creating a climate of open communication where stakeholders were allowed to voice opinions, share concerns, insights, and ideas thereby actively participating in decision making.An evaluation had shown that this process was successfully implemented to the satisfaction of patients, and staff in general.This successful change should encourage other nurses to become more proactive in identifying areas for change management in order to improve our health care system. The shift handover in this ward was conducted as "a ritual inheritance," [This study was undertaken in a 28 – bedded gynaecological ward catering for female patients aged 16 and above. There were 21 nurses based in this ward of whom 14 were qualified and the remaining were health care assistants, with experience ranging from 1 The verbal handover was derived from written information on the office white board which included the patient's name, bed number, medical diagnosis and the treating doctor. This was in line with the findings of Sherlock  who arguThe root cause of the problem identified was the model of handover used to communicate clinical information. As a benchmark, the findings from evidence on the bedside handover were used to give meaning and strength to the proposed change. Bedside handovers offer an immediate solution to the many problems that are associated with the traditional handover ,15,16. IUnfreezing, Moving and Refreezing provided us with useful frameworks for our change management [An adaptation of Spradley's 8-step model and Lewin's 3-step model of nagement ,14.Unfreezing is about encouraging people think about the current situation and helping them recognise the need for change . Change The first move therefore was to create awareness by communicating the proposed change to all those who were going to be affected by the new practice: the nurses, patients and the ward manager so that they all had a shared vision of an improved handover system. A goal-seeking behavior with a clear logical sequence of action, were demonstrated throughout the process as advocated by Lancaster and Lancaster ,17. ReseThe proposed change was announced in advance by using different communication channels, e.g. personal contact with individual nurses, staff information/notice board by the authors. This initiated informal discussion among nurses of the ward by creating a cognitive dissonance which led to a quest for more information about the new handover. This consultation phase allowed the nurses to discuss various clinical scenarios and analyse the constraints and benefits of the new proposal in the local context. They were also involved in group work to identify and make proposals on how to deal with some of the problems that we may encounter in our local context e.g. handover coinciding with ward rounds or emergency situations and patients too distressed to talk. Case studies and research articles on this topic were used for discussion and to further reinforce the beliefs of staff of the ward that the current practice had shortcomings and could be improved. The status quo was therefore unsettled and this enabled us to rule out the first resistance through a normative re-educative strategy. A group of senior nurses who had experience in this particular area agreed take turn to act as mentors in order to facilitate this process and offer support to their junior colleagues in the first week until they become confident to carry out the process without supervision.The extensive literature search also provided us with options for alternatives to bedside handover. These were thoroughly debated before reaching a decision. The options considered were the following:1) Tape recorded handover2) Computer generated handover using information technology3) Bedside handover, based on individualized care planThe 'SMART' criteria were used to evaluate the feasibility of the alternatives to bedside of handover. The tape recorded handover would require a tape recorder being taken around to each of the patients and the interaction recorded. An informal discussion with the patients revealed that this method was distractive and the majority of them did not feel comfortable about their conversation being recorded. With regards to the computer generated handover using information technology, the patients felt this system will not enable them to engage fully in the process. It was also felt that since the first two options required extra financial, technical resources for implementation, these would not be feasible in the first instance whereas the bedside handover gained unanimous support from both patients and staff. This was also more realistic in term of its applicability in our practice area. It was specific, measurable in terms of its performance and achievable within existing resources and a defined time frame. Its foundation rested on evidence base practice, which showed theoretical soundness.There was a shared vision about the worth of the proposed change by the team and consequently bedside handover was logically considered as the best option for change. The vision formulated was that in three months' time, bedside handover would become the normal shift handover process of the ward. The mission statement agreed was "all handovers would be carried out at the patients' bedside between the incoming and outgoing nursing staff with the patients' involvement."A force field analysis, as shown in table Careful planning is essential if trauma is to be minimized . It was th of February 2003 up to 8th May 2003. One-month time was judged sufficient to unfreeze the situation and the remainder to implement and evaluate the change.The time frame earmarked to implement the change was three months starting from the 8Choosing a strategy for the change process depended upon various factors and good interpersonal relationship was a critical factor. It has been proposed that strong leadership and excellent communication skills were essential if an atmosphere of trust was to be engendered ,8. With Confidential issues related to matters that the patients brought up during the admission procedure and during their stay, certain issues that were brought up during ward rounds and from the patients own requests.In cases of occasional lateness in resuming work, the handover would proceed with the other patients in first the instance and if the staff was still late, then some other colleague would step in her place. Reassurance was given with respect to 'no substantial overlapping' of shift in that it would not have major bearing on the handover process by explaining that shorter handover can reduce the likelihood of information overload and result in concise and pertinent information being exchanged as per care plans. There was a general agreement that fifteen minutes as officially allocated for handover would be sufficient for this purpose. Assurance was also given that confidentiality of patients' clinical information would be taken into consideration in drafting a protocol for bedside handover, as shown in table Several meetings were organized with different groups of nurses to explain and clarify any shortcomings and to reach a consensus. This approach was recommended by Driscol , as it eth of March 2003. For the first week, six senior staff who had experience in this area volunteered and took turn to continue to be present in as many handovers as observers and participants, to monitor and reinforce the established protocol step by step.Following a pilot handover session involving senior staff in a participant and an observer capacity over 2 morning and 2 evening handover sessions, which did not require any major changes, implementation of the bedside handover was started on 8They also provided clarification and support to staff in cases of difficulty, and helped evaluate the extent of change that had taken place in an effective manner. The nurses present during the handover had no difficulty in adapting to this new situation, using a care plan incorporating a more psychosocial and patient-centered approach to bedside handover with the patients' participation.The evaluation of the implementation of bedside handover was carried out in two distinct phases. A protocol, as shown in table th criteria at 90%. In one of the sessions, the nurse had left the patient whilst the bedside handover was in progress to attend to another patient without explaining the reason for this short absence to him which accounts for the 90%.Analysis of results of the observational data on 10 handovers, Table Analysis of the results of semi-structured interviews with 40 patients, Table The result was evaluated at a full staff meeting and the ward manager and colleagues recognized the change. Despite unlearning of the old practice had taken place two nurses still displayed some difficulties with the new handover as they were always eager to report everything themselves rather than allowing the patients to have a say. After a reassessment of the situation, accurate feedback was given to them. With the group support, they became used to the new system by observing their colleagues in action during the handover and doing it in turn. After a couple of sessions they became fully conversant with the new system. By this time, this project was ready for the refreezing stage.One of the major difficulties encountered was to rally everybody behind this project. The normative re-education, in line Bernhard and Walsh , was useManaging change in a hospital set up is a daunting task as it involves a change in the attitude and behavior of staff in a complex environment in order to gain their collaboration. The concept of no pain no gain was very evident throughout the process. Lewin's 3 – stage model was useful in implementing the change in a planned and structured way. Resistance was overcome by creating a climate which encouraged open communication. The support of the ward manager and key stakeholders were significant. Evaluation has shown that the new system of handover is working well but monitoring will be ongoing with evaluation of a larger sample of patients. This change has been an enriching experience for the staff, and has generated enthusiasm and given them confidence to question some of the practices on the ward. This new approach to handover can therefore be implemented in other areas of practice and evaluated to ensure that they are meeting patients' satisfaction. Further studies can be undertaken to explore how the multidisciplinary team could further consolidate this process.The author(s) declare that they have no competing interests.HKK taught this module and supervised this change management project. ZBJ implemented this change in the gynaecological ward as part of her assessment in the "Management Development" module. Both authors wrote this manuscript, read and approved the final version.The pre-publication history for this paper can be accessed here:


Perineodynia , anal and urinary incontinence are the main symptoms of the pudendal canal syndrome (PCS) or entrapment of the pudendal nerve. The first aim of this study was to evaluate the effect of bilateral pudendal nerve decompression (PND) on the symptoms of the PCS, on three clinical signs  and on two neurophysiological tests: electromyography (EMG) and pudendal nerve terminal motor latencies (PNTML). The second aim was to study the clinical value of the aforementioned clinical signs in the diagnosis of PCS.In this retrospective analysis, the studied sample comprised 74 female patients who underwent a bilateral PND between 1995 and 2002. To accomplish the first aim, the patients sample was compared before and at least one year after surgery by means of descriptive statistics and hypothesis testing. The second aim was achieved by means of a statistical comparison between the patient's group before the operation and a control group of 82 women without any of the following signs: prolapse, anal incontinence, perineodynia, dyschesia and history of pelvi-perineal surgery.When bilateral PND was the only procedure done to treat the symptoms, the cure rates of perineodynia, anal incontinence and urinary incontinence were 8/14, 4/5 and 3/5, respectively. The frequency of the three clinical signs was significantly reduced. There was a significant reduction of anal and perineal PNTML and a significant increase of anal richness on EMG. The Odd Ratio of the three clinical signs in the diagnosis of PCS was 16,97 (95% CI = 4,68 – 61,51).This study suggests that bilateral PND can treat perineodynia, anal and urinary incontinence. The three clinical signs of PCS seem to be efficient to suspect this diagnosis. There is a need for further studies to confirm these preliminary results. The objective of perineology is to treat each defect of the perineum with the right procedure -3. PudenBefore going into details of this procedure, it is necessary to remember the anatomy of the pudendal nerve. This anatomy is still controversial.While summarizing the data of the literature and the results of our dissections, the likeliest anatomy of the pudendal nerve presents itself as follows. The pudendal nerve is a mixed nerve carrying motor and sensory fibers. Its fibers are derived from the sacral roots S2, S3 and S4 . Once thThe pudendal canal syndrome (PCS) and its surgical treatment have been described by Shafik in 1991 . This syThe cause of the PCS is not always clear but it is often possible to find a compression (biking, long time sitting, haematoma...) or a stretching (descending perineum, surgery, delivery....) of the pudendal nerve in the Alcock's canal -19 in thThe clinical signs and investigation results proposed by Shafik  to confiThe trans-gluteal approach proposed by Robert to treat pudendal neuralgia aimed to open also the "clamp" between the sacro-spinal and the sacro-tuberous ligament by cutting one or two of them .Since Shafik's study in 1991, some questions about the effect of PND on the PCS remained open. No peer reviewed publications confirming the efficacy of this surgery on anal incontinence or on urinary incontinence could be found. Even the existence of a genuine PCS has never been validated.The aim of this study was to answer the following questions:Is there any effect of the bilateral PND according to Shafik on:- three main symptoms of PCS ?           - perineodynia             - anal incontinence           - urinary incontinence- three clinical signs of PCS ?           - abnormal sensibility           - painful Alcock's canal           - painful "skin rolling test" - two neurophysiological tests ?           - electromyography (EMG) of the anal sphincter and of the bulbocavernosus muscles.           - pudendal nerve terminal motor latencies (PNTML) of the anal and perineal branches.What is the clinical value of the aforementioned three clinical signs in the diagnosis of PCS ?A retrospective analysis to study the effects of a bilateral PND. The studied sample comprised 74 female patients who underwent a bilateral PND between 1995 and 2002 done by the same surgeon. The average age was 56.1 years (range: 28 – 77). All these patients underwent a complete history and clinical examination following the three perineal axis  according to the concept of perineology .The frequency of the 3 main symptoms of the PCS  in the 74 patients before surgery is presented in Figure Associated surgical procedures were performed at the same time as the PND to treat all the defects revealed by the clinical examination, and are presented in Table The following variables were used:For perineodynia, four situations were encountered: no pain, proctalgia, unilateral pain, bilateral pain. The effect of surgery was estimated by the patient using one of the following proposals: cured, improved, unchanged or worsened.For anal incontinence, a four levels ordinal scale was used: no incontinence, gas incontinence, liquid incontinence, solid incontinence. "Cured" was defined as "no incontinence". The patient was considered "improved" if there was a change of at least one level in the scale going from "solid" to "gas" incontinence. The patient was defined as "worsened" if there was a change of at least one level in the opposite direction.For urinary incontinence, a four levels ordinal scale was used: no incontinence, mild incontinence, moderate incontinence and severe incontinence. The two types of urinary incontinence, stress and urge incontinence, were evaluated separately even if both were present in the same patient (mixed incontinence). "Cured" was defined as "no incontinence". The patient was considered "improved" if there was a change of at least one level in the scale going from "severe" to "mild" incontinence. If the change observed was in the opposite direction the patient was considered "worsened".Sensibility was tested with a needle comparing the left and the right sides of the vulva and of the skin 2 cm lateral to the anus. The interpretations of the results were done using a four levels ordinal scale: 0 = total anaesthesia, 1 = reduced sensibility, 2 = normal sensibility, 3 = hypersensibility. 0, 1 and 3 were considered as "abnormal sensibility".The pain induced by the palpation of the pudendal canal by rectal examination was evaluated using a seven levels ordinal scale : 0 = no pain, 1 = mild pain, 2 = mild pain with Tinel sign (irradiation of the pain), 3 = moderate pain, 4 = moderate pain with Tinel sign, 5 = severe pain, 6 = severe pain with Tinel sign. The Alcock's canal was considered "painful" if the pain was 4 or more.Beginning from 5 cm behind the level of anus the skin was pinched and then rolled to the front until the skin fold was at the level of the clitoris. The skin rolling test was considered "painful" if it induced a severe pain at least at one level Figure .Concentric needle EMG was done at rest and during voluntary contraction on both sides of the external anal sphincter and on each bulbocavernosus muscle. The richness of the EMG was grossly evaluated using a six levels scale: 1 = simple, 2 = poor, 3 = intermediate poor, 4 = intermediate, 5 = intermediate rich and 6 = rich.Anal and perineal PNTML were measured before and after the operation using the St Marks electrode to stimulate the pudendal nerve by the rectal route just under the ischial spine. For anal PNTML the electrical potentials induced in the striated anal sphincter were collected using the ring of this electrode. For the perineal PNTML the method described by Kiff  and SnooAt least one of the 3 following symptoms resistant to conservative treatments (physiotherapy, drugs, infiltrations, modification of diet or behaviour):a. Anal incontinenceb. Perineodyniac. Urinary incontinenceAssociated with at least two of the five following criteria:a. increased anal or perineal PNTMLb. pathological EMG of the anal sphincter or bulbocavernosus muscles (neurogenic trace, reduced activity: richness "poor" or "simple").c. painful Alcock's canal on rectal examination (at least on one side)d. abnormal perineal sensibility (at least at one level)e. painful "skin rolling test" (at least on one side).Surgical procedure as described by Shafik in 1991 . The opeThe different steps of the procedure were:- Vertical incision of the skin between the anus and the ischial tuberosity.- Opening of the ischio-rectal fossa with scissors.- The inferior rectal nerve is hooked under the finger and followed to the entrance of the Alcock's canal Figures  and 4.- Opening of this canal .- Control of the haemostasis.- Self draining closing of the skin with nylon.The efficacy on the symptoms, on the clinical signs and on the neurophysiological tests was evaluated during a follow up consultation one year or more after the surgical procedure because the nerve healing can be very slow .Firstly, the efficiency of the PND on the symptoms and clinical signs was studied by means of descriptive statistics. Tests of hypothesis were done to compare the mean values of the neurophysiological tests before versus after PND.Secondly, the diagnostic value of the clinical signs was evaluated in a "case control" setting. A subject belongs to the "controls group" when PCS is considered to be absent, namely if the patient does not present any of the following symptoms, signs or risk factors for PCS: perineodynia, anal incontinence, prolapse, previous surgery in the area, dyschesia. The clinical signs are not used to decide if a subject belongs to the controls or cases group. The statistical comparison was done between the patient's group before ("cases group") and after the operation, and the "controls group" of 82 women (average age: 48.8 years, extremes 27–76).Statistical analysis of differences was performed using chi-square testing for categorical variables and t-tests for continuous variables.The effect of PND on the symptoms of PCS is presented in Table In order to treat completely the patient, PND was frequently associated with other procedures which might have an effect on the symptom studied. Therefore, the results for each symptom were presented in two columns: the first corresponds to the entire sample  and the second to the small group of patients in which the symptom was treated by PND only ("without").On the 26 patients with pain before the operation, 18 were reviewed 12 months or more after the operation. The pain had disappeared in 11 and was reduced or had another origin  in 3. The cure rate with a mean follow-up of 22,2 months was 61,1 % (77,7% cured or improved).As none of the surgical associated procedures used in this study were known to improve or cure perineodynia, the only procedure removed was levatorplasty. Theoretically this operation can reduce the stretching on the pudendal nerves by reducing the sagging of the levator plate. The results were similar in the group without levatorplasty.On the 46 patients with anal incontinence before the operation, 36 were reviewed 12 months or more after the operation. 23 of them were cured, 7 improved, 2 were worse and 4 reported no change. The cure rate with a mean follow-up of 26.4 months was 63.9 % (83,3% cured or improved).The results according to the severity of incontinence are presented in Table To study the real impact of PND on anal incontinence, we removed the following cases in which PND was associated with anal sphincteroplasty, levatorplasty or cure of rectocele by fascia and perineal body restoration:- 2 patients had anal sphincteroplasty together with the PND: one was cured and the other improved.- Levatorplasty according to Shafik  was used- 30 cases had a cure of rectocele by fascia and perineal body restoration  and 1 improved (liquid incontinence).Anal ultrasound was done before the operation in 13 of the 36 patients reviewed. Only 4 were normal, 3 showed a rupture of the internal and external sphincters, and 6 presented a disruption of the external sphincter alone.In the 7 patients who had a rupture of the anal sphincter  without anal sphincteroplasty and a follow up of more than 12 months (mean 18.5 months), 4 were cured and 3 were a failure.5 patients who were still incontinent after 1 year follow up (2 incontinences for flatus and 3 for liquid) became continent 2 years after the operation.Five patients presenting urinary incontinence (4 urge and 1 stress incontinence) had PND without any other procedure around the urethra. The mean follow up was 18,5 months for the 4 patients with urge incontinence. In this small group, 3 patients were cured and one was a failure. The patient with stress urinary incontinence was improved (the number of pads used per day was reduced from 9 to 4) one year after surgery.The effect of PND on the three clinical signs is described in Table Because levatorplasty can theoretically reduce the stretching of the pudendal nerve, the evaluation of the effect on the clinical signs has been done for the entire sample  and for the same group without the patients who had a levatorplasty ("without: levat").The cure rate of the 3 clinical signs was between 60 and 70 % depending of the sign and of the type of sample studied.38 patients underwent a complete EMG evaluation before and after surgery. A relevant comparison was possible in 35 patients. 3 patients were excluded because one of the two EMG explorations was insufficient for technical reasons. The average follow up was 16,9 months (range: 12 – 35,4 months).Left and right values for one parameter correspond to two different nerves. Therefore, these values were considered independent .The effect of PND on EMG and PNTML is presented in Table The "Anal Richness" on EMG after surgery was significantly higher than before. The mean "Bulbocavernosus Richness" after surgery was slightly higher than before but this difference was not significant. Both anal and perineal PNTML after PND were significantly reduced compared to values before.The box-plots of the 4 studied parameters are presented in Figures We present here the results concerning the evaluation of the three clinical tests: abnormal sensibility, painful Alcock's canal and painful "skin rollling test" as diagnostic tests for PCS.The statistical analysis is based on the following contingency tables presented in Tables The proportions of observations in the "Cases Before Surgery" and "Controls" columns of the contingency table vary significantly from row to row , whereas no significant difference is observed between the proportions of observations between "Cases After Surgery" and "Controls" .Estimated sensibility, specificity, predictive values (positive and negative) and odd ratio  corresponding to each of the three clinical tests and combinations of all of them are presented in Tables The most sensible test is the "Painful Alcock's canal" and the most specific is the "Skin rolling test".Using the three signs altogether, the most sensible combination is "At least 1 positive versus All negative" and the most specific combination is the "All positive versus All negative".During one operation a heavy bleeding coming from the pudendal artery just near the pudendal nerve was very difficult to treat (selective ligature). This patient had a blood transfusion but no long term side effect. Since the operation, one patient has presented sometimes a short lasting clitoridal pain. This patient had also an increase in her anal incontinence (gas incontinence became a liquid incontinence). Three patients had wound healing problems which resolved with simple disinfection.In the literature there is no data available about the prevalence of the PCS. Therefore, it seems to be a rare event. In this study, we evaluated the prevalence of the PCS in an outpatient perineology clinic. By using three different methods during the last 24 months  the estimated prevalence should be around 20%.Before discussing the results of surgery, the first important issue is about the interest of a bilateral decompression. The benefit – risk ratio must be studied. The results of Shafik were obtained after bilateral decompression ,29,30. FThe treatment of pain starts with a holistic approach of the woman (drugs, psychotherapy, relaxation...) with exclusion of other causes of pain: piriformis syndrome, coccygodynia, interstitial cystitis, endometriosis... The other neurological causes must be excluded by a complete electrophysiological study of the perineum  and imaging of the spinal cord . If the Even with the transgluteal approach where the "clamp" between the sacro-spinal and the sacro-tuberous ligament is opened by sectioning the sacro-spinal ligament, the cure rate remains around 50%. In the 4 cases of proctalgia fugax the results were better (3 cured and 1 improved). Shafik [For Robert early diagnosis appears to be the determining factor in improving results . He usedFor anal incontinence, our results were in the same range as Shafik . In a prMore interesting was the cure rate in the group of patients with a clear rupture of one or the two anal sphincters. The traumatic rupture of the anal sphincter (delivery, sphincterotomy...) usually induces an immediate anal incontinence. In the patients who remained continent the power of the broken muscles remain sufficient to avoid flatus or faeces leakage. In the long term the continence is probably maintained with the help of the fibrous tissue located between the two edges of the ruptured muscle which acts like a bridge and therefore enables the sphincter to be efficient during many years. The aging process of the muscle and the pudendal neuropathy reduce the power of the muscle  with time and explain the appearance of an anal incontinence. Therefore it is logical to restore continence by improving the conduction in the pudendal nerve. This fact can also explain why the results of sphincteroplasty decrease with time especially in the non diagnosed or treated pudendal neuropathies .The fact that 5 patients were cured from their anal incontinence only 2 years after surgery emphasized the importance of a long follow up period to obtain relevant cure rates. Surprisingly, the cure rate seems to be not dependant of the degree of anal incontinence but the number of solid incontinences  was too small to validate this impression.The results of the pudendal nerve decompression seem to be equivalent to these of neuromodulation  and the For urinary incontinence the number of cases is too small to give a relevant cure rate but there were enough cases to suggest that this surgery can treat some patients with stress or urge incontinence.In a previous study, 3 of the 7 patients presenting a stress urinary incontinence were cured by bilateral pudendal nerve decompression alone ,37.In Shafik's study 6 patients were cured from their stress urinary incontinence, 5 improved and one was a failure . For thiThis study is the first one dealing with a possible effect of the pudendal nerve decompression on urge incontinence. It is probably due to a better control of the urethral sphincter which can reduce urethral instability  and imprOne weakness of this study is the rough evaluation of the symptoms. We did not use any scoring system, pad test, quality of life questionnaires or "visual analog pain scale". Furthermore the number of anal and urethro-vesical manometries done before and after PND was too small to give relevant results.The objective evaluation of PND was done using two neurophysiological tests and the clinical examination. Like Shafik ,30 we foShafik described many clinical signs of the PCS ,29,30. ICompared to patients with negative clinical signs, those having positive clinical signs have a 4,42 ; 5,52 and 6,56 higher likelihood of PCS for "Abnormal sensibility", "Painful Alcock's canal" and "Painful skin rolling test", respectively Table . When paThe most specific sign was the "Painful skin rolling test" and the most sensitive was the "Painful Alcock's canal". The association of the three positive tests had a very high specificity in the diagnosis of a PCS (89 %). This high specificity was confirmed by the low frequency of this association after the operation (return to the same level as the control group).Therefore, in some cases the clinical examination should be sufficient to prove the existence of a PCS. For example, a patient presenting anal incontinence, an intact sphincter proven by ultrasound and the three clinical signs positive has almost certainly a PCS. Of course, from a scientific point of view it is still interesting to perform a complete electrophysiological study and a precise neurological examination to exclude a central problem (multiple sclerosis, tumor...) or a polyneuropathy.However, making the diagnosis of PCS is not usually an easy task. Many times, there is a high degree of suspicion but, as in many illness, all the symptoms or signs are not present. In this study, we decided to operate when at least two of the five clinical and neurophysiological signs described in the methods section were associated with one or more of the 3 classical symptoms . At the beginning of this study, it was usually "increased PNTML" and "painful Alcock's canal". With the introduction of the "skin rolling test" and of the "sensibility test", clinical examination became more important in the decision. The more symptoms  and signs were present, the more confident we were in the diagnosis of PCS. Further studies are necessary to validate this and to define more precisely the minimal criteria needed for the PCS diagnosis.The pudendal nerve decompression by the perineal route is a blind procedure. The search for the inferior rectal nerve and the opening of the Alcock's canal are done under finger control. In our experience it is not easier with retractors. Therefore it is necessary to have a clear anatomical vision of this area before performing the operation.Maybe the use of a laparoscope would help  but the Despite the blind character of the procedure we only had one heavy bleeding probably coming from the pudendal artery. One patient still presents with a mild intermittent clitoridal pain and a worsening of anal incontinence. Because the nerve of the clitoris leaves the pudendal nerve just before the entrance into the Alcock's canal this problem is probably the result of a too large dissection in the upper part of this canal. The two cases of anal incontinence worsening (gas incontinence becoming liquid incontinence), including the aforementioned patient, are difficult to explain. Maybe the neuropathy increased with the stretching involved in the procedure, the scarring process or a too large dissection. It could also be the result of the changes in the posterior level anatomy induced by concomitant procedures (easier expulsion of gas or faeces). For the 2 patients the EMG data and the clinical examination after the operation did not improve therefore showing that the neuropathy was not healing.Because the roughly estimate prevalence of PCS is around 20%, this "defect" seems to be a very frequent problem in Perineology. Therefore it should be logical to search for it in each clinical examination of a patient presenting with prolapse, perineodynia, urinary or anal incontinence.Pudendal neuropathy is probably a frequent "defect" in perineology. Pudendal nerve decompression seems to be the defect specific procedure indicated in such a problem. In fact it can treat perineodynia, anal and probably urinary incontinence. Anal incontinence can be cured by pudendal nerve decompression alone even in the presence of a clear disruption of the anal sphincter on anal ultrasound. Anal richness on EMG increases and PNTML decrease significantly after surgery proving an objective effect on the nerve. The frequency of abnormal puncture sensibility, painful Alcock's canal and painful "skin rolling test" are significantly reduced by the operation. This study suggests that the three clinical tests could be used in practice to confirm or suspect the diagnosis of pudendal neuropathy in case of pain, urinary and/or anal incontinence. However, further studies are necessary to confirm these preliminary results.PCS = pudendal canal syndromePND = pudendal nerve decompressionEMG = electromyographyPNTML = pudendal nerve terminal motor latencyThe authors declare that they have no competing interests.JB conceived the study, carried out surgery and clinical follow up and drafted the manuscript.DC participated in the design of the study and performed the statistical analysis.MB carried out the neurophysiological examinations.All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here: