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Worldwide prevalence of adult overweight and obesity is a growing public health issue. Adults with overweight/obesity often have chronic musculoskeletal pain. Using a mixed-methods review, we aimed to quantify the effectiveness and explore the appropriateness of weight loss interventions for this population. Electronic databases were searched for studies published between 01/01/90 and 01/07/16. The review included 14 randomized controlled trials that reported weight and pain outcomes and three qualitative studies that explored perceptions of adults with co-existing overweight/obesity and chronic musculoskeletal pain. The random-effects pooled mean weight loss was 4.9 kg (95%CI:2.9,6.8) greater for intervention vs control. The pooled mean reduction in pain was 7.3/100 units (95%CI:4.1,10.5) greater for intervention vs control. Study heterogeneity was substantial for weight loss (I 2  = 95%, tau = ±3.5 kg) and pain change (I 2  = 67%, tau = ±4.1%). Meta-regression slopes for the predictors of study quality, mean age and baseline mean weight on mean study weight reduction were shallow and not statistically significant (P > 0.05). The meta-regression slope between mean pain reduction and mean weight lost was shallow, and not statistically significant, -0.09 kg per unit pain score change (95%CI:-0.21,0.40, P = 0.54). Meta-synthesis of qualitative findings resulted in two synthesized findings; the importance of healthcare professionals understanding the effects of pain on ability to control weight and developing management/education programmes that address comorbidity., (© 2018 World Obesity Federation.)

The aim of this systematic review was to evaluate the effect of visual feedback techniques on pain perception by analysing the effect of normal-sized, magnified or minified visual feedback of body parts on clinical and experimentally-induced pain. Databases searched: Medline, Embase, PsychInfo, PEDro, CINAHL, CENTRAL and OpenSIGLE. Studies investigating pain patients and pain-free participants exposed to experimentally-induced pain were analysed separately. Risk of bias was assessed and data were meta-analysed. Thirty four studies were included. A meta-analysis of clinical data favoured mirror visual feedback (six trials; mean difference = -13.06 mm; 95% CI = -23.97, -2.16). Subgroup analysis favoured mirror visual feedback when used as a course of treatment (three trials; mean difference = -12.76 mm; 95% CI = -24.11, -1.40) and when used for complex regional pain syndrome for complex regional pain syndrome (three trials; standard mean difference = -1.44; 95% CI = -1.88, -0.99). There is insufficient evidence to determine differences between normal-sized view and a size-distorted view of the limb. Mirror visual feedback was not superior to object view or direct view of the hand for reducing experimental pain in pain-free participants. There were inconsistencies in study findings comparing normal-sized reflection of a body part and a reflection of an object, or a magnified or minified reflection. There is tentative evidence that mirror visual feedback can alleviate pain when delivered as a course of treatment, and for patients with complex regional pain syndrome. It was not possible to determine whether normal-sized, magnified or minified visual feedback of body parts affects pain perception because of contradictory findings in primary studies., Significance: It was not possible to determine whether normal-sized, magnified or minified visual feedback of body parts affected pain perception in clinical or experimental settings because of contradictory findings in primary studies. This emphasizes the need for higher quality studies., (© 2017 European Pain Federation - EFIC®.)

Background: Studies suggest that observing magnified and minified body parts using mirrors, lenses and virtual reality may affect pain perception. However, the direction of effect varies between studies. The aim of the present study was to evaluate the effect of observing a normal-sized, magnified and minified reflection of a hand on perceptual embodiment and contact-heat stimuli., Methods: Participants (n = 46) observed a normal-sized, magnified and minified reflection of the hand and a no-reflection condition while performing synchronized finger movements for 3 min (adaptive phase). Measurements of embodiment were taken before adaptive phase, pre- and post-contact-heat stimuli., Results: There were no differences in pain threshold nor tolerance between reflection and no-reflection conditions. Altering the size of the reflection of the hand did not affect estimates of pain threshold nor tolerance. The temperature for warm detection threshold was lower when participants were observing the magnified reflection of the hand compared with the no-reflection condition. Perceptual embodiment of the reflection of the hand was stronger after an adaptive phase with visuo-motor feedback, and the painful stimuli did not weaken the perceptual experience., Conclusion: Observing a reflection of the hand in front of a mirror did not alter heat pain threshold nor tolerance when compared with a no-reflection condition, and altering the size of the reflection did not affect pain perception. Researchers and clinicians using visual feedback techniques may consider including an adaptive phase with visuo-motor feedback to facilitate embodiment of the viewed body part., Significance: An adaptive phase with visuo-motor feedback enhances the perceptual experience of embodiment of a reflection of a hand and a painful stimulus does not weaken the experience. This should be considered when using visual feedback techniques for pain management., (© 2017 European Pain Federation - EFIC®.)

Background: The aim of this study was to investigate the influence of body fat percentage and its distribution on sensory detection and pain sensitivity responses to experimentally induced noxious stimuli in otherwise pain-free individuals., Methods: Seventy-two participants were divided into three equal groups according to their body mass index (BMI: normal, overweight and obese). Percentage body fat was estimated using a four-site skinfold method. Measurements of cold pressor pain threshold, tolerance and intensity; contact thermal sensory detection and heat pain threshold and tolerance (TSA-II - NeuroSensory Analyzer, Medoc); and blunt pressure pain threshold (algometer, Somedic SenseLab AB) were taken at the waist and thenar eminence., Results: Mean ± SD pressure pain threshold of the obese group (620.72 ± 423.81 kPa) was significantly lower than normal (1154.70 ± 847.18 kPa) and overweight (1285.14 ± 998.89 kPa) groups. Repeated measures ANOVA found significant effects for site for cold detection threshold (F 1,68  = 8.3, p = 0.005) and warm detection threshold (F 1,68  = 38.69, p = 0.001) with waist having lower sensory detection thresholds than thenar eminence. For heat pain threshold, there were significant effects for site (F 1,68  = 4.868, p = 0.031) which was lower for waist compared with thenar eminence (mean difference = 0.89 °C)., Conclusion: Obese individuals were more sensitive than non-obese individuals to pressure pain but not to thermal pain. Body sites may vary in their response to different types and intensities of stimuli. The inconsistency of findings within and between research studies should catalyse further research in this field., Significance: This study provided evidence that body mass index and distribution of body fat can influence sensory detection and pain sensitivity. Obese individuals were more sensitive than normal range body mass index individuals to pressure pain but not to thermal pain. Pain response varied according to subcutaneous body fat at different body sites. These findings strengthen arguments that weight loss should be a significant aspect of a pain management programme for obese pain patients., (© 2017 Crown copyright. European Journal of Pain © 2017 European Pain Federation - EFIC®.)

Literature suggests that pain perception diminishes in old age. The most recent review used search strategies conducted over a decade ago and concluded that study findings were equivocal. The aim of this systematic review, with meta-analysis, was to determine age-related changes in pain sensitivity in healthy pain-free adults, children and adolescents. A search of PubMed, Science Direct, and PsycINFO identified studies that compared pain sensitivity response to noxious stimuli at different time points in the lifespan of healthy individuals. Selected studies were assessed for methodological quality and data pooled and meta-analysed. Publication bias was tested using Funnel plots. Twelve studies were included in the review (study sample sizes 30-244 participants). Seven of nine studies found statistically significant differences in pain sensitivity response between old (mean ± SD 62.2 ± 3.4 to 79 ± 4 years) and younger adults (22 ± 1.5 to 39.1 ± 8.8 years), but the direction of change was inconsistent. Meta-analysis found that pressure pain threshold was lower in old adults compared with younger adults (p = 0.018, I 2  = 60.970%). There were no differences in contact heat pain thresholds between old and younger adults (p = 0.0001, I 2  = 90.23%). Three studies found that younger children (6-8.12 years) were more sensitive to noxious stimuli than older children (9-14 years). Methodological quality of studies was high, with a low risk of publication bias. There was substantial statistical and methodological heterogeneity. There is tentative evidence that pressure pain threshold was lower in old adults compared with younger adults, with no differences in heat pain thresholds. Further studies are needed., Significance: There is tentative evidence that old adults may be more sensitive to mechanically-evoked pain but not heat-evoked pain than young adults. There is a need for further studies on age-related changes in pain perception., (© 2017 European Pain Federation - EFIC®.)

Background: Gender role expectations of pain (GREP) have been shown to mediate sex differences in experimental pain. Few studies have investigated the role of ethnicity in shaping GREP. The aim of this study was to examine interactions between ethnicity and GREP on experimentally induced pressure and ischaemic pain in Libyan and white British students in their respective countries., Methods: Libyan (n = 124) and white British (n = 51) students completed a GREP questionnaire and their response to experimental pain was measured. Blunt pressure pain threshold (PPT) was measured over the 1st interosseous muscle using algometry. Pain intensity and pain unpleasantness (100 mm visual analogue scale) were measured at 1-min intervals during a submaximal effort tourniquet test on the forearm., Results: Multivariate analysis of variance detected significant effects for Sex and Ethnicity on pain measurements. Men had higher PPTs than women (p < 0.001). Libyans had higher PPTs than white British participants (p < 0.001). There were significant effects for Sex and Ethnicity for pain intensity ratings (p < 0.01) but no significant differences between the sexes in pain unpleasantness (p > 0.05). Libyan participants had higher pain intensity (p < 0.01) and pain unpleasantness (p < 0.05) ratings compared with white British participants. There were effects for Sex and Ethnicity for all GREP dimensions. Libyan participants exhibited stronger stereotypical views in GREP than white British participants (p < 0.001)., Conclusions: GREP was the mediator of sex but not ethnic differences in pain report, suggesting that gender stereotypical attitudes to pain account for differences in pain expression between men and women., (© 2012 European Federation of International Association for the Study of Pain Chapters.)

Gender role refers to the culturally and socially constructed meanings that describe how women and men should behave in certain situations according to feminine and masculine roles learned throughout life. The aim of this meta-analysis was to evaluate the relationship between gender role and experimental pain responses in healthy human participants. We searched computerized databases for studies published between January 1950 and May 2011 that had measured gender role in healthy human adults and pain response to noxious stimuli. Studies were entered into a meta-analysis if they calculated a correlation coefficient (r) for gender role and experimental pain. Searches yielded 4465 'hits' and 13 studies were eligible for review. Sample sizes were 67-235 participants and the proportion of female participants was 45-67%. Eight types of gender role instrument were used. Meta-analysis of six studies (406 men and 539 women) found a significant positive correlation between masculine and feminine personality traits and pain threshold and tolerance, with a small effect size (r = 0.17, p = 0.01). Meta-analysis of four studies (263 men and 297 women) found a significant negative correlation between gender stereotypes specific to pain and pain threshold and tolerance, with a moderate effect size (r = -0.41, p < 0.001). In conclusion, individuals who considered themselves more masculine and less sensitive to pain than the typical man showed higher pain thresholds and tolerances. Gender stereotypes specific to pain scales showed stronger associations with sex differences in pain sensitivity response than masculine and feminine personality trait scales., (© 2012 European Federation of International Association for the Study of Pain Chapters.)

Background: The TNM classification for renal cell cancer (RCC) should accurately predict and assign prognostic information for patients. In this study the recent 2010 revision to the TNM classification was compared with the previous 2002 classification with regard to survival outcomes., Methods: All patients having radical nephrectomy for RCC in the 5-year period 2004-8 at a tertiary referral centre were included. Pathological and radiological records were reviewed to identify TNM stage (2002 and 2010 classification) and survival data were captured., Results: 345 patients with RCC were identified. Based on the 2002 TNM staging system and using outcomes in T1 staged tumours as a baseline, statistically significant differences in disease-specific survival were noted between patients with T1 and T3b tumours (log rank p<0.001) but not between those with T1 and T3a tumours (p=0.33). However, when tumour stage was reassigned according to the 2010 classification, patients with T3a tumours were also found to do statistically worse than T1 staged disease (p<0.001)., Conclusion: In our cohort, the new 2010 TNM reclassification of T3 tumours showed better correlation with predicting worsening outcomes compared with localised disease.

Previous studies found a relationship between response to experimentally-induced pain and scores for the gender role expectations of pain (GREP) questionnaire. Findings were similar in individuals from America, Portugal and Israel suggesting that gender role expectations may be universal. The aim of this study was to translate and validate Arabic GREP using Factor Analysis and to investigate if sex differences to cold-pressor pain in healthy Libyan men and women are mediated through stereotypical social constructs of gender role expectations and/or pain-related anxiety. One hundred fourteen university students (58 women) underwent two cycles of cold pressor pain test to measure pain threshold, tolerance, intensity, and unpleasantness. Participants also completed the Arabic GREP questionnaire and the Pain Anxiety Symptom Scale-Short form (PASS-20). It was found that Libyan men had higher pain thresholds and tolerances than women (mean difference, 95% CI: threshold = 4.69 (s), -0.72 to 10.1, p = 0.005; tolerance = 13.46 (s), 0.5-26.4, p = 0.018). There were significant differences between sexes in 6 out of 12 GREP items (p < 0.004 after Bonferonni adjustment). The results of mediational analysis showed that GREP factors were the mediators of the effects of sex on pain threshold (z = -2.452, p = 0.014 for Self Sensitivity); (z = -2.563, p = 0.01, for Self Endurance) and on pain tolerance (z = -2.538, p = 0.01 for Self Endurance). In conclusion, sex differences in response to pain were mediated by gender role expectations of pain but not pain-related anxiety., (© 2011 European Federation of International Association for the Study of Pain Chapters.)

Objective: To identify through case study the presentation and possible pathophysiological cause of complex regional pain syndrome and its preferential response to stellate ganglion blockade., Setting: Complex regional pain syndrome can occur in an extremity after minor injury, fracture, surgery, peripheral nerve insult or spontaneously and is characterised by spontaneous pain, changes in skin temperature and colour, oedema, and motor disturbances. Pathophysiology is likely to involve peripheral and central components and neurological and inflammatory elements. There is no consistent approach to treatment with a wide variety of specialists involved. Diagnosis can be difficult, with over-diagnosis resulting from undue emphasis placed upon pain disproportionate to an inciting event despite the absence of other symptoms or under-diagnosed when subtle symptoms are not recognised. The International Association for the Study of Pain supports the use of sympathetic blocks to reduce sympathetic nervous system overactivity and relieve complex regional pain symptoms. Educational reviews promote stellate ganglion blockade as beneficial. Three blocks were given at 8, 10 and 13 months after the initial injury under local anaesthesia and sterile conditions. Physiotherapeutic input was delivered under block conditions to maximise joint and tissue mobility and facilitate restoration of function., Conclusion: This case demonstrates the need for practitioners from all disciplines to be able to identify the clinical characteristics of complex regional pain syndrome to instigate immediate treatment and supports the notion that stellate ganglion blockade is preferable to upper limb intravenous regional anaesthetic block for refractory index finger pain associated with complex regional pain syndrome., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Integration of prosthetic limb awareness into body schema is likely to aid manual control of the prosthesis. Physiotherapists and prosthetists use techniques to generate mechanical, visual and/or auditory feedback related to stimulation of the stump and proximal residual limb to improve prosthetic limb awareness. Electrical stimulation of afferent nerves using implanted electrodes can generate sensations of touch, joint movement, and position, in the missing, phantom limbs of amputees. We report here a novel hypothesis that non-invasive transcutaneous electrical nerve stimulation (TENS) could be used to facilitate the process of perceptual embodiment of a prosthesis into the body schema of amputees. Using a modified version of the rubber hand illusion (RHI), we have found that TENS paraesthesiae can be made to feel like it is emanating from a prosthetic hand in healthy participants with intact limbs. In addition, participants reported perceptual embodiment of the prosthetic hand into their body schema, i.e. it felt as if it is part of their body. We predict that projecting TENS paraesthesiae into the prosthetic limb(s) of amputees will provide sufficient sensory input to facilitate perceptual embodiment. This could prove to be a simple and inexpensive training aid to improve ambulation and prosthesis success.

Background: Home exercise programmes and exercise programmes carried out in a clinical setting are commonly advocated for the treatment of lateral elbow tendinopathy (LET), a very common lesion of the arm with a well-defined clinical presentation. The aim of this study is to describe the use and effects of strengthening and stretching exercise programmes in the treatment of LET., Eccentric Exercises: Slow progressive eccentric exercises for LET should be performed with the elbow in extension, forearm in pronation, and wrist in extended position (as high as possible). However, it is unclear how the injured tendon, which is loaded eccentrically, returns to the starting position without experiencing concentric loading and how the "slowness" of eccentric exercises should be defined. Nor has the treatment regimen of the eccentric exercises of a supervised exercise programme been defined., Stretching Exercises: Static stretching is defined as passively stretching a given muscle-tendon unit by slowly placing and maintaining it in a maximal position of stretch. We recommend the position should be held for 30-45 s, three times before and three times after eccentric exercises during each treatment session with a 30 s rest interval between each procedure. The treatment region of static stretching exercises when a supervised exercise programme is performed is unknown., Discussion: A well designed trial is needed to study the effectiveness of a supervised exercise programme for LET consisting of eccentric and static stretching exercises. The issues relating to the supervised exercise programme should be defined so that therapists can replicate the programme.

Objective: Our aim was to assess the efficacy of polarized polychromatic noncoherent light (Bioptron light) in the treatment of idiopathic carpal tunnel syndrome., Background: Carpal tunnel syndrome is the most common compression neuropathy, but no satisfactory conservative treatment is available at present., Method: An uncontrolled experimental study was conducted in patients who visited our clinic from mid-2001 to mid-2002. A total of 25 patients (22 women and three men) with unilateral idiopathic carpal tunnel syndrome, mild to moderate nocturnal pain, and paraesthesia lasting >3 months participated in the study. The average age of the patients was 47.4 years and the average duration of patients' symptoms was 5.2 months. Polarized polychromatic noncoherent light (Bioptron light) was administered perpendicular to the carpal tunnel area. The irradiation time for each session was 6 min at an operating distance of 5-10 cm from the carpal tunnel area, three times weekly for 4 weeks. Outcome measures used were the participants' global assessments of nocturnal pain and paraesthesia, respectively, at 4 weeks and 6 months., Results: At 4 weeks, two patients (8%) had no change in nocturnal pain, six (24%) were in slightly less nocturnal pain, 12 (48%) were much better in regard to nocturnal pain and five (20%) were pain-free. At 6 months, three patients (12%) were slightly better in regard to nocturnal pain, 13 (52%) were much better regarding nocturnal pain, and nine patients (36%) were pain-free. At 4 weeks, four patients (16%) had no change in paraesthesia, five (20%) were slightly better, 13 patients (52%) were much better, and three patients (12%) were without paraesthesia. At 6 months, two patients (8%) had no change in paraesthesia, two (8%) were slightly better, 14 (56%) were much better, and seven (28%) were without paraesthesia., Conclusions: Nocturnal pain and paraesthesia associated with idiopathic carpal tunnel syndrome improved during polarized polychromatic noncoherent light (Bioptron light) treatment. Controlled clinical trials are needed to establish the absolute and relative effectiveness of this intervention.

Randomised controlled trials were reviewed to evaluate the evidence of the effectiveness of extracorporeal shock wave therapy in the management of tennis elbow. Seven relevant trials were found, which had satisfactory methodology but conflicting results. Further research with well designed randomised control trials is needed to establish the absolute and relative effectiveness of this intervention for tennis elbow.

Tennis elbow or lateral epicondylitis is one of the most common lesions of the arm with a well defined clinical presentation, which significantly impacts on the community. Many treatment approaches have been proposed to manage this condition. One is Cyriax physiotherapy. The effectiveness and reported effects of this intervention are reviewed.

Peroxisome proliferator-activated receptor (PPAR) alpha is a member of the nuclear receptor superfamily of ligand-activated transcription factors. PPARalpha is activated by peroxisome proliferators and fatty acids and has been shown to be involved in the transcriptional regulation of genes involved in fatty acid metabolism. In rodents, the PPARalpha-mediated change in such genes results in peroxisome proliferation and can lead to the induction of hepatocarcinogenesis. Using the mRNA differential display technique and Northern blot analysis, we have shown that chronic exposure of the prostate cancer epithelial cell line LNCaP to the synthetic androgen mibolerone results in the down-regulation of PPARalpha mRNA. Levels of PPARalpha mRNA are reduced to approximately 40% of control levels in LNCaP cells exposed to 10 nM mibolerone for 96 h. PPARalpha-responsive reporter plasmids derived from human ApoA-II and muscle carnitine palmitoyl-transferase I genes were stimulated by the PPARalpha-activating ligand Wy-14,643 in LNCaP cells. In situ hybridization and immunohistochemical analyses showed that PPARalpha expression in prostate is confined to epithelial cells. In benign prostatic tissue, PPARalpha mRNA was either absent or only weakly expressed in the basal epithelial cells. In 11 of 18 (61%) poorly differentiated (Gleason score, 8-10) prostatic carcinoma specimens, there was strong expression of PPARalpha compared with 4 of 12 Gleason score 7 tumors and 2 of 11 Gleason score 3-6 tumors (P < 0.01). These results suggest that PPARalpha is found and functional in human prostate and is down-regulated by androgens. The role of PPARalpha may be to integrate dietary fatty acid and steroid hormone signaling pathways, and its overexpression in advanced prostate cancer may indicate a role in tumor progression with the potential involvement of dietary factors.

Background: Apoptosis-regulating genes have been shown to be important in the biology of prostate cancer. The aim of this study was to examine and correlate the expression of the apoptosis-regulating genes bcl-2, bax, and p53 with the frequency of apoptosis and rate of proliferation in benign prostatic epithelium (BP), prostate cancer, and high-grade prostatic intraepithelial neoplasia (HGPIN), which is currently considered the most likely precursor of prostate cancer., Methods: Forty-four patients with histologically proven prostate cancer were investigated. All the men underwent radical prostatectomy. Immunohistochemistry was performed to assess expression of bcl-2, bax, and p53, and proliferation rate, as measured by the Ki-67 index. The frequency of apoptotic bodies was assessed by morphological criteria., Results: The apoptotic index (AI) was highest in prostate cancer, and was significantly greater in HGPIN compared to benign prostate. The Ki-67 index was greatest in cancer, intermediate in HGPIN, and lowest in BP. The AI was increased in areas of BP in patients treated with neoadjuvant androgen ablation. No change in AI was seen in treated cases of HGPIN or cancer. Accumulation of p53 protein was infrequent in prostate cancer (2/43: 4.6%), and was absent in HGPIN. Bcl-2 overexpression was present in 2.3% of cancers (1/43) and in 34.9% of cases of HGPIN (15/43). Bax expression was seen in all cases of cancer and HGPIN. There was no correlation between bcl-2 expression and the apoptotic and Ki-67 indices in HGPIN., Conclusions: p53 and bcl-2 expression is infrequent in clinically organ confined prostate cancer. Bcl-2 expression is significantly higher in HGPIN than in both the associated prostate cancer and BP. The AI and Ki-67 index appeared intermediate in the putative precursor lesion HGPIN compared to prostate cancer and BP.

Prostatic adenocarcinoma commonly metastasizes to bone. Unlike most other bony secondaries, the majority of skeletal prostatic metastases are osteoblastic rather than osteolytic in nature. Several growth factors which are known to stimulate bone formation are expressed in benign and malignant prostate cells, but none has been specifically linked to osteosclerotic metastases. Bone morphogenetic proteins (BMPs) induce ectopic bone formation in vivo. We have reported previously that BMP-6 mRNA and protein are expressed in the majority of primary prostatic carcinomas with established skeletal metastases but rarely in clinically organ-confined tumours. This study examines the expression of BMP-6 mRNA in matched prostatic primary and secondary bony lesions and in isolated skeletal metastases from prostatic adenocarcinomas, as well as other common human malignancies, by in situ hybridization. BMP-6 mRNA was detected in 11 out of 13 bone metastases from prostate carcinoma and in three paired samples of primary prostate carcinoma and matching skeletal metastasis. Weak signals for BMP-6 were also present in 5 out of 17 skeletal deposits from non-prostatic malignancies. BMP-6 mRNA appears to be strongly expressed in prostatic adenocarcinomas, both in the primary tumour and in bone metastases. It is also expressed, though less frequently, in skeletal metastases from other human carcinomas. Our findings suggest that BMP-6 may hold potential as an attractive marker and possible mediator of skeletal metastases, particularly in prostate carcinoma.

Prostatic adenocarcinoma is emerging as a major cause of morbidity and mortality in the male population in the western world. Programmed cell death (apoptosis) in the prostate is activated by hormone ablation and is under the control of several regulating genes including the tumour suppressor gene p53 and the proto-oncogene bcl-2. Bcl-2 belongs to a rapidly expanding family of genes which form two functionally antagonistic groups controlling cell death and survival. Apoptosis regulating genes appear to play an important role in the development and progression of prostatic adenocarcinoma and offer a potential target for future therapeutic strategies.

Propylene glycol is a solvent that is used in many oral, injectable, and topical medications. Although uncommon, acute renal failure has been attributed to propylene glycol. The mechanism of propylene glycol-mediated renal injury is unknown. We report a case of acute renal failure in a 16-year-old boy given large doses of pentobarbital and phenobarbital, both of which are solubilized with propylene glycol. A renal biopsy showed proximal renal tubular cell swelling and vacuole formation. The data from this case suggest that the reversible acute renal failure caused by propylene glycol is attributable to proximal renal tubular cell injury.

We report a case of traumatic duodenal perforation where the diagnosis was first considered during abdominal ultrasound examination. A subsequent CT scan identified the site of perforation which was confirmed at laparotomy. This condition typically produces few clinical signs or symptoms initially but has a high mortality related to delayed diagnosis. The ultrasound findings that prompted early diagnosis are described.

Objective: To describe a patient with early gastric cancer, Menetrier's disease, lymphocytic gastritis and Helicobacter pylori infection., Design: A single patient case report., Patient: A 73-year-old man presenting with lower limb deep venous thrombosis was found to have a gastric adenocarcinoma on upper gastrointestinal endoscopy. He subsequently had a total gastrectomy., Results: Histological examination of the resected stomach showed an early gastric cancer and changes typical of Menetrier's disease, lymphocytic gastritis and Helicobacter-associated chronic gastritis., Conclusion: This case suggests a link between gastric adenocarcinoma, Menetrier's disease and lymphocytic gastritis. The presence of H. pylori is postulated as a possible aetiology.

This case report describes the unusual complications of a simple fall in a person with a profound neurological disorder, Hallervorden-Spatz disease. The fall produced a laceration of the forehead, skull fractures and severe occipital contrecoup contusions. Such contrecoup contusions are rare and may be a feature of this case because of the abnormal limb rigidity displayed in Hallervorden-Spatz disease. The mechanisms of injury are discussed.

Aims: To investigate the feasibility of using fixed cells with the polymerase chain reaction (PCR) in situ hybridisation and to investigate possible reasons for reaction failure., Methods: Fixed SiHa and CaSki cells were used in an experimental model of PCR in situ hybridisation for the detection of low and intermediate copy number viral infection in fixed cells., Results: PCR in situ hybridisation was able to detect one to two copies of human papillomavirus (HPV) 16 in SiHa cells, using small fragment amplicons (120 base pairs), confirming the high detection sensitivity and flexibility of the technique. Problems were encountered with localisation of PCR amplified product in CaSki cells (200-300 copies of HPV 16 per cell) owing to diffusion of product post amplification. Overall, 40% of reactions were successful, which confirms the current unreliability of the technique. Within cell preparations, about 50% of cells contained amplified product., Conclusion: PCR in situ hybridisation represents the marriage of two revolutionary molecular pathological techniques. However, it is currently unreliable, with reaction failure common. Standardised, dedicated equipment is urgently required if the technique is to achieve universal acceptance. In the future, the technique may be used to detect chromosomal translocations in human tumours and to study cellular gene expression.

Conventional solution-phase polymerase chain reaction (PCR) and in situ PCR/PCR in situ hybridization are powerful tools for retrospective analysis of fixed paraffin wax-embedded material. Amplification failure using these techniques is now encountered in some centres using archival fixed tissues. Such 'failures' may not only be due to absent target DNA sequences in the tissues, but may be a direct effect of the type of fixative, fixation time and/or fixation temperature used. The type of nucleic acid extraction procedure applied will also influence amplification results. This is particularly true with in situ PCR/PCR in situ hybridization. To examine these effects in solution-phase PCR, beta-globin gene was amplified in 100 mg pieces of tonsillar tissue fixed in Formal saline, 10% formalin, neutral buffered formaldehyde, Carnoy's Bouin's, buffered formaldehyde sublimate, Zenker's, Helly's and glutaraldehyde at 0 to 4 degrees C, room temperature and 37 degrees C fixation temperatures and for fixation periods of 6, 24, 48 and 72 hours and 1 week. DNA extraction procedures used were simple boiling and 5 days' proteinase K digestion at 37 degrees C. Amplified product was visible primarily yet variably from tissue fixed in neutral buffered formaldehyde and Carnoy's, whereas fixation in mercuric chloride-based fixatives produced consistently negative results. Room temperature and 37 degrees C fixation temperature appeared most conducive to yielding amplifiable DNA template. Fixation times of 24 and 48 hours in neutral buffered formaldehyde and Carnoy's again favoured amplification.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent research findings point to a spectrum of alcohol-induced immune dysfunctions in animal models and humans. Use of alcohol in vivo causes abnormalities in the function and/or structure of a broad array of cells involved in humoral and cellular immunity, including lymphocytes, Kupffer cells and other macrophages, as well as the endothelium of blood vessels and lymphatics. Regulatory cytokines and neuroendocrine factors can mediate some of these immunomodulatory effects which may be further re-phased, exaggerated or unbalanced by other drugs of misuse. A variety of animal models is available to study acute and chronic alcoholism, non-alcohol drug misuse, AIDS as well as other opportunistic infections, and neoplasias, which hold promise of clarifying the role of alcohol as an immunomodulator.

The ability to purify and recombine populations of peripheral neurons, Schwann cells and fibroblasts in tissue culture has enabled us to examine the contribution of fibroblasts to Schwann cell basal lamina assembly and ensheathment of unmyelinated rat superior cervical ganglion neurites in vitro. Purified perinatal superior cervical ganglion neurons were grown in culture either with Schwann cells or with Schwann cells plus fibroblasts derived from either superior cervical ganglion capsule or cranial periosteum. The cultures were maintained for 2-8 weeks on a collagen substratum in a medium known to promote Schwann cell differentiation (myelin, basal lamina formation) in the presence of dorsal root ganglion neurons. The extent of Schwann cell differentiation (ensheathment, basal lamina formation) in the presence of superior cervical ganglion neurons was evaluated in this study using electron microscopy. In superior cervical ganglion neuron plus Schwann cell cultures (without fibroblasts), Schwann cells achieved only a moderate degree of ensheathment; also, Schwann cell basal lamina was discontinuous and extracellular collagen fibrils were sparse. Although only discontinuous basal lamina was demonstrable by electron microscopy in these cultures, surprisingly, Schwann cell/neurite fascicles were uniformly immunostained for laminin, type IV collagen, and heparan sulfate proteoglycan. The addition of fibroblasts to superior cervical ganglion neuron plus Schwann cell cultures increased the deposition of basal lamina around the Schwann cell/neurite units, the number of collagen fibrils, and the extent of neurite ensheathment. We propose that the presence of basal lamina increases the Schwann cell's ability to ensheathe superior cervical ganglion neurites, possibly through an augmentation of specific extracellular matrix components or by increasing in some way the capacity of these components to become organized into basal lamina. We conclude that, unlike dorsal root ganglion neurons, superior cervical ganglion neurons are unable to stimulate full Schwann cell extracellular matrix expression with the result that these Schwann cells require the extraneuronal influence of fibroblasts to deposit basal lamina and attain their mature phenotype in culture.

This retrospective study of long-term use of transcutaneous electrical nerve stimulation (TENS) at Newcastle Pain Relief Clinic indicates that TENS has been a successful analgesic treatment for 58.6% of 1582 patients attending the clinic over a period of 10 years. A wide range of pain conditions were found to respond to TENS and many patients continued to use the treatment for several years. Most patients not responding to TENS (during a home trial) returned stimulators at the first follow-up appointment. Thus TENS should be considered as a simple, safe and reusable first line treatment for many pain conditions.

A case is described of symmetrical cavitating brain stem necrosis produced by cardiac arrest in a premature infant. Two months after birth this 25-week gestational age infant suffered a prolonged episode of bradycardia. She was resuscitated and then died 3 weeks later. The autopsy revealed striking bilateral cavitation of the brain stem tegmentum extending in a columnar fashion from the upper portion of the spinal cord to the hypothalamus. The findings in this case are identical to the brain stem injury experimentally produced by complete cardiac arrest in the rhesus monkey.

The present study examines the effects of auricular transcutaneous electrical nerve stimulation (TENS) on electrical pain threshold measured at the ipsilateral wrist and autonomic functions including skin temperature, blood pressure and pulse rate in 24 healthy subjects. TENS was administered as low frequency trains of pulses delivered at a 'strong but comfortable' intensity to 1 of 3 auricular points to be examined: (i) autonomic effects (autonomic point), (ii) pain threshold effects (wrist point), and (iii) placebo effects at an unrelated point (face point). A fourth untreated group was designated as a situation control. The main finding of the study was that auricular TENS produced no significant overall effects on experimental pain threshold or autonomic functions recorded under the present conditions. However, pain threshold was found to increase by over 50% of its pretreatment baseline in 4 subjects and by 30% in 6 subjects. This rise was not dependent upon the site of auricular TENS. The possible mechanisms of such changes are discussed.

This study records the consistency of transcutaneous electrical nerve stimulation (TENS) pulse frequency and pulse pattern used by 13 chronic patients over a 1 year period. The results show that patients prefer specific pulse frequencies and pulse patterns unique to the individual and that they turn to such frequencies and patterns on subsequent treatment sessions. Pulse frequencies and pulse patterns were not related to the cause and site of pain, a finding consistent with previous study in this laboratory. This observation, coupled with the large variability in pulse frequencies and pulse patterns used between individuals, implies that patients prefer such frequencies and patterns for reasons of comfort which may not be related to mechanisms specific to the pain system.

This in-depth study examines the relationships between patient, stimulator and outcome variables in a large number of chronic pain patients utilising TENS on a long-term basis. 179 patients completed a TENS questionnaire designed to record age, sex, cause and site of pain and TENS treatment regime. Of these 179 patients, 107 attended our research unit for assessment of the electrical characteristics of TENS during self-administered treatment. Although a remarkable lack of correlation between patient, stimulator and outcome variables was found to exist, the analysis revealed much information of importance: 47% of patients found TENS reduced their pain by more than half; TENS analgesia was rapid both in onset (less than 0.5 h in 75% patients) and in offset (less than 0.5 h in 51% patients); one-third of patients utilised TENS for over 61 h/week; pulse frequencies between 1 and 70 Hz were utilised by 75% of patients; 44% of patients benefitted from burst mode stimulation. The clinical implications of these findings are discussed.

The analgesic efficacy of various pulse patterns of transcutaneous electrical nerve stimulation (TENS) were assessed in 84 normal healthy subjects using the cold pressor pain technique. Burst, modulation, random and continuous TENS all significantly elevated ice pain threshold. Continuous (80 Hz) TENS produced the greatest mean elevation in threshold but the response to random TENS showed the least inter-subject variation. Ice pain tolerance was increased by all modes of TENS, continuous TENS producing the greatest magnitude of response, although these changes did not reach statistical significance. Increasing the size of electrodes reduced the effect of continuous TENS. The clinical implications of these findings are discussed.

Under certain culture conditions, neonatal rat superior cervical ganglion neurons display not only a number of expected adrenergic characteristics but, paradoxically, also certain cholinergic functions such as the development of hexamethonium-sensitive synaptic contacts and accumulation of choline acetyltransferase (ChAc). The purpose of this study was to determine whether the entire population of cultured neurons was aquiring cholinergic capabilities, or whether this phenomenon was restricted to a subpopulation. After 1--6 and 8 wk in culture, neurons were fixed in KMnO4 after incubation in norepinephrine and prepared for electron microscopy analysis of synaptic vesicle content to determine whether vesicles were dense cored or clear. ChAc, acetylcholinesterase (AChE), and DOPA-decarboxylase (DDC) activities were assayed in sister cultures. In the period from 1 to 8 wk in culture, the average ChAc activity per neuron increased 1,100-fold, and the DDC and AChE activities increased 20- and 30-fold, respectively. After 1 wk in culture, 48 of 50 synaptic boutons contained predominantly dense-cored vesicles, but by 8 wk the synaptic vesicle population was predominantly of the clear type. At intermediate times, the vesicle population in many boutons was mixed. The morphology of the synaptic contacts on neuronal surfaces was that characteristic of autonomic systems, with no definite clustering of the vesicles adjacent to the area of contact. Increased vesicle size correlated with increasing age in culture and the presence of a dense core. Considering these data along with available physiological studies, we conclude that these cultures contain one population of neurons that is initially adrenergic. Over time, under conditions of this culture system, this population develops cholinergic mechanisms. That a neuron may, at a given time, express both cholinergic and adrenergic mechanisms is suggested by the approximately equal numbers of clear and dense-cored vesicles in the boutons found at the intermediate times.

In an attempt to document progression rate differences in the development of glomerular lesions in mink infected with Aleutian disease virus (ADV), the glomeruli of Aleutian and non-Aleutian mink experimentally infected with ADV were evaluated by light, fluorescent, and electron microscopy. The animals were also examined for the presence of interstitial infiltrate, neutrophils, and arterial lesions. One hundred percent of the Aleutian mink had glomerular cell proliferation and interstitial infiltrate, while 95% of the Aleutian and 41% of the non-Aleutian mink had neutrophilic infiltrates and arteritis, respectively. Of the non-Aleutian mink, 91, 83, 42, and 12.5% had glomerular cell proliferations, glomerular neutrophils, interstitial infiltrate, and arterial lesions in, that order. All the Aleutian mink had glomerular depositions of gamma-globulin (IgG) and complement (C3), whereas 75% of non-Aleutian mink had deposits of IgG and C3. One hundred percent of both genotypes had glomerular deposits of immunoglobulin M (IgM). Ultrastructural glomerular changes consisting primarily of depositions of granular electron-dense material on basement membranes were observed in Aleutian mink 6 weeks after infection and 12 weeks after infection in non-Aleutian mink. These findings document progression rate differences in the development of glomerular lesions in Aleutian disease-affected Aleutian and non-Aleutian mink. Further, they emphasize the need for exploration of pathogenetic mechanisms involved in progression rate differences in lesion development.

To determine the relationship between growth cone structure and motility, we compared the neurite extension rate, the form of individual growth cones, and the organization of f-actin in embryonic (E21) and postnatal (P30) sympathetic neurons in culture. Neurites extended faster on laminin than on collagen, but the P30 nerites were less than half as long as E21 neurites on both substrata. Growth cone shape was classified into one of five categories, ranging from fully lamellipodial to blunt endings. The leading margins of lamellipodia advanced smoothly across the substratum ahead of any filopodial activity and contained meshworks of actin filaments with no linear f-actin bundles, indicating that filopodia need not underlie lamellipodia. Rapid translocation (averaging 0.9-1.4 microns/min) was correlated with the presence of lamellipodia; translocation associated with filopodia averaged only 0.3-0.5 microns/min. This relationship extended to growth cones on a branched neurite where the translocation of each growth cone was dependent on its shape. Growth cones with both filopodial and lamellipodial components moved at intermediate rates. The prevalence of lamellipodial growth cones depended on age of the neurites; early in culture, 70% of E21 growth cones were primarily lamellipodial compared to 38% of P30 growth cones. A high percentage of E21 lamellipodial growth cones were associated with rapid neurite elongation (1.2 mm/day), whereas a week later, only 16% were lamellipodial, and neurites extended at 0.5 mm/day. Age-related differences in neurite extension thus reflected the proportion of lamellipodial growth cones present rather than disparities in basic structure or in the rates at which growth cones of a given type moved at different ages. Filopodia and lamellipodia are each sufficient to advance the neurite margin; however, rapid extension of superior cervical ganglion neurites was supported by lamellipodia independent of filopodial activity.

Superior cervical ganglion (SCG) neurons taken from perinatal rats and dissociated in culture develop cholinergic properties. This report examines this "plasticity" of neurotransmitter function with regard to its dependence on the stage of neuronal development. Explants of SCG from rats ranging in age from 2 d to adult were cultured, and the number of neurons surviving after 6 wk in culture was evaluated. The activities of choline acetyltransferase (ChAc) and DOPA decarboxylase (DDC) were assayed for each age group over time in culture, and the cytochemistry of the synaptic vesicle population was studied after norepinephrine loading and KMnO4 fixation. The specific activity of ChAc in all explants fell during the first 3--4 d in culture (secondary to degeneration of presynaptic terminals), with an increase during the next 30 d in explants from all age groups except in those from the 22-d-old and adult rats. The highest activity found after 1 mo in culture was in explants from 2-d-old rats (62.5 mmol per kg dry wt per h); the lowest was in explants from adults (1.3 nmol per kg dry wt per h). After 1 mo in vitro, there were no significant differences in DDC activity among explants from animals of any age (similar to approximately 220 mmol per kg dry wt per h). Co-culture of the SCG explants with heart muscle increased even further the ChAc activity in explants from 2-d-old rats but not in explants from 16-d-old and 6.5-wk-old animals. The cytochemistry of the synaptic vesicle population in 1-mo-old cultures correlated well with the ChAc activity; when the ChAc activity was high, the proportion of synaptic vesicles with clear centers was 71--88%. In explants from adult animals, only 12% of the vesicles contained clear centers. From these data we conclude that the maturity of the SCG neuron influences the degree to which it is able to adjust its neurotransmitter mechanisms. That the axons of this neuron are interacting with target tissues during the time that neurotransmitter plasticity is retained suggests that interaction with the target may play a role in the determination of transmitter type.

The extension of filopodia from growth cones of regenerating neurites from rat superior cervical ganglion neurons in tissue culture was studied. Cultures were grown on a thin layer of fibrous collagen and maintained in a medium containing serum and nerve growth factor. Time-lapse cinematography and computer-assisted morphometry were used to observe and measure the kinetics of extension of individual filopodia. Filopodia extended from the growth cone margin, trailing neurite, or from each other. Frequently, extension was preceded by the appearance at the cone margin of a nodule of cytoplasm which appeared dense in phase-contrast optics. Branch points between adjacent extending filopodia remained fixed with respect to the growth cone while the filopodia lengthened. The rate of extension was maximum just after initiation (0.12 +/- 0.4 micron/sec; mean +/- SD; n = 36) and declined thereafter until the filopodium collapsed. This initial rate of extension was directly correlated with the eventual length of the filopodium (r = 0.67). Filopodia of growth cones arising from embryonic neurons exhibited higher initial extension rates (range: 0.07 to 0.20 micron/sec; mean = 0.13 micron/sec) than those of postnatal neurons (range: 0.01 to 0.13 micron/sec; mean = 0.09 micron/sec). These data are discussed in relation to a model proposed by Tilney and Inoue [1982] for the extension, by distal addition of G-actin to growing filaments, of another type of elongating process filled with microfilaments, the acrosomal process of Thyone sperm.

Studies on cellular interactions in the developing nervous system are greatly facilitated by the availability of tissue culture preparations that contain single or combined populations of neurons and non-neuronal cells (NNCs). Using superior cervical ganglia (SCG) from early E15 rats on air-dried collagen, we were able to prepare cultures containing neurons along with Schwann cells (SCs) as the only NNC type present without the use of antimitotic treatment and cultures containing only neurons, following brief antimitotic treatment. Light-microscopic observation of E15 outgrowth showed a uniform population of flattened cells, unlike that of E20 cultures, which contained a mixture of spindle-shaped and flattened cells. Autoradiograms following [3H]thymidine administration to E15 cultures revealed a striking gradient of nuclear labeling: Only a few cells were labeled near the explant and nearly all cells were labeled at the growth front. This was in marked contrast to E20 cultures, in which nuclei were labeled throughout the outgrowth. The conclusion that the labeling gradient is explained by the presence of SCs without other NNC types in E15 cultures was confirmed by immunocytochemical studies. Anti-laminin antibodies stain only those extracellular matrix components related to the SC surface, whereas anti-fibronectin antibodies stain fibroblast-related components (Cornbrooks et al., 1983a). Anti-laminin antibodies stained cell surfaces in both E15 and E20 outgrowth. E15 outgrowth did not stain with anti-fibronectin antibodies although marked staining was obtained in E20 cultures. Electron microscopy confirmed the presence of only SCs in E15, and of both SCs and fibroblasts in E20 outgrowth. Thus, it appears that there is a narrow developmental window in which the ganglia contain neurons and SCs but relatively few fibroblast components; cultures prepared from ganglia at this stage form outgrowth containing only neurites and SCs without antimitotic treatment. Surprisingly, neither SC ensheathment nor SC basal lamina formation was normal in E15 and E20 outgrowth. When either E15 or E20 SCG SCs were transplanted onto dorsal root ganglion neurons free of endogenous SCs, however, the sensory neurites were typically ensheathed or myelinated and basal lamina appeared 9 d later, identifying the SCG NNCs as functionally competent SCs.(ABSTRACT TRUNCATED AT 400 WORDS)

Analysis of breeding data revealed that the muscular dystrophy trait in a pedigree of mink is transmitted in an autosomal recessive manner. Variation in skeletal muscle fiber diameter size is the most pronounced and consistent change in the dystrophic mink. Other changes include centralization of nuclei, degenerative change, increase in endomysial and perimysial connective tissue, and regenerative attempts. These changes are not present in known heterozygotes.

We compared the ability of prenatal and postnatal rat sympathetic neurons to form dendrites in tissue culture. Dendrites were distinguished from axons by light microscopic criteria after intracellular dye injection and by differential immunostaining with antibodies to microtubule-associated protein-2 and to both non-phosphorylated and phosphorylated forms of the M and H neurofilament subunits. When maintained in the absence of serum and non-neuronal cells, most (72%) prenatal neurons were unipolar and had only an axon. In contrast, most (89%) neurons derived from postnatal ganglia were multipolar and extended both axons and dendrites. The dendritic morphology of postnatal neurons was usually simple with cells commonly having 2-5 short (50-200 microns), relatively unbranched dendrites. Thus, as the development of the dendritic arbor progresses in situ, sympathetic neurons acquire an enhanced ability to extend dendrites in tissue culture. To determine whether changes in the capacity to develop dendrites might occur with aging in vitro, ganglia were removed from prenatal rats and grown as explants for 3 weeks in the presence of non-neuronal cells; under these conditions, prenatal neurons within the explant became multipolar. When neurons derived from aged explants were subsequently maintained in dissociated cell culture, most formed dendrites. In cultures treated with an antimitotic agent, neurons typically had 1-4 unbranched dendrites; greater amounts of dendritic growth occurred in cultures in which ganglionic non-neuronal cells were allowed to proliferate. We conclude that: (1) the acquisition of the capacity to form dendrites in dissociated cell culture does not require either normal afferent input or physical contact with the target tissue; and (2) even after aging in vitro, sympathetic neurons remain responsive to the dendrite-promoting activity of ganglionic non-neuronal cells.

Cultures of dissociated rat superior cervical ganglion neurons (SCGN) were treated with the sympatholytic agent, guanethidine. When treated within the first couple of weeks in vitro, the neurons were rapidly destroyed. The cells grew less susceptible to the toxic effects of guanethidine with age in vitro. Moreover, the apparent affinity, Km, of the transport molecule for norepinephrine (NE) and guanethidine remained essentially unchanged between 2 and 7 wk in culture, as did the maximum velocity of transport (Vmax). This is at a time when previous studies have shown these neurons to be using acetylcholine (ACh) as their neurotransmitter. Cultures which were grown without supporting cells and from which cholinergic synaptic interactions were recorded physiologically were processed for autoradiography after incubation with [3H]NE. All cell bodies and processes seen had silver grains accumulated over them. These experiments show that sympathetic neurons in vitro maintain their amine uptake system relatively unchanged, even though they use ACh as their transmitter. The implications of these findings are discussed.

Neurites of superior cervical ganglion neurons from embryonic, perinatal, and adult rats extended at different rates when placed in tissue culture on similar collagen substrata. Using high resolution cinematography and a time-lapse video recording system, we concluded that these differences arise from variations in individual growth cone behavior. Growth cones of embryonic and perinatal neuronal origin exhibited high peak rates of advance and filopodial and lamellipodial excresences. Perinatal cones differed from embryonic ones in that they were somewhat larger, advanced in straighter paths, and retracted less, consequently translocating at 14 to 29 microns/hr compared with 8 to 22 microns/hr for embryonic cones (ranges of 4-hr means). The growth cones of neurons obtained from adult rats had scant cytoplasm and short branched filopodia, lacked definitive lamellipodia, and traversed the terrain at 4 to 13 microns/hr due to lack of high peak rates of advance and more time spent in stationary or minimal advance phases. Periodic pauses lasting 10 to 20 min, occurring every 20 to 90 min, interrupted the forward advance of growth cones of all ages. During pauses or slow forward movement, the growth cone displayed numerous filopodia whereas, during brief episodes when embryonic and perinatal growth cones moved at peak rates of 200 microns/hr or more, the cone periphery was predominantly lamellipodial. We conclude that the predominance of a lamellipodial or filopodial conformation correlates with the rate of growth cone advance and that age-dependent variations in neurite extension rates are related to differences in growth cone form and pattern of translocation. This is the first documentation of differing behavior of single growth cones of neurons of varying developmental ages in culture.