Case series of non-freezing cold injury: the modern clinical syndrome.

BACKGROUND: Non-freezing cold injury (NFCI) occurs when peripheral tissue is damaged by cold exposure but not to the extent of freezing. Historically, the phenotype of NFCIs sustained was severe, whereas today the spectrum of injury represented in the UK military predominantly comprises subtler injuries. The diagnostic challenge of recognising these injuries, both in the acute and chronic settings, can lead to mismanagement and subsequent morbidity. METHODS: We characterised a recent case series of 100 UK Service Personnel referred with suspected NFCI to a Military UK NFCI clinic. We characterised the acute and chronic phenotype of those diagnosed with NFCI (n=76) and made comparison to those who received alternate diagnoses (n=24), to find discriminatory symptoms and signs. RESULTS: The most common acute symptoms of NFCI were the extremities becoming cold to the point of loss of feeling for more than 30 min (sensitivity 96%, specificity 90%, p<0.001), followed by a period of painful rewarming (sensitivity 81%, specificity 67%, p<0.001). In-field foot/hand inspections took place in half of the NFCI cases. Importantly, remaining in the field and undergoing multiple cycles of cooling and rewarming after an initial NFCI was associated with having double the risk of the NFCI persisting for more than a week. The most common and discriminant chronic symptoms and signs of NFCI were having extremities that behave differently during cold exposures (sensitivity 81%, specificity 75%, p<0.001) and having abnormal pinprick sensation in the affected extremity (sensitivity 88%, specificity 88%, p<0.001). CONCLUSIONS: A small collection of symptoms and signs characterise acute and chronic NFCIs and distinguish this vasoneuropathy from NFCI mimics.

Case series of non-freezing cold injury: epidemiology and risk factors.

BACKGROUND: Non-freezing cold injury (NFCI) occurs when the peripheral tissue is cooled sufficiently that damage occurs, but not to the point of tissue freezing. Historically, the phenotype of the injuries studied was often severe, and it is unclear whether knowledge gained from these cases is entirely relevant to the frequently subtle injuries seen today. METHODS: We therefore sought to characterise a recent case series of 100 patients referred with suspected NFCI to a military UK NFCI clinic. Their demographics, medical history and situational risk factors leading to their injuries were analysed, and comparison was made between those subsequently diagnosed with NFCI (n=76) and those receiving alternate diagnoses (n=24). RESULTS: Statistically significant predisposing factors for NFCI in the UK service personnel (SP) were being of African-Caribbean ethnicity and having a short duration of service in the Armed Forces. Past or current smoking was not identified as a risk factor. Injuries were almost always suffered on training exercises (most commonly in the UK); being generally cold and being on static duties were statistically significant situational risk factors. Non-significant trends of risk were also found for having wet clothing, wet boots and immersion. Self-reported dehydration was not found to be a risk factor for NFCI. CONCLUSIONS: Our demographic findings are in general agreement with those of previous studies. Our situational risk factor findings, however, highlight a pattern of NFCI risk factors to the modern UK SP: winter training exercises, when troops are generally cold and extremities often wet, with static duties frequently implicated in the disease mechanism.

Young Children's Structure Production: A Revision of the Index of Productive Syntax.

Purpose: The Index of Productive Syntax (IPSyn; Scarborough, 1990) is widely used to measure syntax production in young children. The goal of this article is to promote greater clarity and consistency in machine and hand scoring by presenting a revised version of the IPSyn (IPSyn-R) and comparing it with the original IPSyn (IPSyn-O). Method: Longitudinal syntax production in 10 30- and 42-month-old typically developing children drawn from the Child Language Data Exchange System (MacWhinney, 2000) Weismer corpus was examined, using both the IPSyn-O and the IPSyn-R. Results: The IPSyn-R provided nearly identical scores to the IPSyn-O with the exception of scores affected primarily by 1 modified noun phrase structure. Structures ranked as more advanced were produced less frequently. The results also reveal which of the IPSyn-R's 59 structures were most and least likely to be produced by this sample at these ages. Conclusions: The qualitative and quantitative differences between the IPSyn-O and the IPSyn-R are relatively minor. The IPSyn-R can make it easier to score the IPSyn, both by clinicians and researchers, and facilitate the IPSyn's move to machine scoring of language samples.

Dyslipidaemia and the military patient.

Dyslipidaemias refer to abnormal levels of circulating lipids and high cholesterol and is related to cardiovascular death. This paper examines the types and prevalence of dyslipidaemia with specific reference to a military population and describes who to target in screening strategies used to detect people with abnormal lipid profiles. The diagnostic limits for a diagnosis of dyslipidaemia are explored. Finally, medical management of hyperlipidaemia is discussed and how this may affect military medical grading.

Synthesis and SAR of geminal substitutions at the C5' carbosugar position of pyrimidine-derived HCV inhibitors.

The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.

Synthesis and SAR of pyridothiazole substituted pyrimidine derived HCV replication inhibitors.

Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.

Pyridofuran substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.

Neural circuitry associated with two different approaches to novel word learning.

Skilled reading depends upon successfully integrating orthographic, phonological, and semantic information; however, the process of becoming a skilled reader with efficient neural circuitry is not fully understood. Short-term learning paradigms can provide insight into learning mechanisms by revealing differential responses to training approaches. To date, neuroimaging studies have primarily focused on effects of teaching novel words either in isolation or in context, without directly comparing the two. The current study compared the behavioral and neurobiological effects of learning novel pseudowords (i.e., pronouncing and attaching meaning) trained either in isolation or in sentential context. Behavioral results showed generally comparable pseudoword learning for both conditions, but sentential context-trained pseudowords were spoken and comprehended slightly more quickly. Neurobiologically, fMRI activity for reading trained pseudowords was similar to real words; however, an interaction between training approach and reading proficiency was observed. Specifically, highly skilled readers showed similar levels of activity regardless of training approach. However, less skilled readers differentiated between training conditions, showing comparable activity to highly skilled readers only for isolation-trained pseudowords. Overall, behavioral and neurobiological findings suggest that training approach may affect rate of learning and neural circuitry, and that less skilled readers may need explicit training to develop optimal neural pathways.

5-Benzothiazole substituted pyrimidine derivatives as HCV replication (replicase) inhibitors.

Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.

Novel substituted pyrimidines as HCV replication (replicase) inhibitors.

Compound 1 was identified as a HCV replication inhibitor from screening/early SAR triage. Potency improvement was achieved via modulation of substituent on the 5-azo linkage. Due to potential toxicological concern, the 5-azo linkage was replaced with 5-alkenyl or 5-alkynyl moiety. Analogs containing the 5-alkynyl linkage were found to be potent inhibitors of HCV replication. Further evaluation identified compounds 53 and 63 with good overall profile, in terms of replicon potency, selectivity and in vivo characteristics. Initial target engagement studies suggest that these novel carbanucleoside-like derivatives may inhibit the HCV replication complex (replicase).

Management of malignant (necrotising) otitis externa.

Although malignant (necrotising) otitis externa is not a common diagnosis, there have been a number of recently reported cases with pathogens other than Pseudomonas aeruginosa as the causative organism. In addition, there are many published reports of resistance to antibiotics in cases of malignant otitis externa caused by Pseudomonas aeruginosa. This review aims to assess the cases reported and to clarify the current opinion on the diagnostic criteria and management of such cases.

Relative Effectiveness of Reading Intervention Programs for Adults with Low Literacy.

To compare the efficacy of instructional programs for adult learners with basic reading skills below the seventh grade level, 300 adults were randomly assigned to one of three supplementary tutoring programs designed to strengthen decoding and fluency skills, and gains were examined for the 148 adult students who completed the program. The three intervention programs were based on or adapted from instructional programs that have been shown to benefit children with reading levels similar to those of the adult sample. Each program varied in its relative emphasis on basic decoding versus reading fluency instruction. A repeated measures MANOVA confirmed small to moderate reading gains from pre- to post-testing across a battery of targeted reading measures, but no significant relative differences across interventions. An additional 152 participants who failed to complete the intervention differed initially from those who persisted. Implications for future research and adult literacy instruction are discussed.

International albumin use: 1995 to 2006.

Over the last ten years more reliable information regarding the risks and benefits of the use of albumin for fluid resuscitation has emerged. To determine what influence this has had on clinical practice, we sought to document albumin use (from mass of albumin supplied to hospitals) in 16 industrialised countries between 1995 and 2006. Data on national albumin and synthetic colloid use was sought from independent intensive care researchers and albumin issuers. The mass of albumin supplied per 10,000 persons on an annual basis by country and aggregated across the study countries was calculated. Volumes of synthetic colloid supplied per 10,000 persons were calculated. Data were obtained for 15 countries. Albumin use varied significantly between countries and throughout the observation period. Overall, aggregate albumin use decreased from a peak of 2.54 kg per 10,000 persons in 1995 to 1.40 kg per 10,000 persons in 1999; use has remained relatively constant since. Data on supply of synthetic colloids was available in only three countries and varied from 11.7 litres per 10,000 persons in Canada in 1995, to 231.8 litres per 10,000 persons in Denmark in 2004. Between 1995 and 1999 albumin use decreased and has been materially constant since; where data were available, use of synthetic colloids increased. Whether these practice changes have resulted in a net health gain or in harm requires further research.

Relationships among reading skills of adults with low literacy.

In this study, confirmatory factor analyses were used to examine the interrelationships among latent factors of the simple view model of reading comprehension (word recognition and language comprehension) and hypothesized additional factors (vocabulary and reading fluency) in a sample of 476 adult learners with low literacy levels. The results provided evidence for reliable distinctions between word recognition, fluency, language comprehension, and vocabulary skills as components of reading. Even so, the data did not support the hypothesis that the simple view needs to be expanded to include vocabulary or fluency factors, as has been posited in a few prior studies of younger and more able readers. Rather, word recognition and language comprehension alone were found to account adequately for variation in reading comprehension in adults with low literacy.

Topical treatments for fungal infections of the skin and nails of the foot.

BACKGROUND: Fungal infections of the feet normally occur in the outermost layer of the skin (epidermis). The skin between the toes is a frequent site of infection which can cause pain and itchiness. Fungal infections of the nail (onychomycosis) can affect the entire nail plate. OBJECTIVES: To assess the effects of topical treatments in successfully treating (rate of treatment failure) fungal infections of the skin of the feet and toenails and in preventing recurrence. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (January 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE and EMBASE (from inception to January 2005). We screened the Science Citation Index, BIOSIS, CAB - Health and Healthstar, CINAHL DARE, NHS Economic Evaluation Database and EconLit (March 2005). Bibliographies were searched. SELECTION CRITERIA: Randomised controlled trials (RCTs) using participants who had mycologically diagnosed fungal infections of the skin and nails of the foot. DATA COLLECTION AND ANALYSIS: Two authors independently summarised the included trials and appraised their quality of reporting using a structured data extraction tool. MAIN RESULTS: Of the 144 identified papers, 67 trials met the inclusion criteria. Placebo-controlled trials yielded the following pooled risk ratios (RR) of treatment failure for skin infections: allylamines RR 0.33 (95% CI 0.24 to 0.44); azoles RR 0.30 (95% CI 0.20 to 0.45); ciclopiroxolamine RR 0.27 (95% CI 0.11 to 0.66); tolnaftate RR 0.19 (95% CI 0.08 to 0.44); butenafine RR 0.33 (95% CI 0.24 to 0.45); undecanoates RR 0.29 (95% CI 0.12 - 0.70). Meta-analysis of 11 trials comparing allylamines and azoles showed a risk ratio of treatment failure RR 0.63 (95% CI 0.42 to 0.94) in favour of allylamines. Evidence for the management of topical treatments for infections of the toenails is sparser. There is some evidence that ciclopiroxolamine and butenafine are both effective but they both need to be applied daily for prolonged periods (at least 1 year). The 6 trials of nail infections provided evidence that topical ciclopiroxolamine has poor cure rates and that amorolfine might be substantially more effective but more research is required. AUTHORS' CONCLUSIONS: Placebo-controlled trials of allylamines and azoles for athlete's foot consistently produce much higher percentages of cure than placebo. Allylamines cure slightly more infections than azoles and are now available OTC. Further research into the effectiveness of antifungal agents for nail infections is required.

A randomized controlled trial comparing the accuracy of general diagnostic upper gastrointestinal endoscopy performed by nurse or medical endoscopists.

BACKGROUND AND STUDY AIMS: Rising demand for general diagnostic upper gastrointestinal endoscopy in the UK is outgrowing the capacity of doctors to provide this service within a reasonable time. One solution is to train nurses to carry out the procedure, but it is not known whether nurses can perform general diagnostic upper gastrointestinal endoscopy as competently as doctors. PATIENTS AND METHODS: A randomized controlled non-inferiority trial compared the adequacy and the accuracy of diagnostic upper gastrointestinal endoscopies performed by five medical and two nurse endoscopists. The videotaped procedures were assessed by a consultant gastroenterologist blinded to the identity of the endoscopist. RESULTS: 641 patients were randomly allocated (before attendance and consent procedure) to endoscopy carried out either by a doctor or a nurse. Of these, 412 were enrolled and 367 (89 %) were included in the analysis. An adequate view was obtained throughout in 53.4 % (93/177) of doctor endoscopies and 91.6 % (174/190) of nurse endoscopies (difference 38.2 %, 95 % CL 30.5 %, 47.2 %). In adequately viewed areas, the mean agreement between doctor and expert was 81.0 % and between nurse and expert it was 78.3 % (difference between the means 2.7 %, 95 % CL - 1.0 %, 6.4 %). There was no difference between doctors and nurses in the rate of biopsy performance (90.4 % and 91.1 %, respectively, P = 0.862). Nurses took longer (8.1 minutes vs. 4.6 minutes, P < 0.001) and used intravenous sedation more often (57.6 %, P = 0.027). Adequacy of view correlated positively with endoscopy duration ( P < 0.001), but diagnostic accuracy correlated inversely with duration ( P < 0.001). Neither adequacy or accuracy correlated significantly with use of intravenous sedation. CONCLUSIONS: In endoscopies performed by nurses, the proportion of adequate examinations was much higher than that found for doctors. In areas with an adequate view, there is no significant difference in accuracy between nurses and doctors. Nurses can provide an accurate general diagnostic upper gastrointestinal endoscopy service as competently as doctors.

Identification, preparation, and characterization of several polymorphs and solvates of terazosin hydrochloride.

The phenomenon of polymorphism is prevalent in pharmaceuticals, yet it is unusual to identify more than three or four forms for any particular drug. Terazosin hydrochloride has been found to exist at room temperature in four solvent-free forms that can be isolated directly, one solvent-free form that can be prepared by desolvation of a methanolate, a methanol solvate, and a dihydrate. This study presents characterization and methods for preparation of each of these forms. Data are also presented demonstrating the relative stability of these forms.

Interventions for chronic palmoplantar pustulosis.

BACKGROUND: Chronic palmoplantar pustulosis (PPP) is a chronic inflammatory skin condition characterised by crops of sterile pustules (yellow pus spots) on the palms and soles which erupt repeatedly over months or years. The affected areas tend to become red and scaly; cracks may form and these are often painful. Many different treatments have been used for palmoplantar pustulosis but none is generally accepted as being reliably effective. OBJECTIVES: To assess the effects of treatments for palmoplantar pustulosis, both in reducing disease severity and in maintaining remission once achieved. SEARCH STRATEGY: We searched the Cochrane Skin Group Specialised Register (January 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2003), MEDLINE (1966 to February 2003), EMBASE (1988 to February 2003). We also cross-checked with the Salford Database of Psoriasis Trials and reference lists of articles. We also contacted authors included trials, members of the Cochrane Skin Group and dermatologists interested in psoriasis. SELECTION CRITERIA: Any randomised controlled trial in which patients with chronic palmoplantar pustulosis were randomised to receive one or more interventions. DATA COLLECTION AND ANALYSIS: At least two reviewers independently assessed trial eligibility and quality. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: Twenty-three trials involving 724 people were included. There is evidence supporting the use of systemic retinoids (improvement rate difference 44%, 95 CI 28 to 59%), oral PUVA (improvement rate difference 44%, 95 CI 26 to 62%). However, a combination of PUVA and retinoids is better than the individual treatments. The use of topical steroid under hydrocolloid occlusion is beneficial. It would also appear that low dose ciclosporin, tetracycline antibiotics and Grenz Ray Therapy may be useful in treating PPP. Colchicine has a lot of side effects and it is unclear if it is effective and neither was topical PUVA (rate difference of 0.00, 95% CI -0.04 to +0.04). There is no evidence to suggest that short-term treatment with hydroxycarbamide (hydroxyurea) is effective. AUTHORS' CONCLUSIONS: Many different interventions were reported to produce "improvement" in PPP. There is, however, no standardised method for assessing response to treatment, and reductions in pustule counts or other empirical semi-quantitative scoring systems may be of little relevance to the patient. This review has shown that the ideal treatment for PPP remains elusive and that the standards of study design and reporting need to be improved to inform patients and those treating them of the relative merits of the many treatments available to them.

Interventions for bullous pemphigoid.

BACKGROUND: Bullous pemphigoid is the most common autoimmune bullous disease in the West. Oral steroids are considered the standard treatment. OBJECTIVES: To assess the effects of treatments for bullous pemphigoid. SEARCH STRATEGY: We searched the Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE to March 2003 and bibliographies from identified studies. SELECTION CRITERIA: Randomised controlled trials of treatments for patients with immunofluorescence confirmed bullous pemphigoid. DATA COLLECTION AND ANALYSIS: Two reviewers evaluated the studies in terms of the inclusion criteria, five extracted data independently; disagreements were resolved by discussion. Statistical pooling of the data was inappropriate because of heterogeneity of treatments. MAIN RESULTS: We found seven randomised controlled trials with a total of 634 patients. All studies involved different comparisons, none included a placebo group. Different doses, different formulations of corticosteroids and the addition of azathioprine failed to show significant differences in measures of disease control. However, patients who took azathioprine were able to almost halve the amount of prednisone required for disease control. Plasma exchange plus prednisone achieved significantly better disease control than prednisone alone; this favourable effect was not apparent in another study. The latter study also compared plasma exchange or azathioprine plus prednisone, but failed to show significant differences for disease control or mortality, although total adverse events at six months almost reached statistical significance in favour of plasma exchange plus prednisone. Comparing tetracycline plus nicotinamide with prednisolone, no significant difference for disease response was shown. A very potent topical corticosteroid was compared to oral prednisone in patients with moderate and extensive disease. In patients with extensive disease, the topical steroid group showed significantly better survival and disease control, and less severe complications, while no significant differences for these outcomes were seen in patients with moderate disease. Most of the reported deaths were in patients taking high doses of oral corticosteroids. AUTHORS' CONCLUSIONS: Very potent topical steroids are effective and safe treatments for bullous pemphigoid; their use in extensive disease may be limited by side effects and practical factors. Starting doses of prednisolone greater than 0.75 mg/kg/day do not seem to give additional benefit, lower doses may be adequate for disease control; this could reduce the incidence and severity of adverse reactions. The effectiveness of the addition of plasma exchange or azathioprine to corticosteroids has not been established. Combination treatment with tetracycline and nicotinamide may be useful; this needs further validation.