Training and accrediting international surgeons.

BACKGROUND: Formal international medical programmes (IMPs) represent an evolution away from traditional medical volunteerism, and are based on the foundation of bidirectional exchange of knowledge, experience and organizational expertise. The intent is to develop multidirectional collaborations and local capacity that is resilient in the face of limited resources. Training and accreditation of surgeons continues to be a challenge to IMPs, including the need for mutual recognition of competencies and professional certification. METHODS: MEDLINE, Embase and Google Scholar™ were searched using the following terms, alone and in combination: 'credentialing', 'education', 'global surgery', 'international medicine', 'international surgery' and 'training'. Secondary references cited by original sources were also included. The authors, all members of the American College of Academic International Medicine group, agreed advice on training and accreditation of international surgeons. RESULTS AND CONCLUSION: The following are key elements of training and accrediting international surgeons: basic framework built upon a bidirectional approach; consideration of both high-income and low- and middle-income country perspectives; sourcing funding from current sources based on existing IMPs and networks of IMPs; emphasis on predetermined cultural competencies and a common set of core surgical skills; a decentralized global system for verification and mutual recognition of medical training and certification. The global medical system of the future will require the assurance of high standards for surgical education, training and accreditation.

Traumatic wound microbiome workshop.

On May 9-10, 2011, the Walter Reed Army Institute of Research, as the Army Center of Excellence for Infectious Disease, assembled over a dozen leaders in areas related to research into the communities of microorganisms which colonize and infect traumatic wounds. The objectives of the workshop were to obtain guidance for government researchers, to spur research community involvement in the field of traumatic wound research informed by a microbiome perspective, and to spark collaborative efforts serving the Wounded Warriors and similarly wounded civilians. During the discussions, it was made clear that the complexity of these infections will only be met by developing a new art of clinical practice that engages the numerous microbes and their ecology. It requires the support of dedicated laboratories and technologists who advance research methods such as community sequencing, as well as the kinds of data analysis expertise and facilities. These strategies already appear to be bearing fruit in the clinical management of chronic wounds. There are now funding announcements and programs supporting this area of research open to extramural collaborators.

Factors affecting patient flow in a neurosurgery department.

INTRODUCTION: Patient flow is the process by which movement of patients and clinical productivity is achieved. The objectives of this study were to implement and evaluate the NHS Improvement SAFER patient flow bundle, evaluate the impact of the Red2Green initiative, and assess the impact of frailty on patient flow. MATERIALS AND METHODS: All patients admitted to a neurosurgery unit from 1 September to 30 November 2017 were included. Using guidance set out by NHS, data were prospectively collected from daily ward lists and patient notes, including demographics, admission and discharge details, length of stay, anticipated discharge date, red days with reasons and frailty (Rockwood Clinical Frailty Scale). NHS reference costs were used for cost analyses. RESULTS: A total of 420 patients (55% elective) were included, totalling 3909 bed days. All patients received daily senior reviews before midday, and anticipated discharge dates were set at daily multidisciplinary team meetings. Ten per cent of patients were discharged before midday. There were 21% (837) red days, significantly more (76%) for emergency patients (639 vs 198 elective; P < 0.001); 63% red days were attributed to awaiting a bed in a local hospital; 25% (106) patients were classed as frail (50 elective), which was associated with a significantly longer length of stay (17.3 vs 6; P < 0.01), and more red days (615 vs 222; p<0.01). Considering excess bed charges and lost revenue (with penalties), red days cost over £1 million per year. CONCLUSIONS: SAFER has identified areas for improvement in patient flow, with obvious cost implications. It has created a platform for discussion within the referral network and identified a role for a geriatric liaison service.

Serum-induced macrophage activation is related to the severity of septic shock.

BACKGROUND: It seems that a balance between anti and pro-inflammatory responses must be kept to eliminate the pathogen without inducing inflammatory damage in the host. Thus we determined the relation between macrophage activation and the severity and clinical outcome in septic patients. MATERIAL AND METHODS: This was a prospective study at a tertiary general intensive care unit. Thirty-three patients admitted with sepsis, severe sepsis or septic shock were included. As a control group, healthy volunteers were included matched to septic patients by age and sex. Peritoneal rat macrophages were cultured with 2% serum from healthy volunteers or from septic patients for determination of phagocytic potential or the capacity to produce cytokines. RESULTS: TNF and IL1 secretion by macrophages activated with serum from sepsis and severe sepsis patients was higher than with serum from healthy controls. In addition, proinflammatory cytokines released in vitro from macrophages, but not determined directly in the serum from patients, were lower in non-survivor septic patients when compared to survivors. In contrast, IL-10 secretion by macrophages activated with serum from septic patients was higher in nonsurvivors. In the septic shock group we observed a diminution in the phagocytic index compared to sepsis and severe sepsis groups, and the phagocytic index was higher in sepsis survivors. CONCLUSIONS: Markers of antiinflammation are predominant in more severe types of sepsis suggesting that antiinflammation is related to mortality.

Long-term therapy with low-dose isotretinoin for prevention of basal cell carcinoma: a multicenter clinical trial. Isotretinoin-Basal Cell Carcinoma Study Group.

BACKGROUND: High-dose isotretinoin has been reported to have a prophylactic effect on nonmelanoma skin cancer, although it is associated with significant toxicity. PURPOSE: To test the effectiveness of the long-term administration of low-dose isotretinoin in reducing the occurrence of basal cell carcinoma at a new site in patients with previously treated basal cell carcinomas and to measure the toxicity associated with this regimen, we conducted a clinical trial at eight cancer centers. METHODS: Nine hundred and eighty-one patients with two or more previously confirmed basal cell carcinomas were randomly assigned to receive either 10 mg of isotretinoin or a placebo daily. Patients were followed for 36 months and monitored at 6-month intervals for skin cancer and toxic effects. RESULTS: After 36 months of treatment, no statistically significant difference in either the cumulative percent of patients with an occurrence of basal cell carcinoma at a new site or the annual rate of basal cell carcinoma formation existed between patients receiving isotretinoin and those receiving the placebo. Elevated serum triglycerides, hyperostotic axial skeletal changes, and mucocutaneous reactions were more frequent in the group receiving isotretinoin than in the control group, and these differences were all statistically significant (P less than .001). CONCLUSION: This low-dose regimen of isotretinoin not only is ineffective in reducing the occurrence of basal cell carcinoma at new sites in patients with two or more previously treated basal cell carcinomas but also is associated with significant adverse systemic effects. IMPLICATION: The toxicity associated with the long-term administration of isotretinoin, even at the low dose used in this trial, must be weighted in planning future prevention trials.

Characterization of the NIST seaweed Standard Reference Material.

The National Institute of Standards and Technology (NIST) Standard Reference Material (SRM) for seaweed was developed through an interlaboratory comparison with 24 participants from 16 countries. After evaluating different techniques to calculate certified values for the radionuclides, the median method was found to be the most representative technique. The certified values were provided for 13 radionuclides and information values were given for 15 more radionuclides. Results for the natural decay series showed disequilibrium in both the uranium and thorium series.

Survival of patients receiving a liver transplant for hepatocellular carcinoma, and risk of tumor recurrence.

OBJECTIVE: The goal of this research has been to evaluate the survival, in long and short term, of the patient receiving liver transplant for hepatocellular carcinoma (HCC), the risk of post-transplant tumor relapse and factors related to this complication. DESIGN: Retrospective study of a consecutive series of patients having had liver transplant for HCC. PATIENTS AND METHODOLOGY: Transplant patients for HCC from 1989 to November 2003. Patients were selected due to general limitations of nodule size and quantity, which were subsequently published as Milan criteria. Also, criteria agreed in the Conference of Barcelona were followed in the pre-transplant diagnosis. RESULTS: The survival of this 81 patients group was of the 80, 61 and 52% for 1, 5 and 10 years respectively. In the 32% of the cases the HCC was an incidental finding in the explant. In the 12.3%, the tumor relapse was verified. The multivariate research identified the size of the nodule (OR=1,7944) (IC 95%=1,1332-2,8413) and the vascular invasion (OR=6,6346) (IC 95%=1,4624-30,1003) as risk factors of relapse. CONCLUSIONS: The liver transplant in selected patients with HCC has good results in medium and long term. The risk of post-transplant tumor relapse becomes notably reduced and is associated with the size of the nodule and the microscopic vascular invasion.

Double-blind evaluation of efficacy and tolerability of metformin in NIDDM.

OBJECTIVE: To test the efficacy and tolerability of metformin. RESEARCH DESIGN AND METHODS: An 8-mo double-blind placebo-controlled parallel-group trial was performed at University hospital diabetic clinics on 60 patients with non-insulin-dependent diabetes mellitus (NIDDM) treated by diet alone. Metformin was administered and built up to a maximum dosage of 1 g three times daily. RESULTS: Mean HbA1 fell from 11.7 +/- 0.4 to 10.3 +/- 0.4% (means +/- SE) on metformin but rose from 11.8 +/- 0.4 to 13.3 +/- 0.4% on placebo (P less than 0.001). Final mean fasting blood glucose was 5.1 mM lower with metformin than placebo (P less than 0.001). No other biochemical variable differed significantly, and weight did not change. A favorable glycemic response was not restricted to the obese. The mean final dosage of metformin was 1.7 +/- 0.1 g and was well tolerated. CONCLUSIONS: Metformin achieved a 23% lower mean HbA1 than placebo without weight gain or significant unwanted effects.

Effects of retinoic acid on embryonic chick skin.

The influence of vitamin A on differentiating epithelia was examined in explants of skin from 14-day chick embryos exposed to retinoic acid (RA) in low, moderate, and high doses. The changes observed in RA-treated cultures are both dose- and time-dependent and are reversible when explants are transferred to control medium. The periderm sloughs prematurely and horizontal stratification is lost. Keratinization is inhibited and fewer desmosomes and tonofilaments are seen. Surface epidermal cells develop microvilli, bulge upwards, and detach. Golgi elements, rough endoplasmic reticulum, and polyribosomes are unusually prominent. Mucin granules form and gland-like structures develop with intercellular canaliculi characterized by tight junctions, brush borders, and dense secretory contents. On the basis of present evidence there are several possible mechanisms by which RA could alter epidermal differentiation. RA-induced gaps in the basal lamina allow direct contact between epidermal basal cells and fibroblasts and collagen fibers which could result in inappropriate dermal signals reaching the epidermis. In younger embryos the entire epidermis, including the mitotically inactive surface cells, appears to respond to RA, and this could imply an epigenetic modulation of cell phenotype. Finally, after the formation of a stratum corneum in older embryos only the relatively undifferentiated basal layer shows a metaplastic response, indicating that RA could be acting directly on the genome.

Circulating IgA immune complexes in patients with psoriasis.

The sera of 21 patients with psoriasis were examined for the presence of IgA-containing circulating immune complexes (CIC) using the Raji IgA radioimmunoassay. In addition, the Raji IgG radioimmunoassay and 125I-Clq binding assay were used to detect IgG- and IgM-containing CIC. Twenty-five patients with other hyperkeratotic skin disorders were studied as controls. Patients were studied before institution of systemic therapy with etretinate (20 patients) or 13-cis-retinoic acid (1 patient). In addition, sera of 15 of the patients treated with etretinate were studied before, during, and after therapy. The extent of pretreatment disease involvement as well as response to therapy were evaluated in a blinded fashion. Fourteen of 21 (67%) patients with psoriasis had evidence of IgA-containing CIC at some time during the course of their disease, as compared to only 1 of 25 patients with other hyperkeratotic skin disorders. In contrast, only 2 of 19 (11%) had evidence of IgG-containing CIC using the Raji IgG assay, and only 1 of 19 (5%) had evidence of IgG- or IgM-containing CIC using the 125I-Clq binding assay. A positive correlation was found between the extent of pretreatment disease involvement and the level of IgA-containing CIC by linear regression analysis (p = 0.01). There was, however, no correlation between clinical improvement and the presence or level of IgA-containing CIC in 15 patients followed during therapy. Sucrose density gradient analysis of the IgA-containing CIC found in 2 of these patients demonstrated IgA-containing CIC in the 9S to 13S region. The finding of IgA-containing CIC in a significant number of patients with psoriasis and the relative absence of IgG- or IgM-containing CIC suggest that IgA-containing CIC may play a role in psoriasis. The lack of correlation with clinical improvement, however, suggests these IgA-containing CIC are not directly related to the cutaneous manifestations of psoriasis, but may be important in the modification of immune or inflammatory responses in these patients.

Adrenal function in women with idiopathic acne.

The adrenal secretion of androgens were examined in 9 women (ages 19-39 yr) with postadolescent idiopathic acne and compared to age and sex-matched normal controls. Plasma dehydroepiandrosterone (DHA), dehydroepiandrosterone sulfate (DHAS), androstenedione (delta 4-delta), cortisol, 17-hydroxyprogesterone, 11-deoxycortisol, and testosterone were measured by radioimmunoassay in the basal state and during a 48 hr ACTH infusion. The mean plasma and time-integrated plasma levels of the 3 adrenal androgens in patients with acne were 15-25% higher than normal controls, but the groups were not significantly different (p greater than .05). The plasma testosterone values, on the other hand, were similar in both groups. In addition, cortisol, 11-deoxycortisol and 17-hydroxyprogesterone basal plasma values and responses to ACTH in patients with acne were similar to the normal control values. These findings suggest that adrenal androgen secretion is at most mildly elevated in patients with idiopathic acne and is unlikely to be the sole cause of acne since many patients without acne have similar hormone levels. Increased sensitivity of the sebaceous gland to androgens or increased local metabolism of androgen hormones in the skin to potent androgen metabolites may offer alternative mechanisms for the pathogenesis of this disorder.

Etretinate: effect of milk intake on absorption.

Since etretinate, an aromatic retinoid useful in the treatment of psoriasis and other skin disorders is lipid-soluble, it may be poorly absorbed in the absence of a fat load. We therefore studied serum concentrations of etretinate and its major metabolite (Ro 10-1670) after the controlled administration of etretinate. After an overnight fast, 6 Darier's disease and 4 psoriatic patients received a 1 mg/kg morning dose of etretinate with water or 1 pint of whole milk (fat load). There was a 260% increase (p less than 0.0005) in the mean of each patient's increase in the baseline-corrected peak serum concentration of etretinate after administration with milk (115 +/- 15 micrograms/dl) compared to after administration with water (32 +/- 4 micrograms/dl). Over a 24-h period there was an overall 296 +/- 26% (p less than 0.0005) increase in serum etretinate after administration with milk compared to water in 5 patients with Darier's disease. In contrast to the serum etretinate, there was a 17% mean decrease (p less than 0.025) in the corrected peak serum concentration of Ro 10-1670 in all 10 patients after administration of etretinate with milk compared to water. The net result of these alterations is that the mean corrected serum concentration of etretinate is higher than Ro 10-1670 at all time points measured after milk administration. In contrast, after administration of etretinate with water the major retinoid in the serum is Ro 10-1670. Establishing the clinical significance of these alterations may require controlled clinical trials.

Adrenal androgen secretion in postadolescent acne: increased adrenocortical function without hypersensitivity to adrenocorticotropin.

Basal and ACTH-stimulated plasma levels of cortisol, delta 4-androstenedione, and dehydroepiandrosterone (DHEA) were measured in a group of 11 female patients with postadolescent acne resistant to or relapsing after conventional therapy and in a group of 10 normal women without acne or hirsutism. Each patient received, in a blinded random fashion, a series of 5 1-h ACTH tests. For each test a different dose of ACTH-(1-24) was administered, ranging from 0-1 microgram/kg, given as an iv bolus. Blood samples were collected 0, 10, 30, and 60 min after ACTH bolus injection. Patients with acne had slightly higher concentrations of basal cortisol, delta 4-androstenedione, and DHEA than normal controls (P less than 0.05). After ACTH-(1-24) stimulation, the same patients had greater peak and time-integrated DHEA concentrations (P less than 0.03). The ED50 values of the cortisol dose-response curves were similar in patients and normal women (P less than 0.05), suggesting that there are no differences in the sensitivity of the adrenal cortex to ACTH between the acne patients and the controls studied. The ratio of DHEA to cortisol response was significantly elevated in women with acne compared to that in control women, suggesting some preponderance of the delta 5 pathway of steroidogenesis in acne (P less than 0.05). These findings of basal and ACTH-stimulated hypersecretion of delta 5-androgens in patients with postaldolescent acne are consistent with an increased volume of androgen-secreting tissue, rather than hypersensitivity of the adrenal zona reticularis to ACTH.

Normal pressure hydrocephalus. Recognition and relationship to neurological abnormalities in Cockayne's syndrome.

Normal pressure hydrocephalus (NPH) in adults is a well-known cause of dementia. We describe NPH in children having the recessively inherited Cockayne's syndrome (CS). Cockayne's syndrome is characterized by cachectic dwarfism, neurological dysfunction, and cutaneous sunlight sensitivity. We noted that the NPH-associated triad of dementia, gait disturbance, and incontinence developed in CS patients. Computerized tomography of the brain in our four CS patients showed hydrocephalic enlargement of the brain ventricles greatest in the older patients. There was no evidence of cortical atrophy except in the one patient who had CS with xeroderma pigmentosum. Lumbar puncture and radionuclide cisternography in the two patients tested showed normal CSF pressure, with complete blockade to flow of radionuclide above the tentorium cerebelli, ventricular reflux, and delayed absorption. Studies of NPH in CS may elucidate the pathophysiology of NPH and methods to alter its sequelae.

Clinical and laboratory adverse effects associated with long-term, low-dose isotretinoin: incidence and risk factors. The Isotretinoin-Basal Cell Carcinomas Study Group.

Adverse effects associated with the long-term low-dose regimens of retinoids used in cancer chemoprevention studies are not well described. In order to examine the clinical and laboratory adverse effects of 3 years of intervention with isotretinoin (10 mg/day) and to assess potential risk factors for developing these, we collected adverse effect data on patients participating in a randomized, placebo-controlled trial designed to evaluate the effectiveness of isotretinoin in preventing the subsequent occurrence of new basal cell carcinoma. Our results showed a significantly higher incidence of adverse mucocutaneous effects and serum triglyceride elevations in the isotretinoin group (P < 0.001). Associated risk factors included male gender, very fair skin, and elevated pretreatment triglyceride levels. The toxicity observed, although less severe and less frequent, was similar to that seen with higher doses and should be weighed with adverse skeletal effects when considering long-term treatment of patients with moderate cancer risk.

Carbon-13 magnetic resonance spectroscopy of drugs. Sulfonamides.

The natural abundance 13C magnetic resonance spectra of a series of sulfonamide drugs(sulfanilamide, sulfaguanidine,sulfathiazole, sulfasuxidine, sulfadiazine, sulfamerazine, sulfamethiazine, and sulfapyridine) have been determined at 25.15 MHz employing the pulse Fourier transform technique. The chemical shefts have been assigned with the aid of off-resonance and selective proton decoupling techniques, as well as by long-range carbon-13 proton coupling patterns.

Abnormal retinal function associated with fenretinide, a synthetic retinoid.

Five patients with basal cell carcinoma received fenretinide. Two patients while receiving the drug had evidence of abnormal rod photoreceptor function that reversed rapidly on cessation of therapy. We speculate that fenretinide may interfere with the binding of vitamin A to opsin or with the transport of vitamin A.

Drug physical state and drug-polymer interaction on drug release from chitosan matrix films.

Four different grades of chitosan varying in molecular weight and degree of deacetylation were used to prepare chitosan films. Salicylic acid and theophylline were incorporated into cast chitosan films as model acidic and basic drugs, respectively. Crystalline characteristics, thermal behavior, drug-polymer interaction and drug release behaviors of the films were studied. The results of Fourier transform infrared and solid-state 13C NMR spectroscopy demonstrated the drug-polymer interaction between salicylic acid and chitosan, resulting in salicylate formation, whereas no drug-polymer interaction was observed in theophylline-loaded chitosan films. Most chitosan films loaded with either salicylic acid or theophylline exhibited a fast release pattern, whereas the high viscosity chitosan films incorporated with salicylic acid showed sustained release patterns in distilled water. The sustained release action of salicylic acid from the high viscosity chitosan films was due to the drug-polymer interaction. The mechanism of release was Fickian diffusion control with subsequent zero order release. It was suggested that the swelling property, dissolution characteristics of the polymer films, pK(a) of drugs and especially drug-polymer interaction were important factors governing drug release patterns from chitosan films.

Cornifying Darier disease--a unique variant. II. Surgical treatment.

A case of severe cornifying Darier disease (keratosis follicularis) was successfully treated by deep dermal excision of diseased skin and subsequent dermabrasion, resulting in a remission lasting more than four years to date. Persistent loss of the papillary dermis was observed in the surgically treated, disease-free areas.