Spontaneous resolution of keratoacanthoma centrifugum marginatum.

Keratoacantnoma centrifugum marginatum (KCM) is a rare variant of keratoacantnoma, with > 40 cases reported world wide. Spontaneous resolution of KCM is very rare. To our knowledge, this is the first case of KCM with spontaneous resolution as documented by serial photographs.

Digitial endochondroma.

A patient with Ollier disease presenting with onycholysis and nail dystrophy related to a subungual enchondroma is presented.

Distinguishing direct binding interactions from allosteric effects in the protease-HK97 prohead I δ domain complex by amide H/D exchange mass spectrometry.

A major question in mapping protein-ligand or protein-protein interactions in solution is to distinguish direct-binding interactions from long-range conformational changes at allosteric sites. We describe here the applicability of amide hydrogen deuterium exchange mass spectrometry (HDXMS) in addressing this important question using the bacteriophage HK97 capsid proteins' interactions with their processing protease. HK97 is a lambda-like dsDNA bacteriophage that is ideal for studies of particle assembly and maturation. Its capsid precursor protein is composed of two main regions, the scaffolding protein (δ-domain, residues 2-103), and the coat subunit (residues 104-385), which spontaneously forms a mixture of hexamers and pentamers upon association. Activation of the viral protease, which occurs after particle assembly, is initiated by the protease mediated digestion of the scaffolding domains to yield Prohead-2. This irreversible step is obligatory for activation of the virus maturation pathway. Here we provide an "addendum" to our previous study of Prohead I and Prohead I+pro (a transient complex of Prohead I and the protease) where we investigated the interactions between the δ domain and the packaged protease using HDXMS. Our results revealed two sites on the δ domain: one set of contiguous peptides that showed decreased exchange at the protease binding site at early time points of deuterium labeling and another separate set of continuous peptides that showed decreased exchange at later time points. Even though this cannot reveal the time scales of molecular processes governing binding and allostery, we believe this differential pattern of exchange across deuteration times can allow spatial distinction between binding sites and long range conformational changes with allosteric implications. This partitioning can be discerned from the lag between noncontiguous regions on a protein showing maximal changes in deuterium exchange and highlights a powerful application of HDXMS in distinguishing direct binding in transient protein-protein interactions from allosteric changes.

[Sclerodermatous changes in porphyria cutanea tarda: six cases]. / Lésions sclérodermiformes dans la porphyrie cutanée tardive : six observations.

BACKGROUND: The clinical features of porphyria cutanea tarda (PCT) are usually distinctive and include blistering on sun-exposed areas, fragile skin, hypertrichosis and hyperpigmentation. Sclerodermatous changes are much less common, and may either reveal PCT or else appear later. We carried out a retrospective study of the files of six female patients presenting such lesions. PATIENTS AND METHODS: Six women (age: 45 to 72 years) were referred for sclerodermatous lesions on sun-exposed areas of the upper body. In four patients, these lesions revealed PCT and in the remaining two patients they were indicative of previously treated but relapsing PCT. Four had sclerodermatous skin changes mimicking morphea of the neck and neckline, the top of the back and the face, while one presented more diffuse facial and cervical sclerosis. Associated alopecia was seen in three patients. The last patient presented isolated sclerodermiform alopecia. Associated malar hypertrichosis was seen in five cases and facial hyperpigmentation was noted in three cases. Four exhibited no blisters, cutaneous fragility, milia or photosensitivity. Histological findings were consistent with morphea or scleroderma in all cases. All patients presented abnormal liver tests: cirrhosis was present in four cases (primitive biliary cirrhosis, alcoholic cirrhosis and hepatitis C) and fatty liver in two cases. In four cases, there was excessive alcohol intake. Uroporphyrin levels were above the normal range in all cases. Local corticosteroid therapy associated with phlebotomy and/or low-dose hydroxychloroquine resulted in complete normalisation of porphyrin levels in four patients, with complete resolution of the cutaneous lesions in two patients and partial improvement in the other two. DISCUSSION: Sclerodermatous changes are uncommon in PCT. They are not always late and secondary to the process of healing of blisters but can in fact constitute the first cutaneous symptom of the disease while revealing the underlying liver disease. Even in the absence of blisters, photosensitivity or cutaneous fragility, a diagnosis of PCT must be suspected in a setting of sclerodermatous changes distributed on the neck and face, or the neckline, or scarring alopecia, if associated with abnormal liver tests. Skin biopsy to confirm the diagnosis of scleroderma may delay the diagnosis, which is in fact based on porphyrin level. Normalization of the latter parameter under treatment allows regression of lesions.

Electrocardiographic effects of methylphenidate overdose.

OBJECTIVES: Stimulants used in the management of attention-deficit hyperactivity disorder have been associated with an increased risk of sudden cardiac death. One mechanism could involve drug-induced repolarization delay, reflected as prolongation of the QT interval on the electrocardiogram, which has been described in some recipients of methylphenidate in therapeutic doses. Because QT prolongation is usually dose-related, this study was performed to investigate effects of methylphenidate overdose on the QT interval. METHODS: Adults with methylphenidate overdose identified retrospectively were matched for sex and heart rate with a control subject with overdose of a noncardiotoxic substance, mainly acetaminophen. Notes were reviewed for clinical details and coingestants. Admission 12-lead electrocardiograms were individually calibrated and analyzed using a manual digitizer in a blinded manner by a single investigator. Mean QRS and QT intervals were calculated and differences between groups were analyzed. RESULTS: Twenty-three cases of methylphenidate overdose (median reported dose 120 mg, range 40-1,500 mg) were identified (10 males, 13 females, mean age 27.8 years). There were multiple coingestants. Level of consciousness and mean hemodynamic variables were within normal limits for all cases. Symptoms recorded in cases included anxiety (32%), dilated pupils (20%), abdominal pain (16%), vomiting (12%), palpitations (12%), and chest pain (8%). No arrhythmias were recorded. Mean heart rate was 92.4/min in methylphenidate cases and 93.8/min in the heart rate-matched controls. There were no significant differences between the groups in mean QRS (cases 86.1, controls 86.2, mean difference 0.1, 95% confidence interval = -5.1 to 5.0 ms) or mean QT intervals (cases 354, controls 355, mean difference -0.8, 95% confidence interval = -10.7 to 9.2 ms). CONCLUSIONS: Methylphenidate overdose is unlikely to have substantial effects on the QRS or QT intervals.

Molecular mechanism for dimerization to regulate the catalytic activity of human cytomegalovirus protease.

Biochemical studies indicate that dimerization is required for the catalytic activity of herpesvirus proteases, whereas structural studies show a complete active site in each monomer, away from the dimer interface. Here we report kinetic, biophysical and crystallographic characterizations of structure-based mutants in the dimer interface of human cytomegalovirus (HCMV) protease. Such mutations can produce a 1,700-fold reduction in the kcat while having minimal effects on the K(m). Dimer stability is not affected by these mutations, suggesting that dimerization itself is insufficient for activity. There are large changes in monomer conformation and dimer organization of the apo S225Y mutant enzyme. However, binding of an activated peptidomimetic inhibitor induced a conformation remarkably similar to the wild type protease. Our studies suggest that appropriate dimer formation may be required to indirectly stabilize the protease oxyanion hole, revealing a novel mechanism for dimerization to regulate enzyme activity.

Investigating the role of histidine 157 in the catalytic activity of human cytomegalovirus protease.

Herpesvirus proteases belong to a new class of serine proteases and contain a novel Ser-His-His catalytic triad, while classical serine proteases have an acidic residue as the third member. To gain a better understanding of the molecular basis for the functional role of the third-member His residue, we have carried out structural and biochemical investigations of human cytomegalovirus (HCMV) protease that bears mutations of the His157 third member. Kinetic studies showed that all the mutants have reduced catalytic activity. Structural studies revealed that a solvent molecule is hydrogen-bonded to the His63 second member and Ser134 in the H157A mutant, partly rescuing the activity of this mutant. This is confirmed by our kinetic and structural observations on the S134A/H157A double mutant, which showed further reductions in the catalytic activity. The structure of the H157A mutant is also in complex with the PMSF inhibitor. The H157E mutant has the best catalytic activity among the mutants; its structure, however, showed conformational readjustments of the His63 and Ser132 residues. The Ser132-His63 diad of HCMV protease has similar activity as the diads in classical serine proteases, whereas the contribution of the His157 third member to the catalysis is much smaller. Finally, structural comparisons revealed the presence of two conserved structural water molecules at the bottom of the S(1) pocket, suggesting a possible new direction for the design of HCMV protease inhibitors.

Hospital practices in maternity wards in Lebanon.

This study was conducted in Lebanon with the main objectives of acquiring baseline data on practices and routines applied in the obstetrics ward for women having normal delivery; estimating the frequency of certain practices; and assessing whether women are given choice in these practices. A national sample of 39 hospitals was selected. The director, head midwife, or head nurse of the obstetrics department was interviewed using a semi-structured questionnaire. The hospitals studied are largely equipped to cope with emergencies and services are available 24 hours a day. On average, the caesarean section rate is 18% and the stillbirth rate is 10 per 1000, but with considerable variability between facilities. The majority of hospitals do not have written policies or standard birth procedures and lack mechanisms for evaluation. Generally, minimal prenatal information is given to women. Companions are allowed during labour but this access is more restricted in delivery. The reported configuration of professional care during labour and delivery is favourable to high quality care. In terms of mobility during labour, most hospitals allow women to move. However, 31 hospitals set an i.v. drip to all women and some use continuous fetal monitoring method. Mobility is restricted in delivery; in 23 hospitals women are tied down. Nearly all hospitals give intra-muscular anaesthesia whereas epidurals are used less frequently. As for postpartum care, most hospitals do not initiate breastfeeding within one hour of birth and few have rooming in. The majority of hospitals do not provide women with family planning methods and a few do not even discuss methods with them. The approach used in this study constitutes a tool for understanding and assessing maternity services that should be applied in other settings. The tool is available from the authors.

A T14C variant of Azotobacter vinelandii ferredoxin I undergoes facile [3Fe-4S]0 to [4Fe-4S]2+ conversion in vitro but not in vivo.

[4Fe-4S]2+/+ clusters that are ligated by Cys-X-X-Cys-X-X-Cys sequence motifs share the general feature of being hard to convert to [3Fe-4S]+/0 clusters, whereas those that contain a Cys-X-X-Asp-X-X-Cys motif undergo facile and reversible cluster interconversion. Little is known about the factors that control the in vivo assembly and conversion of these clusters. In this study we have designed and constructed a 3Fe to 4Fe cluster conversion variant of Azotobacter vinelandii ferredoxin I (FdI) in which the sequence that ligates the [3Fe-4S] cluster in native FdI was altered by converting a nearby residue, Thr-14, to Cys. Spectroscopic and electrochemical characterization shows that when purified in the presence of dithionite, T14C FdI is an O2-sensitive 8Fe protein. Both the new and the indigenous clusters have reduction potentials that are significantly shifted compared with those in native FdI, strongly suggesting a significantly altered environment around the clusters. Interestingly, whole cell EPR have revealed that T14C FdI exists as a 7Fe protein in vivo. This 7Fe form of T14C FdI is extremely similar to native FdI in its spectroscopic, electrochemical, and structural features. However, unlike native FdI which does not undergo facile cluster conversion, the 7Fe form T14C FdI quickly converts to the 8Fe form with a high efficiency under reducing conditions.

MPO-ANCA necrotizing glomerulonephritis related to rheumatoid arthritis.

Two patients with rheumatoid arthritis (RA) developed necrotizing crescentic glomerulonephritis with high titers of anti-myeloperoxidase antibodies (MPO) in the absence of overt extrarenal vasculitis. We therefore suggest that in some patients with RA, MPO-ANCA necrotizing glomerulonephritis (GN) may occur as a kidney-limited form of rheumatoid vasculitis, and that RA should be added to the list of diseases potentially associated with necrotizing GN with anti-MPO antibodies. These observations also point out the importance of repeatedly evaluating titers of anti-MPO antibodies in the course of RA, especially if renal impairment or abnormal urinary sediment are present.

Antipsychotic drugs for non-psychotic patients: assessment of the benefit/risk ratio in generalized anxiety disorder.

Antipsychotic drugs (neuroleptics, major tranquillizers) are frequently prescribed for the relief of anxiety symptoms. A recent survey of a representative sample of psychiatrists found that these drugs are often given to patients who are not suffering from psychotic disorders, a practice that also appears to be common among general practitioners. Many authors have commented on the value of antipsychotics in relieving anxiety symptoms, both in the short and long term, as an alternative to benzodiazepines (with their associated risk of possible tolerance and dependence), although few recent papers recommend their use in this respect. This paper summarizes the evidence from treatment studies of antipsychotic drugs in patients with generalized anxiety disorder (GAD), and compares this with the advice given in major psychiatric textbooks. Most of the studies identified on the use of antipsychotic drugs in GADs appear to have major methodological flaws, and no study has considered the benefit/risk ratio carefully.

[How to diagnose and treat peritoneal infections in patients with terminal chronic renal insufficiency treated by peritoneal dialysis]. / Comment diagnostiquer et traiter les infections péritonéales chez les malades en insuffisance rénale chronique terminale traités par dialyse péritonéale?

There have been improvements in the technique of peritoneal dialysis (PD) over the last ten years. However, peritoneal infections remain the major complication associated with this treatment, and the risk of infection cannot be accurately predicted. Nevertheless, it is widely accepted that simple connections should be replaced by improved systems of connection, and that patient training is important. Peritoneal infection should be suspected when the dialysate is turbid, whether or not associated with peritoneal irritation. None of the various techniques used for the culture of dialysates has been shown to be either more sensitive or more specific than any of the others. Thus, collaboration between the physicians supervising the dialysis and microbiologists is necessary to choose the culture techniques best adapted. The sensitivity should be at least 85 to 90%. If the sensitivity is lower, the techniques used should be reconsidered. There have been several hundred publications assessing treatments of peritoneal infections associated with PD. However, no particular antibiotic treatment has been demonstrated to be systematically superior. The use of associated antibiotics seems to be preferable initially, until the causative agent has been identified. For example, vancomycin with a third generation cephalosporin seems to be the association of choice, because of its efficacy, tolerance and ease of use. The optimal duration of treatment has not been established by randomised study, but 10 days is commonly used for Gram-positive infections, and longer for Gram-negative. Whatever the treatment used, the success rate should be at least 80 to 90%. Randomised trials with sufficiently large numbers of patients are required to determine the indications and delay before withdrawal of the DP catheter in cases of peritonitis which do not respond to antibiotics.

The management of uraemia in the elderly: treatment choices.

The particularity of geriatric medicine and the lack of information due to the fact that geriatric nephrology dates back only 10 years explains why the management of chronic uraemia among the elderly presents itself as a succession of difficult dilemmas. (1) Should causes of chronic renal failure be systematically determined and treated? Risk-benefit assessments of the investigations and treatments involved in preventing or slowing down the evolution to end-stage renal disease (ESRD) are required to answer this question. (2) In cases of ESRD, should dialysis always be considered? The fact that life expectancy is limited for the aged does not justify depriving them of treatment. Nevertheless, in some borderline situations, conservative treatment may be preferable. (3) When should dialysis be started? Currently the mortality before the 90th day of dialysis is very high among elderly patients. To improve results it is probably necessary to determine appropriate criteria for starting treatment before complications occur. (4) What is the best method for the first treatment? There is much controversy about the respective advantages of haemodialysis and peritoneal dialysis. The choice depends on the individual's medical and social conditions. (5) Should dialysis treatment be stopped, and, if so, in this case, when? The large acceptance rate of elderly patients for dialysis implies that withdrawal of treatment must sometimes be considered. Fears linked to this dilemma probably explain why some physicians choose to exclude elderly patients from dialysis. It seems to us more ethical to treat this group of patients and assume responsibility for stopping treatment should it be necessary.

Fungal peritonitis in patients on peritoneal dialysis.

Fungal peritonitis (FP) is a serious complication of peritoneal dialysis, both in terms of morbidity and mortality. Available data on the effectiveness of fluconazole in eradicating FP without catheter removal are still controversial. We reviewed 20 FP cases that occurred among 325 patients who underwent peritoneal dialysis in our center between January 1984 and January 1992, in order to establish whether a profile of patients at risk of developing FP could be identified and to evaluate the effectiveness of fluconazole in treating FP (7 cases). Age, sex, a particular cause of end-stage renal disease, and the presence of diabetes did not correlate significantly with the development of FP. The risk of FP increased in patients on immunosuppressive treatment. Sixteen of our 20 patients had bacterial peritonitis during the month before they developed FP. Nineteen were treated with antibiotics. Neither the type of bacterial organism isolated during the bacterial peritonitis preceding FP nor modality and duration of antibiotic treatment correlated significantly with the development of FP. Patients who subsequently developed FP were more frequently treated with antibiotics while in hospital (p < 0.001). Candida species accounted for 15 of our 20 FP cases (75%), with Candida albicans being by far the most common isolate. Treatment strategies varied among the 20 patients. The combination of intravenous or intraperitoneal administration of 5-fluorocytosine and oral administration of fluconazole was used in 7 cases: only 1 patient was cured without catheter removal, 1 patient died within the first 4 days of treatment, removal of peritoneal catheter was necessary in the other 5 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoimmune haemolytic anaemia after ABO-match, ABDR full match kidney transplantation.

We report a case of autoimmune haemolysis after an ABO- and ABDR-identical kidney transplantation which leads to the discussion of the role of cyclosporin A (CsA). A 46-year-old woman with end-stage renal disease and no history of auto-immune disease received an ABO- and ABDR-identical first renal allograft from a cadaver donor. On day 16, while on a heavy sequential immunosuppressive regimen including anti-thymoglobulins, azathioprine (Aza), prednisolone (Pred) and CsA, she developed an autoimmune haemolysis with positive Coombs test, IgM+C type. Elution of antierythrocyte antibodies did not enable us to identify any specificity. Haemolysis lasted 45 days before haemoglobin slowly increased after CsA had been greatly reduced. Direct antiglobulin tests remained positive 5 months after transplantation and became negative the following month. Eight months after the transplantation the patient had a normal haemoglobin level and normal renal function. Although the typing of autoantibodies was not possible, our data suggest that this patient's haemolysis may be related to the clonal development of donor B lymphocytes in the recipient, favoured by an HLA A-B-DR identity and post-transplant CsA therapy, as exceptionally reported in the literature.

Didanosine pharmacokinetics in patients with normal and impaired renal function: influence of hemodialysis.

The pharmacokinetics of didanosine were investigated following oral administration of a single 375-mg dose to eight human immunodeficiency virus-seropositive patients with normal renal function and eight human immunodeficiency virus-seropositive uremic patients. In uremic patients, the plasma half-life was longer than that in control patients (respectively, 4.5 +/- 2.2 and 1.6 +/- 0.4 h). The ratio of total plasma clearance to absolute bioavailability was four- to fivefold lower in uremic patients than in patients with normal renal function (respectively, 491 +/- 181 and 2,277 +/- 738 ml/min). Because of the decrease in elimination, concentrations in plasma were higher for uremic patients than for control patients; the maximum concentrations of drug in plasma were, respectively, 3,978 +/- 1,607 and 1,948 +/- 994 ng/ml; the areas under the concentration-time curve were, respectively, 14,050 +/- 4,262 and 3,000 +/- 956 ng.h/ml. Didanosine was removed by hemodialysis with an extraction ratio of 53% +/- 8%, a hemodialysis clearance value of 107 +/- 21 ml/min, and a fractional drug removal during a 4-h dialysis of 20% +/- 8% of the dose. Dosage adjustments are necessary in uremic patients.