Practical considerations for the evaluation and management of Attention Deficit Hyperactivity Disorder (ADHD) in adults.

Attention deficit with or without hyperactivity disorder (ADHD) is one of the most frequent neuropsychiatric disorders, and affects 2-4% of adults. In contrast with many European countries, the identification and management of adult ADHD remains underdeveloped in France, and a subject of controversy. This review provides a practical update on current knowledge about ADHD in adults for French-speaking professionals who have to detect or manage adult patients with ADHD. ADHD is classified as a neurodevelopmental disorder in the recent update of the international diagnostic classification. While symptoms and impairment due to ADHD are frequently severe during childhood, they often evolve as children grow older, with frequent persistent disabilities in adulthood. In adulthood, the clinical presentation, as in childhood, involves the symptom triad of inattention, hyperactivity and impulsivity. However, differences are noted: hyperactivity is more often internalized, symptoms of inattention may be masked by anxiety symptoms or obsessive-like compensation strategies. ADHD is often diagnosed during childhood, but it is not rare for the diagnosis to be made later. Failure to recognise symptoms resulting in misdiagnosis, or alternatively well-developed compensation factors could be two underlying reasons for the long delay until diagnosis. Other symptoms, such as emotional deregulation or executive function-related symptoms are also usually observed in adults. In addition, in adults, ADHD is often associated with other psychiatric disorders (in 80% of cases); this makes the diagnosis even more difficult. These disorders encompass a broad spectrum, from mood disorders (unipolar or bipolar), to anxiety disorders, and other neurodevelopmental disorders and personality disorders, especially borderline and antisocial personality disorder. Substance-use disorders are very common, either as a consequence of impulsivity and emotional dysregulation or as an attempt at self-treatment. Sleep disorders, especially restless leg syndrome and hypersomnolence, could share common pathophysiological mechanisms with ADHD. ADHD and comorbidity-related symptoms are responsible for serious functional impairment, in various domains, leading to academic, social, vocational, and familial consequences. The impact on other psychiatric disorders as an aggravating factor should also be considered. The considerable disability and the poorer quality of life among adults with ADHD warrant optimal evaluation and management. The diagnostic procedure for ADHD among adults should be systematic. Once the positive diagnosis is made, the evaluation enables characterisation of the levels of severity and impairment at individual level. A full examination should also assess medical conditions associated with ADHD, to provide personalized care. In recent years, a growing number of assessment tools have been translated and validated in French providing a wide range of structured interviews and standardized self-report questionnaires for the evaluation of core and associated ADHD symptoms, comorbidities and functional impairment. The treatment of ADHD in adults is multimodal, and aims to relieve the symptoms, limit the burden of the disease, and manage comorbidities. The most relevant and validated psychological approaches are psycho-education, cognitive-behavioural therapy and "third wave therapies" with a specific focus on emotional regulation. Cognitive remediation and neurofeedback are promising strategies still under evaluation. Medications, especially psychostimulants, are effective for alleviating ADHD symptoms with a large effect size. Their safety and tolerance are satisfactory, although their long-term clinical benefit is still under discussion. In France, methylphenidate is the only stimulant available for the treatment of ADHD. Unfortunately, there is no authorization for its use among adults except in continuation after adolescence. Hence the prescription, which is subject to the regulations on narcotics, is off-label in France. This article aims to provide practical considerations for the management of ADHD and associated disorders in adults, in this particular French context.

[Community-acquired Staphylococcus aureus pneumonia following influenza and the choice of empirical antibiotic treatment]. / Thuis opgelopen pneumonie door Staphylococcus aureus na influenza en de keuze voor empirische antibiotische behandeling.

A 30-year-old man presented with community-acquired pneumonia (CAP), directly following influenza. Sputum Gram stain confirmed Staphylococcus aureus pneumonia. Initial empirical antimicrobial therapy did not cover S. aureus. The isolated S. aureus strain contained genes encoding exotoxins, such as Panton-Valentine leukocidin (PVL). This exotoxin is associated with high mortality and methicillin resistance, but in this patient the strain was susceptible to methicillin. The patient died. In the Netherlands the risk of methicillin resistance in PVL-positive S. aureus CAP is low but real. This should be taken into account when selecting empirical treatment, which can include the combination of flucloxacillin and rifampicin. This case report illustrates the difficulty in predicting the causative agent in CAP and highlights the usefulness of the sputum Gram stain. Moreover, clinical awareness and recognition of S. aureus CAP remains essential to the early initiation of directed therapy.

Treatment of childhood migraine attacks with oral zolmitriptan and ibuprofen.

The authors conducted a double-blind, placebo-controlled, crossover study to investigate the efficacy of oral zolmitriptan in the treatment of migraine in children and adolescents. Patients (n = 32) received placebo, zolmitriptan 2.5 mg, and ibuprofen 200 to 400 mg to treat three consecutive migraine attacks. Pain relief rates after 2 hours were 28% for placebo, 62% for zolmitriptan, and 69% for ibuprofen (p < 0.05). Both drugs are well tolerated with only mild side effects.

[The abdominal compartment syndrome]. / Het abdominaal compartimentsyndroom.

In two patients, a man aged 67 and a woman aged 80, an abdominal compartment syndrome was diagnosed. The man had been treated surgically for an abdominal aortic aneurysm; he recovered after re-operation. The woman had been treated by sigmoidectomy because of ileus. A Bogota bag and a vacuum-assisted wound-closure system were applied to the abdominal wound. Her condition deteriorated, an intestinal perforation became apparent, of which she did not recover and died. An abdominal compartment syndrome should always be kept in mind when a patient at risk presents with increased intra-abdominal pressure and at least one of the following symptoms: oliguria, decreased cardiac output, increased pulmonary-artery pressure, hypotension and acidosis. Measurement of the bladder pressure remains the method of choice to establish the abdominal pressure level. However, there is a lack of correlation between the measured pressure and the clinical condition of the patient. Therefore, the combination of clinical findings and the observed trend in serial measurements of the bladder pressure is preferred to a single pressure measurement.

Mapping and structure of DMXL1, a human homologue of the DmX gene from Drosophila melanogaster coding for a WD repeat protein.

The DmX gene was recently isolated from the X chromosome of Drosophila melanogaster. TBLASTN searches of the dbEST databases revealed sequences with a high level of similarity to DmX in a variety of different species, including insects, nematodes, and mammals showing that DmX is an evolutionarily highly conserved gene. Here we describe the cloning of the cDNA and the chromosomal localization of one of the human homologues of DmX, Dmx-like 1 (DMXL1). The human DMXL1 gene codes for a large mRNA of 11 kb with an open reading frame of 3027 amino acids. The putative protein belongs to the superfamily of WD repeat proteins, which have mostly regulatory functions. The DMXL1 protein contains an exceptionally large number of WD repeat units. The DMXL1 gene is located on chromosome 5q22 as determined by radiation hybrid mapping and fluorescence in situ hybridization. Although the function of the DMXL1 gene and its homologues in other species remains to be discovered, the high level of evolutionary conservation together with the unusual structure suggests that it probably has an important function.

A pilot study of melphalan, tumor necrosis factor-alpha and 41.8 degrees C whole-body hyperthermia.

PURPOSE: To evaluate the feasibilitv of sequencing (based on preclinical modeling) tumor necrosis factor-a (TNF) at two dose levels with melphalan (L-PAM) and 41.8 C whole-body hyperthermia (WBH) for 60 min. PATIENTS AND METHODS: Nine patients with refractory cancer were treated from October 1995 to June 1997. The study encompassed a total of 20 trimodality treatment courses. Three patients were treated at TNF dose level I (50 microg/m2) and six patients were treated at TNF dose level II (100 microg/m2). TNF was delivered as a 24-h intravenous infusion, 48 h prior to the combination of L-PAM and WBH; L-PAM was given over 10 min at target temperature at a dose of 17.5 mg/ m2 based on a previous phase I WBH/L-PAM trial. WBH was administered with an Aquatherm radiant heat device. RESULTS: Myelosuppression was the major toxicity associated with therapy, but there were no instances of bleeding or neutropenic fevers. Grade 3 thrombocytopenia was seen with 15% of treatments. Regarding absolute neutrophil count, 15% of treatments were associated with grade 3 toxicity, and 45% with grade 4 toxicity, and regarding white blood cell count, 50% of treatments were associated with grade 3 toxicity and 10% with grade 4 toxicity. The myelosuppression observed was equivalent to that seen in our earlier phase I study of WBH and L-PAM (without TNF). Only mild toxicities (grade 1 or 2) were associated with TNF; these were seen with <25% of treatments and included nausea, vomiting, diarrhea, fevers, and headache. There were no instances of hypotension. There was no relationship between toxicities observed and the two TNF dose levels. Mild WBH toxicities were seen with less than 15% of treatments; these included nausea, vomiting, and herpes simplex I. Responses included two complete remissions (malignant melanoma, TNF dose level I; breast cancer, TNF dose level II), and two disease stabilizations (both malignant melanoma, TNF dose level I). CONCLUSION: We conclude that the combination of TNF, L-PAM, and WBH is well tolerated at the dose levels studied. The clinical results justify further clinical investigation for this trimodality treatment approach.

[Posterior synechiae after Nd:YAG laser iridotomy. A clinical study]. / Hintere Synechien nach Nd:YAG-LASER-Iridotomie. Eine klinische Studie.

METHODS: In 146 eyes/patients who underwent Nd:YAG laser iridotomy after glaucomatous attack or after prophylactic iridotomy, we evaluated whether the frequency of posterior synechiae depends on (1) glaucomatous attack, (2) preoperative miotic therapy, (3) postoperative antiglaucomatous therapy or (4) mode of intraoperative laser therapy. Out of 616 eyes with YAG iridotomy between 1983 and 1987, 146 eyes/patients fulfilled the inclusion criteria: observation time of minimum 3 months after iridotomy, preoperative examination without signs of preexisting synechiae, postoperative examination at discharge and a later control examination in mydriasis to exclude posterior synechiae. RESULTS: Eyes with and without glaucomatous attack and eyes with an without pre-operative long-term miotic therapy showed no significant difference in frequency of posterior synechiae. Eyes with postoperative long-term therapy with miotics or beta-blockers showed posterior synechiae significantly more often than eyes without post-operative miotic or beta-blocker therapy. Eyes that received DPE in the early post-operative period developed posterior synechiae significantly less often. The number of laser pulses and the mean total energy used were significantly higher in eyes which later developed posterior synechiae. In the group of patients with glaucomatous attack women outnumbered men by four to one, but there was no significant difference in refraction between women and men. CONCLUSIONS: Patients with glaucomatous attack are not at a higher risk of developing posterior synechiae than those without glaucomatous attack. Post-operative antiglaucomatous therapy, the number of laser pulses and the total energy alter the frequency of postoperatively developed posterior synechiae.

The new gene DmX from Drosophila melanogaster encodes a novel WD-repeat protein.

DmX is a novel gene from Drosophila melanogaster located on the X chromosome in region 5D5/6-E1. The molecular analysis of the genomic and cDNA sequences of DmX shows that the gene spans appr. 16kb and displays a mosaic structure with 15 exons. The 12kb long DmX transcript is present in Drosophila embryos, larvae and adults of both sexes. The open reading frame of DmX encodes a novel WD-repeat protein, containing at least 30 WD-repeat units. WD-repeat proteins contain a conserved motif of approximately 40 amino acids (aa), usually ending with the dipeptide Trp-Asp (WD). Homologues of the DmX gene exist in other dipteran species, in Caenorhabditis elegans and human, revealing that DmX is an evolutionarily well conserved gene. The inferred DMX amino acid sequence shows also limited, but significant similarity to a yeast ORF with unknown function. 1998 Elsevier Science B.V.

Effect of lead acetate on neurobehavioral development of rats.

We investigated the effects of lead exposure during the pre- and postnatal period on the neurobehavioral development of female Wistar rats (70-75 days of age, 120-150 g) using a protocol of lead intoxication that does not affect weight gain. Wistar rats were submitted to lead acetate intoxication by giving their dams 1.0 mM lead acetate. Control dams received deionized water. Growth and neuromotor development were assessed by monitoring daily the following parameters in 20 litters: body weight, ear unfolding, incisor eruption, eye opening, righting, palmar grasp, negative geotaxis, cliff avoidance and startle reflex. Spontaneous alternation was assessed on postnatal day 17 using a T maze. The animals' ability to equilibrate on a breaker rim was measured on postnatal day 19. Lead intoxication was confirmed by measuring renal, hepatic and cerebral lead concentration in dams and litters. Lead treatment hastened the day of appearance of the following parameters: eye opening (control: 13.5 +/- 0.6, N = 88; lead: 12.9 +/- 0.6, N = 72; P < 0.05), startle reflex (control: 13.0 +/- 0.8, N = 88; lead: 12.0 +/- 0.7, N = 72; P < 0.05) and negative geotaxis. On the other hand, spontaneous alternation performance was hindered in lead-exposed animals (control: 37.6 +/- 19.7; lead: 57.5 +/- 28.3% of alternating animals; P < 0.05). These results suggest that lead exposure without concomitant undernutrition alters rat development, affecting specific subsets of motor skills.

Effect of lead acetate on neurobehavioral development of rats

We investigated the effects of lead exposure during the pre- and postnatal period on the neurobehavioral development of female Wistar rats (70-75 days of age, 120-150 g) using a protocol of lead intoxication that does not affect weight gain. Wistar rats were submitted to lead acetate intoxication by giving their dams 1.0 mM lead acetate. Control dams received deionized water. Growth and neuromotor development were assessed by monitoring daily the following parameters in 20 litters: body weight, ear unfolding, incisor eruption, eye opening, righting, palmar grasp, negative geotaxis, cliff avoidance and startle reflex. Spontaneous alternation was assessed on potnatal day 17 using a T maze. The animals'ability to equilibrate on a beaker rim was measured on postnatal day 19. Lead intoxication was confirmed by measuring renal, hepatic and cerebral lead concentration in dams and litters. Lead treatment hastened the day of appearance of the following parameters: eye opening (control: 13.5 + 0.6, N= 88; lead: 12.9 + 0.6, N=72; P<0.05), startle reflex (control: 13.0 + 0.8, N= 88; lead: 12.0 + 0.7, N=72; P<0.05) and negative geotaxis. On the other hand, spontaneous alternation performance was hindered in lead-exposed animals (control: 37.6 + 19.7; lead: 57.5 + 28.3 percent of alternating animals; P<0.05). These results suggest that lead exposure without concomitant undernutrition alters rat development, affecting specific subsets of motor skills.

The nucleotide sequence of a 39 kb segment of yeast chromosome IV: 12 new open reading frames, nine known genes and one genes for Gly-tRNA.

The complete nucleotide sequence of a 39,090 bp segment from the left arm of yeast chromosome IV was determined. Twenty-one open reading frames (ORFs) longer than 100 amino acids and a Gly-tRNA gene were discovered. Nine of the 21 ORFs (D0892, D1022, D1037, D1045, D1057, D1204, D1209, D1214, D1219) correspond to the previously sequenced Saccharomyces cerevisiae genes for the NAD-dependent glutamate dehydrogenase (GDH), the secretory component (SHR3), the GABA transport protein (UGA4), the high mobility group-like protein (NHP2), the hydroxymethylbilane synthase (HEM3), the methylated DNA protein-cysteine S-methyltransferase (MGT1), a putative sugar transport protein, the Shm1 protein (SHM1) and the anti-silencing protein (ASF2). The inferred amino acid sequences of 11 ORFs show significant similarity with known proteins from various organisms, whereas the remaining ORF does not share any similarity with known proteins.

Phase I clinical trial of melphalan and 41.8 degrees C whole-body hyperthermia in cancer patients.

PURPOSE: To evaluate the biologic interactions and toxicities of melphalan (L-PAM) combined with 41.8 degrees C whole-body hyperthermia (WBH) for 60 minutes. PATIENTS AND METHODS: Sixteen patients with refractory cancer were treated (May 1992 to May 1995) with WBH alone during week 1) thereafter patients were randomized to receive either L-PAM alone on week 2 and L-PAM plus WBH on week 5, or the reverse sequence. Patients who demonstrated clinical improvement received WBH plus L-PAM monthly. Dose levels of L-PAM were 10 mg/m2 (n = 3), 15 mg/m2 (n = 3), 17.5 mg/m2 (n = 6), and 20 mg/m2 (n = 4). L-PAM was administered at target temperature; WBH was administered with an Aquatherm radiant-heat device (patent pending; Cancer Research Institute, New York, NY). RESULTS: Comparisons of mean WBC count and platelet nadirs for L-PAM alone and L-PAM plus WBH demonstrated that the addition of WBH resulted in nadir counts that were, on average, 25% lower. There were no instances of febrile neutropenia or bleeding. Toxicities allowed for escalation of L-PAM to 20 mg/m2; all four patients at this level experienced grade 4 myelosuppression. No significant myelosuppression was observed at 10 and 15 mg/m2. Grade 3 myelosuppression was observed in two of six patients at 17.5 mg/m2. Responses included complete remission (CR) of pancreatic cancer (10 mg/m2), partial remission (PR) of malignant melanoma in two patients (20 mg/m2), and transient clinical and/or serologic improvement in five patients. The pharmacokinetics of L-PAM were not altered by WBH. Observed cytokine induction by WBH is also discussed in detail. CONCLUSION: We conclude that L-PAM with 41.8 degrees C WBH is well tolerated. Clinical results are consistent with preclinical predictions and provide a foundation for second-generation trials now in progress.

Time of diagnosis, reoperations and long-term results of goniotomy in the treatment of primary congenital glaucoma: a clinical study.

PURPOSE: The aim of our study was to get information about the development of visual acuity, visual field and cup-disc ratio of patients with primary congenital glaucoma after IOP-regulating goniotomy by means of a katamnestic inquiry. The preoperative conditions of IOP, corneal diameter and corneal opacity were related to postoperative findings of visual acuity, visual field and cup-disc ratio reported by the treating ophthalmologists. METHODS: 196 patients were contacted, who had a goniotomy in the period from 1965 to 1983 at the University Eye Hospital Würzburg. Out of the 92 returned replies, the address of the treating ophthalmologists could be ascertained from 77 patients. Sixty of the 77 patients fulfilled the inclusion criteria: (1) primary congenital glaucoma and (2) IOP-regulating goniotomy as last surgery. RESULTS: I. In 76% of 106 eyes childhood glaucoma was diagnosed during the first year of life. II. In 72% of 60 eyes/patients with primary congenital glaucoma one goniotomy was sufficient to reach a normal IOP. In 18% a second and in 10% a third goniotomy was necessary, but without influence on the visual outcome. III. Even in the groups of eyes with a preoperative IOP of more than 40 mmHg, preoperative corneal diameter of more than 13 mm and preoperative severe corneal opacity more than 50% reached a visual acuity of 0.4-1.2 and more than 80% had a normal visual field. Only 9% of the eyes showed a cup-disc ratio of 0.6 or more. CONCLUSIONS: In primary congenital glaucoma even eyes with high preoperative IOP, large corneal diameters and severe corneal edemas had a good prognosis of visual outcome after goniotomy.

Does a sodium-free buffer affect QRS width in experimental amitriptyline overdose?

STUDY OBJECTIVES: We carried out this study to determine the effects of pH alteration on QRS width with administration of tromethamine, a non-sodium-containing buffering agent, in experimental amitriptyline overdose. DESIGN: Prospective, nonblinded trial. PARTICIPANTS: Adult mongrel dogs. INTERVENTIONS: Pentobarbital-anesthetized dogs were overdosed with amitriptyline 5 mg/kg followed by infusion at 1.0 mg/kg/minute until the QRS width doubled, then decreased to .5 mg/kg/minute until the end of the experiment. At two defined points of toxicity, the dose of tromethamine required to raise the pH to 7.50 +/- 4 was given. pH and QRS width at a speed of 100 mm/second were measured over a 30-minute period after each tromethamine dose. Data were analyzed with non-linear-regression analysis. RESULTS: At toxicity 1 the mean pH was 7.32, with a QRS width of 11.6 mm. Two minutes after the tromethamine dose the pH rose to 7.51, with narrowing of the QRS width to 8.4 mm. At toxicity 2 the pH was 7.40, with QRS width of 10.6 mm. Two minutes after tromethamine, the pH rose to 7.49 and the QRS width decreased to 9.7 mm. Regression analysis showed a correlation between pH and QRS width; as pH increased, QRS width decreased (P = .0001). CONCLUSION: Cardiac toxicity of amitriptyline overdose, as manifested by QRS widening, is reversible by pH changes alone.

The sex determining region of Chironomus thummi is associated with highly repetitive DNA and transposable elements.

The dominant male sex determiner in chromosome III of the midge Chironomus thummi thummi is closely linked to a large cluster of tandem-repetitive DNA elements, the Cla elements, which are otherwise highly repetitive and distributed over more than 200 sites on all chromosomes. Chromosome III displays a hemizygous cluster of Cla elements in males but not in females. The chromosomal location of this hemizygous Cla element cluster is in the region of the male determiner M as localized by cytogenetic analysis. With Cla elements as hybridization probe, it was possible to clone a large part of the sex determining region. Molecular analysis of the DNA of males and females in this region displayed a number of differences between the two sexes. One striking difference is an unusual transposable element associated with the male sex determining region. The sex determining region also contains several other tandem-repetitive DNA elements in addition to the Cla elements. They are interspersed with single copy DNA. The accumulation of repetitive elements in the sex determining region interpreted as the result of a lack of recombination between the male/female heteromorphic region, although recombination in the other sections of chromosome III occurs.

The CD56 adhesion molecule is the major determinant for detecting non-major histocompatibility complex-restricted cytotoxic mononuclear cells from the intestinal lamina propria.

In this study, specific antibodies against natural killer (NK) cell surface markers identify these cells to be commonly present in normal intestinal mucosa of inflammatory bowel disease (IBD) and carcinoma patients. Cells expressing the CD56 adhesion molecule were found to be far more abundant than CD16+ cells. Functional studies revealed that cells mediating non-major histocompatibility complex-restricted cytotoxicity (NK activity) in the lamina propria express the CD56 surface antigen, whereas only a minority of this activity resides in the population with CD16 expression. This is in contrast with peripheral blood NK cells, which were found to be almost exclusively both CD16+ and CD56+. Moreover, in the lamina propria of the intestine we found CD3+ T lymphocytes not to be involved in spontaneous cell-mediated killing of tumor cells. Considerably higher numbers of cells with the CD16 or CD56 surface markers were found to be present in normal mucosa of IBD patients compared with normal mucosa of carcinoma patients, which was also reflected in higher levels of cytotoxicity detected in lamina propria mononuclear cell preparations from normal IBD mucosa. Because of the disease-related localization of the mucosa studied from both patient groups, i.e. ileum vs. colon, the observed differences may be related to tissue characteristics. Within the IBD group, relatively high levels of cytotoxicity were found in cell preparations from normal mucosa of Crohn's disease patients compared with ulcerative colitis patients, which might support the current concept that Crohn's disease affects the whole of the gastrointestinal tract.

Intravenous administration of bombesin in man stimulates natural killer cell activity against tumour cells.

Peptides from both the nervous and endocrine system have been shown to influence immune functions. This study describes the stimulatory effect of bombesin on natural killer cell activity of peripheral blood mononuclear cells. The stimulation of cytotoxicity by bombesin in vivo was much higher than found in vitro. In vitro studies with bombesin and gastrin revealed that the stimulatory effect of bombesin in vivo can for a major part be attributed to other stimulatory mediators which are released by BBS. These results indicate that neuropeptide release might rapidly interfere, both directly and indirectly, with natural killer activity of peripheral blood mononuclear cells.