Cryptococcosis due to Cryptococcus gattii in Germany from 2004-2013.

The fungal pathogen Cryptococcus gattii was considered to be restricted to tropic and sub- tropic regions. A recent outbreak in North America due to isolates belonging to molecular type VG II, affecting mostly non-immunocompromised hosts, documented the potential public health impact of this fungal pathogen also in temperate regions. Surveillance of these infections in Germany is challenging, as cryptococcosis is not notifiable and often C. gattii is diagnostically not distinguished from the more prevalent Cryptococcus neoformans. We used hospital discharge data and identified cryptococcal isolates received by the German cryptococcosis reference laboratory at the species level to gain insights into the epidemiology of C. gattii-infections in Germany between 2004 and 2013. Between 49 and 60 (Median 57) hospitalizations for cryptococcosis are documented per year. Between 5 and 28 (Median 14) isolates were received at the reference laboratory per year. Among 155 single patient isolates, four C. gattii (3%) of the molecular types VGI and VG III were identified from patients with meningoencephalitis, including one interspecies hybrid. Patient histories and molecular typing suggest that half of the infections were acquired abroad. Only one patient survived the infection. C. gattii remains rarely identified as agent of cryptococcosis in Germany but underestimation is likely. Definition of environmental niches occupied by C. gattii in Germany may help to assess the associated risk of infection and prevent this deadly fungal infection.

Low novelty seeking and high self directedness scores in alcohol-dependent patients without comorbid psychiatric disorders homozygous for the A10 allele of the dopamine transporter gene.

The gene for the human dopamine transporter DAT1 displays several polymorphisms, including a 40-bp variable number of tandem repeats (VNTR) ranging from 3 to 13 copies in the 3'-untranslated region (UTR) of the gene. Some hints for an association of certain VNTR with psychiatric disorders, behavioural problems and temperament traits have been found. This study explored possible associations between the most frequent DAT1 polymorphism, namely the A10 VNTR, and personality traits as measured by the Temperament and Character Inventory (TCI) and the NEO Five Factor Inventory (NEO-FFI) in alcohol-dependent patients (ADP). One hundred and forty-four ADP and 144 age-, educational level- and sex-matched controls (CO) were genotyped and interviewed with the TCI and NEO-FFI. ADP showed higher neuroticism, lower extraversion, lower openness, lower agreeableness and lower conscientiousness than CO on the NEO-FFI and higher scores in harm avoidance, reward dependence and self transcendence and lower scores in self directedness and cooperativeness on the TCI than controls. There were no genetic links regarding those personality traits, the diagnosis of alcohol dependence and the VNTR. Only in a subgroup of ADP, those without psychiatric co-diagnoses and homozygous for A10, significantly lower scores in novelty seeking and higher scores in self directedness than in all the other ADP and CO could be detected. Summarizing, the 40-bp VNTR did not help to differentiate between ADP and CO, but might contribute to some personality dimensions in certain ADP subgroups.

Confirmation of association of the GABRA2 gene with alcohol dependence by subtype-specific analysis.

OBJECTIVES: Three recent studies revealed a haplotypic association of alcohol dependence with the gene encoding the alpha2 subunit of the gamma-aminobutyric acid type A (GABAA) receptor (GABRA2). The present study examined whether variation of the GABRA2 gene confers susceptibility to different subtypes of alcohol dependence in the German population. METHODS: A total of 257 German alcohol-dependent patients and 88 healthy population controls were genotyped for six single-nucleotide polymorphisms covering the middle part and the 3' end of GABRA2. Allelic, genotypic and haplotypic comparisons were done for subgroups of alcohol-dependent patients with a presumed high genetic load. RESULTS: The overall alcohol-dependent patients vs. control group comparison confirmed positive allelic association for five of six single-nucleotide polymorphisms mapping from intron 3 to the 3' end of GABRA2 (P=0.01-0.02). Haplotype analysis revealed two common haplotypes accounting for approximately 90% of the chromosomes within the patients and controls. The less frequent haplotype was significantly more prevalent among the alcohol-dependent patients (45%) than among the controls [29%; odds ratio (OR)=1.97, 95% confidence interval (CI): 1.30-2.96]. The strength of association increased, if the subsets of alcohol-dependent patients with a positive family history (OR=2.60, 95% CI: 1.63-4.13), withdrawal seizures (OR=2.22, 95% CI: 1.30-3.79) or an early onset (OR=2.19, 95% CI: 1.24-3.88) were analyzed. CONCLUSIONS: Although our study was limited by the number of cases being larger than the number of controls, the results confirm GABRA2 as a susceptibility gene for alcohol dependence in the German population. We found a consistent increase of the susceptibility effect in alcohol-dependent patients with a presumed strong genetic predisposition.

The TPH intron 7 A218C polymorphism and TCI dimension scores in alcohol-dependent patients: hints to nonspecific psychopathology.

AIMS: A linkage of certain alleles of the tryptophan hydroxylase (TPH) intron 7 A218C polymorphism to suicidality and antisocial behaviour has been described. The aim of our study was to find any association between dimensions of the Temperament and Character Inventory (TCI) indicating impulsivity and the TPH polymorphism alleles in unselected alcohol-dependent patients and age-matched controls. METHODS: We examined 159 alcohol-dependent patients and 161 controls with the TCI and genotyped them for the TPH intron 7 A218C polymorphism alleles. RESULTS: Although homozygous TPH genotypes were found more often in alcohol-dependent patients than in controls, an association between TCI dimensions and TPH alleles was not observed in the complete sample. Alcohol-dependent patients, however, scored significantly higher for harm avoidance (HA) and lower for self-directedness (SD) than controls regardless of TPH genotype. Among controls, for those with the A/A genotype, harm avoidance was as high as in the group of alcohol-dependent patients, persistence (P) in that genotype was significantly lower than for all other genotypes in the patient and control group. CONCLUSION: Even if there is no association between TCI dimensions and TPH genotype in our sample, hints to nonspecific psychopathology in connection with the A/A genotype are found.

Polymorphisms in the NMDA subunit 2B are not associated with alcohol dependence and alcohol withdrawal-induced seizures and delirium tremens.

OBJECTIVE: Ethanol-inhibited glutamatergic neurotransmission has been shown to mediate pathophysiological mechanisms in the development of alcoholism, including withdrawal symptoms. NMDA-receptor 2B (NR2B) is a subunit that confers a high sensitivity to ethanol-induced inhibition. Previously we had reported a lack of association between the single nucleotide polymorphism (SNP) rs1806201 in the NR2B gene (GRIN2B) and alcoholism. Shortly thereafter, an association between the polymorphism and early-onset alcoholism has been reported. One aim of the present study was to test whether the association between the GRIN2B polymorphism rs1806201 and early-onset alcoholism can be replicated in a larger sample. Moreover, we hypothesized that another genetic variation within GRIN2B (rs1806191) may have an effect in the etiology of alcoholism or withdrawal-related traits. METHODS: We extended our original study sample to a size of 377 patients and 464 healthy volunteers and performed a replication study, including the second GRIN2B SNP. Associations between allele, genotype and haplotype frequencies of the two polymorphisms and alcoholism as well as with patients' phenotypes were investigated. RESULTS: No associations were found between any of the two polymorphisms, tested individually or as haplotypes, and alcoholism, respectively withdrawal-related traits. CONCLUSION: Neither the analyzed SNPs nor any of their haplotypes likely modify susceptibility to alcohol dependence or withdrawal-related phenotypes.

Distigmine bromide induced acute psychotic disorder in a patient with multiple sclerosis.

A female patient with multiple sclerosis (MS) suffered from an acute psychotic disorder after taking distigmine bromide for detrusor dysfunction. She showed a dramatic relief of her symptoms after the medication, distigmine bromide, was stopped. Distigmine is not supposed to penetrate the blood-brain barrier (BBB). However, in MS patients a leakage of the BBB could be hypothesized.

Early improvement under mirtazapine and paroxetine predicts later stable response and remission with high sensitivity in patients with major depression.

OBJECTIVE: Current clinical knowledge holds that antidepressants have a delayed onset of efficacy. However, the delayed onset hypothesis has been questioned recently by survival analytical approaches. We aimed to test whether early improvement under antidepressant treatment is a clinically useful predictor of later stable response and remission. METHOD: We analyzed data from a randomized double-blind controlled trial with mirtazapine and paroxetine in patients with major depression (DSM-IV). Improvement was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) score reduction of > or = 20%. Stable response was defined as > or = 50% HAM-D-17 score reduction at week 4 and week 6, and stable remission as a HAM-D-17 score of < or = 7 at week 4 and week 6. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Improvement occurred in a majority of the analyzed patients within 2 weeks (mirtazapine: 72.7% of 109 patients; paroxetine: 64.9% of 103 patients). Early improvement was a highly sensitive predictor of later stable response or stable remission for both drugs. NPV approached maximum values as early as week 2 for mirtazapine and week 3 for paroxetine. After 2 weeks of treatment with mirtazapine and 3 weeks with paroxetine, almost none of the patients who had not yet improved became a stable responder or stable remitter in the later course. CONCLUSION: Our results strongly suggest that early improvement predicts later stable response with high sensitivity. These empirically derived data question the delayed onset hypothesis for both antidepressants tested and provide important clinical clues for an individually tailored antidepressant treatment.

Symptom-triggered versus standard chlormethiazole treatment of inpatient alcohol withdrawal: clinical implications from a chart analysis.

To evaluate clinical effectiveness and safety of 2 different detoxification treatment protocols, a chart analysis of hospital inpatients consecutively admitted for alcohol withdrawal during one year was undertaken. Records of 33 patients receiving symptom-triggered treatment (using a modified version of the revised Clinical Institute Withdrawal Assessment for Alcohol Scale) were compared with those of patients treated by applying a fixed-dose regimen (n = 32). Patients (45.3 +/- 9.8 years, 21% female) of both groups were comparable regarding illness severity, epidemiologic parameters as well as complications during the observed treatment period. Under symptom-triggered therapy, chlormethiazole (CMZ) treatment duration (4.2 +/- 3.5 vs. 7.5 +/- 3.3 days, Mann-Whitney U test: p = 0.0003) and cumulative CMZ dosage (4352 +/- 4589 vs. 9921 +/- 6599 mg, Mann-Whitney U test: p = 0.0004) were significantly reduced. The daily CMZ dose was significantly lower at days 1-5 in the group receiving symptom-triggered treatment. There was no influence of age on the outcome parameters of either treatment group. In conclusion, an individualized symptom-triggered treatment of alcohol withdrawal with CMZ seems to be equally safe but more efficient than a scheduled regimen.

Add-on combination and maintenance treatment: case series of five obese patients with different eating behavior.

Obesity is a general medical condition associated with an increase in morbidity and mortality. Although it would be desirable to use efficacious prevention programs, the success rates reported to date have been rather disappointing. In this observational study, a new drug treatment regimen was evaluated in five obese patients with a mean age of 39.6 +/- 4.2 years and an initial body mass index between 34.5 and 38.3 kg/m for a period of 96 weeks. The patients showed restrained and unrestrained eating patterns according to a German version of the Three-Factor Eating Questionnaire and were treated in an add-on regimen with the combination of three drugs with different anorectic properties that were consecutively introduced in an interval of 16 weeks. First, orlistat (120 mg three times a day) was given as a monotherapy. Sibutramine (15 mg in the morning) and then topiramate (in a dose dependent on appetite suppression and side effects) were added for a total duration of 48 weeks. A 48-week maintenance and relapse prevention treatment period with topiramate monotherapy followed the discontinuation of orlistat and sibutramine. This outpatient treatment procedure was tolerated well, although side effects occurred in all patients depending on the phase of the treatment regimen. After 96 weeks, the mean body mass index was 25.7 +/- 1.2 kg/m. Moreover, a normalization of eating patterns according to the Three-Factor Eating Questionnaire could be noticed. Factor 3, hunger, was significantly reduced. This treatment plan may be highly effective and safe in a subpopulation of obese patients.