Decoding diagnosis and lifetime consumption in alcohol dependence from grey-matter pattern information.

OBJECTIVE: We investigated the potential of computer-based models to decode diagnosis and lifetime consumption in alcohol dependence (AD) from grey-matter pattern information. As machine-learning approaches to psychiatric neuroimaging have recently come under scrutiny due to unclear generalization and the opacity of algorithms, our investigation aimed to address a number of methodological criticisms. METHOD: Participants were adult individuals diagnosed with AD (N = 119) and substance-naïve controls (N = 97) ages 20-65 who underwent structural MRI. Machine-learning models were applied to predict diagnosis and lifetime alcohol consumption. RESULTS: A classification scheme based on regional grey matter attained 74% diagnostic accuracy and predicted lifetime consumption with high accuracy (r = 0.56, P < 10-10 ). A key advantage of the classification scheme was its algorithmic transparency, revealing cingulate, insular and inferior frontal cortices as important brain areas underlying classification. Validation of the classification scheme on data of an independent trial was successful with nearly identical accuracy, addressing the concern of generalization. Finally, compared to a blinded radiologist, computer-based classification showed higher accuracy and sensitivity, reduced age and gender biases, but lower specificity. CONCLUSION: Computer-based models applied to whole-brain grey-matter predicted diagnosis and lifetime consumption in AD with good accuracy. Computer-based classification may be particularly suited as a screening tool with high sensitivity.

Extension of the clinical and molecular phenotype of DIAPH1-associated autosomal dominant hearing loss (DFNA1).

In about 20% of non-syndromic hearing loss (NSHL) cases, inheritance is autosomal dominant (ADNSHL). DIAPH1 mutations define the ADNSHL locus DFNA1. We identified two new families with heterozygous truncating DIAPH1 mutations (p.Ala1210Serfs*31 and p.Arg1213*). In contrast to the extensively studied original DFNA1 family, hearing loss was not confined to low frequencies, but congenital manifestation and rapid progression were confirmed. In line with a recent unrelated study, we identified an association with thrombocytopenia, reclassifying DFNA1 as a syndrome. Consequently, we suggest to include the blood count into the initial clinical workup of patients with autosomal dominant hearing loss to guide the genetic diagnosis. We provide the first data on DIAPH1 expression in the organ of Corti, where it localizes to the inner pillar cells, at the base of the outer hair cells. Homozygous truncating DIAPH1 mutations located N-terminally to the DFNA1 mutations have recently been identified in autosomal recessive microcephaly. It is therefore noteworthy that we found DIAPH1 expression also in spiral ganglion neurons and in the barrier between the myelinating glia of the peripheral nervous system and oligodendrocytes that form the myelinating glia of the central nervous system (CNS).

Implementation of minimally invasive percutaneous nephrolithotomy (MIP): comparison of the initial learning curve with the later on clinical routine in a tertiary centre.

OBJECTIVE: We report on the comparison of clinical results of the early phase of implementation of minimally invasive PNL (MIP) in a mentor-based approach with the later on clinical routine in a tertiary centre. PATIENTS AND METHODS: From January 2010 until January 2015 MIP was performed in 190 patients. Stone and patient characteristics were recorded in prospective manner. Perioperative complications were recorded within the Clavien-Classification. The first 120 consecutive patients undergoing MIP were evaluated and divided into three groups of 40 patients each. Mentor-based introduction of MIP was done within the first 40 patients (group A). Further patients were treated on routine clinical practice basis (group B and C). Treatment outcome was compared within the three groups. RESULTS: The groups did not significantly differ with regard to patient characteristics, operation time and decline in haemoglobin. In the mentor-based series mean stone size was 21.7 ± 12.6 vs. 15.6 ± 7.9 and 16.1 ± 8.4 mm in group B and C (p = 0.033). Primary stone-free rates were 65, 87.5 and 87.5% for the three groups (p = 0.015). Stone-free rate was higher in smaller and simple stones. Overall, complication rate was 41.7% including 36.7% Clavien grade I and II complications. CONCLUSIONS: MIP can be implemented safe and effectively with mentor-based approach. MIP has a high safety profile, which allows high safety and efficacy of MIP at the time of implementation.

Anatomoclinical study of 30 cases of sclerosing sweat duct carcinomas (microcystic adnexal carcinoma, syringomatous carcinoma and squamoid eccrine ductal carcinoma).

BACKGROUND: Microcystic adnexal carcinoma (MAC), syringomatous carcinoma (SC) and "Squamoid eccrine ductal carcinoma" (SEDC) are rare sclerosing adnexal tumours. OBJECTIVE: To understand the histogenesis of these tumours and possible clinical implications. METHODS: We conducted a retrospective study of 30 cases, 18 MAC, 5 SC and 7 SEDC reviewed and classified by a panel of dermatopathology experts, with immunohistochemical analysis of keratins, including K77, a new keratin specific of eccrine ducts, and PHLDA1 expressed in adnexal structures. RESULTS: There was a strong female predominance, with only five cases occurring in men. Patients with MAC and SC were younger (mean age 56 and 47 years) than those with SEDC (mean age 81 years). The most common localization was the cheek in SC and SEDC and the periocular area in MAC. Two cases of SEDC were found in organ transplant patients. No recurrence or metastases were observed after complete surgery of MAC, or SC (mean follow-up 7.2 years and 4.7 years), whereas one case of SEDC recurred and another could not be fully excised. MAC and SC had similar histological features, except for cysts. In MAC, calcifications, granulomas, connection to follicles, keratin expression pattern, PHLDA1 positivity and K77 negativity indicated a follicular histogenesis, whereas in SC, K77 positivity and keratin expression pattern were consistent with a differentiation towards eccrine apparatus. SEDC was composed of strands centred by ducts and nests with squamous differentiation and displayed K77 ductal positivity in all cases, a finding consistent with an eccrine origin. CONCLUSION: Our study demonstrated that MAC and SC have similar clinical characteristics, although histogenesis differs and show arguments for the individualization of SEDC.

Altered expression of securin (Pttg1) and serpina3n in the auditory system of hearing-impaired Tff3-deficient mice.

INTRODUCTION: Tff3 peptide exerts important functions in cytoprotection and restitution of the gastrointestinal (GI) tract epithelia. Moreover, its presence in the rodent inner ear and involvement in the hearing process was demonstrated recently. However, its role in the auditory system still remains elusive. Our previous results showed a deterioration of hearing with age in Tff3-deficient animals. RESULTS: Present detailed analysis of auditory brain stem response (ABR) measurements and immunohistochemical study of selected functional proteins indicated a normal function and phenotype of the cochlea in Tff3 mutants. However, a microarray-based screening of tissue derived from the auditory central nervous system revealed an alteration of securin (Pttg1) and serpina3n expression between wild-type and Tff3 knock-out animals. This was confirmed by qRT-PCR, immunostaining and western blots. CONCLUSIONS: We found highly down-regulated Pttg1 and up-regulated serpina3n expression as a consequence of genetically deleting Tff3 in mice, indicating a potential role of these factors during the development of presbyacusis.

Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate.

In alcoholism, both relapse to alcohol drinking and treatment response are suggested to be genetically modulated. This study set out to determine whether the top 15 single nucleotide polymorphisms (SNPs) of a recent genome-wide association (GWA) and follow-up study of alcohol dependence are associated with relapse behavior and pharmacological treatment response in 374 alcohol-dependent subjects who underwent a randomized, double-blind, placebo-controlled trial with acamprosate, naltrexone or placebo. The single nucleotide polymorphism, rs13273672, an intronic SNP in the gene for GATA-binding protein 4 (GATA4), was associated with relapse within the 90-day medical treatment period (P<0.01). Subsequent pharmacogenetic analyses showed that this association was mainly based on patients treated with acamprosate (P<0.01). In line with the observation that natriuretic peptide promoters are modulated by GATA4, a significant gene dose effect on the variance of atrial natriuretic peptide (ANP) plasma concentration in the different GATA4 genotypes (P<0.01) was found. Hence, genetic variations in GATA4 might influence relapse and treatment response to acamprosate in alcohol-dependent patients via modulation of ANP plasma levels. These results could help to identify those alcohol-dependent patients who may be at an increased risk of relapse and who may better respond to treatment with acamprosate.

The role of annexins I, II and IV in tumor development, progression and metastasis of human penile squamous cell carcinomas.

PURPOSE: The outcome of patients with penile squamous cell carcinomas (PSCC) largely depends on occurrence of metastasis. Therefore, prognostic markers indicating the risk for tumor cell spreading would be useful. Since Annexins are potential prognostic markers in a variety of tumors, we immunohistochemically examined the expression of Annexins I, II and IV (ANX AI, ANX AII and ANX AIV) in PSCC. METHODS: Samples originated from 29 patients subjected to surgical resection of invasive PSCC. Immunohistochemistry was done on paraffin-embedded sections using monoclonal antibodies against ANX AI, ANX AII and ANX AIV. Expression of ANXs was compared with clinical data. RESULTS: ANX AI expression was found in conventional PSCC and was absent in basaloid and sarcomatoid subtypes. High ANX AI score was significantly associated with higher T stages (P = 0.006). Strong expression in the invasion front of carcinomas was significantly associated with the occurrence of lymph node metastasis (P = 0.001). ANX AIV expression was weak in conventional PSCC, while it was strong in basaloid and sarcomatoid subtypes. Strong expression of Annnexin IV in the invasion front also showed a significant association with metastasis (P = 0.019). CONCLUSION: Expression of ANXs was different in histologic subtypes of penile carcinomas. Strong expression of ANX AI and ANX AIV in the invasion front seems to indicate a higher risk of lymph node metastasis.

Acute alcohol does not impair attentional inhibition as measured with Stroop interference scores but impairs Stroop performance.

RATIONALE: Inhibition is a core executive function and refers to the ability to deliberately suppress attention, behavior, thoughts, and/or emotions and instead act in a specific manner. While acute alcohol exposure has been shown to impair response inhibition in the stop-signal and Go/NoGo tasks, reported alcohol effects on attentional inhibition in the Stroop task are inconsistent. Notably, studies have operationalized attentional inhibition variably and there has been intra- and inter-individual variability in alcohol exposure. OBJECTIVE: This study aimed to examine the acute effects of alcohol on attentional inhibition, considering previous limitations. METHODS: In a single-blind, cross-over design, 40 non-dependent participants with a medium-to-high risk drinking behavior performed a Counting Stroop task (CST) under a baseline and an arterial blood alcohol concentration (aBAC) clamp at 80 mg%. Attentional inhibition was assessed as the alteration of reaction times (RT), error rates (ER), and inverse efficiency scores (IES) between incongruent and congruent trials (interference score). Stroop performance was also assessed regardless of trial-type. RESULTS: Compared to saline, acute alcohol exposure via an aBAC clamp did not affect CST interference scores but increased RTs and IES in both incongruent and congruent trials. CONCLUSIONS: Attentional inhibition (Stroop interference score) was not impaired by clamped moderate alcohol exposure. Acute alcohol impaired Stroop performance evidenced by a general increase in response times. Our findings suggest that response and attentional inhibition do not share the same neurocognitive mechanisms and are affected differently by alcohol. Results could also be explained by automated behaviors known to be relatively unaffected by acute alcohol.

The del/del genotype of the nuclear factor-kappaB -94ATTG polymorphism and its relation to aggressive periodontitis.

BACKGROUND AND OBJECTIVE: Periodontitis is influenced by specific host-dependent immune responses. Periodontopathogens induce innate immune responses, amongst others, via toll-like receptor 2 (TLR2), resulting in activation of the nuclear transcription factor nuclear factor-kappaB (NF-kappaB). The aim of this case-control study was to evaluate links between genetic variants of these genes and chronic/aggressive periodontitis in a multivariate model. MATERIAL AND METHODS: A total of 141 patients with periodontitis (63 with chronic periodontitis and 78 with aggressive periodontitis) and 81 controls without periodontitis were included in the study. Polymorphisms in TLR2 (Arg677Trp, Arg753Gln) and in NF-kappaB (-94ins/delATTG) were determined by restriction fragment length polymorphism and fragment length analyses, respectively. Subgingival bacterial colonization was evaluated using a PCR/DNA probe test (micro-Ident). RESULTS: Although there was no association of the TLR2 polymorphism Arg753Gln with periodontitis, heterozygous carriers (Arg/Gln) were at a higher risk for colonization with bacteria of the 'red complex' (corrected p-value = 0.042). The del/del genotype of the NF-kappaB polymorphism was associated with aggressive periodontitis considering age, gender, smoking and approximal plaque index as potential confounders (odds ratio = 2.81, p = 0.035, 95% confidence interval: 1.08-7.33). del/del carriers had a higher risk for subgingival colonization with Aggregatibacter actinomycetemcomitans (odds ratio = 2.36, p = 0.030, 95% confidence interval: 1.09-5.1; adjusted for age, gender, smoking and pocket depth(bacteria)). CONCLUSIONS: The del/del genotype of NF-kappaB was shown to be associated with the occurrence of aggressive periodontitis.

Tracers determine movement of soil moisture and evapotranspiration.

The downward movement of water in soil is a layered one. Marking a certain layer with hydrogen-isotope tracer, and watching its displacement, makes possible a water balance and gives information on evaporation and groundwater recharge.

Interleukin-2 -330 and 166 gene polymorphisms in relation to aggressive or chronic periodontitis and the presence of periodontopathic bacteria.

BACKGROUND AND OBJECTIVE: As a pro-inflammatory cytokine, interleukin-2 mediates the activation, growth and differentiation of T and B lymphocytes and natural killer cells. Promoter polymorphisms of the interleukin-2 gene have been associated with altered interleukin-2 production or identified as prognostic markers for various infectious diseases. Therefore, the aim of this study was to evaluate two polymorphisms at positions -330 T/G and 166 G/T in patients with generalized chronic periodontitis (n = 58) or generalized aggressive periodontitis (n = 73) in comparison with periodontitis-free controls (n = 69). MATERIAL AND METHODS: Both interleukin-2 polymorphisms were analyzed using the polymerase chain reaction with sequence-specific primers. Distributions of single alleles, genotypes and haplotypes were calculated using the chi-square test. Risk factor analyses were carried out by logistic regression with respect to established cofactors for periodontitis. The presence of subgingival bacteria in an individual were analyzed using a molecular biological method (the micro-Ident test). RESULTS: The interleukin-2 genotype -330 TG occurred less frequently in patients with chronic periodontitis (25.9% vs. 49.3%). Moreover, this genotype decreased the adjusted odds ratio for chronic periodontitis (odds ratio = 0.394), whereas the interleukin-2 genotype 166 TT and the haplotype combination interleukin-2 -330,166 TT : TT were associated with an increased adjusted odds ratio (odds ratio = 2.82 or 2.97). For the latter interleukin-2 combination, a positive association for the subgingival presence of Porphyromonas gingivalis (81.3% vs. 59.5%) and bacteria of the 'red complex' (78.1% vs. 56.0%) was shown. CONCLUSION: The interleukin-2 genotypes -330 TG and 166 TT, as well as the combination genotype interleukin-2 TT : TT, could be putative prognostic factors for chronic periodontitis.

A non-invasive probe for online-monitoring of turgor pressure changes under field conditions.

An advanced non-invasive, field-suitable and inexpensive leaf patch clamp pressure probe for online-monitoring of the water relations of intact leaves is described. The probe measures the attenuated output patch clamp pressure, P(p), of a clamped leaf in response to an externally applied input pressure, P(clamp). P(clamp) is generated magnetically. P(p) is sensed by a pressure sensor integrated into the magnetic clamp. The magnitude of P(p) depends on the transfer function, T(f), of the leaf cells. T(f) consists of a turgor pressure-independent (related to the compression of the cuticle, cell walls and other structural elements) and a turgor pressure-dependent term. T(f) is dimensionless and assumes values between 0 and 1. Theory shows that T(f) is a power function of cell turgor pressure P(c). Concomitant P(p) and P(c) measurements on grapevines confirmed the relationship between T(f) and P(c). P(p) peaked if P(c) approached zero and assumed low values if P(c) reached maximum values. The novel probe was successfully tested on leaves of irrigated and non-irrigated grapevines under field conditions. Data show that slight changes in the microclimate and/or water supply (by irrigation or rain) are reflected very sensitively in P(p).

Evidence for discontinuous water columns in the xylem conduit of tall birch trees.

The continuity of the xylem water columns was studied on 17- to 23-m tall birch trees (trunk diameter about 23 cm; first branching above 10 m) all year round. Fifty-one trees were felled, and 5-cm thick slices or 2-m long boles were taken at regular, relatively short intervals over the entire height of the trees. The filling status of the vessels was determined by (i) xylem sap extraction from trunk and branch pieces (using the gas bubble-based jet-discharge method and centrifugation) and from trunk boles (using gravity discharge); (ii) (1)H nuclear magnetic resonance imaging of slice pieces; (iii) infusion experiments (dye, (86)Rb(+), D(2)O) on intact trees and cut branches; and (iv) xylem pressure measurements. This broad array of techniques disclosed no evidence for continuous water-filled columns, as postulated by the Cohesion-Tension theory, for root to apex directed mass transport. Except in early spring (during the xylem refilling phase) and after extremely heavy rainfall during the vegetation period, cohesive/mobile water was found predominantly at intermediate heights of the trunks but not at the base or towards the top of the tree. Similar results were obtained for branches. Furthermore, upper branches generally contained more cohesive/mobile water than lower branches. The results suggest that water lifting occurs by short-distance (capillary, osmotic and/or transpiration-bound) tension gradients as well as by mobilisation of water in the parenchymatic tissues and the heartwood, and by moisture uptake through lenticels.

A comparative study of freezing single cells and spheroids: towards a new model system for optimizing freezing protocols for cryobanking of human tumours.

Cryopreservation of human tumour cells and tissue is a valuable tool for retrospective analysis and for the transport and handling of biopsy material. Tumour tissue consists of different cell types, which have different optimal freezing conditions, and extracellular matrix. A well-defined and authentic model system is required for developing new freezing protocols and media. This work describes the use of L929 and PC-3 spheroids as new model systems for freezing human tumours. Cell suspension and spheroids were frozen in different vessels (1 ml cryovials and a special, cryo-compatible 30 x 25 microl multi well plate) at slow rate (1 degrees C/min). Freezing media were combinations of culture or tumour transport medium (Liforlab) with the cryoprotective agents, Me(2)SO, trehalose and modified starch. We also present a new method of evaluating the viability of three dimensional multicellular systems to compare thawed spheroids objectively. Best viability (70%) of L929 spheroids occurred with a combination of Liforlab and starch hydrolysis product. The best cryopreservation results for spheroids were found with extracellular cryoprotectants, while optimum viability of single cells was achieved with Me(2)SO.

Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors.

Part C of the guideline is preceded by Part B General Pharmacology IJCPT. 2008; 46: 600 - 617. Included in Part C are practical guidelines for improving the therapy of some age-specific diseases and problems commonly encountered in general practice. The article in this issue is dedicated to the therapy of Dementia and M. Parkinson. Further guidelines for the other age specific diseases and problems named above will be published in the following issues of IJCPT. An important feature of these guidelines are the inclusion of Levels of Evidence and of the Strength of Recommendations for the therapy which are shown when reliable studies are available. (For both see levels of evidence at the end of this article.).

Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors - Part C Special Pharmacology.

This article contains the 4th part of the Pharmacotherapy Guidelines for the Aged by Family Doctors for Family Doctors. Part 4 is dedicated to fecal incontinence and chronic constipation. The diagnostic categories are divided according to severity and dysfuntion of bowel and pelvic floor, sphincter and neural control. Therapy is also outlined. Importance is given to patient history, in particular the use and abuse of drugs that stimulate peristalsis and promote constipation. Therapy in the elderly is guided by the maxim: use the most conservative therapy possible, where stool training has considerable importance. Drug therapy based on symptoms can only be recommended when non-drug measures continue to fail. In patients with fecal incontinence: 1) opiates (which reduce colonic motility), 2) loperamide (which has the capacity to dilate the rectum) and 3) anion exchangers which have the capacity to prevent cholonic diarrhea. In patients with chronic obstipation: 1) trial: stool-forming laxatives (ensure intake of sufficient amount of fluids) 2) trial: laxatives with an osmotic effect and 3) trial: stimulating laxatives (beware abuse, do not use in cases of acute abdomen).

Pharmacotherapy guidelines for the aged by family doctors for the use of family doctors: part C--Special pharmacology.

The part "Special pharmacology of the aged" of this guideline contains recommendations for typical conditions in the family doctors practice: in the January issue 2009 dementia and Morbus Parkinson, in this issue osteoporosis and urinary incontinence and in the next issue rectal incontinence and obstipation. This issue of the IJCPT contains the third part of the Pharmacotherapy guidelines for the aged by family doctors for family doctors. Part 3: Osteoporosis and urinary incontinence. Osteoporosis is a systematic disease characterized by low bone mass and declining bone structure. Exercise, adequate diet, nicotine abstinence as well as reduction of alcohol consumption may counteract the progression of the disease. Osteoporosis manifests in bone fractures with minimal trauma. Attention must be given to the risk of falling, e.g., by avoiding drugs that increase the risk of falling: e.g., psychotropic agents, analgesic drugs and antiarrhythmic agents. Specific osteoporosis medication e.g. calcium, vitamin D, biphosphonates and SERM (selective estrogen receptor modulators) is evaluated by family doctors according to indication, dosage, contraindications, long-term therapy and nature of any fracture. Duration of therapy is at least 3 - max. 5 years followed by reassessment of indication. There are 3 types of urine incontinence (urge-, stress-, and overflow-incontinence). Another standardization of urinary incontinence follows dysfunctions of the pelvic floor: detrusor muscle-dependent, due to sphincter spasm, prostate gland dependent. Urge incontinence with a dysfunction of the detrusor muscle is the most common type. Mixed types are frequent. Non-drug measures (e.g. pelvic muscle training, bladder training, toilet training are first choice treatments. Drug therapy (estrogen, imipramine) are without proven effect.