Cognitive endpoints as disease biomarkers: optimizing the congruency of preclinical models to the clinic

Cognition is a complex set of processes, including attention, learning and memory, that refers to the capacity to encode, consolidate, store and retrieve recent and remotely stored fact (semantic) and experience-based (episodic) memory. The development of cognitive enhancers is of particular importance to society and the pharmaceutical industry, as cognitive dysfunctions are observed across a wide range of neuropsychiatric and neurodegenerative disorders; however, developing such therapeutics has proven difficult. There is poor congruency between the abundance of positive results observed in animal studies compared with clinical outcome. For example, from 1982 to 2002 there was a 6000% increase in studies on cognitive processing in rodents that had little or no impact on the outcome of phase II and III clinical trials. The effects of therapeutics on models of cognition that demonstrate the potential to improve preclinical-to-clinical congruency, focusing on attention, impulsivity and episodic memory, are summarized in this review. Changes in attention, impulsivity and episodic memory are tractable 'disease biomarkers' that correlate with the disease phenotypes that are potential therapeutic targets. In the context of the development of cognitive enhancing drugs, one of the major goals of translational medicine is to improve the congruency between preclinical models and clinical results. Improved translatability could improve discovery, validation and implementation of biomarkers to inform clinical outcome studies and decision making, and to establish proof-of-concept for efficacy and safety based on targeted mechanisms of action.     

Dermatoglyphic study in children with phenylketonuria

Summary Dermatoglyphic findings in 19 patients with phenylketonuria (11 male and 8 female), 39 of their relatives (18 female and 21 male) and 500 controls (TRC) were not statistically significant among the three groups studied. There was no definite relationship between the phenylketonuric gene and the dermatoglyphic patterns.The parents of half the phenylketonuria cases are not consanguineous; thus the phenylketonuria gene may be more frequent in Turkey than other European countries.     

Chronic renal failure in a patient with Sotos syndrome due to autosomal dominant polycystic kidney disease

Sotos syndrome is characterised by accelerated growth, acromegalic appearance, mental retardation and social maladjustment. Most cases are sporadic, but familial cases have also been reported. We report a case of Sotos syndrome presenting with chronic renal failure due to autosomal dominant polycystic kidney disease (ADPKD). Ultrasonographic examination of the patient, his father and other family members revealed polycystic kidneys. Renal failure was present only in the Sotos case, who also had considerably larger cysts than other family members. We suggest that the underlying mechanism responsible from the somatic overgrowth in Sotos syndrome may also be linked with the development of larger cysts and earlier onset of renal failure in ADPKD. Although Sotos syndrome has been associated with urological abnormalities, chronic renal failure is very rare. To our knowledge, Sotos syndrome associated with ADPKD has not been reported before.     

Coryneform bacteria isolated from blood cultures and their antibiotic susceptibilities

We aimed to determine the types of corynebacteria isolated from the blood of patients at Gaziantep University Hospital, Turkey, and their antibiotic susceptibilities. Between February 1999 and June 2001, 3530 blood samples were cultured, of which 915 were found to be positive, and these were further investigated in the bacteriology laboratory. Among positive blood cultures, coryneform bacteria were identified in 31 (3.4%) isolates. Of these, 16 (51.6%) were Corynebacterium jeikeium, six (19.4%) were Corynebacterium striatum, four (12.9%) were Corynebacterium amycolatum, two (6.5%) were Cellulomonas species, two (6.5%) were Corynebacterium afermentans and one isolate (3.2%) was Corynebacterium propinquum. Antibiotic susceptibility tests showed that C. jeikeium was resistant to various antibiotics, whereas all isolates were susceptible to vancomycin and teicoplanin. This study illustrates the importance of taking coryneform bacteria into consideration when culturing blood samples. The need to identify the species and determine its antibiotic sensitivity is emphasized.     

Drug-resistant tuberculosis at the University Hospital in Gaziantep, South-eastern Turkey

We aimed to determine the present status of drug resistance of Mycobacterium tuberculosis at the Gaziantep University Hospital in south-east Turkey. Data for 1995 to 1999 were retrospectively evaluated with respect to smear-positive cases, first positive culture for Mycobacterium tuberculosis for each patient and drug-susceptibility tests for the major antituberculous drugs. Cultures were done using the Bactec 460 TB method. A total of 106 (40.2%) strains were resistant to at least one drug. Single drug resistance was observed in 47 strains (17.8%) and resistance to two or three drugs was found in 28 and 29 strains (10.6 and 11.0%), respectively. Two strains (0.8%) were resistant to all four drugs. While multidrug resistance was observed in 52 (19.7%) strains, resistance to isoniazid + rifampin was observed in 20 (7.6%) strains. This retrospective study showed that combined drug resistance of M. tuberculosis is highly prevalent in southeastern Turkey. Possible reasons for the failure of current control policies were considered.     

Dual left lobe living donor liver transplantation using donors unacceptable for right lobe donation: a case report

Living donor liver transplantation (LDLT) has become a viable alternative for end-stage liver disease. The shortage of brain-dead donors has led to development of advanced surgical approaches. Dual lobe LDLT has been performed successfully in the recent years. The major indication for this complex procedure has been insufficient graft size from a single donor or insufficient remnant in the donor. We performed a dual left lobe LDLT using 2 donors who were unacceptable for right lobe donation.     

Two siblings with isolated GH deficiency due to loss-of-function mutation in the GHRHR gene: successful treatment with growth hormone despite late admission and severe growth retardation

Patients with growth hormone releasing hormone receptor (GHRHR) mutations exhibit pronounced dwarfism and are phenotypically and biochemically indistinguishable from other forms of isolated growth hormone deficiency (IGHD). We presented here two siblings with clinical findings of IGHD due to a nonsense mutation in the GHRHR gene who reached their target height in spite of late GH treatment. Two female siblings were admitted to our clinic with severe short stature at the age of 13.8 (patient 1) and 14.8 years (patient 2). On admission, height in patient 1 was 107 cm (-8.6 SD) and 117 cm (-6.7 SD) in patient 2. Bone age was delayed in both patients (6 years and 9 years). Clinical and biochemical analyses revealed a diagnosis of complete IGHD (peak GH levels on stimulation test was 0.06 ng/mL in patient 1 and 0.16 ng/mL in patient 2). Patients were given recombinant human GH treatment. Genetic analysis of the GH and GHRHR genes revealed that both patientscarried the GHRHR gene mutation p.Glu72X (c.214 G>T) in exon 3 in homozygous (or hemizygous) state. After seven years of GH treatment, the patients reached a final height appropriate for their target height. Final height was 151 cm (-1.5 SD) in patient 1 and 153 cm (-1.2 SD) in patient 2. In conclusion, genetic analysis is indicated in IGHD patients with severe growth failure and a positive family history. In spite of the very late diagnosis in these two patients who presented with severe growth deficit due to homozygous loss-of-function mutations in GHRHR, their final heights reached the target height.