The effects of ketamine on typical and atypical depressive symptoms.

OBJECTIVE: Ketamine's effects on different dimensions of depressive symptomatology, including typical/melancholic and atypical depression, remain largely unknown. This study examined the effects of a single intravenous dose of ketamine on general depressive symptoms (measured using the Montgomery-Asberg Depression Rating Scale (MADRS), typical/melancholic symptoms (measured using the MADRS5), and atypical symptoms (measured using the Scale for Atypical Symptoms (SAS)). METHODS: Data from 68 participants with treatment-resistant major depressive disorder (MDD) or bipolar depression were pooled from three separate, double-blind, placebo-controlled, crossover studies investigating ketamine's efficacy in depression. MDD participants were unmedicated; bipolar participants received therapeutic-dose lithium or valproate. Clinical symptoms were collected preinfusion and up to 14 days postinfusion. Effect sizes were calculated for days 1 and 3 postinfusion. The primary measures of interest for this exploratory analysis were total MADRS, MADRS5, and SAS scores. Individual symptoms were also analyzed in an exploratory manner. RESULTS: Scores improved significantly at Day 1 postinfusion (MADRS: Cohen's d = 0.64; MADRS5: Cohen's d = 0.61; SAS: Cohen's d = 0.41) and continued to be significantly improved over placebo at Day 3 (MADRS: Cohen's d = 0.49; MADRS5: Cohen's d = 0.43; SAS: Cohen's d = 0.39). Effect sizes were greater for typical/melancholic than atypical symptoms at Day 1 postinfusion. CONCLUSION: Ketamine appears to effectively treat both the typical/melancholic and atypical symptoms of depression, but may have early preferential effects for the former.

Acute ketamine administration corrects abnormal inflammatory bone markers in major depressive disorder.

Patients with major depressive disorder (MDD) have clinically relevant, significant decreases in bone mineral density (BMD). We sought to determine if predictive markers of bone inflammation-the osteoprotegerin (OPG)-RANK-RANKL system or osteopontin (OPN)-play a role in the bone abnormalities associated with MDD and, if so, whether ketamine treatment corrected the abnormalities. The OPG-RANK-RANKL system plays the principal role in determining the balance between bone resorption and bone formation. RANKL is the osteoclast differentiating factor and diminishes BMD. OPG is a decoy receptor for RANKL, thereby increasing BMD. OPN is the bone glue that acts as a scaffold between bone tissues matrix composition to bind them together and is an important component of bone strength and fracture resistance. Twenty-eight medication-free inpatients with treatment-resistant MDD and 16 healthy controls (HCs) participated in the study. Peripheral bone marker levels and their responses to IV ketamine infusion in MDD patients and HCs were measured at four time points: at baseline, and post-infusion at 230 min, Day 1, and Day 3. Patients with MDD had significant decreases in baseline OPG/RANKL ratio and in plasma OPN levels. Ketamine significantly increased both the OPG/RANKL ratio and plasma OPN levels, and significantly decreased RANKL levels. Bone marker levels in HCs remained unaltered. We conclude that the OPG-RANK-RANKL system and the OPN system play important roles in the serious bone abnormalities associated with MDD. These data suggest that, in addition to its antidepressant effects, ketamine also has a salutary effect on a major medical complication of depressive illness.

Ketamine for rapid reduction of suicidal ideation: a randomized controlled trial.

BACKGROUND: Suicide is a devastating public health problem and very few biological treatments have been found to be effective for quickly reducing the intensity of suicidal ideation (SI). We have previously shown that a single dose of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, is associated with a rapid reduction in depressive symptom severity and SI in patients with treatment-resistant depression. METHOD: We conducted a randomized, controlled trial of ketamine in patients with mood and anxiety spectrum disorders who presented with clinically significant SI (n = 24). Patients received a single infusion of ketamine or midazolam (as an active placebo) in addition to standard of care. SI measured using the Beck Scale for Suicidal Ideation (BSI) 24 h post-treatment represented the primary outcome. Secondary outcomes included the Montgomery-Asberg Depression Rating Scale--Suicidal Ideation (MADRS-SI) score at 24 h and additional measures beyond the 24-h time-point. RESULTS: The intervention was well tolerated and no dropouts occurred during the primary 7-day assessment period. BSI score was not different between the treatment groups at 24 h (p = 0.32); however, a significant difference emerged at 48 h (p = 0.047). MADRS-SI score was lower in the ketamine group compared to midazolam group at 24 h (p = 0.05). The treatment effect was no longer significant at the end of the 7-day assessment period. CONCLUSIONS: The current findings provide initial support for the safety and tolerability of ketamine as an intervention for SI in patients who are at elevated risk for suicidal behavior. Larger, well-powered studies are warranted.

Germline MSH2 and MLH1 mutational spectrum including large rearrangements in HNPCC families from Poland (update study).

Germline mutations in the DNA mismatch repair genes MSH2 and MLH1 account for a significant proportion of hereditary non-polyposis colorectal cancer (HNPCC) families. One approach by which development of an efficient DNA-testing procedure can be implemented is to describe the nature and frequency of common mutations in particular ethnic groups. Two hundred and twenty-six patients from families matching the Amsterdam II diagnostic criteria or suspected HNPCC criteria were screened for MSH2 and MLH1 germline mutations. Fifty different pathogenic mutations were found, 25 in MSH2 and 25 in MLH1. Twenty-four of these had not previously been described in other populations. Among our 78 families with MSH2 or MLH1 mutations, 54 (69.2%) were affected by recurrent mutations including 38 found at least twice in our own series. Two of the most frequent alterations were a substitution of A to T at the splice donor site of intron 5 of MSH2 and a missense change (A681T) of MLH1 found in 10 and eight families, respectively. Among large deletions detected by the multiplex ligation-dependent probe amplification assay, exon 9 deletions in the MSH2 gene were found in two families. Our results indicate that a screening protocol specific for the Polish population that is limited to the detection of all reported mutations will result in the identification of the majority of changes present in MLH1 and MSH2 genes in Polish HNPCC kindreds.

Diverting a protein from its cellular location by intracellular antibodies. The case of p21Ras.

We describe the use of phage libraries to derive new antibodies against p21Ras to be used for intracellular expression in mammalian cells. A panel of single-chain antibody fragments, binding to Ras, were analyzed and characterized for their capacity to interfere in vitro with (a) the intrinsic GTPase activity of Ras and (b) the binding of Ras to its effector Raf, and were found not to neutralize its function, according to these biochemical criteria. When expressed intracellularly in mouse 3T3 K-Ras transformed cells all the anti-Ras single-chain variable fragments (scFv) tested inhibited cell proliferation, as assessed by bromodeoxyuridine incorporation. Double immunofluorescence analysis of transfected cells using confocal microscopy confirmed that anti-Ras antibody fragments colocalize with endogenous Ras, at subcellular locations where the protein Ras is not normally found. These data suggest that the ability of phage-derived anti-Ras scFv fragments to inhibit the function of Ras in vivo is a rather general and frequent property and that the range of antibodies that can be successfully used for intracellular inhibition studies is much greater than anticipated, exploiting the mode of action of diverting protein traffic.

Measurement of vertebral rotation: a comparison of two methods based on CT scans.

This study compared Ho's and Aaro's method to measure vertebral axial rotation in order to find the more accurate one. Two hundred fifty-nine CT scans were taken from 11 cadaver vertebrae. The scans were performed with vertebrae in neutral position and angulated up to 20 degrees in the sagittal and frontal plane to simulate kyphosis/lordosis and side bending. Axial rotation was measured according to both methods. The mean difference between true and measured values was 3.7 +/- 6.7 (95% confidence limit) (Ho's method) and 2.3 +/- 3.7 (Aaro's method), respectively. Correlation with true axial rotation was r2 = 0.66 (Ho's method) and r2 = 0.77 (Aaro's method). We recommend using Aaro's method as the more accurate measure of axial rotation in scoliotic vertebrae.

The mode of action of Y13-259 scFv fragment intracellularly expressed in mammalian cells.

The anti-p21ras Y13-259 single-chain Fv fragment (scFv) neutralizes the activity of p21-ras when intracellularly expressed in different systems. We have studied the mode of action of this inhibition in 3T3 K-ras fibroblasts and demonstrated that (i) this antibody fragment is highly aggregating when cytoplasmically expressed and (ii) the p21-ras antigen is sequestered in these aggregates in an antibody-dependent manner. This co-segregation leads to an efficient inhibition of DNA synthesis. These results suggest that an antigen can be diverted from its normal location inside the cells in an antibody mediated way, prospecting a new mode of action for intracellular antibodies in vivo.

Molecular cloning, gene structure and expression profile of mouse C1 inhibitor.

The gene encoding C1 inhibitor, the major control element of activation of the classical pathway of complement and a major inhibitor of several plasma serine proteases, has been studied only in man, where deficiency of C1 inhibitor results in the dominantly transmitted disease hereditary angioedema. Full-length mouse C1 inhibitor cDNA and genomic clones were isolated and characterized as a first step towards the complete characterization of the pattern of C1 inhibitor expression and the production of an animal model of C1 inhibitor deficiency. Restriction-enzyme and sequence analyses of a full-length genomic clone demonstrated that the mouse gene has the same structure as the human homologue, but differs in size (9 kb versus 17 kb), mostly due to the presence of repetitive Alu elements in the human gene. Sequence comparisons in the promoter region indicate important similarities, i.e. the absence of a TATA box, the presence of an initiator sequence encompassing the transcription-start site and of a gamma-interferon-activated sequence (GAS) element at position -124 of the human sequence. A stretch of about 100 nucleotides in intron 1 reveals an unusually high degree of conservation for non-coding sequences and contains non-canonical but conserved tandemly arranged GAS elements at positions 369 and 388 of the human sequence. This finding supports the conclusions of functional studies on the human C1INH gene indicating a role of this region in modulation of transcription by interferons. The profile of C1 inhibitor expression in mouse liver, lung, heart, kidney, spleen and brain was determined by quantitative northern blot analysis.

[Rupture or stress injury of the flexor tendon pulleys? Early diagnosis with MRI]. / Ruptur oder Uberlastungsschaden des Ringbandsystems der Beugesehnen? Frühdiagnose im MRT.

Eighteen extreme rock climbers underwent primary clinical and MRI examination because of recent closed injuries to the flexor tendon pulleys. Follow-ups were after approximately 36 months on the average. The recent injuries, which are difficult to diagnose clinically, could be ascertained by means of MRI: This type of injury seems to occur more frequently than is currently diagnosed. Eight patients with overuse syndrome and eight patients with a short pulley rupture were treated conservatively. In two patients with long pulley rupture, the pulleys were reconstructed by means of a tendon graft using Kleinert's technique. Clinically manifest bowstringing or flexion contracture after treatment could not be ascertained on any one of the patients. All except for one showed an almost normal range of motion. By means of control MRI it was, however, possible to ascertain minor bowstringing and scars in most patients. Clinically, this partial instability manifested by lasting swelling. What was most disturbing, however, was reduced strength and the subjective feeling of insecurity during climbing.

The role of dynamic magnetic resonance imaging in the detection of lesions of the ulnocarpal complex.

A prospective study of 32 patients was carried out to investigate the significance of dynamic magnetic resonance imaging (MRI) in diagnosis of triangular fibrocartilage (TFC) lesions. Tears of the TFC can be diagnosed well by means of static MRI and arthroscopy. Dynamic MRI examination has an advantage in evaluating the stability of the TFC and ulnocarpal impingement. By means of dynamic MRI it was possible to make a preoperative diagnosis of an ulnocarpal impingement in five patients, a diagnosis which was confirmed through arthroscopy in all cases. In three further patients, dynamic MRI showed ulnocarpal impingement caused by instability of the ulnar attachment of the TFC. This kind of impingement could not be ascertained arthroscopically. Dynamic MRI extends the possibilities of evaluating obscure ulnar wrist pain. Its significance lies in the non-invasive examination of ulnocarpal impingement as well as the evaluation of TFC stability.

Diagnosis of congenital pericardial defects, including a pathognomic sign for dangerous apical ventricular herniation, on magnetic resonance imaging.

OBJECTIVE: To establish criteria for the accurate diagnosis of different forms of left sided pericardial defects on magnetic resonance imaging. Early detection of a partial apical defect is essential as it is potentially fatal. DESIGN: Examination of four children with congenital pericardial defects by magnetic resonance imaging, the results being compared with the features on conventional chest radiography and echocardiography and with published data. RESULTS: Magnetic resonance imaging improved the ability to diagnose and distinguish between complete and partial left sided pericardial defects. A deep myocardial crease was visualised in a patient with apical pericardial defect, indicating the risk of a life threatening ventricular strangulation. A prominent left atrial appendage was, in contrast to many reports, not a reliable sign for partial left sided pericardial defect. CONCLUSIONS: The various forms of congenital left sided pericardial defects cannot reliably be diagnosed in plain chest radiographs or on echocardiography. Their diagnosis and the distinction between partial and complete defects, however, is of clinical importance and can be accomplished more confidently by magnetic resonance imaging.

[Diagnosis of the ulnocarpal complex in MRI cineradiography]. / Diagnostik des ulnokarpalen Komplexes im MR-Movie.

73 patients with persistent ulnar wrist pain of undetermined origin were examined by Magnetic Resonance Imaging (MRI). A series of 15 coronal slices was acquired using a T2* weighted gradient echo sequence. With repetitive measurement of those three slices that showed the triangular fibrocartilage complex (TFCC) best, the carpus was imaged 12 times during radial-ulnar deviation in increments of five degrees. The single images were combined according to their slice positions and continuously displayed on an image workstation, allowing for kinematic evaluation. Three different types of impingement of the TFCC were identified.

[Destabilization of the discus articularis with rupture of the ulnar styloid apex in distal radius fracture. Diagnosis with dynamic MR]. / Destabilisierung des Discus articularis mit Abriss der ulnaren Styloidspitze bei distaler Radiusfraktur. Diagnostik mit MR-Movie.

An avulsion of the ulnar styloid apex led--because of a simultaneous rupture of the ulnar collateral ligament and a rupture of the disc's insertion in the fovea ulnaris--to a displacement of the triangular fibrocartilage. During movements in the frontal plane, the latter underwent a deformation, was displaced, compressed and blocked ulnar abduction. This pathology and the ulnar impingement could be observed in a "MRI-movie".

[The value of sonography in ruptures of the rotator cuff]. / Die Wertigkeit der Sonographie bei Rupturen der Rotatorenmanschette.

In 375 patients ultrasonography of the rotator cuff was carried out before operation. All the patients underwent acromioplasty, either alone or with additional repair of a full-thickness tear. The ultrasound findings were then compared with the intraoperative findings. Two hundred and seventy-two tears of the rotator cuff were seen on ultrasonography, and in 262 cases this was confirmed at operation. In 103 patients no rupture was diagnosed by ultrasound, but in 26 of these cases a full-thickness tear was detected on operation. These figures yield sensitivity of 91%, specificity of 89% and accuracy of 90%; the positive predictive value was 96%, the negative predictive value 75%. In most cases of incorrect evaluation the size of the tears was underestimated by ultrasonography.

MR imaging of late onset orbital rhabdomyosarcoma with intracranial extension.

Today, patients with alveolar rhabdomyosarcoma have a favorable prognosis with a survival rate of more than 80%, due to modern radiotherapy. However, those patients with secondary meningeal involvement are still afflicted with a mortality rate of 90% unless a different therapeutic approach is taken. We report a case of a young adult with invasion of the tumor into the anterior cranial fossa. MRI aided in the assessment of the intracranial tumor spread and allowed for a direct visualization of the meningeal membranes. The signal characteristics of the tumor and the adjacent tissue in unenhanced and postcontrast MRI is discussed. MRI was clearly superior to CT and indicative for the choice of treatment.

Carpal tunnel syndrome: diagnosis with high-resolution sonography.

OBJECTIVE: Carpal tunnel syndrome is characterized by typical anatomic changes that can be shown with high-resolution sonography. To determine whether these findings are reliable and can be used to establish the diagnosis, sonograms of patients with the disease were compared with sonograms obtained in patients with normal wrists. Also compared were sonograms and MR images obtained in the patients with carpal tunnel syndrome. SUBJECTS AND METHODS: Twenty wrists in 18 consecutive patients with clinical symptoms of carpal tunnel syndrome and with abnormal nerve conduction studies were examined with real-time sonography and MR imaging. The sonograms and MR images were evaluated quantitatively by two unbiased observers with regard to the size and shape of the median nerve and the palmar bowing of the flexor retinaculum. A t test was used to compare these data with those from previous sonographic studies of 28 normal wrists. Correlation coefficients for the measurements obtained with sonography and with MR were calculated. The relative accuracies of different diagnostic criteria for the diagnosis of carpal tunnel syndrome were assessed by using receiver-operating-characteristic analytical techniques. RESULTS: Characteristic findings on both MR and CT scans of the 20 wrists with carpal tunnel syndrome included swelling of the median nerve in the proximal part of the carpal tunnel in 16 wrists, flattening of the median nerve in the distal part of the carpal tunnel in 13 wrists, and increased palmar bowing of the flexor retinaculum in nine wrists. Comparison with the data of 28 normal wrists proved that these findings were significant (p less than .01 to p less than .001). Receiver-operating-characteristic analysis showed that the discrimination between wrists in normal subjects and in patients with carpal tunnel syndrome achieved with each of the three diagnostic criteria was not significantly different. Measurements of the size and flattening of the median nerve obtained from sonograms were similar to those on MR images, whereas sonography was less accurate for measuring the palmar bowing of the flexor retinaculum. CONCLUSION: We conclude that the results of sonography are reliable, and that the diagnosis of carpal tunnel syndrome can be established on the basis of sonographic findings.

[Isolated injuries of the pulley of the finger flexor tendon sheath--injuries in extreme climbing sports]. / Isolierte Ringbandverletzungen im Fingerbereich--Verletzungen des extremen Klettersportes.

Injuries of pulleys are quite common in mountain climbing. The clinically diagnosed rupture of a pulley can now be verified by MRI. Partial ruptures, which in MRI always showed as scars, can frequently lead to intrinsic bow-stringing. The injuries were primarily treated non-surgically. With regard to chronic, recurring cases or large ruptures, however, annular ligament plastics have to be considered. As a prophylaxis we recommend special training exercises for climbers on wide ledges with changing exertion patterns and a tape-bandage for the fingers. During climbing, the PIP-joint should best not be strained in an obtuse angle. Warming-up and stretching exercises before climbing are absolutely necessary.