Hypertrophic Cardiomyopathy

Opinion statement When an individual is diagnosed with hypertrophic cardiomyopathy (HCM), all relatives potentially affected by Mendelian autosomal-dominant inheritance should be evaluated with an electrocardiogram (ECG) and echocardiogram. Genetic testing should be considered in high-risk mutations where there are diagnostic uncertainties. Symptom relief depends on β-blockers as first-line therapy. If the disease is nonobstructive, then calcium channel blockers can be added or used alone. If there is a significant left ventricular outflow tract (LVOT) gradient then disopyramide can be used, ideally in combination with a β-blocker. Verapamil should be used with care due to potential exacerbation of the LVOT gradient. Nonmedical therapy for obstructive disease consists of surgical myectomy, alcohol septal ablation, or dual-chamber pacing. Surgery is the gold standard, although in experienced hands and directed appropriately, septal ablation achieves good results. Pacing is generally less effective. The development of atrial fibrillation (AF) or left atrial enlargement carries a significant risk of thromboembolism. All patients should be closely observed for AF and thromboembolic risk, and the threshold for initiation of anticoagulation should be low in patients with sustained palpitations, atrial enlargement, and nonsustained supraventricular arrhythmia on Holter. All patients with HCM should be assessed for their risk of sudden death regardless of severity of symptoms or morphology. The factors predictive of risk are 1) previous cardiac arrest; 2) unexplained syncope; 3) family history of premature sudden death; 4) abnormal blood pressure response to exercise; 5) nonsustained ventricular tachycardia; and 6) severe left ventricular hypertrophy ≥ 30 mm.     

67Ga-citrate and 99Tcm-MDP for estimating the severity of vertebral osteomyelitis

The aim of this study was to evaluate the roles of 67Ga-citrate and 99Tcm-methylene diphosphonate (99Tcm-MDP) planar and single photon emission tomographic (SPET) imaging in patients with vertebral osteomyelitis. Thirty patients (22 females, 8 males) aged 62.7 +/- 16.4 years (mean +/- s) were enrolled prospectively between May 1995 and May 1998. The patients had been on antibiotics for 7 +/- 4 weeks prior to the study. Histology was available for all but nine patients with mild infections, who were evaluated by a combination of magnetic resonance imaging (MRI), clinical and laboratory tests. 67Ga-citrate (185 MBq) and three-phase bone (555 MBq 99Tcm-MDP) planar and SPET imaging were performed in all patients, together with MRI as a comparison. In total, 67 infectious foci were detected. Based on histology, there were four cases of severe, 13 cases of moderate and four cases of mild osteomyelitis; nine mild infections were also classified by the combination of MRI, clinical and laboratory results. Combined MRI and 67Ga-citrate SPET correctly classified all patients; MRI detected all 67 infectious foci, whereas 67Ga-citrate SPET identified 54 only. False-negative results were seen with all other modalities, especially in cases of mild and moderate infection. 67Ga-citrate SPET identified unsuspected cases of endocarditis (n = 2), paravertebral abscess (n = 1), subaxillary soft tissue abscess (n = 1) and rib osteomyelitis (n = 1). For 67Ga-citrate SPET, the target-to-background ratio was 2.24 +/- 0.31, 1.76 +/- 0.07 and 1.30 +/- 0.18 for severe, moderate and mild osteomyelitis, respectively. Significant differences were noted between severe and moderate infection (P = 0.0051) and between severe and mild infection (P < 0.0001); that between moderate and mild infection was non-significant. For 99Tcm-MDP planar and SPET imaging, and for planar 67Ga-citrate imaging, there was no correlation with severity. We conclude that 67Ga-citrate SPET is able to identify vertebral osteomyelitis and detect additional sites of infection. It can also aid in determining the severity of infection and, potentially, the response to therapy.     

Technical failure rates of double crown-retained removable partial dentures

Removable partial dentures (RPD) can be retained using conical crowns or parallel-sided telescopic double crowns. The purpose of this study was to evaluate and compare the technical failure rate of the two retainer systems. One hundred seventeen dentures made by dentists of the medical school were included. Seventy-four RPD were retained with parallel-sided crowns (n=251) and 43 with conical crowns (n=160). Following the medical report follow-ups from January 1992 to December 1998, technical RPD failures were noted and analyzed. Technical problems occurred during the observation time in 48.8% of the conical retained dentures and 34.2% of the parallel-sided retained dentures. In both cases, loss of cementation was most frequently noted, while loss of the facings occurred only with conical crowns. Other technical failures did not depend on the type of retainer system used. These were most frequently problems with the denture base, e.g., fracture of artificial teeth or the metal framework. We conclude that there were different technical failures of both double crown retainer systems. These problems were not insignificant in number but treatable. Received: 14 December 1999 / Accepted: 19 January 2000     

Targeting of cholecystokinin-B/gastrin receptors in vivo: preclinical and initial clinical evaluation of the diagnostic and therapeutic potential of radiolabelled gastrin

The outstanding sensitivity of pentagastrin in detecting the presence of primary, recurrent or metastatic medullary thyroid cancer (MTC) suggests widespread expression of the corresponding receptor type in human MTC. Indeed, recent autoradiographic studies have demonstrated the presence of cholecystokinin (CCK)-B (= gastrin) receptors not only in more than 90% of MTCs but also in a high percentage of small cell lung cancers, stromal ovarian cancers, astrocytomas and several other tumour types. The aim of this study was to evaluate whether radiolabelled gastrin may be suitable for targeting CCK-B receptor-expressing tumours in vivo. For this purpose, the biodistribution of the radioiodinated human heptadecapeptide gastrin-I was studied in nude mice bearing subcutaneous xenografts of the human MTC cell line, TT. Initial therapy experiments were undertaken. Finally, the biodistribution of iodine-131- labelled gastrin-I was studied in a patient with metastatic MTC. At a peptide amount of approximately 1 μg, maximum tumour uptake (8.9±2.9%ID/g) was observed in animals at 1 h post injection, with tumour-to-blood ratios as high as 6.3±1.9. Physiological CCK-B receptors in the stomach, gallbladder and pancreas of the mice were targeted as well. The major route of excretion was renal, but strong evidence for a biliary excretion pathway also exists. Pilot therapy studies with ¹³¹I-labelled gastrin showed significant anti-tumour efficacy as compared with untreated controls. In accordance with the preclinical data, good receptor targeting was observed in the tumour sites, stomach, gallbladder and pancreas of a patient with metastatic MTC. These data suggest that gastrin and its analogues may represent a useful new class of receptor binding peptides for diagnosis and therapy of a variety of tumour types, including MTC and small cell lung cancer. Future preclinical and clinical studies will address in more detail the molecular features that render CCK-B receptor binding agents potentially useful candidates for in vivo scintigraphy and radionuclide therapy. Received 19 December 1997 and in revised form 6 January 1998     

Die Gelbfleckigkeit des SpinatesSpinacia oleracea L.

Ohne Zusammenfassung     

Epithelial-mesenchymal transition in colonies of rhesus monkey embryonic stem cells: a model for processes involved in gastrulation

Rhesus monkey embryonic stem (rhES) cells were grown on mouse embryonic fibroblast (MEF) feeder layers for up to 10 days to form multilayered colonies. Within this period, stem cell colonies differentiated transiently into complex structures with a disc-like morphology. These complex colonies were characterized by morphology, immunohistochemistry, and marker mRNA expression to identify processes of epithelialization as well as epithelial-mesenchymal transition (EMT) and pattern formation. Typically, differentiated colonies were comprised of an upper and a lower ES cell layer, the former growing on top of the layer of MEF cells whereas the lower ES cell layer spread out underneath the MEF cells. Interestingly, in the central part of the colonies, a roundish pit developed. Here the feeder layer disappeared, and upper layer cells seemed to ingress and migrate through the pit downward to form the lower layer while undergoing a transition from the epithelial to the mesenchymal phenotype, which was indicated by the loss of the marker proteins E-cadherin and ZO-1 in the lower layer. In support of this, we found a concomitant 10-fold upregulation of the gene Snail2, which is a key regulator of the EMT process. Conversion of epiblast to mesoderm was also indicated by the regulated expression of the mesoderm marker Brachyury. An EMT is a characteristic process of vertebrate gastrulation. Thus, these rhES cell colonies may be an interesting model for studies on some basic processes involved in early primate embryogenesis and may open new ways to study the regulation of EMT in vitro.     

Entorhinal cortex entrains epileptiform activity in CA1 in pilocarpine-treated rats

Layer III neurons of the medial entorhinal cortex (mEC) project to CA1 via the temporoammonic pathway and exert a powerful feed-forward inhibition of CA1 pyramidal neurons. The present study evaluates the hypothesis that disrupted inhibition of CA1 pyramidal neurons causes an eased propagation of entorhinal seizures to the hippocampus via the temporoammonic pathway. Using a method to induce a confined epileptic focus in brain slices, we investigated the spread of epileptiform activity from the disinhibited mEC to CA1 in control and pilocarpine-treated rats that had displayed status epilepticus and spontaneous recurrent seizures. In pilocarpine-treated rats, the mEC showed a moderate layer III cell loss and an enhanced susceptibility to epileptiform discharges compared to control animals. Entorhinal discharges propagated to CA1 in pilocarpine-treated rats but not in controls. Disconnecting CA3 from CA1 did not affect the spread of epileptiform activity to CA1 excluding its propagation via the trisynaptic hippocampal loop. Mimicking the invasion of epileptiform discharges by repetitive stimulation of the temporoammonic pathway caused a facilitation of field potentials in CA1 that were contaminated by population spikes and afterdischarges in pilocarpine-treated but not control rats. Single cell recordings of CA1 pyramidal neurons revealed a dramatic loss of feed-forward inhibition and the occurrence of strong postsynaptic excitatory potentials in pilocarpine-treated rats. Excitatory responses in CA1 were characterized by multiple NMDA receptor-mediated afterdischarges and a strong paired-pulse facilitation in response to activation of the temporoammonic pathway. Our results suggest that, irrespective of the enhanced seizure-susceptibility of the mEC in epileptic rats, the loss of feed-forward inhibition and the enhanced NMDA receptor-mediated excitability CA1 pyramidal cells ease the spread of epileptiform activity from the mEC to CA1 via the temporoammonic pathway bypassing the classical trisynaptic hippocampal loop.     

Electrical and chemical long-term depression do not attenuate low-Mg2+-induced epileptiform activity in the entorhinal cortex

PURPOSE: Low-frequency electrical and magnetic stimulation of cortical brain regions has been shown to reduce cortical excitability and to decrease the susceptibility to seizures in humans and in vivo models of epilepsy. The induction of long-term depression (LTD) or depotentiation of a seizure-related long-term potentiation has been proposed to be part of the underlying mechanism. With the low-Mg(2+)-model of epilepsy, this study investigated the effect of electrical LTD, chemical LTD, and depotentiation on the susceptibility of the entorhinal cortex to epileptiform activity. METHODS: The experiments were performed on isolated entorhinal cortex slices obtained from adult Wistar rats and mice. With extracellular recording techniques, we studied whether LTD induced by (a) three episodes of low-frequency paired-pulse stimulation (3 x 900 paired pulses at 1 Hz), and by (b) bath-applied N-methyl-D-aspartate (NMDA, 20 microM) changes time-to-onset, duration, and frequency of seizure-like events (SLEs) induced by omitting MgSO(4) from the artificial cerebrospinal fluid. Next we investigated the consequences of depotentiation on SLEs themselves by applying low-frequency stimulation after onset of low-Mg(2+)-induced epileptiform activity. RESULTS: LTD, induced either by low-frequency stimulation or by bath-applied NMDA, had no effect on time-to-onset, duration, and frequency of SLEs compared with unconditioned slices. Low-frequency stimulation after onset of SLEs did not suppress but induced SLEs that lasted for the time of stimulation and were associated with a simultaneous increase of the extracellular K(+) concentration. CONCLUSIONS: Our study demonstrates that neither conditioning LTD nor brief low-frequency stimulation decreases the susceptibility of the entorhinal cortex to low-Mg(2+)-induced epileptiform activity. The present study does not support the hypothesis that low-frequency brain stimulation exerts its anticonvulsant effect via the induction of LTD or depotentiation.     

The Effect of a Two-Hour, Room Temperature Incubation of Human Spermatozoa in TEST-Yolk Buffer on the Rate of Fertilization in Vitro

PURPOSE: To reassess the use of TEST-yolk buffer (TYB) in an in vitro fertilization (IVF) program by comparing fertilization rates achieved in a glucose-free cleavage medium by the standard IVF preparation of sperm versus a 2-h, room temperature incubation of sperm in TYB. METHODS: Oocytes collected for IVF were randomly split into two groups and inseminated with either TYB-treated sperm or IVF-prepared sperm. SETTING: Stanford Reproductive Endocrinology and Infertility Center. PATIENTS: Fifty couples undergoing IVF with at least 10 mature oocytes. MAIN OUTCOME MEASURES: Fertilization rates in vitro. RESULTS: Fertilization rates were significantly higher (p = 0.015) with TYB treatment. The average 2PN fertilization rate was 49.6% (188/379) for the IVF group and 57.4% (221/385) in the IVF with TYB group. CONCLUSIONS: A 2-h, room temperature incubation of sperm in TYB produces significantly higher 2PN fertilization rates as compared to standard IVF preparation of sperm in a current generation cleavage medium.     

Case report: drug interference with MIBG uptake in a patient with metastatic paraganglioma

Metaiodobenzylguanidine (MIBG) labelled with iodine-131 ((131)I) has become a well established therapeutic tool for inoperable metastastic tumours of paraganglioma. There are different pharmacological substances known to interfere with MIBG-uptake which may result in a false negative MIBG scan. We present the case of a 26-year-old male polytoxicomanic patient with metastatic paraganglioma, who underwent MIBG therapy. During earlier therapies, MIBG uptake in the metastatic lesions was very high. A post-therapeutic whole-body scan subsequent to recent (131)I-MIBG therapy failed to detect the vast majority of metastatic lesions-except for two. (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) showed metastases with a similar distribution to the initial MIBG scan. The possible reasons for the discrepancy in the findings of the MIBG scans and the (18)F-FDG-PET scan are discussed with special emphasis on drug intake prior to MIBG administration, increased MIBG turn-over and unknown drug mixture interference with MIBG uptake.