Ischemic mitral valve regurgitation: the new challenge for magnetic resonance imaging.

Ischemic mitral valve regurgitation (IMVR) refers to mitral regurgitation in patients with ischemic heart disease (IHD) in the presence of a structurally normal mitral valve. IMVR contributes significantly to morbidity and mortality in patients with IHD. The thresholds for clinical management, surgical intervention, and the choice of surgical procedure continue to evolve and independent determinants for surgical success in the pre- and post-operative evaluation of IMVR are still controversial. Although echocardiography has been valued as the gold standard in the evaluation of IMVR, new technologies such as magnetic resonance imaging (MRI) may be seen as applicable to the investigation of this complex pathology. MRI may allow for detection of parameters that could help clinicians and surgeons to better assess IMVR and eventually guide appropriate treatment whenever necessary. The present article discusses the main parameters that should be routinely investigated while adopting MRI technology to assess patients with IMVR. The review is the result of a multidisciplinary approach to this complex etiopathogenic entity and involves expertise spanning from radiology, cardiology, to cardiac surgery.     

Solitary bronchioloalveolar carcinoma: CT criteria

The computed tomographic (CT) scans of 30 patients with solitary bronchioloalveolar carcinoma were reviewed. Common features at CT included the peripheral or subpleural location of a pulmonary mass (25 cases), pseudocavitation (18 cases), heterogeneous attenuation (17 cases), irregular margins forming a star pattern (22 cases), and pleural tags (21 cases). Using these CT criteria, four independent observers attempted to identify cases of bronchioloalveolar carcinoma from a larger sample of lung cancers and benign lesions by categorizing a series of test cases into four probability categories. Although the bronchioloalveolar carcinomas were correctly ranked in the two highest probability categories 75% of the time (in 45 of 60 cases), there was considerable overlap with other lung lesions, particularly with adenocarcinoma and large cell undifferentiated carcinoma. However, even though the typical features of bronchioloalveolar carcinoma are not invariable or highly specific, they are characteristic enough to suggest the diagnosis.     

Combined heart and liver transplantation for familial amyloidotic neuropathy.

Familial amyloidotic polyneuropathy (FAP) is an inherited disease characterized by an abnormal systemic deposition of a mutant protein called transthyretin (TTR) with elective involvement of the peripheral nervous system, but often determining cardiac, gastrointestinal, and urinary tract dysfunction. FAP commonly affects the liver and the heart until end-organs failure. Transthyretin amyloidosis is today an accepted indication for orthotopic liver transplantation (OLT). Combined heart and liver transplantation (CHLT) may be an attractive and rational treatment option when both organs are contemporary involved by this type of amyloidotic disease. Nowadays, surgical indications and techniques are far from being consolidated because only few cases of CHLT have been previously reported in literature. From November 1999 to May 2006, we performed five orthotopic combined heart and liver transplantations for FAP at our institution. Our surgical experience and clinical outcomes are herein reported.     

Identification of a gene disrupted by a microdeletion in a patient with X-linked retinitis pigmentosa (XLRP)

The gene for the most frequent from of X-linked retinitis pigmentosa (XLRP), RP3, has been assigned by genetic and physical mapping to a segment of less than 1000 kbp, which is flanked by the marker DXS1110 and the ornithine transcarbamylase (OTC) gene. In search of microdeletions, we have screened the DNA of 30 unrelated patients with XLRP by employing a representative set of YAC-derived DNA fragments that were generated by restriction enzyme digestion and PCR amplification. In one of these patients, a 6.4 kbp microdeletion was detected which was not present in the DNA of 444 male controls. A cosmid contig spanning the deletion was constructed and used to isolate cDNAs from retina-specific libraries. Exons corresponding to these expressed sequences as well as other putative exons were identified by sequencing more than 30 kbp of the critical region. So far, no point mutations in these putative exon sequences have been identified.      

Positional cloning of the gene for X-linked retinitis pigmentosa 3: homology with the guanine-nucleotide-exchange factor RCC1

The gene for retinitis pigmentosa 3 (RP3), the most frequent form of X- linked RP (XLRP), has been mapped previously to a chromosome interval of less than 1000 kbp between the DXS1110 marker and the OTC locus at Xp21.1-p11.4. Employing a novel technique, YAC Representation Hybridization (YRH)', we have recently identified a small XLRP associated microdeletion in this interval, as well as several putative exons including the 3' end of a gene that was truncated by the deletion. cDNA library screening and sequencing of a cosmid centromeric to the deletion has now enabled us to identify numerous additional exons and to detect several point mutations in patients with XLRP. The predicted gene product shows homology to RCC1, the guanine-nucleotide- exchange factor (GEF) of the Ras-like GTPase Ran. Our findings suggest that we have cloned the long-sought RP3 gene, and that it may encode the GEF of a retina-specific GTP-binding protein.      

Multiple islet cell tumors with predominance of glucagon-producing cells and ulcer disease

Two cases of multiple islet cell tumors mostly composed of glucagon-producing cells and associated with severe ulcer disease are presented. Multiple endocrine neoplasia type I (MEN-I) was present in both patients, although symptomatically latent in case 2. Immunohistochemistry showed that glucagon (A) cells were a major cell population (i.e., accounting for at least 30% of the tumor cell population) in 24 of 43 tumors (either macroadenomas or microadenomas) studied in case 1 and in 12 of 17 tumors studied in case 2. A major pancreatic polypeptide (PP) cell population was found in 12 and 7 tumors of case 1 and 2, respectively. In contrast, insulin (B) and somatostatin (D) cells were scarce in most adenomas. Gastrin-producing cells were not identified in any tumors, despite the use of different antigastrin antisera. Extrapancreatic or residual gastrinomas were not found at postmortem examination in case 1 or on appropriate surgical inspection done 24 years after the onset of the ulcer disease in patient 2. On the basis of these and of 17 additional cases collected in the literature, it is concluded that multiple A-cell tumors of the pancreas are an expression of the MEN-I and are mostly associated with ulcer disease and/or with hypergastrinemia of frequent uncertain origin. The mechanisms regulating the nonrandom phenotypic hormonal differentiation of these genetically determined tumors remain unknown.     

Effects of lorazepam on short latency afferent inhibition and short latency intracortical inhibition in humans

Experimental studies have demonstrated that the GABAergic system modulates acetylcholine release and, through GABA_A receptors, tonically inhibits cholinergic activity. Little is known about the effects of GABA on the cholinergic activity in the human central nervous system. In vivo evaluation of some cholinergic circuits of the human brain has recently been introduced using a transcranial magnetic stimulation (TMS) protocol based on coupling peripheral nerve stimulation with TMS of the motor cortex. Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short latency afferent inhibition, SAI). We investigated whether GABA_A activity enhancement by lorazepam modifies SAI. We also evaluated the effects produced by lorazepam on a different TMS protocol of cortical inhibition, the short interval intracortical inhibition (SICI), which is believed to be directly related to GABA_A activity. In 10 healthy volunteers, the effects of lorazepam were compared with those produced by quetiapine, a psychotropic drug with sedative effects with no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors, and with those of a placebo using a randomized double-blind study design. Administration of lorazepam produced a significant increase in SICI  ( F _3,9= 3.19, P = 0.039)  . In contrast to SICI, SAI was significantly reduced by lorazepam  ( F _3,9= 9.39, P = 0.0002)  . Our findings demonstrate that GABA_A activity enhancement determines a suppression of SAI and an increase of SICI.     

Dissociated effects of diazepam and lorazepam on short-latency afferent inhibition

Peripheral nerve inputs have an inhibitory effect on motor cortex excitability at short intervals (short-latency afferent inhibition, SAI). This can be tested by coupling electrical stimulation of peripheral nerve with transcranial magnetic stimulation (TMS) of the motor cortex. SAI is reduced by the anticholinergic drug scopolamine, and in patients with Alzheimer's disease. Therefore, it is possible that SAI is a marker of central cholinergic activity important for memory function. The benzodiazepine lorazepam also reduces SAI. Since benzodiazepines impair memory formation, but do not do so uniformly, with a maximum amnesic effect after lorazepam but less or no effect after diazepam, we were interested in testing in this non-behavioural study to what extent the effects of lorazepam and diazepam on circuits involved in SAI could be dissociated. In addition, and for control, we tested the effects of lorazepam and diazepam on short-interval intracortical inhibition (SICI), a motor cortical inhibition mediated through the GABA_A receptor. Lorazepam markedly reduced SAI, whereas diazepam slightly increased it. In contrast, both benzodiazepines uniformly increased SICI. Our findings demonstrate opposite effects of lorazepam and diazepam on SAI, an inhibition modulated by central cholinergic activity, but the same effects on SICI, a marker of neurotransmission through the GABA_A receptor. This dissociation suggests, for the first time, that TMS measures of cortical inhibition provide the opportunity to segregate differences of benzodiazepine action in human central nervous system circuits.